NZ794535A - 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. icularly 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 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 ularly 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 ses 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 t, but does not cause icant sedation.

NZ 794535 Use of Sublingual Dexmedetomidine for the treatment of Agitation FIELD OF' THE INVENTION [l] The present invention discloses a method of ng 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 ceutically acceptable can-iers and/or excipients, along with the preparation thereof CROSS NCE 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. ,164 filed 31 December, 2016, U.S. Provisional Application Serial No. 62/471,393 filed 15 March, 2017 and U.S. ional Application Serial No. 62/542,323 fiied 8 , 2017, the disclosures of which are herein incorporated by reference in their ty for all purposes.

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

Agitation is characterized by non-productive, diffuse and ive over-activity both motor (akathisia) and cognitive, and accompanied by an inner sant tension. 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 ally known as dementia. ias include mer's disease dementia (AD), Pronto-temporal dementia (FTD), Vascular dementia, Lewy body disease (LBD), and Down ia. Dementia in adults, gradually destroy a person's memory and ability to learn, reason, malte judgments, communicate and carry out daily activities. in later stages, patients may ence changes in personality and behavior, such as anxiety, suspicion, ion and aggression. [5} Sebastiaan Engelhorghs et al in Nenrocheniistry International 2007 Nov, 52(6): l052— U1 60, disclosed that, in l‘rontotemporal dementia, increased activity of dopaminergic neurotransmission and altered serotonergic modulation of dopaminergic neurotransmission are associated with ed 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<e phenotypes in these mice may form a correlation to some of the behavioral disturbances ed in advanced Alzheimer’s disease (AD) and Prontoternporal dementia (ETD). Nathan l-lerrnann et. al,, in l of sychiatry 2004 Aug, l6(3): 26l—276, disclosed that a compensatory increase in activity within the noradrenergic system may contribute to the behavioral and psychological symptoms of agitation and aggression in Alzheimer’s disease. [6} Agitation can also be associated with neuropsychiatric conditions such as schizophrenia, bipolar illness such as bipolar disorder or mania, depression, delirium, etc or agitation can be ated with alcohol and nce ahuse withdrawal. Acute agitation, represented by a state of motor restlessness and accompanying mental tension, is a serious medical problem that can be present in some atric disorders, including schizophrenia and bipolar mania, and may escalate quickly to aggressive behavior Acute agitation is characterized by signs that include pacing, hand wringing, tist clenching, red speech, yelling, and threatening people with escalated agitation. [7} To date, there is no single medication considered as the “standard of care” for treating agitation in patients with dementia or phrenia. Generally, three classes of medications are used most frequently, depending on the severity of the agitation, namely first-generation ychotics, —generation antipsychotics, and henzodiazepines, administered orally, intramuscularly or enously, intramuscular injection of typical antipsychotics and benzodiazepines, given alone or in combination, has been a treatment of choice for agitation over the past few decades. The tly preferred treatment paradigm for acute agitation is to use atypical antipsychotic drugs administered with or without supplemental henzodiazepines. [8} More specifically, ts with agitation are usually prescribed beta blockers such as propranolol and Pindolol, anxiety medications such as Buspirone, henzodiazepines such as Lorazepam, anti—convulsants such as Valproate and igine, antinpsychotics such as li-laloperidoi, Droperidol, Ziprasidone and other high-potency dopamine—hli‘iclting agents, and atypical antipsychotics such as ()lanzapine. However, Buspirone, Valproate, Haloperidol, Droperidol and Ziprasidone have potential adverse effects, and optimal dosage and long~terrn efficacy in the management of chronic agitation in dementia is very limited. Lorazepam is only effective for treating ion in patients when used before medical procedures. l_.oxapine (an U1 antipsychotic) is FDA approved for treating agitated patients via, inhalation, but is associated with a black box warning for hronchospasm and increased mortality in elderly patients with dementia—related psychosis (FDA label, Loxapine or Adasuve®) {)lanzapine, Ziprasidone or its ation with Haloperidol, is also associated with QT gation, and extrapyramidal side effects should be watched very carefully in hospital set ups. Reports of adverse events (including eight fatalities) associated with intramuscular olanzapine underscores the need to follow strict prescribing guidelines and avoid simultaneous use with other CNS depressants.

The Expert sus Guidelines for treatment of behavioral emergencies cite speed of onset as one of the most important s in ng a drug and its route of administration.

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 s. For example, henzodiazepines or fast—acting sedatives quickly calm a, severely ed 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 es is still limited because of the ial for significant side effects ated 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 antimagitation 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] Alpha—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 ine, Guanfacine, Guanabenz, Guanoxahenz, hidine, Xylazine, Tizanidinet lit/ledetornidine, Dexniedetomidine, Methyldopa, Methylnorepinephrine, 3C) Fadolrnidine, lodoclonidine, aclonidine, Detomidine, Lofe‘xidine, Amitraz, Mivazerol, Azepexol, Talipexol, idine, Naphazoline, Oxyrnetazoline, tazoline, ahydrozoline, 'l‘rarnazoline, 'l'alipe‘xole, Romilidine, propylhexedrine, Norfenefrine, Octopamine, dine, Lidamidine, Tolonidine, 4, Di—Z’l-éll, ST—Ql, RWLSZBSi ’l‘CG-ltlllt), 4~(3—aminornethyl—cy'cloliex~3~enylmethyl)—l,3—dihydro~imidazole—Zwthione, and 4—(3—hydroxyniethylacycloheX—Ziuenylniethyl)~l,3wdihydro—iinidazole~2—thione. The inventors of the present invention have unexpectedly found that the sub—lingual stration of an alpha—2 adrenergic 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 (Dexrnedetonridine) is commercially available as an injectable formulation for on of initially ted and mechanically ventilated patients during treatment in an intensive care setting, and for non— intuhated patients prior to and/or during surgical and other ures. [l3] Dexniedetornidine is reported to have anti—agitational effects when stered intravenously or huccally during surgical procedures and intensive care unit (ICU) setups. For example, he et. al., in Anesthesiaé’: Analgesia 2004 (l):60~3, discloses the administration of an intravenous single—dose of detomidine 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 ive Care 20M) lan, 38(l):82—90, and loseph D. Tohias in l 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. ver, the focus ofW0 Od ldl 3 is the administration of Dextnedetoniidine sublingually at doses appropriate to treat sleep disorders and induce significant sedation. We have now surprisingly found that Dexrnedetornidine or a pharnraceutically acceptable salt thereof, administered gually, can effectively treat agitation, including agitation associated with neurodegenerative diseases (eg. Alzheirnerls disease, fronto-ternporal dementia, and sundown syndrome in Alzheimer’s disease/dementia), ion associated with neuropsychiatric ions (eg. bipolar disorder, schizophrenia, r 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 adrninistered 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 ion in a subject in need thereof, comprising administering an effective amount of an aiphauZ rgic 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, frontotemporai dementia, or sonism, or associated with a sychiatric condition like schizophrenia, bipolar er, bipolar mania, delirium, or depression, or associated 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 causing significant sedation. [i 6] in a preferred aspect, the t invention provides a method of treating agitation or the signs of agitation in a subject in need thereof, comprising administering an effective arnount of Dexmedetomidine or a pharmaceuticallv acceptable salt thereof subiinguaily to the subject. In a particular aspect, the agitation is suppressed without also causing significant on. [l7] Another aspect of the present invention es a method of treating agitation or the signs of agitation in a subject in need thereof, n said agitation is associated with neurodegenerative disease, comprising administering an effective amount of etomidine or a pharmaceuticallv acceptable salt thereof subiingually to the subject. In a particular aspect, the agitation is suppressed without also causing significant sedation, [i 8] Yet another object of the present ion 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 stering an ive amount of Dexrnedetonridine or a pharmaceuticaliy acceptable salt thereof suhiinguaily to the subject, in a particular aspect, the agitation is suppressed without also causing icant sedation. [l9] Another object of the present invention provides a method of treating agitation or the signs of ion in a subject in need thereof, wherein said agitation is associated with schizophrenia, bipolar disorder, bipolar mania, delirium, depression, or another related neuropsyehiatrie condition, comprising administering an effective amount of Dexrnedetornidine or a. pharmaceuticaliy acceptable sait thereof sublinguailv to the subject. In a particular , the agitation is suppressed without also causing significant sedation. [20} A further object of the present invention provides a method of treating, preventing or reducing the signs of agitation in a subject in need thereof, wherein said agitation is associated with sundown syndrome in mer’s disease/dementia, comprising administering an effective amount of etonridine or a til'iarrn,aceuticai,l3i acceptable salt thereof sublingualiy to the subject. in a particular aspect, the agitation is suppressed without also causing i 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 t in need thereof, n said agitation is associated with an {)PD/EPD procedure (eg. MR1, CT or CAT scan, lumbar puncture, bone marrow aspiration/biopsy, tooth extraction or other dental procedures), comprising administering an effective amount of Dexmedetoniidine or a pharrnaceuticailv acceptable salt thereof sublingually to the t. in a particular aspect, the agitation is suppressed without also causing significant sedation.

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 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 agitation is suppressed without also causing significant sedation. [23} A further aspect of the present ion provides a suhiingual composition for treating agitation or the signs of agitation in a subject in need f, wherein said agitation is associated with a neurodegei'ierative disease, and said sublingual composition comprises an effective amount of Dexmedetoniidine or a pharmaceutically acceptable salt f, together with one or more pharmaceutical acceptable carriers and/or excipients, [24} Another aspect of the t invention provides a subiinguai composition for treating agitation or the signs of agitation in a subject in need f, wherein said agitation is associated with schizophrenia, bipolar disorder, bipolar mania, delirium, depression, or another related sychiatric condition, and said gual composition comprises an effective amount of Dexmedetonridine or a ceuticailv able. salt thereof, together with one or more pharrnaceutically acceptable carriers and/or excipients. [25} An additional aspect of the present invention provides a sublingual composition for treating agitation or the signs of agitation in a subject in need thereof, wherein said ion is associated with sundown syndrome in Alzheimer’s disease/dementia, and said gual composition comprises an effective amount of Dexniedetornidine or a pharmaceuticallv acceptable 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 ure (cg. MRI, CT or CAT scan, lumbar puncture, bone marrow aspiration/biopsy, tooth extraction or other dental procedures), and said U1 subiingual ition comprises an effective amount of Dexmedetomidine or a pharmaceutically acceptable salt f 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 associated with agitation in a subject in need thereof, wherein said agitation is associated with an alcohol and substance abuse withdrawal, and said gual composition comprises an effective amount of Dexmedetomidine or a pharmaceutically acceptable salt thereof together with one or more pharmaceutically acceptable carriers and/or excipients, Another object of the t invention provides a sublingual composition comprising an effective amount of Dexmedetomidine or a pharmaceutically acceptable salt thereof together with one or more pharmaceutically acceptable carriers and/or ents, wherein said sublingual composition is selected, from the group ting of a film, wafer, patch, lozenge, gel, spray, tablet, liquid drops or the like.

A further object of the present invention 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 ion, the dosage administered sublinguaily may iently be in the range of n about 3 micrograms to about lQQ rams, Examples of suitable s include: about 5 micrograms to about 100 micrograms, about 5 micrograms to about 90 micrograms, about 5 micrograms to about 85 micrograms, about 5 micrograms to about 80 micrograms, about 5 micrograms to about '75 micrograms, about 5 micrograms to about ’70 micrograms, about 5 micrograms to about 65 micrograms, about 5 micrograms to about 60 micrograms, about 5 micrograms to about 55 micrograms, about 5 3C) 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 39 micrograms, about 5 micrograms to about 25 micrograms, about 5 micrograms to about 20 rams, about 5 rams 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) ranis, about 12 micrngranis, abeut i4 micregrams? abnut l5 microgramg about 16 micrograms, about 18 niicrngraina about 20 micrograms, abcut 30 micregrams? about 50 rnicrngrams. The dese may be administered One er more times a day.

U1 BRIEF DESCRIFTEGN GP THE BEX‘WENGS Figure lA. Effect of sublinguaily administered Dexmedeteniidine hloride (Dex) at varying deses (0. 5— 3 fag/kg) en tive 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<OiOL YYYp<QOOi and YYYYp<thOtll vs vehicle is (vehicle).

Figure 13. Effect Of subiingually administered Dexntedetnmidine bydrncltlcride (Dex) at g doses (05— 3 gig/kg) en frequency of aggressive and agitated behaviors. Data expressed as Mean :: SEEM. Oneuway ANOVA fellcwed by Dunnettls cc test. Yp<fi05 YYp<OOl ."il and YYYY l343.0001 vs vehicle controls (vehicle .

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<O.05 YY J<O.OL YYY J<O.Otil and Y Y YY <0000l l l l3 vs vehicle controls ’velticle).l Figure ll). Effect of intravenously administered Dexmedetnmidine liydrncbleride (Dex) at g dnses (0. 5—3 gig/kg) en ncy of aggressive and agitated behavinrs. Data expressed as ifs/lean ri: SEEM ()neavay ANEWA followed by Durinett’s pest—hoe test. Yp<0.05 YYp<O.Ol, YYY <0001 and YYYY <90001 l5 9 vs vehicle ccntrcls vehicle).

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

Figure 2B. Eltect el’ intravenously stered detnmidine hydrochloride (Dex) at varying dcses (0.5—3 rig/kg) nn Latency to attack. Data is expressed as Mean :: SEEM. Statistical analysis was performed by One—way ANOVA ved by Dunnett’s pestmhoc test. Yp<005 YYp<O.Ol, YYYp<Otltll and YYYYp<OOOOi vs vehicle centrnls (vehicle).

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 ation. 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 ** l, *** ll<Oi00l and *M‘l‘ l3<0.0(llll vs vehicle controls vehicle‘s.

Figure 33. Effect of sublingually administered Dexrnedetomidine hydrochloride (Dex) at varying doses (0.543 ) 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 followed by Dunnett’s post—hoc test. *p<0iGS **p‘<10.0l, **"‘p<0.00l and **l‘*r_i<<ll.00lll vs vehicle controls (vehicle).

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 expressed 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 0l, ***p<0i00l and ****l‘p<ifl.000l vs vehicle controls (vehicle).

Figure 31). Effect of intravenously administered Dexrnedetoini dine hloride (Dex) at varying doses (0.56 rig/kg) on tive duration of Neutral behaviors such as grooming, and exploration. Data expressed as Mean rit- SEM. Data is sed as Mean :l: SEM. tical analysis was performed by One-way ANOVA followed by Dunnett’s postehoc test. *p<0.05 El) 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 ) on Frequency of Neutral behaviors such as grooming and exploration. Data expressed as Mean i SEM. Data is expressed as Mean :: SEM. Statistical analysis was performed by y ANOVA followed by Dunnett’s postehoc test. *p<0.05 0l, ***p<0.0fll and ****p<0.0001 vs vehicle controls (vehicle).

Figure 3F. Effect of intravenously administered etornidine hydrochloride (Dex) at varying doses (0.56 rig/kg) on Neutral behaviors such as immobile/quiet tirne. Data expressed as Mean :: SEM. Data is sed 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 hydrochloride administration in rats. Data expressed as Mean rit- SD Figure 48: Mean . concentrations foiiowing intravenous (IV) Dexmedetomidine hydrochloride administration in rats Data expressed as Mean fir: SD DETAELED DESCRIPTEQN 0F THE INVENTEGN {a EA'E‘EONS: 'i7he foiiowing abbreviations are used throughout this specification: AD: Alzheimer’s disease AUC: Area under the curve BZDs: Benzodiazepines CNS: Centrai nervous system Cf/CAT scan: computed tomography scan 11.5 me: Maximum (or peak) serum concentration 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: ive care unit IPD: in~Patient department MR1: ic resonance imaging Mg: Miliigrarn NE: Noruepinephrine OED: Outnpatient department PTSD: Post-traumatic stress disorders RES: Ramsay sedation score RET: Rat er test SLGS: 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 ology 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 y es otherwise.

U1 Thus, for example, reference to ”a solvent” includes one or more such solvents and the lilre. [32} Unless defined ise, 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 s and materials r, or equivalent, to those described herein can he used in the practice of the present invention, the preferred n'iaterials and methods are described herein. [33} The terms "treating," and ”treatment,“ as used herein refer to curative therapy, prophylactic therapy, and/or preventative therapy and can he used interchangeably.

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

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

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

As used , “pharmaceutically 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 hydrochloric, hydrohromic, hydroiodic, 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 subject can be any animal, including rnan mammals, such as mice, rats, other rodents, s, dogs, cats, swine, cattle, sheep, horses, or primates.

The term “agitation” as used herein, means a irritability, emotional outburst, impaired thinking, or excess motor and verbal activity that may occur due to either ction of specific brain regions such as frontal lobes or due to dysfunction of neurotransmitter systems such as ne and nor~epinepln~ine In the present invention, agitation also includes U1 aggression and hyperearousal in raumatic stress disorder. The agitation may he acute or '39] The term “the signs of agitation” includes excessive motor ty (examples include: pacing, g, 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, shoving, pushing, clenching hands into lists, resisting, hitting others, locking s or people, hing, biting, throwing 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 ularly exist in neuropsychiatric conditions.

Acute agitation may lead to chronic agitation if it remains untreated. [41} The term “chronic agitation” means ion developed over a long period of time, and is less severe than acute agitation. Chronic agitation may be associated 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 e, frontotemporal dementia (or Piclr’s disease), ia, Dementia with l.,ewy bodies, post- traumatic stress disorder, Parkinson's disease, vascular dementia, vascular cognitive impairment, il-luntington‘s disease, le sclerosis, Creutzfeldt—lakoh disease, multiple system atrophy, ssive supranuclear palsy or other related neurodegenerative diseases.

The term “neuropsychiatric conditions” includes, but is not limited to, schizophrenia, bipolar illness (bipolar er, bipolar mania), depression, delirium or other related neuropsychiatric conditions 3C) [44] “Sundown syndrome” is a latewday circadian syndrome of increased confusion and ssness, generally in a patient with some form of dementia. it seems to occur more ntly during the middle stages of Alzheimer dementia. it seems to subside with the progression of a patient's dementia. About 20—45% of Alzheimer type ts 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 agitation , 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 substances via the mouth in such a way that the substances 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, y reducing the hood of deleterious side effects and providing a cost benefit to the manufacturer. [47} “Sedation” as used herein means depressed consciousness in which a patient or subject retains the ability to independently and continuously maintain an open airway and a regular breathing pattern, and to respond appropriately and rationally to physical stimulation and verbal cornrnands As used herein “without causing significant on” means that the patient experiences a level of sedation not greater than Level 3 on the Ramsay Sedation Scale. Level 3 means sedated 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 rgic agoni st or a pharmaceutically 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 agonist includes, but is not limited to, Clonidine? Guantacine, enz, Guanoxabenz, Guanethidine, Xylazine, 'l‘izanidine, Medetomidine, Dexmedetoinidine, Methyldopa, Methylnorepinephrine, Fadolmidine, lodoclonidine, Apraclonidine, dine, ltol’exidine az, Mivazerol, Azepexol? 'l‘alipexol, idine, Naphazoline, Qxymetazoline, Xylometazoline, ahydrozoline, zoline, Talipexole, i dine? propylhexedrine, Norfenefrine, Gctoparnine, Moxonidine? dine, 'l'olonidine, lJKl4304, DJ-7l4l, S'l‘w9l RW’lk. 2353, ’l‘CGwl 000, 4— {3 naminomethylacycloheX—3 ethyl)— 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 preferred ment, the present invention es a method of treating U1 agitation 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 ssed without also causing significant sedation. [5 l} Agitation may be effectively treated using a relatively low dose of etoinidine 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 reduced or no side effects (for e, cardiac or atory 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 able salt thereof sublingually to the subject to provide fastuaeting relief without a substantial portion of Dexmedetomidine or its pharmaceutically acceptable salt thereof 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 pharmaceutically acceptable salt thereof via a sublingual composition to the subject, wherein the sublingual composition is selected from a film, wafer, patch, lozenge, gel, spray, tablet, and liquid drops.

In a further embodiment, the present invention provides a method of treating agitation or the signs of agitation in a subject in need thereof, comprising administering to the subject an effective amount of an 2 rgic agonist together with one or more pharmaceutically acceptable carriers and/or excipients via a suhlingual composition, n the sublingual composition is a sublingual film. In a particular aspect, the agitation is associated with a egenerative disease or neuropsychiatric ion, In another particular aspect, the treatment is effective without g significant on. [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 er 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 ated with a neurodegenerative disease or neuropsychiatric ion. in another particular aspect, the treatment is effective t causing significant sedation. in yet other embodiment, the present invention provides a method of treating ion or signs of agitation in a subject in need thereof, comprising administering to said subject an U1 effective amount of an 2 adrenergic agoni st or a pharm aceutically acceptable salt thereof at a dosage that does not cause a significant on. Suitable aloha—2 adrenergic agonists include, but are not limited to, Clonidine, Guantacine, (Itoanabenz, Guanoxabenz, Guanethidine, Xylazine, Tizanidine, Medetomidine, Dexmedetomidine, Methyldopa, Methyinorepinephrine, Fadoirnidine, iodoclonidine, Abraclonidine, Detornidine, l..ol’exidine, Amitraz, Mivazerol, Azepexol, Talipexol, Rilmenidine, Naphazoline, Qxyrnetazoline, Xylornetazoline, Tetrahydrozoline, Tran'iazoline, Talipexole, Romifidine, propylhexedrine, Norfenefrine, Octopamine, Moxonidine, dine, 'l‘olonidine, 04, Diu7'i41, l, BERG—52353, TCG—lOOO, 4~(3—arninometliyi—cyciohex~3menylnietliyl}l,3—dil1ydro~imi dazole— 2—thione, 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 micrograms to about lth micrograms. [57} 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 to said subject an effective amount of Dexmedetomidine or a pharrnaceuticaliy 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 f used in the sublingual composition is from about 3 rams to about lOO micrograms. Examples of suitable dosages include: about 5 micrograms to about lt‘rQ micrograms, about 5 micrograms to about 90 micrograms, about 5 rams to about 85 rams, 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 ograms, about 5 n'iicrograms to about an micrograms, about 5 micrograms to about 55 micrograms, about 5 micrograms 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 rams, 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 rams 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 rams, about 20 micrograms, about 30 micrograms, about 50 rams, 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 agitation in a t in need eof, 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 ram s/kg, about 01 micrograms/kg to about 0.4 micrograins/hg, about 0.1 micrograms/kg to about 0.3 micrograms/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 rams/kg, about 017 micrograms/kg, about 0.8 micrograms/kg, about 0.9 micrograms/kg, about 1.0 micrograms/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 ion associated with neurodegenerative e in a subject in need thereof, comprising stering to said subject an effective amount of an aiphauZ adrenergic agonist or a pharmaceuticaiiy abie sait thereof at a dosage that does not cause a significant sedation. Suitable a1pha~2 adrenergic agonists include, but are not innited to, Cionidine, Guanfacine, Guanabenz, Guanoxabenz, Guanethidine, Xyiazine, Tizanidine, h/iedetomidine? Dexmedetoinidine, Methyidopa, Methyinorepinephrine, Fadoiinidine iodocionidine, Apracionidine, idine, Lofexidine, Antitraz, roi, Azepexoi, xoi, Riimenidine, Naphazohne, ()Xj/inetazoiine, Xyiometazoiine, Tetrahydrozohne, Ti‘ramazoiine, Taiipexoie, Romiiidine, propyihexedrine, Nortenefrine, Oetoparnine, Moxonidine, Lidamidine, Toionidine, UK14304, menu, sir—91, RW]~52353, n, 4—(3— aminoniethyincyciohexfi menyimethy1)— 1 ,3 "dihydro—nnidazoie—Z—thione, and 4%? n hydroxyme‘thyi—cyciohex~3—enyimethyi)—1,3—dihydro~imidazo1e—Z-thione or a pharmaceutieaiiy acceptable 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 agitation or the signs of ion associated with neurodegenerative e in a subject in need thereof, comprising sub1ingua11y administering to said subject an effective amount of Dexmedetomidine or a pharmaceuticaliy acceptable salt thereof at a dosage that does not cause unwanted (eg, significant) on, The dosage of Dexmedetomidine or a pharmaceutically acceptable 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 rams to about U1 90 rams, 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 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 rams, about 6 micrograms, about 7 micrograms, about 8 micrograms, about 9 micrograms, about to micrograms, about i2 micrograms, 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 invention provides a method of treating agitation or signs of agitation associated with neuropsychiatric condition in a subject in need thereof, comprising administering 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 2 adrenergic agonists include, but are not limited to, Cionidine, Guanfacinc, Guanabenz, Guanoxabenz, Guanetliidme, ne, Tizanidine, h/iedetomidine? Dexmedetomidine, h/iiethyldopa, Methyinorepinephrine, Fadolmidine, lodocionidine, Apracionidine, Detomidine, Lofexidine, Amitraz, Mivazeroi, Azepexoi, Taiipexol, Riinienidine, Napbazoiine, ()thirnetazoiine, Xyiometazoiine, 'i7etrahydrozoline, Trarnazoiine, Taiipexole, dine, propylhexedrine, Nortenefrine, Oetopamine, Moxonidine, Lidamidine, Toionidine, unmet, rat—7141, sr—ai, nutrssasa, c, 4—(3— aminomethyincyclohexfi menylniethyi)— 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 ition is convenientiy trom about 3 micrograms to about too micrograms In another embodiment, the t invention provides a method of treating agitation or the signs of agitation associated with neuropsychiatric condition in a subject in need thereof, comprising administering to said subject an ive amount of Dexmedetoinidine or a pltarmaceutically able salt f gually at a dosage that does not cause significant sedation, The dosage medetomidine or a pharmaceutically acceptable salt thereotused in a sublingual composition may conveniently be from about 3 micrograms to about 1th micrograms, e. g. about 5 rams to about lot“) 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 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 micrograms 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 micrograms, 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 able sedation when treating a subject according to a method of the t invention is preferably at or below Level 3 ing 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, comprising adrnini 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 rams, thereby achieving an RSS at or below Level 3 (eg. Level 2 or Level 3).

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

The sublingual ceutical 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, ring agents, coloring agents and so on. [do] The sublingual pharmaceutical compositions of the present invention may be administered to a subject alone or in combination with one or more other suitable active ingredients. in one embodiment, the present invention, provides a gual pharmaceutical U1 composition sing an effective amount of Dexniedetornidine or a pharmaceutically able salt thereof for the ent of agitation in a subject, e. g. agitation associated with neurodegenerative disease, sundown syndrome in Alzheimer’s disease or dementia. in a particular aspect, the sublingual ceutical composition effectively treats agitation in a subject t causing significant sedation.

[68] In another ment, the present invention provides a sublingual pharmaceutical composition comprising an effective amount of etomidine or a pharmaceutically acceptable salt f for the treatment of agitation in a subject associated with schizophrenia, r disorder, bipolar mania, other bipolar illness, depression, delirium or another related neuropsychiatric condition. in a particular aspect, the sublingual pharmaceutical composition effectively treats agitation in a subject without causing significant sedation.

The sublingual ceutical 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 invention, the sublingual pharmaceutical composition is in the form of a tablet or packed powder. [7H in another embodiment of the invention, the gual pharmaceutical compositi on is in the form of a patch or film (eg thin film). The patch may have adhesive qualities to prevent movement or swallowing of the patch. The patch may be ingestible in case of accidental wing 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 e 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 diluent for the solution may particularly be physiological saline solution or water. The amount of on administered may iently 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 . in a particular embodiment of the invention, Dexmedetomidine 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 able 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%,

[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 applied and held in place for a similar amount of time. Surprisingly, this procedure noticeably ses the effect of the composition of the invention in the treatment of agitation or the signs of agitation. [78} in another embodiment, the sublingual composition of etomidine or a pharmaceutically able salt thereof is a hard tablet or a compressed powder tablet. The tablet may conveniently be designed to ve under the tongue in about 30 to ill) seconds 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 f is a hard tablet having a low grit component for an organoleptically pleasant mouth feel. The tablet (or particles thereof containing the active ingredient which, can be compressed to form the tablet) may also se a protective outer coating, eg any polymer conventionally used in the ion of microparticles, matrix—type articles and microcapsules. in a further embodiment, the sublingual composition of Dexmedetomidine or a pharmaceutically acceptable salt thereof is a hard, compressed, 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 include, for example, lactose or mannitol, and suitable lubricants include ium stearate, silicon dioxide 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 friability of about % or less and a ss of about l5 to about 50 Nest/tons. [8G] Another aspect of the t invention provides a method of making a packaged, sublingual 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 disintegrahle particles (eg. beads) including the active ingredient distributed in the sublingually dissolyable matrix; and to) storing the product in bulk prior to packaging, in another embodiment, the dosage forms are then ed 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 ving tablets adapted for direct oral dosing as bed above.

[Si] in another ment, 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 weight, based on the weight of the finished tablet, and more ularly in an amount ol‘between about 309/6 and about 80% by weight. Sullicient effervescent al is included in the tablet composition to generate 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 es carbon dioxide e. g, as a result of the reaction of a soluble acid source with an alkaline carbonate or bicarbonate. The acid source may iently include food acids and acids such as citric acid, ic, arnalic, tunieric, adipic and succinic acid, Carbonate and bicarbonate sources include dry solid carbonate and bicarbonate salts such as sodium bicarbonate, sodium ate, ium bicarbonate, potassium carbonate, magnesium carbonate 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 solvents, 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, propylene carbonate, pharmaceutically acceptable oils (cg, soybean, wer, peanut, peppermint etc.) and the like. The aceutically acceptable liquid is selected, either to dissolve the active pharmaceutical ingredient, to produce a stable, homogenous suspension or solution of it, or to form any combination of a suspension or solution.

Furthermore, gual, 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, s, and the like). One ular polymer that may conveniently be used is polyvinylpyrroliclone (PVP), The vi scositysmoclulating material may conveniently be present in the amount of from about Q.Ol% to about 65% by weight of the spray formulation Other examples of carritars/"excipients include preservatives (eg, ethanol, benzyl alcohol, propylparaben and inethylparaben). vatives may conveniently be present in, the amount of from about ODOlll/o to about 10% by weight of the spray formulation Carriers/excipients may also be flavoring agents, sweeteners (eg. sugars such as sucrose, glucose, dextrose, maltose, fructose, etc), artificial sweeteners (eg. saccharin, aspartame, acesulfanie, sucralose etc), or sugar alcohols (eg. mannitol, xylitol, lactitol, maltitol syrup etc.) t 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 present in an amount of from about OOOl‘i/o to about l% by weight of the spray ation), 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 /o to about lO‘l/o by weight of the spray formulation), and oam 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 appropriate carriers/exeipients in the spray formulations of the t invention.

One particular aspect of the present invention provides a sublingual film comprising Dexmedetomidine or a pharmaceutically able salt thereof, together with one or more carriers and/or ents, for the treatment of agitation. 3C) [86] Excipients which may be incorporated into the gual films of the present invention e one or more of the following: film forming agents, mouth feel irnprovers, plasticizers, stabilizers, surfactants, preservatives, sweetening agents, colorants, flavourants, fiers, 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 ably about 50% to about 90% by weight of the composition. Film forming agents that can be ed as part of the film composition of the present invention U1 include, but are not limited to, cellulose ethers, modified starches, natural gums, edible polymers, d 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 limited to, acid and enzyme yzed corn and potato starches, derivatives f and combinations thereof.

Examples of natural gums include, but are not limited to, gum arabic, guar gum, locust bean gum, carrageenan gum, acacia, lraraya, ghatti, tragacanth agar, tamarind gum, xanthan gum, derivatives thereof and ations thereof. [9i] Zliixarnples of edible rs include, but are not d to, microcrystalline ose, cellulose ethers, xanthan, derivatives thereof and combinations thereof. [92} Seaweed extract examples include, but are not limited to, sodium alginate, carrageenans, derivatives thereof and. ations thereof. [93} Land plant extracts include, but are not limited to, horijac, pectin, arabinoglactan, derivatives thereof and combinations thereof.

Particular filin forming agents e pullulan, sodium alginate, polyvinylpyrrolidone, inethylcellulose and methylhydroxycellulose (Ml-KI), [95} The term “solvent” generally refers to liquids that will dissolve s. A t may he used to dissolve film—forming agents and other excipients to prepare film—forming itions of the present invention. Solvents include, but are not limited to, deinineralized/distilled water, ethyl alcohol, isopropyl alcohol, methyl ethyl ltetone, propylene glycol methyl ether acetate, iyl acetamide, ethylene glycol monompropyl ether, and toluene. A sublingual film of the present ion 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 combinations 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, Suitable disintegrants for use in an edible film of the present invention include, but are not limited, to, c acid, microcrystalline cellulose and yniethylcellulose. Special disintegrants known as super—disintegrants are also suitable for use in an edible film of the present invention. Super—disintegrants include cross—linked polymers (eg, crospovidone), cross~linlted starches (eg, sodium starch glycolate), and cross“ linked celluloses (eg. a modified yrnethylcellulose such as croscarrnellose). These supermdisintegrants are insoluble in water and most other solvents, have rapid swelling properties, and have good water uptake with high capillary , 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 egrants or super—disintegrants are conveniently present in a gual composition 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 limited to, gurn , carrageenan, triethanol amine steara‘re, nary ammonium compounds, acacia, gelatin, lecithin, bentonite, veeguni, derivatives f and combinations thereof. Enrulsitiers can be used in a composition of the present invention in an amount up to about 40%, more particularly up to about 25%, by weight of the composition. The ernulsiti er can be a stabilizer creating an oil/water emulsion encapsulating volatile oils and flavoring agents, thereby essentially acting as a flavor ve, A ular 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 present 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 limited to, glycerin, sorbitol, triacetin, nronoacetin, diacetin, polyethylene glycol, ene glycol, hydrogenated starch hydrolysates, corn , low molecular weight propylene glycol s, phthalate derivatives like dirnethyl, tliethyl and dibutyl phtlialate, citrate derivatives such as tributyl, yl, acetyl e and castor oil derivatives thereof and combinations thereof. Particular plasticizing agents of the t ion include sorbitol and glycerin. [lull The term “preservative” generally refers to an excipient used to loll microorganisms or U1 prevents, inhibits or retards their growth and reproduction, and is included in a product in a concentration only sufficient to prevent spoilage or the growth of inadvertently added microorganisms. Suitable vative 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 pharmaceutical composition Suitable sweetening agents for use in a coinpositi on of the present invention include, but are not limited to, aspartanie, dextrose, glycerin, mannitol, ri 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 composition.

{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, l, red ferric oxide, and natural coloring agents such as grape skin t, 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 ition. [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 ceutical composition. Suitable flavorants include, but are not limited to, synthetic ing oils, flavoring arornatics, natural oils, extracts from whole plants or parts thereof such as leaves, flowers, fruits or combinations f. Examples include cinnamon oil, Wintergreen oil, mint 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 e vanilla, citrus fruit oils such as lemon, orange, grape, lime or grapefruit oil, and fruit essences such as apple, pear, peach, strawberry, rry, 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 thereof. 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 iently be present in the composition in an amount of from about Otlt‘ilo/Er to about 10% Vv’/W of the cornpositi on.

El 05] The term ”salivating agent" is an agent that promotes greater salivati on during use of a composition of the present invention. This may he an important feature if the ition 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 e, 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, polyethoxylated esters, mono—, dim, and triglycerides, diacetyl tartaric esters of monoglycerides, polyglycerol esters, 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 unsaturated. it should be noted that some of the emulsifiers that are salivating agents may also function as binders. Examples of food acids useful as salivating agents include 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 ses. Suitable idants include, for example, ic acid, ascorbyl palrnitate, butylated hydroxyanisole, butylated hydroxytoluene, hypophosphorous acid, monothio—glyceroi, propyl gallate, sodium ascorbate, citric acid, sodium ite, sodium tormaldehyde suifoxyiate, sodium metabisultite, EDTA and sodium e. The antioxidant may conveniently be present in the composition in an amount ot‘from about 0.00l% to about % w,"vv of the composition.

Elm} The term “permeation enhancer” generally refers to an ent used to e 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, solubilizers such as alcohols, polyethylene glycol s, ing agents (e.g. cyclodextrins), sucrose iaurate or sucrose oleate. The permeation enhancer may conveniently be present in the composition in an amount of from about Lilli/ii to about 5% w/w of the composition. [108} In one embodiment ofthe t invention, the sublingual ceutical ition of the present invention includes a rnucosal permeation enhancer 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 appropriate quantities ot‘the foregoing ingredients in accordance with standard good manufacturing practices. The relative amounts of each ingredient should not interfere with the desirable pharmacological and pharrnacolrinetic properties of the resulting formulation. [llO] Suhlingual detornidine 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 applications are incorporated herein in entirety and includes US. Pat. or Publication Nos. 9585961, 7470397, 7727466, 6, 9545376, 201 741087084, 9662297, 1, 2017—0246108, 20l7«0252294, 9441142 assigned to ARK LLC and 7425292, 7357891, 8663687, 8685437, 7897080, 8241661, 8617589, 8936825, 956119l, 9303918, 9346601, 8282954, 7972618, 9073294 assigned, to h/lonosol For. [l l 1] in preparing the suhlingual film of the present invention the active agent, erg, Dexmedetornidine or a pharrnaceutically acceptable salt thereof, film g agents and optionally one or more carriers and/or excipients selected from the group comprising of mouth feel iniprover, plasticizer, stabilizer, surfactant, preservative, sweetening agent, colorant, rant, emulsifier, disintegrant, salivating agent, antioxidant, permeation enhancer are dissolved in a compatible solvent to form a film forming composition. ible solvents include water, alcohols such as ethanol, ethyl acetate, e, and mixtures thereofi The film forming composition is cast on a able 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 le 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 t invention can also he ed by other ished processes eg. extrusion (for example, Hot melt extrusion, 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 , the present invention provides a sublingual composition comprising an alpha—2 adrenergic agonist or a pharmaceutically acceptable salt thereof, administered to a subject in an amount sufficient to effectively treat agitation The amount of alpha—2 adrenergic U1 agonist is sufficient to effectively treat agitation without causing 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 r aspect, the present ion provides a sublingual composition comprising Dexmedetomidine or a pharmaceutically acceptable salt thereof, administered to a subject in an amount sufficient to effectively treat ion in a ular aspect, the amount of Dexmedetomidine or a pharmaceutically acceptable salt thereofused is sufficient to effectively treat ion 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 administered via a single dosage form or via multiple dosage forms~ [l l4] Following administration of a ition of this invention to a subject, a therapeutic {ie gitation) effect may begin within about 60 minutes (eg within about 30, 20, l5, l0, , 3, 2 or 1 minutes) 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 minutes. 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 minutes, [l l5] Treatment protocols may include one or more dosage intervals (eg two or more dosage intervals, live or more dosage intervals, or ten or more dosage als). Depending on the physiology of the t and the d therapeutic effect, the on of dosage intervals and treatment protocol s according to embodiments of the present invention may vary. it l6} flexmedetomidine or a phannaceutically acceptable salt thereof 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 composition or as two or more te compositions, which can be administered simultaneously, sequentially or separated by an appropriate period of time. [117} Where Dexmedetomidine or a pharmaceutically acceptable salt thereof is administered with a second active agent to treat ion 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 example; 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 tively the second active agent, to Dexmede‘tornidine or a pharmaceutically acceptable 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 edetoniidine or a pharmaceutically acceptable salt tl'iercof 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 tood that all ranges between the quoted ranges are also covered herein; and constitute thither particular aspects of this invention Vi. DGSENG REGlh/IEN [118} The dosing regimen employed may depend on several s; such as the type of agitation treated? the severity of the signs; and whether the agitation is due to an underlying medical ion. [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 rams 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 rams; about 5 micrograms to about 20 rams; about 5 micrograms to about 15 micrograms; about 5 rams 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 micrograms, about 15 micrograms, 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 abie sait thereof may be administered U1 guaiiy in any appropriate dose to a human. in some variations, the human dose may be from about 0.05 micrograms/kg weight of subject to about 1.5 micrograms/kg weight of subject. Exampies of suitab1e s 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 micrograms/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 micrograms/kg, about 0.9 micrograms/kg, about 1.0 micrograms/kg, about 1.1 rams/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. SPECIFIC 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 ion or the signs of ion in a subject in need thereof comprising administering to said subject an effective amount of Dexmedetomidine or a pharmaceuticaiiy abie sait thereof, wherein said Dexmedetomidine or a pharmaceuticahy acceptable sait thereof is sub1inguaiiy administered 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 aeoeptabie sa1t thereof is in range of from about 3 micrograms to about 100 micrograms (e.g. about 5 micrograms to about 100 rams, about 5 micrograms to about 90 micrograms, about 5 micrograms to about 85 micrograms, about 5 rams to about 80 micrograms, about 5 micrograms to about '75 rams, 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 rams to about 50 micrograms, about 5 micrograms to about 45 micrograms, about 5 rams to about 49 micrograms, about 5 micrograms to about 35 micrograms, about 5 micrograms to about 30 rams, 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 rams (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 mammal, preferably hnman $25} Embodiment 5. The method according to any one of Embodiments l to 4, wherein said agitation is associated with a egenerative disease. [lilo] Embodiment 6. The method according to Embodiment 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 impairment, Huntington's disease, multiple sis, Creutzt‘eltit-Jakob disease, multiple system atrophy, and progressive uclear palsy. [l27l Zliinibodiment 7~ The method according to any one of Embodiments l to 4, wherein the agitation is associated with a neuropsychiatric ion.

[L28] Embodiment 8. The method according to Embodiment 7, wherein said neuropsychiatric ion is selected from schizophrenia, bipolar illness (such as mania, disorder), delirium, and depression, [izst bodiment 9. The method according to Embodiment 5, wherein the agitation is associated 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, n said agitation is not perioperatiye agitation and said sublingual ition comprises an effective amount ot‘Dexmedetomidine or a pharmaceutically acceptable 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 subject in need thereof, wherein said agitation is associated with a neurodegeneratiye e and said sublingual composition comprises an effective amount of Dexmedetomidine or a pharmaceutically acceptable salt thereof 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 sublingual composition for use in the treatment of agitation or the signs of agitati on in a subject in need thereof, wherein said agitation is associated with sundown syndrome in dementia or Alzheimer’s e and said sublingnal composition comprises an effective amount of Dexmedetomidine or a pharm aceutically acceptable salt thereof and one or more ceuticaliy acceptable rs/excipients.

U34] Embodiment l4. The soblingoal composition according to Embodiment ll, wherein said neurodegenerative disease is selected from the group consisting of mer e, 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, multiple 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 ed from dementia, frontotemporal dementia, mer’s disease and Parkinson’s disease.

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

H37} Embodiment 17. The stiblingnal composition according 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] ment lit. The sublingual composition according to Embodiment l7, wherein the composition is a film.

H39] Embodiment l9. The snhiingnal composition ing 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, n Dexm edetomidine or a pharmaceutically able salt thereot‘is administered at a dosage that treats agitation or the signs of agitation without causing significant sedation. {ll-ll] ment 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 according 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 rams to about 109 micrograms (e. g. about 5 micrograms to about 100 rams, about 5 micrograms to about U1 90 micrograms, about 5 rams to about 85 micrograms, about 5 micrograms to about 80 micrograms, about 5 micrograms to about ‘75 micrograms, about 5 rams 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 rams 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 micrograms), about 10 micrograms, about 12 micrograms, about l4 micrograms, about l5 rams, about l6 micrograms, about l8 rams, about 20 micrograms, about 30 micrograms, about 50 micrograms).

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

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

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

U46] Embodiment 26. The method according to Embodiment 24, wherein the neuropsychiatric condition is selected from the group consisting of schizophrenia, bipolar illness (eg. bipolar 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 t causing significant sedation.

B48] Embodiment 28. The method ing to any one of Embodiments 23 to 27, wherein Dexmedetomidine or a pharmaceutically able salt thereof is stered in form of a film, wafer, patch, e, gel, spray, tablet, liquid drops or the like. [lag] Embodiment 29. A method of treating 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 ures), and said method comprises administering to said subject sublingually an effective amount of Dexmedetomidine or a pharmaceutically acceptable salt thereof. [l50] Embodiment 30. A method of ng of agitation or the signs of agitation in a subject in need thereof, n said agitation is associated with an alcohol and nce abuse withdrawal and said method comprises administering to said subject sublingually an effective amount of Dexmedetomidine or a pharmaceutically acceptable salt thereof. [lit] Embodiment 31. The method according to Embodiment 29 or 30, wherein said etomidine or a pharmaceutically acceptable salt thereof is sublingually administered at a dosage that treats said agitation or the signs of agitation without causing significant sedation. [lSZ] Embodiment 32 The method according to ment 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 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 so micrograms, about 5 rams 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 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) rams (eg. about 5, a, ’7, 8, or 9 micrograms), about it) micrograms, about 12 micrograms, about 14 micrograms, about l5 micrograms, about 16 micrograms, about 18 micrograms, about 20 micrograms, about 39 micrograms, about 50 micrograms), $53} Embodiment 33 The ition or method according to any preceding Embodiment, n 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 Dexmedetomidine or a oharmaceutically acceptable. salt eof is administered in a manner that produces a eutic effect in less than about 60 minutes, ularly within about 30 s to about 30 minutes, U1 H.515} Embodiment 35. A method of ng 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 acceptable sait thereof. rise} ment 3a A method of treating ion or the signs of agitation in a subject in need thereof comprising administering to said subject an effective amount of an, 2 adrenergic agonist or a pharmaceutically acceptable salt thereof, wherein 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 agonist is in range of from about 3 micrograms to about 100 micrograms (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 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 rams, about 5 micrograms to about 40 micrograms, about 5 micrograms to about 35 micrograms, about 5 micrograms to about 39 micrograms, about 5 micrograms to about 25 micrograms, about 5 micrograms to about 20 micrograms, about 5 micrograms to about 15 micrograms, about 5 micrograms to about 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 ing to Embodiments 35, 36 or 37, wherein said subject is m animai, ably human. 3C) [l 59] Embodiment 39. The method according to any one of Embodiments 35 to 38, wherein said agitation, is associated with a neurodegenerative disease. {rec} Embodiment 40. The method according to ment 39, wherein said neurodegenerative disease is selected from Alzheimer disease, fronto—temporai dementia (ETD), dementia, dementia with Lewy bodies , post—traumatic stress disorder, Parkinson's disease, vascular dementia, ar cognitive impairment, Huntington‘s disease, multiple sclerosis, zl‘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 according to Embodiment All, wherein said neuropsychiatric ion is selected from schizophrenia, bipolar illness (such as mania, disorder), um, and depression. [l63] Embodiment 43. The method according to Embodiment 39, wherein the agitation is associated with n 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 re, bone marrow aspiration/biopsy, tooth extraction or other dental procedures), [rest Embodiment 45. The method according to any one of Embodiments 35 to 38, wherein said ion is associated with an l and substance abuse withdrawal [l 66] Zliimhodiment 46. The method according to any one of Embodiments 35 to 38, n said alphani’, adrenergic agonist include, but is not limited to, Clonidine, Gnanf’aeine, Guanabenz, Gnanoxahenz, Guanethidine, Xyiazine, 'l‘izanidine, h/liedetomidine, etornidine, Methyidopa, norepinephrine, Eadoirnidine lodoclonidine, Aprael oni dine, Detoniidine, Lofexidine, Antitraz, h/livazerol, Azepexol, Talipexol, Rilmenidine, Naphazoline, Oxymetazoiine, Xyiometazoiine, Tetrahydrozoline, 'l‘raniazoline, xole, Romitidine, propylhexedrine, el’rine, Octopamine, Moxoni dine, Lidamidine, Tolonidine, UKl4304, lid—714i, S‘Tw9l, RWQE—52353, TCG—lOOO, 4~(3- aminomethylncyclohexfi 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 cing the present invention, alternative or additional Embodiments may be provided.

Vii} . EEK/5tM PLES: The following 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 excipients 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 fluid—bed drier er ether suitable one such as tray drier. The dried granules are then sized riately in quadromeo—rnill er inulti-mill, The sized granules are then leaded inte a suitable r such as V-hlender and lubricated with ium stearate and Talc and then the final lubricated, blend is then used, fer compressing into tablets 0f specific dimensions using ia‘te reeling, Fermulatien 2: Stibdingiml Film Table 2: Com vesition fer a t" ieal Sub-linouel film fermuiatien used for sublin rial delivew 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 s Dexrnedetemidine hydrochloride aleng with t1l1n fanningpelvnrers and othe1 exeipients are dissolved / dispersed inte a pharmaceutically acceptable selvent rably water) and the resulting selution is then coated (spread / east) en an inert backing layer. Dexmedetonridlne liydreehleride containing polymeric layer is further dried. ted and cut inte suitable sizes using appropriate die toels and then packed as per the requirement.

Fermrrla’tien 3: SubwlirLual S rav Table 3: Corn esition for at ' ieal Sub—linoual s ra ' ferrnulatien used fer sublin atal rv Dexniedetornidine lrlCl (equivalent te base) microorarns Pmpylene Glycol l.0_ 40110/ Manufacturino 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 g.

They are further processed with, Metered nozzles so that a specified 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 gual tlelive Dextnedetemidine 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 tration or" ling/ml ef the sublingual drepsr Example 2: Evaluate the effect of suhlinguai and intravenous adrninistratien 0f Dexmedetemidine hydrochloride in rat ent—intmder’ rnedel nf agitation er aggression at varying dosages.

The resident“ intruder model is an established preclinical inedel ef aggression and ion? and allows spentaneeus and natural expressien ef heth Offensive aggressien/agitatien and ive hehavier in laboratory redehts in a semi l laheratory setting. When rodents are expesed te a novel male in their home cage environment, they ve the nevel male animal as an “intruder” and demonstrate a repertoire 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 intruder rats were hensed in greups of 3 with ether male rats of similar age/hedy weight. All animals were maintained in a centreiied nment 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 experiments were conducted in anee with the guidelines of the Committee fer the Purpese of Central and Supervisien 0f ments en Animals (CPCSEA), Government of lndia the Association for Assessment and Accreditation of Laboratory Animal Care international C).

Formulation tested: The required quantity (Al-"Formulation 4 of dexrn edetornidine hydrochloride was d 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. mental Procedure: Following atization for a period of 3 — 5 days) each resident male rat was housed with a female rat for 8 days. Qn day 8, basal sion in the resident males was tested by exposing them to an der rat” for l0 minutes. (lnly animals that 1E) demonstrated aggression in this basal aggression test were used for the study. These animals were then randomized using body weight stratification . The weight variation of the animals did not exceed 20% of the mean hotly weight in a group at the time of ization.

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 aggressive behavior in the nt animals After randomization, animals were assigned a permanent number. Cages were identified 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 Dexrnedetomidine hydrochloride (Dex) l5 minutes prior to the behavioral 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 ed 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 is 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 non—toxic paint. For analysing the potential effects of Dexmedetomidine hydrochloride on agitation, we quantified various behavioral parameters such as anogenitai sniffing, chasing, biting, attacking and y to attack as well as neutral behavioral parameters 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 * venods dosing * Formulation 4i ed to Dexnredetomitline hydrochloride l'oilowin doses in water or Normal saline Normal Control Vehicle control Vehicle control Dexmedetornidine hydrochloride detornidine hydrochloride Dexniedetomidine hydrochloride Dexmedetoinldine hydrochloride l,0t /l~:‘ (limo ‘ Dexmedetomidine hydrochloride Dexniedetomidine hydrochloride (l s) OSes/ks) Dexmedetornidine hydrochloride Dexrnedetornidine hydrochloride (30 its/ks) (3.0 its/ks) if! Statistical Analysis: Statistical analysis was med using validated statistical software (Graplil’ad Prism 6). Data is represented as Mean :: “EELM; Onewway ANOVA sis of variance) ed by “Dunnett’s le 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 nt~intrttder model of aggression 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 ors 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 non—resident male is perceived as intruder and the resident male gets agitated and attacks the intruder male to protect their home territory. in the present experiments, vehicle treated rats demonstrated a wide repertoire of aggressive 210 behaviors and the intruder rat was subjected to anogenital sniffing, . 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 related nranner (Figure lA, and Figure lB). Significant reduction was observed in chasing and attacking compared to vehicle control group. Similarly, intravenous administration 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 e controls was observed at doses ahove 0‘5 ug/hg (Figure ll: and Figure ill). Reference compound diazepam (filing/leg, in) also produced, significant reduction in all the indices of aggressive and agitated ors evaluated in this study (Figure l A— ll?) ll) Effect of gually/iutravenously administered Dexmedetomidine hydrochloride on latency to attack in addition to the change in frequency and duration of attack by the resident male, we also evaluated the effect of Dexniedetomidine hydrochloride (Dex) on the latency to attach the intruder rat, We observed an se in the latency to attack the intruder rat following suhlingual administration of Dexmedetomidine hydrochloride (Dex) in a dose related n indicating a reduction in sion and agitation (Figure 2A). When detomidine hydrochloride (Dex) was administered intravenously, a similar increase in the latency to attack the intruder rat occurred in a dose related fashion that was icant compared to vehicle controls at a dose of mtg/kg (Figure 28), Animals treated with diazepanr demonstrated a complete lack of ing behavior (Figure 2A and EB).

Effect of suhlingually/intravenously administered Derrmedetomidine hydrochloride on Neutral ors Neutral behaviors li l<e grooming, ation and inrnrohile/quiet time were assessed following treatment with Dexmedetomidine hydrochloride. No significant changes occurred in the grooming and exploration following suhlingual administration of Dexniedetornidine hydrochloride except a reduction in exploration observed at doses of l5 rig/leg & Bug/kg (Figure 3A and 33), ed to vehicle ls. Similarly, intravenously administered Dexmedetomidine hydrochloride did not significantly affect grooming and exploration in compari son to vehicle ls except at a dose of '3 ug/lrgln case of irnrn obile/ouiet time, there was no significant effect of suhlingually administered Dexniedetomidine hydrochloride ed to vehicle controls however, intravenously administered Dexinedetoniidine hydrochloride significantly sed the immobile/quiet time at a dose of 3 ng/ltg (Figure 3C, and Figure 3?). Reference compound Diazeparn (Sing/kg, in) significantly reduced the ncy and duration of all neutral behaviors evaluated in this study.

Interpretation U1 in the present study, we investigated the potential of Dexrnedetomidine hloride in reducing aggression and agitation in rat residentuintruder model. The residentwintruder model is an ished preclinical model of sion/agitation and allows spontaneous and natural expression of both ive aggression/agitation and defensive behavior in laboratory rodents in a semi natural tory setting. ll) 1. Suhlingual administration of Dexrnedetomidine hydrochloride resulted in a dose related reduction in several behavioral indices of aggression and agitation such as anogenital 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 administered Dexnredetornidine 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) effectively reduced the behavioral indiees of aggression and agitation t rnajorly impacting the neutral behaviors.

Conclusion: Dexniedetoniidine hydrochloride ively 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 ion without rnajorly impacting the neutral ors.

In the present study the efficacy of sublingually administered Dexniedetomidine hydrochloride correlates with intravenously administered Deninedetomidine hloride at these doses (Table to. p values obtained after statistical cornpari son of suhlinguai vs intravenous route of administration using Stud ent’s t—test Duration (sec‘ Chasing Biting /Fighting itah 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 sublingual and intraveneus mates} were ed in the duratinn at the helravieral indites at aggressien and agitatinn ing, biting, attack, anngenital sniffing latency tn attack} when ed between sublingual and intravennus u: mates {if dexniedetemidine liydrnelilnride adininistra‘tien at classes at l and 15 ugikg‘ Statistieal analysis was nei‘i’nrined using t tutest. 9 “peter “*ndlotltii and **‘*"’"‘p<tl.tlfil}l Suhlingual vs intraveneus rnutes of administration.

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 estimate Dexmedetemidine levels in rat plasma s obtained 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 dexniedetornidine, Demnecletemidine hydreehleride was administered sublihgually er enously 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 Dexrnedetninidine tratinn was analyzed.

Materials and methnds Preparation (ifstamiard min[ions A standard stock solution of dexrnedeteinidine hydreeliloride was prepared by dissolving 1.358nig of dexmedeteinidine hydreehleride in 1358 ill at rnilliuQ water to achieve a tratinn nf 829.07ln1g/ml g selutions at different tratinns were prepared by using diluent (inetlianel: water (50:50) % \r/vl.I 'l‘nlbutanride was used as an internal 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 eeneentratiens were prepared by using a diluent (:aeetenitrile: water (50:50) % w’y), Solution preparation t‘er SPE and tegraphy: Mehile phase A, ( l 0min arnni eninni fennate, pH 3 .50): 0.6306gms of ammonium ferniate was weighed and transferred to a lOOOrnl U1 t . To this, lOOOrnl ut‘rnilli a water was added and {ill at the resulting solutien was adjusted to 3.5 using fermie acid.

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

Wash selutien: lt‘iOul of arnnienia was mixed with 100ml 0f milli q. Resulting selutien was used as wash selntien Elutien 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 y ll 1-1916 system eeupled tn AB Seiex Triple Quad instrument (Alli—5000). Chrernategraphie separatien was done using Agilent Zorhax Eclipse 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 n. The M S instrument was operated in the positive mede (581+). For analysis, 2 2E) pL of sample was injected into the LOMS/"MS instrument. Auto sampler temperature was Quality l (QC) samples were prepared as following as per table 7: Table 7 """"{ Dtxmtaaamidm e “'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 sed.

Sample pretreatment: To 50rd of plasma, lOpl of amide working on was added (Tolhutamide 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 g 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 dges.

After loading pretreated plasma samples, cartridges were washed with l OOpl of G. l% ammonia solution. Finally, hound arialyte was eluted with 50rd of O. l% t‘onnic acid in itrile This step was repeated twice for complete eluti on. Final eluent volume was lOO pl... To lOO pL of eluent, 50 hit of lOmM ammonium formate (pH 3.5) was added samples were vortex mixed and transferred to a 96-well l-lPLC sample plate (Agilent) and suhmitted for LC—lVlS/lylS analysis. For LCnMS/lylS analysis, 2 pL of sample was injected. Calibration standards and QCs were processed the same way as done for study samples.

Mean plasma concentrations of etornidine in various rat plasma samples at various ti rne points was determined by l_,C~MS/MS method using Analyst l.6.2 software (Table 8 and Figures 4A and 43‘) with a ation 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 criteria 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 calibration 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 trations following Snblingnal or Intravenous 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 fication of the assay (LOQ: 0.05ng/ml) SL: sublingua ; iv: intravenous Data expressed as Mean i Si) interpretation and conclusion Following sublingual administration edetornidine hydrochloride, a dose~related effect on plasma concentrations was ed at doses ranging from 0,53 rig/kg (Figure 4A, table 8).

Following enous administration or" Dexmedetornidine hydrochloride, a dose—dependent effect on plasma concentrations 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 l behaviors. Plasma concentrations following administration of dose 0f '1 [nag/kg (Via snblinguai and intravenous mute) between '15 tn 30 min (time pnnding to the time ef‘nehavioral response observed in the efficacy study; drug administered 15 min prior tn agitatien hehavier test :32: animal nbsewed for 15min) range fmm 43 i {3.5 tn 90 i 12.1 pg/In} (Table 8), Similafiy, piaema concentrations fellewing stratien 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).

Claim l. A method of treating agitation or the signs of agitation in a subject comprising suhlingually stering to said subject an effective amount of BeXinedetomidine or a. pharmaceutically acceptable salt thereof without also causing significant sedation.

Claim 2. A method of treating agitation or the signs of agitation in a subject comprising sublingually administering to said subject an effective amount of Bexmedetomidine or a phannaceutically acceptable salt thereof, wherein the agitation is associated with a neurotlegenerative disease.

Claim 3. The method according to Claim 2, n the treatment is effective to suppress agitation or the symptoms of agitation in a sub} ect without also causing significant sedation.

Claim 4. The method according to Claim 2 or Claim 3, n said neurotlegenerative disease is selected from the group consisting of Alzheimer disease, frontotemporal dementia (Fill), dementia, dementia with Lewy bodies (DEB), post—traumatic stress disorder, Parkinson‘s disease, vascular dementia, vascular cognitive impairment, Huntington’s disease, multiple sclerosis, i‘eldt—lakoh disease, multiple system atrophy, and progressive supranuclear palsy.

Claim 5. The method according to Claim 4, wherein said neurodegenerative disease is selected from the group consisting of dementia, ii‘ontoternporal dementia, Alzheimer’s disease and Parkinson’s disease.

Claim 6. A method of treating agitation or the signs of agitation in a subject comprising suhlingually administering to said subject an effective amount of Dexmedetomidine or a pliarniaceutically acceptable salt f, n the agitation is associated with a neuropsyehiatric e~ Claim 7. The method according to Claim 6, wherein the treatment is effective to suppress agitation or the signs of agitation in a t Without also causimr icant sedationJ Claim 3. The method according to Claim 6 or Claim 7, wherein said neuropsychiatric disease i- selected from the group ting of schizophrenia, bipolar disorder, hipolar mania, delirium, and depression Claim 9. The method according to Claim l, wherein said Dexmedetomidine or a pliamiaeeutically acceptable salt thereof is administered sublingually in a dosage form selected from the group ting of a film, wafer, patch, lozenge, gel, spray, tablet and liquid drops, Claim lt‘i. The method according to Claim 2, wherein said Dexmedetomidine or a pharmaceutically acceptable salt thereof is administered sublingually in a dosage form selected from the group consisting of a film, water, patch, lozenge, gel, spray, tablet and liquid drops.

Claim ll. The method according to Claim 6, n said Dexmedetomidine or a pharmaceutically acceptable salt thereo‘l’is administered suhlingually in a dosage form ed from the group consisting of a film, wafer, patch, lozenge, gel, spray, tablet and liquid drops.

Claim l2. The method accordinrE; to Claim 1 wherein said Dexmedetomidine or a phamiaeeutically acceptable salt thereof is administered sublingually at a dosage in the range of about 3 rams to about lOO micrograms.

Claim £3. The method according to Claim l2, wherein said dosage is about 5 micrograms to about '30 micrograms, Claim l4. A sublingual composition for treating agitation or the signs of agitation comprising an effective amount of [Jenniedetomidine or a pharmaceutically acceptable salt f and one or more pharmaceutically acceptable carriers/excipients.

Claim l5. The sublingual composition ing to Claim l4, wherein said treatment is ive to suppress agitation or the signs of agitation in a subject without also causing significant sedation.

Claim l6. The sublingual composition according to Claim lél, wherein the agitation is associated with a neurodegenerative e.

Claim 17. The sublingual composition according to Claim l6, wherein said treatment is effective to suppress agitation or the signs of agitation in a subject without also causing significant sedation.

Claim lit. The sublingual composition according to Claim l6, wherein said neurodegenerative disease is ed from the group consisting of mer disease, frontotemporal dementia (Fill), dementia, ia with Lewy bodies (DLB), post~trauniatic stress disorder, llarlcinson's disease, vascular dementia, vascular ive impainnent, l-luntington’s disease, multiple sclerosis, Creutzfeldtulakoh disease, multiple system atrophy, and progressive supranuelear palsy.

Claim l9. The sublingual composition according to Claim l8, wherein said neurodegenerative disease is selected from the group ting of dementia, frontoteniporal dementia, mer’s disease and Parkinson’s disease.

Claim 20. The sublingual composition according to Claim l4, wherein the agitation is associated with a psychiatric disease.

Claim 2i, The suhlingual ition according to Claim 20, wherein said treatment is effective to suppress agitation or the signs of agitation in a subject without also g significant sedation.

Claim 22. The sublinpual com osition accordin to Claim 20 wherein said neuro :3) 9 svchiatric disease is selected from the group ting ol‘schizophrenia, bipolar disorder, bipolar mania, delirium, and depression.

Claim 23. The sublingual composition according to Claim 14, wherein the dosage form is selected from the group consisting of a film, wafer, patch, lozenge, gel, spray, tablet and liquid drops.

Claim 24. The suhlinoual com osition according to Claim 23. wherein said dosaoe form is a 22‘ v , 22‘ thin film.

Claim 25. The sublingual composition according to Claim 23 or Claim 24, wherein said film is niucoadhesive in nature and provides a quick, onset of aetion.

Claim 26. The suhlingual composition according to Claim l6, wherein the dosage form is selected from the group consisting of a film, wafer, patch, lozenge, gel, spray, tablet and liquid drops.

Claim 27. "The sublingual composition ing to Claim 26, wherein said dosage form is a thin film.

Claim 28‘ The sublmgual composition according to Claim 26 or Claim 27, wherein said film is mucoadhesi‘ve in nature and provides a quick onset of action.

Claim 29. The sublingual composition according to Claim 20, wherein the dosage form is selected from the group consisting of a film, wafer, patch, lozenge, gel? spray, tablet and liquid drops.

Claim 39. The sublinoual com osition ing to Claim 29. wherein said dosaoe form is a 22‘ v , 22‘ thin film , Claim 3l. 'll’ie sublingual composition according to Claim 29 or Claim 30, n said film is mucoadhesive in nature and, es a quick, onset of action Claim 32. The sublingual composition according to Claim 23 or Claim 24, wherein said composition comprises Dexmedetomidine or a pharmaceutically acceptable salt thereof at a dosage in the range of about 3 micrograms to about ltli) rams.

Claim 33 The subhngual composition according to Claim 32% wherein said. dosage is about 5 micrograms to about 39 micrograms.

Claim 34. The sublmgual composition according to Claim 26 or Claim 27, wherein said composition comprises Dexmedetomidine or a ceutically able salt thereof at a dosage in the range of about 3 micrograms to about 100 micrograms.

Claim 35. The sublingual composition according to Claim 34, wherein said dosage is about 5 rams to about 30 micrograms.

Claim 36. The sublmgual composition according to Claim 29 or Claim 39, wherein said composition comprises Dexmedetomidine or a ceutically acceptable salt thereof at a dosage in the range of about 3 micrograms to about 100 micrograms, Claim 37. The sublingual composition according to Claim 36, wherein said dosage is about 5 micrograms to about 30 micrograms.

Claim 38. The sublingual composition according to claim 14, which upon administration produces a therapeutic effect to suppress agitation in about 30 seconds to about 30 minutes Without causing significant sedation.

Claim 39. A sublinguai composition for treating ion or the signs of ion in a subject comprising an effective amount of etomidine or a pliatniaeetitically acceptable salt the reef, wherein said agitation is not periopeiative agitation» Claim 49. A method of treating agitation or the signs of agitation in a subject comprising siibiinguaily administering to said subject an effective amount of Dexmedetomidine or a. pitarmaceutically acceptable salt thereof, wherein said agitation is not periopei'ative agitation fimgfkuta“ k4" Diazepam; behavimg fl 3ugfkgg eé 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; ng Eii'fiex; \ ““ “‘ 54w“ Anagenifai ‘x... fi‘ifehicié «*1 m (:3 m 31‘: C3 m' m” m {3x} 5) EEGQLEE’SJHEE} flaggfign [Hn :3 Figure 1A. Effect Of subiinguaiiy administered Dexmedemmidiiw hydmchiaride (Dex) at varying doses (0.5— 3 pig/kg) 0n cumulative {iuratien 0f aggressive and agitated behavium.

Data exprsssed as Mean i SEM. Que—way ANOVA faliewed by Dunnett’s post—hot, tsst. *p<0.05 **p<0.01, “fir/4000} and 00001 VS ‘vehicie Ci‘mtmis (which).

BmgIkg; Diazegam; ars figfig; agiiaiefi. [E am U". aggzfleggive LU {22? M Frequency :23 Sniffmg is Anageraé‘tai LU {ii} smgma‘g‘ag gamgfig gm: aims 33.3.8332 gs} fiaugnbmg Figure EB, Effects: 9? saabiinguaiiy administered Dexmedemmidine hydrochiaride (Dex) at varying 010565 {06- *‘r .: gig/kg) (m ncy 0f aggressive and agitated hethaviers. Data expressed as Mean :: SEM. fine—way ANOVA faliewed by t’s pestmhoc tsst. *p<0.05 ** <00}, *** <000} and ”*3“ p p p<0.00()1 vs which} controls (\iebicie‘s.1 Etngfkg; *iazepam; hehavmm1 Ki Engikg; {flied {3‘2‘3 ESSEX; am? N ,'g/f:g; %"? ' gym flex; 3g fi a? n: immiafi 1::ng i mam; EVE? W umuia?‘ { fing 5m E3209x;8f3:1gfl>:g; Anaganiitai fi‘dehéde M M {33:53} imaging} :m‘g::§::§‘amn;} Figure 1C. Effect 0f intravenmmiy administered Dexmedetumidine hydmchfiuride (Dex) at varying (10363 (035— 3 ) on cumuiative duratian of aggressive and ed ers. Data expressed as Mean i SEEM. One~way ANOVA folicwed by Dunnett’s pest~ hm: tesi; **p<10.05 W134101a ***:J<G.OO£ and ****p<030001 vs \Ishicle controls (vehicle). 3.;9. 3mgfkg; Efiiazemm; 1. ZB’W‘EM‘S Iflzgfkg; E3221 Dex; mm} W 21g}? Cugfhg; 31’“ § _ 18):; oSSE“? aggm 5:35 23f - ., fi‘aqmmy :; 1.4": Sniffing x [Kai a: s. y} 1:) {D m N {a} s-mgmqmg Emmag‘éfi: pm: my 5 mafia! g6 g Figure 11)., Effect of intravenmusiy administered Dexmedemmidine hydmchluride (Dex) at varying 60385 (0.56 gig/kg) am frequency of aggressive and agitated ars. Data expressed as Mean :: SEM. One—way A’NQVA fflflowed by Dunnett’s postuhec test. *p<0.05 * *p<0.0 L * * *p<0.001 and * * * *p<0.0001 vs Vth (:16. ois (vehiclé), mm; W: gaze i A r5-."’ ‘.‘....‘....‘ ' z a 2..t mL flag/k5!A E.\\\\\\\\\\\\ zigl’kg; $373 “v.) a.» 111 3 Si $59; fl.;lg;g’i::g; $23 Si.

‘W g; 1343: flex; ,,If §.\\\\\\\\\\\\\ mi f {mm} imam: {ii mafia-:63 Figure 2A. Effect {if nguaiiy administered Daxmademmidine hydmchiuride (DEX) at g (leases (0.5— 3 gig/kg) m1: Latency to attack. Data is expressad as Mean 2%: SEEM.

Statistical analysis was perfarmed, by Onemway ANOVA fellowed by Dunnet‘t’s past—hoe test. *p<0.05 *i‘p<0,01y *Wp<0.00l and ****p<0.000l vs vc-jhicle controls (vehicle). m; ML £333 Emgfkg; .3? Egagfkg; pg LSngk’i‘; m W m 2:; a\\\\\\\\\\\\\\ I. . 223K; g? 2? 9*. 134%? fi W was . :\““““‘“ ax; :rIF 5ggfk}; Vehicie 6*; a E: ”.5 at: was“ {332 s} warm: {3; ééztaamm Figure 28. Effect Gf eneusiy administered Bennedgwmidine hydmchfiflride (Dex) at varying doses (0.53 gig/kg) (m Latency to attack. Data is expressad 213 Mean r}: SEEM.

Statistical analysis was performed by Onewway A’NQVA fcfllowed; by Dunnett"s past—hoe test. *p<0.05 ”$1001? <10.001 and ****p<0.0001 vs cle controls (vehicle). 37/14 'LK.Q‘J Expieratian fl iflffii (flag;_rr. o M._,I‘j.

Eieimv Ebexv' memes}! ifiugfikg; Q Dex; § ea him: 91 IV? “ling/kg; (female? £864; Grelomimg ‘31 afiggfkg; flit?.; N r“: {we} ixewzseaip maegmmm Figure 3A. Effect 9f saibiinguaiiy administered Dexmedetemidine hydreehleride (Dex) at varying doses (0.5—3 gig/kg) en Cumuiative dumtien ei" l behaviours each as greeming, and expiemtion, Data expressed as Mean 2% SEM. Data is expressed as Mean i SEEM. Statistical analysis was performed by One—way ANOVA foliewed by Bennett’s pest— hee test. *p<0.05 **p<0.fil, .GOI and; ****p<0.0001 vs vehicle e0nt1‘eis(vehicie).

Bmgjy’kg; iazepam; on 3 g): Begin; oEVE} H9691; :34 iSwi’Kg, :3 £02m; 3...; Q 8L :31“. fl , fii iugj'ézg; Q) a Fin: Bee; L58: E Grooming eg; ’7 flk’ehécie {a} magmas; gmmw 31} mueflmeg Figure SB. Effect Of subfiinguaily administered emmidine hydroehieride (Dex) at varying defies (0.5—3 gig/kg) 0n Frequency 0f Neutrafi hehavieurs such as greenfing, and expioratien. Data expressed as Mean r}: SEM. Data is expressed as Mean it SEW. Statisticai anaiysis was performed by {)neeway ANQVA foiiawed by Dunnettfis post-Ewe test. *pK’SOOS **p<0.0L ***p<0.001 and ****p<0.0001 VS vehicle controls (vehicle).

§.\\\\\\\\\\\\\\\\\\\\\\ E Dex; W} I‘M (“xi v4 W4 {33$} emu; Figure 3C. Effect 9f satbiingualiy administered Dexmedetemidine hydreehleride (Dex) at g deset (0.56 gig/kg) mt Neutrai behavieurs such as immebiEe/quiet time. Data expressed; as Mean i SEEM. Data is expressed as Mean 1 SEM. Statistical analysis was pertbmxed by One—way ANOVA feliowed by Dunnett’s pest—hoe test: *p<0)05 **p<<0.0L *** <0001 and **** P p«3.0001 vs vehicle s vehicle). /14 24:). 4;. l! Brztgfiaz Diammm; by“! nggfkg; $551 Dex; £79 Li; m W $31 ifiugfkg; E Sex; Q a ‘1'”? 235 W a iggfkg; E3 321K; :5 fl rimming W {-3 CEngkg; vghide N V“: {3333‘ magma? mggaégmu'n;} Figure 31). Effect of intraveimusly adminifimed Dexmedemmidiiw hydrochiaride {Dex} at varying (£9563 (0.5—3 pig/kg) (m ive duratian (3f Neutrai behaviwrs such a3: gmaming and expimatian. Data Expressed as Mean :: SEM. Data is expressed as Mean :: SEEM. tical analysia was perfarmed by fine—way ANOVA faiiawed by Summit’s post— hoc test. *p<0.05 **p<0.01, .001 and, ****p<0.0001 vs vehicle contrals (vehicle). 11/14 i. CE behav :19 neutral Le Frequeney 4; 93% IBE- m :3, L 'flE} FEDEX; ‘iehéeie 1:) (2| t2} I23 (:31 Kt: m N": N {u} Megmztgm mama; $3 iamnfimgfi Figure 3E Effect 0f intraveneusiy administered Dexmedemmidine hydmehfieride (Dex) at varying deses (OS—3 gig/kg) {m Frequency 0f Neutrai behavieurs such 2m greeming, and expiemtien. Data expressed as Mean i SEEM. Data is expressed as Mean 1 SEM. Statistical analysis was perfemled by One—way ANOVA fbllewed by Dunnefi’s postmhee test, *p<0.05 **p<0.01, ***p<0.001 and ****p<0(0001 vs vehicle controls (vehieie) 12/14 g““““““““ . g Ci). ("Q C?! V L3“: m ,7 ‘2»! m“: (”<4 (\1 N {335} 3331331; Figum 3?. Effect {if intraveimiisiy administered Daxmedemmidina hydmitiiiiiride (flax) at varying 605% (0.543 gig/kg) (m Nautmi ours with as immubiie/quiet time. Data expresged 213 Miami SEMh Data is (expressed as Mean ria- SEM) Statistical anaiysis was perfm‘med by One~way ANQVA ffliiowed by Dunnett’s pastuhoc test. *p<0.05 **p<0.01, ***p<0.001 and ****p<0~0001 vs e GOEU‘OiS (vehicle) 13/14 a {min} ”Kim? «&~fi\\\\3'33 .\ \ .,\\ :' 3 fi 3 a g a a m N N M m gmgé‘fisfi' {gaygmgimmmg Figure 4A: Mean plasma conmmtmtiuns faliawing ngual (SL3 Dexmedemmidina hydmchinridc administratien in rats. Data, expressed as Mean r}: 31) 14/14 ? § mix mw as.“ 22$.“ €333 m if: am; 3%. m M M m 531%.»!‘4 ‘ $3!” > \\“““““~ @ 3 8 g g g g m m m 8:: m N M Emigd ismgmmmumge Figure 43: Mean piasma cmmemmtiflm f‘aiiawing Entravmmm (IV) Dexmgdemmidine hydrachiaride administratinn in rats. Data expressed as Mean :: SD