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WO2009033250A1 - Composition et procédé pour augmenter l'état anabolique de cellules musculaires - Google Patents

Composition et procédé pour augmenter l'état anabolique de cellules musculaires Download PDF

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Publication number
WO2009033250A1
WO2009033250A1 PCT/CA2007/001615 CA2007001615W WO2009033250A1 WO 2009033250 A1 WO2009033250 A1 WO 2009033250A1 CA 2007001615 W CA2007001615 W CA 2007001615W WO 2009033250 A1 WO2009033250 A1 WO 2009033250A1
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WO
WIPO (PCT)
Prior art keywords
acid
dissolution
hydroxy
composition
rate
Prior art date
Application number
PCT/CA2007/001615
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English (en)
Inventor
Michele Molino
Joseph Macdougall
Original Assignee
Multi Formulations Ltd.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Multi Formulations Ltd. filed Critical Multi Formulations Ltd.
Priority to AU2007358961A priority Critical patent/AU2007358961A1/en
Priority to EP07800615A priority patent/EP2192898A1/fr
Priority to PCT/CA2007/001615 priority patent/WO2009033250A1/fr
Publication of WO2009033250A1 publication Critical patent/WO2009033250A1/fr

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES, NOT OTHERWISE PROVIDED FOR; PREPARATION OR TREATMENT THEREOF
    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/22—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P21/00—Drugs for disorders of the muscular or neuromuscular system
    • A61P21/06—Anabolic agents

Definitions

  • the present invention relates to a nutritional supplement for inducing an anabolically-favored state for muscle by substantially simultaneously maintaining blood and muscle physiological pH levels as well as increasing cellular concentrations of branched-chain amino acids. More specifically, the present invention relates to a nutritional supplement comprising a combination of ethyl pyruvate and a- hydroxyisocaproic acid (HICA).
  • HICA hydroxyisocaproic acid
  • MCT monocarboxylate transport
  • lactate appears to be a consequence rather then the cause of cellular events which cause acidosis.
  • the physiological state of muscle cells are such that lactate never has hydrogen available to decrease pH in the surrounding solution.
  • Acidosis is actually a result of the hydrolysis of ATP, wherein hydrogen ions are released into the surrounding solution.
  • ATP is produced and utilized quickly in the cytoplasm causing a rapid decrease in cellular pH.
  • the buffering systems of the tissues are rapidly overcome and pH drops resulting in a state of acidosis.
  • BCAA branched-chain amino acids
  • the present invention is directed towards a nutritional supplement, comprising at least a therapeutically effective amount of ethyl pyruvate and a therapeutically effective amount of ⁇ -hydroxyisocaproic acid (HICA).
  • HICA ⁇ -hydroxyisocaproic acid
  • the ⁇ -hydroxyisocaproic acid may be replaced by other ⁇ -hydroxy branched-chain amino acid metabolites, such as a- hydroxy-/?-methylvaleric acid (HIMVA), and ⁇ -hydroxy-isovaleric acid (HIVA), for example.
  • the composition of the present invention may include one or more of the a- hydroxyisocaproic acid (HICA), ⁇ -hydroxy-/?-methyl valeric acid (HIMVA), and ⁇ -hydroxy- isovaleric acid (HIVA).
  • the present invention is directed towards a nutritional supplement, for inducing an anabolically-favored state in muscle by substantially simultaneously maintaining blood and muscle physiological pH levels as well as increasing cellular concentrations of Leucine.
  • the term 'anabolic' is understood to represent metabolic processes where complex molecules are synthesized from more simple ones, i.e. synthesis of muscle proteins from amino acids. Additionally, as used herein, the term 'anabolic' also includes mechanisms of action which are anti-catabolic, such as destructive processes wherein the break down or larger molecules into smaller molecules occurs.
  • ' ⁇ -hydroxyisocaproic acid' makes reference to the chemical 2- hydroxy-4-methylvaleric acid, (CAS Registry No. 498-36-2), also known as HICA, or leucic acid. Additionally, as used herein, the term ' ⁇ -hydroxyisocaproic acid' also includes derivatives of ⁇ -hydroxyisocaproic acid such as esters, and amides, and salts, as well as other derivatives, including derivatives having substantially similar pharmacoproperties to ⁇ -hydroxyisocaproic acid upon metabolism to an active form.
  • the term ' ⁇ -hydroxy branched-chain amino acid metabolite' includes nitrogen-free metabolites of the branched-chain amino acids, Leucine, lsoleucine and Valine. More specifically, the term ' ⁇ -hydroxy branched-chain amino acid metabolite' refers to ⁇ -hydroxyisocaproic acid (HICA), ⁇ -hydroxy-/?-methylvaleric acid (HIMVA), and ⁇ - hydroxy-isovaleric acid (HIVA).
  • HICA ⁇ -hydroxyisocaproic acid
  • HIMVA ⁇ -hydroxy-/?-methylvaleric acid
  • HIVA ⁇ - hydroxy-isovaleric acid
  • the term 'nutritional supplement' includes dietary supplements, diet supplements, nutritional compositions, supplemental dietary and other compositions similarly envisioned and termed not belonging to the conventional definition of pharmaceutical interventions as is known in the art.
  • 'nutritional supplements' as disclosed herein belong to category of compositions having at least one physiological function when administered to a
  • Pyruvate or pyruvic acid
  • pyruvate is a simple ⁇ -ketocarboxylate which is an important intermediate of glucose metabolism as well as being an endogenous antioxidant and free radical scavenger (Brand KA, Hermfisse U. Aerobic glycolysis by proliferating cells: a protective strategy against reactive oxygen species. FASEB J. 1997 Apr;11 (5):388-95). This recognition of pyruvate as an effective free radical scavenger prompted a surge of investigation for therapeutic uses.
  • Pyruvate is endogenously produced in cells as a result of the metabolism of glucose by glycolysis. In situations where a cell has an adequate supply of oxygen the pyruvate is converted into acetyl-coenzyme A, transported into the mitochondria, and enters a series of reactions collectively known as the Krebs cycle. However, in situations of oxygen deficiency, often occurring in muscle as a result of extended periods of exercise, the pyruvate is converted into lactate. While pyruvate can be transported directly into the mitochondria, most of it is reduced to lactate in the cytosol, prior to transport.
  • Lactate resulting from the conversion of pyruvate, can be transported into the mitochondria where it can be oxidized (Butz CE, McClelland GB, Brooks GA. MCT1 confirmed in rat striated muscle mitochondria. J Appl Physiol. 2004 Sep;97(3): 1059-66), or it can be exported out of the cell and taken up by oxygen-rich muscle cells.
  • the transport of lactate into the mitochondria is facilitated by MCT proteins, which are proton-linked transporters, i.e. protons are co-transported into the mitochondria with lactate (Roth DA, Brooks GA. Lactate and pyruvate transport is dominated by a pH gradient-sensitive carrier in rat skeletal muscle sarcolemmal vesicles.
  • ethyl pyruvate in a nutritional supplement will increase cellular levels of pyruvate. This increased concentration of cellular pyruvate will facilitate greater conversion to lactate, thus greater consumption of free protons, and increased regeneration of NAD + .
  • the increased regeneration of NAD + WiII facilitate greater levels of glycolytic energy production required by the working muscle and the increased consumption of free cytosolic protons will buffer against acidosis resulting from the increased glycolytic energy production.
  • the nutritional composition comprises ethyl pyruvate.
  • a serving of the nutritional composition comprises from about 0.0001 g to about 0.75 g of ethyl pyruvate.
  • ⁇ -Hydroxyisocaproic acid (HICA) ⁇ -Hydroxyisocaproic acid is an end product of the metabolism of the branched chain amino acid, Leucine.
  • HICA is a reduction product of the ⁇ -keto acid analog of Leucine, ⁇ -ketoisocaproic acid (KICA), and as such contributes to the free pools of branched chain amino acids (BCAA).
  • KICA ⁇ -ketoisocaproic acid
  • BCAA branched chain amino acids
  • Branched chain amino acid analogues are essentially nitrogen-free amino acids and may serve three roles in cases of nitrogen accumulation, 1 ) providing the dietary requirement of the corresponding branched-chain amino acid without increasing nitrogen intake; 2) reducing the amount of nitrogen that must be excreted from the body; and 3) increasing levels of Leucine, which plays a key role in protein turnover and prevents wasting of lean body mass. It is important to note that nitrogen accumulation can result from a number of situations including the catabolism of proteins in muscle during exercise.
  • branched chain amino acid analogues may be reaminated back to amino acid, e.g. HICA can be converted to KICA which can subsequently be converted back to Leucine, they can act to provide the dietary requirements for BCAA without increasing level of ingested nitrogen (Boebek KP, Baker DH. Comparative utilization of the ⁇ -keto and D- and L- ⁇ -hydroxy analogs of Leucine, lsoleucine and Valine by chicks and rats. J Nutr. 1982 Oct;112(10): 1929-39). This reamination will act to reduce accumulation of nitrogen in working cells, which will result in a reduction in the occurrence of delayed onset muscular soreness.
  • HICA HICA ⁇ -Hydroxyisocaproic acid - a Leucine metabolite for muscle recovery following exercise, www.elmomed.com
  • both ⁇ -keto acids and ⁇ -hydroxy acid metabolites of branched chain amino acids may be oxidized for energy instead of the branched chain amino acids themselves (Staten MA, Bier DM, Matthews DE. Regulation of valine metabolism in man: a stable isotope study. Am J Clin Nutr. 1984 Dec;40(6):1224-34).
  • HICA deaminated metabolites
  • aminated forms e.g. Leucine
  • ⁇ -hydroxy acid analogues like HICA, can be reaminated to yield the corresponding branched chain amino acids (Hoffer LJ, Taveroff A, Robitaille L, Mame OA, Reimer ML. Alpha-keto and alpha-hydroxy branched-chain acid interrelationships in normal humans. J Nutr. 1993 Sep; 123(9): 1513-21 ).
  • oral administration of at least one ⁇ -hydroxy branched-chain amino acid metabolite will act to increase levels of the corresponding branched-chain amino acid present in skeletal muscle.
  • Leucine is able to stimulate protein synthesis and inhibit protein breakdown (Tischler ME, Desautels M, Goldberg AL. Does Leucine, leucyl-tRNA, or some metabolite of Leucine regulate protein synthesis and degradation in skeletal and cardiac muscle? J Biol Chem. 1982 Feb 25;257(4): 1613-21 ), both of which would be favorable in working muscle as they result in increased skeletal muscle growth and decreased recovery time. It is herein understood by the inventors that oral administration of HICA will act to increase muscular concentrations of Leucine by acting as a substitute for Leucine in catabolism for energy as well as potentially being reaminated to form Leucine.
  • Increased levels of Leucine will stimulate protein synthesis and inhibit protein breakdown, thereby inducing an anabolically-favorable state for the cell. Additionally, it is herein understood by the inventors that oral administration of HIMVA and HIVA will act to increase muscular concentrations of lsoleucine and Valine, respectively, by at least the mechanisms discussed above.
  • the nutritional composition comprises ⁇ -hydroxyisocaproic acid.
  • a serving of the nutritional composition comprises from about 0.00001 g to about 0.75 g of ⁇ -hydroxyisocaproic acid.
  • the nutritional composition comprises ⁇ -hydroxy-/?-methylvaleric acid.
  • a serving of the nutritional composition comprises from about 0.00001 g to about 0.75 g of ⁇ -hydroxy- ⁇ -methyl valeric acid.
  • the nutritional composition comprises ⁇ -hydroxy-isovaleric acid.
  • a serving of the nutritional composition comprises from about 0.00001 g to about 0.75 g of ⁇ -hydroxy-isovaleric acid.
  • the nutritional supplement comprises ethyl pyruvate and at least one ⁇ -hydroxy branched-chain amino acid metabolite.
  • the nutritional supplement is provided in any acceptable and suitable oral dosage form as known in the art.
  • a synergistic anabolically-favorable state for the cell, via substantially simultaneously maintaining physiological pH levels and increasing cellular concentrations of branched- chain amino acids, is induced and carried out in an individual by administration of the composition of the present invention.
  • the nutritional supplement of the present invention may be administered in a dosage form having controlled release characteristics, e.g. time-release
  • the controlled release may be in forms such as a delayed release of active constituents, gradual release of active constituents, or prolonged release of active constituents.
  • active constituent release strategies extend the period of bioavailability or target a specific time window for optimal bioavailability.
  • the nutritional supplement may be administered in the form of a multi-compartment capsule which combines both immediate release and time-release characteristics. Individual components of the nutritional supplement may be contained in differential compartments of such a capsule such that specific components are released rapidly while others are time-dependently released. Alternatively, a uniform mix of the various components of the present invention may be divided into both immediate release and time-release compartments to provide a multi- phasic release profile
  • the present invention is comprised of components which act to attenuate acidosis in working muscle by increasing the conversion of pyruvate to lactate, which consumes free cytostolic protons (H + ) Additionally, increased concentrations of lactate, which result, will increase the co- transport of lactate and cytostolic H + into the mitochondria, thereby decreasing the concentration of cytostolic protons and increasing substrates in the mitochondria which are available to fuel the citric acid cycle Both of the aforementioned mechanisms will enhance the buffering ability of the cell Since decreased cellular pH has been linked to cell damage (Bevilacqua L, Ramsey JJ, Haqopian K, Weindruch R, Harper ME.
  • the present invention comprises components which have been shown to increase levels of branched-chain amino acids. It is herein understood by the inventors that inclusion of HICA in the nutritional supplement will act to increase muscular concentrations of Leucine by acting as a substitute for Leucine in catabolism for energy as well as potentially being reaminated to form Leucine. Increased levels of Leucine will stimulate protein synthesis and inhibit protein breakdown, thereby inducing an anabolically-favorable state for the cell.
  • administering ethyl pyruvate and HICA concomitantly in a single serving of the nutritional supplement act substantially simultaneously to induce an anabolically-favorable state in cells.
  • Administration of ethyl pyruvate increases cellular concentrations of lactate which are preferentially utilized for energy, thereby sparing the concentrations of BCAA, such as Leucine.
  • BCAA such as Leucine
  • HICA will spare the concentrations of BCAA, however, HICA has the additional capability of conversion to Leucine, thereby not only conserving Leucine, but also acting to increase the concentrations of Leucine. Therefore, administration of ethyl pyruvate and HICA together will conserve and increase Leucine concentrations, wherein an anabolically-favorable state for the cell is induced.
  • Additional embodiments of the present invention may also include portions of the composition as fine-milled ingredients.
  • the nutritional supplement may be consumed in any form.
  • the dosage form of the nutritional supplement may be provided as, e.g., a powder beverage mix, a liquid beverage, a ready-to-eat bar or drink product, a capsule, a liquid capsule, a tablet, a caplet, or as a dietary gel.
  • the preferred dosage forms of the present invention are as a caplet or as a liquid capsule.
  • the dosage form of the nutritional supplement may be provided in accordance with customary processing techniques for herbal and nutritional supplements in any of the forms mentioned above.
  • the nutritional supplement set forth in the example embodiment herein disclosed may contain any appropriate number and type of excipients, as is well known in the art.
  • a method for inducing an anabolically-favorable state for the cell by substantially simultaneously maintaining blood and muscle physiological pH levels and increasing cellular concentrations of Leucine is provided.
  • the method of the present invention comprises at least the step of administering to an individual a therapeutically acceptable amount of the composition of the present invention.
  • a nutritional supplement comprising the following ingredients per serving is prepared for consumption as a caplet three times daily prior to meals:
  • HICA ⁇ -hydroxyisocaproic acid
  • Example 2 A nutritional supplement comprising the following ingredients per serving is prepared for consumption as a caplet three times daily prior to meals:
  • HICA ⁇ -hydroxyisocaproic acid
  • a nutritional supplement comprising the following ingredients per serving is prepared for consumption as a time-release multi-compartmented capsule twice daily prior to meals, preferably once before the first meal and once before the last meal of the day:
  • HICA ⁇ -hydroxyisocaproic acid
  • a nutritional supplement comprising the following ingredients per serving is prepared for consumption as a capsule to be taken once daily prior to exercise: about 0.01 g of ethyl pyruvate, about 0.001 g of ⁇ -hydroxyisocaproic acid (HICA), about 0.001 g of ⁇ -hydroxy-/?-methylvaleric acid (HIMVA), and about 0.001 g of ⁇ -hydroxy- isovaleric acid (HIVA).
  • HICA ⁇ -hydroxyisocaproic acid
  • HMVA ⁇ -hydroxy-/?-methylvaleric acid
  • HIVA ⁇ -hydroxy- isovaleric acid
  • a nutritional supplement comprising the following ingredients per serving is prepared for consumption as a caplet to be taken once daily following exercise:
  • HICA ⁇ -hydroxyisocaproic acid
  • HMVA tf-hydroxy-/?-methylvaleric acid
  • HIVA ⁇ -hydroxy- isovaleric acid

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  • Orthopedic Medicine & Surgery (AREA)
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Abstract

La présente invention porte sur un supplément nutritionnel comprenant une quantité thérapeutiquement efficace de pyruvate d'éthyle et une quantité thérapeutiquement efficace d'au moins un métabolite d'acide aminé à chaîne ramifiée α-hydroxy. Les ingrédients du présent supplément nutritionnel conservent de manière sensiblement simultanée des valeurs de pH physiologiques dans le sang et les muscles, de même qu'ils augmentent les concentrations cellulaires des acides aminés à chaîne ramifiée.
PCT/CA2007/001615 2007-09-11 2007-09-11 Composition et procédé pour augmenter l'état anabolique de cellules musculaires WO2009033250A1 (fr)

Priority Applications (3)

Application Number Priority Date Filing Date Title
AU2007358961A AU2007358961A1 (en) 2007-09-11 2007-09-11 Composition and method for increasing the anabolic state of muscle cells
EP07800615A EP2192898A1 (fr) 2007-09-11 2007-09-11 Composition et procédé pour augmenter l'état anabolique de cellules musculaires
PCT/CA2007/001615 WO2009033250A1 (fr) 2007-09-11 2007-09-11 Composition et procédé pour augmenter l'état anabolique de cellules musculaires

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PCT/CA2007/001615 WO2009033250A1 (fr) 2007-09-11 2007-09-11 Composition et procédé pour augmenter l'état anabolique de cellules musculaires

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2012143405A1 (fr) * 2011-04-18 2012-10-26 Nestec S.A. Compositions nutritionnelles comprenant de l'alpha-hica et de l'alpha-cétoglutarate
WO2013014245A1 (fr) * 2011-07-26 2013-01-31 Helmholtz Zentrum München Deutsches Forschungszentrum Für Gesundheit Und Umwelt (Gmbh) Composition phytosanitaire contenant des acides alpha-hydroxylés

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1998004254A1 (fr) * 1996-07-26 1998-02-05 Beale Paxton K Composition a base de pyruvate et de proteine et procede augmentant la teneur en proteines de l'organisme d'un mammifere
US20050059738A1 (en) * 1999-10-07 2005-03-17 Xanthus Life Sciences, Inc. Pyruvate ester composition and method of use for resuscitation after events of ischemia and reperfusion

Patent Citations (2)

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WO1998004254A1 (fr) * 1996-07-26 1998-02-05 Beale Paxton K Composition a base de pyruvate et de proteine et procede augmentant la teneur en proteines de l'organisme d'un mammifere
US20050059738A1 (en) * 1999-10-07 2005-03-17 Xanthus Life Sciences, Inc. Pyruvate ester composition and method of use for resuscitation after events of ischemia and reperfusion

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Title
BOEBEL K. AND BAKER D.: "Comparative utilization of the alpha-keto and d- and l-alpha-hydroxy analogs of leucine,isoleucine and valine by chicks and rats", JOURNAL OF NUTRITION, vol. 112, 1982, pages 1929 - 1939, XP008116826 *
VAN SOMEREN ET AL.: "Supplementation with beta-hydroxy-beta-methylbutyrate(HMB) and alpha-ketoisocaproic acid(KIC) reduces signs and symptoms of exercise-induced muscle damage in man", INTERNATIONAL JOURNAL OF SPORT NUTRITION AND EXERCISE METABOLISM, vol. 15, 2005, pages 413 - 424, XP008131176 *
YOSHIZAWA F.: "Regulation of protein synthesis by branch-chain amino acids in vivo", BIOCHEMICAL AND BIOPHYSCIAL RESEARCH COMMUNICATIONS, vol. 313, 2004, pages 417 - 422, XP004480399 *

Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2012143405A1 (fr) * 2011-04-18 2012-10-26 Nestec S.A. Compositions nutritionnelles comprenant de l'alpha-hica et de l'alpha-cétoglutarate
WO2012143403A1 (fr) * 2011-04-18 2012-10-26 Nestec S.A. Compositions nutritionnelles comprenant de l'alpha-hica et de la citrulline
WO2012143404A1 (fr) * 2011-04-18 2012-10-26 Nestec S.A. Compositions nutritionnelles comprenant de l'alpha-hica et de l'acide eicosapentaénoïque
WO2012143402A1 (fr) * 2011-04-18 2012-10-26 Nestec S.A. Compositions nutritionnelles comprenant de l'alpha-hydroxyisocaproïque
CN103458710A (zh) * 2011-04-18 2013-12-18 雀巢产品技术援助有限公司 具有α-HICA和瓜氨酸的营养组合物
CN103476274A (zh) * 2011-04-18 2013-12-25 雀巢产品技术援助有限公司 具有α-HICA和α-酮戊二酸的营养组合物
CN103476275A (zh) * 2011-04-18 2013-12-25 雀巢产品技术援助有限公司 包含α-羟基异己酸的营养组合物
CN103491804A (zh) * 2011-04-18 2014-01-01 雀巢产品技术援助有限公司 具有α-HICA 和二十碳五烯酸的营养组合物
JP2014519483A (ja) * 2011-04-18 2014-08-14 ネステク ソシエテ アノニム α−ヒドロキシイソカプロン酸を含有する栄養組成物
WO2013014245A1 (fr) * 2011-07-26 2013-01-31 Helmholtz Zentrum München Deutsches Forschungszentrum Für Gesundheit Und Umwelt (Gmbh) Composition phytosanitaire contenant des acides alpha-hydroxylés

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EP2192898A1 (fr) 2010-06-09

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