NZ753804A

NZ753804A - Use of sublingual dexmedetomidine for the treatment of agitation

Info

Publication number: NZ753804A
Application number: NZ753804A
Authority: NZ
Inventors: Krishnan Nandabalan; Sameer Sharma; Frank Yocca
Original assignee: Bioxcel Therapeutics Inc
Priority date: 2016-12-31
Filing date: 2017-12-29

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 alpha-2 adrenergic agonist, more particularly Dexmedetomidine, 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 pharmaceutically 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 pharmaceutically 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

WO 2018/126182 PCT/US2017/069030 Use of Stihlingual Derrrnedetorriidine for the treatment of Agitation FIELD (BF T INVENTEON [ll The present invention discloses an inetliocl of treating agitation or the signs of agitation in a subject comprising sublingually administering an effective amount of an alphaml adrenergic agoni st, more particularly l}e> CROSS REFERENCE TU RELATED APPLECATEGN [2] This application claims the benefit of priority to US. Provisional Application Serial No. 62/'4-4-l,l64 tiled 3l December, 20l6, US. Provisional Application Serial No. 62/I-'l7l,393 tiled l5 l\/larcli, 20l7 and U l’rox/isional Application Serial No. 62/542,323 tiled 8 August, 2017, the disclosures of which are herein incorporated by reference in their entirety for all purposes.

BACKGRGUND GE THE INVENTIGN [3] Agitation is an umbrella term that can refer to a range of behavioral disturbances or disorders, including aggression, cornbativeness, hyperactivity, and (.ll,Sll"lllll)lllOIl,. Agitation is a nonspeciﬁc constellation of relatively unrelated behaviors that can be seen in several different clinical conditions, usually presenting a fluctuating course. Agitation maybe caused by several different medical conditions and drug interactions or by any circum stances that worsen the persons ability to think. Multiple underlying pathopliysiologic abnormalities are mediated by dysregulatiions of dot3ai’ninergic, serotonergic, noradrenergic, and GABAergic systems; Agitation is characterized by non—prodnctive, diffuse and excessive over—activity both motor (al<,a.tliisia) and cognitive, and accompanied by an inner unpleasant tension, The lcey to safety is to intervene early to prevent progression of agitation to aggression and violence. {4} Agitation can lie associated witli nenrodegenerative disorders, Qne of the important manifestations of long—terin progressive neurodegenerative process is clinically known as dementia. Dernentias include Alzheimer's disease dementia (AD), Frontmtemporal dementia (F'l‘D), Vascular dementia, Lewy body disease (LED), and Down dernentia. Dementia in WO 2018/126182 PCT/US2017/069030 adults, gradually destroy a person’s rneniory and ability to learn, reason, make judgments, cornniunicate and carry out daily activi‘ties. In later stages, patients may experience changes in personality and behavior‘, such as anxiety, suspicion, agitation and aggression. [5] Sebastiaan gelborghs et al ., in l‘l6Uf0€5ll,€Il’1lSl.'Ij/ international 2007 Nov, 52(6): l052— 60, disclosed that, in frontoternporai dementia, increased activity of dopaminergic neurotransmission and altered serotonergic modulation of dopaniinergic neurotransniission are associated with agiltated and aggressive behavior respectively. Pia lul et al., in Journal of Alzheimer’s disease 20l5 Sep, Ll-9{_3):‘783—95, disclosed that rTg/l-5li_"i mice exhibited P30lL— tau—depe.rident hyperacti.Vity, and agitation.-like phenotypes in these mice may form a correlation to some of the behavioral disturbances obseiyed in advanced Alzheimer’s disease (AD) and Frontoteiriporal. denientia (ETD). Natlrian l-lerrnann et. al., in Journal of Neuropsychiatry 2004 Aug, l6(3): 2ol—2"/'6, disclosed that a cornpensatory increase in activity within the noradrenergic system may contribute to the behavioral and psychological syrnptorns of agitation and aggression in Al.zheimer’s disease. is} 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 associated with alcohol and substance abuse 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 psychiatric disorders, including schizophrenia and bipolar mania, and may escalate quickly to aggressive behavior. Acute agitation characterized by signs that include pacing, hand wringing, fist clenching, pressured speech, yellin and threatening people with escalated agitation. {7} To date, there is no single medication considered the "sta.ndard of care" for treating agitation in patients with dementia or schizophrenia. Generally, three classes of medications are used most frequently, depending on the severity of the agitation, namely tirst-generation antipsychotics, second-generation antipsychotics, and benzodiazepines, administered orally, intrarnuscularly or intravenously. lntrarnuscular 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 currently prefei'red treatment paradigrn for acute agitation is to use atypical antipsychotic drugs administered with or without supplemental benzodiazepines. {8} More specifically, patients with agitation. are usually prescribed beta blockers such as propranolol and Pindolol, anxiety medications such as Buspirone, henzodiazepines such as Lorazepain, anti-convulsants such as Valproate and Larnotrigine, iillll-pSyCl’lOtlCS such as li-ialoperidol, Droperidol, Ziprasidone and other high-potency dopaniine—hlocl«:ing agents, and WO 2018/126182 PCT/US2017/069030 atypical antipsychotics such as Glanzapine. However, Buspirone, Valproate, Haloperidol, Droperidol and Ziprasidone have potential adverse effects, and optimal dosage and long-term efficacy in the management of chronic agitation in dementia is very limited. Lorazepani is only elfective for treating agitation in patients when used before medical procedures. Loxapine (an £1ll’tlpS§/Cll0’liC:) is FDA approved for treating agitated patients via. inhalation, but is associated with a black box warning for bronchospasm and increased mortality in elderly patients with denientia—related psychosis (FDA. label, Loxapine or Adasuve®). Olanzapine, Ziprasidone or its combination with Haloperidol, is also associated with QT prolongation, 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 t‘ol.low strict prescribing guidelines and avoid si.rn.ultar1eous use with other CNS depressants. {9} The Expert Consensus Guidelines for treatment of behavioral emergencies cite speed of onset as one of the most iniportant factors in choosing a drug and its route of 2iClI}’1ll’1l,S’lI'£il',lO1'l, However, antipsychotic medications can talre from days to weelts before having a roliust antipsychotic effect. Nevertheless, they do generally have a calniing effect on agitated patients within minutes. For example, henzodiazepines or l‘a,st-acting sedatives quickly calm a severely agitated patient, but continuous treatnient with these drugs leads to tolerance.

{Ml} Therefore, the treatment of agitation. in patients with neuropsychiatric conditions (such as schizophrenia or bipolar mania) and neurodegenerative diseases is still limited because of the potential for signiticant side effects associated with currently used drugs, their route of atlniinistration (intravenousfintramuscular) and the consequent need for hospital set ups for administering these drugs. in an ideal. situation, an antiegitation 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. ll ll including hypertension, congestive heart failure, angina pectori s, spasticity, glaucoma, diarrhea Alphafl adrenergic agoni sets have been used thera.peutically for a number of conditions, and for suppression of opiate withdrawal syrnptorn s. EX3.li’l1'.ll€3S ofalplia—2 adrenergic agonists Clonidine, Guanfacine, Guanabenz, Guanoxabenz, Guanethidine, Methyldopa, include Xylazine, Tizanidine, Medetoi'nidine, Dexniedetornidine, Methylnorepinephrine, Fadolrnitline, lodoclonidine, Apraclonidine, Detornidine, Lofexidine, Aniitraz, Mivazerol, Azepexol, Talipexol, Rilrnenidine, Naphazoline, Oxyn1eta.zoline, Xyloinetazoline, 'l‘etraliydrozoline, Trarnazoline, Talipexole, Rornifitline, propylhexedrine, Norfenefrine, Octopamine, Moxonidine, Lidainidine, Tolonidine, UKl43i’.‘:-4, D3-71-41, ST—9l, RWL52353, 'l7CCé-ltlllt), 4~(3—arninornethyl—cyclohex~3-enylmethyl)»l,3—dihydro~irnidazole—2—thione, and WO 2018/126182 PCT/US2017/069030 4—(l3 —hydroxym ethyl—cyclohex—3 uenyl methyl)» l , 3 ~dil1ydro—imidazole-2—thione. The inventors of the present invention have unexpectedly found that the sub—lingual adrninistration of an alpha—2 adrenergic agonist or a pharniaceutically acceptable salt thereof is a particularly effective and safe intervention for the treatment of agitation, {l2} (S)—4—{ l —(2,3 —l)irnethylphenyl)etliyl}~3l-l—iniidazol e (Deronedetoniidlne) is commercially available as an injectahle forrnulation for sedation of initially intuhated and rneclianically ventilated patients during treatnient in an intensive care setting, and for non- intuhated patients prior to and/or during surgical and other procedures. ll3l intravenously or huccally during surgical procedures and intensive care unit (_lCU) setups. For Dexn'1edetornid.ine is reported to have anti—agitational et'fec’ts when adrn.inistered ex.an:iple, Ibacache et, al.., in A.nesthesi.a& Analgesia 2004 lan_;98(1):60~3, discloses the administration of an intravenous single—dose of Dexnredetornidine to reduce agitation folliowing sevoflurane anesthesia in children. Other intravenous £l(ll"Il,iI1lSll‘€t.lLl,O1'lS are reported by leanne Boyer et al., in Nursing Critical care 20'l 0 Jan, 5{_l):30—34, Yahya Shehabi et. al., in Anesthetic Intensive Care 2010 Jan, 38(l):82—9i_":, and Joseph D. Tobias in Journal of Pediatric l,3’l‘13.l'lT12lCOi(')g‘y Therapeutic, .i‘an—Mar 20l0, l5(l); 43~~~48. NC!‘ 02720705 (clinical trial identification nurnher from cliniealtrialsgov) discloses the administration of transhuecal l)exnredetornidine for the prevention of emergence agitation in preschool children treated with sevoflurane in an intensive care unit setting.

{E4} The sublingual use of lZ‘a‘exrned.etorni dine is disclosed in WC 20l6/06l_4l3. However‘, the focus of WO Z2016/O6 Mi 3 is the adrninistration of Dexinedetoniitline suhlingually at doses appropriate to treat sleep disorders and induce gniticant seda.ti.on. We have now surprisingly l‘"ound that Dexrnedetornidine or a pharmaceutically acceptable salt thereof, adrninistered sublingually, can effectively treat agitation, including agitation associated with neurodegenerative diseases (eg. Alzheiineﬁs disease, fronto-ternporal dementia, and sundown syndrorne in Alzheiniefs disease/’dernentia), agitation associated with neuropsychiatiic conCli‘tioris (eg. bipolar disorder, SCi1lZO[)l1I'€l"li,E1, bipolar rnania, delirium and depression), agitation associated with alcohol and substance abuse withdrawal or agitation associated with other conditions such OPD,/lPl) procedures (eg. l\/,lRl, CT or CAT scan, lurnhar puncture, bone marrow aspiration/biopsy, tooth extraction or other dental procedures). The dose to be administered sublingually may be selected to he ellective to treat agitation, yet insut"tici.en.t to causing significant sedation.

WO 2018/126182 PCT/US2017/069030 SUM i‘tilAR‘r’ (3 E4‘ TE- EIC ENV'Ei‘l'E‘E(}i‘*l [E 5} 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 an aipha—2 adrenergic agoni st or a pha.rn:iaceuticaily a.ccepta.ble salt thereof sublingoaily to the subject, wherein the said agitation is associated with a neurodegenerative disease like dernentia, Aizheinier’s disease, frontoternporal dementia, or Parkinsonisrn, or associated with a neuropsychiatric condition like schizophrenia, bipolar disorder, bipolar mania, delirium, or depression, or associated with an OPD/IPD procedure (e. g. NR1, CT or CAT scan, lumbar puncture, bone marrow aspiration/‘oi.opsy, tooth extraction or other dental procedures), or associated with an alcohol and substance abuse withdrawal. in a particular aspect, the agitation is suppressed without also causing sign.iticant sed.a.ti.on. [i 6} in a preferred aspect, the present invention provides a method of treating agitation or the signs of agitation in a. subject in need thereof, comprising administering an effective arn cunt of Dexrnedetoinidine or a pharinaceuticaliy acceptable salt thereof subiingually to the subject. in a particular aspect, the agitation is suppressed without also causing significant sedation.

U7} Another aspect of the present invention provides a method of treating agitation or the signs of agitation in a subject in need thereof, wherein said agitation is associated with neurodegenerative disease, comprising adrninistering an effective amount of Dexniedetoniidine or a pharmaceutically acceptable salt thereof suhlinguaily to the subject. in a particular aspect, the agitation is suppressed without also ca.u.sing signiticant sedation. [i 8} Yet another object of the present invention provides a method of treating agitation or the signs of agitation in a. subject in need. thereof, wherein. said agitation is associated with Aizheimens disease, dementia, Parl«:insonisrn or other dementia, frontoternporai neurodegenerative diseases, comprising administering an effective amount of Dexinedetomidine or a pha.rrnaceuticaliy acceptable salt thereof sublinguaily to the subject. in a particular aspect, the agitation is suppressed. without also causing significant sedation. {l9} Another object of the present invention provides a method of treating agitation or the signs of agitation in a subject in need thereof, wherein said agitation is associated with schizophrenia, bipolar disorder, bipolar mania, deliriurn, depression, or another related neuropsyehiatric condition, comprising administering an effective amount of Dex.rnedetoinidine or a phan:naceuti.caliy acceptable salt thereof sublinguaily to the subject. in a particular aspect, the agitation is suppressed without also causing significant sedation. id="p-20" id="p-20"

[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 WO 2018/126182 PCT/US2017/069030 with sundown syndrorne in Alzheirner’s disease/denientia, comprising administering an effective amount of Dexmerietomidine or a phanniaceu‘ticaily acceptable salt thereof sublingually to the subject. ln a particular aspect, the agitation is suppressed without also causing signiﬁcant sedation.

{Z1} Yet another objective of the present invention provides a method for treating agitation or the associated with agitation in a subject in need thereof, wherein said agitation is a.ssociated with an {)PD./{P13 procedure (eg. MR1, CT or (.‘,A’l7 scan, lumbar puncture, bone marrow aspiration/biopsy, tooth extraction or other dental procedures), comprising administering an effec‘ti.ve amount of D€X]’I1€d€:l‘0I}'1idi.I’l€ or a pharmaceuticaily acceptable salt thereof suhlingually to the subject. in a particular aspect, the agitation is suppressed without also causing signiii.can_t sedation. {:22} Yet another objective of the present invention provides a method for treating agitation or the signs associateri with agitation in a subject in need thereof, wherein said agitation is associated with an alcohol and substance abuse withdrawal, comprising aclrninistering an effective amount of Dexrnedetoniitiine or a pharinaceuticaily acceptable salt thereof suhlingualiy to the subject. in a particular aspect, the agitation is suppressed without also causing signiﬁcant sedation.

{Z3} A. further aspect of the present invention provides a suhiingual composition for treating agitation or the signs of agitation in a subject in need thereof, wherein said agitation is associated with a neurodegenerative disease, and said sublingual. coi:npositi.on comprises an effective amount of Dexrnedetoniidine or a pharmaceutically acceptable salt thereof, together with one or more phannaceutical. acceptable carriers and/or e,\:cipien‘ts. {.24} Another aspect of the present invention provides a suhlinguai composition for treating agitation or the signs of agitation in a subject in need thereof, wherein said agitation is associated with schizophrenia, hipoiar disorder, bipolar mania, deiiriuin, depression, or another related neuropsychiatric condition, and said sublinguai composition comprises an effective amount of D€XIYlt3.d€fOﬂi1idi,!lt3 or a pharrriaceuticaily acceptable salt thereof, together with one or more phannaeeuticaily acceptable carriers and/or excipients.

{Z5} An additional aspect of the present invention provides a sublinguai composition for treating agitation or the signs of agitation in a subject in need thereof, wherein said agitation is associated with sundown syndrome in Alzheiitnefs disease,/dern.en.tia, and said sublingual composition comprises an effective amount of Dexniedetornitline or a pharmaceutically acceptable salt thereof together with one or more pharmaceutically acceptable carriers and/or excipients.

WO 2018/126182 PCT/US2017/069030 {.26} Yet another aspect of the present invention provides a sublingual eornposition for treating agitation or the signs associated with agitation in a subject in need thereof, wherein said agitation is associated with an CPD/’lPD procedure (eg. MRI, CT or CAT scan, lumbar puncture, bone niarrow aspiration./biopsy, tooth extraction or other dental procedures), and said sublingual composition comprises an e'fl’ective amount of Dexmecletomidine or a izsliarinaceutically acceptable salt thereof together with one or more pharmaceutically acceptable carriers and/or exeipients. [27} 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 alcohol and substance abuse withdrawal, and said sublingual composition. comprises an et‘.t‘ective amount of lT>exrn.edeton1i.dine or a pharmaoeutioal.ly acceptable salt thereof together with one or more pliarinaceutically acceptable carriers anal/or‘ excipients. {.28} Another object of the present invention provides a sublingual eoinposition comprising an effective amount of Dexrnedetoinidine or a pbarrnaceutioally acceptable salt thereof together with one or more phar'rnaceutica,lly aeceptaible carriers arid/or exoipients, wherein said sublingual composition is selected from the group consisting of a film, wafer, pateh, lozenge, gel, spray, tablet, liquid drops or the like id="p-29" id="p-29"

[29] A further object of the present invention provides a method of sublingually administering an eft‘e<:ti.ve amount of Dexn1edetorn.idine or a. pharmaoeutieally acoepta.ble salt thereot‘ to a subjects oral mucosa to treat agitation or the signs of agitation at a dosage which does not cause signi.ti cant sedation BO} ln a particular aspect of the invention, the dosage aclministererl sublingually may conveniently be in the range of between about 3 rnierograrns to about l:_"iO micrograms, Examples of suitable dosages include: about 5 micrograms to about 100 rniorograrns, about 15 micrograms to about 90 micrograms, about 5 micrograms to about 85 niierograins, about 5 rniorograrns to about 80 micrograms, about 5 micrograms to about 75 miorograrn s, about 5 rnicrograms to about 70 niiorograins, about 5 niiorograms to about 65 micrograms, about 5 rnicrograms to about 60 micrograms, about 5 rniorograms to about 55 microgranis, about 5 niicrograins to about 50 micrograms, about 5 inicrogranis to about 45 niiorograins, about 5 miorograrns to about 40 m.ierogran'1s, about 5 micrograms to about 35 niicrograrns, about 5 micrograms to about 3t‘: micrograms, about 5 micrograms to about 25 micrograms, about 5 rnicrogranis to about 2:’) micrograms, about 5 niiorograrns to about l5 micrograms, about 5 rnierograins to about l0 rnicrograms, less than l0 micrograms (eg about 5, 6, 7, 8, or 9 WO 2018/126182 PCT/US2017/069030 micrograms), about 10 micrograms, about 12 micrograms, about 14 micrograms, about l5 mierograrns, about 16 micrograms, about 18 micrograms, about 20 microgra.ms, about 36 nticrograms, about 50 micrograms. The dose may be administered one or more times a day.

BRIEF BESCREFTEGN OF THE DR_r’§i‘WING-S lligure lA. Effect of sublirigually administered Dexrnedetomidine hydrochloride (Dex) at varying doses (0. 5» 3 pg/kg} or: cumulative duration of aggressive and agitated behaviors. Data expressed as Mean —.-l.-. SEM. One-way ANOVA, followed by Durmetfs post~lioc test. *pO01 vs vehicle controls (vehicle).

Figure 1B. Effect of sulilingually administered Dexniedetomidine hydrochloride (Dex) at Varying doses (0.53 3 .ug/ltg) on frequency ot‘aggressiye and agitated behaviors. Data expressed as Mean i SEM. One—way AN{)VA followed by Dunnetfs post~hoc test. *p<.{l.O5 **p<0.0l, <0.0:_":l and <0.0001 vs vehicle controls (Vehicle .

P l3 Figure lC. Effect of intravenously administered Dexmedetomidine hydroeliloride (Dex) at "varying doses (O.5- 3 rig/kg) on cuinulative duration of aggressive and agitated behaviors. Data expressed as Mean i SEM, O1‘lt3-‘Way ANOVA followed by Dunnetfs post—hoe test. **p<0.05 ** ;><0.0'l, ;i<0.0{l1 and I3 P Figure 2A. Effect of sublingiially administered Dexmedetomidine hydrochloride (Dex) at Varying doses (O.5~ 3 pg/kg) on .‘l_,atency to attack. Data is expressed as Mean Sl3l‘vi Statistical analysis was performed by One~way ANOVA followed by Dunnetfs post—l1oc test. *p Figure 2B. l?;i’i"et:t of intravenously admiriistered iltexmiedetornidine liydroeliloride (Dex) at varying doses (GS-3 lug/’l WO 2018/126182 PCT/US2017/069030 Figure 3A. Effect nf snblingnally administered Dexmedetcmidine liydrochleride (Dex) at varying doses (O.:">—3 rig/kg) on Cumulative duration of Neutral behaviors such as grooming, and exploratien. Data expressed as Mean i SEM. Data is expressed as Mean :t SEM. Statistical analysis was performed by One-way ANOVA fellewed by Durmetfs pest-hoe test. *p()01 vs vehicle controls (vehicle).

Figure 38. Effect of sublingually adininistered Dexrnedeteinidine liydrcchleride (Dex) at varying doses (:_":.5—3 gag/lrg) on Frequency of Neutral behaviors such as grooming, and explr>ra.tion Data expressed as Mean ri: SEEM. Data. is expressed as Mean .-.t SEM. Statistical analysis was performed by One—way ANOVA followed by Durmetfs post—hoc test. *p<0.(‘:5 *"‘p‘ Figure 3C. Effect of su.blingua.lly administered Dexrnedeteinidine liydrochleride (Dex) at varying doses (0.56 ug./'l<:g) on Neutral behaviors such as immebile/quiet time. Data expressed Mean rt.-. SEEM. Data is expressed as Mean rt.-. SEEM. Statistical analysis was performed by One- way ANDVA followed by Dunnett’s post—liec test. *p<0.05 **p<0.0l, *""*p<0.00l and ****p Figure 3D. l?,ffect er‘ intravenously administered Dexrnedetomi dine l'1jy’£lE‘OCl’ll0I'ldt.’. (Dex) at varying doses (0.5-3 pg/leg} on Cumulative duration of Neutral behaviors such as grooming, and e.xpleration. Data expressed as Mean :t: SEM. Data is expressed as Mean rt: SEM. Statistical analysis was performed by ()ne-way AN‘()\/’A followed by Dunnett’s p0st—hec test. *p Figure 3E Effect of intravenously administered. Dexrnedeteniidine hydrochleride (Dex) at "varying doses (0.5-3 pg/kg) on Frequency of Neutral behaviors such gleaming, and exploration. Data expressed as Mean i SEM. Data is expressed as Mean i SEM. Statistical analysis was performed by ()ne-way AN'()\/’A followed by Dunnett’s post-hoc test. *p<0.05 **p<.0.0l, ***p<0.0{)l and ****p<0.000l vs vehicle centrnls (vehicle).

Figure 3F. Effect ef intravenously administered Dexrnedeteniidine hydrnchleride (Dex) at "varying dcses (O. 53: pg./kg) on Neutral behaviors such as immobile/quiet time. Data expressed as Mean i SEM. Data is expressed as Mean 2% SEM. Statistical analysis was performed by One» way AFEOVA followed by Dn.n.nett’s post-hec test. *p<0.05 **p<0.0l, "‘*"*p WO 2018/126182 PCT/US2017/069030 Figure 4A: Mean plasma CGﬁCE3l‘1ti"€i’EiO‘€’lS feiiowiiig Subiiriguai (SL) Dexmedetomidme hydr‘oci'1}cr'iide adrrﬁnistration in rats. Data. expressed as 'Mear1:~E.- SD .Fi.gux'e 4B: Mean plasma. C0r1c:r.2ritratioris following iritravenous (IV) Dexrn.c:det0mi.dirie hydrochleride adinmistratioii in rats. Data. expressed as Mean -3?: SD BETAILED DESCRIPTEQN GET THE INVENTEGN E. ABBREVIA'I‘}I{)NS: The foiiriwing e:i'sbre\ria.tior1s are used ti1r'0ughr31it‘ti1is speciﬁesatirm: AD: Aizheimefs disease AUC: Area under the curve BZDSZ Benzodiazepines CNS: Centre} nervous system CT/CAT scan: computed tomography scan Cm": Maximum (or peak) serum conceritraticri that a drug achieves in a specified compartm erit BPS: Extrapyramidai side effects FD & C: i?5e.de.r'2;.i §§"<'>r.s GABA: Garnma—amirioautyric Acid. —iE-{T1 5-Hydr0xytr'yptarnine ICU: Intensive care unit IPD: In~P‘atier1tdepartrnerit MRI: Magnetic resonance imaging Mg: Miiii gram N0r—epi:iephi‘irie OPD: Out—patierit department P’1‘SiEI>: P0st~traumatic stress disorders RSS1 Ramsay sedation score RH‘: Rat intruder test SL-OS: Smith—Lemii Opitz syndrome '§7m_q,\_-: Time at which the Cmax is observed.

WO 2018/126182 PCT/US2017/069030 l l. E} E F ll"€ E'l"l (ENS [Lil] it will be understood that the tern1inol.ogy used herein is for the purpose of describing embodiments only, and is not intended to be limiting. As used in this speciﬁcation, the singular forms "a", "an" and "the" include plural referents unless the context clearly dictates otherwise.

Thus, for example, reference to "a solvent" includes one or more such solvents and the like, [32} Unless defined otherwise, all technical and scientific terms used herein have the same meaning as cornrnonly understood by one of ordinary sltill in the art to which the invention pertains. Although other methods and materials similar, or equivalent, to those described herein can be used in the practi.ce of the present invention, the preferred materials and methods are described herein. {'33} The terms ‘‘treating,'‘ and "treatrnen.t_," as used herein refer to curative therapy, prophylactic therapy, and/or preventative therapy and can be used interchangeably.

[Still 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 i.e. l)e> B5} As used herein, the term "an effective amount" is interchangeable with "therapeutically effective dose," or "therapeutically el’fec'tive arnount," and refers to an an'1oun.t sufficient to produce the desired effect. An effective amount is sufficient to cause an improvement in a clinically significant condition of the subject. 36} As used herein, "pharinaceutica.lly acceptable salt" refers to a salt known to be non-toxic and commonly used in the pharmaceutical literature. Typical inorganic acids used to form such salt include hydrochloric, hydrobromic, hydroiodic, nitric, sulfuric, phosphoric, hypophosphoric, and the like. Salts derived from organic acids, such as aliphatic mono and dicarboxylic acids, phenyl substituted alltanoic acids, hydro>r_vall-tanoic and hydroxyl alkandioic acids, aromatic acids, aliphatic and aromatic sulfonic acids may also be used. A preferred salt is the hydrochloride salt. id="p-37" id="p-37"

[37] As used herein, the term "subject" prefe1'ably refers to a human patient. in some embodiments, the subject can be any animal, including non~human mammals, such as mice, rats, other rodents, rabbits, dogs, cats, swine, cattle, sheep, horses, or primates.

WO 2018/126182 PCT/US2017/069030 B8} The term "agitation", as used herein, means irritability, emotional outburst, impaired thinl<,ing, or excess motor and verbal activity that may occur due to either dysfunction of speciﬁc brain regions such as frontal lobes or due to dysfunction of neurotransmitter systems such as dopaniine and nonepinephrine. in the present invention, agitation also includes aggression and hyper—arousal in post—traumatic stress disorder. The agitation may be acute or chronic.

E39} The term "the signs of agitation" includes excessive motor activity (examples include; pacing, rocking, gesturing, pointing ﬁngers, restlessness, performing repetitious mannerisms), Verbal. aggression (cg. 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, l<.lCl.{ilf1g objects or people, scratching, biting, throwing objects, hitting self, slamming doors, tearing things, and destroying property).

{Kill} The term "acute agitation" means agitation that occurs rapidly and is severe and sudden in onset. Acute agitation may be associated with, for example, neurodegenerative disease and neuropsychiatric conditions, although it may particularly exi st in neuropsychiatric conditions.

Acute agitation may lead to chronic agitation if it remains untreated, {ill} The term "chronic agitation" means agitation 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 particularl.y exi st in neurodegenerative diseases. [42} The term. "neurodegenerative disease" includes, but is not limited to, Alzheinier disease, t"ront.otemporal dementia (or Picl<’s disease), Dementia, Dementia with Lewy bodies, post- traumatic stress disorder, Parkinson's disease, vascular dementia, vascular cognitive impairment, ll-luntington‘s disease, multiple sclerosis, (lreutzfeldtdalroli disease, multiple system atrophy, progressive suprannclear palsy or other related neurodegenerative diseases. {:43} The term "neoropsychiatric conditions" includes, but not limited to, schizopln'enia, bipolar illness (bipolar disorder, bipolar mania), depression, delirium or other related neuropsychiatric conditions.

E44} "Sundown syndrome" is a latewday circadian syndrome of increased confusion and restlessness, generally in a patient with some form of dementia. it seems to occur more frequently during the middle stages of Alzheimer dementia. it seems to subside with the progression of a patient's dementia. About 2<’.‘:—r-l5% of Alzheimer type patients will experience WO 2018/126182 PCT/US2017/069030 some sort of sundowning confusion. Confusion and agitation worsen in the late afternoon and evenings or as the sun goes down. [ail "Elie term "perioperative agitation" means agitation before, during or after any surgical procedure or ECU agitation unassociated with a netirodegenerative disease or neuropsycliiatric condition. {46} The term "suhlingual" 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. Sublingual absorption occurs through the highly va.sculaiized suhlingual niucosa, which allows a substance direct access to the blood circulation, thereby providing for direct systemic administration independent of gastrointestinal intluenees and avoiding undesirable tirst~pass hepatic metabolism. Accordingly, the total amount of Dexinedetornidine or a pharniaceutically acceptable salt thereof in the forrnulati on may he reduced, "thereby reducing the likeltihood of deleterious side effects and providing a cost benefit to the manufacturer.

E47} "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 coinmands. As used herein "without causing significant sedation" means that the patient experiences a level of sedation not greater than Level 3 on the Ramsay Sedation Scale. Level 3 means sedated but responds to com.rn.a.n.ds.

Ill. ll/E I'E‘}?l(}l}S {48} The present invention provides a method of treating agitation or the signs of agitation in a subject comprising administering an effective aniount of an alpha~2 adrenergic agonist or a pharniaceutically acceptable salt thereof sublingually’ to the subject. In a particular aspect, the agitation is suppressed without also causing signiﬁcant sedation. {£39} In one einbodiinent, the alpha—2 adrenergic agonist includes, but is not limited to, Clonidine, (}ua,nt‘atcine, Gtuanahenz, Guanoxaheiiz, Guanethidine, Xylazine, Tizatnidiire, Medetomidine, Fadolrnidine, Dexmetletoinidine, Miethyldopa, ‘ivletliyliiorepinephrine, lodoclonidine, Apraclonidine, Detornidine, Lofexitdine, Arnitraz, Mivazerol Azepexol? Talipexol, Rilmenidine, Naphazoline, Oxymetazoline, Xylometazoline, Tetrahydrozoline, Tra.n'1azoline, Talipexole, Roniiﬁdine, Norfenefi'ine, l\/loxoni dine, Li darnidine, Tol oni dine, UK l43 04, DJ-7 l 4 l , ST49 l , RW.l'-523 53 , ".E‘CG~l 000, 4- propylhexedrine, Octoparnine, WO 2018/126182 PCT/US2017/069030 (3 —aminomethyl—cycloheX—3—enylmethyl)— l ,3 —dihydro~imitlazole—2—thi one, and 4—(3 ~ hydroxyrnethyl—cyclohex—3—er1ylrnethyl,)—l ,3—di hy<.lro—in1idazole—2-thione or a pharmaceutically acceptable salt thereof.

{S0} in one. preferred embodilment, the present invention provides a m ethod of treating agitation or the signs of agitation in a subject comprising administering an effective amount of Dexrnedetomidine or a pharmaceutically acceptable salt thereof suhlingually to the subject. in a. particular aspect, the agitation is suppressed without also causing Signiﬁcant sedation. [fill or a pharmaceutically acceptable salt tl:1ereofvia the sublingual. route. Consequentl.y, in addition Agitation may be effectively’ treated using a relatively low dose of Dexmedetoinidine to provitling relief from agitation without causing significant sedation, the treatment is also e.ffecti_ve with reduced or no side effects (for example, cardiac or respiratory side effects).

{S2} in a further embodiment, the present invention is directed to a method of treating agitation or the signs of agitation in a subj ect comprising administering Dexrnedetornidine or a pliarinaceuticaliy acceptable salt thereof suhiingually to the stihject to provide fast—aeting relief without a substantial portion of Dexrnedetornitline or its pharmaceutically acceptable salt thereof passing into the liver of the patient. {:33} in another embodiment, the present invention provides a method of treating agitation or the signs of agitation in a subject in need thereof, comprising adrninistering an effective amount of Dexmedetornidine or a pharrnaceuticaily acceptable salt thereof via a suhlingual composition. to the subject, wherein the sublingual composition is selected from a film, wafer, patch, lozenge, gel, spray, tablet, and liquid drops.

{S4} In a further embodiment, the present invention provides a method of treating agi.tati.on or the signs of agitation in a subject in need thereof, cornprisin g adrninistering to the subject an effective amount of an alpha—2 adrenergic agoni st together with one or more pharmaceutically acceptable carriers and/or excipients via a sublingual composition, wherein the suhlingual cornposition is a sublingual film. In a particular aspect, the agitation is associated with a neurodegenerative disease or neuropsychiatric condition. In another particular aspect, the treatment is effective without causing significant sedation.

{S5} in a further ernbodirnent, 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 l3exrriedeton:iitlirie or a ph.a.rn:iaceutically acceptable salt thereof together with one or more pharmaceutically acceptable carriers and/or excipients via a suhiingual composition, wherein the sublingual composition is a sublingual film. In a particular aspect, WO 2018/126182 PCT/US2017/069030 the agitation is associated with a neurodegenerative disease or neuropsychiatric condition. in another particular aspect, the treatment is eft'ective without causing significant sedation. [set in yet other embodiment, the present invention provides a method of treating agitation or signs of agitation in a subject in need tbereot’, comprising administering to said subject an effective amount of an alpha—2 adrenergic agoni st or at pbarm aceuticaily acceptable salt thereof at a dosage that does not cause a significant sedation. Suitable alpha—2 adrenergic agonists include, but are not limited to, Cionidine, Guanfacine, (Iluanabenz, Guarioxaberiz, Guanethidine, Xylazine, Tizanidine, Medetomidine, Dexmedetornidine, Methyldopa, Methylnorepinephrine, l:7adolmidin.e_, Iodocionidine, Apraclonidine, Detomidine, l_..ofexi.dine, Amitraz, Mivazerol, Azepexol, Talipexol, Rilnienidine, Naphazoline, Qxymetazoiine, Xyiometazoline, Tetrahydrmroline, Trama;:olin.e, Talipexole, Rorniﬁ.di.ne, propylb.exedrine, Noifeiiefrine, Octopamine, Moxonidine, Lidamidine, Toionidine, UKl4304, D.B"—7‘l4i, S'IL9‘l , RWL523 5 3 , TCG— l 000, 4—(3 —arninom ethyl —cyc1 obex—3 -€:t1j,7i1’lI1C'E,l‘tyl,)— 1 ,3 —dihydro—in1idazole— 2—thione, and 4—(3 whydroxymethyl—cyciohex-3—enyimetiiyi)—i,3-dihydro—imidazoie—2utbione or a pharmaceutically acceptable salt thereof. In a particular aspect of the invention, the dosage ot"aipha~2 adrenergic agonist used in the composition is from about 3 micrograms to about 100 micrograms.

{S7} 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 et‘fecti.Ve amount of Dexniedetomidine, or a plriaritnaceuticaily acceptable salt thereof sublingualiy at a dosage that does not cause signiﬁcant sedation. In a particular aspect of the invention, the dosage ot"Dexrnede'toinidine or a pharnziaceutically acceptable salt thereof used in the subiingual composition is from about 3 micrograms to about 100 micrograms. LiEiXamples of suitable dosages include: about 5 micrograms to about 190 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 niierograms, about 5 micrograms to about 76 micrograms, about 5 micrograms to about 65 micrograms, about 5 micrograms to about so micrograms, about 5 niicrograms 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 3% rnicrograrns, about 5 micrograms to about 25 micrograms, about 5 rnicrograms to about 20 micrograms, about 5 micrograms to about ‘i 5 micrograms, about 5 micrograms to about 10 micrograms, less than 10 micrograms (eg. about 5, 6, 7, 8, or 9 micrograms), about micrograms, about l2 micrograms, about l4 micrograms, about l5 micrograms, about to WO 2018/126182 PCT/US2017/069030 micrograms, about 18 micrograms, about 20 micrograms, about 30 micrograms, about 50 rnicrogranis. The dose may be adrninistered one or more times a day.

{S8} in a further embodiment, the present invention provides a method of treating agitation or the signs of agitation in a subject in need thereof, £‘.~OI1’1pI‘i,Si1'lg adrn.inisten‘i'ig to said subject an effective amount of Dexrnedetornidine or a pharniaceutically a.eceptable salt thereof subiingually at a dosage of from about 0.05 niierogr*atns./kg weight of subject to about 1.5 rnicrograins/lrg weight of subject. Examples of suitable dosages include: about 0.1 niiorograrns/kg to about l rnicrogranis/kg, about 0.1 rnicrograms./kg to about 0.5 niicrograrns/l<.g, about 0.i n:iic.r~ogi'ai:ns,/kg to about 0.4 n'1icrograrns/kg, about 01 micrograms/'i id="p-60" id="p-60"

[60] in a yet further ernbodinient, the present invention provides a method of treating agitation or the signs of agitation associated with neurodegenerative disease in a subject in need thereof, comprising sublingcuaiiy adniinistering to said subject an effective amount of WO 2018/126182 PCT/US2017/069030 Dexmedetomidine or a pharmaceuticaiiy acceptabie sait thereof at a dosage that does not cause unwanted (eg. signiﬁcant) sedation, The dosage of Dexniedetomidirie or a pharm aceuticaiiy acceptabie salt thereof used may conveniently be from about 3 micrograms to about 100 micrograms, 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 niicrograms, about 5 niicrograms 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 m.icrogra.n:is to about 40 micrograms, about 5 micrograms to about 35 micrograms, about 5 micrograms to about 30 m.icr'ogran1s., about 5 nriicrograms to about 25 rmcrograms, about 5 m.ict'ogran1s to about 20 micrograms, about 5 micrograms to about 15 micrograms, about 5 micrograms to about 10 micrograms, iess than 10 micr'ogra.ms, about 5 micrograms, about 6 micrograms, about 7 micrograms, about 8 micrograms, about 9 micrograms, about 10 micrograms, about ‘E22 micrograms, about 14 micrograms, about 16 micrograms, about 18 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 as subject in need thereof, comprising administering to said subject an effective amount of an aipha—2 adrenergic agonist or a pharmaceuticaiiy acceptable salt thereot‘ at a dosage that does not cause a significant sedation. Suitable aipha~2 adrenergic agonists include, but are not iimited to, Cionidine, Guanfacirie, Guanabenz, Guanoxabenz, Gua.n.et]:ii.dine, Xyiazirie, Tizanidine, Medetomidine, Fadoimidine, iodocionidine, Dexmedetomidine, Miethyidopa, Methylnorepinephrine, Apracionidine, Detomidine, Lofexidine, Amitraz, Mivazeroi, Azepexoi, Taiipexoi, Riimenidine, Napbazoiine, Coqtirnetazoiine, Xyiometazoiine, Tetrahydrozoiine, Trarnazoiirie, Taiipexoie, Norfenefrine, ST—9]_, RWL52353, TCG-1000, 4—(3— 44:3 _ Rornitidine, propyihexedrine, Octopamine, Moxonidine, Lidamidirie, Toionidine, UKM304, 133-7141, aminoniethyi-cyciohex-3 -enyim ethyi)— i ,3 —dihydi‘o—imida.zoie—2—thione, and bydroxyme'tbyi—cycioheX~3-enyirnetbyi)—1,3—dihydro~irnidazoie—2~thi-one or a pharmaceuticaiiy acceptable salt thereof. The dosage of aipha—2 adrenergic agonist used in the composition is conven.ientiy from about 3 micrograms to about 100 rnicrograrns. id="p-62" id="p-62"

[62] in another embodiment, the present 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 effective amount of Dexm edetomi dine or a WO 2018/126182 PCT/US2017/069030 pliarinaceutically acceptable salt thereof sublingually at a dosage that does not cause significant sedation, The dosage ot‘Dexmetie'tomidine or a pharmaceutically acceptable salt thereofused in a sublingual composition may conveniently be from about 3 niicrograms to about 100 micrograms, about 5 micrograins to about lO0 micrograrns, about 5 micrograms to about 90 micrograms, about 33 micrograms to about 85 micrograms, about 5 micrograms to about 80 micrograms, about 5 micrograms to about 75 micrograms, about 5 niicrograms 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 mi.crograms to about 45 micrograrns, 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 microgratns to about 20 micrograms, about 5 micrograms to about ‘£5 micrograms, about 5 micrograms to about it‘: micrograms, less than l0 micrograins, about 5 micrograms, about 6 micrograms, about '7 micrograms, about 8 micrograms, about 9 micrograms, about 10 micrograms, about l2 micrograms, about 14 micrograms, about l5 micrograms, about l6 micrograms, about l8 micrograms, about 20 micrograms, about 30 micrograms, about 50 micrograms. The dose may be administered; one or more times a day. {bit} The level of acceptable sedation when treating a subject according to a method of the present invention is preferably at or below Level 3 according to the Ramsay sedation scoring (RS3) system. Thus, a particular en'1bo "IV. PHARR/lACE'{l"l'I CAL COM'PQS'E'l‘ii()NS [64} The present inventiori also provides sublingual pharmaceutical compositions comprising an effective amount of an alpha—2 adrenergic agonist or a pharmaceutically acceptable salt thereof, preferably Dexrriedetomitline or a pharmaceutically acceptable salt thereof. [65l The sublingual pharmaceutical cornpositions ol’ the present invention may also comprise a pharmaceutically acceptable carrier and/or excipient. Suitable pharmaceutically acceptable carriers include water, sodium chloride, bintlers, penetration enhancers, diluents, lubricants, flavourin g agents, coloring agents and so on.

WO 2018/126182 PCT/US2017/069030 }66} The suhlingual pharmaceutical compositions of the present invention may be administered to a subject alone or in combination with one or more other suitable active ingredients. [67} in one embodiment, the present invention provides a sublingual pharmaceuti.ca.l composition comprising an e'l’fective amount of lC)ex'rnedetomidine or a pharinaceutica.lly acceptable salt thereof for the treatment of agitation in a subject, e. g. agitation associated with neurodegenerative disease, sundown syndrome in Al;3.heirner’s disease or dementia. in a particular aspect, the sublingual pharmaceutical composition effectively treats agitation in a subject without causing si. gniti cant sedation. }68} Tn another embodiment, the present invention provides a suhlingnal pharmaceutical composition comprising an effec'tive amount of Dexiinedetomidine or a pharrna.ceutical.ly acceptable salt thereof for the treatment of agitation in a subject associated with schizophrenia, bipolar disorder, bipolar mania, other bipolar illness, depression, delirium or another related neuropsychiatric condition. in a particular aspect, the suhlingual pharmaceutical composition effectively treats agitation in a subject without causing significant sedation. {€19} The sublingual pharmaceutical composition of the present invention may be, for example, a film, wafer, patch, lozenge, gel, spray, tablet, liquid drops or the lilze. }7{)} in one embodiment of the invention, the suhlingual pha.rrnaceutical composition is in the form of a tablet or packed powder l7ll in the form of a patch or film (eg. thin film). The patch may have adhesive qualities to prevent in another enibodiment of the invention, the suhiingual pharmaceutical composition is movement or swallowing of the patch. The patch may be ingestible in case of acci.denta.l swallowing or to allow for its easy disposal, or the patch may he removed from under the tongue after a prescribed time. {'72} En 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} Tn a further embodiment of the invention, the sublingual pharmaceutical composition is in a liquid (e. g. as a. solution, suspension or emulsion), and may he, for example, presented as a spray or as drops. Solutions include the active ingredient together with a diluent such as water, normal. saline, sodium chloride solution, or any other suitable solvent such propylene glycol, glycerol, ethyl alcohol and so on. The diluent for the solution may particularly be physiological saline solution or water. The amount of solution administered may conveniently be about 0.01 ml to about l ml (eg. about 0.025-0.5 ml).

WO 2018/126182 PCT/US2017/069030 {'74} The non—solid compositions of the invention may conveniently be administered by spraying, dripping, painting or squirting the ooniposition under the tongue. {'75} ln a particular embodiment of the invention, Dexniedetoniidine or a pharmaceutically acceptable salt tliere..of is sublingually adininistered in liquid form, eg. in a flavored or unflavored physiological saline solution. The liquid coinpositi on may conveniently be administered under the tongue as drops or as a spray. {'76} Dexrnetletoinidine, or a. pliarmaceutically acceptable salt thereof may conveniently represent from about Q.0Ol‘?/o to about 99.99‘?/ii of the overall composition, e. g. about 0.0l% to about 90%, more particul.arl y about 0.0 .9» 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 predeterniined time, for ex.a.n1ple 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 oftime. Surprisingly, this procedure noticeably increa.ses the etlect of the composition of the invention in the treatment of agitation or the signs of agitation.

E78} In another embodiment, the sublingual composition of Dexmedetomidine or a pharrnaceutically acceptable salt tliereot" is a hard tablet or a compressed powder tablet. The tablet may conveniently be designed to dissolve under the tongue in about 30 to l;2G seconds as disclosed in U Pat. No. 6,2‘2l,392 to Khanlrari, et al., incorporated herein by reference. ln a particular embodiment, the sublingual composition of Dexmedetomidine or a pharina.ceutical.ly acceptable salt thereof is a hard tablet hayin.g a low grit component. for an organoleptically pleasant mouth feel. The tablet (or particles thereof containing the active ingredi_ent whi.ch. can be compressed to forth. the tablet) may also coi:npii.se a protective outer coating, eg. any polymer conventionally used in the forrnatiori of rnicroparticles, rna.tr'ix—ty'pe rnicroparticles and rnicrocapsules. {'79} En a further embodiment, the sublingual composition of Dexinetletoniidine or a pharniaceutieally acceptable salt thereof is a hard, compressed, rapidly dissolvable tablet. The tablet conveniently includes the active ingredient within a matrix. The matrix may be com posed of, for example, at least one tiller and a lubricant. Fillers include, for example, lactose or rnannitol, and suitable lubricants include magnesiuni stearate, silicon dioxide and tale. The matrix may also include one or more of: a binder (eg. povidone, a sugar or carboxyniethylcellulose), a disi.ntegra.nt (eg. croscarm.ell.ose sodiuni, crospovidone 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 hardness of about 15 to about 5:’) New/tons.

WO 2018/126182 PCT/US2017/069030 {$0} Another aspect of the present invention provides a method of making a packaged, sublingual tablet. The method includes the steps of: (a) forming a mixture comprising Dexrnedetornidine or a pharmaceutically acceptable salt thereof and a matrix including at least a non—direct conipression tiller and a. lubricant; (b) corn pressing the rnixture to l’orn1 a plurality of hard, compressed, rapidly disintegrable particles (e. g. beads) including the active ingredient distributed in the sublingually dissolvable matrix; and ( c) storing the product in bulk prior to pacltaging. in another embodiment, the dosage tionns are then packaged in a lumen of a package such that there are more than one per package. Direct compression is the preferred. method of fornriirig the dosage forrns. There is also provided hereby an openable and reclosable package containing a plurality of hard, compressed, rapidly dissolving tablets adapted for direct oral dosing as described above. lllll efl’ervescent agent. The effervescent agent may conveniently be present in an amount up to ln another embodiment, the present invention is a sublingual tablet comprising an about 95% by weight, based on the weight of the ﬁnished tablet, and more particularly in an amount of between about 3&1"?/6 and about 80% by weight. Sufficient effervescent material is included in the tablet composition to generate more than about 5 cm3 but less that about 3% crn3 of gas upon exposure of the tablet to an aqueous environment. Sublingual compositions comprising effervescent agents are disclosed in U Pat. No. 6,200,604, which is incorporated herein by reference.

E82} in one pa.rticular einbodiinent, an eft‘ervescen.t agent releases carbon dioxide eg. as a result of the reaction of a soluble acid source with an alkaline carbonate or bicarbonate The acid source may conveniently include food acids and acids such citric acid, tartaric, arnalic, llJ1’llel‘lC, adipic and succinic acid. Carbonate and bicarbonate sources include dry solid carbonate and bicarbonate salts such as sodium bicarbonate, sodium carbonate, potassium bicarbonate, potassium carbonate, magnesium carbonate and the like {S3} Spray compositions of the present invention for sublingual administration may include one or more pl1arrna.ceu‘tica.lly acceptable liquids ( e. g. present in the aniount of about 30% to about 99.99% by weight of the composition). Such liquids may be solvents, co-solvents, or non—solvents for Dexrnedetornidine or a pbarniaceutically acceptable salt thereof. Exaniples of pharmaceutically acceptable liquids include water, ethanol, dimethyl sulfoxide, propylene glycol, polyethylene glycol, propylene carbonate, pharniaceutically acceptable oils (cg, soybean, sunﬂower, peanut, peppermint etc.) and tlie like. "Elie pharniaceutically acceptable liquid is selected either to dissolve the active pharmaceutical ingredient, to produce a stable, WO 2018/126182 PCT/US2017/069030 lioniogenous suspension or solution of it, or to form any combination of a suspension or solution.

{S4} Furthermore, sublingual, spray formulations of Dexrnedetoniidine or a phainraoeutically acceptable salt thereot‘ may include one or more carriers and/or excipients. lixainples of carri ers/excipients include yiseosity—moolulating materials (eg. polymers, sugars, sugar alcohols, gums, clays, silicas, and the like). One particular polymer that may conveniently be used is polyvinyl pyrroli clone (P‘v’P). The viscosity—rnoclu1ating materi al may conveniently be present in the amount of from about 0.0l% to about 65% by weight of the spray forrnulation. Other examples of Carriers./excipients include pre.servatives (e. g. ethanol, benzyl alcohol, propylparaben and inethylparaben). Preservatives may conveniently be present in the amount of froth. about 0,00l% to about .l0% by weight of the spray t‘orrnulati on.

Carriers/excipients may also be ﬂavoring agents, sweeteners (eg. sugars such as sucrose, glucose, dextrose, maltose, fructose, etc), artitieial sweeteners (eg. saccharin, aspartame, acesulfanie, sueralose etc..), or sugar alcohols (eg. inannitol, xylitol, lactitol, nialtitol syrup etc.) present conveniently in an amount of from about 0.001% to about 65% by weight of the spray forrnulation. Other exarnples of carriers/excipients include bruffers and pl-ikanljusting agent (eg, sotliurn hytlroxide, citrate, and citric acid.) conveniently present in an amount of from about 0.01% to about 5% by weight of the spray formulation. Coloring agents (e. g. present in an amount of from about 0.00l% to about 5% by wei ght of the spray formulation), fragrances (eg. present in an amount of from about 0.00l.% to about l% by weight of the spray formulation), chelating agents such as EDTA (e. present in an amount of from about 0.00 % to about 1% by weight of the spray forrnulatiori), UV absorbers (eg. present in an amount of from about 0.00l% to about l0% by weight of the spray forrnulatiorr), and anti—foani agents ( e. g. low molecular weight alcohols, dimethieone) conveniently present in an amount of from about 0.00 % to about 5% by weight of the spray l"orrnulation may also be included as appropriate carriers./exeipients in the spray formulations of the present invention. {$5} One particular aspect of the present invention pt'0Vlt.leS a. sublingual ﬁlm oornpri sing Dexrnedetomitline or a pharmaceutically acceptable salt thereof, together with one or more carriers and/or excipients, for the treatrnent of agitation.

{S6} Exeipients which maybe incorporated into the sublingual films of the present invention include one or more of the ‘l’oll.owing: tilrn forirning agents, mouth feel irnproyers, plasticizers, stabilizers, surfactants, preservatives, sweetening agents, colorants, flavourants, emulsifiers, clisintegrants, salivating agents, antioxidants, permeation enlianeers, solvents and the like.

WO 2018/126182 PCT/US2017/069030 [871 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 lO% to about 99%, more preferably about 50% to about 90% by weight of the composition. Film forming agents that can be utilized as part of the film composition of the present invention include, but are not limited to, cellulose ethers, modilied starches, natural gums, edible polymers, seaweed extracts, land plant extracts, pullulan, polyvinylpyrrolidone, derivatives thereof and combinations thereof.

{S3} Examples of cellulose ethers include, but are not limited to, niethylhydroxycellulose, n1ethylcel.lulose, ethylcellulose, hydroxyethylcellulose, car‘oox.yrnethylcellulose, derivatives thereof and combinations thereof. {'89} Modified starelres include, but are not limited to, acid and enzyme hydrolyzed corn and potato starches, derivatives thereof and combinations thereof. {(90} Exarnples 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 combinations thereof. ll-ill cellulose ethers, xanthan, derivatives thereof and combinations thereof. l92l Lliixainples of edible polymers include, but are not limited to, microcrystalline cellulose, Seaweed extract examples include, but are not limited to, sodium alginate, carrageenans, derivatives thereof and. combinations thereof. {.93} Land plant extracts include, but are n.ot linziited to, lgonjac, pectin, arabinoglactan, derivatives thereof and combinations thereof. [94l Particular film forming agents incl ude pullulan, sodium. alginate, polyvin.ylpyrrolidone, methylcelhilose and methylliydroxycelitulose (Ml-lC). {$95} The term "solvent" generally refers to liquids that will dissolve solutes. A solvent may be used to dissolve film—forming agents and other excipients to prepare 'l’ilm—forming compositions of the present invention. Solvents include, but are not limited to, demineralized/distilled water, ethyl alcohol, isopropyl alcohol, methyl ethyl lretone, propylene glycol methyl ether acetate, dirnethyl acetamide, ethylene glycol inono—propyl ether, and toluene. A sublingual film of the present invention rn ay conveniently comprise a. solvent in an amount up to about 1% W/w. [96j 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 lie, for example, in the range of about 0% to about 45%, WO 2018/126182 PCT/US2017/069030 more particularly about % to about 25%, by weight of the composition. Examples of suitable s’tabilizin.g agents of the present invention include, but are not limited to, gum arabic, niicrocrystalline cellulose, carrageenan, Xanthan gum, locust bean gum, derivatives thereof and coinbinations thereof. Particular stabilizing agents of the present invention include gum arabic and microcrystalline cellulose. {97} "Disintegrants" can aid the dissolution of edible films allowing for the efficacy of the tilin to be realized sooner. Suitable disintegrants for use in an edible film of the present invention include, but are not liniited to, alginic acid, microcrystalline cellulose and carboxynriethylcellulose. Special. disintegrants known as super—di.sintegrants are also suitable for use in an edible film of the present invention. Supentlisintegrants include cross—linl H00] A "plasticizing agent" or "plasticizer" may be utilized to improve ﬂexibility and reduce brittleness of an etlible film composition of the present invention. The plasticizing, agent may conveniently constitute up to about 30%, up to about l5% by weight of the cornposition.

Examples of suitable plasticizing agents include, but are not limited to, glycerin, sorbitol, tiiacetin, nionoacetin, diacetin, polyethylene glycol, propylene glycol, hydrogenated starch hydrolysates, corn syrups, low molecular weight propylene glycol s, phthalate derivatives like WO 2018/126182 PCT/US2017/069030 diinethyl, diethyl and dihutyl phthalate, citrate derivatives such as trihutyl, triethyl, acetyl citrate and castor oil derivatives thereof and coinhinations thereof. Particular pl.astici;:in.g agents of the present invention include sorhitol and glycerin. [loll The term "preservative" generally refers to an excipient used to lrill rnicroorganisins or prevents, inhibits or retards their growth and reproduction, and is included in a product in a concentration only sutlicient to prevent spoilage or the growth of inadvertently added rnicroorga.nisnis. Suitable preservative includes, but are not limited to, inethylparahen, propylparaben and sodium henzoate. The preservative may conveniently he present in the coinposition t‘roi:.n about 0.001% to about l0% W/W of the composition.

[M2] The term "sweetening agent" generally refers to an excipient used to impart sweetness to a pharniaceiitical composition. Suitable sweetening agents for use in a coi:npositi_on of the present invention include, hut are not limited to, aspartanie, dextrose, glycerin, mannitol, sa.ccl'1arin sodiuin, sorbitol and sucrose. The sweetening agent may conveniently he present in the composition in an amount of from about 5% to about 20% W/w of the composition. [li_":3} The term "coloring agent" or "colorant" generally refers to an excipient used to impart color to a pharmaceutical composition. Suitable colorants include, but are not limited to, Fl)&C Red No. 3, FD&C Red No. 20, FD&C Yellow No. 6, FD&C Blue No. 2, D&C Green No. 5, l)&C Orange No. 5, D&C Red (No. 8, other Fl). & C. dyes, caramel, red ferric oxide, and natural coloring agents such as grape skin extract, heet red powder, heta~carotene, annatto, carrnine, turmeric or papril<.a. ".l"h.e col orant inay con.ven.ien'tly be present in the cornposition in an amount of from about 0.00 % to about i 0% W/w of the composition. [ltlzll The term "flavoring agent" or "fl.avorant" generally refers to an excipient used. to impart a pleasant ﬂavor (and often also odor) to a pharrnaceutical composition. Suitable llavorants include, but are not limited. to, synthetic ﬂavoring oils, flavoring aromatics, natural oils, extracts trorn whole plants or parts thereof such as leaves, flowers, fruits or cornhinations thereof. Examples include cinnamon oil, Wintergreen oil, peppermint oil, clove oil, bay oil, anise oil, eucalyptus oil, thyrne oil, cedar leave oil, nutrneg oil, sage oil, bitter almond oil and cassia oil. Other useful flavorants include vanilla, citrus fruit oils such as lemon, orange, grape, lime or grapefruit oil, and fruit essences such apple, pear, peach, strawberry, raspberry, cherry, plum, pineapple or apricot essence. Flavorants of particular interest for use in a cornposition of the present invention include conirnercially 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 truit ll avors such as orange flavor: The ilavorant may WO 2018/126182 PCT/US2017/069030 conveniently be present in the composition in an amount of from about 0.001% to about 10% w/W of the composition. [l 05] The term "salivating agent" is an agent that promotes greater salivati on during use of a coinposition of the present invention. This may he an important ftaattire if the composition is intended to be taken hy the patient without the aid of water to help in the transporting of the composition to the stomach of the patient. The salivating agent can be, for example, an emulsifier or a food acid that initiates salivation in the mouth of the patient. Iliixainples of emulsiﬁers useful as salivating agents include allcyl aryl sulfonates, allryl sulfates, sulfonated amides and a.rnii:ies, sulfated and sulfona’ted esters and ethers, alkyl sulfon ates, polyethoxylated esters, mono—, dim, and triglycerides, diacetyl tartaric esters of monoglyceritles, polyglycerol esters, sorbitan esters and ethoxylates, laetylated esters, phospholipids such as lecithin, polyoXy'ethylene sorhitan esters, proplyene glycol esters, sucrose esters, and mixtures thereof.

The einulsitler may he either saturated or unsaturated. It should be noted that some of the ernulsifiers that are salivating agents may also function as hinders. 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 of from about 0.3% to 0.4% by weight of the composition.

{No} The term. "anti.o.\ii.dant" generally refers to an excipient used to inhibit oxidation and thus prevent deterioration of active agents by oxiclative processes. Suitable antioxidants include, for exanziple, ascorbic acid, ascorhyl palmitate, butylated hydroxyanisole, butylated hydroxytoluene, hypophosphorous acid, monotliioglycerol, propyl galiate, sodium ascorbate, citric acid, sodium bisulfite, sodium forrnaldeliyde sulfoxylate, sodium inetahisulﬁte, EDTA and sodium edetate. The aiiti~oxidarit may conveniently be present in the composition in an amount offrorn about 0.00l% to about 2% w/W of the composition. [l0"/‘l The term "permeation enhancer" generally refers to an excipient used to enhance permeation of an active agent to cellular membranes or enhance the local/systeniic ahsorption of the active agent. Permeation enhancers that may he used in the present invention include, but are not limited to, solubilizers such as alcohols, polyethylene glycol s, chelating agents (eg. eyclodextrins), sucrose laurate or sucrose oleate. The pe.n'nea.ti.on enhancer may conveniently be present in the composition in an amount of from about 0.1% to about 5% w/w of the composition.

WO 2018/126182 PCT/US2017/069030 i108] ln one enibodinient of the present invention, the sublingual pharmaceutical composition of the present invention includes a rnuoosal permeation enhancer appropriate for enhancing the niucosal absorption of the composition.

H09} Sublingual Dexrn edetoini dine ionnul ations (such as sprays, drops, and the like) may he made by mixing appropriate quantities ofthe foregoing ingredients in accordance with standard good nianufaeturing practices. The relative amounts of each ingredient should not interfere with the desirable pharmacological and pharrnaeol-ginetic properties of the resulting fonnulation. {"110} Sublingual Dexnziedetomidine films of the present in.ven.tion may be conveniently prepared using l.’liarrnFilrn@ technology (owned by MonoSol) or technology owned by ARK jl.,l..C. Various patents an.d patent applications are incorporated herein in entirety and includes US. Fat. or Publication Nos. 9585961, 7470397, 7727466, 9248146, 9545376, 201 7~O087084, 9662297, 9662301, 2017-0246108, 2017-0252294, 9441142 assigned to ARK 'L1'_,C and 7425292, 7357891, 8663687, 8685437, 7897980, 8241661, 8617589, 8936825, 956ll9l, 9303918, 9346661, 8282954», 7972618, 9073294 assigned to lvlonosol RX.

El 1 ll ln preparing the suhlingiial film of the present invention the active agent, e.g.

Dexrnedetoniidine or a pharrnaceutically acceptable salt thereof, filrn forming agents and optionally one or more Carri ers and/"or excipients selected from the group comprising 0l"Il’lO'u'El1 feel iinprover, plasticizer, stabilizer, surfactant, preservative, sweetening agent, colorant, i‘.lavouran.t, enziulsitier, d.isin.tegi'an't, salivating agent, antioxidant, permeation enl1a.n.cer are dissolved in a compatible solvent to form a film forniing composition. Compatible solvents include water, alcohols such as ethanol, ethyl. acetaE.e, acetone, and rn.ix.tures thereof, The tilni t"orniing composition is cast on a releasable carrier and dried to form a. sheet/iilin. The carrier material must have a surface tension which allows the filth solution to spread evenly across the intended carrier width without soalting to form a destructive bond ‘between the film carrier substrates. Examples of suitable carrier materials include glass, stainless steel, Teflon and polyethyleneirnpregnated paper. Drying of the tihn may be carried out at high ternperature using a drying oven, drying terrninal, vacuum drier, or any other suitable drying equipment which does not adversely al'l"ect the ingredients of which the tilrn is composed, The suhlingual film of the present invention can also he prepared by other established processes eg. extrusion (for example, Hot melt extrusion, Solid dispersion extrusion), casting (for exaignple, solid casting or serniwsolid casting), Rolling inethods and the like.

WO 2018/126182 PCT/US2017/069030 v. ADlVtENES'i‘RA’i‘l()N [l l2} In an aspect, the present invention provides a sublingual composition comprising an alplia—2 adrenergic agonist or a pharmaceutically acceptable salt thereof, administered to a subj ect in an amount suflicient to effectively treat agitation. The amount of alpha—2 adrenergic agonist is sufficient to effectively treat agitation without causing significant sedation. The alpha—2 adrenergic agoni st may conveniently be delivered on an "as needed basis" in one, two or more doses per day to the animal {e.g. human) subject. The composition may also be administered. via a single dosage form or via multiple dosage forms. [l 13} In another aspect, the present invention. provides a sublingual. composition coi:npri.sing Dexmedetornidine or a pharmaceutically acceptable salt thereof, administered to a subject in an angiount suflicient to efftactivelyr treat agitation. in a particular aspect, the a.n:ioim.t of Dexmedetomidine or a pharmaceutically acceptable salt thereof used is sufficient to effectively treat agitation without causing signiﬁcant sedation. The Dexmedetornidine or a pliarrhaceutically acceptable salt thereof may conveniently be delivered on an "as needed basis" in one, two or more doses per day to the animal (e.g_ human) subject. The composition may also be administered via a single dosage form or via multiple dosage fQr‘IY1S'r ll l4} Following administration of a composition of this invention to a subject, a therapeutic {ie anti—agitation) effect may begin within about 60 minutes (eg. within about 30, 20, 1:3, 10, , 3, 2 or l 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‘ adm.in.istra.ti.on, and more typically within about 5 to about 30 minutes. A second dose of the composition of 'tl:1i.s invention maybe aclnriinistered to the suhj ect if the signs of agitation. are not relieved within about 60 minutes. [l 15} Treatment protocols may include one or more dosage intervals {_ two or more dosage interval s, five or more dosage intervals, or ten or more dosage inteiw/a.lsi). Diepeiirliiig on the physiology of the subject and the desired tlierapeutic effect, the duration of dosage intervals and treatrn ent protocol s a.ceoi'din g to ei'til.iodii'rrents of the present invention may vary. ll 16} Dexrnetletriinidine or a pliarrnaceutically acceptable salt thereof may be administered a sublinguai composition to treat agitation or the signs of agitatiori either alone or in coniitrination with one or more further active agents. W hen used in combination, the active agents can either be formulated as a single composition or as two or more separate compositions, which can be administered sirnultaneously, sequentially or separated by an appropriate period oftirne.

WO 2018/126182 PCT/US2017/069030 id="p-117" id="p-117"

[117] W here Dexmedetomitiiiie or a pharmaceuticaiiy acceptable sait thereof is 3Ci111i111SEa":1‘€'-d with a Sé3<.?O!'1€.1 a.cti\re agent to treat agitation or ‘the signs of agitation, tbe weight ratio of respectively Dexme-zietomidine or a pharmaceuticaiiy acceptable sait thereof to the secoiiti active agent may geuera11y be in the rat: from about 1 :2 to about 133.5; about 12.5 to about 1:3; about 1:3 to about 1 :35 about 113.5 to about 114; about 1 :4 to about 1:45; about 1 :45 to about 1:5; about 1:5 to about 1:10; ariti about 1:10 to about 1:25. For exampie, the weight ratio pa.r'ti.cu1a.r1y be between about 1:1 to about 1.:5;, about 1:5 to about 1:1 (It: about .1111) to about 1:15; or about 1:15 to about 1:25. A1ter:iiatix/eiy, the weight ratio of respectiveiy tbe second active agent to Dexoietietomidiue or a. ph.a.r.n:iac-cuticaiiy acceptabie sait may be in the r‘an,<_.-je offrom about 2:1 to about 2.551, about 2.5: 1 to about 3 :1; about 3 :1 to about 35:1; about 3.511 to about 4:1, about 41:1. to about 45:1; about 45:1 to about 5:1, about 5:1. to about 10:1; anti about 10:1 to about 25:1. For e:»«:amp1e, the weight ratio of r‘e..~:pective1y the second active agent to Déi.‘-:11’1.4E:(i£::1’OI1‘1i(11116: or a pba.rn1iaceutioa11y acceptable sait titereof m ay pa.rt:icu1a.r1y 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 understooti that a11 ranges between the quoted ranges also covered bereiu, arid constitute furtiter particuiar aspects of this invention.

VI. DOSING REG1iV1F.-N [1181 The closing regimen empioyed may depend on severai factors, such as the type of agitation. treated., the severity of the signs, and whet1:ier the agitation. due to an underiyin g medicai condition. [1191 Dexrnedeton'1i.di.r1e or a pharmaceuti ca.11.y acceptab1e salt t1iereof may be a<1m.in.istered subiiriguaiiy in arty appropriate dose to an araimai tie. g. humarr). 111 certain embodimerits, the human dose may be from about 3 niicrograms to about 100 micrograms (eg. 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 rriicrograms 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 rnicrograrn s, about 5 micrograms to about 50 micrograms., about 5 micrograms to about 45 micrograms, about 5 micrograms to about 40 micrograms, about 5 micrograrns to about 35 micrograms, about 5 micrograms to about 30 micrograrns, about 5 micrograms to about 25 micrograms, about 5 micrograms to about 20 micrograms, about 5 micrograms to about 15 micrograms, about 5 micrograms to about 10 micrograms, iess than micrograms (eg. about 5, 6, 7, 8, or 9 micrograms), about 111 micrograms, about 12 WO 2018/126182 PCT/US2017/069030 micrograms, about 14 micrograms, about 15 micrograms, about 16 micrograms, about 18 micrograms, about 20 micrograms, about 30 mi erogram s, about 50 micrograms). The dose may be administered one or more times a day. [1201 Dexnietietornidine or a pbarrncaceutieaiiy acceptabie salt thereof may be administered subiinguaiiy 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 suitable dosages inciudez about 0.1 micr'og1‘ams/kg to about 1 micrograms/kg, about 0.1 micrograms/kg to about 0.5 micrograms/i<;g, about 0.1 micrograms/i<.g to about 0.4 rnicrograms/kg_, about 0.1 micrograms/kg to about 03 micrograms/'1 VII. SPECEFEIC Ei7*viB{}DT{.M§ENTS OF THE ENVEN'.E‘I€)N E121} Embodiment 1. A method of treating agitation or the signs of agitation in a subject in need thereof t.:orr1pii.sing adrn.in.isterii:1g subiinguaiiy to said subject an et‘t‘ecti.Ve amount of Dexmedetomidine or a pharrnaceuticaiiy aceeptabie salt thereof. [1221 Embodi.rn.ent 2, A method of treating agitation or the signs of agitation in a subject in need an effective amount of thereof comprising administering to said subject Dexmedetomidine or a pbarmaceuticaliy aceeptabie salt thereof, wherein said Dexmecietornidine or a pharmaceuticaiiy acceptable sait tbereot" is subiinguaiiy administered at a dosage that treats agitation or the signs of agitation without causing significant sedation. id="p-123" id="p-123"

[123] E1’1'1bOdi1’1'1€-1'1't 3. The rnetbod a.ccordiiig to Embodimerlt i or 2, wherein said dosage of Dexmedetomitiine or a pbarmaceutieaiiy aeceptabie salt thereof is in range of from about 3 micrograms to about 100 rnierograms (eg. about 5 micrograms to about 100 rnicrogram s, about micrograms to about 90 micrograms, about 5 micrograms to about 85 micrograms, about 5 micrograms to about 80 m.icrogran'1s, about 5 micrograms to about 75 micrograms, about 5 micrograms to about 7t‘: micrograms, about 5 micrograms to about 65 micrograms, about 5 micrograms to about 6:’) micrograms, about 5 micrograms to about 55 micrograms, about 5 micrograms to about 50 micrograms, about 5 micrograms to about 45 micrograms, about 5 WO 2018/126182 PCT/US2017/069030 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 rnicrograrns to about it) micrograms, less than 10 micrograms (e. g. about 5, 6, 7, 8, or 9 micrograms), about 10 micrograms, about 12 micrograrhs, about l4 micrograms, about if} micrograms, about 16 micrograms, about 18 micrograms, about 20 micrograms, about 30 micrograms, about :30 micrograms).

[E24-_} Embodiment 4. The method according to Embodiments l, 2 or 3, wherein said subject is mammal, preferably human. {l2:i] Embodiment 5. The method according to any one of Embodiments l to 4, wherein said agitation. i.s associated. with a rieurodegenerative disease.

{E26} Embodiment 6. The method according to Embodiment 5, wherein said neurodegenerative disease is selected from Alzheimer disease, t‘ronto-teniporal dementia (ETD), dementia, dementia with Lewy bodies (DLB), post-traumatic stress disorder, Parkinson's disease, vascular dementia, vascular cognitive impairment, Huntington's disease, multiple sclerosis, C/I'E:’tl't2i‘l"€3l(it-.ia.k0b disease, multiple system atrophy, and progressive supranuclear palsy.

H27} Einibodirnent 7. The method according to any one ofiilinbodirnents l to 4, wherein the agitation is associated with a neuropsychiatric condition. {l28j Embod.in1ent8. The method according to Embodiment 7, wherein said i:ieuropsychiatri.c condition is selected from schizophrenia, bipolar illness (such as mania, disorder), delirium, and depression [l29} Embodiment 9. The method according to Embodirnent 5, wherein the agitation is associated with sundown syndrome in dementia or Alzheirner’s disease.

U30} Embodiment it). A sublingual composition for use in the treatment of agitation or the signs of agitation in a subject in need thereof, wherein said agitation is not perioperative agit.a.tior1 and said sublingual composition cornpri ses an effective amount ofDexmedetornidine or a pharmaeeutically acceptable salt thereof and one or more phannaceuticaliy acceptable carriers/excipients.

{E31} Embodiment l l. A suhlingual composition for use in the treatment of agitation or the signs of agita.ti.oi:i in a subject in need thereof, wherein said agitation is associated with a neurodegenerative disease and said sublingual composition comprises an effective amount of Dexmedetomidine or a pharmaceutically acceptable salt thereof and one or more pharm aceuticaily acceptable carriers/excipients.

WO 2018/126182 PCT/US2017/069030 [B2] Embodiment l2. A suhlingual 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 neuropsyehiatrie condition and said sublingual composition comprises an effective amount of Dexrnedetomidine or a pharrnacentiically acceptable salt thereof and one or more ph armaceuticall y acceptab l e carriers/exci pi ents.

H33] Embodiment l3. A suhlingual composition for use in the treatment of agitation or the signs ofagitati on in a subj eat in need thereof, wherein said agitation is associated with sundown syndrome in dementia or Alzheimer’s disease and said sublingnal composition comprises an efl’ecti‘ve amount of Dexniedetornidine or a pharmaceutically a.ceepta.ble salt thereof and one or more pharmaceutically acceptable carriers/excipients.

{I34} En1l_>odin1ent 14. The sublingnal composition according to Em.bodi.rn.en.t ll, wherein said neurodegeneratiye disease is selected from the group consisting of Alzheimer disease, liontotemp-oral denientia (ETD), dementia, dementia with Lewy bodies (DLB), post—trauntatic stress disorder, i38.‘fl{illSDl’l'S disease, vascular dementia, Vascular cognitive impairment, Huntingtons disease, multiple sclerosis Creutzfeldtdaliob disease, multiple system atrophy, and progressive supram,iclea,r pal sy. [l35_} Embodiment l5. The sublingual composition according to Embodiment 14, wherein said nenrodegenerati‘ve disease is selected from dementia, frontotemporal dementia, Alzheimer’s disease and Parkinson’s disease.

H36} Emhodintent .16. The sublingnal. cornpositiori according to Eln.bodi.rn_en.t 12, wherein said neuropsychiatric condition is selected from the group consisting of schizophrenia, bipolar illness (such as mania, disorder), deliriuirn and depression. [l37l Embodiment 17. The sublingual composition according to any one of Embodirnents it) to 16, wherein said composition is selected from a film, wafer, patch, lozenge, gel, spray, tablet, liquid drops or the like {i383 Embodiment l8. The sublinguai composition according to Embodiment l7, wherein the composition is a. tilm.

{B9} Emhodirnent l9. The snblingnal composition according to Embodiment l8, wherein the film is rnucoadhesive in nature and provides a quick onset of action.

{E40} Embodiment 20. The sublingual composition according to any one of Embodiments ll‘: to 19, wherein illexm edetonndine or a pharmaceutically acceptable salt thereoit‘is adrnmistered at a dosage that treats agitation or the signs of agitation without causing significant sedation. ll-’-ll} Embodiment 21. The sublingual composition according to Embodiment 2:’) wherein the observed level of sedation is not greater than 3 on the Ramsay sedation scale.

WO 2018/126182 PCT/US2017/069030 id="p-142" id="p-142"

[142] Embodiment 22. The sublingual composition according to any one of Embodiments ‘l O to 23, wherein Dexmedetomidine or a pha.rn'1aceuticaily acceptable salt thereofis adminis'tered to said subject (e. g. human) at a dosage in the range of from about 3 micrograms to about 100 micrograms (e. g. about 5 micrograms to about lO0 micrograms, about 5 micrograms to about 90 micrograms, about 33 micrograms to about 85 micrograms, about 5 micrograms to about 80 micrograms, about 5 micrograms to about 75 micrograms, about 5 micrograms to about 70 micrograms, about 5 micrograms to about 65 micrograms, about 5 micrograms to about 60 micrograms, about 5 micrograms to about 55 micrograms, about 5 micrograms to about 50 micrograms, about 5 micrograms to about 45 micrograms, about 5 micrograms to about 40 micrograms, about 5 micrograms to about 35 micrograms, about 5 micrograms to about 30 micrograms, about 5 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, less than l0 micrograms (eg. about 5, 6, 7, 8, or 9 rnicrograms), about 10 micrograms, about 12 micrograms, about l4 micrograms, about l5 micrograms, about ‘lo micrograms, about 18 micrograms, about 20 micrograms, about 30 micrograms, about 50 micrograms). [l4-3} 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 pbarmaceuticaily acceptable salt thereof, wherein the agitation. is not perioperative agitation.

{E44} Embodiment 24. The method according to Embodiment 23, wherein the agitation is associated with a neurodegenera’ti.ve disease and/or neuropsychi.atric conditi.on [l45} Embodiment 25. The method according to l31’i‘ii‘Jt')(iimE:I‘!'E 24, wherein the neurodegenerative disease is selected from the group consisting of Alzheimer disease, frontotemporal dementia (FTD), dementia, dementia with Lewy bodies (Dl...B), post~traumatic stress disorder, Parkinsorrs disease, vascular dementia, vascular cognitive impairment, Huntington's disease, multiple sclerosis, Creu‘t;:feldt—i’a.i {E46} Enibodirriertt 26. The method according to Embodiment 24, wherein the neuropsycbiatric condition is selected from the group consisting of scbizzzophrenia, bipolar illness (cg. bipolar disorder or bipolar mania), deiirium and depression.

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

WO 2018/126182 PCT/US2017/069030 id="p-148" id="p-148"

[148] Embodiment 28. The method according to any one of Embodiments 23 to 27, wherein Dexniedetornidihe or a pharm,a.ceuticai,ly acc:epta.bie sait thereof is adniinistered in form of a film, wafer, patch, lozenge, gei, spray, tabiet, liquid drops or the hire.

{M9} Embodirn ent 29. A method of treating of agitation or the signs of agitation in a subject in need thereof, wherein said agitation is associated with an GED/'iiPl) procedure (eg MR1, CT or CAT scan, lumbar puncture, bone marrow aspiration/biopsy, tooth extraction or other dental procedures), and said method comprises administering to said subject subtingually an effective amount of Dexmedetomidine or a pharmaceutically acceptable salt thereof. ['l50} E.mbodi.m.ent 30. A method ct‘ treating of agitation or the signs ct‘ agitation in a subject in need thereof, wherein said agitation is associated with an alcohol and substance abuse withdrawal and said method comprises administering to said subject sublingualiy an et7t‘ecti_ve amount of Dexmedetomidine or a pharmaceuticaliy acceptable salt thereof.

{E51} Embodiment 31. The method according to "Embodiment 29 or 30, wherein said Dexmedetomidine or a pharmaceuticaiiy acceptable sait thereof is subiinguaily administered at a dosage that treats said agitation or the signs of agitation without causing significant sedation. ['i52_} Embodiment The method according to Embodiment 31, wherein said dosage of Dexrnedetomidine or a pharmaceuticaiiy acceptabie salt thereof is in range of from about 3 micrograms to about 100 micrograms (e. g. about 5 micrograms to about lOO micrograms, about micrograms to about 90 micrograms, about 5 rnicrograms to about 85 rnicrograms, about 5 micrograms to about 80 micrograms, about 5 micrograms to about 75 micrograms, about 5 micrograms to about 70 microg.ran1s, about 5 micrograms to about 65 micrograrn s, about 55 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 33 micrograms to about 30 micrograms, about 5 micrograms to about 25 micrograms, about 5 micrograms to about 20 microgra.n'1s, about 5 micrograms to about l5 microgram s, about 5 micrograms to about it": micrograms, less than 10 micrograms (eg about 5, 6, 7, 8, or 9 micrograms), about 10 micrograms, about 12 rnicrograrns, about l4 micrograms, about i5 micrograms, about 16 micrograms, about 18 micrograms, about 20 micrograms, about 39 micrograms, about 50 n:iicrograms). id="p-153" id="p-153"

[153] Embodiment The composition or method according to any preceding Embodiment, wherein Dexmedetomidine or a pharmaceuticaliy acceptable salt thereof is administered once, twice or thrice daily or on an "as needed" basis.

WO 2018/126182 PCT/US2017/069030 id="p-154" id="p-154"

[154] Embodiment 34. The composition or method according to any preceding Embodiment, wherein 'Dexrnedetomidine or a pharrnaceuticaiiy acceptable salt thereof is administered in a manner that produces a therapeutic effect in iess than about 60 minutes, particulariy within about 30 seconds to about 30 minutes.

{I55} Embodiment 35. A method of treating agitation or the signs of agitation in a subject in need thereof comprising administering su.biingu.ai1y to said subject an effective amount of an alpha-2 adrenergic agoni st or a pharm aceuticaiiy acceptable sait thereof. [1 56} Embodiment 36. A method of treating agitation or the signs of agitation in a subject in need thereof comprising adini.nis'terin.g to said subject an effective amount of an aipha—2 adrenergic agonist or a pharmaceuticaiiy acceptabie salt thereof, wherein said aiphawll adrenergic agoni st is subiinguaily a.dn:iiiiistered at a dosage that treats agita.ti_on or the signs of agitation without causing significant sedation.

{I57} Enibodirnent 37 . The method according to Ernbodirnent 35 or 36, wherein said dosage of aipha—2 adrenergic agonist is in range of from about 3 micrograms to about 100 micrograrns (eg. about 5 micrograms to about 100 micrograms, about 5 micrograms to about 96 micrograms, about 5 micrograms to about 85 mi crograrns, about 5 micrograms to about 80 micrograms, about 5 micrograms to about 75 micrograms, about 5 micrograms to about 70 micrograms, about 5 mi crogranis to about 65 micrograms, about 5 micrograms to about 60 micrograms, about 5 microgranis to about 55 micrograms, about 5 micrograms to about 50 micrograms, about 5 micrograms to about 45 rnicrograrns, about 5 rni.crograms to about 4% micrograms, about 5 micrograms to about 35 micrograms, about 5 micrograms to about 3t‘: micrograms, about 5 rnicrograms to about 25 micrograms, about 5 niicrogranis to about 20 micrograms, about 5 micrograms to about 15 micrograms, about 5 micrograms to about i0 micrograms, less than '10 micrograms (eg. about 5, 6, 7, 8, or 9 micrograms), about 10 micrograms, about 12 micrograms, about 14 micrograms, about 35 rnicrograms, about 16 micrograms, about 18 micrograms, about 20 micrograms, about 30 niicrograms, about 5:_’‘: mi crograrn s).

{E58} Embodiment 38. The method. according to Embodiments 35, 36 or 37, wherein said subject is m a.n'irnai, preferably human. ['5 59} Embodiment 39. The method according to any one of Embodiments 35 to 38, wherein said agitation is associated with a neurodegenerative disease.

{I60} Embodiment 40. The method according to Embodiment 39, wherein said neurodegenerative disease is selected from Alzheimer disease, fronto~tempora1 dementia (ETD), dementia, dementia with Lewy bodies (DLB), post-traumatic stress disorder, WO 2018/126182 PCT/US2017/069030 l’arl [U32] Embodiment 42. The method according to Embodiment -ill, wherein said neuropsychiatric condition is selected from schizophrenia, bipolar illness (such as mania, disorder), delirium, and depression.

H63} Enibodinient 43. The nziethod according to Ern.bodirn.ent 39, wherein the agitation i.s associated with sundown syndrome in dementia or Alzheinier’s disease.

H64} l?.n1l_>od.in1ent 44. The niethod accordi.r1g to any one ofﬁnmhodiments 35 to 38, wherein said agitation is associated with an OPD./'ll’D procedure (e. ll/lRl, CT or CAT scan, lumbar pimeture, bone marrow aspiration/’hiopsy, tooth extraction or other derital procedures).

[M35] Embodiment 45. The method according to any one of Enihodiments 35 to 38, wherein said agitation is associated with an alcohol and substance abuse withdrawal. [l 66] Eirnbodirnent 46. The method according to any one oflilrnbodiinents 35 to 38, wherein said alpha-2, adrenergic agonist include, but is not limited to, Clonidine, Guanfacine, Guanahenz, Guanoxahenz, Guanetliidine, Xyiazine, Tizanidine, Medetoinidine, Dexmedetomidine, Methyldopa, Methylnorepinephrine, Fadolrnidine lodoclonidine, ApI'i:lC-l.Ot1i.diIlC;._ Deton:1idi.ne, Lofexidine, Anii.tra.z, Mivazerol, Azepex.ol, Talipexol, Rilmenidine, Naphazoline, Oxymetazoline, Xyiometazoiine, Tetrahydrozoline, ‘Traniazoline, Talipexole, Roinitidine, pr'opylhexedi'ine, Noi'feneli'ii'1e, Ul<.l 4304, i)J—7l4 l , Octoparnine, Moxoiriidine, S’l‘~9], RW§E—52353, 'l"CG-1000, 4~(3- 4_(3- Lidamidiire, Tolonidine, aminoniethyl-cyclohex~3 -enylni ethyl} l ,3 -dihydro—in1ida.zole—2—thione, and hydroxyrnethyl~cycloheX—3—enylmethyl)~l ,3~dihydi'o~—irnidazole-2—thione or a pharniaceutieally acceptable salt thereof. ['l67] The Eniibodiniients hereinabove are not intended to be limiting, and, in practicing the present invention, alternative or additional Embodiments may be provided.

Vll} . EXA M PL ES: The following "Examples are intended to he illustrative and not limiting: WO 2018/126182 PCT/US2017/069030 Examggle l: Formulation 1: Sub-lingual Tablet Table l: Coninesitien fer a tvpieal Sub-lingual tablet fennularien used for sulalinwual delivery ingredients Quantity Ranges Dexniedetemldine E-Iliill 50 (equivalent to base) micrograms l’0‘~'id0H9 5.0 ing 1.0 — 10.0 % Croscarrnellose Snclium 740 mg 5 _ 15 :3/0 Sucmlﬂﬁs 1.0 mg 0.05 — % Magnesium Stearate Q75 mg 0 1 _ 2.9 9/0 W6 0.75 mg 0 1 — 2.9 % Wmilﬂl qs 75.0 mg q 3. lO0 % Water q_S i>;li?ni:ilf§:_9_ll_1_ii31e.:i2:5_2s2es; Dexmedetomlrline hydrochloride and excipients such as binder and sweetener are dissolved /disperse<:l inte a pharmaceutically acceptable solvent (meferahly water) and this solution is used to granulate the sifted blend efall O'll"if.’,I°l,llgI'6(iiE.21’1‘lS except lubrlrzanr and glidam in suitable nrixer/granularer. The granules are then dried in a fluid—l)ed drier or ether suitable one such as rmy drier. The dried granules are then sized apmepriaiely in qua.dro—eo-mill ern1n}ti—mill. The sized granules are then leaded into a suitalile blender such as V-blender and lubricated with Magnesiuni stearate and Tale and then {lie ﬁnal lubricated blend is then used for compressing into tablets of specific dirnensiens using appromiate tooling.

Fermulatiml 2: Suimlinginal Film 'l7a.ble 2: Coinpesition fer a. tvnieal Sub-lingual film ferniulailrin used fer sublinszual rleiiverv ingredients Quanim/iv, Raniges Dexmedetemidine HCl 5 0 {equivalent to base) micmgrains Pelyethylene exicle 50 mg 3 25 % WO 2018/126182 PCT/US2017/069030 Polyethylene Glycol :, 0 mg 3 25 % SUCI‘ﬁl0S€ 0.2 mg 0.05 3.0 % le*ia\''<*‘"m% agent q.s. 0.01 1.0 % Cﬁlsfine 32%" qs. 0.01 1.0% Povidone (1.5. 50 mg qs. i00 % "Manufacturing process Dexmedetomidine hydrochloride along with film forming polymers and other exeipients are dissolved /' dispersed into a pnar‘n‘iaeeutie-aliy a.ceepta.ble solvent. ( preferably water) and the resulting solution is then coated ( spread / cast) on an inert backing layer. Dexmedetornidine i’i‘_V(lI'OCl'1l,Ol"'i,(lf3 containing pol ynrerie iayer is further dried, separated and out into suitable sizes using appropriate die tools and their packed as per the requirerrient.

Formulation 3: Sub~lir:2ual Sprav Table 3: Composition for a typical Sub—iir1,<.>,11ai spray formulatiori used for subiinrruai deiiverv Ihgredierits Quantity Rariges Dexniedetornidine HCl 50 (equivalent to base) micrograms Propyiene Glycol lg EL 10 _ 40.9 9/0 Alcohol 5 5114 L0 _ 43;; 9/9 Citric acid Q2 mg Q‘; _ m % Pepperniirit (iii 1 P114 Q05 3.9 % Puriﬁed water qbsb mg ‘UL gs‘ 3 0g % Mariui'"aeturin.6 rocess Dexmecletomidihe hydrochloride along with all other excipierits are mixed in a suitable order.

The resulting solution /' dispersion is then filled into spray canisters using appropriate tooiing.

They are further processed with Metered nozzles so that a S‘p€Ci,‘.iEl ed amount of Dexriiedetorniriine is delivered after actuation each time.

WO 2018/126182 PCT/US2017/069030 Fnrinnlation I-‘l: Snb—lingnal Liquid drops Table 4-: Composition for tvnicel Sub—linguai liquid tlrons used for sublingual rleliverv ingredients Quanﬁty Dexrnecleto-niidine i-{Cl (equivalent to base) 10 mg l\loi‘inal saline (0.9% Soclioru Cl'1iOl'l,(.lE3) (ls Manufacturing rocess Dexinedetomidine hydroeltloride «Catalogue No. SMl'_,O956) was dissolved in hlorinal saline in order to yield the concentration of ling/ml of the suhlingual drops.

Exarnple 2: Evaluate the effect of suhlingual and intravenous aclrninistration of Dexniedetomidine hydrochloride in rat ‘resident—intrutler’ model of agitation or aggression at varying dosages.

The resi.dent— intruder model is an established precliui.cai model of aggression. and agitation, and allows spontaneous and natural expression of both offensive aggression/’agitatiori and defen.si.ve helziavior in laboratory rodents in a semi. natural. laboratory setting. When rodents are exposed to a novel male in their home eage environment, they perceive the novel male animal as an "intruder" and demonstrate a repertoire of defensive behaviors such as ano—genital sniffing, chasing, biting and attaciring (Nelson et ai, ILAR Journal (2000) 41(3): l53~l6‘2).

Materials and Methods: Animals: 12-l3weel< old male Wistar rats weighing 380 400g were used as resident males. 74% weeks old male rats weighing 280 — 300g were userl as the "intruder". Resident rats were housed with female rats for 8 days to establish territoriality. The intruder rats were housed in groups of 3 with other male rats of similar age/body weight. All animals were maintained in a controlled environrnent with 22:}.-.3" C ternperature, SC)-£20‘?/n hurnidity, a light/dark cycle of i2 hours each and il 5----20 fresh air changes per hour and had access to food and water ad-lihituin.

All anirnal experirnents were conducted in accordance with the guidelines of the Cornniittee for the Purpose of Control and Supervision of Experiments on Animals (CPCSEA), WO 2018/126182 PCT/US2017/069030 Government of India the Association for Assessment and Accreditation of Laboratory Animal Care international QAAALAC). .lForn'1ulation tested: The required quantity oflioirrtulation. 4 of dexrn edetomidin.e hydr'ochloride was weighed and serial dilutions were made to obtain respective doses as per the Table 5.

Dilutions were Egepared fresh every day prior to dosing using 09% normal saline from the t"orrnulati on 4 for the entire study. l3Lr Animals were housed with the female rat for an additional day. (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 l’acili‘tate dominant, aggressive behavior in the resident animals. After randomization, animals were assigned a permanent number. Cages were ideiititied by cage cards indicating the study number, study code, group number, sex, dose, cage number and animal nurnber details.

Resident male rats were dosed with different doses of Dexrnedetoniidine hydrochloride (Dex) l5 minutes prior to the behavioral testing either suhlingually or intravenously (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. Dexrnedetomidine hydrochloride was then administered sublingually liquid drops at speciﬁc concentration using a rnicropipette and allowed to be absorbed for a duration of 50-69 seconds. Diazepam was used as a reference coinpound and was dosed intraperitoneally. Vehicle controls were trea.ted with 0.9% saline adrninistered sublingually or in'trav‘enous.l y, [Normal controls (NC) did not received any treatment.

The behavior of the resident rat was recorded using an overhead video camera for 15 minutes and oflline behavioral analysis was done using the Noldus Ethovision XT softvar'e. To distinguish the resident rat from the intruder rat in the video recording, the intruder rat was rnarl§lC paint. For analysing the potential effects of Dexrnedetornidine hydrochloride on agitation, we quantified various behavioral parameters such as anogenital WO 2018/126182 PCT/US2017/069030 sniffing, chasing, biting, attaching and latency to attack as well as neutral behavioral parameters such exploration grooming, and irnmohiile quiet ’tiﬁ:1€4 Table 5. Efficacy Study: Drug treatment groups Group No. of Cohort l Coliort 2 No. animals (Sublingual dosing ~ (Intraveiious dosing ~ Fornitilation 4 adjusted to Dexniedetomidine hydrochloride following doses) in water or Normal saline) l 8 Norrnal Control 2 8 Vehicle control Vehicle control 3 8 Dexrn ede*tomidin.e hydrochloride Dexmedetoniidine hydrochloride (Gina/ks) (0.5ns/ks) 4 8 Dexniedetornidirie hydrochloride Dexrnedetoinidine hydrochloride (1 mtg/kg) (1 Oitg/kg) 8 Dexinedetornidine hydrochloride Dexrnedetornidine hydrochloride (E .5tis/l Results: The present study was performed to evaluate the effect of suhiingually/intravenously administered different doses ofﬁexinedetornidine hydrochloride on agitated behavior in a rat I°€3Sl(l€3fil7~lIli‘i’Llilt3l‘ model of aggression and agitation behavior.

Effect of siihlingnally/intravenously adniiriisteretl Dexniedetornidine liydroehloride on aggressive/agitative behavior in the rat resident intruder model: The rats demonstrate a variety of defensive agitated behaviors such as anogenital sniffing, olriasing, biting and attat:ki.ng (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 rotate to protect their home terri*toryi in the present experiments, vehicle treated rats dernonstrated a wide repertoire of aggressive behaviors and the intruder rat was subjected to anogenitai snifiirig, attacir, chasing and biting hy the resident or dorninant rat.

WO 2018/126182 PCT/US2017/069030 Dexrnedetornidine hydrochloride (Dex) administered snblingnaliy reduced the frequency and duration of these behaviors in a dose related manner (Figure 1A, and Figure lit). Signiﬁcant reduction was observed in chasing and attacking compared to vehicle control group. Similarly, intravenous adrninistrati on of dexmedetomidine hydr‘ochloride (Dex) reduced all the indices of aggressive and agitated behaviors (Figure ltil and Figure B3‘). A signiti cant reduction in anogenital sniffing, biting and attaching compared to vehicle controls was observed at doses above 06 Eng/kg (Figure ll: and Figure ll)). Pteference cont pound diazepani (Sing/kg, ip) also produced significant reduction in all the indices of aggressive and agitated behaviors evaluated in this study (Figure l.A— ll?) Effect of suhlingually/intravenously administered Dexmedetnrnidine 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 attack the intruder rat. We observed an increase in the latency to a‘ttacl:<’ the intruder rat following sublingual administration of Dexmedetomidine hydrochloride (Dex) in a dose related fashion indicating a reduction in aggression and agitation. (Figure 2A). When Dexmedetornidine hydrochloride (Dex) was administered intra.venotisly, a similar increase in the latency to attacl: the intruder rat occurred in a dose related fashion that was significant compared to vehicle controls at a dose of 3ttg/kg (Figure 28). Anirnals trea.ted with Cli£i.2'.€p3Ill demonstrated a complete lack of attacking behavior ( Figure 2A and 28).

Effect of snblingnally/intravenously administered Dexmedetomidine hydrochloride on Neutral behaviors Neutral behaviors like grooming, exploration and intnioliile/rntiet time were assessed following treatment with Dexniedetoniidine hydrochloride. No significant changes occurred in the grooming and explora.tior1 foil-owing su‘oli.ngual a.dministi'ation of Dexniedetornidine hydrochloride except a reduction in exploration observed at doses of l.5 ng/kg & 3ttg/kg (Figure 3A. and 33), compared to vehicle controls. Similarly, intravenously admi.ni.s'tered Dexmedetomidine hydrochloride did not significantly affect grooming and exploration in comparison to vehicle controls except at a dose of 3 ;ig,r’l.i‘niedeternidine hydrochleri de as compared to the vehicle control grcup. 3. No changes were observed in neutral behavior of animals, indicating the lack ct‘ overt a1:ixiety—like behavier in the resident rats treated with sublhtgually administered Dexniedetornidine hydreclileride. 4. Of the doses that were used in the study (0.5 — 3!ug/l<:g), doses of l— ‘l.5_ug/l<:g (doses administered su.‘olinguall.y or i.ntraven0usl.y) elifectiv/el.y reduced the behavioral indices of aggression and agitation without majorly impacting the neutral behaviors.

Conclusion: Dexniecletcrnidine l1y(ll‘GCillOl"lCi€ effectively reduces various intlices of agitatlnn and aggression in rat resident intruder model. Dose of l -1.5 ug,/kg eft‘ec‘tively reduced the behavioral indices of aggressl on and agitation without rnaj erly impacting the neutral liehaviors.

In the present study the efficacy cf sublingually adrninistered Dexrnetletcniidine hydrochloride correlates with intravenously administered Dexinedeteniidirie hydrochlerltle at these closes (Table Group adniinnttration using Stud ent’s t—test p values obtained after‘ statistical comparison of sublingual vs intravenous route of Duration (sec) Chasing Biting Attacl<:/.l?'igliting Anogenital— Latency tn attack sniffing WO 2018/126182 PCT/US2017/069030 NC l .000 1.000 l .000 1000 l .000 Vehicle 0207 0.069 0.290 0.753 0. l 36 l g,i.g/'l-zg 0.506 0. l02 0.204 0.090 0.207 l.5;.Lg/kg 0.l25 0.059 0.l07 0.727 0.508 Table 6: No significant differences (Le. similar elleoi: via sublirignal and intravenous routes} were observed in the dnratinn of the behavioral imlites of a.ggre.<.:sion and agitamsn (i:.l3asing, biting, a.ttael~;, anogenitai sniffing i?af.e‘.’.§3{°.y to attatélig when cnnnpared between snljslingnal and intravenous routes of dexnzezdetoniidine lsydrmzizlrwlde administration at doses of l and 1.5 gig/kg. Statistical using student Hest. *n<0.,05., **p<=€l.{B{i€}l Snbiingual vs intraveiinus routes of adininistratlon.

Based on l~l .5 _ug/kg rat eff} oaey doses, the liurnan equivalent sublingual doses are calculated to be 0. lél gig/‘kg & 0.242 gig/'l Example 3: Estimation of Dexinedetnmidine (lL5—3ng/kg) in Rat plasma samples by LC— MS/I\/IS illbjective: To estimate ﬂexmedetoinidine levels in rat plasma samples obtained after dosing animals Via intravenous and sublingual routes at doses of 0.5; 1, l5 and Bng./kg.

Blood colleeti on: To deterrnine the plasma concentration of dexniedetornidine, Dexinecletornidine hydrochloride was administered sul>lingua.lly or intravenously in rats (n===3) at different doses (Formulation 4 adjusted to 0.5, l, 1.5, 3ag./l<;g). Blood was collected under mild isoﬂurane anesthesia from the retrdorbital plexus at O, 5, 15, 30, 60 and E20 minutes post dosing. Plasma was separated and stored at —80°C until Dexrnedetornidine concentration was analyzed.

Materials and methods Prepamﬂon r»y’sto'i/zciczrd .mZu lions A standard stock solution of dexmede‘tomidine hydrochloride was prepared by dissolving l.358n1g of dexmedetomidine hydrochloride in 1358 pl of milli—Q water to achieve a concentration of 829.07ln1g«’inl. Working solutions of different concentrations were prepared by using diluent (methanol: water (50:50) 9‘/éa WV). 'l‘olbutarnide was used as an internal standard and its stock solution was prepared by dissolving 25mg of tolbutarnide in l000_ul ofDMSO to achieve a concentration of 25n1g/ml. Working WO 2018/126182 PCT/US2017/069030 solutions of different concentrations were prepared by using a diluent (iaeetonitrilez water (50:50) % V/V).

Solution preparation for" SPE and elrirom atography: lVlo‘oi.le phase A ( l Orrim ar.nrn.oniurn. forrnate, pH 3 50): 0.6306gins of ammonium forniate was weighed and transferred to a l0OOml 1'eagerit‘oottle. To tliis, lOO0nil. ofrnilli :1 water was added and pl:-li of the resulting solutiori was adjusted to 3.5 using formic acid.

Mobile phase B: l0O% aeetoriitrile Diluent (rn.etl:ianol: water (56:50) % v/V): 50ml of methanol was mixed with 50 ml of lilllll-(.1 water. Resulting solution was used as diluent.

Wash solution: lllfﬁul of anirnonia was mixed with 100ml of milli q. Resulting solution was used as wash solution.

Elution solvent: lﬁﬁul of formic acid was mixed with lO0ml of aeetonitrile. Resulting solution was used as elution solvent.

Analytical Methods: Samples were analysed by using Agilent l290 lrifinity ll HPLC system coupled to AB Sciex Triple Quad instrument (Al-$5000). Cnroinatographic separation was done using Agilent Zorbax Eclipse plus Cl 8 column (50*'2.l_n:1n‘1, l.8um) in gradient mode.

The mobile pliase consisted of lDnil\/l Ammonium Forrnate with pH 3 . 5 (Mobile phase A) and lOi’.‘i% Aeetonitrile (Mobile phase B). The column temperature was 40°C and flow rate was 0.35 nils/rnin. The M S instrument. was operated in the positive mode (E81-t-—). For analysis, 2 pl, of sample was injected into the LOMS/"MS instrument. Auto sampler temperature was '/"C.

Quality control {QC} sarnples were prepared as follovving as per table 7: Table 7 Dexruedetomidin Vglume QC e cone {Solution Qf Blank Total Final Calibration ll) A‘ t - ) Sglumm plasma (_uI_.) Volume l:§J.L:l Cone (pg/rnl.) ' I ' A i’ L WO 2018/126182 PCT/US2017/069030 l.ll4 2 48 50 44.57l LQC .424 2 48 50 lll-856.962 928.560 2 48 50 371 42.406 HQC Sample preparation WCX SPE 96 well plate was used for sample preparation. :30pl of plasma sample was used for extraction. Along with study samples, one set of linearity and two sets of quality eontrols(QC)were also processed.

Sample pretreatment: To 50pl of plasma, lOpl of tolbutaniide worlring solution was added ( Tolbutan1i.de 250ng/ml). After rnixing, SG_u_l_, of buffttr solution (lOrn.M Ammoniurn .Forn'1ate pH 3.5‘) was added. Contents were vortex mixed and loaded to preconditioned SPE plate.

LC—MS/MS ANALYSIS After placing the cartri clges in the negative pressure SPE unit, they were conditioned by passing 200al of lOO% metlianol followed by 200p.l of water. The pretreated plasma samples were then loaded to ‘tilt: pre—conditioned cartridges.

After loading pretreated plasma samples, cartridges were waslied with l Oﬂpl of 0. 1% ammonia solution. Finally, bound analyte was eluted witli 50p]. of O. l% formic acid in acetoni‘tri.le. This step was repeated twice for complete elution. Final eluent Volume was lOO _nl_... To lOO pl, of eluent, 50 l.tL of lGrnM ammonium formate (pH 3.5) was added samples were vortex mixed and transferred to a 96-well .l.-lPl,C sample plate (Agilent) and sulirnitted for LC-l‘vlS/ll/liS analysis. For LCmMS/lylS analysis, 2 pL of sample was injected. Calibration standards and QCs were processed the same way as done for study samples. ll/lean plasma concentrations of Dexniedetomidine in various rat plasma samples at Various time points was determined by l_,C~MS/MS method using Analyst l.6.2 software (Table 3 and Figures 4A and 4B) with a calibration curve in the range of 0.01 l—53.06’l ng/nil prepared in blank rat plasma matrix. The cal.i‘oratiol1 curve was titted by linear regression. The concentrations in the QC and test samples (pg/inL) were obtained from the Analyst software based on the calibration curve. Acc.epta.nce criteria for the oalforation curve and QCs are as t"ollows: l) At least 75% of tlie non—zero calilnation standards must be included in tlie calibration curve with all back—calculated concentrations within i 20% deviation from nominal WO 2018/126182 PCT/US2017/069030 concentrations (except for the lower level of quantification, LLOQ, where i 220% deviation is acc:epta.ble). 2) The <:orrela.ti.on coef‘ﬁci.ent (r) of the caﬁbration curve must be greater thari. or equal to 0.99. 3) At least two~ti1irds (4 out of 6) QC samples must be within :‘c 20% relative error (aeeura.c.y) Results: Table 8: Mean rat plasma concentrations foiiowing Sublinguai or Intravenous clexntedetemidine hy’drochloride administration at varying doses Mean Concentrationt in pg/mL at Concentration in pg/mid at various time paints after dosing various time points after dosing 0 5 15 30 60 120 min min min min min min Gmin 5min 15 30 60 120min min min min BL 48 :t 5} J: 87 3: i7 :t BLQ BLQ '70 :L 461: 35 :i: E9 5: BLQ Q 29,}. 89.7 0.7’ 7.2 14.2 4.9 3.5 BL Slzt. 47$ 435: Bi 1.9 Q 44-.’.7 22.4 13.5 2.8 $7.07 ELQ 174- :i: 90 :1: 45 :5: 63 5: i‘3i..Q ,l2.5 12.} i.7 58.0 BL 84 + 27 i 3} 1 37 i 36 i ELQ 158 :2 114 65 '1 3.1: 2}. -_t 8.89 Q 37.7 7.} 5.5 i6? 636 56} :1; EH} E03 }.’7 BL 771i 431i 160i 936i ‘Bi Q 52.0 E31) H79 21.5 53.95 BLQ 471i 266 i'59i 8/ "V 34 i 9.6}, 24.9 1- I80 E 3i1.6 .4 .t.. 6-» i ELQ: Below the Lowest limit of Qua1ttificatio11 of the assay (LOQ: 0.05ng/ml) SL: subiingual; i.v.: intravenous Data expressed. as Mean i interpretation and conclusion Following sublingual administration ofDeXrnedetornid.ine ltydreciiloricle, a dose~reiated effect 21.5 on plasma concentrations was observed at doses ranging from 0.5-3 gig,/kg (Figure 4A, tabie 8).

Foilowing intrai/eno1.is administration of Dexmedetomidine hyrirochioride, a dose—dependent effect on plasma concentrations was observed at doses ranging from 0.5—3;.tg/’kg (Figure 4B, table 8).

Doses of 1 and 1 .5g.,tg/kg effectiveiy reduced various indiees of agitation and aggression without rnajoriy impacting neutral behaviors. Plasma concentrations foliowing administration of dose WO 2018/126182 PCT/US2017/069030 0f '1 pg/kg (via sublingual and intravenous mute) between "E 5 to 30 min (time correspending to the time ofbehavioral response observed in the eﬁiczacy study; drug administered 15 min pric-er to agitatien hehaviol‘ test animal ehserved for 15min) range from 43 i ‘E35 to 90 i 12.1 pg/ml (Tabie 8), Similarly, piaema conceratratiens folkxwing administra.tie01'1 of dose of 1.5 g,a,g/kg (via sublingual and intravenous route) between 15 to 30min range from 27 vi: 7.} I M 2% 1.7pg/m1(Tabie 8).

WO 2018/126182 PCT/US2017/069030

Claims

1.Claims:Claim l. A method of treating agitation or the signs of agitation in a subject comprisingsuhltirigually administering to said subject an effective amount of Bexinedetoinidine or apl1a.rma.c.eutiea1ly acceptable salt thereof without also causing significant sedation.Claim

2. A method of treating agitation or the signs of agitation in a subject comprisingsublingually administering to said siihject an effective amount of Dexmedetomidine or aphaimaceiitically acceptable salt thereof, wherein the agitation is associated with aneuroclegenerative disease.Claim

3. The method according to Claim 2, wherein the treatment is effective to suppressagitation or the symptoms of agitation in a sub} ect without also catising signiticaiit sedation.Claim

4. The method according to Claim 2 or Claim 3, wherein said neuroclegeiierative diseaseis selected from the group consisting of Alzheimer disease, froiitotemporal clementia (E"I"D),dementia, dementia with Lewy bodies (DLB), post—traiimatic stress disorder, Parkinsoifsdisease, vascular dementia, vascular cognitive impairment, l-ltintingtorfs disease, inultiplesclerosis, Cretitzfel(lt—lal