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WO 2016/001643 Al 7 January 2016 (07.01.2016) P O P C T

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WO 2016/001643 Al 7 January 2016 (07.01.2016) 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 2016/001643 Al 7 January 2016 (07.01.2016) P O P C T (51) International Patent Classification: (74) Agents: GILL JENNINGS & EVERY LLP et al; The A61P 25/28 (2006.01) A61K 31/194 (2006.01) Broadgate Tower, 20 Primrose Street, London EC2A 2ES A61P 25/16 (2006.01) A61K 31/205 (2006.01) (GB). A23L 1/30 (2006.01) (81) Designated States (unless otherwise indicated, for every (21) International Application Number: kind of national protection available): AE, AG, AL, AM, PCT/GB20 15/05 1898 AO, AT, AU, AZ, BA, BB, BG, BH, BN, BR, BW, BY, BZ, CA, CH, CL, CN, CO, CR, CU, CZ, DE, DK, DM, (22) International Filing Date: DO, DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, 29 June 2015 (29.06.2015) HN, HR, HU, ID, IL, IN, IR, IS, JP, KE, KG, KN, KP, KR, (25) Filing Language: English KZ, LA, LC, LK, LR, LS, LU, LY, MA, MD, ME, MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI, NO, NZ, OM, (26) Publication Language: English PA, PE, PG, PH, PL, PT, QA, RO, RS, RU, RW, SA, SC, (30) Priority Data: SD, SE, SG, SK, SL, SM, ST, SV, SY, TH, TJ, TM, TN, 141 1570.3 30 June 2014 (30.06.2014) GB TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, ZW. 1412414.3 11 July 2014 ( 11.07.2014) GB (84) Designated States (unless otherwise indicated, for every (71) Applicant: MITOCHONDRIAL SUBSTRATE INVEN¬ kind of regional protection available): ARIPO (BW, GH, TION LIMITED [GB/GB]; 39 Glasslyn Road, London GM, KE, LR, LS, MW, MZ, NA, RW, SD, SL, ST, SZ, N8 8RJ (GB). TZ, UG, ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, RU, TJ, TM), European (AL, AT, BE, BG, CH, CY, CZ, DE, (72) Inventors: POMYTKIN, Igor Anatolievich; c/o Mito DK, EE, ES, FI, FR, GB, GR, HR, HU, IE, IS, IT, LT, LU, chondrial Substrate Invention Limited, Glasslyn Road, LV, MC, MK, MT, NL, NO, PL, PT, RO, RS, SE, SI, SK, London N8 8RJ (GB). CHERNOPIATKO, Anton; c/o SM, TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, GN, GQ, Mitochondrial Substrate Invention Limited, 39 Glasslyn GW, KM, ML, MR, NE, SN, TD, TG). Road, London N8 8RJ (GB). ANDREEVA, Larisa; c/o Mitochondrial Substrate Invention Limited, 39 Glasslyn Published: Road, London N8 8RJ (GB). — with international search report (Art. 21(3)) o (54) Title: NUTRIENTS SOLUTIONS FOR ENHANCEMENT OF COGNITIVE FUNCTION o (57) Abstract: The present invention relates to dietary supplements, medical foods, or pharmaceutical compositions for use in the enhancement of cognitive function in healthy subjects and/or subjects person suffering from a cognitive deficit, comprising aqueous solution of a nutrient, wherein solution comprises a water having content of deuterium from 90 to about 135 ppm, wherein the con tent of 1 0 isotopologue in the water is equal or less than 99.759%. In one embodiment of the invention relates to a succinate salt of choline as the nutrient. NUTRIENTS SOLUTIONS FOR ENHANCEMENT OF COGNITIVE FUNCTION Field of the Invention [0001 ] The present invention relates to food industry, specifically to nutrients solutions for enhancement of cognitive function. Background of the invention [0002] Cognition is a mental process related to information processing and storage, It includes knowing, specifically the process of being aware, thinking, learning, judging, ability to memory, attention, perception, action, problem solving, and mental imagery. A progressive decline of cognition is observed during normal aging. The decline in numeric ability begins at age about 25. The decline in perceptual speed begins at age about 40. The decline in inductive reasoning and spatial orientation begins at age about 50. The decline in verbal ability and verbal memory begins at age about 60. Schaie K W et al, Neuropsychol Dev Cogn B Aging Neuropsychol Cogn 2004, 11(2-3):304-24. Individual rates of the cognitive decline may vary. Compared to persons found to have no cognitive impairment, rate of cognitive decline during follow-up increased approximately twofold in mild cognitive impairments and fourfold in Alzheimer's disease. Wilson RS et al, Neurology 2010, 74(12):951-955. Early changes in cognitive functions are predictive for onset of dementia with aging, given that these changes may be observed as early as 14 years prior to diagnosis of dementia. Schaie K W et al, Neuropsychol Dev Cogn B Aging Neuropsychol Cogn 2004, 11(2-3):304-24. Among such early changes, diminished attention to novel events and loss of curiosity are important signs indicating the risk or onset of early stage of dementia, while increased attention to novelty is associated with successful cognitive aging and sustained interest in the novel aspects of the environment (curiosity) enhances cognitive function and diminishes cognitive decline. Nakashima Y et al, Psychogeriatrics 2010, 10:124-130. Daffner KR et al, J Cognitive Neuroscience 2003, 15(2):294-313. Daffner KR et al, Neurology 2001, 56:1377-1383. Daffner KR et al, J Cognitive Neuroscience 2006, 18(10):1 759-1 773. Wilson RS et al, JAMA 2002, 287 (6) 742-748. Thus, there is a great need in safe and effective agents for enhancing cognitive function to prevent or delay the onset of dementia. 6 [0003] Natural water is a composition of nine water isotopologues ( H2 O, 7 8 6 2 7 2 8 2 2 6 2 7 2 8 H2 O, H2 O, H O H , H O H , H O H , H2 O, H2 O, H2 O) formed by stable isotopes of hydrogen H and 2H (D, deuterium) and oxygen ( 6O, 7O, and 8O). The sum of fractional abundances of four major 6 8 7 6 2 isotopologues H2 O (i.e. H2O), H2 0 , H2 O, and H O H (i.e. HOD) is 0.99999952, wherein the individual abundances are as follows: 0.99731 7 8 7 (H2O); 0.001 99983 ( H2 O); 0.000372 ( H2 O); 0.00031 069 (HOD). Rothman LS et al, J Quantitative Spectroscopy &. Radiative Transfer 2003, 82:9. Natural abundances of the rest five deuterium-bearing isotopologues 7 2 8 2 2 6 2 7 2 8 ( H O H , H O H , H2 O, H2 O, and H2 O) are too small to be measured by currently available methods. Thus, deuterium is completely incorporated in HOD isotopologue, which content in natural water is 0.031069 mol. % . [0004] The deuterium content in water samples is measured by isotope ratio mass-spectrometry and expressed as deuterium-to-protium ratio R=D/H, in ppm units, where D is the number of deuterium atoms, and H is the number of protium atoms. Ocean water contains deuterium at level of 155 ppm (Vienna Standard Mean Ocean Water 2 , VSMOW2). Continental waters slightly differ from ocean water in deuterium content, since isotope fractionation occurs during water evaporation-precipitation process in nature. A vast majority of people reside at places, where they consume water having deuterium content from 140 to 155 ppm. Kendall et al, Hydrol Processes 2001, 15(7).-1363-1393. Bowen et al, Water Resour Res 2007, 43, W03419. [0005] RU Patent No. 2338542 discloses the use of water having less than 0.01 8 mol.% HOD for the improvement of cognitive function and the treatment of neurodegenerative diseases. Given that deuterium in natural water is completely incorporated in HOD isotopologue, the range HOD<0.01 8 mol. % corresponds to the deuterium content D/H<90 ppm. [0006] Choline is an essential nutrient for healthy metabolic functioning. Choline is needed for biosynthesis of acetylcholine and essential components of cell membranes; and for methyl-group metabolism. An adequate intake level for choline is 550 mg/day for men and 425 mg/day for women. Choline deficiency leads to neurological disorders. Zeisel SH et al, Nutr Rev. 2009, 67(1 1): 615-623. The de novo choline synthesis is not sufficient to meet human requirements and choline must be obtained through the diet, for example as choline salts. Choline citrate, choline bitartrate, choline succinate (2:1 ) salt, and choline chloride are commercially available and contain 2 1% , 4 1% , 64%, and 74% of choline, respectively. To provide fast delivery of choline to a human body, such choline supplements are frequently formulated as a beverage. However, choline salts give a specific unpleasant taste to the beverage, unacceptable to a consumer, when taken in amounts recommended by FDA (>55 mg of choline per serving). This common disadvantage generally limits the use of choline salts as ingredients in beverages. Brief Description of the Drawing Figure 1 shows the scheme of the process for preparing water having deuterium content from 90 to about 135 ppm and up to 99.759% of 6 isotopologue H2 O. Detailed Description of the Invention [0007] The present invention provides an aqueous solution of a nutrient for use in the enhancement of cognitive function in a subject, the solution comprising a water having content of deuterium from 90 to about 135 ppm, 6 wherein the content of H2 O isotopologue in the water is equal or less than 99.759%. [0008] Further, the present invention provides a beverage for use in the enhancement of cognitive function in a subject, comprising (a) an aqueous solution of a nutrient and (b) water having content of deuterium from 90 to 6 about 135 ppm and 99.759% or less of isotopologue H2 0 . [0009] Further, the present invention provides a digestible capsule containing an aqueous solution of a nutrient, comprising a water having content of deuterium from 90 to about 135 ppm and 99.759% or less of 6 isotopologue H2 0 .
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