NZ794716A - Use of sublingual Dexmedetomidine for the treatment of agitation - Google Patents

Abstract

The present invention discloses a method of treating agitation or the signs of agitation in a subject comprising the sublingual administration of an effective amount of an a!pha-2 adrenergic agonist, more particularly Dexmedetornidine, or a pharmaceutically acceptable salt thereof. The method is particularly suitable for the treatment of agitation associated with neurodegenerative and/or neuropsychiatric diseases. The present invention also discloses the sublingual administration of an alpha-2 adrenergic agonist, more particularly Dexmedetomidine or a pham1aceutically acceptable salt thereof at a dose that is effective to treat agitation or the signs of agitation in a subject, but does not cause significant sedation. ticularly suitable for the treatment of agitation associated with neurodegenerative and/or neuropsychiatric diseases. The present invention also discloses the sublingual administration of an alpha-2 adrenergic agonist, more particularly Dexmedetomidine or a pham1aceutically acceptable salt thereof at a dose that is effective to treat agitation or the signs of agitation in a subject, but does not cause significant sedation.

Description

The present invention discloses a method of treating ion or the signs of agitation in a subject comprising the sublingual administration of an effective amount of an 2 rgic agonist, more particularly Dexmedetornidine, or a pharmaceutically acceptable salt thereof. The method is particularly suitable for the treatment of agitation associated with neurodegenerative and/or neuropsychiatric diseases. The present invention also discloses the sublingual administration of an 2 adrenergic agonist, more particularly Dexmedetomidine or a pham1aceutically acceptable salt thereof at a dose that is effective to treat agitation or the signs of agitation in a subject, but does not cause significant sedation.

NZ 794716 Use of Sublingual Dexmedetomidine for the treatment of Agitation FIELD OF' THE INVENTION [l] The present invention discloses a method of treating agitation or the signs of agitation m a subject comprising sublingually administering an effective amount of an alpha-2 adrenergic agonist, more particularly etomidine or a pharmaceutically acceptable salt thereof. The present invention also discloses a sublingual composition fo r treating agitation or the signs of agitation cornprising an effective amount of Dexmedetornidine or a pharmaceutically acceptable salt thereof together with one or more pharmaceutically acceptable can-iers and/or excipients, along with the preparation f CROSS REFERENCE TO RELATED APPLICATION This application is a divisional application of New Zealand application no. 753804, filed on 29 December 2017, which claims the benefit of priority to tJ .S. Provisional Application Serial No. 62/441,164 filed 31 December, 2016, U.S. Provisional Application Serial No. 62/471,393 filed 15 March, 2017 and U.S. Provisional ation Serial No. ,323 fiied 8 August, 2017, the disclosures of which are herein incorporated by reference in their ty for all purposes.

BACKGROUND OF THE ION Agitation is an umbrella term that can refer to a range of behavioral disturbances or disorders, including aggression, combativeness, ctivity, and disinhibition. Agitation is a nonspecific constellation of vely unrelated behaviors that can be seen in l different clinical conditions, usually presenting a fluctuating . Agitation may be caused by several different medical conditions and drug interactions or by any stances that worsen the person's ability to think. Multiple underlying pathophysiologic abnormalities are mediated by dysregulations of dopaminergic, serotonergic, noradrenergic, and GABAergic systerns.

Agitation is characterized by non-productive, e and excessive over-activity both motor (akathisia) and cognitive, and accompanied by an inner unpleasant n. The key to safety is to intervene early to prevent progression of agitation to aggression and violence.

Agitation can be associated \vith neurodegenerative disorders. One of the important manifestations of long-term progressive neurodegenerative process is clinically known as dementia. Dementias include Alzheimer's disease dementia (AD), Pronto-temporal dementia (FTD), Vascular dementia, Lewy body disease (LBD), and Down ia. Dementia in adults, lly destroy a person's memory and y to learn, reason, malte judgments, communicate and carry out daily ties. in later stages, patients may experience changes in personality and behavior, such as anxiety, suspicion, agitation and aggression. [5} Sebastiaan Engelhorghs et al in Nenrocheniistry International 2007 Nov, 52(6): l052— U1 60, disclosed that, in l‘rontotemporal dementia, increased ty of dopaminergic ransmission and d serotonergic modulation of dopaminergic neurotransmission are associated with agitated and aggressive behavior respectively. Pia lul et al, in l of Alzheimer’s disease 20l5 Sep, 49(3):?83—95, disclosed that rTgll-Slt": mice exhibited P30lL— tau—dependent hyperactivity, and agitation~lil The Expert Consensus Guidelines for treatment of behavioral emergencies cite speed of onset as one of the most important factors in choosing a drug and its route of stration.

However, antipsychotic medications can take from days to weeks before having a robust antipsychotic effect. Nevertheless, they do generally have a calming effect on agitated patients within minutes. For example, henzodiazepines or cting sedatives quickly calm a, severely agitated patient, but continuous treatment with these drugs leads to tolerance. [ltll Therefore, the treatment of agitation in patients with neuropsychiatric conditions (such as schizophrenia or bipolar mania) and neurodegenerative diseases is still d because of the potential for significant side effects associated with currently used drugs, their route of administration (intravenous/intramuscular) and the consequent need for hospital set ups for administering these drugs. in an ideal situation, an gitation drug for schizophrenics or dementia patient should have a rapid on set of calming without sedation, be well tolerated and easy to administer with a high safety margin. [l l] 2 adrenergic agoni sts have been used therapeutically for a number of conditions, including hypertension, congestive heart failure, angina pectoris, spasticity, glaucoma, diarrhea and for suppression of opiate withdrawal symptoms, Examples of alpha—2 adrenergic agonists include Clonidine, Guanfacine, Guanabenz, Guanoxahenz, Guanethidine, Xylazine, Tizanidinet lit/ledetornidine, Dexniedetomidine, Methyldopa, Methylnorepinephrine, 3C) Fadolrnidine, lodoclonidine, it"spraclonidine, Detomidine, Lofe‘xidine, z, Mivazerol, Azepexol, Talipexol, Rilmenidine, Naphazoline, Oxyrnetazoline, Xylometazoline, 'l‘etrahydrozoline, 'l‘rarnazoline, 'l'alipe‘xole, Romilidine, propylhexedrine, Norfenefrine, mine, Moxonidine, Lidamidine, Tolonidine, UKl4304, Di—Z’l-éll, ST—Ql, RWLSZBSi ’l‘CG-ltlllt), 4~(3—aminornethyl—cy'cloliex~3~enylmethyl)—l,3—dihydro~imidazole—Zwthione, and ydroxyniethylacycloheX—Ziuenylniethyl)~l,3wdihydro—iinidazole~2—thione. The inventors of the present ion have unexpectedly found that the sub—lingual administration of an 2 rgic agonist or a pharmaceutically acceptable salt thereof is a particularly effective and safe intervention for the treatrnent of agitation.

U1 [lZl (S)-4—[ l —(2,3 —Dirnethylphenyl)ethyl]~3l—i—irnidazol e edetonridine) is commercially ble as an injectable formulation for sedation of initially intuhated and mechanically ventilated patients during ent in an intensive care setting, and for non— intuhated patients prior to and/or during surgical and other procedures. [l3] Dexniedetornidine is reported to have anti—agitational effects when administered intravenously or huccally during surgical procedures and intensive care unit (ICU) setups. For e, lbaeache et. al., in Anesthesiaé’: Analgesia 2004 lan;98(l):60~3, discloses the stration of an intravenous single—dose of Dexniedetomidine to reduce agitation following sevoflurane anesthesia in children. Other intravenous administrations are reported by leanne Boyer et al., in Nursing Critical care ZOl 0 Jan, 5(l):3O—3Kl, Yahya Shehabi et. al., in Anesthetic intensive Care 20M) lan, 38(l):82—90, and loseph D. Tohias in Journal of Pediatric Pharmacology Therapeutic, Jan—Mar ZOlG, l5( l); 43-48. NCT 02720705 (clinical trial identification number from clinicaltrialsgov) discloses the administration of transhuccal Dexniedetornidine for the prevention of emergence agitation in preschool children treated with sevoflurane in an intensive care unit setting.

{M} The sublingual use of Dexrnedetorni dine is disclosed in WO 20l6/06l4l3. l-lowever, the focus ofW0 EOliS/Od ldl 3 is the administration of Dextnedetoniidine sublingually at doses riate to treat sleep disorders and induce significant sedation. We have now surprisingly found that detornidine or a pharnraceutically acceptable salt thereof, administered sublingually, can effectively treat agitation, including agitation ated with egenerative diseases (eg. Alzheirnerls disease, fronto-ternporal dementia, and n syndrome in mer’s disease/dementia), agitation associated with neuropsychiatric conditions (eg. bipolar disorder, schizophrenia, bipolar rnania, delirium and depression), agitation associated with alcohol and substance abuse withdrawal or agitation associated with other conditions such as OPD/lPD procedures (eg. MRl, CT or CAT scan, lumbar puncture, 3C) bone marrow aspiration/biopsy, tooth extraction or other dental procedures). The dose to be istered sublingually may he selected to he effective to treat agitation, yet insufficient to causing si 0C2nificant sedation.

SUMMARY 0 if THE ENVEN’E‘EGN [i 5} The present invention provides a. method of treating agitation or the signs of agitation in a t in need thereof, comprising administering an effective amount of an aiphauZ adrenergic agoni st or a pharmaceuticaily acceptable salt thereof sublinguaily to the subject, U1 wherein the said agitation is associated with a neurodegenerative disease like dementia, Alzheimer’s disease, temporai dementia, or Parkinsonism, or associated with a sychiatric condition like schizophrenia, bipolar disorder, bipolar mania, delirium, or depression, or ated with an CPD/ED procedure (cg. i‘dRi, CT or CAT scan, lumbar puncture, bone marrow aspiration/hi,oj;isy, tooth extraction or other dental procedures), or associated with an alcohol and substance abuse withdrawal. in a ular aspect, the agitation is suppressed t also g significant sedation. [i 6] in a preferred aspect, the present invention es a method of treating ion or the signs of agitation in a t in need thereof, comprising administering an effective arnount of Dexmedetomidine or a pharmaceuticallv acceptable salt thereof subiinguaily to the t. In a particular aspect, the agitation is suppressed without also causing significant sedation. [l7] Another aspect of the present invention provides a method of ng agitation or the signs of agitation in a subject in need thereof, wherein said agitation is associated with neurodegenerative disease, comprising administering an effective amount of Dexmedetomidine or a pharmaceuticallv acceptable salt thereof subiingually to the subject. In a particular aspect, the agitation is ssed without also causing significant sedation, [i 8] Yet another object of the present invention provides a method of treating agitation or the signs of agitation in a. subject in need thereof, wherein said agitation is associated with dementia, Alzheimer’s disease, frontotemporai dementia, Parkinsonisrn or other neurodegenerative diseases, comprising administering an effective amount of detonridine or a pharmaceuticaliy acceptable salt thereof suhiinguaily to the subject, in a particular aspect, the agitation is suppressed without also causing significant sedation. [l9] Another object of the present invention provides a method of treating agitation or the signs of ion in a subject in need f, wherein said agitation is associated with schizophrenia, bipolar disorder, r mania, delirium, depression, or another related neuropsyehiatrie condition, comprising stering an effective amount of Dexrnedetornidine or a. pharmaceuticaliy acceptable sait thereof sublinguailv to the subject. In a particular aspect, the agitation is ssed without also causing significant sedation. [20} A further object of the present invention provides a method of ng, preventing or reducing the signs of agitation in a subject in need thereof, wherein said agitation is associated with sundown syndrome in Alzheimer’s e/dementia, comprising administering an effective amount of Dexmedetonridine or a til'iarrn,aceuticai,l3i acceptable salt f sublingualiy to the subject. in a particular aspect, the ion is suppressed without also causing signiii cant sedation.

U1 [2H Yet another objective of the present invention provides a method for treating agitation or the signs associated with agitation in a subject in need thereof, wherein said agitation is associated with an {)PD/EPD ure (eg. MR1, CT or CAT scan, lumbar puncture, bone marrow aspiration/biopsy, tooth extraction or other dental procedures), comprising administering an effective amount of etoniidine or a pharrnaceuticailv acceptable salt thereof sublingually to the subject. in a particular aspect, the agitation is suppressed without also causing significant sedation.

Yet another objective of the present ion provides a method for treating agitation or the signs associated with agitation in a subject in need thereof, n said agitation is associated with an alcohol and substance abuse withdrawal, comprising administering an effective amount of Dexmedetoniidine or a pliarrnaceutically acceptable salt thereof sublingualiy to the subject in a particular aspect, the ion is suppressed without also causing significant sedation. [23} A further aspect of the present invention provides a suhiingual composition for treating agitation or the signs of agitation in a subject in need thereof, n said ion is associated with a neurodegei'ierative disease, and said sublingual composition comprises an effective amount of Dexmedetoniidine or a pharmaceutically acceptable salt thereof, together with one or more pharmaceutical acceptable carriers and/or excipients, [24} Another aspect of the present invention provides a subiinguai composition for treating ion or the signs of agitation in a t in need thereof, n said agitation is associated with schizophrenia, bipolar disorder, bipolar mania, delirium, depression, or another related neuropsychiatric condition, and said sublingual composition comprises an effective amount of etonridine or a phannaceuticailv acceptable. salt thereof, together with one or more pharrnaceutically acceptable carriers and/or excipients. [25} An additional aspect of the present invention provides a gual composition for treating agitation or the signs of agitation in a subject in need thereof, wherein said agitation is associated with sundown syndrome in Alzheimer’s disease/dementia, and said sublingual composition comprises an effective amount of Dexniedetornidine or a pharmaceuticallv able salt thereof together with one or more pharmaceutically acceptable carriers and/or excipients.

Yet another aspect of the present invention provides a sublingual composition for treating agitation or the signs associated with agitation in a subject in need thereof, wherein said agitation is associated with an OPE/{PD procedure (cg. MRI, CT or CAT scan, lumbar puncture, bone marrow aspiration/biopsy, tooth extraction or other dental procedures), and said U1 subiingual composition comprises an effective amount of Dexmedetomidine or a pharmaceutically acceptable salt thereof together with one or more pharmaceutically acceptable carriers and/or excipients. [27} Yet another aspect ofthe present invention provides a sublingual composition for treating agitation or the signs ated with agitation in a subject in need thereof, wherein said agitation is associated with an alcohol and substance abuse withdrawal, and said sublingual composition comprises an effective amount of etomidine or a pharmaceutically acceptable salt f together with one or more pharmaceutically acceptable carriers and/or excipients, r object of the present invention provides a sublingual composition sing an effective amount of Dexmedetomidine or a pharmaceutically acceptable salt thereof together with one or more pharmaceutically acceptable carriers and/or ents, wherein said sublingual composition is selected, from the group consisting of a film, wafer, patch, e, gel, spray, tablet, liquid drops or the like.

A further object of the present ion provides a method of sublingually administering an effective amount of Dexniedetomidine or a pharmaceutically acceptable salt thereof to a subject’s oral mucosa to treat agitation or the signs of agitation at a dosage which does not cause signiti cant sedation, [30} ln a particular aspect of the invention, the dosage administered sublinguaily may conveniently be in the range of between about 3 rams to about lQQ micrograms, Examples of le dosages include: about 5 micrograms to about 100 micrograms, about 5 micrograms to about 90 micrograms, about 5 micrograms to about 85 rams, about 5 micrograms to about 80 micrograms, about 5 micrograms to about '75 micrograms, about 5 micrograms to about ’70 micrograms, about 5 micrograms to about 65 micrograms, about 5 rams to about 60 micrograms, about 5 micrograms to about 55 micrograms, about 5 3C) micrograms to about 50 micrograms, about 5 micrograms to about 45 micrograms, about 5 rams to about 40 micrograms, about 5 micrograms to about 35 micrograms, about 5 rams to about 39 micrograms, about 5 micrograms to about 25 micrograms, about 5 micrograms to about 20 micrograms, about 5 micrograms to about l5 micrograms, about 5 micrograms to about l0 micrograms, less than l0 micrograms (eg, about 5, 6, 7, 8, or 9 micrcgrams), about it) micregranis, about 12 micrngranis, abeut i4 micregrams? abnut l5 microgramg about 16 micrograms, about 18 niicrngraina about 20 micrograms, abcut 30 micregrams? about 50 grams. The dese may be stered One er more times a day.

U1 BRIEF DESCRIFTEGN GP THE BEX‘WENGS Figure lA. Effect of sublinguaily stered Dexmedeteniidine hydrochloride (Dex) at varying deses (0. 5— 3 fag/kg) en cumulative duration of aggressive and agitated bebavinrs. Data expressed as Mean :l: SEM. fine—way ANOVA followed by Dunnett’s pest~licc test. Yp<005 YYp Figure 13. Effect Of gually administered Dexntedetnmidine ltlcride (Dex) at varying doses (05— 3 ) en frequency of aggressive and agitated behaviors. Data expressed as Mean :: SEEM. y ANOVA fellcwed by Dunnettls postuhcc test. Yp<fi05 YYp Figure 1C_ Effect of intravenously administered Dexniedeternidine hydreeiiieride (Dex) at varying doses (0.5! 3 rig/kg) on cumulative duration of aggressive and agitated behavinrs. Data expressed as Mean i SEM. Onenvvay ANGVA fellnvved by Dunnett’s pestmboc test. YYp Figure 2A. Effect nf subiinguaiiy administered Dexrnedetcmidine liydrocblcride (Dex) at varying doses (05— 3 ug/kg) on Latency to attack Data is expressed as Mean SEEM.

Statistical analysis was performed by Onewway A’NQVA fnilnwed by Dunnetts pest—boo test. <0.05 YY l3<00}, YYY l3<0.00l and YYYYD<0.000l vs e centrels (vehicle).

Figure 2B. Eltect el’ intravenously administered Dexrnedetnmidine hydrochloride (Dex) at varying dcses (0.5—3 rig/kg) nn Latency to . Data is expressed as Mean :: SEEM. Statistical analysis was performed by One—way ANOVA ved by Dunnett’s pestmhoc test. Yp<005 YYp Figure 3A. Effect of snblingnally administered Dexmedetomidine hydrochloride (Dex) at varying doses (O.5~3 gig/kg) on Cumulative duration of Neutral behaviors such as grooming, and exploration. Data expressed as Mean i SEM. Data is expressed as Mean i SEM. Statistical analysis was performed by Dnemway ANDVA followed by Dunnett’s post—hoe test *p<0.05 U1 ** ll Figure 33. Effect of sublingually administered Dexrnedetomidine hloride (Dex) at varying doses (0.543 rig/kg) on Frequency of Neutral behaviors such as grooming, and, exploration Data expressed as Mean :i: SEMl Data is expressed as Mean 1: SEM. Statistical analysis was performed by One—way ANGVA ed by Dunnett’s post—hoc test. *p<0iGS 0.0l, **"‘p<0.00l and **l‘*r_i< Figure 3C. Effect of sublingually administered Dexntedetomidine hydrochloride (Dex) at g doses (0.56 rig/kg) on Neutral behaviors such as immobile/quiet time. Data sed as Mean :l: SEM. Data is expressed as lvliean rt: SEM. Statistical analysis was performed by Dne— way ANDVA followed by Dunnett’s post—hoe test. *p<0.05 **p<0.0l, ***p<0i00l and ****l‘p Figure 31). Effect of enously administered Dexrnedetoini dine hydrochloride (Dex) at varying doses (0.56 ) on Cumulative duration of Neutral behaviors such as grooming, and exploration. Data expressed as Mean rit- SEM. Data is expressed as Mean :l: SEM. Statistical is was performed by One-way ANOVA followed by Dunnett’s postehoc test. 5 El) **p<0.0l, ***p<0.00l and ****p<0.0001 vs vehicle controls (vehicle).

Figure 3E. Effect of intravenously administered Dexrnedetornidine hydrochloride (Dex) at varying doses (0.5—3 gig/kg) on Frequency of Neutral behaviors such as grooming and exploration. Data expressed as Mean i SEM. Data is sed as Mean :: SEM. Statistical analysis was performed by One-way ANOVA followed by Dunnett’s postehoc test. *p<0.05 **p<0.0l, ***p<0.0fll and ****p<0.0001 vs vehicle controls (vehicle).

Figure 3F. Effect of intravenously administered Dexmedetornidine hydrochloride (Dex) at varying doses (0.56 rig/kg) on l ors such as immobile/quiet tirne. Data expressed as Mean :: SEM. Data is expressed as Mean :: SEEM. Statistical analysis was performed by One way ANDVA followed by Dnnnett’s post—hoe test. *p<0.05 **p<<0.0l, **l‘p<10.00l and ****p<0.000l vs vehicle controls (vehicle) Figure 4A: Mean plasma concentrations following Subiingnai (8L) Dexmedetomidine hloride administration in rats. Data expressed as Mean rit- SD Figure 48: Mean plasma. concentrations foiiowing intravenous (IV) Dexmedetomidine hydrochloride administration in rats Data expressed as Mean fir: SD DETAELED DESCRIPTEQN 0F THE INVENTEGN {a ABBEEVEA'E‘EONS: 'i7he ing abbreviations are used throughout this cation: AD: Alzheimer’s e AUC: Area under the curve BZDs: Benzodiazepines CNS: Centrai nervous system Cf/CAT scan: computed tomography scan 11.5 me: Maximum (or peak) serum tration that a drug achieves in a specified eompartrn ent EPS: Extrapyramidai side effects ED & C: Eederai ifiood, Drug, and Cosmetic ETD: ii‘ronto—temporai dementia GABA: Gamma—aminoautyrie Acid 5—HT: S-i-{ydroxytryptamine ICU: intensive care unit IPD: ient department MR1: Magnetic resonance imaging Mg: Miliigrarn NE: Noruepinephrine OED: Outnpatient department PTSD: Post-traumatic stress disorders RES: Ramsay sedation score RET: Rat intruder test SLGS: Smith—Lemii Opitz syndrome Tmax: Time at which the Cum is observed. l l. l} E FENE'E‘EONS [3H lt will be understood that the terminology used herein is for the e of describing embodiments only, and is not intended to be limiting. As used in this specification, the singular forms H H l a 'an" and "the" include plural referents unless the context clearly dictates otherwise.

U1 Thus, for example, nce to "a solvent" includes one or more such solvents and the lilre. [32} Unless defined otherwise, all technical and scientific terms used, herein have the same meaning as commonly understood by one of ordinary slrill in the art to which the invention pertains. Although other methods and materials similar, or equivalent, to those described herein can he used in the practice of the present invention, the preferred n'iaterials and s are described herein. [33} The terms "treating," and ment," as used herein refer to curative therapy, prophylactic therapy, and/or tative therapy and can he used interchangeably.

As used herein, unless indicated otherwise, the terms "pharmaceutical composition", "composition", "formulation" and sition of the invention," are used interchangeably.

Unless stated otherwise, the terms are meant to ass, and are not limited to, pharmaceutical compositions containing drug substance ie Dexmedetomidine, The composition may also contain one or more "excipients" that are "inactive ingredients" or "compounds" devoid of pharmacological activity or other direct effect in the diagnosis, cure, mitigation, treatment, or prevention of e or to affect the structure or any function of the human body.

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

As used herein, aceutically acceptable salt" refers to a salt known to he non-toxic and commonly used in the pharmaceutical literature. Typical inorganic acids used to form such salt include hloric, hydrohromic, odic, nitric, sulfuric, phosphoric, hypophosphorie, and the like. Salts derived from organic acids, such as aliphatic mono and dicarhoxylic acids, phenyl substituted alhanoic acids, hydroxyallranoic and hydroxyl alhandioic acids, aromatic acids, aliphatic and aromatic sulfonie acids may also be used. A preferred salt is the hydrochloride salt.

As used herein, the term "subject" preferably refers to a human patient. in some embodiments, the t can be any animal, including nonmhurnan s, such as mice, rats, other rodents, rabbits, dogs, cats, swine, cattle, sheep, horses, or primates.

The term "agitation" as used herein, means a irritability, emotional st, impaired thinking, or excess motor and verbal activity that may occur due to either dysfunction of specific brain regions such as frontal lobes or due to dysfunction of neurotransmitter systems such as dopamine and nor~epinepln~ine In the present invention, agitation also includes U1 aggression and hyperearousal in postwtraumatic stress disorder. The agitation may he acute or chronic. '39] The term "the signs of agitation" includes excessive motor activity (examples include: pacing, rocking, gesturing, pointing fingers, restlessness, performing repetitious mannerisms), verbal aggression (eig. yelling, speaking in an excessively loud voice, using profanity, screaming, shouting, threatening other people), physical aggression (eg. grabbing, g, pushing, ing hands into lists, resisting, hitting others, g objects or people, scratching, biting, ng objects, hitting self, slamming doors, tearing things, and destroying property).

The term "acute agitation" means agitation that occurs rapidly and is severe and sudden in onset. Acute agitation may he associated with, for example, neurodegenerative disease and neuropsychiatric conditions, although it may particularly exist in neuropsychiatric ions.

Acute agitation may lead to chronic agitation if it remains ted. [41} The term "chronic agitation" means agitation developed over a long period of time, and is less severe than acute agitation. Chronic agitation may be ated with, for example, neurodegenerative disease and neuropsychiatric conditions, although it may particularly exist in neurodegenerative diseases.

The term "neurodegenerative disease" includes, but is not limited to, Alzheimer disease, frontotemporal dementia (or Piclr’s disease), Dementia, Dementia with l.,ewy bodies, post- traumatic stress disorder, son's disease, vascular dementia, vascular cognitive impairment, il-luntington‘s disease, multiple sis, feldt—lakoh disease, multiple system atrophy, progressive supranuclear palsy or other related neurodegenerative diseases.

The term "neuropsychiatric conditions" es, but is not limited to, schizophrenia, bipolar s (bipolar disorder, r mania), depression, delirium or other related neuropsychiatric conditions 3C) [44] "Sundown syndrome" is a latewday circadian me of increased confusion and restlessness, generally in a patient with some form of dementia. it seems to occur more frequently during the middle stages of Alzheimer dementia. it seems to e with the progression of a patient's dementia. About 20—45% of mer type patients will experience some sort of sundowning confusion. Confusion and agitation worsen in the late afternoon and evening? or as the sun goes down, The term "perioperative agitation" means ion before, during or after any surgical procedure or lCU agitation unassociated with a neurodegenerative disease or neuropsychiatric U1 condition. [46} The term "sublingual" literally means "under the tongue" and refers to a method of administering nces via the mouth in such a way that the nces are rapidly absorbed via the blood vessels under the tongue rather than via the digestive tract. gual absorption occurs through the highly vascularized snblingnal mucosa? which allows a substance direct access to the blood circulation, thereby providing for direct systemic administration independent of gastrointestinal influences and avoiding undesirable tirst~pass hepatic metabolism. Accordingly, the total amount of Dexrnedetomidine or a pharmaceutically acceptable salt thereof in the formulation may he reduced, thereby reducing the likelihood of deleterious side effects and providing a cost benefit to the manufacturer. [47} ion" as used herein means depressed ousness in which a patient or subject retains the ability to independently and continuously in an open airway and a regular breathing pattern, and to d appropriately and rationally to physical stimulation and verbal ands As used herein "without causing significant sedation" means that the patient experiences a level of sedation not greater than Level 3 on the Ramsay Sedation Scale. Level 3 means d hut responds to comm ands. ll l. l‘v’tE'l‘liQfiS [48} The present invention provides a method of treating agitation or the signs of agitation in a subject comprising administering an effective amount of an alpha~2 adrenergic agoni st or a ceutically acceptable salt thereof sublingually to the suh‘iect. in a particular aspect, the agitation is suppressed without also causing significant sedation.

In one embodiment, the alpha—2 adrenergic t includes, but is not limited to, Clonidine? Guantacine, Guanabenz, Guanoxabenz, Guanethidine, Xylazine, 'l‘izanidine, Medetomidine, etoinidine, Methyldopa, Methylnorepinephrine, Fadolmidine, lodoclonidine, Apraclonidine, Detomidine, ltol’exidine Arnitraz, Mivazerol, Azepexol? 'l‘alipexol, idine, Naphazoline, azoline, Xylometazoline, 'l‘etrahydrozoline, Traniazoline, Talipexole, Roniili dine? propylhexedrine, Norfenefrine, Gctoparnine, Moxonidine? Lidamidine, 'l'olonidine, lJKl4304, DJ-7l4l, S'l‘w9l RW’lk. 2353, ’l‘CGwl 000, 4— {3 naminomethylacycloheX—3 —enylmethyl)— l , 3 udihydrowirni dazole—Zuthi one, and 443 ~ hydroxymethyl—cyclohex~3—enj,iln:iethyl)—l ,3—dihydro-intidazole—2~thione or a pharmaceutically acceptable salt thereof.

In one red embodiment, the present invention provides a method of treating U1 ion or the signs of agitation in a t comprising administering an effective amount of Dexmedetomidine or a pharmaceutically acceptable salt thereof sublingually to the subject. In a particular aspect, the agitation is suppressed without also causing significant on. [5 l} Agitation may be effectively treated using a relatively low dose of Dexmedetoinidine or a pharmaceutically acceptable salt tl’iereof via the sublingual route. Consequently, in addition to providing relief from agitation without causing significant sedation, the treatment is also effective with d or no side effects (for e, cardiac or respiratory side effects), In a further embodiment, the present invention is directed to a method of treating agitation or the signs of agitation in a subject comprising administering Dexmedetornidine or a pharmaceuticallv acceptable salt thereof sublingually to the subject to provide fastuaeting relief without a substantial portion of etomidine or its pharmaceutically acceptable salt f passing into the liver of the t. [53} In another embodiment, the present invention provides a method of treating agitation or the signs of agitation in a subject in need thereof, comprising administering an effective amount of Dexmedetomidine or a ceutically acceptable salt thereof via a sublingual composition to the subject, n the sublingual composition is selected from a film, wafer, patch, lozenge, gel, spray, tablet, and liquid drops.

In a further embodiment, the present invention es a method of treating agitation or the signs of agitation in a t 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 suhlingual composition, wherein the sublingual composition is a sublingual film. In a particular aspect, the ion is ated with a neurodegenerative disease or neuropsychiatric ion, In another ular aspect, the treatment is effective without causing significant sedation. [55} In a turther embodiment, the present invention provides a method of treating agitation 3C) or the signs of agitation in a subject in need thereof, comprising administering to the subject an effective arn ount of Dexmedetomidine or a pharmaceutically acceptable salt tl’iereof together with one or more pharniaceutically acceptable carriers and/or excipients via a sublingual composition, wherein the sublingual composition is a sublingual film. In a particular aspect, the agitation is associated with a neurodegenerative disease or neuropsychiatric condition. in r particular aspect, the treatment is ive t causing cant sedation. in yet other embodiment, the present invention provides a method of treating agitation or signs of agitation in a t in need thereof, comprising administering to said subject an U1 effective amount of an alpha—2 adrenergic agoni st or a pharm aceutically acceptable salt thereof at a dosage that does not cause a significant sedation. Suitable 2 adrenergic agonists include, but are not d to, Clonidine, Guantacine, (Itoanabenz, Guanoxabenz, Guanethidine, Xylazine, Tizanidine, Medetomidine, etomidine, Methyldopa, Methyinorepinephrine, Fadoirnidine, iodoclonidine, Abraclonidine, Detornidine, l..ol’exidine, Amitraz, Mivazerol, Azepexol, Talipexol, Rilmenidine, Naphazoline, Qxyrnetazoline, Xylornetazoline, Tetrahydrozoline, Tran'iazoline, Talipexole, Romifidine, hexedrine, Norfenefrine, Octopamine, Moxonidine, Lidamidine, 'l‘olonidine, UK'i4304, 41, Slut—ll, BERG—52353, TCG—lOOO, 4~(3—arninometliyi—cyciohex~3menylnietliyl}l,3—dil1ydro~imi dazole— ne, and 4—(3 whydroxyrnethyl—cyclohex~3—enylrnethyl)—l,3—dihydrouimidazole—Zutbione or a pharmaceutically acceptable salt thereof. in a particular aspect of the invention, the dosage ot‘alphafl adrenergic agonist used in the composition is from about 3 rams to about lth micrograms. [57} in another embodiment, the present ion provides a method of treating agitation or the signs of agitation in a subject in need thereof, comprising administering to said subject an effective amount of Dexmedetomidine or a aceuticaliy acceptable salt thereof sublingually at a dosage that does not cause significant sedation. in a particular aspect of the irwenti on, the dosage ot‘Dexrnedetornidine or a pharmaceuticaliy acceptable salt thereof used in the sublingual composition is from about 3 micrograms to about lOO micrograms. es of suitable dosages include: about 5 micrograms to about lt‘rQ micrograms, about 5 micrograms to about 90 micrograms, about 5 micrograms to about 85 micrograms, about 5 micrograms to about 80 micrograms, about 5 micrograms to about 75 micrograms, about 5 micrograms to about 70 micrograms, about 5 micrograms to about 65 n'iicrograms, about 5 n'iicrograms to about an micrograms, about 5 micrograms to about 55 micrograms, about 5 rams to about 50 micrograms, about 5 micrograms to about 45 micrograms, about 5 microgran'is to about 40 micrograms, about 5 micrograms to about 35 micrograms, about 5 micrograms to about 30 micrograms, about 5 micrograms to about 25 n'iicrograms, about 5 n'iicrograms to about 29 micrograms, about 5 micrograms to about i 5 micrograms, about 5 micrograms to about it) micrograms, less than 10 micrograms (eg. about 5, 6, 7, 8, or 9 micrograms), about l0 micrograms, about l2 micrograms, about l4 micrograms, about l5 micrograms, about lb micrograms, about 18 micrograms, about 20 micrograms, about 30 micrograms, about 50 micrograms, The dose may be administered one or more times a day. in a further embodiment, the present invention provides a method of treating agitation or the signs of ion in a t in need t1'iereof, comprising administering to said subject U1 an effective amount of Dexmedetomidine or a pharniaceuticahy acceptabie sait thereof subiinguaiiy at a dosage of from about 0.05 micrograms/14g weight of subject to about 1.5 micrograms/hg weight of subject. Exampies of suitabie dosages inc1ude: about 0.1 micrograms/kg to about 1 micrograms/kg, about 0.1 micrograms/kg to about 0.5 microgram s/kg, about 01 micrograms/kg to about 0.4 micrograins/hg, about 0.1 micrograms/kg to about 0.3 rams/kg, about 0.1 micrograms/kg to about t»,J"z i micrograms/kg about 0.07 micrograms/kg about 0.05 micrograms/kg, about 01 micrograms/kg, about 0.2 mierograrn s/hg, about 0.3 micrograms/kg, about 0.4 micrograms/kg, about 0.5 micrograms/kg, about 0.6 micrograms/kg, about 017 micrograms/kg, about 0.8 micrograms/kg, about 0.9 micrograms/kg, about 1.0 rams/kg, about 1.1 micr‘ograms/hg, about 1.2 micrograms/kg, about 1.3 micrograms/kg about 1.1-1 micrograms/kg, about 1.5 micrograms/1%. The dose may be administered one or more times a day. [59} In yet other embodiment, the present invention provides a method of treating agitation or signs of agitation associated with neurodegenerative disease in a subject in need thereof, comprising stering to said t an effective amount of an aiphauZ adrenergic agonist or a pharmaceuticaiiy acceptabie sait thereof at a dosage that does not cause a icant on. Suitable a1pha~2 adrenergic agonists include, but are not innited to, Cionidine, Guanfacine, Guanabenz, Guanoxabenz, Guanethidine, ne, Tizanidine, h/iedetomidine? Dexmedetoinidine, Methyidopa, norepinephrine, Fadoiinidine iodocionidine, Apracionidine, Detoniidine, dine, Antitraz, Mivazeroi, Azepexoi, Taiipexoi, Riimenidine, Naphazohne, ()Xj/inetazoiine, Xyiometazoiine, Tetrahydrozohne, Ti‘ramazoiine, Taiipexoie, Romiiidine, propyihexedrine, Nortenefrine, Oetoparnine, Moxonidine, Lidamidine, Toionidine, UK14304, menu, sir—91, 353, reunion, 4—(3— aminoniethyincyciohexfi menyimethy1)— 1 ,3 ro—nnidazoie—Z—thione, and 4%? n hydroxyme‘thyi—cyciohex~3—enyimethyi)—1,3—dihydro~imidazo1e—Z-thione or a pharmaceutieaiiy able sa1t thereof. The dosage of aipbauZ adrenergic agonist used in the composition is convenientiy from about 3 micrograms to about 100 micrograms In a yet further embodiment, the present invention provides a method of treating ion or the signs of agitation associated with neurodegenerative disease in a subject in need thereof, comprising sub1ingua11y stering to said subject an effective amount of Dexmedetomidine or a pharmaceuticaliy acceptable salt thereof at a dosage that does not cause unwanted (eg, significant) sedation, The dosage of Dexmedetomidine or a pharmaceutically able salt f used may conveniently be from about ,{4 u micrograms to about 190 micrograms, e. g. about 5 micrograms to about 100 micrograms, about 5 micrograms to about U1 90 micrograms, about 5 micrograms to about 85 micrograms, about 5 micrograms to about 80 micrograms, about 5 micrograms to about ‘75 micrograms, about 5 micrograms to about 70 micrograms, about 5 micrograms to about 65 micrograms, about 5 micrograms to about 60 micrograms, about 5 micrograms to about 55 micrograms, about 5 micrograms to about 50 micrograms, about 5 micrograms to about 45 micrograms, about 5 micrograms to about 40 micrograms, about 5 micrograms to about 35 micrograms, about 5 micrograms to about 30 micrograms, about 5 n'iicrograms to about 25 micrograms, about 5 micrograms to about 20 micrograms, about 5 micrograms to about 15 micrograms, about 5 micrograms to about 10 micrograms, iess than 10 rams, about 5 micrograms, about 6 micrograms, about 7 micrograms, about 8 micrograms, about 9 micrograms, about to micrograms, about i2 rams, about i4 micrograms, about l6 micrograms, about l8 micrograms. The dose may be administered one or more times a day, {oi} in yet other embodiment, the present ion provides a method of treating agitation or signs of ion associated with neuropsychiatric condition in a subject in need thereof, comprising stering to said subject an effective amount of an aipbauZ adrenergic agonist or a pharmaceutically acceptable sait thereof at a dosage that does not cause a significant sedation. Suitable alpha~2 adrenergic agonists include, but are not limited to, Cionidine, Guanfacinc, enz, Guanoxabenz, liidme, Xyiazine, dine, h/iedetomidine? Dexmedetomidine, h/iiethyldopa, Methyinorepinephrine, Fadolmidine, lodocionidine, Apracionidine, Detomidine, Lofexidine, Amitraz, Mivazeroi, Azepexoi, Taiipexol, Riinienidine, Napbazoiine, ()thirnetazoiine, Xyiometazoiine, 'i7etrahydrozoline, Trarnazoiine, Taiipexole, Romifidine, propylhexedrine, Nortenefrine, Oetopamine, Moxonidine, dine, Toionidine, unmet, rat—7141, sr—ai, nutrssasa, rcoaccc, 4—(3— aminomethyincyclohexfi iethyi)— i ,3 ndihydro—imidazole—Z—tbione, and 4%? n yme‘thyi—cyciobex~3—enyimethyi)—l,3—dihydro~imidazoie—Z-thione or a 3C) pharmaceuticaily acceptable salt thereof. The dosage of alpha—2 adrenergic agonist used in the composition is convenientiy trom about 3 micrograms to about too micrograms In another embodiment, the present invention provides a method of treating agitation or the signs of agitation associated with sychiatric condition in a subject in need thereof, comprising administering to said subject an ive amount of Dexmedetoinidine or a aceutically acceptable salt thereof sublingually at a dosage that does not cause significant sedation, The dosage ot‘Dexmedetomidine or a pharmaceutically acceptable salt tused in a sublingual composition may conveniently be from about 3 micrograms to about 1th micrograms, e. g. about 5 micrograms to about lot") rams, about 5 rams to about U1 90 micrograms, about 5 micrograms to about 85 micrograms, about 5 micrograms to about 80 micrograms, about 5 micrograms to about ‘75 micrograms, about 5 micrograms to about 70 micrograms, about 5 micrograms to about 65 micrograms, about 5 micrograms to about so micrograms, about 5 micrograms to about 55 micrograms, about 5 micrograms to about 50 micrograms, about 5 micrograms to about 45 micrograms, about 5 micrograms to about 40 micrograms, about 5 micrograms to about 35 micrograms, about 5 micrograms to about 30 micrograms, about 5 rams to about 25 microgram s, about 5 micrograms to about 20 micrograms, about 5 micrograms to about l5 micrograms, about 5 micrograms to about ll‘i micrograms, less than 10 micrograms, about 5 micrograms, about 6 micrograms, about '7 micrograms, about 8 rams, about 9 micrograms, about l0 micrograms, about l2 micrograms, about l4 micrograms, about 15 micrograms, about 16 micrograms, about l8 micrograms, about 20 micrograms, about 30 micrograms, about 50 micrograms. The dose may be administered one or more times a day. [63} The level of acceptable sedation when treating a subject according to a method of the present invention is preferably at or below Level 3 according to the Ramsay sedation scoring (R88) system Thus, a particular en'ibodiment of the present invention provides a method of treating ion or the signs of agitation in a human subject in need thereof, sing i stering Dexmedetomidine or a pharmaceutically acceptable salt thereof sublingually to said subject at a dose in the range of about 3 micrograms to about 100 micrograms, thereby ing an RSS at or below Level 3 (eg. Level 2 or Level 3).

{V} PHARi‘leCEETECAL CGMPQSETIONS The present invention also provides sublingual pharmaceutical itions comprising an effective amount of an alpha—2 rgic agonist or a pharmaceutically able salt thereof, preferably Dexmedetomidine or a pharmaceutically acceptable salt 3C) thereof.

The sublingual pharmaceutical compositions of the present invention may also comprise a pharmaceutically acceptable carrier and/or excipient. Suitable pharmaceutically acceptable carriers include water, sodium chloride, binders, penetration enhancers, diluents, lubricants, flavouring agents, coloring agents and so on. [do] The sublingual pharmaceutical compositions of the present invention may be administered to a t alone or in combination with one or more other suitable active ingredients. in one ment, the present invention, provides a gual pharmaceutical U1 composition comprising an effective amount of Dexniedetornidine or a pharmaceutically acceptable salt thereof for the treatment of agitation in a subject, e. g. agitation associated with neurodegenerative disease, sundown syndrome in Alzheimer’s e or dementia. in a particular , the sublingual pharmaceutical composition effectively treats agitation in a subject without g significant on. id="p-68" id="p-68" id="p-68"

[68] In another embodiment, the present ion es a sublingual pharmaceutical composition comprising an effective amount of etomidine or a pharmaceutically acceptable salt thereof for the treatment of agitation in a subject associated with schizophrenia, bipolar disorder, bipolar mania, other bipolar illness, depression, delirium or another related neuropsychiatric condition. in a particular , the sublingual pharmaceutical composition effectively treats agitation in a subject without causing cant sedation.

The sublingual pharmaceutical composition of the present invention may be, for example, a film, wafer, patch, lozenge, gel, spray, tablet, liquid drops or the like. [70} in one embodiment of the ion, the sublingual pharmaceutical composition is in the form of a tablet or packed powder. [7H in another embodiment of the invention, the sublingual pharmaceutical compositi on is in the form of a patch or film (eg thin film). The patch may have ve qualities to prevent movement or swallowing of the patch. The patch may be ingestible in case of accidental swallowing or to allow for its easy disposal, or the patch may be removed from under the tongue after a prescribed time. in yet another embodiment of the invention, the sublingual pharmaceutical composition is in the form of a paste, gel or ointment. The viscosity of the paste, gel or ointment can be adjusted to allow for retention under the tongue. [73} In a further embodiment of the invention, the sublingual pharmaceutical composition is in a liquid (e. g. as a. solution, suspension or emulsion), and may be, for example, presented as a spray or as drops. Solutions include the active ingredient together with a diluent such as water, normal saline, sodium chloride solution, or any other suitable solvent such as propylene glycol, glycerol, ethyl alcohol and so on. The t for the solution may particularly be physiological saline on or water. The amount of solution administered may conveniently be about {Mil ml to about l rnl (eg. about 0025-06 nil)~ The non—solid compositions of the invention may conveniently be administered by spraying, dripping, painting or squirting the composition under the tongue. in a particular embodiment of the invention, etomidine or a pharmaceutically acceptable salt thereof is sublingually administered in liquid fori'n, eg. in a flavored or U1 unilavored physiological saline solution. The liquid composition may conveniently be administered under the tongue as drops or as a spray.

Dexmedetomidine, or a pharmaceutically acceptable salt thereof may conveniently represent from about 0.00l% to about 99.99% of the overall composition, eg. about 0.0l% to about 90%, more particularly about 0,0 7% to about 30%, id="p-77" id="p-77" id="p-77"

[77] When the composition is a liquid or gel, a first unit dose is applied and held in place under the tongue for a predetermined time, for example for at least about 30 seconds, or more particularly about 60 seconds or more. A second unit dose may then be d and held in place for a similar amount of time. Surprisingly, this procedure noticeably increases the effect of the composition of the invention in the treatment of agitation or the signs of agitation. [78} in another embodiment, the sublingual ition of Dexmedetomidine or a pharmaceutically acceptable salt thereof is a hard tablet or a compressed powder tablet. The tablet may conveniently be designed to dissolve under the tongue in about 30 to ill) s as disclosed in US Pat. No. 6,22l ,392 to Khanltari, et al, incorporated herein by reference. in a particular embodiment, the sublingual composition of Dexmedetomidine or a pharmaceutically acceptable salt thereof is a hard tablet having a low grit component for an organoleptically pleasant mouth feel. The tablet (or particles f ning the active ient which, can be ssed to form the tablet) may also comprise a protective outer coating, eg any polymer conventionally used in the formation of microparticles, matrix—type microparticles and microcapsules. in a further embodiment, the sublingual composition of Dexmedetomidine or a ceutically acceptable salt thereof is a hard, ssed, rapidly dissolvable tablet. The tablet conveniently includes the active ingredient within a matrix. The matrix, may be composed of, for example, at least one tiller and a lubricant. Fillers e, for example, lactose or mannitol, and suitable lubricants include magnesium te, silicon e and talc. The 3C) matrix may also include one or more of: a binder (eg. povidone, a sugar or carboxymetliylcellulose), a disintegrant (eg, croscarmellose sodium, crospo‘vidone or sodium starch glycolate‘), a sweeting agent (eg. sucralose‘) and the like. The tablet may conveniently have a lity of about % or less and a hardness of about l5 to about 50 Nest/tons. [8G] Another aspect of the present invention provides a method of making a packaged, gual tablet. The method includes the steps of: (a) forming a mixture comprising Dexmedetomidine or a pharmaceutically acceptable salt thereof and a matrix including at least a nonmdirect compression tiller and a lubricant, (b) compressing the mixture to form a plurality U1 of hard, compressed, rapidly egrahle les (eg. beads) including the active ient distributed in the sublingually dissolyable matrix; and to) storing the product in bulk prior to packaging, in another embodiment, the dosage forms are then packaged in a lumen of a package such that there are more than one per package. Direct compression is the preferred, method of forming the dosage forms, There is also provided hereby an openable and reclosable package containing a plurality of hard, compressed, rapidly dissolving s adapted for direct oral dosing as described above.

[Si] in another embodiment, the present invention is a sublingual tablet comprising an effervescent agent. The escent agent may conveniently be present in an amount up to about 95% by , based on the weight of the finished tablet, and more particularly in an amount ol‘between about 309/6 and about 80% by weight. Sullicient effervescent material is included in the tablet composition to te more than about 5 cm3 but less that about 30 cm3 of gas upon exposure of the tablet to an aqueous environment. Sublingual compositions comprising effervescent agents are disclosed in US Pat. No 6,200,604, which is incorporated herein by reference. [82} in one particular embodiment, an effervescent agent releases carbon dioxide e. g, as a result of the reaction of a soluble acid source with an alkaline carbonate or onate. The acid source may conveniently include food acids and acids such as citric acid, tartaric, arnalic, tunieric, adipic and succinic acid, Carbonate and bicarbonate sources include dry solid carbonate and bicarbonate salts such as sodium bicarbonate, sodium carbonate, potassium bicarbonate, potassium carbonate, magnesium ate and the like. [83} Spray compositions of the present invention for sublingual administration may include one or more pharmaceutically acceptable liquids (e. g. present in the amount of about 30% to about 99.99% by weight of the composition). Such liquids may be ts, co~solvents, or non—solvents for Dexmedetomidine or a ph arniaceutically acceptable salt th ereof. Examples of pharniaceutically acceptable liquids include water, ethanol, diniethyl sulfoxide, propylene glycol, polyethylene glycol, ene carbonate, pharmaceutically able oils (cg, soybean, wer, peanut, peppermint etc.) and the like. The pharniaceutically acceptable liquid is ed, either to dissolve the active pharmaceutical ingredient, to produce a stable, homogenous suspension or solution of it, or to form any combination of a sion or solution.

Furthermore, sublingual, spray formulations of Dexmedetoniicline or a pharmaceutically acceptable salt thereof may include one or more carriers anti/or excipients, U1 Examples of carri ers/excipients include viscosity—moolulating materials (eg, polymers, sugars, sugar alcohols, gums, clays, silicas, and the like). One particular polymer that may iently be used is nylpyrroliclone (PVP), The vi scositysmoclulating material may iently be present in the amount of from about Q.Ol% to about 65% by weight of the spray formulation Other examples of carritars/"excipients e preservatives (eg, ethanol, benzyl l, propylparaben and inethylparaben). vatives may conveniently be t in, the amount of from about ODOlll/o to about 10% by weight of the spray formulation Carriers/excipients may also be flavoring agents, ners (eg. sugars such as sucrose, glucose, dextrose, e, fructose, etc), artificial sweeteners (eg. saccharin, aspartame, fanie, sucralose etc), or sugar alcohols (eg. mannitol, xylitol, lactitol, maltitol syrup etc.) present conveniently in an amount of from about 0.00l% to about 65% by weight of the spray formulation Other examples of carriers/excipients include buffers and pit—adjusting agent (eg, sodium hydroxide, citrate, and citric acid) conveniently present in an amount of from about 0.0 % to about 5% by weight of the spray formulation. Coloring agents (eg present in an amount offrom about OOOlWé to about 5% by weight ofthe spray formulation), fragrances (eg t in an amount of from about OOOl‘i/o to about l% by weight of the spray formulation), chelating agents such as EDTA (e.g present in an amount of from about 0.00l% to about l% by weight of the spray formulation), UV absorbers (eg, present in an amount of from about OOOl‘l/o to about lO‘l/o by weight of the spray formulation), and anti—foam agents (e g. low molecular weight alcohols, dimethicone) conveniently present in an amount of from about 0.00l% to about 5% by weight of the spray formulation may also be included as riate carriers/exeipients in the spray formulations of the present invention.

One particular aspect of the present invention provides a sublingual film comprising Dexmedetomidine or a pharmaceutically acceptable salt thereof, together with one or more carriers and/or excipients, for the treatment of agitation. 3C) [86] Excipients which may be incorporated into the sublingual films of the present invention include one or more of the following: film forming agents, mouth feel irnprovers, plasticizers, stabilizers, surfactants, preservatives, sweetening agents, colorants, flavourants, emulsifiers, disintegrants, salivating agents, antioxidants, permeation enhancers, solvents and the like.

Film forming agents generally mean agents that provide structure to the film of the present invention. The effective amount of the film forming agent ranges from about l0% to about 99%, more preferably about 50% to about 90% by weight of the composition. Film forming agents that can be utilized as part of the film composition of the present invention U1 include, but are not limited to, cellulose , modified starches, natural gums, edible polymers, seaweed extracts, land plant extracts, pullulan, polyvinylpyrrolidone, derivatives thereof and combinations thereof, [88} Examples of cellulose ethers include, but are not limited to, methylhydroxycellulose, methylcellulose, ethylcellulose, hydroxyethylcellulose, carhoxymetl'iylcellulose, derivatives thereof and combinations thereof. [89} Modified starches include, but are not d to, acid and enzyme yzed corn and potato starches, derivatives thereof and combinations thereof.

Examples of natural gums include, but are not limited to, gum arabic, guar gum, locust bean gum, carrageenan gum, acacia, a, ghatti, tragacanth agar, tamarind gum, xanthan gum, derivatives thereof and combinations f. [9i] rnples of edible polymers e, but are not limited to, microcrystalline cellulose, ose ethers, xanthan, derivatives thereof and ations thereof. [92} d extract es include, but are not d to, sodium alginate, eenans, derivatives thereof and. combinations thereof. [93} Land plant extracts include, but are not limited to, horijac, pectin, arabinoglactan, derivatives thereof and combinations thereof.

Particular filin forming agents include pullulan, sodium alginate, polyvinylpyrrolidone, inethylcellulose and methylhydroxycellulose (Ml-KI), [95} The term "solvent" generally refers to liquids that will dissolve solutes. A t may he used to dissolve film—forming agents and other excipients to prepare orming compositions of the present invention. Solvents include, but are not limited to, deinineralized/distilled water, ethyl l, isopropyl alcohol, methyl ethyl ltetone, propylene glycol methyl ether acetate, dimetliyl acetamide, ethylene glycol monompropyl ether, and toluene. A sublingual film of the present invention may conveniently comprise a solvent in an 3C) amount up to about lo/fi w/w.

The term "stabilizer" generally refers to an agent that will impart stability to the formulation during its shelf life. Stabilizers of the present invention can include, for example, oil/water emulsifiers and flavor fixatives. The effective amount of a stabilizer agent in a composition of the invention may be, for example, in the range of about 0% to about 450/25, more particularly about 4% to about 25%, by weight of the composition. Examples of suitable stabilizing agents of the present invention include, but are not limited to, gum arabic, niicrocrystalline cellulose, carrageenan, xanthan gum, locust bean gum, derivatives thereof and ations thereof. Particular stabilizing agents of the present inventi on include guni arabic U1 and crystalline cellulose, [97} "Disintegrants" can aid the dissolution of edible tilnrs ng for the efficacy of the film to be realized sooner, le disintegrants for use in an edible film of the present invention include, but are not limited, to, alginic acid, microcrystalline cellulose and carboxyniethylcellulose. Special disintegrants known as super—disintegrants are also suitable for use in an edible film of the present invention. Super—disintegrants include cross—linked rs (eg, crospovidone), cross~linlted starches (eg, sodium starch glycolate), and cross" linked celluloses (eg. a modified carhoxyrnethylcellulose such as croscarrnellose). These disintegrants are insoluble in water and most other solvents, have rapid swelling properties, and have good water uptake with high capillary action, resulting in fast disintegration. Their insolubility in many solvents also means they enable the manufacture of sublingual compositions of this invention in a single step process as opposed to costly multi— step processes. [98} The disintegrants or super—disintegrants are conveniently t in a sublingual ition of this invention (eg an edible film) in an amount ranging from about l% to about lO‘l/o, more particularly about l% to about 5% by weight of the composition "Ernulsifiers" suitable for use in an edible film of the present invention include, but are not d to, gurn arabic, carrageenan, triethanol amine steara‘re, nary ammonium compounds, acacia, gelatin, lecithin, bentonite, veeguni, derivatives thereof and combinations thereof. Enrulsitiers can be used in a composition of the present ion in an amount up to about 40%, more particularly up to about 25%, by weight of the ition. The ernulsiti er can be a stabilizer creating an oil/water emulsion encapsulating volatile oils and flavoring agents, thereby essentially acting as a flavor fixative, A particular ernul siti er for use in an edible film of the present invention is gum arabic. [lOO] A "plasticizing agent" or "plasticizer" may be utilized to improve flexibility and reduce brittleness of an edible filrn composition of the t invention. The plasticizing agent may conveniently constitute up to about 30%, eflg up to about l5% by weight of the composition.

Examples of suitable plasticizing agents include, but are not d to, glycerin, sorbitol, triacetin, cetin, diacetin, hylene glycol, propylene glycol, hydrogenated starch hydrolysates, corn syrups, low molecular weight propylene glycol s, phthalate derivatives like dirnethyl, tliethyl and dibutyl phtlialate, e derivatives such as tributyl, triethyl, acetyl citrate and castor oil derivatives thereof and combinations thereof. Particular plasticizing agents of the present invention include sorbitol and in. [lull The term "preservative" generally refers to an ent used to loll microorganisms or U1 prevents, inhibits or s their growth and reproduction, and is included in a product in a concentration only sufficient to prevent spoilage or the growth of rtently added microorganisms. Suitable preservative includes, but are not limited to, inethylparaben, propylparaben and sodium benzoate. The preservative inay conveniently be present in the cornposition from about 0.001% to about l0% w/w of the composition. $02} The term "sweetening agent" generally refers to an excipient used to impart sweetness to a ceutical composition Suitable sweetening agents for use in a coinpositi on of the present invention include, but are not limited to, aspartanie, dextrose, glycerin, mannitol, sacchari n sodiuin, sorbitol and sucrose. The sweetening agent may conveniently be present in the composition in an amount of from about 5% to about 20% w/w of the ition.

{HR} The term "coloring agent" or "colorant" generally refers to an excipient used to impart color to a pharmaceutical ition, Suitable colorants include, but are not limited to, lilhitC Red No. 3, FD&C Red No. 20, FD&C Yellow No. 6, FD&C Blue No. 2, D&C Green No. 5, 3035C Orange No, 5, D6116 Red No, 8, other El)~ & C, dyes, caramel, red ferric oxide, and natural coloring agents such as grape skin extract, beet red powder, beta~carotene, annatto, carniine, turmeric or paprika, The colorant rnay conveniently be present in the composition in an amount of from about OOOl‘B/o to about l 0% w/w of the composition. [llhl] The term "flavoring agent" or "fl avorant" generally refers to an excipient used to impart a pleasant flavor (and often also odor) to a pharmaceutical composition. Suitable ants include, but are not d to, synthetic flavoring oils, ing arornatics, natural oils, ts from whole plants or parts f such as , flowers, fruits or combinations thereof. Examples include cinnamon oil, Wintergreen oil, peppermint oil, clove oil, bay oil, anise oil, eucalyptus oil, thyme oil, cedar leave oil, nutmeg oil, sage oil, bitter almond oil and cassia oil. Other useful flavorants include vanilla, citrus fruit oils such as lemon, orange, grape, lime or grapefruit oil, and fruit es such as apple, pear, peach, strawberry, raspberry, 3C) cherry, plum, pineapple or apricot essence. Flavorants of particular interest for use in a cornposition of the present invention include commercially available orange, grape, cherry and bubble gum flavors and mixtures f. The amount of flavoring used will depend on a number of factors, including the organoleptic effect desired. Particular flavorants include grape and cherry fl avors, and citrus fruit fl avors such as orange flavor The flavorant may conveniently be present in the composition in an amount of from about Otlt‘ilo/Er to about 10% Vv’/W of the siti on.

El 05] The term "salivating agent" is an agent that promotes greater salivati on during use of a composition of the t invention. This may he an important feature if the composition is U1 intended to be taken by the patient without the aid of water to help in the transporting of the composition to the stomach of the patient. The salivating agent can be, for example, an emulsifier or a food acid that initiates salivation in the mouth of the patient Examples of emulsifiers useful as salivating agents e alhyi aryl sulfonates, alhyl sulfates, sulfonated amides and amines, sulfated and sulfona‘ted esters and ethers, alhyl sulfonates, hoxylated esters, mono—, dim, and triglycerides, diacetyl tartaric esters of monoglycerides, polyglycerol , sorbitan esters and lates, lactyiated esters, phospholipids such as lecithin, polyoxyethylene sorhitan esters, proplyene glycol esters, sucrose esters, and mixtures thereof.

The ernulsiti er may be either saturated or rated. it should be noted that some of the fiers that are salivating agents may also function as binders. Examples of food acids useful as salivating agents e citric acid, malic acid, tartarate, food salts such as sodium chloride and salt substitutes, potassium chloride, and mixtures thereof. The amount of salivating agent present in a sublingual film of the present invention may convenient be up to about l5% by weight of the final composition, e. g. in the range or" from about 0. % to 0.4% by weight of the composition. {ice} The term "antioxidant" generally refers to an excipient used to inhibit oxidation and thus prevent deterioration of active agents by oxidative processes. Suitable antioxidants include, for example, ascorbic acid, ascorbyl palrnitate, butylated hydroxyanisole, butylated hydroxytoluene, osphorous acid, monothio—glyceroi, propyl gallate, sodium ascorbate, citric acid, sodium bisultite, sodium tormaldehyde suifoxyiate, sodium metabisultite, EDTA and sodium edetate. The antioxidant may conveniently be present in the ition in an amount m about 0.00l% to about % w,"vv of the composition.

Elm} The term "permeation enhancer" generally refers to an excipient used to enhance permeation of an active agent to cellular membranes or enhance the local/systemic absorption of the active agent. Permeation enhancers that may he used in the present invention include, 3C) but are not limited to, lizers such as alcohols, polyethylene glycol s, chelating agents (e.g. cyclodextrins), sucrose iaurate or sucrose oleate. The permeation enhancer may iently be present in the composition in an amount of from about Lilli/ii to about 5% w/w of the composition. [108} In one ment ofthe present ion, the sublingual pharmaceutical composition of the t invention includes a rnucosal permeation er appropriate for enhancing the niucosal absorption of the composition. [lll9l Suhlingual Dexrn edetomirline formulations (such as sprays, drops, and the like) may he U1 made by mixing riate quantities ot‘the foregoing ingredients in accordance with standard good manufacturing practices. The relative amounts of each ient should not interfere with the desirable pharmacological and pharrnacolrinetic properties of the resulting formulation. [llO] gual Dexniedetornidine lilrns of the present invention may be conveniently prepared using Pharml‘ilrn® technology (owned by MonoSol) or technology owned by ARK LLC, Various patents and patent ations are incorporated herein in entirety and includes US. Pat. or Publication Nos. 9585961, 7470397, 7727466, 9248146, 9545376, 201 741087084, 9662297, 9662301, 2017—0246108, 20l7«0252294, 9441142 ed to ARK LLC and 7425292, 7357891, 8663687, 7, 7897080, 8241661, 8617589, 8936825, 956119l, 9303918, 9346601, 8282954, 7972618, 9073294 assigned, to sol For. [l l 1] in preparing the suhlingual film of the present invention the active agent, erg, etornidine or a pharrnaceutically acceptable salt thereof, film g agents and ally one or more carriers and/or excipients selected from the group comprising of mouth feel iniprover, plasticizer, izer, surfactant, preservative, sweetening agent, colorant, ilavourant, emulsifier, disintegrant, salivating agent, antioxidant, permeation enhancer are dissolved in a compatible solvent to form a film forming composition. Compatible solvents include water, alcohols such as ethanol, ethyl acetate, acetone, and mixtures fi The film forming composition is cast on a releasable carrier and dried to form a sheet/film, The carrier rnaterial must have a surface tension which allows the li1rn solution to spread, even1y across the intended carrier width without soalting to form a destructive bond hetween the film carrier substrates. Examp1es of suitable carrier materials include glass, stainless steel, Teflon and polyethylene~irnpregnated paper. Drying of the film may he carried out at high temperature using a drying oven, drying terminal, vacuum drier, or any other suitable drying equipment which does not adversely allect the ingredients of which the film is composed, The suhlingual 3C) film of the present invention can also he prepared by other established processes eg. extrusion (for example, Hot melt ion, Solid dispersion extrusion), casting (for example, solid casting or SBHIinGlid casting), Rolling methods and the like.

V. A DMIENES'E‘RA'I‘E ()N [l l2] in an 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 ively treat agitation The amount of alpha—2 adrenergic U1 agonist is sufficient to effectively treat agitation without g significant sedation The alpha—2 adrenergic agoni st may conveniently be delivered on an "as needed basis" in one, two or more doses per day to the animal {eg human) subject, The composition may also be administered, via a single dosage form or via multiple dosage forms. [l l3} In another aspect, the present invention provides a sublingual composition sing Dexmedetomidine or a pharmaceutically acceptable salt thereof, administered to a subject in an amount sufficient to effectively treat ion in a particular aspect, the amount of etomidine or a pharmaceutically acceptable salt thereofused is sufficient to effectively treat agitation without causing significant sedation. The Dexmedetornidine or a pharmaceutically acceptable salt thereof may conveniently be delivered on an "as needed basis" in one, two or more doses per day to the animal (eg. human) subject. The composition may also be stered via a single dosage form or via multiple dosage forms~ [l l4] Following administration of a composition of this invention to a t, a therapeutic {ie antiwagitation) effect may begin within about 60 minutes (eg within about 30, 20, l5, l0, , 3, 2 or 1 s) after administration, or within about 30 seconds after administration. The signs of agitation may also relieved within about l to about 60 minutes after administration, and more typically within about 5 to about 30 s. A second dose of the composition of this invention may be adn'iinistered to the subject it‘the signs of agitation are not relieved within about 60 s, [l l5] ent protocols may include one or more dosage intervals (eg two or more dosage intervals, live or more dosage intervals, or ten or more dosage intervals). Depending on the physiology of the subject and the desired therapeutic effect, the duration of dosage intervals and treatment protocol s according to embodiments of the present invention may vary. it l6} flexmedetomidine or a ceutically acceptable salt f may be administered as a sublingual composition to treat agitation or the signs of agitation either alone or in combination with one or more further active agents, When used in combination, the active agents can either be formulated as a single ition or as two or more separate compositions, which can be administered simultaneously, sequentially or separated by an appropriate period of time. [117} Where Dexmedetomidine or a pharmaceutically acceptable salt f is administered with a second active agent to treat agitation or the signs of agitation the weight ratio ot‘ respectively Dexmedetomicline or a pharmaceutically acceptable salt thereof to the second active agent may generally be in the range from about 1:2 to about 1:25; about 1:25 to about U1 1:3; about 1:3 to about 1:35 about 1:3.5 to about 1:4; about 1:4 to about 1:4.5; about 1:45 to about 1:5; about 1:5 to about 1:111; and about 1:10 to about 1:25. For e; the weight ratio may particularly be between about 1:1 to about 1:5; about 1:5 to about 1:111; about 1:11) to about 1:15; or about 1:15 to about 1:25. Alternatively, the weight ratio of respectively the second active agent, to Dexmede‘tornidine or a pharmaceutically able salt may be in the range offrom about 2:1 to about 25:1; about 25:1 to about 3 :1; about 3 :1 to about 3.5:1; about 3.511 to about 4:1; abtuit~111 to about 451; about 45:1 to about 5:1; about 5:1 to about 10:1; and about 10:1 to about 25:1. For example; the weight ratio of respectively the second active agent to Dexrriedetoniidine or a ceutically acceptable salt cof in ay particularly be in the range of from about 1:1 to about 5: 1; about 5:1 to about 10:1; about 10:1 to about 15:1; or about 15:1 to about 25: 1. it is to be understood that all ranges between the quoted ranges are also covered herein; and tute r particular s of this invention Vi. DGSENG REGlh/IEN [118} The dosing regimen employed may depend on several factors; such as the type of agitation d? the severity of the signs; and r the agitation is due to an underlying medical condition. [119} Dexrncdetoniidine or a pl'iarrnaceutically acceptable salt tl'iereof may be administered sublingually in any appropriate dose to an animal (cg. human). in certain embodiments; the human dose may be from about 3 micrograms to about 100 micrograms (eg. about 5 micrograms to about 100 micrograms; about 5 micrograms to about 90 microgram s; about 5 micrograms to about 85 micrograms; about 5 micrograms to about 80 micrograms; about 5 micrograms to about 75 micrograms; about 5 micrograms to about '70 micrograrn s; about 5 micrograms to about 65 micrograms; about 5 micrograms to about 60 micrograms; about 5 micrograms to about 55 n'iicrograrns; about 5 micrograms to about 511 micrograms; about 5 3C) micrograms to about 45 micrograms; about 5 micrograms to about 411 micrograms; about 5 micrograms to about 35 micrograms; about 5 micrograms to about 30 micrograrn s; about 5 micrograms to about 25 micrograms; about 5 micrograms to about 20 micrograms; about 5 micrograms to about 15 micrograms; about 5 micrograms to about 10 micrograms; less than micrograms (eg. about 5; 6,, H I; 8; or 9 micrograms) about 111 micrograms; about 12 micrograms, about 14 rams, about 15 rams, about 16 micrograms, about 18 micrograms, about 20 micrograms, about 30 mi crograrn s, about 50 micrograms). The dose may be administered one or more times a day. [120} Dexmedetomidine or a phar’maceuticaiiy acceptabie sait thereof may be administered U1 subiinguaiiy in any appropriate dose to a human. in some variations, the human dose may be from about 0.05 micrograms/kg weight of t to about 1.5 micrograms/kg weight of subject. Exampies of suitab1e dosages inciude: about 0.1 micrograms/kg to about 1 micrograms/kg, about 0.1 micrograms/kg to about 0.5 micrograms/kg, about 0.1 micrograms/kg to about 0.4 micrograms/kg, about 0.1 micrograms/kg to about 0.3 micrograms/kg, about 0.1 micrograms/kg to about 0.2 micrograms/kg, about 0.07 micrograms/kg, about 0.05 rams/kg, about 0.1 micrograms/kg, about 0.2 micrograms/kg, about 0.3 mierogram s/kg, about 0.4 micrograms/kg, about 0.5 micrograms/kg, about 0.6 micrograms/kg, about 0.7 micrograms/kg, about 0.8 rams/kg, about 0.9 micrograms/kg, about 1.0 micrograms/kg, about 1.1 micrograms/kg, about 1.2 micrograms/kg, about 1.3 micrograms/kg, about 1.4 micrograms/kg, about 1.5 micrograms/kg. The dose may be administered one or more times a day.

Vii. IC ENIBGDIMENTS ()1? THE ENVENTIGN [121} Embodiment 1. A method of treating ion or the signs of agitation in a subject in need thereof comprising administering subiinguaiiy to said subject an effective amount of Dexmedetomidine or a pharmaceuticaiiy acceptable sait thereof. [122} Embodiment 2. A method of treating agitation or the signs of agitation in a subject in need thereof comprising administering to said subject an effective amount of Dexmedetomidine or a pharmaceuticaiiy acceptabie sait thereof, wherein said Dexmedetomidine or a pharmaceuticahy acceptable sait thereof is guaiiy stered at a dosage that treats agitation or the signs of agitation without causing significant sedation. [123} Embodiment 3. The method according to Embodiment i or 2, wi'ierein said dosage of Dexmedetomidine or a ceutieaiiy abie sa1t thereof is in range of from about 3 micrograms to about 100 micrograms (e.g. about 5 rams to about 100 micrograms, about 5 micrograms to about 90 micrograms, about 5 micrograms to about 85 micrograms, about 5 micrograms to about 80 micrograms, about 5 micrograms to about '75 micrograms, about 5 micrograms to about 70 micrograms, about 5 micrograms to about 65 micrograms, about 5 micrograms to about 60 rams, about 5 micrograms to about 55 micrograms, about 5 micrograms to about 50 micrograms, about 5 micrograms to about 45 micrograms, about 5 micrograms to about 49 micrograms, about 5 micrograms to about 35 rams, about 5 micrograms to about 30 micrograms, about 5 micrograms to about 25 micrograms, about 5 micrograms to about 20 micrograms, about 5 micrograms to about l5 micrograms, about 5 micrograms to about it) micrograms, less than l0 micrograms (eg. about 5, 6, 7, 8, or 9 U1 micrograms), about it) micrograms, about 12 micrograms, about l4 micrograms, about l5 micrograms, about l6 micrograms, about l8 micrograms, about 20 micrograms, about 30 micrograms, about 50 micrograms). [£24] Embodiment 4. The method according to Embodiments l, 2 or 3, wherein said subject is , preferably hnman $25} Embodiment 5. The method according to any one of Embodiments l to 4, wherein said ion is associated with a neurodegenerative e. [lilo] Embodiment 6. The method ing to ment 5, wherein said neurodegenerative disease is selected from Alzheimer disease, t‘rontomteniporal dementia (ETD), dementia, dementia with Lewy bodies (DLB‘), post~traumatic stress disorder, Parkinson’s disease, vascular dementia, vascular cognitive ment, Huntington's e, multiple sclerosis, Creutzt‘eltit-Jakob disease, multiple system atrophy, and progressive supranuclear palsy. [l27l Zliinibodiment 7~ The method according to any one of Embodiments l to 4, wherein the agitation is ated with a neuropsychiatric condition.

[L28] ment 8. The method according to Embodiment 7, wherein said neuropsychiatric condition is selected from schizophrenia, bipolar illness (such as mania, disorder), delirium, and depression, [izst Zliinibodiment 9. The method according to Embodiment 5, wherein the agitation is ated with sundown syndrome in dementia or Alzheimer’s disease.

U30] Embodiment ll). A sublingual composition for use in the treatment of agitation or the signs of agitation in a subject in need thereof, wherein said agitation is not eratiye agitation and said sublingual composition comprises an effective amount ot‘Dexmedetomidine or a pharmaceutically able salt thereof and one or more pharmaceutically acceptable carriers/excipients, [l 3 l] Embodiment l l. A sublingual composition for use in the treatment of agitation or the signs of agitation in a t in need thereof, wherein said agitation is associated with a neurodegeneratiye disease and said sublingual composition comprises an effective amount of Dexmedetomidine or a pharmaceutically acceptable salt f and one or more pharrn aceuticaliy acceptable carriers/excipients.

B32} Embodiment l2. A sublingual composition for use in the treatment of agitation or the signs of agitation in a subject in need thereof, wherein said agitation is associated with a neuropsychiatric condition and said subiingual composition comprises an effective amount of Dexmedetornidine or a pharmaceotically acceptable salt thereof and one or more U1 ph armacetitically acceptable carriers/exci pi ents.

H33] Embodiment l3. A gual composition for use in the treatment of agitation or the signs of agitati on in a subject in need f, wherein said agitation is associated with sundown syndrome in dementia or mer’s disease and said sublingnal composition ses an ive amount of Dexmedetomidine or a pharm aceutically acceptable salt thereof and one or more ceuticaliy acceptable carriers/excipients.

U34] Embodiment l4. The soblingoal composition according to Embodiment ll, wherein said neurodegenerative disease is selected from the group ting of Alzheimer disease, trontoteinporal dementia (ETD), dementia, dementia witl'i Lewy bodies (DEB), post~traumatic stress disorder, Parkinson‘s disease, vascular ia, vascular cognitive impairment, Huntington's disease, le sclerosis Creutzfeldt—lakoh disease, multiple system atrophy, and progressive snprannclear palsy [BS] Embodiment l5. The sublingual composition according to Embodiment 14, wherein said nenrodegenerative disease is selected from dementia, frontotemporal dementia, Alzheimer’s disease and Parkinson’s disease.

U36] ment l6. The soblingoal composition ing to Embodiment 12, wherein said neuropsychiatric condition is selected from the group consisting of schizophrenia, bipolar illness (such as mania, disorder), delirium and depression.

H37} Embodiment 17. The stiblingnal composition ing to any one or" Embodiments l0 to lo, wherein said composition is selected from a film, wafer, patch, lozenge, gel, spray, tablet, liquid drops or the like.

[BS] Embodiment lit. The sublingual composition ing to Embodiment l7, wherein the composition is a film.

H39] Embodiment l9. The gnal ition according to Embodiment l8, wherein the film is mucoadhesive in nature and provides a quick onset of action.

[MO] Embodiment 20. The sublingnal composition according to any one of Embodiments ill to l9, wherein Dexm edetomidine or a pharmaceutically acceptable salt thereot‘is administered at a dosage that treats agitation or the signs of agitation without causing significant sedation.

] Embodiment 2l. The sublingual composition according to Embodiment 20 wherein the observed level of sedation is not greater than 3 on the Ramsay sedation scale~ B42] Embodiment 22. The sublinguai composition ing to any one of Embodiments l O to 2i, wherein Dexmedetomidine or a pharmaceuticaliy acceptable salt thereofis administered to said subject (e. g. human) at a dosage in the range of from about 3 micrograms to about 109 micrograms (e. g. about 5 micrograms to about 100 micrograms, about 5 micrograms to about U1 90 micrograms, about 5 micrograms to about 85 micrograms, about 5 micrograms to about 80 micrograms, about 5 micrograms to about ‘75 micrograms, about 5 micrograms to about 70 rams, about 5 micrograms to about 65 micrograms, about 5 micrograms to about 60 micrograms, about 5 micrograms to about 55 micrograms, about 5 micrograms to about 50 micrograms, about 5 micrograms to about 45 micrograms, about 5 micrograms to about 40 micrograms, about 5 micrograms to about 35 micrograms, about 5 micrograms to about 30 micrograms, about 5 micrograms to about 25 mi crograrn s, about 5 micrograms to about 20 micrograms, about 5 micrograms to about 15 micrograms, about 5 micrograms to about if; micrograms, less than if) micrograms (eg. about 5, 6, 7, 8, or 9 rams), about 10 micrograms, about 12 micrograms, about l4 micrograms, about l5 micrograms, about l6 micrograms, about l8 micrograms, about 20 micrograms, about 30 micrograms, about 50 micrograms).

Elli-3] Embodiment 23. A method of ng agitation or the signs of agitation in a subject in need thereof, the method comprises subiinguaiiy administering to said t an effective amount of detomidine or a ceuticaliy acceptable salt thereof, wherein the agitation is not perioperative agitation.

[Md] ment 24. The method according to Embodiment 23, wherein the agitation is associated with a neurodegenerative disease and/or neuropsychiatric condition.

H45} Embodiment 25. The method according to liimbodiment 24, wherein the neurodegenerative e is selected from the group consisting of mer disease, frontotemporai dementia (ETD), dementia, ia with Lewy bodies (DEB), post~traum atic stress disorder, Parkinson‘s disease, vascular dementia, ar cognitive impairment, ington’s disease, multiple sclerosis, Creutzfeldt—lahob disease, multiple system atrophy, progressive supranuciear palsy or other related neurodegenerative er.

U46] Embodiment 26. The method according to Embodiment 24, wherein the neuropsychiatric condition is selected from the group consisting of schizophrenia, bipolar illness (eg. r disorder or bipolar mania), delirium and depression.

[M7] Embodiment 27. The method according to any one of Embodiments 23 to 26, wherein agitation or the signs of agitation are treated effectively without causing significant sedation.

B48] Embodiment 28. The method according to any one of Embodiments 23 to 27, n etomidine or a pharmaceutically acceptable salt thereof is administered in form of a film, wafer, patch, lozenge, gel, spray, tablet, liquid drops or the like. [lag] Embodiment 29. A method of ng of agitation or the signs of agitation in a subject U1 in need thereof, wherein said agitation is associated with an DPS/3P1) procedure (eg MRl, CT or CAT scan, lumbar puncture, bone marrow aspiration/biopsy, tooth extraction or other dental procedures), and said method comprises administering to said subject sublingually an ive amount of Dexmedetomidine or a pharmaceutically acceptable salt thereof. [l50] Embodiment 30. A method of treating of agitation or the signs of agitation in a subject in need thereof, wherein said agitation is associated with an alcohol and substance abuse withdrawal and said method comprises administering to said subject gually an effective amount of Dexmedetomidine or a pharmaceutically acceptable salt thereof. [lit] ment 31. The method according to Embodiment 29 or 30, wherein said Dexmedetomidine or a ceutically acceptable salt f is sublingually administered at a dosage that treats said agitation or the signs of agitation without causing significant sedation. [lSZ] Embodiment 32 The method ing to Embodiment 31, wherein said dosage of Dexmedetornidine or a, pharmaceutically acceptable salt thereof is in range of from about 3 micrograms to about lt‘rO micrograms (e.g. about 5 micrograms to about 100 rams, about 5 micrograms to about 90 rams, about 5 micrograms to about 85 micrograms, about 5 rams to about 80 micrograms, about 5 micrograms to about 75 micrograms, about 5 micrograms to about 70 micrograms, about 5 micrograms to about 65 micrograms, about 5 micrograms to about so micrograms, about 5 micrograms to about 55 micrograms, about 5 micrograms to about 50 micrograms, about 5 micrograms to about 45 rams, about 5 micrograms to about 40 micrograms, about 5 micrograms to about 35 micrograms, about 5 micrograms to about 30 micrograms, about 5 micrograms to about 25 micrograms, about 5 micrograms to about 20 micrograms, about 5 micrograms to about l5 micrograms, about 5 micrograms to about it": micrograms, less than it) micrograms (eg. about 5, a, ’7, 8, or 9 micrograms), about it) micrograms, about 12 micrograms, about 14 micrograms, about l5 micrograms, about 16 rams, about 18 micrograms, about 20 micrograms, about 39 micrograms, about 50 micrograms), $53} Embodiment 33 The composition or method according to any preceding Embodiment, wherein Dexmedetomidine or a pharmaceutically acceptable salt thereof is administered once, twice or thrice daily or on an "as needed" basis. {lid} Embodiment 34. The composition or method according to any preceding Embodiment, wherein etomidine or a oharmaceutically acceptable. salt tl’iereof is administered in a manner that produces a therapeutic effect in less than about 60 minutes, particularly within about 30 s to about 30 minutes, U1 H.515} Embodiment 35. A method of treating agitation or the signs of agitation in a subject in need thereof comprising administering subiingually to said subject an effective amount of an alpha-2 adrenergic agoni st or a pharm aceuticaliy able sait thereof. rise} Embodiment 3a A method of treating agitation or the 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, n said alphawZ adrenergic agoni st is subiingualiy administered at a dosage that treats agitation or the signs of agitation without causing significant sedation. [l57] Embodiment 37, The method according to Embodiment 35 or 36, wherein said dosage of alpha—2 adrenergic t is in range of from about 3 micrograms to about 100 rams (eg. about 5 micrograms to about lOO micrograms, about 5 micrograms to about 90 micrograms, about 5 micrograms to about 85 micrograms, about 5 micrograms to about 80 rams, about 5 micrograms to about 75 micrograms, about 5 micrograms to about ’70 micrograms, about 5 micrograms to about 65 micrograms, about 5 micrograms to about 60 micrograms, about 5 micrograms to about 55 micrograms, about 5 micrograms to about 50 micrograms, about 5 micrograms to about 45 rams, about 5 micrograms to about 40 micrograms, about 5 micrograms to about 35 micrograms, about 5 rams to about 39 micrograms, about 5 rams to about 25 micrograms, about 5 micrograms to about 20 micrograms, about 5 rams to about 15 micrograms, about 5 micrograms to about it) micrograms, iess than l0 micrograms (eg. about 5, 6, 7, 8, or 9 micrograms), about 10 micrograms, about 12 micrograms, about 14 micrograms, about i5 micrograms, about to micrograms, about 18 micrograms, about 20 micrograms, about 30 micrograms, about 50 microgram s). {l58} Embodiment 38. The method according to Embodiments 35, 36 or 37, wherein said subject is m animai, preferably human. 3C) [l 59] Embodiment 39. The method according to any one of Embodiments 35 to 38, wherein said agitation, is ated with a neurodegenerative disease. {rec} Embodiment 40. The method according to Embodiment 39, wherein said neurodegenerative disease is selected from Alzheimer disease, fronto—temporai dementia (ETD), dementia, dementia with Lewy bodies (Didi), raumatic stress disorder, Parkinson's disease, vascular ia, vascular cognitive impairment, Huntington‘s disease, multiple sclerosis, Cr‘eutzl‘eldt—laltob disease, multiple system atrophy, and progressive supranuciear palsy. [loll Enihodinient Ill The method according to any one of Embodiments 35 to 38, wherein U1 the agitation is associated with a neuropsychiatric condition.

{M2} Embodiment 42. The method ing to Embodiment All, wherein said sychiatric condition is selected from schizophrenia, bipolar illness (such as mania, er), delirium, and depression. [l63] Embodiment 43. The method according to Embodiment 39, wherein the agitation is associated with sundown syndrome in dementia or Alzheimer’s disease. [m4] Embodiment 44. The method according to any one of Embodiments 35 to 38, wherein said agitation is associated with an OPE/TED procedure (eg MR1, CT or CAT scan, lumbar puncture, bone marrow aspiration/biopsy, tooth extraction or other dental ures), [rest ment 45. The method according to any one of Embodiments 35 to 38, wherein said agitation is associated with an alcohol and substance abuse withdrawal [l 66] odiment 46. The method according to any one of Embodiments 35 to 38, wherein said alphani’, adrenergic agonist e, but is not limited to, Clonidine, Gnanf’aeine, Guanabenz, Gnanoxahenz, Guanethidine, Xyiazine, 'l‘izanidine, h/liedetomidine, Dexmedetornidine, Methyidopa, norepinephrine, nidine lodoclonidine, Aprael oni dine, Detoniidine, Lofexidine, Antitraz, h/livazerol, ol, Talipexol, Rilmenidine, Naphazoline, Oxymetazoiine, Xyiometazoiine, Tetrahydrozoline, 'l‘raniazoline, Talipexole, Romitidine, propylhexedrine, Norfenel’rine, Octopamine, Moxoni dine, Lidamidine, Tolonidine, UKl4304, lid—714i, S‘Tw9l, 2353, TCG—lOOO, 4~(3- ethylncyclohexfi menylmethyl)— l ,3 ndihydro—imidazole—Z—thione, and 4%? n hydroxymethyl~cycloheX—3—enylmethyl)~l ,3wdihydro—imidazole-Z—thione or a pharmaceutically acceptable salt thereof.

[M7] The Embodiments hereinabove are not intended to be limiting, and, in practicing the present invention, alternative or additional Embodiments may be provided.

Vii} . EEK/5tM PLES: The ing Examples are intended to be illustrative and not limiting: Examgle i: E‘ermulatien 1: thulinnal Tablet Table 1: Cent esitien fer a tV ical Sub—linvuel tablet i‘errnularien used fer sublinvual deliver Dexmedetemidine EEC} (equivalent to base) rnieregrarns Dexmedeternidine hydrechleride and ents such as binder and sweetener are dissolved fdispersed inte a pharmaceutically acceptable selvent rably water) and this solutien is used to granulate the sifted blend efall other ingredients except lubricant and glidant in suitable nrixer/granulstnr. The granules are then dried in a ed drier er ether le one such as tray drier. The dried granules are then sized appropriately in quadromeo—rnill er inulti-mill, The sized granules are then leaded inte a suitable blender such as V-hlender and lubricated with Magnesium stearate and Talc and then the final lubricated, blend is then used, fer compressing into tablets 0f specific dimensions using appmpria‘te reeling, Fermulatien 2: ngiml Film Table 2: Com vesition fer a t" ieal Sub-linouel film fermuiatien used for sublin rial w ingredients Quantitv Ranges Dexrnedetnrnidine HCl {equivalent t0 base) micrograms Polyethylene wide Polyethylene Glycol Sueral ose 0.05 3 .0 9/0 Flavering agent qs. 0.01 1.1) 9/0 Manufacturing preeess Dexrnedetemidine hydrochloride aleng with t1l1n fanningpelvnrers and othe1 exeipients are dissolved / dispersed inte a pharmaceutically acceptable selvent (preferably water) and the resulting selution is then coated (spread / east) en an inert backing layer. Dexmedetonridlne liydreehleride containing polymeric layer is r dried. separated and cut inte suitable sizes using appropriate die toels and then packed as per the requirement.

Fermrrla’tien 3: rLual S rav Table 3: Corn esition for at ' ieal noual s ra ' ferrnulatien used fer sublin atal deliverv Dexniedetornidine lrlCl (equivalent te base) microorarns Pmpylene Glycol l.0_ 40110/ cturino recess Dexrnedetenridine hydrochloride aleng with all other exeipients are mixed in a suitable order.

The resulting solutien / dispersion is then filled inte spray canisters using apprepriate tooling.

They are further processed with, Metered nozzles so that a ed arneunt of Dexmedetemidine is delivered after actuation each time. li‘nrmniatien 4: Sub—lineal Linid dre s Table 4-: Cent esitien fert ieal Subnlincrual li ruid, tire .., s used ter sublingual tlelive detemidine l-lCl . , i0 rng (equtvalent to base) Nerrnal saline (0.9% Sodium Cl’ileride) Manufacturing nreeess if! Dexrnedetonridine hydroehleride ((Catalegue Net Sh/fllttgfie) was dissolved in Nerinal saline in order te yield the concentration or" ling/ml ef the sublingual drepsr Example 2: Evaluate the effect of suhlinguai and intravenous adrninistratien 0f Dexmedetemidine hydrochloride in rat ‘resident—intmder’ rnedel nf agitation er aggression at varying dosages.

The nt" intruder model is an established preclinical inedel ef aggression and agitation? and allows neeus and natural expressien ef heth Offensive aggressien/agitatien and defensive hehavier in tory s in a semi natural laheratory setting. When rodents are expesed te a novel male in their home cage environment, they perceive the nevel male animal as an "intruder" and demonstrate a oire nf defensive behaviers such as and—genital sniffing, chasing, biting and attacking (Nelson et at, iLAR Journal (2000) 41(3): i53~l62).

Materials and Metheds: Aniinais: lZ—lSweek eld male Wistar rats weighing 380 400g were used as resident males. 74% weeks eld, male rats weighing 280 — 300g were used as the "intruder". Resident rats were housed with female rats for 8 days to establish territoriality. The er rats were hensed in greups of 3 with ether male rats of similar age/hedy weight. All s were maintained in a centreiied environment with 272th0 (3 temperature, 502t209/n hninidityg a light/dark cycle et‘ l2 heurs each and 'i 3-20 fresh air changes per beer and had access te feed and water adwlihitnin.

All animal ments were conducted in aeeerdanee with the guidelines of the Committee fer the Purpese of Central and Supervisien 0f ments en Animals (CPCSEA), ment of lndia the Association for ment and Accreditation of Laboratory Animal Care ational (AAALAC).

Formulation tested: The required quantity (Al-"Formulation 4 of dexrn edetornidine hydrochloride was weighed and serial dilutions were made to obtain respective doses as per the Table 5.

U1 Dilutions were prepared fresh every day prior to dosing using 0.9% normal saline item the formulation 4 for the entire study.

Experimental ure: Following acclimatization for a period of 3 — 5 days) each resident male rat was housed with a female rat for 8 days. Qn day 8, basal aggression in the resident males was tested by exposing them to an "intruder rat" for l0 minutes. (lnly animals that 1E) demonstrated aggression in this basal aggression test were used for the study. These animals were then ized using body weight stratification method. The weight variation of the s did not exceed 20% of the mean hotly weight in a group at the time of randomization.

Animals were housed with the fern ale rat for an additional days (in day 9, the resident animal was paired with intruder animal of an appropriate bodyweight such that the body weight of the resident was always higher than the intruder. This was to facilitate dominant sive behavior in the resident animals After randomization, animals were assigned a permanent number. Cages were fied by cage cards indicating the study nurnber, study code? group number, sex, dose, cage number and animal number details.

Resident male rats were dosed with different doses of detomidine hydrochloride (Dex) l5 minutes prior to the oral testing either suhlingually or intra 'enously (Table 5). For sublingual dosing, the rats were held in one hand and using a blunt spatula the tongue was moved to one side of the mouth. Dexmedetomidine hydrochloride was then administered sublingually as liquid drops at specific concentration using a rnicropipette and allowed to be absorbed for a duration of 50—69 seconds. Diazeparn was used as a reference compound and was dosed intraperitoneally. Vehicle controls were treated with 0.9% saline administered sublingually or intravenously Normal controls (NC) did not received any treatrn ent.

The behavior of the resident rat was recorded using an overhead video camera for l5 minutes and offline behavioral analysis was done using the Noldus Ethovision XT softyare. To distinguish the resident rat from the intruder rat in the video recording, the intruder rat was marked with xic paint. For analysing the potential effects of Dexmedetomidine hydrochloride on agitation, we quantified various behavioral parameters such as anogenitai sniffing, chasing, biting, attacking and latency to attack as well as neutral oral ters such as exploration grooming, and irnrnohile quiet time.

Table 5. Efficacy Study: Drug treatment groups Group No. of Cohort l (iohort 2; animals (thlingual dosing * (lntravenods dosing * Formulation 4i adjusted to Dexnredetomitline hydrochloride win doses in water or Normal saline Normal Control Vehicle control Vehicle control Dexmedetornidine hydrochloride detornidine hydrochloride Dexniedetomidine hydrochloride etoinldine hydrochloride l,0t /l~:‘ (limo ‘ Dexmedetomidine hydrochloride Dexniedetomidine hydrochloride (l Sits/ks) OSes/ks) Dexmedetornidine hydrochloride Dexrnedetornidine hydrochloride (30 ) (3.0 its/ks) if! Statistical is: Statistical analysis was performed using validated statistical software (Graplil’ad Prism 6). Data is represented as Mean :: "EELM; Onewway ANOVA (analysis of variance) followed by "Dunnett’s Multiple Comparison Test" at 95% confidence interval was applied for comparison of the relevant groups. p<0.05 was considered significant.

Results: The present study was performed to evaluate the effect of suhlinguaily/intravenously administered different doses ol‘Dexmedetomidine hydrochloride on agitated behavior in a rat resident~intrttder model of sion and agitation behavior.

Effect of suhlinguaily/intraveneusly administered Beamedetornidine hydrochloride on aggressive/agitative behavior in the rat resident intruder model: The rats demonstrate a variety of defensive ed behaviors such as anogenltal sniffing, chasing? biting and attaching (indices of agitative and aggressive behavior) when exposed to a novel male in their home cage environment. The sident male is perceived as intruder and the resident male gets ed and attacks the intruder male to protect their home territory. in the present experiments, vehicle treated rats trated a wide repertoire of aggressive 210 behaviors and the intruder rat was subjected to anogenital sniffing, attach. chasing and biting by the resident or dominant rat.

Dexnredetornidine hydrochloride (Dex) administered suhlingually reduced the frequency and duration of these behaviors in a dose d nranner (Figure lA, and Figure lB). Significant ion was observed in g and ing ed to vehicle control group. Similarly, intravenous stration of dexrnedetomi dine hydrochloride (Dex) reduced all the indices of U1 aggressive and agitated behaviors (Figure if? and Figure ill). A significant reduction in anogenital sniffing, biting and attaching compared, to vehicle controls was observed at doses ahove 0‘5 ug/hg (Figure ll: and Figure ill). nce compound diazepam (filing/leg, in) also ed, significant reduction in all the indices of aggressive and agitated behaviors evaluated in this study (Figure l A— ll?) ll) Effect of suhlingually/iutravenously administered Dexmedetomidine hydrochloride on latency to attack in on to the change in frequency and duration of attack by the resident male, we also evaluated the effect of Dexniedetomidine hydrochloride (Dex) on the y to attach the intruder rat, We observed an increase in the latency to attack the intruder rat following suhlingual administration of Dexmedetomidine hydrochloride (Dex) in a dose related fashion indicating a reduction in aggression and agitation (Figure 2A). When Dexrnedetomidine hydrochloride (Dex) was administered intravenously, a similar increase in the latency to attack the intruder rat occurred in a dose related fashion that was significant compared to vehicle controls at a dose of mtg/kg (Figure 28), Animals treated with diazepanr demonstrated a complete lack of attacking behavior (Figure 2A and EB).

Effect of suhlingually/intravenously administered Derrmedetomidine hydrochloride on Neutral behaviors Neutral behaviors li l Interpretation U1 in the present study, we investigated the potential of Dexrnedetomidine hydrochloride in reducing aggression and agitation in rat residentuintruder model. The residentwintruder model is an established preclinical model of aggression/agitation and allows spontaneous and natural expression of both offensive aggression/agitation and defensive or in laboratory rodents in a semi natural laboratory setting. ll) 1. Suhlingual administration of Dexrnedetomidine hydrochloride ed in a dose related reduction in l behavioral s of aggression and ion such as ital sniffing, chasing, attacking and biting. 2. A significant increase in the latency to attack the intruder rat was observed in a dose related manner with pri or treatment with Dexniedetornidine hydrochloride as ed to the vehicle control group. 3. No changes were observed in neutral behavior of anirnals, indicating the lack of overt anxietymlike behavior in the resident rats treated with sublingually stered detornidine hydrochloride. 4. Of the doses that were used in the study (0.5 — Bug/kg), doses of 'l— l5ug/lrg (doses administered sublingually or intravenously) ively reduced the behavioral s of aggression and agitation without rnajorly impacting the neutral behaviors.

Conclusion: Dexniedetoniidine hydrochloride effectively reduces various indices of agitation and aggression in rat resident intruder models Dose of l —l.5 lug/leg effectively reduced the behavioral indices of aggression and agitation without rnajorly impacting the neutral behaviors.

In the present study the efficacy of sublingually administered detomidine hydrochloride correlates with intravenously administered Deninedetomidine hydrochloride at these doses (Table to. p values ed after statistical cornpari son of guai vs intravenous route of administration using Stud ent’s t—test Duration (sec‘ Chasing Biting Attack/Fighting Anogenitah Latency to attack muting___________________________________________________________________________ 1000 1.000 1.000 0207 0:069 0.2.90 Ol36 0.102 0.204 0090 0.207 0125 0059 0.107 0.508 Table 6: Ne significant differences tie. snnilai' elleet via gual and intraveneus mates} were deserved in the duratinn at the helravieral indites at aggressien and agitatinn (aliasing, biting, attack, anngenital sniffing latency tn attack} when mannered between sublingual and ennus u: mates {if dexniedetemidine liydrnelilnride adininistra‘tien at classes at l and 15 ugikg‘ Statistieal analysis was nei‘i’nrined using student tutest. $430959 "peter "*ndlotltii and **‘*"’"‘p Based on l-l .5 lug/leg rat efficacy doses, the human equivalent sublingual deses are calculated te he 0. lél gag/kg & 0.242 gig/kg. The tetal huinan equivalent dese fer a (lo—leg human weuld ll) be l0 and 15 ug (https:.I".:"swx«‘w'.l‘da.gov/downlnadsx’drugs/EMidances/ueniO7893Zpdf)..

Example 3: Estimatinn at" Demnedetnmidine (lifi—Sng/kg) in Rat plasma samples by LC— MSKMS Objective: To te Dexmedetemidine levels in rat plasma samples ed after desing animals Via intravenous and sublingual routes at doses at" 0.5, 1, l6 and 3ng/ltg.

Blond collection: Tn determine the plasma eoneentration 0f detornidine, Demnecletemidine hydreehleride was administered sublihgually er intravenously in rats (n23) at different doses (Fennulation 4 adjusted to 0.5, l, l5, Bug/kg). Bleed was ted under mild iseflurane anesthesia freni tne retrowerhital plexus at O, 5? l5, 30, 60 and lZO minutes pest dnsing. Plasma was separated and stored at —80°C until detninidine tratinn was analyzed.

Materials and methnds Preparation (ifstamiard min[ions A standard stock solution of dexrnedeteinidine hydreeliloride was prepared by dissolving ig of dexmedeteinidine hydreehleride in 1358 ill at rnilliuQ water to achieve a cencentratinn nf ln1g/ml Working selutions at different cententratinns were ed by using diluent (inetlianel: water (50:50) % \r/vl.I 'l‘nlbutanride was used as an al standard and its steek selution was prepared by dissolving 25mg nf telbutaniide in lOGOul of DMSG to achieve a eeneentratien of 25nig/rnl. Working selutiens pf different tratiens were prepared by using a diluent (:aeetenitrile: water (50:50) % w’y), Solution preparation t‘er SPE and ehremategraphy: Mehile phase A, ( l 0min arnni eninni fennate, pH 3 .50): gms of ammonium ferniate was weighed and erred to a lOOOrnl U1 reagent bottle. To this, lOOOrnl ut‘rnilli a water was added and {ill at the ing solutien was adjusted to 3.5 using fermie acid.

Mobile phase lit: lGO‘E/o aeetenitrile Diluent (methanol: water (50:50) % v/v): 50nd 0f methanol was mixed with 50 ml of rnilli—q water. ing selutien was used as diluent.

Wash selutien: lt‘iOul of arnnienia was mixed with 100ml 0f milli q. Resulting selutien was used as wash selntien n solvent: lGOpi ef fermic acid was mixed with lOOrnl of aeetenitiiie. Resulting solution was used as elutien solvent.

Analytical Metheds: Samples were analysed by using Agilent l290 infinity ll 1-1916 system eeupled tn AB Seiex Triple Quad instrument (Alli—5000). ategraphie separatien was done using Agilent Zorhax e plus Cl 8 column (50*2.lninn liiinrn) in gradient mode, The meliile phase censisted 0f lOniM Ammenium Fermate with pH 3.5 (Melaile phase A) and 100% Aeetenitrile (Mehile phase B). The column temperature was 400C and flow rate was 0.35 nil/min. The M S instrument was operated in the positive mede (581+). For is, 2 2E) pL of sample was injected into the LOMS/"MS instrument. Auto sampler temperature was Quality eentrel (QC) samples were prepared as following as per table 7: Table 7 """"{ Dtxmtaaamidm /0hrrne "'er""" e eene {Solution Blank Total Final Calibration ll) salutien-t plasma (pl) Vplume {his} Cone (pg/mils) (A UglL) (fig/31L) i Sample preparation WCX SPE 96 well plate was used for sample preparation. SOpl of plasma sample was used for extraction. Along with study samples, one set of linearity and two sets of quality U1 eontr‘ol,s(QC)were also processed.

Sample atment: To 50rd of plasma, lOpl of tolhutamide working solution was added (Tolhutamide ZSOng/rnl), After mixing, 50le of buffer solution (lOrnM Ammonium Forn'iate pH 3.5) was added. Contents were vortex mixed and loaded to preconditioned SPE plate.

LC—MS/MS ANALYSIS After placing the cartridges in the negative pressure SPE unit, they were conditioned hy passing 200m of l00% methanol followed by 200E~ll of water. The pretreated plasma samples were then loaded to the preconditioned cartridges.

After loading pretreated plasma samples, cartridges were washed with l OOpl of G. l% ammonia solution. y, hound arialyte was eluted with 50rd of O. l% t‘onnic acid in acetonitrile This step was repeated twice for complete eluti on. Final eluent volume was lOO pl... To lOO pL of eluent, 50 hit of lOmM um formate (pH 3.5) was added samples were vortex mixed and transferred to a l l-lPLC sample plate (Agilent) and suhmitted for LC—lVlS/lylS is. For LCnMS/lylS analysis, 2 pL of sample was ed. Calibration rds and QCs were processed the same way as done for study samples.

Mean plasma concentrations of Dexmedetornidine in various rat plasma samples at various ti rne points was ined by l_,C~MS/MS method using Analyst l.6.2 software (Table 8 and Figures 4A and 43‘) with a calibration curve in the range of 0.0l l—53.06l rig/ml prepared in blank rat plasma matrix. The calibration curve was fitted by linear regression. The concentrations in the QC and test samples (pg/mL) were obtained from the Analyst software based on the calibration curve. Acceptance ia for the calibration, curye and QCs are as follows: l) At least 75% of the non—zero calibration standards must be included in the calibration curve with all hack—calculated concentrations within :: 20% deviation from nominal concentrations (except for the lower level of quantification, LLOQ, where i 20% deviation is acceptable). 2) The correlation coefficient (r) of the ation curve must be greater than or equal to 0.99. 3) At least twowthirds (4 out of 6) QC samples must be Within i 20% relative error (accuracy) Results: Table 8: Mean rat plasma concentrations following Snblingnal or enous dexmedetoniidine hydrochloride administration at varying doses Mean Concentration in pg/niL at Concentration in pg/inL at various time various time 3. oints after desin oints after desin is an so 120 l min min 21 i 839 ELQ: Below the Lowest limit of Quantification of the assay (LOQ: 0.05ng/ml) SL: sublingua ; iv: intravenous Data expressed as Mean i Si) retation and conclusion Following sublingual administration ofDexmedetornidine hydrochloride, a dose~related effect on plasma concentrations was ed at doses ranging from 0,53 rig/kg (Figure 4A, table 8).

Following intravenous administration or" Dexmedetornidine hloride, a dose—dependent effect on plasma trations was observed at doses ranging from 0.5n3itg/kg (Figure 43, table 8).

Doses of l and l Gog/kg effectively reduced various indices of agitation and aggression without majorly impacting neutral behaviors. Plasma concentrations following administration of dose 0f '1 [nag/kg (Via snblinguai and intravenous mute) between '15 tn 30 min (time cerrespnnding to the time ef‘nehavioral response observed in the efficacy study; drug administered 15 min prior tn agitatien hehavier test :32: animal d for 15min) range fmm 43 i {3.5 tn 90 i 12.1 pg/In} (Table 8), Similafiy, piaema concentrations ing administratien of dese of 1.5 U1 pig/kg (via sublingue} and intravenous route) between 15 in 30min range frem 27 vi: 7.} t M :: 1.7pg/Ini (Table 8).

Claims (16)

Claims:

1. Claim 1. Use of Dexmedetomidine or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment of agitation in a human subject, wherein the medicament is formulated for an oromucosal administration, and wherein the medicament 5 produces an anti-agitation effect in less than about 60 minutes after the administration without also causing icant sedation.

2. Claim 2. The use according to Claim 1, wherein the medicament is in a dosage form selected from the group consisting of a film, wafer, patch, lozenge, gel, spray, tablet, and liquid drops.

3. Claim 3. The use according to Claim 2, n said film is mucoadhesive in . 10

4. Claim 4. The use according to Claim 1, wherein said dosage is about 5 micrograms to about 30 micrograms.

5. Claim 5. The use according to any one of Claims 1-4, wherein the ion is acute agitation.

6. Claim 6. The use according to any one of Claims 1-4, wherein the agitation is chronic agitation.

7. Claim 7. The use according to any one of Claims 1-4, wherein the agitation is severe agitation. 15

8. Claim 8. The use according to any one of Claims 1-8, wherein said Dexmedetomidine is present as etomidine hydrochloride.

9. Claim 9. The use ing to Claim 2, wherein said dosage form is a film.

10. Claim 10. The use ing to Claim 1, wherein said dosage is about 30 micrograms.

11. Claim 11. The use according to Claim 1, wherein said dosage is about 60 micrograms. 20

12. Claim 12. The use according to Claim 1, wherein said dosage is about 90 micrograms.

13. Claim 13. The use according to Claim 1, wherein said dosage is about 5 micrograms to about 80 micrograms.

14. Claim 14. The use according to Claim 1, wherein said dosage is about 5 micrograms to about 70 micrograms.

15. Claim 15. The use according to Claim 1, wherein said dosage is about 5 micrograms to about 60 rams. 5

16. Claim 16. The use according to Claim 1, wherein said dosage is about 5 micrograms to about 40 micrograms. ta“ k4" Diazepam; behavimg fl 3ugfkgg agitaieé Dex; ii 3L Q ugfkut1*- k4' 9% g m Q93 1 138'} M flex; gig E3 fim‘aiigii 9’71: iggjkgfi; flag}; fiiaiiiiiiafi‘w 3L Ungfkg; Sniffing Eii'fiex;