EP2651406A1 - Composition à base de resvératrol, de l-tryptophane, d'acide l-aspartique, et de vitamine b3, conçue pour des applications pharmaceutiques, nutritionnelles et cosmétiques - Google Patents

Composition à base de resvératrol, de l-tryptophane, d'acide l-aspartique, et de vitamine b3, conçue pour des applications pharmaceutiques, nutritionnelles et cosmétiques

Info

Publication number
EP2651406A1
EP2651406A1 EP11813401.4A EP11813401A EP2651406A1 EP 2651406 A1 EP2651406 A1 EP 2651406A1 EP 11813401 A EP11813401 A EP 11813401A EP 2651406 A1 EP2651406 A1 EP 2651406A1
Authority
EP
European Patent Office
Prior art keywords
resveratrol
composition according
tryptophan
composition
aspartic acid
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.)
Withdrawn
Application number
EP11813401.4A
Other languages
German (de)
English (en)
Inventor
David DELLA MORTE
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.)
MK Pharma Srl
Original Assignee
MK Pharma Srl
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 MK Pharma Srl filed Critical MK Pharma Srl
Publication of EP2651406A1 publication Critical patent/EP2651406A1/fr
Withdrawn legal-status Critical Current

Links

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
    • A61K31/045—Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates
    • A61K31/05—Phenols
    • 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
    • A61K31/403—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 condensed with carbocyclic rings, e.g. carbazole
    • A61K31/404—Indoles, e.g. pindolol
    • A61K31/405—Indole-alkanecarboxylic acids; Derivatives thereof, e.g. tryptophan, indomethacin
    • 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
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • 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 composition
  • a composition comprising resveratrol, L-tryptophan, L- aspartic acid and vit.
  • B3 able to control the biosynthesis of nicotinamide adenine dinucleotide (NAD + ) for the purpose of producing a greater amount of substrates for reactions catalysed by Sirtuinl (SIRT1) and increasing the action of resveratrol.
  • SIRT1 Sirtuinl
  • the invention also relates to the use of such a composition in the pharmaceutical, nutritional and cosmetic fields.
  • resveratrol may be able to protect the heart (Daset al.,1999), brain (Della-Morte et al, 2009) and kidneys (Giovannini et al.,2001) against damage caused by ischemia/reperfusion.
  • the protective effects are based on the ability of resveratrol to reduce lipid peroxidation, to promote vasodilation, reduce serum levels of cholesterol and triglycerides, and to reduce platelet aggregation and consequently control all mechanisms associated with the development of atheroma plaques (Fuhrman et al.,1995; Hao and He, 2004; Zern et al., 2003).
  • resveratrol has also been shown to exhibit a protective effect in the case of Parkinson's disease, cerebral oedema, Alzheimer's disease and lateral amyotrophic sclerosis (Savaskan et al., 2003; Zhuang et al.,2003; Raval et al.,2008). Recently, in vitro and in vivo studies have demonstrated how resveratrol is able to extend the average life expectancy in all tested animals (Yang et al., 2007; Baur et al., 2006).
  • IPC ischemic preconditioning
  • Resveratrol is a candidate compound in treatment aimed at restoring the protective effects of IPC in senior subjects.
  • SIRT1 is a member of the family of the 7 sirtuins. Just like the other 6, it is orthologue of Sir2 (silent information regulator 2) and possesses NAD + -dependent deacetylase activity (Blander and Guarente, 2004; North et al., 2003). In cells, SIRT1 is localised in the nucleus. It is certainly the most studied among the family of sirtuins. It is transcribed ubiquitously in numerous human tissues and its activation is controlled by calorie restriction (Cohen et al., 2004).
  • the cosmetic efficacy of products activating SIRT1 is mainly based on the ability to repair nuclear DNA, having a significant effect against the signs of senescence (Moreau et al., 2007).
  • the object of the present invention is to provide a composition which can boost the effect of resveratrol through the production of a greater amount of substrates for reactions catalysed by SIRT1 , and also the use of said composition in the pharmaceutical, nutritional and cosmetic fields.
  • Fig. 1 , Fig. 2 and Fig. 3 show the results of tests comparing the effects of the composition according to the invention and of compositions belonging to the prior art.
  • Tryptophan is an amino acid which is essential to the human organism, that is responsible for the increase in plasma serotonin and melatonin levels and consequently promotes an improvement in mood and in the sleep-wake cycle. It is the amino acid necessary in the biosynthetic pathway of NAD * .
  • L-aspartic acid is a non-essential amino acid involved in the synthesis of adenosine triphosphate (ATP) and of arginine which promotes an improvement in the response of the organism to stress and fatigue. Similarly to tryptophan, it is involved in the direct synthesis of NAD + .
  • Vitamin B3 reduces the plasma levels of cholesterol and triglycerides in the organism and is known to contain more biologically active isoforms.
  • vitamin B3 in particular nicotinamide, as the isoform ⁇ - nicotinamide adenine dinucleotide hydrate, as an inhibitor of SIRT1 activation and, consequently, as an inhibitor of the beneficial effects of resveratrol.
  • the present invention relates to a composition
  • a composition comprising resveratrol, L-tryptophan, L- aspartic acid and ⁇ -nicotinamide adenine dinucleotide hydrate for the purposes of producing a greater amount of substrates for the reactions necessary for SIRT1 activation, boosting the beneficial action of resveratrol.
  • the administration of the composition according to the invention may take place both directly and by the substantially simultaneous administration of the active ingredients.
  • the present invention also relates to the use of the composition as a food supplement or as a medicament in itself or as a cosmetic for topical use.
  • the present invention proposes a strengthening system for SIRT1 activation, providing the chemical substrates necessary for greater activation by resveratrol and therefore greater beneficial activity of SIRT1.
  • composition comprising resveratrol, L-tryptophan, L-aspartic acid and ⁇ -nicotinamide adenine dinucleotide hydrate is able to increase SIRT1 activity in various tissues, increasing the effect of resveratrol.
  • oral bioavailability defines the percentage of the administered dose which effectively enters systemic circulation and is able to be distributed to the entire organism.
  • a substance administered intraperitoneally which is a route commonly used in experimental and toxicological medicine, is generally absorbed by portal circulation and must pass through the liver before reaching other organs, similarly to oral administration.
  • the dose is increased if administered orally since the passage through the gastric tract has to be included.
  • the following doses of a preferred composition were developed in the experimental tests: resveratrol 100 mg, L-tryptophan 17.5 mg, aspartic acid 35 mg and ⁇ -nicotinamide adenine dinucleotide hydrate 7.5 mg, these being doses at which it was possible to provide the following composition which proved to be effective (in percent):
  • aspartic acid 17 - 24% preferably 22%
  • composition according to the present invention in addition to the above-mentioned active ingredients, may also contain additives and vehicles which are pharmaceutically tolerable or which are commonly used in food supplements and/or cosmetic products.
  • a test of induction of cerebral ischemia was carried out in four groups of male SD rats (250-350 grams).
  • the components of the above compound were solubilised in the doses stated above and were proven to be able to activate SIRT1 , injected i.p. in a single dose 48 hours before induction of 8 minutes of CA.
  • the reference period was selected to be 48 hours since this is the period in which ischemic preconditioning has the greatest effect and in which resveratrol is able to mimic the neuroprotective effect of said ischemic preconditioning (Delia Morte D. et al., 2009).
  • the new tested complex (resveratrol, tryptophan, aspartic acid, ⁇ -nicotinamide adenine dinucleotide hydrate) increased the number of living neurons by 350% compared to the ischemia test group (p ⁇ 0.01) and by 130% compared to resveratrol alone (p ⁇ 0.02), thus demonstrating a rather powerful neuroprotective effect with regard to cerebral ischemia (Fig. 2).
  • the present preliminary data clearly demonstrates how the coordinated use of resveratrol, L-tryptophan, aspartic acid and ⁇ -nicotinamide adenine dinucleotide hydrate solubilised in a single complex is more effective at increasing SIRT1 activity and consequently at protecting against cerebral ischemia compared to resveratrol used alone in the same doses.
  • the use of such a compound may have a beneficial and cosmetic purpose by utilising the anti-ageing properties of SIRT1 activation.
  • the present invention also relates to the use of the composition in the pharmaceutical, nutritional and cosmetic fields, in the latter case by topical application.
  • the composition may be used for the prevention of age-related diseases, in particular cardiovascular and neurodegenerative diseases, and of systemic and cutaneous signs of ageing, especially caused by UVB.
  • SIRT1 activity cerebral tissue was removed from the hippocampus of rats 1 hour after pre-treatment with resveratrol and the composition of the invention.
  • the nuclear extract was fractionated using the technique described previously in detail by Raval and colleagues (Raval, 2006).
  • the enzyme activity of SIRT1 was measured using the kit based on the fluor de Lys-SIRT1 substrate peptide (BioMol International, Madison Meeting, PA, USA), able to measure the enzyme activity of SIRT1 via fluorescence.
  • the sensitivity of the activation of the suramin was considered as the enzyme activity of SIRT1.
  • CA Cardiac arrest
  • CA was induced by disconnection of the ventilator from the endotracheal tube.
  • the rats were anaesthetised with isoflurane and perfused with a mixture of 40% formaldehyde, glacial acetic acid and methanol mixed at a ratio of 1 :1 :8 (Perez-Pinzon, 1997).
  • the brains were thus removed from the skull and treated with paraffin; the coronal sections were cut to a thickness of 10 ⁇ and stained by the haematoxylin/eosin method.
  • the entire hippocampus was examined both the anterior and the posterior part. The number of normal neurons was counted inside the CA1 region of the hippocampus 3.8 mm behind the bregma.
  • the neurons which showed cellular modifications relating to the ischemia were identified by: 1) nucleus eosinophilic cytoplasm, 2) dark colouration of the nuclear agglomerates, 3) eosinophilic colouration of the nucleole. For each group of rats subjected to ischemia, the neurons were counted over 18 lines per section, from the medial part to the lateral part along the entire CA1 region of the hippocampus.
  • C. elegans neurodegeneration may be induced by a genetic mutation in the "6 touch sensing neurons". This mutation induces hyperactivation of the MEC-4 channel Na + /Ca 2+ of the DEG/ENaC family (mec-4(d)).
  • Neurodegeneration induced by (mec- 4(d)) shows numerous characteristics which are typical of neuronal death induced by ischemia/reperfusion including hyperactivation of the DEG/EnaC channel, intracellular increase in the concentration of Ca 2+ and swelling of the cellular body.
  • the data shows the comparison between the control mec-4(d), resveratrol and the composition of the invention in the model of C. elegans mec-4(d) able to induce neurodegeneration.
  • composition of the invention was added at a concentration equal to 5 ⁇ (concentrations used previously in various in vitro studies) (Raval A et al., 2009) in culture dishes for C. elegans. C. elegans eggs were then added to the dishes. Neurodegeneration after treatment was assessed by counting the number of neurons still surviving after treatment with the compound at stage L4 of F0 and F1 generation compared to the number of neurons in mec-4(d), used as a control in our experiments. With regard to the treatment with resveratrol, the same concentrations used for our compound were used. For each experiment an average number of 250 to 350 animals was used. Our data (Fig.
  • composition of the invention consistently yields results better than resveratrol, which in turn yields results better than the control
  • the compound is able to significantly increase (*p ⁇ 0.05) the number of animals having 2, 3 and 4 living neurons compared to both the control and the animals treated with resveratrol, indicating a powerful neuroprotective effect.
  • IARC No component of this product present at a level greater than or equal to 0.1 % has been identified as a known or expected carcinogenic by IARC.
  • IARC No component of this product present at a level greater than or equal to 0.1% has been identified as a known or expected carcinogenic by IARC.
  • Inhalation May be harmful if inhaled. May cause irritation of the airways.
  • Skin May be harmful if absorbed through the skin. May cause skin irritation.
  • L-tryptophan is present in nature in many food products and the studies carried out have not established whether it is the product itself or an impurity introduced during the preparation or distribution process which is the cause of such problems.
  • IARC No component of this product present at a level greater than or equal to 0.1% has been identified as a known or expected carcinogenic by IARC.
  • IARC No component of this product present at a level greater than or equal to 0.1 % has been identified as a known or expected carcinogenic by IARC.

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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)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

La présente invention concerne une composition à base de resvératrol, de L-tryptophane, d'acide L-aspartique, et de vitamine B3. Cette composition permet de maîtriser la biosynthèse du nicotinamide adénine dinucléotide (NAD+) de façon, d'une part à produire une plus grande quantité de substrats destinés aux réactions catalysées par la sirtuine 1 (SIRT1), et d'autre part à augmenter l'action du resvératrol.
EP11813401.4A 2010-12-13 2011-12-13 Composition à base de resvératrol, de l-tryptophane, d'acide l-aspartique, et de vitamine b3, conçue pour des applications pharmaceutiques, nutritionnelles et cosmétiques Withdrawn EP2651406A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
ITRM2010A000650A IT1406221B1 (it) 2010-12-13 2010-12-13 Composizione contenente resveratrolo l/triptofano acido l/aspartico e vitamina b3 (nad+) per l'impiego in campo farmaceutico nutrizionale e cosmetico
PCT/IB2011/055642 WO2012080952A1 (fr) 2010-12-13 2011-12-13 Composition à base de resvératrol, de l-tryptophane, d'acide l-aspartique, et de vitamine b3, conçue pour des applications pharmaceutiques, nutritionnelles et cosmétiques

Publications (1)

Publication Number Publication Date
EP2651406A1 true EP2651406A1 (fr) 2013-10-23

Family

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EP11813401.4A Withdrawn EP2651406A1 (fr) 2010-12-13 2011-12-13 Composition à base de resvératrol, de l-tryptophane, d'acide l-aspartique, et de vitamine b3, conçue pour des applications pharmaceutiques, nutritionnelles et cosmétiques

Country Status (3)

Country Link
EP (1) EP2651406A1 (fr)
IT (1) IT1406221B1 (fr)
WO (1) WO2012080952A1 (fr)

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2020016543A2 (fr) * 2018-03-13 2020-01-23 Nuchido Limited Méthode de traitement
WO2020230011A1 (fr) * 2019-05-13 2020-11-19 Guglielmo Buonamici Supplément nutraceutique humain

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
PT1755391E (pt) * 2004-06-04 2016-02-03 Univ Washington Métodos e composições para o tratamento de neuropatias
MX2011001702A (es) * 2008-08-12 2011-04-28 Sirtris Pharmaceuticals Inc Benzoxazoles, benzotiazoles y analogos relacionados como moduladores de sirtuina.

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO2012080952A1 *

Also Published As

Publication number Publication date
IT1406221B1 (it) 2014-02-14
ITRM20100650A1 (it) 2012-06-14
WO2012080952A1 (fr) 2012-06-21

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