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(12) United States Patent (10) Patent No.: US 9.446,006 B2 Fowler Et Al

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(12) United States Patent (10) Patent No.: US 9.446,006 B2 Fowler Et Al USOO9446.006B2 (12) United States Patent (10) Patent No.: US 9.446,006 B2 FOWler et al. (45) Date of Patent: Sep. 20, 2016 (54) HYDROXYTYROSOL COMBINATIONS FOR A6II 3L/205 (2006.01) ENHANCING MITOCHONORAL FUNCTION A6II 3/44.15 (2006.01) AND ENERGY PRODUCTION A63L/455 (2006.01) A6II 3/74 (2006.01) (71) Applicants: Ann Fowler, Rheinfelden (CH): (Continued) Angelika Friedel, Binzen (DE); Darko (52) U.S. Cl. Knutti, Riehen (CH), Karin Kuratli, CPC .............. A61 K3I/05 (2013.01); A23K 20/III Reinach (CH), Daniel Raederstorff, (2016.05); A23K 20/121 (2016.05); A23K Flaxlanden (FR), Ying Wang-Schmidt, 20/147 (2016.05); A23K 20/174 (2016.05); Stallikon (CH), Karin Wertz, A2.3L I/296 (2013.01); A23L 1/30 (2013.01); Rheinfelden (DE) A2.3L I/3002 (2013.01); A23L I/302 (2013.01); A23L 1/3004 (2013.01); A23L (72) Inventors: Ann Fowler, Rheinfelden (CH): I/3051 (2013.01); A23L 2/52 (2013.01); A61 K Angelika Friedel, Binzen (DE); Darko 3 1/122 (2013.01); A61K 31/145 (2013.01); Knutti, Riehen (CH); Karin Kuratli, A61K 31/19 (2013.01); A61K 31/195 Reinach (CH); Daniel Raederstorff, (2013.01); A61K 31/197 (2013.01); A61 K Flaxlanden (FR); Ying Wang-Schmidt, 3 1/205 (2013.01); A61K 3 1/34 (2013.01); Stallikon (CH); Karin Wertz, A6 IK3I/352 (2013.01); A61K 31/4188 Rheinfelden (DE) (2013.01); A61 K3I/4406 (2013.01); A61 K 3 1/44.15 (2013.01); A61K 31/455 (2013.01); (73) Assignee: DSM IPASSETS B.V., Heerlen (NL) A6 IK3I/51 (2013.01); A61 K3I/522 (2013.01); A61 K3I/525 (2013.01); A61 K (*) Notice: Subject to any disclaimer, the term of this 3 1/714 (2013.01); A61K 36/63 (2013.01); patent is extended or adjusted under 35 A61K 45/06 (2013.01); A23 V 2002/00 U.S.C. 154(b) by 55 days. (2013.01) (58) Field of Classification Search (21) Appl. No.: 14/450,073 CPC ... A61K 31/05; A61K 31/122: A61K 36/63; A61K 3 1/522: A61K 31/195; A61K 31/19; (22) Filed: Aug. 1, 2014 A61K 31/51; A61K 31/145; A61K 31/34; A61K 31/352: A61K 31/4188: A61K 31/525; (65) Prior Publication Data A61K 31/4406; A61K 31/714; A23L 1/3004 USPC ........... 424/94.1: 514/263.34, 393, 456, 473, US 2015/OO30579 A1 Jan. 29, 2015 514/52, 561, 565, 665, 733 See application file for complete search history. Related U.S. Application Data (56) References Cited (62) Division of application No. 13/264,819, filed as application No. PCT/EP2009/063492 on Oct. 15, U.S. PATENT DOCUMENTS 2009, now abandoned. 8,841,264 B2 * 9/2014 Raederstorff .......... A61K 31,05 (60) Provisional application No. 61/202,888, filed on Apr. 514/32 17, 2009. FOREIGN PATENT DOCUMENTS (30) Foreign Application Priority Data EP 1714 658 10, 2006 Apr. 17, 2009 (WO)................. PCT/EP2009/054585 20d., G., 1939. (51) Int. Cl. (Continued) A6 IK3I/05 (2006.01) OTHER PUBLICATIONS 3. Ei 3:08: Romero et al. Analysis of Total Contents of Hydroxytyrosol and A 6LX 3L/95 (2006.015 Tyrosol in Olive Oils. J. Agric. Food Chem. 60:90 17-9022, 2012.* A6 IK3I/SI (2006.01) (Continued) A6 IK3I/I9 (2006.01) Primary Examiner — Clinton Brooks A6 IK 3L/45 (2006.01) Assistant Examiner — Yih-Horng Shiao 3. i. 3.08: (74) Attorney, Agent, or Firm — Nixon & Vanderhye P.C. A6 IK 3/488 (2006.01) (57) ABSTRACT A6 IK3I/525 (2006.01) Hydroxytyrosol or olive juice containing hydroxytyrosol in A6 IK3I/4406 (2006.01) combination with at least one of the compounds selected A2.3L I/29 (2006.01) from the group consisting of creatine, coenzyme Q10. A2.3L I/30 (2006.01) resveratrol, caffeine, carnitine, B vitamins (B1, B2, B3, B5, A2.3L I/302 (2006.01) B6, and/or B12) and ginseng (preferably: root) extract.can A2.3L I/305 (2006.01) be used to maintain or increase mitochondrial biogenesis in A2.3L 2/52 (2006.01) cardiac muscle, skeletal muscles, and liver tissue. A 6LX 3L/97 (2006.01) 6 Claims, 15 Drawing Sheets US 9,446,006 B2 Page 2 (51) Int. Cl. Vékey et al. Biophenol Protein Supramolecular Models by Fast A6 IK 36/63 (2006.01) Atom Bombardment—Mass Spectrometric Experiments, J. Agric. Food Chem. 1997, 45, 2447-2451. A6 IK 45/06 (2006.01) Ali Ibn-e-Abbaas Majoosi Kaamil-al-Sena’ah, Part II (10th century AD) Page(s) being submitted—05 (p. No. 04-08) (Ref. pg. No. of (56) References Cited publication: 105) Publication Date-2005 AD Publisher—Central Council for Research in Unani Medicine Place of Publication— FOREIGN PATENT DOCUMENTS New Delhi, India.it Abu Bakr Mohammad Bin Zakariyya Al-Razi Kitaab-al-Haawi-fil JP 2009-511522 3, 2009 Tibb, vol. XX (9th century AD) Page(s) being submitted 04 (p. WO 2004/032873 4/2004 No. 09-12) (Ref. pg. No. of publication:555) Publication Date— WO 2007/042271 4/2007 1967 AD Publisher—Dayerah-al-Ma'aarif Usmania, Place of Pub WO WO2007/112996 * 10/2007 lication—Hyderabad, India. WO 2008/006581 1, 2008 Aminuddaulah Abul Far Ibn Al-Quff Maseehi Kitaab-al-Umdah WO 2008/128552 10, 2008 fil-Jeraahat, Part II (13th century AD) Page(s) being submitted—04 WO 2008, 1286.29 10, 2008 (p. No. 13-16) (Ref. pg. No. of publication:237) Publication Date— WO 2009. 144093 12/2009 1937 AD Publisher—Dayerah-al-Ma'aarif Usmania Place of Pub OTHER PUBLICATIONS lication—Hyderabad, India. International Search Report for PCT/EP2009/063492, mailed Feb. * cited by examiner 5, 2010. it cited by third party U.S. Patent Sep. 20, 2016 Sheet 1 of 15 US 9,446,006 B2 FIGURE Control O, O 50 Hydroxytyrosol (microM) U.S. Patent Sep. 20, 2016 Sheet 2 of 15 US 9,446,006 B2 FIGURE 2A Control O. 1. O 50 Hydroxytyrosol (microM) U.S. Patent Sep. 20, 2016 Sheet 3 of 15 US 9,446,006 B2 FIGURE 2B 180 - ck : k: 0. 1. 10 50 Hydroxytyrosol (microM) U.S. Patent Sep. 20, 2016 Sheet 4 of 15 US 9,446,006 B2 FIGURE 2C Control 0.1 O 50 Hydroxytyrosol (microM) U.S. Patent Sep. 20, 2016 Sheet 5 Of 15 US 9,446,006 B2 FIGURE 2) 200 p. ck k 180 k 160 100 80 SS 60 O 20 0 i. Control O. O SO Hydroxytyrosol (microM) U.S. Patent Sep. 20, 2016 Sheet 6 of 15 US 9,446,006 B2 FIGURE 3 60 -i- k 40 - ef I 4. Control 0. 10 50 Hydroxytyrosol (microM) U.S. Patent Sep. 20, 2016 Sheet 7 Of 15 US 9,446,006 B2 FIGURE 4 80 --- Control 0. O 50 Hydroxytyrosol (microM) U.S. Patent Sep. 20, 2016 Sheet 8 of 15 US 9,446,006 B2 FIGURE SA 40 | Control O), O 50 Hydroxytyrosol (microM) U.S. Patent Sep. 20, 2016 Sheet 9 Of 15 US 9,446,006 B2 FGURE SE3 140 p. k s 3 100 E 80 3 s 60 S.ŠE N 3 40 20 0 - Control O. O 50 Hydroxytyrosol (microM) U.S. Patent Sep. 20, 2016 Sheet 10 of 15 US 9,446,006 B2 FIGURE SC ck k ck : 20 0. Control 0. 10 50 Hydroxytyrosol (microM) U.S. Patent Sep. 20, 2016 Sheet 11 of 15 US 9,446,006 B2 FIGURE 5) 140 - 120 * 100 60 40 20 Control 0. O 50 Hydroxytyrosol (microM) U.S. Patent Sep. 20, 2016 Sheet 12 of 15 US 9,446,006 B2 FGURE SE 140 ; 120 8 () 6 O 4. O 2 O Control 0. O 50 Hydroxy tyrosol (microM) U.S. Patent Sep. 20, 2016 Sheet 13 of 15 US 9,446,006 B2 FGURE 6 180 60 8 O Control 0. O SO Hydroxytyrosol (microM) U.S. Patent Sep. 20, 2016 Sheet 14 of 15 US 9,446,006 B2 FIGURE 7 Hydroxytyrosol Hydroxytyrosol Hydroxytyrosol (50 mg/kg/BW) (150 mg/kg/BW) (300 mg/kg/BW) U.S. Patent Sep. 20, 2016 Sheet 15 Of 15 US 9,446,006 B2 |f E St - w H + * ca :- 8 S2 l & ; : Li : r + es ca 8c 5 It litre " < x Ca O 2 l C C y t SiOS 3& O US 9,446,006 B2 1. 2 HYDROXYTYROSOL COMBINATIONS FOR In addition to their well known function of Supplying ENHANCING MITOCHONORAL FUNCTION energy to a cell, mitochondria and their components partici AND ENERGY PRODUCTION pate in a number of other cellular activities. For example, mitochondria also control thermogenesis and the apoptosis CROSS-REFERENCE process and are thus involved in the ageing process. The mitochondria contain a high level of oxidants, since This application is a divisional of commonly owned U.S. the respiratory chain generates reactive species, e.g. Super application Ser. No. 13/264,819, filed May 4, 2012 (now oxide anions, if it works with reduced efficiency or during abandoned) which is the national phase application under 35 energy uncoupling. Superoxide anions are generated as USC S371 of PCT/EP2009/063492, filed Oct. 15, 2009 10 by-products in several steps of electron transport chain, Such which designated the U.S. and claims priority to EP Patent as the reduction of coenzyme Q in complex III, where a highly reactive free radical is formed as an intermediate Application No. PCT/EP2009/054585, filed Apr. 17, 2009 (Q.-). This unstable intermediate can lead to electron “leak and U.S.
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