WO2009073944A1 - Utilisation de pyridoxine alpha-hydroxyisocaproate pour réduire l'acidose métabolique et l'accumulation d'ammoniac - Google Patents

Utilisation de pyridoxine alpha-hydroxyisocaproate pour réduire l'acidose métabolique et l'accumulation d'ammoniac Download PDF

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Publication number
WO2009073944A1
WO2009073944A1 PCT/CA2007/002245 CA2007002245W WO2009073944A1 WO 2009073944 A1 WO2009073944 A1 WO 2009073944A1 CA 2007002245 W CA2007002245 W CA 2007002245W WO 2009073944 A1 WO2009073944 A1 WO 2009073944A1
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WO
WIPO (PCT)
Prior art keywords
hydroxyisocaproate
muscle
pyridoxme
muscular
hica
Prior art date
Application number
PCT/CA2007/002245
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English (en)
Inventor
Michele Molino
Joseph Macdougall
Original Assignee
Iovate T. & P. Inc.
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 Iovate T. & P. Inc. filed Critical Iovate T. & P. Inc.
Priority to PCT/CA2007/002245 priority Critical patent/WO2009073944A1/fr
Publication of WO2009073944A1 publication Critical patent/WO2009073944A1/fr

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Classifications

    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4415—Pyridoxine, i.e. Vitamin B6
    • 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
    • A61K9/0087—Galenical forms not covered by A61K9/02 - A61K9/7023
    • A61K9/0092—Hollow drug-filled fibres, tubes of the core-shell type, coated fibres, coated rods, microtubules or nanotubes
    • 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
    • A61K9/4841—Filling excipients; Inactive ingredients
    • A61K9/4858—Organic compounds
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system

Definitions

  • the present invention relates to the method of use of a nutritional supplement for maintaining physiological blood and muscular pH and increasing the time to muscular fatigue in a mammal during periods of repetitive forceful muscular exercise. More specifically, the present invention relates to a method of use for a nutritional supplement comprising at least a salt of pyridoxine and ⁇ -hydroxyisocaproic acid (HICA).
  • HICA ⁇ -hydroxyisocaproic acid
  • the body has a number of mechanisms that act as intracellular buffering systems, including, ammo acids, proteins, inorganic phosphate (P 1 ), bicarbonate, creatine phosphate hydrolysis, and lactate production (Robergs RA, Ghiasvand F, Parker D Biochemistry of exercise-mduced metabolic acidosis Am J Physiol Regul Integr Comp Physiol 2004,287 R502-16), all of which act to bind or consume H + to protect the cell against intracellular proton accumulation
  • these buffering systems are quickly overcome and an H + accumulation results, leading to muscle damage and fatigue
  • the present invention is directed towards the method of use of a nutritional supplement, compnsmg at least a salt of py ⁇ doxine and ⁇ -hydroxyisocaproic acid (HICA)
  • a nutritional supplement compnsmg at least a salt of py ⁇ doxine and ⁇ -hydroxyisocaproic acid (HICA)
  • HICA ⁇ -hydroxyisocaproic acid
  • the present invention is directed towards the administration of a nutritional supplement comprising at least a salt of pyridoxme and ⁇ -hydroxyisocaproic acid (HICA) to an animal or human, wherein specific benefits are conferred by both the py ⁇ doxine component and the HICA component
  • HICA ⁇ -hydroxyisocaproic acid
  • the preferred route of administration is oral
  • Disclosed in the desc ⁇ ption of the present invention is a use of pyridoxme ⁇ -hydroxyisocaproate in producing compositions for oral administration to provide benefits related to maintaining physiological blood and muscular pH and increasing the time to muscular fatigue in a mammal du ⁇ ng periods of repetitive forceful muscular exercise
  • the present invention is particularly well suited for use in tablets, capsules and solutions
  • pyridoxme ⁇ -hydroxyisocaproate possesses a strong buffering action, owing to the base component, pyridoxme The buffering action in the blood, as well as m the muscle, is important in order to mediate decreases in pH as
  • pyridoxme ⁇ -hydroxyisocaproate is to be understood as the salt of pyridoxme with HICA reacted in an equimolar ratio
  • 'pyridoxme' refers to the chemical 2-methyl-3-hydroxy-4,5- dihydroxymethylpyridine, (CAS Registry No 65-23-6), also known as 3-hydroxy-4,5- bis(hydroxymethyl)-2-methylpyridme, 3-hydroxy-4,5-dimethyl-o:-picoline, 5-hydroxy-6-mefhyl- 3,4-py ⁇ dmedimethanol, or Vitamin B6 Additionally, as used herein, 'py ⁇ doxme' also includes derivatives of pyridoxme such as esters, and amides, and salts, as well as other derivatives, including de ⁇ vatives having substantially similar pharmacoproperties to py ⁇ doxine upon metabolism to an active form
  • ' ⁇ -hydroxyisocaproic acid' refers to the chemical 2-hydroxy-4- methylvale ⁇ c acid, (CAS Registry No 498-36-2), also known as HICA, or leucic acid Additionally, as used herein, ' ⁇ -hydroxyisocaproic acid' also includes derivatives of ⁇ - hydroxyisocaproic acid such as esters, and amides, and salts, as well as other de ⁇ vatives, including derivatives having substantially similar pharmacoproperties to ⁇ -hydroxyisocaproic acid upon metabolism to an active form
  • 'nutritional supplement' includes dietary supplements, diet supplements, nut ⁇ tional composition, 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 compositions' as disclosed herein belong to category of compositions having at least one physiological function when administered to a mammal by conventional routes of administration
  • ⁇ -Hydroxyisocaproic acid (HICA) ⁇ -Hydroxyisocaproic acid (HICA)
  • HICA is an end product of the metabolism of the branched- chain ammo acid, Leucine
  • HICA occurs naturally Foods which are produced by fermentation, such as some cheeses, may contain small amounts of HICA HICA is a reduction product of the ⁇ -keto acid analog of Leucine, a- ketoisocaproic acid (KICA), and as such cont ⁇ butes to the free pools of branched-chain ammo acids (BCAA) HICA
  • This reamination reaction will act to reduce ammonia accumulation in plasma and working cells, therefore resulting in diminished central and muscle fatigue and reduced occurrence of delayed onset muscular soreness (DOMS).
  • Administration of about 1.5 g of HICA daily after intense exercise for 42 days (Karila T,
  • HICA ⁇ -Hydroxyisocaproic acid
  • both a- keto acids and ⁇ -hydroxy acid analogues 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).
  • deaminated analogs e.g. HICA
  • aminated forms e.g.
  • HICA ⁇ -hydroxy acid analogues
  • HICA can be reanimated to yield the corresponding branched-chain ammo acids (Hoffer LJ, Taveroff A, Robitaille L, Mame OA, Reimer ML Alpha-keto and alpha-hydroxy branched-cham acid interrelationships in normal humans J Nutr 1993 Sep, 123(9) 1513-21)
  • HICA branched-chain ammo acids
  • oral administration of HICA which is actively taken up in the intestine, can act to increase levels of Leucine present in skeletal muscle, thus reducing the need for supplemental branched-chain amino acids which may detrimentally contribute to an increase unwanted blood and muscular nitrogen levels
  • Leucine produced by the reamination of HICA is able to stimulate protein synthesis as well as inhibit protein breakdown (Tischler ME, Desautels M, Goldberg AL Does
  • HICA namely pyridoxme ⁇ -hydroxyisocaproate
  • a pyridoxme salt of HICA namely pyridoxme a- hydroxyisocaproate
  • HICA will also act to decrease plasma ammonia levels and reduce DOMS following periods of intensive exercise, thus shortening the recovery time between exercise pe ⁇ ods Pyridoxine
  • Py ⁇ doxine is a pyridine ring that contains hydroxyl, methyl and hydroxymethyl substituents, and is converted by the body to its active form, py ⁇ doxal 5-phosphate While pyridoxme is often referred to as Vitamin B6 it is actually only one of three vitamers which make up Vitamin B6, the others being pyridoxal and py ⁇ doxamme
  • the active form of pyridoxme in the body is py ⁇ doxal 5-phosphate, which is a coenzyme for all transamination as well as some decarboxylation and deammation reactions
  • Pyridoxal 5-phosphate is an important coenzyme involved in the decarboxylation of ammo acids resulting in amines (Bender DA Non-nutritional uses of Vitamin B6 Br J Nutr 1999 Jan, 81 (1) 7-20)
  • amines include neurotransmitters such as ⁇ -aminobutyrate, histamine, noradrenaline, and serotonin
  • pyridoxal 5-phosphate is required as a coenzyme for all transamination reactions that occur in the body (Peterson DL, Martinez-Carrion M The mechanism of transamination Function of the histidyl residue at the active site of supernatant aspartate transaminase J Biol Chem 1970 Feb 25,245(4) 806-13)
  • a transamination is the transfer of the amino group from an amino acid to an ⁇ -keto acid, e g ⁇ -ketoisocaproic acid can be converted to Leucine m this manner
  • HICA which can be converted into KICA, would make the formation of Leucine more favorable Pyridoxal 5-phosphate gains its versatility for use in various metabolic pathways, since it is able to form a Schiff base between its aldehyde group and the amino group of an ⁇ -ammo acid (Murray RK, Granner DK, Mayes PA, Rodwell
  • a serving of the present nutritional supplement comprises from about 0 002 g to about 0 2 g of py ⁇ doxme ⁇ -hydroxyisocaproate salt More preferably, a serving of the present nutritional supplement comprises from about 0 050 g to about 0 175 g of py ⁇ doxme a- hydroxyisocaproate salt A serving of the present nutritional composition most preferably comprises from about 0 1 g to about 0 15 g of py ⁇ doxine ⁇ -hydroxyisocaproate salt Additionally, ohydroxyisocaproic acid, in the non-salt form, may be present in the nutritional supplement
  • Pyridoxme ⁇ -hydroxyisocaproate is used advantageously alone or with additional active ingredients, such as, trace elements, other vitamins, mineral substances, or other amino acids as well as, optionally, excipients usually used for the preparation of the respective forms of administration
  • the forms of administration include, particularly, all varieties of tablets, both those that are swallowed without being chewed, and tablets to be chewed or dissolved in the mouth of an individual, as well as those that are dissolved in a liquid before being ingested by an individual
  • the tablet forms include uncoated tablets, one-layer or multilayer or encased form or effervescent tablets
  • Further preferred forms of administration are capsules of hard and soft gelatin, the latter particularly suitable to include a liquid core
  • pyridoxme ⁇ -hydroxyisocaproate can be used advantageously for the preparation of solutions and suspensions and as a powder, either effervescent or granulated Embodiments of the present invention having multi -phasic release profiles may produce physiologically relevant
  • py ⁇ doxine ⁇ -hydroxyisocaproate and its derivatives are useful compounds, since they combine within a single molecule both the pyndoxine and the ⁇ -hydroxyisocaproate, thus resulting in the increase of the useful activities of these two compounds
  • pyridoxme ⁇ hydroxyisocaproate will have enhanced pH stability in water withm a substantially broad range of concentrations
  • the pyridoxine component of the salt will act to increase the transamination of amino acids in muscle.
  • This transamination acts to facilitate the conversion of HICA to Leucine, thereby increasing the levels of Leucine in the muscle. Greater conversion of HICA to Leucine will also act to decrease ammonia accumulation in plasma and muscle, thereby retarding the onset of central and muscle fatigue and reducing DOMS following intensive periods of exercise, thus shortening the recovery time between exercise periods.
  • the ⁇ - hydroxyisocaproate component of the salt will act to increase muscular concentrations of Leucine by supplying a BCAA analogue that may be preferentially catabolized over that of Leucine to produce energy and is reaminated to form Leucine.
  • the components of the present invention will act in concert through at least the aforementioned distinct mechanisms to reduce muscular fatigue following intensive exercise and to attenuate DOMS.
  • Additional embodiments of the present invention may also include portions of the composition as fine-milled ingredients.
  • pyridoxine ⁇ -hydroxyisocaproate may be used advantageously alone or with additional active ingredients to form a nutritional composition that may be consumed in any form.
  • the dosage form of the nutritional composition may be provided as, e.g.
  • a powder beverage mix a liquid beverage, a ready-to-eat bar or ready-to-drink beverage product, a capsule, a liquid capsule, a tablet, a caplet, or as a dietary gel.
  • the preferred dosage forms of the present invention are provided as a caplet or as a liquid capsule.
  • the dosage form of the nutritional composition may be provided in accordance with customary processing techniques for herbal and nut ⁇ tional compositions in any of the forms mentioned above
  • the nut ⁇ tional composition 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 nutritional supplement comprising the following ingredients per serving is prepared for consumption as a caplet to be administered once daily, preferably before meals
  • a nutritional supplement comprising the following ingredients per serving is prepared for consumption as a caplet to be administered once daily, preferably before meals
  • a nut ⁇ tional supplement comprising the following ingredients per serving is prepared for consumption as a powder to be administered before engaging in physical exercise

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
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  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
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  • Orthopedic Medicine & Surgery (AREA)
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  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

L'invention concerne l'utilisation de pyridoxine alpha-hydroxyisocaproate pour réduire l'acidose métabolique et l'accumulation d'ammoniac dans le sang et les muscles. Il en résulte une réduction de la fatigue centrale et musculaire et une diminution des symptômes de douleurs musculaires survenant de manière retardée (DOMS). Plus généralement, ce composé doit être utilisé dans un complément nutritionnel afin de maintenir le pH musculaire et sanguin et améliorer la durée de fatigue musculaire chez un mammifère pendant des périodes d'exercice musculaire important répétitif.
PCT/CA2007/002245 2007-12-12 2007-12-12 Utilisation de pyridoxine alpha-hydroxyisocaproate pour réduire l'acidose métabolique et l'accumulation d'ammoniac WO2009073944A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
PCT/CA2007/002245 WO2009073944A1 (fr) 2007-12-12 2007-12-12 Utilisation de pyridoxine alpha-hydroxyisocaproate pour réduire l'acidose métabolique et l'accumulation d'ammoniac

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
PCT/CA2007/002245 WO2009073944A1 (fr) 2007-12-12 2007-12-12 Utilisation de pyridoxine alpha-hydroxyisocaproate pour réduire l'acidose métabolique et l'accumulation d'ammoniac

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WO2009073944A1 true WO2009073944A1 (fr) 2009-06-18

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Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3784553A (en) * 1972-01-17 1974-01-08 Made Labor Sa Pyridoxine alpha-ketoglutarate and its derivatives
US4100160A (en) * 1974-04-15 1978-07-11 The Johns Hopkins University Therapeutic compositions comprising alpha-hydroxy analogs of essential amino acids and their administration to humans for promotion of protein synthesis and suppression of urea formation
CA1177408A (fr) * 1980-09-22 1984-11-06 Francesco Fici Utilisation de l'alpha-cetoglutarate de pyridoxine dans la prophylaxie de l'hyperlactacidemie
EP0363337A1 (fr) * 1988-09-07 1990-04-11 Kabivitrum Ab Substrat d'énergie contenant un acide hydroxycarboxylique
WO2006042909A1 (fr) * 2004-10-21 2006-04-27 Oy Elmomed Ltd Supplément nutritif et emploi dudit supplément

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3784553A (en) * 1972-01-17 1974-01-08 Made Labor Sa Pyridoxine alpha-ketoglutarate and its derivatives
US4100160A (en) * 1974-04-15 1978-07-11 The Johns Hopkins University Therapeutic compositions comprising alpha-hydroxy analogs of essential amino acids and their administration to humans for promotion of protein synthesis and suppression of urea formation
CA1177408A (fr) * 1980-09-22 1984-11-06 Francesco Fici Utilisation de l'alpha-cetoglutarate de pyridoxine dans la prophylaxie de l'hyperlactacidemie
EP0363337A1 (fr) * 1988-09-07 1990-04-11 Kabivitrum Ab Substrat d'énergie contenant un acide hydroxycarboxylique
WO2006042909A1 (fr) * 2004-10-21 2006-04-27 Oy Elmomed Ltd Supplément nutritif et emploi dudit supplément

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