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WO 2018/152334 Al 23 August 2018 (23.08.2018) W !P O PCT

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WO 2018/152334 Al 23 August 2018 (23.08.2018) W !P O PCT (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 2018/152334 Al 23 August 2018 (23.08.2018) W !P O PCT (51) International Patent Classification: (US). YUCEL, Tuna; 28 Monmouth Avenue, Medford, A61K 9/107 (2006.01) A61K 31/352 (2006.01) MA 02155 (US). BOYLAN, Nicholas, J.; 215 Green A61K 47/26 (2006.01) A61K 9/48 (2006.01) Street, Boylston, MA 01505 (US). A61K 47/14 (2006.01) A61K 9/00 (2006.01) (74) Agent: EISENSCHENK, Frank, C. et al; Saliwanchik, A61K 31/05 (2006 .01) A61P 25/06 (2006 .0 1) Lloyd & Eisenschenk, P.O. Box 142950, Gainesville, FL (21) International Application Number: 32614-2950 (US). PCT/US2018/018382 (81) Designated States (unless otherwise indicated, for every (22) International Filing Date: kind of national protection available): AE, AG, AL, AM, 15 February 2018 (15.02.2018) AO, AT, AU, AZ, BA, BB, BG, BH, BN, BR, BW, BY, BZ, CA, CH, CL, CN, CO, CR, CU, CZ, DE, DJ, DK, DM, DO, (25) Filing Language: English DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, HN, (26) Publication Language: English HR, HU, ID, IL, IN, IR, IS, JO, JP, KE, KG, KH, KN, KP, KR, KW, KZ, LA, LC, LK, LR, LS, LU, LY, MA, MD, ME, (30) Priority Data: MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI, NO, NZ, 62/459,086 15 February 2017 (15.02.2017) OM, PA, PE, PG, PH, PL, PT, QA, RO, RS, RU, RW, SA, 62/546,149 16 August 2017 (16.08.2017) SC, SD, SE, SG, SK, SL, SM, ST, SV, SY,TH, TJ, TM, TN, (71) Applicant: MOLECULAR INFUSIONS, LLC [US/US]; TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, ZW. 5 Forge Parkway, Franklin, MA 02038 (US). (84) Designated States (unless otherwise indicated, for every (72) Inventors: FARACI, William, Stephen; 23 Whittemore kind of regional protection available): ARIPO (BW, GH, Street, Arlington, MA 02474 (US). ZALE, Stephen; 1Nor- GM, KE, LR, LS, MW, MZ, NA, RW, SD, SL, ST, SZ, TZ, cross Road, Hopkinton, MA 01748 (US). PARASKAR, UG, ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, RU, TJ, Abhimanyu; 206 Florence Ave, Arlington, MA 02476 TM), European (AL, AT, BE, BG, CH, CY, CZ, DE, DK, (54) Title: FORMULATIONS 1.4 1.2 1.0 0.8 0.6 x 90% emulsifier 1S% emulsifier □ 50% emulsifier 0.4 0.2 0.0 10 12 14 16 HLB value (1) Figure 6 (57) Abstract: The invention provides for cannabinoid formulations, including self-emulsifying formulations and micellar dispersions, as well as methods of making and using the same. The formulations comprise a cannabinoid and surfactant. The formulations have improved dissolution, stability, and pharmacokinetics, including absorption and/or oral bioavailability. The invention also provides for 00 formulations comprising at least one active ingredient, including self-emulsifying formulations and micellar dispersions, as well as methods of making and using the same. The formulations comprise a least one active ingredient and surfactant. o [Continued on nextpage] WO 2018/152334 Al llll II II 11III II I I II 11III II EE, ES, FI, FR, GB, GR, HR, HU, IE, IS, IT, LT, LU, LV, MC, MK, MT, NL, NO, PL, PT, RO, RS, SE, SI, SK, SM, TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, GN, GQ, GW, KM, ML, MR, NE, SN, TD, TG). Declarations under Rule 4.17: — of inventorship (Rule 4.17(iv)) Published: — with international search report (Art. 21(3)) — before the expiration of the time limit for amending the claims and to be republished in the event of receipt of amendments (Rule 48.2(h)) FORMULATIONS CROSS-REFERENCE TO RELATED APPLICATIONS This application clai ms the benefit of U.S. Provisiona l Patent Application Nos. 62/459,086, filed February 15, 2017 and 62/546,149, filed August 16, 2017. FIELD OF THE INVENTION The present invention relates t o compositions com prising at least one active ingredient, e.g., a ca nna binoid, ca nna binoid extract, terpene, terpene extract, or other active ingredient and a surfacta nt, as wel l as methods of making and using the sa me. The com positions include self-em ulsifying formu lations and form ulations that form micel le sol ution/dispersions. The com positions of the present invention are suitable for oral administration. The compositions increase drug solubilization through col loida l or micel lular dispersion. The com positions may red uce the time of onset, effect of food on absorption, and potentia lly lower hepatic first-pass meta bolism of the ca nnabinoid and/or other active ingredient(s), thereby improvi ng bioavailability. BACKGROUND OF THE INVENTION Self-em ulsifying drug delivery systems (SEDDS) provides a mea ns t o enha nce the dissolution of some actives in an aqueous environment. Exa mples of patents demonstrati ng the potential use of SEDDS or lipid delivery systems for lipophi lic drugs incl ude U.S. Pat. Nos. 5,484,801; 5,798,333; 5,965, 160; 6,008,228; 6,730,330; 9,265,724; U.S. Patent Application No. 20050209345; 20060160888; US20140357708; 20160184258; and PCT Pu blications W096/39142 and WO2016147186. United States Patent US9265724 and U.S. Patent Application 20160184258 exemplify a few SEDDS form ulations com prising ∆ 9 THC. Cannabi noids are a class of active compounds derived from the Cannabis sativa, Cannabis indica, or Cannabis hybrid pla nt com mon ly known as marijua na. The most notable ca nnabinoid is the phytoca nna binoid tetrahydroca nnabinol (THC), the pri mary psychoactive com pound in can nabis. Delta-9-tetra hydrocanna binol (A9-THC) and delta-8- tetrahydroca nnabinol (A8-THC) mimic the actions of ana ndamide and 2-arachidonoylglycerol neurotransmitters produced naturally in the body. These cannabinoids produce the effects associated with cannabis by binding t o the CB1 cannabinoid receptors in the brain. Cannabidiol (CBD) is another major constituent of the cannabis plant. Other cannabinoids include Cannabigerol (CBG), Cannabichromene (CBC), Cannabicyclol (CBL), Cannabivarin (CBV), Tetrahydrocannabivarin (THCV), Cannabidivarin (CBDV), Cannabichromevarin (CBCV), Cannabigerovarin (CBGV), Cannabigerol Monomethyl Ether (CBGM), Tetrahydrocannabinolic acid (THCA), cannabinol (CBN), and Cannabidiolic Acid (CBDA). Synthetic A9-tetrahydrocannabinol (dronabinol) is marketed under the trade name MARINOL®. Dronabinol is approved by the Food and Drug Administration (FDA) for the control of nausea and vomiting associated with chemotherapy and for appetite stimulation of AIDS patients suffering from the wasting syndrome. MARINOL is a formulation of dronabinol in sesame oil presented as a soft gelatin capsule for oral administration. After oral administration, dronabinol has an onset of action of approximately 0.5 t o 1 hours and peak effect at 2 to 4 hours. Duration of action for psychoactive effects is 4 to 6 hours, but the appetite stimulant effect of dronabinol may continue for 24 hours or longer after administration. Dronabinol is almost completely absorbed (90 t o 95%) after single oral doses. Due t o the combined effects of first pass hepatic metabolism and high lipid solubility, only 10 t o 20% of the administered dose reaches the systemic circulation. There is a need for additional, preferably less complex, self-emulsifying and micellar dispersion forming formulations, particularly those that are more stable, faster acting (i.e., have a faster onset of action), avoid or reduce hepatic first-pass metabolism, deliver more of the active ingredient(s) t o the lymphatic system, or increase oral bioavailability for treating a variety of conditions. The present invention addresses this need by providing improved formulations for use in a variety of conditions including pain, nausea and vomiting. SUMMARY OF THE INVENTION A first aspect provides a composition comprising: at least one active ingredient; and a surfactant. In one embodiment, the at least one active ingredient is selected from a cannabinoid, cannabinoid extract, terpene, or terpene extract. In one mbodim nt, the composition comprises: at least one active ingredient; a surfactant; and a fatty acid, monoglyceride, diglyceride, triglyceride, or a combination thereof. In one embodiment, the at least one active ingredient is selected from a cannabinoid, cannabinoid extract, terpene, or terpene extract. In another embodiment, the composition is a non-aqueous formulation. In another embodiment, the composition is a pharmaceutical composition, preferably an oral dosage form, more preferably a solid or semi-solid oral dosage form. Another embodiment, relates to a unit dose of the composition. A second aspect provides a method of making the composition of the first aspect comprising the steps of: providing at least one active ingredient, a surfactant, and, optionally, a fatty acid, monoglyceride, diglyceride, triglyceride, or a combination thereof; combining said at least one active ingredient, said surfactant and, optionally, a fatty acid, monoglyceride, diglyceride, triglyceride, or a combination thereof to form a homogeneous or isotropic mixture. In one embodiment, the active ingredient is selected from a cannabinoid, cannabinoid extract, terpene, or terpene extract. A third aspect provides for a composition and method for a composition for promoting sleep, reducing stress, and/or reducing anxiety; the composition comprising THC, CBD, CBN and, optionally, at least one additional active ingredient In one embodiment, the composition further comprises one or more terpenes, preferably myrcene and limonine. In a further embodiment, the composition further comprises melatonin. A fourth aspect provides for a method of treating or preventing a condition in an animal, e.g., human, including pain, nausea, and/or vomiting, comprising the step of administering to said animal an effective amount of a composition of the first or third aspect. In certain embodiments, the composition is a non-aqueous composition, a pharmaceutical composition, a unit dose, an oral dosage form, or more preferably, a solid or semi-solid, non-aqueous, oral dosage form.
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