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WO 2013/186220 Al 19 December 2013 (19.12.2013) P O P C T

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WO 2013/186220 Al 19 December 2013 (19.12.2013) 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 2013/186220 Al 19 December 2013 (19.12.2013) P O P C T (51) International Patent Classification: AO, AT, AU, AZ, BA, BB, BG, BH, BN, BR, BW, BY, A61K 31/7048 (2006.01) A61P 25/20 (2006.01) BZ, CA, CH, CL, CN, CO, CR, CU, CZ, DE, DK, DM, A61K 31/352 (2006.01) A61P 25/22 (2006.01) DO, DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, A61P 25/00 (2006.01) A61K 45/06 (2006.01) HN, HR, HU, ID, IL, IN, IS, JP, KE, KG, KN, KP, KR, KZ, LA, LC, LK, LR, LS, LT, LU, LY, MA, MD, ME, (21) International Application Number: MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI, NO, NZ, PCT/EP20 13/062046 OM, PA, PE, PG, PH, PL, PT, QA, RO, RS, RU, RW, SC, (22) International Filing Date: SD, SE, SG, SK, SL, SM, ST, SV, SY, TH, TJ, TM, TN, 11 June 2013 ( 11.06.2013) TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, ZW. (25) Filing Language: English (84) Designated States (unless otherwise indicated, for every kind of regional protection available): ARIPO (BW, GH, (26) Publication Language: English GM, KE, LR, LS, MW, MZ, NA, RW, SD, SL, SZ, TZ, (30) Priority Data: UG, ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, RU, TJ, 1039666 11 June 2012 ( 11.06.2012) NL TM), European (AL, AT, BE, BG, CH, CY, CZ, DE, DK, 1218 1673.0 24 August 2012 (24.08.2012) EP EE, ES, FI, FR, GB, GR, HR, HU, IE, IS, LT, LT, LU, LV, MC, MK, MT, NL, NO, PL, PT, RO, RS, SE, SI, SK, SM, (71) Applicant: BIOACTOR B.V. [NL/NL]; Oxfordlaan 70, TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, GN, GQ, GW, NL-6229 EV Maastricht (NL). KM, ML, MR, NE, SN, TD, TG). (72) Inventors: POSSEMIERS, Sam; Oxfordlaan 70, NL- Published: 6229 EV Maastricht (NL). VAN DER SAAG, Antonie Jo¬ — with international search report (Art. 21(3)) hannes; Oxfordlaan 70, NL-6229 EV Maastricht (NL). — before the expiration of the time limit for amending the (74) Agent: ISHIGURO, Masaoki; IPecunia Patents B.V., claims and to be republished in the event of receipt of P.O. Box 593, NL-6160 AN Geleen (NL). amendments (Rule 48.2(h)) (81) Designated States (unless otherwise indicated, for every kind of national protection available): AE, AG, AL, AM, © (54) Title: COMPOSITIONS COMPRISING HESPERIDIN AND/OR APIGENIN LA. FOR MEDICAL USE OR FOR USE IN TREATMENT OF SLEEPING DISORDERS 2 (57) Abstract: The invention relates to a composition comprises hesperidin and apigenin. The invention also relates to a composi - tion comprises hesperidin, wherein the composition is in a form suitable for sublingual and/or buccal administration. The composi - tions may be a food or a beverage or a supplement composition for a food or a beverage, for example a chewing gum. Also, the com- positions may be used as a medicament. The compositions may be used for promoting sleep, for reducing stress, for increased relaxa- tion, for sedation, for tranquilization and/or in the treatment of anxiety disorders, for relieving anxiety, for improving the mood and/or for increasing relaxation in animals, preferably mammals, for example humans. COMPOSITIONS COMPRISING HESPERIDIN AND/OR APIGENIN LA. FOR MEDICAL USE OR FOR USE IN TREATMENT OF SLEEPING DISORDERS This present invention relates to compositions with sedative, sleep inducing and/or anxiolytic effects, more specifically using new application strategies of natural extracts, fractions and substances from orange peels, parsley, celery, dandelion roots, valerian and other potential botanic sources. The invention relates to a composition comprising hesperidin and/or apigenin, said composition for sublingual and/or buccal administration, said composition for use as a medicament, preferably for the treatment of sleeping disorders, for promoting sleep, for reducing stress, for increasing relaxation, as a sedative, as a tranquilizer and/or as an anxiolytic. For many years, sedative and anxiolytic properties have been attributed to natural extracts, usually from the roots of valerian and related plant species. The sleep enhancing quality of these plants has been known for thousands of years, valerian root preparations have been available as very mild sedatives and an online search for relevant scientific articles reveals more than 100 hits since the 1950s. More recently, studies have been carried out to identify the composition of valerian extracts and which substances in this composition may be responsible for the reported effects: in 2003, a method for fractioning the active compounds from valerian roots was described and patented (WO03061 678A1 ). In this description, the sedative effects were attributed to a number of flavonoids, especially Linarin, 6-methyl-Apigenin, and Hesperidin. Given the availability of Hesperidin, its documented safety and absence of induced tolerance, this compound is of particular interest. Several studies confirmed the sleep prolonging, sedative effects of a Hesperidin, both from Valerian and from citrus, and anxiolytic properties of valerian derived 6-methyl-Apigenin, each after intra-peritoneal injection in mice (Marder 2003, Pharm, Biochem Behav 2003, 75(3)). It was furthermore shown that intra-peritoneally administered Apigenin from C. Japonicum (Kim, Arch Pharm Res, 201 2, 35(2)) induced increased sleeping time in these animals, while the combination of intra-peritoneally administered Hesperidin from Valerian and 6-methyl-Apigenin from Valerian potentiated these effects (Marder, Pharm, Biochem Behav 2003, 75(3), Fernandez, Eur. J. Pharm. 2006, 539(3), WO03061678A1). Additionally, Marder and colleagues showed that the 2S-Hesperidin isomer was mostly responsible for these sedative effects, while the R-isoform was far less effective. While Hesperidin showed promising sleep prolonging and sedative effects in mice when administered intra-peritoneally, effects are absent when the substance is ingested orally. While the efficacy of Hesperidin and Apigenin in sleep management and its anxiolytic potential has been previously shown when injected intraperitoneal^ in mice, oral administration of citric flavonoids has not resulted in any meaningful effect on sleep and/or stress. The intraperitoneal route of administration diminishes Hesperidin's and Apigenin's usefulness as a sleep management compound in humans, since injections of any kind pose an additional risk as well as discomfort that is not acceptable to most individuals and regulative bodies. Thereby, the absence of a non-invasive formulation of Hesperidin and/or Apigenin has severely limited the applicability of Hesperidin in food and over the counter medicaments and supplements. It is therefore the object of the invention to provide compositions comprising hesperidin that can be orally administered, while maintaining their sedative, sleep enhancing and/or anxiolytic effects. This object has been achieved by a composition comprising hesperidin and/or apigenin. It was surprisingly found that specific compositions with Hesperidin are capable to induce sedative, sleep enhancing and/or anxiolytic effects, despite the fact that such formulations are orally administered. Here, new means of oral administration and specifically designed compositions yield an orally administered product that can be used as an anxiolytic as well as for sleep management. Modes of administration include: - Sub-lingual films, tablets, or lozenges (tablets that slowly dissolve in the mouth) that ensure uptake of Hesperidin through the sublingual and/or buccal mucosa, bypassing the intestinal microflora and hepatic circulation. - specific combinations of Hesperidin and Apigenin, which are active as a sedative when taken orally. In particular, this object has been by a composition comprising hesperidin and apeginin. In particular, this object has also been achieved by a composition comprising hesperidin, wherein the composition is in a form suitable for sublingual and/or buccal administration. Surprisingly, it has been found that specific compositions with Hesperidin are capable of inducing sedative, sleep enhancing and/or anxiolytic effects, despite being orally administered. The present invention comprises novel specifically designed compositions and/or dosage forms that yield an orally effective product to be used as an anxiolytic or sedative, which may be used in e.g. sleep management. In the following description, for the purposes of explanations, numerous specific details are set forth in order to provide a thorough understanding of the present invention. It will be apparent, however, to one of ordinary skill in the art that the present invention may be practiced without these specific details. The present invention is directed towards a composition for promoting sleep and/or reducing stress. The term 'sleep' for the purposes of the present invention is defined as a natural or artificially induced state of suspension of sensory and motor activity in an individual. It is herein understood that improvements in sleep may be of a quantitative nature e.g. an increase in the length of sleep, a decreased time in the time of sleep onset, and/or of a qualitative nature e.g. a deeper, more restful, more undisturbed period of sleep. Improvement of sleep may consist of any of the improvements mentioned herein, any combination thereof, and/or any other factor that is a scientifically accepted characteristic of sleep quantity and/or quality. It is further understood that improvement in sleep may also be both direct and indirect. For example, sleep will be directly improved by the administration of a substance, which is known to induce sleep or to reduce time to sleep onset. Sleep may be indirectly improved, for example, by the administration of a substance, which is known to result in feelings of relaxation and calmness. 'Stress' is defined as the mental or physical response to a mental of physical challenge, including all hormonal and mental responses.
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