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WO 2017/149392 Al 8 September 2017 (08.09.2017) P O P C T

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WO 2017/149392 Al 8 September 2017 (08.09.2017) P O P C T (12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) (19) World Intellectual Property Organization International Bureau (10) International Publication Number (43) International Publication Date WO 2017/149392 Al 8 September 2017 (08.09.2017) P O P C T (51) International Patent Classification: HN, HR, HU, ID, IL, IN, IR, IS, JP, KE, KG, KH, KN, A61K 9/00 (2006.01) A61P 25/00 (2006.01) KP, KR, KW, KZ, LA, LC, LK, LR, LS, LU, LY, MA, A61K 9/10 (2006.01) A61P 25/14 (2006.01) MD, ME, MG, MK, MN, MW, MX, MY, MZ, NA, NG, A61K 31/00 (2006.01) A61P 25/18 (2006.01) NI, NO, NZ, OM, PA, PE, PG, PH, PL, PT, QA, RO, RS, RU, RW, SA, SC, SD, SE, SG, SK, SL, SM, ST, SV, SY, (21) International Application Number: TH, TJ, TM, TN, TR, TT, TZ, UA, UG, US, UZ, VC, VN, PCT/IB20 17/000266 ZA, ZM, ZW. (22) International Filing Date: (84) Designated States (unless otherwise indicated, for every 3 March 2017 (03.03.2017) kind of regional protection available): ARIPO (BW, GH, (25) Filing Language: English GM, KE, LR, LS, MW, MZ, NA, RW, SD, SL, ST, SZ, TZ, UG, ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, RU, (26) Publication Language: English TJ, TM), European (AL, AT, BE, BG, CH, CY, CZ, DE, (30) Priority Data: DK, EE, ES, FI, FR, GB, GR, HR, HU, IE, IS, IT, LT, LU, 62/303,494 4 March 2016 (04.03.2016) US LV, MC, MK, MT, NL, NO, PL, PT, RO, RS, SE, SI, SK, 62/303,508 4 March 2016 (04.03.2016) US SM, TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, GN, GQ, GW, KM, ML, MR, NE, SN, TD, TG). (72) Inventor; and (71) Applicant : ANAVI-GOFFER, Sharon [IL/IL]; 28 Haha- Published: das St., 4481300 Oranit (IL). — with international search report (Art. 21(3)) (81) Designated States (unless otherwise indicated, for every — before the expiration of the time limit for amending the kind of national protection available): AE, AG, AL, AM, claims and to be republished in the event of receipt of AO, AT, AU, AZ, BA, BB, BG, BH, BN, BR, BW, BY, amendments (Rule 48.2(h)) BZ, CA, CH, CL, CN, CO, CR, CU, CZ, DE, DJ, DK, DM, DO, DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, (54) Title: SELF-EMULSIFYING COMPOSITIONS OF CB2 RECEPTOR MODULATORS Figure 1 Saline+oral formulation (n=6) PCP 5mg/kg+oral formulation (n=6) PCP 5mg/kg+BCP 5mg/kg in oral formulation (n=4) 80 - ♦- PCP 5mg/kg + BCP 10mg/kg in oral formulation (n Two-way ANOVA 60 Saline+oral vs. PCP+oral J P = 0.0316 PCP+oral vs. PCP+5 mg/kg BCP P = 0.0267 2 0 2 4 6 8 Time (min) (57) Abstract: Disclosed are stable self-emulsifying compositions comprising at least one CB2 receptor modulator, a self-emulsify ing vehicle and optionally at least one antipsychotic agent for use in the treatment of mental disorders, methods of preparing such compositions and methods of treating mental disorders using same. Disclosed are also stable sell -emulsifying compositions com - © prising beta caryophyllene (BCP) or HO-308 as sole active agent or in combination with humulene, an antipsychotic for use in the treatment of schizophrenia, methods of making such compositions and methods of treating schizophrenia rising BCP. Disclosed are also stable self- emulsifying compositions comprising 4-0-methylhonokiol (MH) as sole active agent or in combination with caryo - o phyllene oxide, and optionally at least one antipsychotic agent for use in the treatment of tic disorders, methods of making such com positions and methods of treating Tourette syndrome using MH SE E S V G COMPOSITIONS O CB2 RECEPTOR MODULATORS CROSS REFERENCE TO RELATED APPLICATIONS This application claims priorit to U.S. v Patent Application Serial No. 62/303,508, filed o March , 2016, and to V Provisional Patent App i tio Serial, 62/303,494 filed on March 20 , th entire contents of each of which are hereby incorporated by reference i their entirety, FIELD OF THE INVENTIO The present invention is in the field of pharmaceutical compositions and discloses nove compositions for the oral administration of Caiwiabinoid Receptor Type 2 (CB2 modulators an optionally of antipsychotic agen for the treatment of mental disorders BACKGROUND Mental disorders can arise fro multiple sources and affect a large percentage of th population. There are a range of different types of treatment of mental disorders and what s ost suitable depends on the disorder a d oft the individual. Schizophrenia is mental disorder which affects about 1% of the population (Lewis ¾ Lieberman, 2000), and genetic and environmental factors underlie the eventual eruption of the disease (Ross, 2006 }. Schizophrenia is often chronic, characterized by deterioration of social contact cognitive deficits, anxiety and depression, resulting in suicide in about % of the schizophrenic population ew ¾ Liebemian, 2000 . Another important mental disorder is tic disorders, specifically, To rett syndrome (TS), which is characterized by m motor tics and at least one vocal tic. Starting at childhood, T includes ties like blinking, coughing throat clearing, sniffing and facial movements. About 1 of the school-age children an adolescents have Toi ette's .SUMMARY Aspects of the i relate to stable e f- nlsif ing compositions comprising at least one €B2 modulator, a self-emulsifying vehicle and optionally at least one additional antipsychotic agent, methods of the compositions and methods of treatment using same for the t eai nt of mental According t aspects illustrated therein, there is provided stable e f-e s fyir g compositions comprising a therapeutically amount of at least one CB receptor modulator- n substantially pure form, a self-emulsifying vehicle an optionally a therapeutically effective amount of least one antipsychotic agent, for use treating mental disorder in a patient in need thereof. I some embodiments, t e self-emulsifying (o self-e u ifiab e drug delivery systems (SEDDS) can be liquid compositions generally used for ora deliver '. or m r particularly designed for improved delivery of drug moieties with poor solubility (see Nagaraju J. Seminar, M. Pharm. II Sem. 20 , Kakatiya University, Warangai, Department of Pharmaceutics, University College of Pharmaceutical Sciences. According to aspects of the invention, the se -em sify in drug delivery system (SEDDS) compositions enable to reduce the oral dose to correspond to the dose given by iwtraperitoneai injections or a lower dose. Accordi to other aspects- of the Invention, the seif e f i&g dru deliver system (SEDDS) compositions potentiate the therapeutic actions of a CB2 receptor modulator, reducing the required do.se hence its toxicity. According to aspects of d invention, he compositions of thi invention can be formulated as a stable self-emulsifying dreg delivery system (SEDDS) comprising at least one CB receptor modulator, optionally at least one antipsychotic age t and a .self-emulsifying vehicle comprising at least one oil, at least one surfactant with HLB<9, at least one surfactant with B> at least One co-surfactant and at least one antioxidant and' r free-radical scavenger. The antioxidant and/or free-radical scavenger can e selected from vitamin E, d alpha-tocopherol ( - w/w), di-alpha-tocopherol (2-i 5%w/w), dl-aipha-tocopheryi acetate ( % w/w), mixed tocopherols (alpha, beta, gama - 1-10% w/w). d-a p a-tocophery acetate (2- 13% w/w), butylated hydroxyanisoje (BHA, 0.01-0.5% w/w), tocophersolan ( PG . tocopherol PEG est e succinate) (2-10% w/w), vitami , e a te ., butylated hydrox toluene, butylated hydroxyanisole or other FDA-approved antioxidant listed in the FDA's nactiv Ingredients Database ( D), and combinations thereof. n some embodiments, the ratio of antioxidant/CB2 modulator, such as but not limited to BC , is from 1:1 to 2:1 w/w. In so e embodiments, the antioxidaiit /CB2 modulator is fro h to 3:3 w/w. n some embodiments, th ratio of an ito tda « CB2 modulator is from 1 :1 o 4:lw/w. some en bodi err , the ratio of an ioxidaj t B2 modulator is from 1: 1 to 5: w/w \ some embodiments. the ratio of antioxidant/CB2 modulator is rom 2 :1 to 3: 1w/w. In some embodiments, the ratio of antioxidant/CB2 modulator is from 2 : > 4:1 w w. n so e embodiments, the ratio of anti x da t CB modulator is from 2 : to 5: w/w. n some embodiments, the ratio of antioxidant CB2 modulator is from 3:1 to 4 :1w/w. In some embodiments. the ratio of antioxidantCB2 modulator is from 3:1 > 5: 1w/w. In some embodiments. the ratio of antioxidant/CB2 modulator is fro 1:1 t : i . n some embodiments, the ratio of antioxkiant/CB2 modulator ίs from 2:1 o 10:1 w/w. n som embodiments, the rati of antioxidant/CB2 modulator is from 3:1 t 10:1 w/w. In some embodiments. the ratio of antioxidant/CB2 Modulator iS from 4 :1 t 10:1 w/w. In some embodiments, the ratio of antioxidam7CB2 modulator is from 5:1 to 10:1 w/w. n some embodiments, the ratio of antioxid nt CB2 Modulator is from 6:1 to : w/w. n some embodiments, the ratio of antioxidant/CB2 modulator is from 7:1 10:1w/w. some enrbodiments- the rati of ant-oxida»t CB2 Modulator i from ; 1 o νν w. n some emlx dimeu the rati of antioxidant/CB2 Modulator i :s f om 9: t : w/w.
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