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WO2009079739A1 - Utilisation de sel d'acide pyroglutamique de créatine pour favoriser une meilleure santé des neurones - Google Patents

Utilisation de sel d'acide pyroglutamique de créatine pour favoriser une meilleure santé des neurones Download PDF

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Publication number
WO2009079739A1
WO2009079739A1 PCT/CA2007/002369 CA2007002369W WO2009079739A1 WO 2009079739 A1 WO2009079739 A1 WO 2009079739A1 CA 2007002369 W CA2007002369 W CA 2007002369W WO 2009079739 A1 WO2009079739 A1 WO 2009079739A1
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WO
WIPO (PCT)
Prior art keywords
creatine
salt
pyroglutamic acid
increased neural
mammal
Prior art date
Legal status (The legal status 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 status listed.)
Ceased
Application number
PCT/CA2007/002369
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English (en)
Inventor
Michele Molino
Shan Chaudhuri
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
New Cell Formulations Ltd
Original Assignee
New Cell 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 New Cell Formulations Ltd filed Critical New Cell Formulations Ltd
Priority to PCT/CA2007/002369 priority Critical patent/WO2009079739A1/fr
Publication of WO2009079739A1 publication Critical patent/WO2009079739A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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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
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
    • A61K31/198—Alpha-amino acids, e.g. alanine or edetic acid [EDTA]
    • 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
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/4015—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil having oxo groups directly attached to the heterocyclic ring, e.g. piracetam, ethosuximide
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system

Definitions

  • the present invention relates to a method of use for hydrosoluble stable organic salts of creatine and pyroglutamic acid.
  • the present invention discloses a method for facilitating increased neural health in a mammal.
  • Creatine monohydrate is a commonly used supplement. Creatine monohydrate is soluble in water at a rate of 75 ml of water per gram of creatine. Ingestion of creatine monohydrate thereof requires large amounts of water to also be ingested. Additionally, in aqueous solutions, creatine converts to creatinine via an irreversible, pH-dependent, non-enzymatic reaction. Aqueous and alkaline solutions contain an equilibrium mixture of creatine and creatinine. In acidic solutions, on the other hand, the formation of creatinine is complete. Creatinine is devoid of the ergogenic beneficial effects of creatine and is typically excreted in the urine. It is therefore desirable to provide, for use in individuals, e.g. animals and humans, forms and derivatives of creatine with improved characteristics such as stability and solubility. Furthermore, it would be advantageous to do so in a manner that provides additional functionality compared to creatine monohydrate alone.
  • Hydrosoluble creatine monohydrate salts are obtainable and have been described elsewhere.
  • U.S. Patent No. 5,973,199 incorporated herein in its entirety by reference, purports to describe hydrosoluble organic salts of creatine as single combination of one mole of creatine monohydrate with one mole of the following organic acids: citrate, malate, fumarate, tartarate, and malate.
  • dicreatine and tricreatine citrate are claimed to be stable in acidic solution, in a guise to prevent or impede the formulation of creatine to creatinine.
  • the present invention is directed towards the a method of use of a nutritional supplement, comprising at least a hydrosoluble stable organic salt of creatine and D,L-pyroglutamic acid, i.e. creatine pyroglutamate, characterized by high water solubility, i.e. from 2 to 25 times higher than that of creatine itself.
  • the ingredients of the present nutritional supplement act to facilitate increased neural health in a mammal.
  • the present invention is directed towards the administration of a creatine pryoglutamic acid salt to a mammal; specific benefits are conferred by both the creatine component and the pyroglutamate component.
  • the preferred route of administration is oral.
  • Disclosed in the description of the present invention is a use of creatine pyroglutamate in producing compositions for oral administration to provide benefits related to facilitating increased neural health in a mammal.
  • the present invention is particularly well suited for use in tablets, capsules and solutions.
  • 'cognitive functions' refers to any mental component of brain function.
  • cognitive functions include, but are not limited to, attention, concentration, memory and focus.
  • 'Creatine' refers to the chemical N-methyl-N-guanyl Glycine, (CAS Registry No. 57-00-1), also known as, (alpha-methyl guanido) acetic acid, N-(aminoiminomethyl)- N- glycine, Methylglycocyamine, Methylguanidoacetic Acid, or N-Methyl-N-guanylglycine. Additionally, as used herein, 'creatine' also includes derivatives of creatine such as esters, and amides, and salts, as well as other derivatives, including derivatives having substantially similar pharmacoproperties to creatine upon metabolism to an active form.
  • Creatine Creatine is a naturally occurring amino acid derived from the amino acids glycine, arginine, and methionine. Although it is found in meat and fish, it is also synthesized by humans. Creatine is predominantly used as a fuel source in muscle. About 65% of Creatine is stored in muscle as Phosphocreatine (Creatine bound to a Phosphate molecule). Muscular contractions are fueled by the dephosphorylation of adenosine triphosphate (ATP) to produce adenosine diphosphate (ADP) and without a mechanism to replenish ATP stores, the supply of ATP would be totally consumed in 1-2 seconds.
  • ATP adenosine triphosphate
  • ADP adenosine diphosphate
  • Phosphocreatine serves as a major source of Phosphate from which ADP is regenerated to ATP.
  • muscular concentrations of Phosphocreatine drop by almost 50% and Creatine supplementation has been shown to increase the concentration of Creatine in the muscle and further said supplementation enables an increase in the resynthesis of Phosphocreatine leading to a rapid replenishment of ATP within the first two minutes following the commencement of exercise. It may be through this mechanism that Creatine can improve strength and reduce fatigue.
  • Creatine also mediates remarkable neuroprotection in experimental models of amyotrophic lateral sclerosis, Huntington's disease, Parkinson's disease, and traumatic brain injury. Also, oral creatine administration to experimental animals has been shown to increase protection and inhibition of cell-death cascades in neural tissue during periods of stress, such as ischemia. The protective effect of creatine administration has been linked to improved energy balance. This increased energy balance, preservation of ATP levels, inhibits cytochrome c release from the mitochondria. Release of cytochrome c signals caspase-3 activation and cell death often results. Administration of creatine conserves energy balance in neural cells during periods of stress, thereby preserving neural tissue by inhibiting caspase-mediated cell death.
  • Pyroglutamic Acid (CAS 98-79-3) is a naturally occurring amino acid derived from L- glutamic acid and involved in glutathione metabolism. Pyroglutamic acid crosses the blood-brain barrier and is found in high levels in the brain where it is thought to act in improving cognitive function. Pyroglutamate is generally available as arginine pyroglutamate wherein, the primary claim made for this arginine salt of pyroglutamic acid relates to its use in helping overcome memory defects induced by alcohol abuse and in those with some forms of dementia. Pyroglutamic acid has been shown to improve specific aspects of cognitive function in rats. In humans pyroglutamic acid improves age-associated memory impairment.
  • N-terminal pyroglutamate formation from its glutaminyl precursor is an important posttranslational or cotranslational event in the processing of numerous bioactive neuropeptides, hormones, and cytokines.
  • the N-terminal pyroglutamate is required by these regulatory peptides to develop the proper conformation for binding to their receptors, and to protect the peptides from degradation.
  • This N-terminal cyclization reaction is catalyzed by the enzyme glutaminyl cyclase, which is responsible for posttranslational modification.
  • glutaminyl cyclase also catalyzes the N-terminal glutamate cyclization into pyroglutamate.
  • This reaction is related to the formation of several plaque- forming peptides, such as amyloid-/? (A ⁇ ) peptides, which are major peptides within the core of neuritic plaques.
  • a ⁇ amyloid-/?
  • N-terminal pyroglutamate could enhance the hydrophobicity, proteolytic stability, and neurotoxicity of these peptides, thereby causing the accumulation of these A ⁇ peptides in senile plaques and quickening the progression of neurodegeration.
  • pyroglutamate in the form of a creatine salt, for example, will act as a feedback inhibitor to slow down the efficacy of glutaminyl cyclase in catalyzing the N-terminal glutamate cyclization into pyroglutamate, thereby preventing the acquisition of hydrophobic, proteolytic stability and neurotoxic characteristics by the A ⁇ peptides. Creatine Pyroglutamate
  • Creatine Pyroglutamate combines the muscle-enhancing and neuroprotective effects of creatine with the cognition-enhancing activity afforded by pyroglutamic acid.
  • the novel organic compound can be used in sports nutrition as an ergogenic aid to increase strength, muscle volume and size, while affording improved capacity of concentration and mental focus during physical exertion.
  • this creatine salt can find employment in metabolic nutrition by defending against ischemic brain infarction and affording neuroprotection after cerebral ischemia.
  • Creatine pyroglutamic acid salts are used advantageously alone or with additional active ingredients, such as, trace elements, 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 forms or effervescent tablets.
  • Further preferred forms of administration are capsules of hard and soft gelatin, the latter having particularly suitable to include a liquid core.
  • Creatine pyroglutamic acid salts can be used advantageously for the preparation of solutions and suspensions and as a powder, either effervescent or granulated. It is understood by the inventors that creatine pyroglutamic acid salts are useful compounds, since they combine within a single molecule both the creatine and the pyroglutamate, thus resulting in the increase of the useful activities of these two compounds. Particularly, it is herein understood by the inventors that creatine pyroglutamic acid salts will have enhanced increased solubility.
  • the creatine component of the salt will act to preserve cellular bioenergetics and inhibit caspase-mediated cell-death pathway activation. This preservation of ATP levels inhibits cytochrome c release from the mitochondria, thereby reducing caspase-3 activation and cell death thus preserving neural tissue.
  • the pyroglutamate component of the salt will act as a feedback inhibitor to slow down the efficacy of glutaminyl cyclase in catalyzing the N-terminal glutamate cyclization into pyroglutamate, thereby preventing the acquisition of hydrophobic, proteolytic stability and neurotoxic characteristics by the A/3 peptides.
  • the components of the present invention will act in concert through at least the aforementioned distinct mechanisms to facilitate increased neural health in a mammal.
  • Example 1 A nutritional supplement comprising the following ingredients per serving is prepared for consumption as four caplets to be administered in the morning:
  • a nutritional supplement comprising the following ingredients per serving is prepared for consumption as a powder to be mixed with water and consumed in the morning:
  • a nutritional supplement comprising the following ingredients per serving is prepared for consumption as three softgel capsules to be taken in the morning: About 1.500 g of a creatine pyroglutamic acid salt, about 50 mg of ethyl pyruvate, and about 50 mg of geranylgeranylacetone.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Epidemiology (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Biomedical Technology (AREA)
  • Neurology (AREA)
  • Neurosurgery (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Medicinal Preparation (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

Cette invention concerne l'utilisation de sels d'acide pyroglutamique de créatine pour favoriser une meilleure santé des neurones chez le mammifère. D'autres utilisations spécifiées consistent notamment à améliorer la fonction cognitive et à prévenir et lutter contre le stress et ses effets délétères sur les performances mentales et physiques. Les sels d'acide pyroglutamique de créatine sont appropriés pour une administration sous forme de comprimés, de capsules et de solutions.
PCT/CA2007/002369 2007-12-21 2007-12-21 Utilisation de sel d'acide pyroglutamique de créatine pour favoriser une meilleure santé des neurones Ceased WO2009079739A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
PCT/CA2007/002369 WO2009079739A1 (fr) 2007-12-21 2007-12-21 Utilisation de sel d'acide pyroglutamique de créatine pour favoriser une meilleure santé des neurones

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
PCT/CA2007/002369 WO2009079739A1 (fr) 2007-12-21 2007-12-21 Utilisation de sel d'acide pyroglutamique de créatine pour favoriser une meilleure santé des neurones

Publications (1)

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WO2009079739A1 true WO2009079739A1 (fr) 2009-07-02

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Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008031212A1 (fr) * 2006-09-11 2008-03-20 New Cell Formulations Ltd. Sels d'acide pyroglutamique-créatine, leurs procédés de fabrication et leur utilisation chez un individu

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008031212A1 (fr) * 2006-09-11 2008-03-20 New Cell Formulations Ltd. Sels d'acide pyroglutamique-créatine, leurs procédés de fabrication et leur utilisation chez un individu

Non-Patent Citations (5)

* Cited by examiner, † Cited by third party
Title
DRAGO, F ET AL.: "Pyroglutamic acid improves learning and memory capacities in old rats", FUNCTIONAL NEUROLOGY, vol. 3, no. 2, 1988, pages 137 - 143 *
FERANTE, RJ ET AL.: "'Neuroprotective effects of creatine in a transgenic mouse model of Huntington's disease'", THE JOURNAL OF NEUROSCIENCE, vol. 20, no. 12, 15 June 2000 (2000-06-15), pages 4389 - 4397 *
GRIOLI, S ET AL.: "Pyroglutamic acid improves the ages age associated memory impairment", FUNDAMENTAL AND CLINICAL PHARMACOLOGY, vol. 4, 1990, pages 169 - 173 *
SULLIVAN, PG ET AL.: "Dietary supplement creatine protects against traumatic brain injury", ANNALS OF NEUROLGY, vol. 48, no. 5, November 2005 (2005-11-01), pages 723 - 729 *
ZHU, S ET AL.: "Prophylactic creatine administration mediates neuroprotection in cerebral ischemia in mice", THE JOURNAL OF NEUROSCIENCE, vol. 24, no. 26, 30 June 2004 (2004-06-30), pages 5909 - 5912 *

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