WO2022018281A2 - Composition comprising a mixture of extracts of vitis vinifera and vaccinium angustifolium and probiotics to improve cognitive function - Google Patents
Composition comprising a mixture of extracts of vitis vinifera and vaccinium angustifolium and probiotics to improve cognitive function Download PDFInfo
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- WO2022018281A2 WO2022018281A2 PCT/EP2021/070733 EP2021070733W WO2022018281A2 WO 2022018281 A2 WO2022018281 A2 WO 2022018281A2 EP 2021070733 W EP2021070733 W EP 2021070733W WO 2022018281 A2 WO2022018281 A2 WO 2022018281A2
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Definitions
- the invention relates to a composition
- a composition comprising at least one mixture of extracts of Vitis vinifero and of Vaccinium angustifolium, and at least one probiotic bacterium and/or probiotic yeast.
- Such a composition is intended for use as a nutritional product or medicine for improving cognitive functions in humans or animals.
- Cognitive decline and the appearance of the first cognitive disorders in particular neurodegenerative diseases such as Alzheimer's disease or Parkinson's disease mainly affects elderly subjects. Due to the evolution of medicine and the quality of care provided, the elderly population is increasing. There is therefore a high prevalence of these age-related pathologies. It is therefore of interest to develop solutions to prevent or minimize age-related cognitive decline and delay the onset of associated pathologies, in particular to prolong the autonomy of the elderly population and thus maintain their quality of life.
- patent FR3042712 describes a mixture of molecules obtained from Vitis vinifera and Vaccinium angustifolium, comprising at least 1% of catechin and/or epicatechin, and at least 5 ppm of ferulic acid.
- Two clinical studies showing the effectiveness of this mixture of molecules have been published (Bensalem J et al. Polyphenols From Grape and Blueberry Improve Episodic Memory in Healthy Elderly with Lower Level of Memory Performance: A Bicentric Double-Blind, Randomized, Placebo-Controlled Clinical Study. J Gerontol A Biol Sci Med Sci. 2019 Jul 19;74(7):996-1007; Hakkinen PJ. Hair.
- intestinal inflammation can promote cognitive deterioration and dementia.
- a decrease in the abundance of anti-inflammatory bacterial species such as Bifidobacterium breve Al strain and an increase in the abundance of pro-inflammatory flora phyla such as Firmicutes and Bacteroidetes are the most significant alterations. distinct from the gut microbiota of patients with Alzheimer's disease.
- Probiotics are live microorganisms which confer a benefit on the health of the host when they are provided in sufficient quantities.
- the prior art teaches us that taking a probiotic can act effectively on the cognitive functions of the animal (Wang H, Lee IS, Braun C, Enck P. Effect of probiotics on central nervous System functions in animals and humans: A systematic review (Vol. 22, Journal of Neurogastroenterology and Motility. Journal of Neurogastroenterology and Motility; 2016. pp. 589-605). It is also known from the prior art that the use of probiotics of the same species or of different species improved the cognitive functions in subjects suffering from mild cognitive disorders or Alzheimer's disease, possibly by reducing the inflammation and oxidative stress (Deng H, et al.
- the present invention provides a new composition comprising at least one mixture of extracts of Vitis vinifero and Vaccinium angustifolium, and at least one probiotic bacterium and/or probiotic yeast.
- Such a composition is not known from the prior art.
- the combination of a mixture of extracts of Vitis vinifero and of Vaccinium angustifolium and of at least one probiotic bacterium and/or probiotic yeast is particularly advantageous.
- Such a combination makes it possible to obtain a synergistic effect in particular prebiotic due to the polyphenols to improve the cognitive functions compared to a mixture of said extract or of a probiotic consumed individually by humans or animals.
- polyphenols are known to have antimicrobial activity.
- the combination of polyphenols provided concomitantly by extracts of Vitis vinifero and of Vaccinium angustifolium do not show such effects on the probiotics of the invention.
- the invention provides a new nutritional or pharmaceutical composition comprising:
- the probiotic bacterium and/or probiotic yeast integrated into the composition according to the invention is preferably chosen from bacteria and/or yeasts of the genus Lactobacillus, Bifidobacterium, Bacillus, Streptococcus, Saccharomyces, Enterococcus, Pediococcus and Escherichia.
- Such a composition is particularly intended to be administered to humans or animals as a medicament for preventing and/or treating pathologies associated with cognitive decline, but also as a nutritional product for preventing and/or treating normal cognitive decline in a healthy subject.
- composition is also intended for healthy subjects without pathologies associated with cognitive decline.
- Another object of the invention therefore relates to a non-therapeutic use of the composition according to the invention in healthy humans or animals, to improve cognitive functions and/or executive functions, and/or to limit normal age-related cognitive decline.
- nutritional composition is meant within the meaning of the invention any mixture of food compounds intended to be ingested by a healthy subject and comprising a mixture of extracts of Vitis vinifero and Vaccinium angustifolium and at least one probiotic bacterium and/or probiotic yeast.
- the nutritional compositions are in particular food or food compositions, or food supplements.
- health subject in the sense of the invention a subject who may be a human or an animal not suffering from any pathology associated with pathological cognitive decline such as Alzheimer's disease, Parkinson's disease , Huntington's disease, motor neuron disease or age-related macular degeneration (AMD).
- pathology associated with pathological cognitive decline such as Alzheimer's disease, Parkinson's disease , Huntington's disease, motor neuron disease or age-related macular degeneration (AMD).
- pathological subject is understood to mean, within the meaning of the invention, a subject who suffers or is likely to suffer from pathological cognitive decline such as Alzheimer's disease, Parkinson's disease, of Huntington's disease, motor neuron disease or age-related macular degeneration (AMD).
- pathological cognitive decline such as Alzheimer's disease, Parkinson's disease, of Huntington's disease, motor neuron disease or age-related macular degeneration (AMD).
- composition comprising at least one active substance presented as having curative or preventive properties with regard to human or animal diseases used alone or combined with other active or non-active substances and intended to be ingested by a pathological subject.
- a composition comprises in particular a mixture of extracts of Vitis vinifero and of Vaccinium angustifolium and at least one probiotic bacterium and/or probiotic yeast.
- the pharmaceutical composition is therefore a medicament intended for humans or animals in the prevention and/or treatment of pathological cognitive decline such as Alzheimer's disease, Parkinson's disease, Huntington's disease, motor neuron or age-related macular degeneration (AMD).
- pathological cognitive decline such as Alzheimer's disease, Parkinson's disease, Huntington's disease, motor neuron or age-related macular degeneration (AMD).
- a mixture of extracts of Vitis vinifero and Vaccinium angustifolium is meant a set of molecules obtained from a mixture of Vitis vinifero and Vaccinium angustifolium, preferably a mixture of at least one extract of Vitis vinifero and at least one extract of Vaccinium angustifolium.
- the raw material of Vitis vinifero can be the leaves and/or the fruits and/or the pips and/the woods, preferentially the raw material of Vitis vinifero is the aerial part of the plant, that is to say the whole leaves, fruits, skin (skin), seeds and wood, more preferably the skin (skin) and seeds.
- the raw material of Vaccinium angustifolium can be the leaves and/or the fruits, preferentially the raw material of Vaccinium angustifolium is all the leaves and fruits of the plant.
- At least X% of catechins and/or epicatechins is meant either at least X% of catechins if there are no epicatechins in the mixture, or at least X% of epicatechins there are no catechins in the mixture, i.e. at least X% of the mixture of catechins and epicatechins if both catechins and epicatechins are present in the mixture.
- at least X% of the mixture of catechins and epicatechins is meant.
- ppm is meant parts per million (mg/kg) in the mixture. Unless otherwise stated, ppm refers to a weight based on the total weight of the mixture.
- prevention within the meaning of the invention, is meant the reduction to a lesser degree of the risk or the probability of occurrence of a given phenomenon, that is to say, in the context of the present invention, for example, a pathological cognitive disorder.
- treating or “treatment” within the meaning of the invention, is meant a reduction in the progression of the disease or disorder, a stabilization, a reversal or regression, or even an interruption or inhibition of the progression of a disease or disorder. In the context of the invention, these terms also apply to one or more symptoms of said diseases or disorders of the present invention.
- the objective of the invention is therefore to provide a composition having improved efficacy in the fight against cognitive decline.
- the subject of the present invention is therefore a nutritional or pharmaceutical composition
- a nutritional or pharmaceutical composition comprising:
- the extract according to the invention can be obtained by any method making it possible to obtain a mixture of extracts of Vitis vinifero and of Vaccinium angustifolium and will be detailed below in this description.
- the mixture of extracts comprises a mixture of molecules comprising:
- Catechins and epicatechins are compounds of the flavonoid family, in particular of the flavanol subclass. They are also known as catechol and epicatechol and are powerful antioxidants that help in particular to prevent inflammatory and coronary diseases but also to maintain or increase cognitive performance.
- Ferulic acid is known for its effects on the neuronal system, in particular to protect neuronal cells from cell death induced by cerebral ischemia (Cheng SY, et al. Ferulic acid provides neuroprotection against oxidative stress-related apoptosis after cerebral ischemia/reperfusion injury by inhibiting ICAM-1 mRNA expression in rats (Brain Res. 2008;1209:136-150). In addition, its antioxidant activity has been tested in Alzheimer's disease (Sgarbossa A, et al. Ferulic Acid: A Hope for Alzheimer's Disease Therapy from Plants. Nutrients.
- composition is particularly increased and effective when it also comprises: - at least 200 ppm resveratrol, and/or
- Resveratrol is particularly known to be present in grapes. However, it can also be derived from other plant sources, in particular from Polygonum cuspidatum but also by biotechnological means. It has many beneficial activities for humans or animals, including an improvement in working memory, learning, spatial memory and spontaneous motor activity (Abraham J, Johnson RW. Consuming a diet supplemented with resveratrol reduced infection-related neuroinflammation and deficits in working memory in aged mice.Rejuvenation Res [Internet] 2010/01/01.2009;12(6):445-53).
- Quercetin also has significant neuroprotective activity (Dajas F, et al. Neuroprotective actions of flavones and flavonols: mechanisms and relationship to flavonoid structural features. Cent Nerv Syst Agents Med Chem. 2013; 13(l):30-5 ).
- composition according to the invention comprises at least one probiotic bacterium and/or probiotic yeast combined with the mixture of extracts.
- the specific combination as well as the quantity of the molecules found in the present composition makes it possible to obtain an effect on cognitive decline in humans or animals, this effect being better than that of an extract of Vitis vinifera and of Vaccinium angustifolium alone or of at least one probiotic bacterium and/or probiotic yeast alone.
- the probiotic bacterium and/or probiotic yeast can be dead, inactivated, semi-inactivated or alive.
- Said bacterium and/or probiotic yeast preferentially belongs to the genus Lactobacillus, Bifidobacterium, Bacillus, Streptococcus, Saccharomyces, Enterococcus, Clostridium, Lactococcus and Escherichia.
- the mixture, the probiotic bacteria and/or yeast is chosen from bacteria and/or yeast of the genus Lactobacillus, Bifidobacterium, Streptococcus, Enterococcus and Lactococcus.
- the bacterium is chosen from bacteria of the following species: Lactobacillus plantarum, Lactobacillus rhamnosus, Lactobacillus acidophilus, Lactobacillus bulgaricus, Lactobacillus delbrueckii ssp delbrueckii, Lactobacillus casei, Lactobacillus casei Shirota, Lactobacillus curvatus, Lactobacillus brevis, Lactobacillus fermentum, Lactobacillus salivarius, Lactobacillus mucosae, Lactobacillus paracasei, Lactobacillus johnsonii, Lactobacillus pentosus, Lactobacillus helveticus, Bifidobacterium bifidum, Bifidobacterium infantis, Bifidobacterium lactis, Bifidobacterium longum, Bifidobacterium longum spp infantis, Bifidobacterium longum
- the yeast is chosen from yeasts of the following species: Saccharomyces cerevisiae, Saccharomyces boulardii and their mixture.
- the composition according to the invention provides between 1 ⁇ 10 5 and 9 ⁇ 10 12 CFU daily, preferably between 1 ⁇ 10 7 and 9 ⁇ 10 11 of a probiotic bacterium and/or yeast and/or of a mixture.
- the composition may also comprise at least one prebiotic chosen from inulin, oligosaccharides, FOS (fructo-oligosaccharides), GOS (galacto-oligosaccharides), CLA (conjugated linoleic acid), PUFA (polyunsaturated fatty acid), MOS (mannanoligosaccharide) and XOS (xylooligosaccharide).
- prebiotic chosen from inulin, oligosaccharides, FOS (fructo-oligosaccharides), GOS (galacto-oligosaccharides), CLA (conjugated linoleic acid), PUFA (polyunsaturated fatty acid), MOS (mannanoligosaccharide) and XOS (xylooligosaccharide).
- prebiotic makes it possible to reinforce the effectiveness of the composition.
- the composition exhibits an improved effect in the prevention and/or treatment of cognitive decline.
- the composition can be encapsulated or microencapsulated, preferably the composition is encapsulated or microencapsulated in a food carrier chosen from maltodextrin, gum arabic, hydrogenated or non-hydrogenated oil, wax, alginates, starch, hydrolyzed or non-hydrolyzed proteins, phosphatidylcholine, phospholipids, galactomannan, emulsifiers chosen from pectin or polyglycerol polyricinoleate and fibers chosen from polydextrose, HPMC and cellulose.
- Encapsulation is particularly advantageous and makes it possible to stabilize and protect the extract of Vitis vinifero and of Vaccinium angustifolium and/or the probiotic(s) (bacteria and/or yeasts) from its environment, in particular from the organism.
- encapsulation makes it possible to improve the stability, the bioavailability and the use of said extract in food matrices, with in particular masking of the taste and resistance to possible alterations of the compounds during the stages of production of a food product.
- Microencapsulation provides the same advantages as encapsulation but more particularly makes it possible to insert active substances within particles of size between 1 ⁇ m and 1000 ⁇ m and more preferentially between 30 ⁇ m and 500 ⁇ m and even more preferentially between 50pm and 300pm.
- composition according to the invention is intended to be administered as a nutritional or therapeutic product and can therefore be in different forms, preferably in the form of a powder, capsule, tablet, capsule, solution, suspension, emulsion or chewing gum.
- composition When the composition is intended to be administered as a nutritional product, it may be in the form of a food product, preferably in the form of dairy products, purees, cereals, cereal products and beverages.
- the invention When the composition is administered as a therapeutic product, the invention relates to a composition for its use as a medicament for humans or animals.
- Cognitive decline is characterized by an age-related decrease in cognitive and executive functions, in particular concentration, working memory, long-term memory, reasoning, judgment, resolution problems and information processing speed. These deficiencies can lead to a decrease in self-esteem and quality of life.
- Age-related cognitive decline is the term used to describe the non-pathological form of deterioration of memory and cognitive functions consequent to the aging process within normal limits, given a person's age. It is a complex process, with the first signs emerging in humans between 35 and 65 years old, without specific neurodegenerative lesions. Progressive cognitive decline is noticeable by the appearance of minor cognitive problems which affect 15-20% of the population aged 65 or over, but which represent an unstable state. Nevertheless, certain pathological forms may occur in addition to this “normal” cognitive decline.
- Alzheimer's disease is the most common cause of dementia, which affects more than 24 million people worldwide. It is irreversible in our current state of knowledge, the only treatments available being purely symptomatic. In animals, these pathologies can present themselves in a very similar way.
- the cognitive dysfunction syndrome (or CDS) is a widespread pathology characterized by spatio-temporal disorientation, a loss of elementary learning which often induces uncleanliness, an alteration of sleep-wake cycles, and impaired social interactions.
- the composition is intended for use in neuroprotection, and/or improving cognitive functions and/or memory and/or executive functions, and/or alleviating cognitive decline.
- the composition according to the invention exhibits neuroprotective effects and can be used in the prevention and/or treatment of pathologies associated with cognitive decline.
- composition according to the invention can be used in the prevention and/or treatment of pathologies associated with the destruction of neurons, the decrease in cognitive functions, memory, executive functions.
- composition according to the invention is particularly intended for use in the prevention and/or treatment:
- neurodegenerative diseases such as Alzheimer's disease, and/or Parkinson's disease, and/or Huntington's disease, and/or motor neuron diseases and/or age-related macular degeneration (AMD),
- AMD age-related macular degeneration
- CDS mental retardation and/or cognitive dysfunction syndrome
- composition according to the invention is delivered at a dose making it possible to provide humans or animals with:
- composition according to the invention is delivered at a dose making it possible to provide humans or animals with:
- animal may also be a nutritional or therapeutic composition intended for the animal.
- the term “animal” is understood to mean any animal that can receive a nutritional or therapeutic composition according to the invention, for example but in a non-limiting way a pet, a poultry, a pig, a ruminant, a goat, or even a mouse.
- the animal is a pet, such as a cat or a dog. More preferably, the animal is a dog.
- composition according to the invention is also intended to be used as a nutritive product without any therapeutic effect and in a healthy subject.
- the invention also relates to a non-therapeutic use of the composition according to the invention in healthy humans or animals, to improve cognitive functions and/or executive functions, and/or to limit normal age-related cognitive decline.
- the invention relates to a non-therapeutic use of the composition for improving memory and/or attention and/or concentration and/or alertness and/or alertness and/or learning and/or intelligence and/or language and/or mood and/or stress and/or anxiety and/or sleep.
- composition according to the invention in the context of a non-therapeutic use can preferably be delivered in an amount making it possible to provide healthy humans or animals:
- composition according to the invention is delivered in an amount making it possible to provide healthy humans or animals with:
- quercetin and/or quercetin glycosides at least 0.2 pg per kg of body weight of quercetin and/or quercetin glycosides
- ferulic acid preferably at least 10 ppm, even more preferably between 5 and 300 ppm, in particular between 10 and 100 ppm.
- the process makes it possible to obtain a mixture of molecules comprising:
- quercetin and/or quercetin glycosides at least 50 ppm of quercetin and/or quercetin glycosides, 70 ppm of quercetin and/or glycoside, in particular between 50 and 100 ppm, and
- anthocyanidins preferably at least 600 ppm, even more preferably at least 700 ppm.
- a particularly suitable method is a method comprising the following steps:
- an extract of Vitis vinifera a. water and/or ethanol extraction of Vitis vinifera, preferably of all the leaves, fruits, skin, pips and wood of Vitis vinifera.
- the quantity of solvent (30% v/v to 96% V/V) used is between 2 and 10 times the mass of material used.
- the duration of the extraction can be between 30 minutes and 24 hours and the extraction temperature between 20°C and 80°C.
- the raw materials used can be in dry, fresh, or frozen whole or ground form; b. separation of the water and/or ethanol solution from the solid material, for example by centrifugal decantation or by pressing and filtration; vs. evaporation of the ethanol by vacuum evaporation at a temperature preferably below 60° C.
- d membrane separation of the previously desolventized extract so as to preferentially select the proanthocyanidin monomers and oligomers (having a degree of polymerization between 2 and 10 inclusive) and to eliminate the flavanol polymers (> decamers), to obtain an extract comprising at least 1% of catechins and/or epicatechins.
- This step can be carried out using a filtration membrane having a cut-off threshold of less than 15,000 daltons and more preferably less than 3,000 daltons;
- an extract of Vaccinium angustifolium a. water and/or ethanol extraction of Vaccinium angustifolium, preferably all of the leaves and fruits of Vaccinium angustifolium,
- the amount of solvent (30% v/v to 96% V/V) used is between 2 and 10 times the mass of material used.
- the duration of the extraction can be between 30 minutes and 24 hours and the extraction temperature between 20°C and 80°C.
- the raw materials used can be in dry, fresh or frozen form; b. separation of the water and/or ethanol solution from the solid material by centrifugal decantation or by pressing and filtration; vs. evaporation of the ethanol by vacuum evaporation at a temperature preferably below 60° C. and a pressure below 100 mbar; d. drying of the extracts by atomization, vacuum drying or lyophilization with or without a support such as a maltodextrin;
- the method consists of the implementation of the following steps:
- the amount of solvent (30% v/v at 96% V/V) implementation is between 2 and 10 times the mass of material implemented.
- the duration of the extraction can be between 30 minutes and 24 hours and the extraction temperature between 20°C and 80°C.
- the raw materials used can be in dry, fresh or frozen form;
- the method may comprise the following steps:
- Example 1 Nutritional composition intended for humans [0083]
- Example 1 is a 400 mg capsule, consisting of:
- Blend of extracts 300 mg
- Blend of 6 probiotics (Lactobacillus fermentum, L plantarum, L acidophilus, Bfidobacterium lactis, B. longum, B. bifidum) 3c10 L 9 CFU: 50 mg Maltodextrin: 50 mg.
- composition is obtained by mixing the constituents under the conventional conditions known to those skilled in the art, and placed in a capsule according to the conventional conditions as well.
- the recommended dosage is 2 capsules per day.
- Example 2 Nutritional composition intended for humans [0085]
- Example 2 is a sachet of 3200 mg, consisting of:
- Blend of extracts 600 mg
- Blend of 3 probiotics (Lactobacillus acidophilus, Bifidobacterium bifidum, Lactobacillus fermentum) 4c10 L 9 CFU: 2500 mg Maltodextrin: 100 mg.
- the composition is obtained by mixing the constituents under conventional conditions known to those skilled in the art and is in the form of a powder contained in a sachet also under conventional conditions. The recommended dosage is 1 sachet per day.
- Example 3 Nutritional composition intended for animals
- Example B is a soft capsule consisting of:
- Blend of extracts 50 mg
- composition is obtained by mixing the constituents under conventional conditions known to those skilled in the art and is in the form of a soft capsule also under conventional conditions.
- the recommended dosage is 1 capsule per day.
- Example 4 Nutritional Composition Intended for Animals
- Example 4 is a tablet consisting of:
- Blend of extracts 50 mg
- Blend of 5 probiotics (Lactobacillus acidophilus, L. plantarum, L. Brevis, Bifidobacterium animalis lactis, Lactobacillus ramnosus) 2c10 L 9 CFU: 26.5 mg
- composition is obtained by mixing the constituents under conventional conditions known to those skilled in the art and is in the form of a tablet also under conventional conditions.
- the recommended dosage is 1 tablet per day for a 10 kg dog.
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Abstract
The present invention relates to a nutritional or pharmaceutical composition comprising at least one mixture of extracts of Vitis vinifera and Vaccinium angustifolium, and at least one probiotic bacterium and/or probiotic yeast. Such a composition is intended to be used as a nutritional product or a drug for improving cognitive functions in humans or animals.
Description
COMPOSITION COMPRENANT UN MELANGE D'EXTRAITS DE VITIS VINIFERA ET DE VACCINIUM ANGUSTIFOLIUM ET DES PROBIOTIQUES POUR AMELIORER LES FONCTIONS COGNITIVES COMPOSITION COMPRISING A BLEND OF VITIS VINIFERA AND VACCINIUM ANGUSTIFOLIUM EXTRACTS AND PROBIOTICS TO IMPROVE COGNITIVE FUNCTIONS
[0001] Domaine technique [0001] Technical area
[0002] L'invention concerne une composition comprenant au moins un mélange d'extraits de Vitis vinifero et de Vaccinium angustifolium, et au moins une bactérie probiotique et/ou levure probiotique. Une telle composition est destinée à être utilisée comme produit nutritionnel ou médicament pour améliorer les fonctions cognitives chez l'Homme ou l'animal. The invention relates to a composition comprising at least one mixture of extracts of Vitis vinifero and of Vaccinium angustifolium, and at least one probiotic bacterium and/or probiotic yeast. Such a composition is intended for use as a nutritional product or medicine for improving cognitive functions in humans or animals.
[0003] Art antérieur [0003] Prior art
[0004] Le déclin cognitif et l'apparition des premiers troubles cognitifs, en particulier les maladies neurodégénératives telles que la maladie d'Alzheimer ou la maladie de Parkinson affecte principalement les sujets âgés. De par l'évolution de la médecine et de la qualité des soins apportée, la population âgée augmente. Il y a donc une forte prévalence de ces pathologies liées à l'âge. Il est donc d'intérêt de développer des solutions pour prévenir ou minimiser le déclin cognitif lié à l'âge et retarder l'apparition des pathologies associées, en particulier pour prolonger l'autonomie de la population âgée et ainsi maintenir leur qualité de vie. [0004] Cognitive decline and the appearance of the first cognitive disorders, in particular neurodegenerative diseases such as Alzheimer's disease or Parkinson's disease mainly affects elderly subjects. Due to the evolution of medicine and the quality of care provided, the elderly population is increasing. There is therefore a high prevalence of these age-related pathologies. It is therefore of interest to develop solutions to prevent or minimize age-related cognitive decline and delay the onset of associated pathologies, in particular to prolong the autonomy of the elderly population and thus maintain their quality of life.
[0005] Des sujets en bonne santé souffrant d'aucune pathologie sont aussi à la recherche de solutions pour améliorer leurs fonctions cognitives, en particulier la mémoire, l'attention, la concentration, la vivacité, la vigilance, l'apprentissage, le langage, l'humeur, le stress, l'anxiété ou le sommeil et ainsi maintenir un état de bien-être. Il est connu que la nutrition est un facteur important pour prévenir l'altération des fonctions cognitives. [0005] Healthy subjects suffering from any pathology are also looking for solutions to improve their cognitive functions, in particular memory, attention, concentration, alertness, alertness, learning, language , mood, stress, anxiety or sleep and thus maintain a state of well-being. It is known that nutrition is an important factor in preventing cognitive impairment.
[0006] A cette fin, il a été développé, des agents nutritionnels et compléments alimentaires. En particulier, le brevet FR3042712 décrit un mélange de molécules obtenu à partir de Vitis vinifera et de Vaccinium angustifolium, comprenant au moins 1% de catéchine et/ou épicatéchine, et au moins 5 ppm d'acide férulique. Deux études cliniques montrant l'efficacité de ce mélange de molécules ont été publiées (Bensalem J et al. Polyphenols From Grape and Blueberry Improve Episodic Memory in Healthy Elderly with Lower Level of Memory Performance: A Bicentric Double-Blind, Randomized, Placebo-Controlled Clinical Study. J Gerontol A Biol Sci Med Sci. 2019 Jul 19;74(7):996-1007; Hakkinen PJ. Hair. In: Editor-in-Chief: Philip W, editor. Encyclopedia of Toxicology (Second Edition). New York: Elsevier; 2005. p. 475- 7). Un tel mélange est donc connu ainsi que ses effets sur les fonctions cognitives de l'être
humain lors de prise aigue chez le jeune adulte ou de prise chronique chez la personne âgée. [0007] Il est également communément admis que le tractus intestinal de l'Homme ou l'animal héberge un grand nombre de populations microbiennes très diverses, appelé respectivement microbiote et zoobiote. De plus en plus d'études confirment l'importance du microbiote intes tinal pour la santé de l'hôte, y compris pour les fonctions cognitives et psychologiques au tra vers de la communication bidirectionnelle intestin-cerveau (« gut-brain axis ») (Tyler Patterson T, Grandhi R. Gut Microbiota and Neurologie Diseases and Injuries. In: Advances in Experimen tal Medicine and Biology. Springer ; 2020. p. 73-91.). Une dysbiose du microbiote intestinal peut ainsi être associée à des troubles du comportement et de la cognition. [0006] To this end, nutritional agents and food supplements have been developed. In particular, patent FR3042712 describes a mixture of molecules obtained from Vitis vinifera and Vaccinium angustifolium, comprising at least 1% of catechin and/or epicatechin, and at least 5 ppm of ferulic acid. Two clinical studies showing the effectiveness of this mixture of molecules have been published (Bensalem J et al. Polyphenols From Grape and Blueberry Improve Episodic Memory in Healthy Elderly with Lower Level of Memory Performance: A Bicentric Double-Blind, Randomized, Placebo-Controlled Clinical Study. J Gerontol A Biol Sci Med Sci. 2019 Jul 19;74(7):996-1007; Hakkinen PJ. Hair. In: Editor-in-Chief: Philip W, editor. Encyclopedia of Toxicology (Second Edition). New York: Elsevier; 2005. pp. 475-7). Such a mixture is therefore known as well as its effects on the cognitive functions of the being human during acute intake in young adults or chronic intake in the elderly. [0007] It is also commonly accepted that the intestinal tract of humans or animals harbors a large number of very diverse microbial populations, called microbiota and zoobiota respectively. More and more studies confirm the importance of the gut microbiota for the health of the host, including for cognitive and psychological functions through the bidirectional gut-brain communication (gut-brain axis) ( Tyler Patterson T, Grandhi R. Gut Microbiota and Neurology Diseases and Injuries. In: Advances in Experimental Medicine and Biology. Springer; 2020. pp. 73-91.). A dysbiosis of the intestinal microbiota can thus be associated with behavioral and cognitive disorders.
[0008] Par ailleurs, l'inflammation intestinale peut favoriser la détérioration cognitive et la démence. A titre d'exemple, une diminution de l'abondance des espèces bactériennes anti inflammatoires telles que la souche Al de Bifidobacterium brève et une augmentation de l'abondance du phyla de la flore pro-inflammatoire telle que Firmicutes et Bacteroidetes sont les altérations les plus distinctes du microbiote intestinal des patients atteints de la maladie d'Alzheimer. [0008] Furthermore, intestinal inflammation can promote cognitive deterioration and dementia. For example, a decrease in the abundance of anti-inflammatory bacterial species such as Bifidobacterium breve Al strain and an increase in the abundance of pro-inflammatory flora phyla such as Firmicutes and Bacteroidetes are the most significant alterations. distinct from the gut microbiota of patients with Alzheimer's disease.
[0009] La modulation du microbiote intestinal pour améliorer les fonctions cognitives et prévenir la démence constitue donc une approche préventive ou thérapeutique très prometteuse. Il a été démontré que les modifications alimentaires, y compris la supplémentation en prébiotiques et en probiotiques permettaient d'améliorer la composition du microbiote intestinal et ainsi agir favorablement sur les fonctions cognitives. [0009] The modulation of the intestinal microbiota to improve cognitive functions and prevent dementia therefore constitutes a very promising preventive or therapeutic approach. Dietary modifications, including prebiotic and probiotic supplementation, have been shown to improve the composition of the intestinal microbiota and thus act favorably on cognitive functions.
[0010] Les probiotiques sont des micro-organismes vivants qui confèrent un bénéfice sur la santé de l'hôte lorsqu'ils sont apportés en quantités suffisantes. L'art antérieur nous enseigne que la prise de probiotique permet d'agir efficacement sur les fonctions cognitives de l'animal (Wang H, Lee IS, Braun C, Enck P. Effect of probiotics on central nervous System functions in animais and humans: A systematic review. Vol. 22, Journal of Neurogastroenterology and Motility. Journal of Neurogastroenterology and Motility; 2016. p. 589-605). Il est également connu de l'art antérieur que l'utilisation de probiotiques d'une même espèce ou d'espèces différentes améliorait les fonctions cognitives chez des sujets atteints de troubles cognitifs légers ou de la maladie d'Alzheimer, éventuellement en diminuant l'inflammation et le stress oxydant (Deng H, et al. Efficacy of probiotics on cognition, and biomarkers of inflammation and oxidative stress in adults with Alzheimer's disease or mild cognitive impairment-A meta- analysis of randomized controlled trials. Vol. 12, Aging. Impact Journals LLC ; 2020. p. 4010-
39 ; Akbari E, et al. Effect of probiotic supplémentation on cognitive function and metabolic status in Alzheimer's disease: A randomized, double-blind and controlled trial. Front Aging Neurosci. 2016 Nov 10;8(NOV):256; Kobayashi Y, et al. Effects of bifidobacterium breve al on the cognitive function of older adults with memory complaints: A randomised, double-blind, placebo-controlled trial. Benef Microbes. 2019 ; 10(5):511-20). [0010] Probiotics are live microorganisms which confer a benefit on the health of the host when they are provided in sufficient quantities. The prior art teaches us that taking a probiotic can act effectively on the cognitive functions of the animal (Wang H, Lee IS, Braun C, Enck P. Effect of probiotics on central nervous System functions in animals and humans: A systematic review (Vol. 22, Journal of Neurogastroenterology and Motility. Journal of Neurogastroenterology and Motility; 2016. pp. 589-605). It is also known from the prior art that the use of probiotics of the same species or of different species improved the cognitive functions in subjects suffering from mild cognitive disorders or Alzheimer's disease, possibly by reducing the inflammation and oxidative stress (Deng H, et al. Efficacy of probiotics on cognition, and biomarkers of inflammation and oxidative stress in adults with Alzheimer's disease or mild cognitive impairment-A meta-analysis of randomized controlled trials. Vol. 12, Aging. Impact Journals LLC;2020.p.4010- 39; Akbari E, et al. Effect of probiotic supplementation on cognitive function and metabolic status in Alzheimer's disease: A randomized, double-blind and controlled trial. Front Aging Neurosci. 2016 Nov 10;8(NOV):256; Kobayashi Y, et al. Effects of bifidobacterium breve al on the cognitive function of older adults with memory complaints: A randomised, double-blind, placebo-controlled trial. Benef Microbes. 2019; 10(5):511-20).
[0011] Il est donc déjà connu de l'art antérieur des agents nutritionnels comprenant un mélange d'extraits de Vitis vinifero et de Vaccinium angustifolium ou des probiotiques pris individuellement pour améliorer les fonctions cognitives chez l'Homme ou l'animal. [0011] It is therefore already known from the prior art of nutritional agents comprising a mixture of extracts of Vitis vinifero and of Vaccinium angustifolium or probiotics taken individually to improve cognitive functions in humans or animals.
[0012] Or, il existe toujours un besoin pour une nouvelle solution avec une efficacité améliorée par rapport à l'art antérieur afin de prévenir et/ou traiter le déclin des fonctions cognitives dans le cadre du processus normal du vieillissement ou ralentir la progression d'une démence ou maintenir un état cognitif stable ou amélioré pour un sujet sain ne souffrant d'aucune pathologie associée au déclin cognitif. [0012] However, there is still a need for a new solution with improved efficiency compared to the prior art in order to prevent and/or treat the decline of cognitive functions as part of the normal aging process or to slow the progression of dementia or maintain a stable or improved cognitive state for a healthy subject not suffering from any pathology associated with cognitive decline.
[0013] Résumé de l'invention [0013] Summary of the Invention
[0014] Pour répondre à ce besoin, la présente invention propose une nouvelle composition comprenant au moins un mélange d'extraits de Vitis vinifero et de Vaccinium angustifolium, et au moins une bactérie probiotique et/ou levure probiotique. To meet this need, the present invention provides a new composition comprising at least one mixture of extracts of Vitis vinifero and Vaccinium angustifolium, and at least one probiotic bacterium and/or probiotic yeast.
[0015] Une telle composition n'est pas connue de l'art antérieur. Or, l'association d'un mélange d'extraits de Vitis vinifero et de Vaccinium angustifolium et d'au moins une bactérie probiotique et/ou levure probiotique est particulièrement avantageuse. Une telle combinaison permet d'obtenir un effet synergique notamment prébiotique dû aux polyphénols pour améliorer les fonctions cognitives par rapport à un mélange dudit extrait ou d'un probiotique consommé individuellement par l'Homme ou l'animal. En outre, les polyphénols sont connus pour avoir une activité antimicrobienne. Or, de façon inattendue, l'association des polyphénols apportés de façon concomitante par des extraits de Vitis vinifero et de Vaccinium angustifolium ne montrent pas de tels effets sur les probiotiques de l'invention. [0015] Such a composition is not known from the prior art. However, the combination of a mixture of extracts of Vitis vinifero and of Vaccinium angustifolium and of at least one probiotic bacterium and/or probiotic yeast is particularly advantageous. Such a combination makes it possible to obtain a synergistic effect in particular prebiotic due to the polyphenols to improve the cognitive functions compared to a mixture of said extract or of a probiotic consumed individually by humans or animals. Also, polyphenols are known to have antimicrobial activity. However, unexpectedly, the combination of polyphenols provided concomitantly by extracts of Vitis vinifero and of Vaccinium angustifolium do not show such effects on the probiotics of the invention.
[0016] A cet effet, l'invention propose une nouvelle composition nutritionnelle ou pharmaceutique comprenant : To this end, the invention provides a new nutritional or pharmaceutical composition comprising:
-au moins un mélange d'extraits de Vitis vinifero et de Vaccinium angustifolium, et -au moins une bactérie probiotique et/ou levure probiotique. -at least one mixture of extracts of Vitis vinifero and of Vaccinium angustifolium, and -at least one probiotic bacterium and/or probiotic yeast.
[0017] La bactérie probiotique et/ou levure probiotique intégrée dans la composition selon
l'invention est préférentiellement choisie parmi les bactéries et/ou levures du genre Lactobacillus, Bifidobacterium, Bacillus, Streptococcus, Saccharomyces, Enterococcus, Pediococcus et Escherichia. [0017] The probiotic bacterium and/or probiotic yeast integrated into the composition according to the invention is preferably chosen from bacteria and/or yeasts of the genus Lactobacillus, Bifidobacterium, Bacillus, Streptococcus, Saccharomyces, Enterococcus, Pediococcus and Escherichia.
[0018] Une telle composition est particulièrement destinée à être administrée chez l'Homme ou l'animal en tant que médicament pour prévenir et/ou traiter des pathologies associées au déclin cognitif mais également en tant que produit nutritif pour prévenir et/ou traiter le déclin cognitif normal chez un sujet sain. [0018] Such a composition is particularly intended to be administered to humans or animals as a medicament for preventing and/or treating pathologies associated with cognitive decline, but also as a nutritional product for preventing and/or treating normal cognitive decline in a healthy subject.
[0019] Ainsi, la composition est également destinée à des sujets sains sans pathologies associées au déclin cognitif. [0019] Thus, the composition is also intended for healthy subjects without pathologies associated with cognitive decline.
[0020] Un autre objet de l'invention concerne donc une utilisation non thérapeutique de la composition selon l'invention chez l'Homme ou l'animal sain, pour améliorer les fonctions cognitives et/ou les fonctions exécutives, et/ou pour limiter le déclin cognitif normal lié à l'âge. [0021] D'autres caractéristiques et avantages ressortiront de la description détaillée de l'invention et des exemples qui vont suivre. Another object of the invention therefore relates to a non-therapeutic use of the composition according to the invention in healthy humans or animals, to improve cognitive functions and/or executive functions, and/or to limit normal age-related cognitive decline. [0021] Other characteristics and advantages will emerge from the detailed description of the invention and the examples which follow.
[0022] Description détaillée de l'invention [0023] Définition [0022] Detailed description of the invention [0023] Definition
[0024] Par « composition nutritionnelle », on entend au sens de l'invention tout mélange de composés alimentaires destiné à être ingéré par un sujet sain et comprenant un mélange d'extraits de Vitis vinifero et de Vaccinium angustifolium et au moins une bactérie probiotique et/ou levure probiotique. Les compositions nutritionnelles sont notamment des compositions alimentaires ou aliments, ou des compléments alimentaires. [0024] By "nutritional composition" is meant within the meaning of the invention any mixture of food compounds intended to be ingested by a healthy subject and comprising a mixture of extracts of Vitis vinifero and Vaccinium angustifolium and at least one probiotic bacterium and/or probiotic yeast. The nutritional compositions are in particular food or food compositions, or food supplements.
[0025] Par « sujet sain », on entend au sens de l'invention un sujet qui peut être un Homme ou un animal ne souffrant d'aucune pathologie associée au déclin cognitif pathologique telle que la maladie d'Alzheimer, la maladie de Parkinson, la maladie de Huntington, les maladies du motoneurone ou la dégénérescence maculaire liée à l'âge (DMLA). [0025] By "healthy subject" is meant in the sense of the invention a subject who may be a human or an animal not suffering from any pathology associated with pathological cognitive decline such as Alzheimer's disease, Parkinson's disease , Huntington's disease, motor neuron disease or age-related macular degeneration (AMD).
[0026] A l'inverse, par « sujet pathologique », on entend au sens de l'invention un sujet qui souffre ou est susceptible de souffrir de déclin cognitif pathologique telle que la maladie d'Alzheimer, la maladie de Parkinson, la maladie de Huntington, les maladies du motoneurone ou la dégénérescence maculaire liée à l'âge (DMLA). [0026] Conversely, the term "pathological subject" is understood to mean, within the meaning of the invention, a subject who suffers or is likely to suffer from pathological cognitive decline such as Alzheimer's disease, Parkinson's disease, of Huntington's disease, motor neuron disease or age-related macular degeneration (AMD).
[0027] Par « composition pharmaceutique », on entend au sens de l'invention toute composition comprenant au moins une substance active présentée comme possédant des propriétés curatives ou préventives à l'égard des maladies humaines ou animales utilisé seule
ou associée à d'autres substances actives ou non et destiné à être ingéré par un sujet pathologique. Une telle composition comprend notamment un mélange d'extraits de Vitis vinifero et de Vaccinium angustifolium et au moins une bactérie probiotique et/ou levure probiotique. La composition pharmaceutique est donc un médicament destiné à l'Homme ou à l'animal dans la prévention et/ou le traitement du déclin cognitif pathologique telle que la maladie d'Alzheimer, la maladie de Parkinson, la maladie de Huntington, les maladies du motoneurone ou la dégénérescence maculaire liée à l'âge (DMLA). By "pharmaceutical composition" is meant within the meaning of the invention any composition comprising at least one active substance presented as having curative or preventive properties with regard to human or animal diseases used alone or combined with other active or non-active substances and intended to be ingested by a pathological subject. Such a composition comprises in particular a mixture of extracts of Vitis vinifero and of Vaccinium angustifolium and at least one probiotic bacterium and/or probiotic yeast. The pharmaceutical composition is therefore a medicament intended for humans or animals in the prevention and/or treatment of pathological cognitive decline such as Alzheimer's disease, Parkinson's disease, Huntington's disease, motor neuron or age-related macular degeneration (AMD).
[0028] Par « un mélange d'extraits de Vitis vinifero et de Vaccinium angustifolium », on entend un ensemble de molécules obtenues à partir d'un mélange de Vitis vinifero et de Vaccinium angustifolium préférentiellement un mélange d'au moins un extrait de Vitis vinifero et d'au moins un extrait de Vaccinium angustifolium. La matière première de Vitis vinifero peut être les feuilles et/ou les fruits et/ou les pépins et/ les bois, préférentiellement la matière première de Vitis vinifero est la partie aérienne de la plante, c'est-à-dire l'ensemble des feuilles, fruits, peau (pellicule), pépins et bois, plus préférentiellement la peau (pellicule) et les pépins. La matière première de Vaccinium angustifolium peut être les feuilles et/ou les fruits, préférentiellement la matière première de Vaccinium angustifolium est l'ensemble des feuilles et fruits de la plante. [0028] By "a mixture of extracts of Vitis vinifero and Vaccinium angustifolium" is meant a set of molecules obtained from a mixture of Vitis vinifero and Vaccinium angustifolium, preferably a mixture of at least one extract of Vitis vinifero and at least one extract of Vaccinium angustifolium. The raw material of Vitis vinifero can be the leaves and/or the fruits and/or the pips and/the woods, preferentially the raw material of Vitis vinifero is the aerial part of the plant, that is to say the whole leaves, fruits, skin (skin), seeds and wood, more preferably the skin (skin) and seeds. The raw material of Vaccinium angustifolium can be the leaves and/or the fruits, preferentially the raw material of Vaccinium angustifolium is all the leaves and fruits of the plant.
[0029] Par « au moins X% de catéchines et/ou épicatéchines » on entend soit au moins X% de catéchines s'il n'y a pas d'épicatéchines dans le mélange, soit au moins X% d'épicatéchines s'il n'y a pas de catéchines dans le mélange, soit au moins X% du mélange de catéchines et d'épicatéchines si à la fois des catéchines et des épicatéchines sont présentes dans le mélange. Préférentiellement, on entend au moins X% du mélange de catéchines et d'épicatéchines. [0030] Par « ppm » on entend parties par million (mg/kg) dans le mélange. Sauf indication contraire, ppm se réfère à un poids par rapport au poids total du mélange. [0029] By “at least X% of catechins and/or epicatechins” is meant either at least X% of catechins if there are no epicatechins in the mixture, or at least X% of epicatechins there are no catechins in the mixture, i.e. at least X% of the mixture of catechins and epicatechins if both catechins and epicatechins are present in the mixture. Preferably, at least X% of the mixture of catechins and epicatechins is meant. By “ppm” is meant parts per million (mg/kg) in the mixture. Unless otherwise stated, ppm refers to a weight based on the total weight of the mixture.
[0031] Par « prévenir » ou « prévention » au sens de l'invention, on entend la réduction à un degré moindre du risque ou de la probabilité d'occurrence d'un phénomène donné, c'est-à- dire, dans le contexte de la présente invention, par exemple, un trouble cognitif pathologique. [0032] Par « traiter » ou « traitement » au sens de l'invention, on entend une diminution de la progression de la maladie ou du trouble, une stabilisation, une inversion ou régression, voire une interruption ou inhibition de la progression d'une maladie ou d'un trouble. Dans le contexte de l'invention, ces termes s'appliquent également sur un ou plusieurs symptômes desdites maladies ou troubles de la présente invention.
[00BB] Composition [0031] By "prevent" or "prevention" within the meaning of the invention, is meant the reduction to a lesser degree of the risk or the probability of occurrence of a given phenomenon, that is to say, in the context of the present invention, for example, a pathological cognitive disorder. [0032] By "treating" or "treatment" within the meaning of the invention, is meant a reduction in the progression of the disease or disorder, a stabilization, a reversal or regression, or even an interruption or inhibition of the progression of a disease or disorder. In the context of the invention, these terms also apply to one or more symptoms of said diseases or disorders of the present invention. [00BB] Composition
[0034] L'objectif de l'invention est donc de fournir une composition présentant une efficacité améliorée dans la lutte contre le déclin cognitif. [0034] The objective of the invention is therefore to provide a composition having improved efficacy in the fight against cognitive decline.
[0035] A cet effet, la présente invention a donc pour objet une composition nutritionnelle ou pharmaceutique comprenant : To this end, the subject of the present invention is therefore a nutritional or pharmaceutical composition comprising:
-au moins un mélange d'extraits de Vitis vinifero et de Vaccinium angustifolium, et -au moins une bactérie probiotique et/ou levure probiotique. -at least one mixture of extracts of Vitis vinifero and of Vaccinium angustifolium, and -at least one probiotic bacterium and/or probiotic yeast.
[0036] L'extrait selon l'invention peut être obtenu par tout procédé permettant d'obtenir un mélange d'extraits de Vitis vinifero et de Vaccinium angustifolium et sera détaillé ci-après dans la présente description. The extract according to the invention can be obtained by any method making it possible to obtain a mixture of extracts of Vitis vinifero and of Vaccinium angustifolium and will be detailed below in this description.
[0037] Préférentiellement, le mélange d'extraits comprend un mélange de molécules comprenant : [0037] Preferably, the mixture of extracts comprises a mixture of molecules comprising:
- au moins 1% de catéchines et/ou épicatéchines, le pourcentage étant donné en poids par rapport au poids total du mélange, et - at least 1% of catechins and/or epicatechins, the percentage being given by weight relative to the total weight of the mixture, and
- au moins 5 ppm d'acide férulique. - at least 5 ppm of ferulic acid.
[0038] Les catéchines et épicatéchine sont des composés de la famille des flavonoïdes, en particulier de la sous-classe des flavanols. Elles sont aussi connues sous le nom de catéchol et épicatéchol et sont de puissants antioxydants qui aident notamment à prévenir les maladies inflammatoires et coronariennes mais également à maintenir ou augmenter les performances cognitives. [0038] Catechins and epicatechins are compounds of the flavonoid family, in particular of the flavanol subclass. They are also known as catechol and epicatechol and are powerful antioxidants that help in particular to prevent inflammatory and coronary diseases but also to maintain or increase cognitive performance.
[0039] L'acide férulique est connu pour ses effets sur le système neuronal, en particulier pour protéger les cellules neuronales de la mort cellulaire induite par l'ischémie cérébrale (Cheng S.Y, et al. Ferulic acid provides neuroprotection against oxidative stress-related apoptosis after cérébral ischemia/reperfusion injury by inhibiting ICAM-1 mRNA expression in rats. Brain Res. 2008;1209:136-150). De plus, son activité antioxydante a été testée dans la maladie d'Alzheimer (Sgarbossa A, et al. Ferulic Acid: A Hope for Alzheimer's Disease Therapy from Plants. Nutrients. 2015;7(7):5764-82.) et son administration à long terme semble protéger contre les déficits de mémoire et d'apprentissage (Yan J.Y. et al. Protection against b-amyloid peptide toxicity in vivo with long-term administration of ferulic acid. Br J Pharmacol. 2001;133:89-96.). [0039] Ferulic acid is known for its effects on the neuronal system, in particular to protect neuronal cells from cell death induced by cerebral ischemia (Cheng SY, et al. Ferulic acid provides neuroprotection against oxidative stress-related apoptosis after cerebral ischemia/reperfusion injury by inhibiting ICAM-1 mRNA expression in rats (Brain Res. 2008;1209:136-150). In addition, its antioxidant activity has been tested in Alzheimer's disease (Sgarbossa A, et al. Ferulic Acid: A Hope for Alzheimer's Disease Therapy from Plants. Nutrients. 2015;7(7):5764-82.) and its long-term administration appears to protect against memory and learning deficits (Yan JY et al. Protection against b-amyloid peptide toxicity in vivo with long-term administration of ferulic acid. Br J Pharmacol. 2001;133:89-96 .).
[0040] L'effet de la composition est particulièrement augmenté et efficace lorsqu'elle comprend également :
- au moins 200 ppm de resvératrol, et/ou The effect of the composition is particularly increased and effective when it also comprises: - at least 200 ppm resveratrol, and/or
- au moins 50 ppm de quercétines et/ou glycosides de quercétine et/ou - at least 50 ppm of quercetins and/or quercetin glycosides and/or
- au moins 500 ppm d'anthocyanines. - at least 500 ppm of anthocyanins.
[0041] Le resvératrol est particulièrement connu pour être présent dans le raisin. Toutefois, il peut également être issu d'autres sources végétales, en particulier à partir du Polygonum cuspidatum mais également par voie biotechnologique. Il possède de nombreuses activités bénéfiques pour l'Homme ou l'animal parmi lesquelles une amélioration de la mémoire de travail, de l'apprentissage, de la mémoire spatiale et de l'activité motrice spontanée (Abraham J, Johnson RW. Consuming a diet supplemented with resvératrol reduced infection-related neuroinflammation and déficits in working memory in aged mice. Rejuvenation Res [Internet] 2010/01/01. 2009; 12(6) :445-53). Resveratrol is particularly known to be present in grapes. However, it can also be derived from other plant sources, in particular from Polygonum cuspidatum but also by biotechnological means. It has many beneficial activities for humans or animals, including an improvement in working memory, learning, spatial memory and spontaneous motor activity (Abraham J, Johnson RW. Consuming a diet supplemented with resveratrol reduced infection-related neuroinflammation and deficits in working memory in aged mice.Rejuvenation Res [Internet] 2010/01/01.2009;12(6):445-53).
[0042] La quercétine possède aussi une activité neuroprotectrice importante (Dajas F, et al. Neuroprotective actions of flavones and flavonols: mechanisms and relationship to flavonoid structural features. Cent Nerv Syst Agents Med Chem. 2013 ; 13(l):30-5). [0042] Quercetin also has significant neuroprotective activity (Dajas F, et al. Neuroprotective actions of flavones and flavonols: mechanisms and relationship to flavonoid structural features. Cent Nerv Syst Agents Med Chem. 2013; 13(l):30-5 ).
[0043] On sait également que la consommation d'aliments riches en anthocyanidines (aglycones et/ou glycosylées) permet de prévenir les déficiences de mémoire et d'améliorer les performances cognitives (Barros D, et al. Behavioral and genoprotective effects of Vaccinium berries intake in mice. Pharmacol Biochem Behav.2006 ; 84(2):229-34). [0043] It is also known that the consumption of foods rich in anthocyanidins (aglycones and/or glycosylated) makes it possible to prevent memory deficiencies and to improve cognitive performance (Barros D, et al. Behavioral and genoprotective effects of Vaccinium berries intake in mice.Pharmacol Biochem Behav.2006;84(2):229-34).
[0044] La composition selon l'invention comprend au moins une bactérie probiotique et/ou levure probiotique associée au mélange d'extraits. The composition according to the invention comprises at least one probiotic bacterium and/or probiotic yeast combined with the mixture of extracts.
[0045] Or, de manière surprenante, la combinaison spécifique ainsi que la quantité des molécules se trouvant dans la présente composition permet d'obtenir un effet sur le déclin cognitif chez l'Homme ou l'animal, cet effet étant meilleur que celui d'un extrait de Vitis vinifera et de Vaccinium angustifolium seul ou d'au moins une bactérie probiotique et/ou levure probiotique seule. [0045] However, surprisingly, the specific combination as well as the quantity of the molecules found in the present composition makes it possible to obtain an effect on cognitive decline in humans or animals, this effect being better than that of an extract of Vitis vinifera and of Vaccinium angustifolium alone or of at least one probiotic bacterium and/or probiotic yeast alone.
[0046] Préférentiellement, la bactérie probiotique et/ou levure probiotique peut être morte, inactivée, semi-inactivée ou vivante. [0046] Preferably, the probiotic bacterium and/or probiotic yeast can be dead, inactivated, semi-inactivated or alive.
[0047] Ladite bactérie et/ou levure probiotique appartient préférentiellement au genre Lactobacillus, Bifidobacterium, Bacillus, Streptococcus, Saccharomyces, Enterococcus, Clostridium, Lactococcus et Escherichia. Said bacterium and/or probiotic yeast preferentially belongs to the genus Lactobacillus, Bifidobacterium, Bacillus, Streptococcus, Saccharomyces, Enterococcus, Clostridium, Lactococcus and Escherichia.
[0048] De façon particulièrement préférée, le mélange, la bactérie et/ou levure probiotique est choisie parmi les bactéries et/ou levure du genre Lactobacillus, Bifidobacterium,
Streptococcus, Enterococcus et Lactococcus. [0048] Particularly preferably, the mixture, the probiotic bacteria and/or yeast is chosen from bacteria and/or yeast of the genus Lactobacillus, Bifidobacterium, Streptococcus, Enterococcus and Lactococcus.
[0049] Préférentiellement, la bactérie est choisie parmi les bactéries des espèces suivantes : Lactobacillus plantarum, Lactobacillus rhamnosus, Lactobacillus acidophilus, Lactobacillus bulgaricus, Lactobacillus delbrueckii ssp delbrueckii, Lactobacillus casei, Lactobacillus casei Shirota, Lactobacillus curvatus, Lactobacillus brevis , Lactobacillus fermentum, Lactobacillus salivarius, Lactobacillus mucosae, Lactobacillus paracasei, Lactobacillus johnsonii, Lactobacillus pentosus, Lactobacillus helveticus, Bifidobacterium bifidum, Bifidobacterium infantis , Bifidobacterium lactis, Bifidobacterium longum, Bifidobacterium longum spp infantis, Bifidobacterium longum spp longum, Bifidobacterium animalis spp lactis, Bifidobacterium adolescentis, Bifidobacterium breve, Lactococcus lactis, Lactococcus lactis spp lactis, Streptococcus thermophilus, Streptococcus thermophiles, Clostridium butyricum, Enterococus faecalis, et leurs mélanges. Preferably, the bacterium is chosen from bacteria of the following species: Lactobacillus plantarum, Lactobacillus rhamnosus, Lactobacillus acidophilus, Lactobacillus bulgaricus, Lactobacillus delbrueckii ssp delbrueckii, Lactobacillus casei, Lactobacillus casei Shirota, Lactobacillus curvatus, Lactobacillus brevis, Lactobacillus fermentum, Lactobacillus salivarius, Lactobacillus mucosae, Lactobacillus paracasei, Lactobacillus johnsonii, Lactobacillus pentosus, Lactobacillus helveticus, Bifidobacterium bifidum, Bifidobacterium infantis, Bifidobacterium lactis, Bifidobacterium longum, Bifidobacterium longum spp infantis, Bifidobacterium longum spp longum, Bifidobacterium animalis spp lactis, Bifidobacterium adolescentis, Bifidobacterium breve, Lactococcus lactis, Lactococcus lactis spp lactis, Streptococcus thermophilus, Streptococcus thermophiles, Clostridium butyricum, Enterococus faecalis, and mixtures thereof.
[0050] Préférentiellement, la levure est choisie parmi les levures des espèces suivantes : Saccharomyces cerevisiae, Saccharomyces boulardii et leur mélange. Preferably, the yeast is chosen from yeasts of the following species: Saccharomyces cerevisiae, Saccharomyces boulardii and their mixture.
[0051] Selon un mode de réalisation particulier, la composition selon l'invention apporte journalièrement entre lxlO5 et 9xl012 UFC, préférentiellement entre lxlO7 et 9x1o11 d'une bactérie probiotique et/ou levure et/ou d'un mélange. According to a particular embodiment, the composition according to the invention provides between 1×10 5 and 9×10 12 CFU daily, preferably between 1×10 7 and 9×10 11 of a probiotic bacterium and/or yeast and/or of a mixture.
[0052] La composition peut comprendre également au moins un prébiotique choisi parmi l'inuline, les oligosaccharides, FOS (fructo-oligosaccharides), GOS (galacto-oligosaccharides), CLA (conjugated linoleic acid), PUFA (polyunsaturated fatty acid), MOS (mannanoligosaccharide) et XOS (xylooligosaccharide). The composition may also comprise at least one prebiotic chosen from inulin, oligosaccharides, FOS (fructo-oligosaccharides), GOS (galacto-oligosaccharides), CLA (conjugated linoleic acid), PUFA (polyunsaturated fatty acid), MOS (mannanoligosaccharide) and XOS (xylooligosaccharide).
[0053] L'ajout de prébiotique permet de renforcer l'efficacité de la composition. Lorsqu'elles sont associées, mélangées, combinées avec un extrait de Vitis vinifera et de Vaccinium angustifolium et au moins un probiotique, la composition présente un effet amélioré dans la prévention et/ou le traitement du déclin cognitif. [0053] The addition of prebiotic makes it possible to reinforce the effectiveness of the composition. When they are associated, mixed, combined with an extract of Vitis vinifera and of Vaccinium angustifolium and at least one probiotic, the composition exhibits an improved effect in the prevention and/or treatment of cognitive decline.
[0054] Selon un autre objet, la composition peut être encapsulée ou microencapsulée, préférentiellement la composition est encapsulée ou microencapsulée dans un support alimentaire choisi parmi une maltodextrine, une gomme arabique, une huile hydrogénée ou non hydrogénée, une cire, des alginates, de l'amidon, des protéines hydrolysées ou non, de la phosphatidylcholine, des phospholipides, du galactomannane, des émulsifiants choisis parmi la pectine ou polyricinoléate de polyglycérol et des fibres choisies parmi la polydextrose, la HPMC et la cellulose.
[0055] L'encapsulation est particulièrement avantageuse et permet de stabiliser et protéger l'extrait de Vitis vinifero et de Vaccinium angustifolium et/ou la ou les probiotiques (bactéries et/ou levures) de son environnement, notamment de l'organisme. According to another object, the composition can be encapsulated or microencapsulated, preferably the composition is encapsulated or microencapsulated in a food carrier chosen from maltodextrin, gum arabic, hydrogenated or non-hydrogenated oil, wax, alginates, starch, hydrolyzed or non-hydrolyzed proteins, phosphatidylcholine, phospholipids, galactomannan, emulsifiers chosen from pectin or polyglycerol polyricinoleate and fibers chosen from polydextrose, HPMC and cellulose. Encapsulation is particularly advantageous and makes it possible to stabilize and protect the extract of Vitis vinifero and of Vaccinium angustifolium and/or the probiotic(s) (bacteria and/or yeasts) from its environment, in particular from the organism.
[0056] De plus, l'encapsulation permet d'améliorer la stabilité, la biodisponibilité et l'utilisation dudit extrait dans des matrices alimentaires, avec notamment un masquage du goût et une résistance aux possibles altérations des composés pendant les étapes de production d'un produit alimentaire. [0056] In addition, encapsulation makes it possible to improve the stability, the bioavailability and the use of said extract in food matrices, with in particular masking of the taste and resistance to possible alterations of the compounds during the stages of production of a food product.
[0057] La microencapsulation procure les mêmes avantages que l'encapsulation mais permet tout particulièrement d'insérer des substances actives au sein de particules de tailles comprises entre 1 pm et 1000 pm et plus préférentiellement entre 30 pm et 500 pm et encore plus préférentiellement entre 50 pm et 300 pm. Microencapsulation provides the same advantages as encapsulation but more particularly makes it possible to insert active substances within particles of size between 1 μm and 1000 μm and more preferentially between 30 μm and 500 μm and even more preferentially between 50pm and 300pm.
[0058] La composition selon l'invention est destinée à être administrée comme produit nutritif ou thérapeutique et peut donc se présenter sous différentes formes, préférentiellement sous forme de poudre, de gélule, de comprimé, de capsule, d'une solution, d'une suspension, d'une émulsion ou d'une gomme à mâcher. The composition according to the invention is intended to be administered as a nutritional or therapeutic product and can therefore be in different forms, preferably in the form of a powder, capsule, tablet, capsule, solution, suspension, emulsion or chewing gum.
[0059] Lorsque la composition est destinée à être administrée comme produit nutritif, elle peut se présenter sous forme d'un produit alimentaire se présentant préférentiellement sous forme de produits laitiers, purées, céréales, produits céréaliers et boissons. When the composition is intended to be administered as a nutritional product, it may be in the form of a food product, preferably in the form of dairy products, purees, cereals, cereal products and beverages.
[0060] Lorsque la composition est administrée comme produit thérapeutique, l'invention se rapporte à une composition pour son utilisation en tant que médicament pour l'Homme ou l'animal. When the composition is administered as a therapeutic product, the invention relates to a composition for its use as a medicament for humans or animals.
[0061] Le déclin cognitif est caractérisé par une diminution liée à l'âge des fonctions cognitives et exécutives en particulier de la concentration, de la mémoire de travail, de la mémoire à long terme, des capacités de raisonnement, de jugement, de résolution de problèmes et de vitesse de traitement des informations. Ces déficiences peuvent conduire à une diminution de l'estime de soi et de la qualité de vie. Le déclin cognitif lié à l'âge est le terme utilisé pour décrire la forme non pathologique de la détérioration de la mémoire et des fonctions cognitives conséquentes au processus de vieillissement dans les limites normales, compte-tenu de l'âge d'une personne. Il s'agit d'un processus complexe, avec des premiers signes émergeant chez l'Homme entre 35 et 65 ans, sans lésions neurodégénératives spécifiques. Le déclin cognitif progressif est perceptible par l'apparition de problèmes cognitifs mineurs qui affectent 15 à 20% de la population âgée de 65 ans ou plus, mais qui représentent un état instable. Toutefois,
certaines formes pathologiques peuvent survenir en plus de ce déclin cognitif « normal ». Parmi ces pathologies, la maladie d'Alzheimer est la cause la plus commune de démence, qui touche plus de 24 millions de personnes dans le monde. Elle est irréversible dans notre état actuel des connaissances, les seuls traitements disponibles étant purement symptomatiques. Chez les animaux, ces pathologies peuvent se présenter de manière très similaire. Chez le chien par exemple, le syndrome de dysfonctionnement cognitif (ou SDC) est une pathologie largement répandue et caractérisée par une désorientation spatio-temporelle, une perte des apprentissages élémentaires qui induit souvent de la malpropreté, une altération des cycles veille-sommeil, et une altération des interactions sociales. [0061] Cognitive decline is characterized by an age-related decrease in cognitive and executive functions, in particular concentration, working memory, long-term memory, reasoning, judgment, resolution problems and information processing speed. These deficiencies can lead to a decrease in self-esteem and quality of life. Age-related cognitive decline is the term used to describe the non-pathological form of deterioration of memory and cognitive functions consequent to the aging process within normal limits, given a person's age. It is a complex process, with the first signs emerging in humans between 35 and 65 years old, without specific neurodegenerative lesions. Progressive cognitive decline is noticeable by the appearance of minor cognitive problems which affect 15-20% of the population aged 65 or over, but which represent an unstable state. Nevertheless, certain pathological forms may occur in addition to this “normal” cognitive decline. Among these pathologies, Alzheimer's disease is the most common cause of dementia, which affects more than 24 million people worldwide. It is irreversible in our current state of knowledge, the only treatments available being purely symptomatic. In animals, these pathologies can present themselves in a very similar way. In dogs, for example, the cognitive dysfunction syndrome (or CDS) is a widespread pathology characterized by spatio-temporal disorientation, a loss of elementary learning which often induces uncleanliness, an alteration of sleep-wake cycles, and impaired social interactions.
[0062] En particulier, la composition est destinée à être utilisée dans la neuroprotection, et/ou l'amélioration des fonctions cognitives et/ou de la mémoire et/ou des fonctions exécutives, et/ou l'atténuation du déclin cognitif. Ainsi, la composition selon l'invention présente des effets neuroprotecteurs et peut-être utilisée dans la prévention et/ou le traitement des pathologies associées au déclin cognitif. [0062] In particular, the composition is intended for use in neuroprotection, and/or improving cognitive functions and/or memory and/or executive functions, and/or alleviating cognitive decline. Thus, the composition according to the invention exhibits neuroprotective effects and can be used in the prevention and/or treatment of pathologies associated with cognitive decline.
[0063] Préférentiellement, la composition selon l'invention peut être utilisée dans la prévention et/ou le traitement des pathologies associées à la destruction des neurones, la diminution des fonctions cognitives, de la mémoire, des fonctions exécutives. Preferably, the composition according to the invention can be used in the prevention and/or treatment of pathologies associated with the destruction of neurons, the decrease in cognitive functions, memory, executive functions.
[0064] La composition selon l'invention est particulièrement destinée à être utilisée dans la prévention et/ou le traitement : The composition according to the invention is particularly intended for use in the prevention and/or treatment:
- des maladies neurodégénératives telles que la maladie d'Alzheimer, et/ou la maladie de Parkinson, et/ou la maladie de Huntington, et/ou les maladies du motoneurone et/ou la dégénérescence maculaire liée à l'âge (DMLA), - neurodegenerative diseases such as Alzheimer's disease, and/or Parkinson's disease, and/or Huntington's disease, and/or motor neuron diseases and/or age-related macular degeneration (AMD),
- du déclin cognitif pathologique et/ou de la démence et/ou de la dépression et /ou de l'anxiété et/ou de la schizophrénie et/ou du retard mental et/ou du syndrome de dysfonctionnement cognitif (CDS). - pathological cognitive decline and/or dementia and/or depression and/or anxiety and/or schizophrenia and/or mental retardation and/or cognitive dysfunction syndrome (CDS).
[0065] Selon un mode particulièrement avantageux, la composition selon l'invention est délivrée à une dose permettant de fournir à l'Homme ou l'animal : According to a particularly advantageous mode, the composition according to the invention is delivered at a dose making it possible to provide humans or animals with:
- au moins 100 pg par kg de poids corporel de catéchines et/ou d'épicatéchines,- at least 100 pg per kg body weight of catechins and/or epicatechins,
- au moins 0,05 pg par kg de poids corporel d'acide férulique. - at least 0.05 pg per kg body weight of ferulic acid.
[0066] Préférentiellement, ladite composition selon l'invention est délivrée à une dose permettant de fournir à l'Homme ou l'animal : Preferably, said composition according to the invention is delivered at a dose making it possible to provide humans or animals with:
- au moins 10 pg par kg de poids corporel de resvératrol,
- au moins 0,2 pg par kg de poids corporel de quercétine et/ou glycosides quercétines, et - at least 10 pg per kg of body weight of resveratrol, - at least 0.2 pg per kg of body weight of quercetin and/or quercetin glycosides, and
- au moins 1 pg par kg de poids corporel d'anthocyanidines. - at least 1 pg per kg of body weight of anthocyanidins.
[0067] Selon un autre aspect, il peut s'agir aussi d'une composition nutritionnelle ou thérapeutique destinée à l'animal. On entend par « animal » tout animal pouvant recevoir une composition nutritionnelle ou thérapeutique selon l'invention, par exemple mais de manière non limitative un animal de compagnie, une volaille, un porc, un ruminant, un caprin, ou encore une souris. De manière préférentielle, l'animal est un animal de compagnie, tel que le chat ou le chien. De préférence encore, l'animal est un chien. According to another aspect, it may also be a nutritional or therapeutic composition intended for the animal. The term “animal” is understood to mean any animal that can receive a nutritional or therapeutic composition according to the invention, for example but in a non-limiting way a pet, a poultry, a pig, a ruminant, a goat, or even a mouse. Preferably, the animal is a pet, such as a cat or a dog. More preferably, the animal is a dog.
[0068] Utilisation non thérapeutique chez une personne saine [0068] Non-therapeutic use in a healthy person
[0069] Selon un autre aspect, la composition selon l'invention est également destinée à être utilisée comme produit nutritif sans aucun effet thérapeutique et chez un sujet sain. According to another aspect, the composition according to the invention is also intended to be used as a nutritive product without any therapeutic effect and in a healthy subject.
[0070] Ainsi, l'invention se rapporte également à une utilisation non thérapeutique de la composition selon l'invention chez l'Homme ou l'animal sain, pour améliorer les fonctions cognitives et/ou les fonctions exécutives, et/ou pour limiter le déclin cognitif normal lié à l'âge. [0071] De façon particulièrement préféré, l'invention se rapporte à une utilisation non thérapeutique de la composition pour améliorer la mémoire et/ou l'attention et/ou la concentration et/ou la vivacité et/ou la vigilance et/ou l'apprentissage et/ou l'intelligence et/ou le langage et/ou l'humeur et/ou le stress et/ou l'anxiété et/ou le sommeil. [0070] Thus, the invention also relates to a non-therapeutic use of the composition according to the invention in healthy humans or animals, to improve cognitive functions and/or executive functions, and/or to limit normal age-related cognitive decline. [0071] In a particularly preferred manner, the invention relates to a non-therapeutic use of the composition for improving memory and/or attention and/or concentration and/or alertness and/or alertness and/or learning and/or intelligence and/or language and/or mood and/or stress and/or anxiety and/or sleep.
[0072] La composition selon l'invention dans le cadre d'une utilisation non thérapeutique peut être préférentiellement délivrée à une quantité permettant de fournir à l'Homme ou l'animal sain : The composition according to the invention in the context of a non-therapeutic use can preferably be delivered in an amount making it possible to provide healthy humans or animals:
- au moins 100 pg par kg de poids corporel de catéchines et/ou d'épicatéchines,- at least 100 pg per kg body weight of catechins and/or epicatechins,
- au moins 0,05 pg par kg de poids corporel d'acide férulique. - at least 0.05 pg per kg body weight of ferulic acid.
[0073] Préférentiellement, ladite composition selon l'invention est délivrée à une quantité permettant de fournir à l'Homme ou l'animal sain : Preferably, said composition according to the invention is delivered in an amount making it possible to provide healthy humans or animals with:
- au moins 10 pg par kg de poids corporel de resvératrol, - at least 10 pg per kg of body weight of resveratrol,
- au moins 0,2 pg par kg de poids corporel de quercétine et/ou glycosides quercétines, et - at least 0.2 pg per kg of body weight of quercetin and/or quercetin glycosides, and
- au moins 1 pg par kg de poids corporel d'anthocyanidines. - at least 1 pg per kg of body weight of anthocyanidins.
[0074] Procédé [0074] Process
[0075] Le procédé selon l'invention permet d'obtenir un mélange d'extraits comprenant le
mélange de molécules suivant : The process according to the invention makes it possible to obtain a mixture of extracts comprising the following mixture of molecules:
- au moins 1% de catéchine et/ou épicatéchine en poids par rapport au poids total du mélange, préférentiellement au moins 5%, encore plus préférentiellement entre 5% et 50%, notamment entre 7% et 35%, - at least 1% of catechin and/or epicatechin by weight relative to the total weight of the mixture, preferably at least 5%, even more preferably between 5% and 50%, in particular between 7% and 35%,
- au moins 5 ppm d'acide férulique, préférentiellement au moins 10 ppm, encore plus préférentiellement entre 5 et 300 ppm, notamment entre 10 et 100 ppm.- at least 5 ppm of ferulic acid, preferably at least 10 ppm, even more preferably between 5 and 300 ppm, in particular between 10 and 100 ppm.
[0076] De façon particulièrement préféré le procédé permet d'obtenir un mélange de molécules comprenant : Particularly preferably, the process makes it possible to obtain a mixture of molecules comprising:
- au moins 200 ppm de resvératrol, préférentiellement au moins 300 ppm, encore plus préférentiellement au moins 400 ppm, - at least 200 ppm of resveratrol, preferably at least 300 ppm, even more preferably at least 400 ppm,
- au moins 50 ppm de quercétine et/ou glycosides de quercétine, 70 ppm de quercétine et/ou glycoside, notamment entre 50 et 100 ppm, et - at least 50 ppm of quercetin and/or quercetin glycosides, 70 ppm of quercetin and/or glycoside, in particular between 50 and 100 ppm, and
- au moins 500 ppm d'anthocyanidines, préférentiellement au moins 600 ppm, encore plus préférentiellement au moins 700 ppm. - at least 500 ppm of anthocyanidins, preferably at least 600 ppm, even more preferably at least 700 ppm.
[0077] Selon un premier mode de réalisation, un procédé particulièrement adapté est un procédé comprenant les étapes suivantes : According to a first embodiment, a particularly suitable method is a method comprising the following steps:
- obtention d'un extrait de Vitis vinifera : a. extraction à l'eau et/ou à l'éthanol de Vitis vinifera, préférentiellement de l'ensemble des feuilles, fruits, pellicule, pépins et bois de Vitis vinifera. La quantité de solvant (30% v/v à 96% V/V) mise en oeuvre est comprise entre 2 et 10 fois la masse de matière mise en oeuvre. La durée de l'extraction peut être comprise entre 30 minutes et 24 heures et la température d'extraction comprise entre 20°C et 80°C. Les matières premières utilisées peuvent être sous formes sèches, fraîches, ou congelées entières ou broyées ; b. séparation de la solution d'eau et/ou éthanol de la matière solide, par exemple par décantation centrifuge ou par pressage et filtration ; c. évaporation de l'éthanol par évaporation sous-vide à une température préférentiellement inférieure à 60°C et à une pression inférieure à lOOmbars ; d. séparation membranaire de l'extrait préalablement désolvanté de façon à sélectionner préférentiellement les monomères et les oligomères proanthocyanidiques (ayant un degré de polymérisation compris entre 2 et 10 inclus) et d'éliminer les polymères de flavanols (> au décamères), pour obtenir
un extrait comprenant au moins 1% de catéchines et/ou épicatéchines. Cette étape peut être réalisée à l'aide d'une membrane de filtration ayant un seuil de coupure inférieur à 15 000 daltons et plus préférentiellement inférieur à 3000 daltons ; - Obtaining an extract of Vitis vinifera: a. water and/or ethanol extraction of Vitis vinifera, preferably of all the leaves, fruits, skin, pips and wood of Vitis vinifera. The quantity of solvent (30% v/v to 96% V/V) used is between 2 and 10 times the mass of material used. The duration of the extraction can be between 30 minutes and 24 hours and the extraction temperature between 20°C and 80°C. The raw materials used can be in dry, fresh, or frozen whole or ground form; b. separation of the water and/or ethanol solution from the solid material, for example by centrifugal decantation or by pressing and filtration; vs. evaporation of the ethanol by vacuum evaporation at a temperature preferably below 60° C. and at a pressure below 100 mbars; d. membrane separation of the previously desolventized extract so as to preferentially select the proanthocyanidin monomers and oligomers (having a degree of polymerization between 2 and 10 inclusive) and to eliminate the flavanol polymers (> decamers), to obtain an extract comprising at least 1% of catechins and/or epicatechins. This step can be carried out using a filtration membrane having a cut-off threshold of less than 15,000 daltons and more preferably less than 3,000 daltons;
- obtention d'un extrait de Vaccinium angustifolium : a. extraction à l'eau et/ou à l'éthanol de Vaccinium angustifolium, préférentiellement de l'ensemble des feuilles et fruits de Vaccinium angustifolium, La quantité de solvant (30% v/v à 96% V/V) mise en oeuvre est comprise entre 2 et 10 fois la masse de matière mise en oeuvre. La durée de l'extraction peut être comprise entre 30 minutes et 24 heures et la température d'extraction comprise entre 20°C et 80°C. Les matières premières utilisées peuvent être sous formes sèches, fraîches, ou congelées ; b. séparation de la solution d'eau et/ou éthanol de la matière solide par décantation centrifuge ou par pressage et filtration ; c. évaporation de l'éthanol par évaporation sous-vide à une température préférentiellement inférieure à 60°C et une pression inférieure à 100 mbars ; d. séchage des extraits par atomisation, étuve sous vide ou lyophilisation avec ou sans support comme une maltodextrine ; - obtaining an extract of Vaccinium angustifolium: a. water and/or ethanol extraction of Vaccinium angustifolium, preferably all of the leaves and fruits of Vaccinium angustifolium, The amount of solvent (30% v/v to 96% V/V) used is between 2 and 10 times the mass of material used. The duration of the extraction can be between 30 minutes and 24 hours and the extraction temperature between 20°C and 80°C. The raw materials used can be in dry, fresh or frozen form; b. separation of the water and/or ethanol solution from the solid material by centrifugal decantation or by pressing and filtration; vs. evaporation of the ethanol by vacuum evaporation at a temperature preferably below 60° C. and a pressure below 100 mbar; d. drying of the extracts by atomization, vacuum drying or lyophilization with or without a support such as a maltodextrin;
- mélange de l'extrait de l //f/s vinifera et de Vaccinium angustifolium avant ou après l'étape de séchage. - mixing the extract of l //f/s vinifera and of Vaccinium angustifolium before or after the drying step.
[0078] Selon un deuxième mode de réalisation, le procédé consiste en la mise en oeuvre des étapes suivantes : According to a second embodiment, the method consists of the implementation of the following steps:
- mélange de de Vitis vinifera et de Vaccinium angustifolium extraction à l'eau et/ou à l'éthanol de Vaccinium angustifolium, préférentiellement de l'ensemble des feuilles et fruits de Vaccinium angustifolium, La quantité de solvant (30% v/v à 96% V/V) mise en oeuvre est comprise entre 2 et 10 fois la masse de matière mise en oeuvre. La durée de l'extraction peut être comprise entre 30 minutes et 24 heures et la température d'extraction comprise entre 20°C et 80°C. Les matières premières utilisées peuvent être sous formes sèches, fraîches, ou congelées ; - mixture of Vitis vinifera and Vaccinium angustifolium extraction with water and/or ethanol of Vaccinium angustifolium, preferably of all the leaves and fruits of Vaccinium angustifolium, The amount of solvent (30% v/v at 96% V/V) implementation is between 2 and 10 times the mass of material implemented. The duration of the extraction can be between 30 minutes and 24 hours and the extraction temperature between 20°C and 80°C. The raw materials used can be in dry, fresh or frozen form;
- séparation de la solution d'eau et/ou éthanol du marc solide par décantation centrifuge ou par pressage et filtration ; - separation of the water and/or ethanol solution from the solid marc by centrifugal decantation or by pressing and filtration;
- évaporation de l'éthanol par évaporation sous-vide à une température
préférentiellement inférieure à 60°C et une pression inférieure à 100 mbars ; - evaporation of ethanol by vacuum evaporation at a temperature preferably below 60° C. and a pressure below 100 mbar;
- séchage de l'extrait par pulvérisation ou sublimation avec ou sans support comme une maltodextrine. - drying of the extract by spraying or sublimation with or without a support such as a maltodextrin.
[0079] Quelle que soit le mode de réalisation, avant l'étape de séchage, le procédé peut comprendre les étapes suivantes : Whatever the embodiment, before the drying step, the method may comprise the following steps:
- chargement sur une résine des solutions d'extraits mélangées ou non, - loading on a resin of the solutions of extracts mixed or not,
- rinçage de la résine avec de l'eau, - rinsing the resin with water,
- application d'une solution éluante eau/éthanol sur la résine, - application of an eluent water/ethanol solution on the resin,
- récupération de l'éluat purifié, - recovery of the purified eluate,
- évaporation de l'éthanol dudit éluât, - evaporation of the ethanol of said eluate,
- concentration dudit éluât - concentration of said eluate
- séchage dudit extrait aqueux purifié. - drying of said purified aqueous extract.
[0080] L'invention est à présent illustrée par des exemples non limitatifs de compositions selon l'invention et par des résultats. The invention is now illustrated by non-limiting examples of compositions according to the invention and by results.
[0081] Exemples [0081] Examples
[0082] Exemple 1 : Composition nutritionnelle destinée à l'homme [0083] L'exemple 1 est une gélule de 400 mg, constituée par : [0082] Example 1: Nutritional composition intended for humans [0083] Example 1 is a 400 mg capsule, consisting of:
Mélange d'extraits : 300 mg Blend of extracts: 300 mg
Mélange de 6 probiotiques (Lactobacillus fermentum, L plantarum, L acidophilus, Bfidobacterium lactis, B. longum, B. bifidum) 3c10L9 CFU : 50 mg Maltodextrine : 50 mg. Blend of 6 probiotics (Lactobacillus fermentum, L plantarum, L acidophilus, Bfidobacterium lactis, B. longum, B. bifidum) 3c10 L 9 CFU: 50 mg Maltodextrin: 50 mg.
La composition est obtenue par mélange des constituants dans les conditions clas siques connues de l'homme du métier, et mis dans une gélule selon les conditions clas siques également. La posologie préconisée est de 2 gélules par jour. The composition is obtained by mixing the constituents under the conventional conditions known to those skilled in the art, and placed in a capsule according to the conventional conditions as well. The recommended dosage is 2 capsules per day.
[0084] Exemple 2 : Composition nutritionnelle destinée à l'homme [0085] L'exemple 2 est un sachet de 3200 mg, constitué par : [0084] Example 2: Nutritional composition intended for humans [0085] Example 2 is a sachet of 3200 mg, consisting of:
Mélange d'extraits : 600 mg Blend of extracts: 600 mg
Mélange de 3 probiotiques (Lactobacillus acidophilus , Bifidobacterium bifidum, Lactobacillus fermentum) 4c10L9 CFU : 2500 mg Maltodextrine : 100 mg.
La composition est obtenue par mélange des constituants dans les conditions clas siques connues de l'homme du métier et se présente sous forme d'une poudre conte nue dans un sachet selon les conditions classiques également. La posologie préconisée est de 1 sachet par jour. Blend of 3 probiotics (Lactobacillus acidophilus, Bifidobacterium bifidum, Lactobacillus fermentum) 4c10 L 9 CFU: 2500 mg Maltodextrin: 100 mg. The composition is obtained by mixing the constituents under conventional conditions known to those skilled in the art and is in the form of a powder contained in a sachet also under conventional conditions. The recommended dosage is 1 sachet per day.
[0086] Exemple 3 : Composition nutritionnelle destinée à l'animal [0087] L'exemple B est une capsule molle constituée par : [0086] Example 3: Nutritional composition intended for animals [0087] Example B is a soft capsule consisting of:
Mélange d'extraits : 50 mg Blend of extracts: 50 mg
Mélange de 2 probiotiques (Enterocossus faecium, Lactobacillus acidophilus casei) 3c10L9 CFU : 4167 mg Mixture of 2 probiotics (Enterocossus faecium, Lactobacillus acidophilus casei) 3c10 L 9 CFU: 4167 mg
- FOS : 16610 mg - FOS: 16610 mg
La composition est obtenue par mélange des constituants dans les conditions clas siques connues de l'homme du métier et se présente sous forme d'une capsule molle selon les conditions classiques également. La posologie préconisée est de 1 capsule par jour. The composition is obtained by mixing the constituents under conventional conditions known to those skilled in the art and is in the form of a soft capsule also under conventional conditions. The recommended dosage is 1 capsule per day.
[0088] Exemple 4 : Composition nutritionnelle destinée à l'animal [0089] L'exemple 4 est un comprimé constitué par : [0088] Example 4: Nutritional Composition Intended for Animals [0089] Example 4 is a tablet consisting of:
Mélange d'extraits : 50 mg Blend of extracts: 50 mg
Mélange de 5 probiotiques (Lactobacillus acidophilus , L. plantarum, L. Brevis, Bi- fidobacterium animalis lactis, Lactobacillus ramnosus) 2c10L9 CFU : 26.5 mgBlend of 5 probiotics (Lactobacillus acidophilus, L. plantarum, L. Brevis, Bifidobacterium animalis lactis, Lactobacillus ramnosus) 2c10 L 9 CFU: 26.5 mg
- FOS : 250 mg. - FOS: 250 mg.
La composition est obtenue par mélange des constituants dans les conditions clas siques connues de l'homme du métier et se présente sous forme d'un comprimé selon les conditions classiques également. La posologie préconisée est de 1 comprimé par jour pour un chien de 10 Kg.
The composition is obtained by mixing the constituents under conventional conditions known to those skilled in the art and is in the form of a tablet also under conventional conditions. The recommended dosage is 1 tablet per day for a 10 kg dog.
Claims
[Revendication 1] Composition comprenant : [Claim 1] A composition comprising:
-au moins un mélange d'extraits de Vitis vinifero et de Vaccinium angustifolium, et -au moins une bactérie probiotique et/ou levure probiotique. -at least one mixture of extracts of Vitis vinifero and of Vaccinium angustifolium, and -at least one probiotic bacterium and/or probiotic yeast.
[Revendication 2] Composition selon la revendication précédente, caractérisée en que le mélange d'extraits de Vitis vinifero et de Vaccinium angustifolium comprend un mélange de molécules comprenant : au moins 1% de catéchines et/ou épicatéchines, le pourcentage étant donné en poids par rapport au poids total du mélange, et au moins 5 ppm d'acide férulique. [Claim 2] Composition according to the preceding claim, characterized in that the mixture of extracts of Vitis vinifero and of Vaccinium angustifolium comprises a mixture of molecules comprising: at least 1% of catechins and/or epicatechins, the percentage being given by weight per based on the total weight of the mixture, and at least 5 ppm of ferulic acid.
[Revendication 3] Composition selon la revendication précédente, caractérisée en ce que le mélange de molécules comprend également : au moins 200 ppm de resvératrol, et/ou au moins 50 ppm de quercétines et/ou glycosides de quercétine et/ou au moins 500 ppm d'anthocyanines. [Claim 3] Composition according to the preceding claim, characterized in that the mixture of molecules also comprises: at least 200 ppm of resveratrol, and/or at least 50 ppm of quercetins and/or quercetin glycosides and/or at least 500 ppm of anthocyanins.
[Revendication 4] Composition selon l'une des revendications précédentes, caractérisée en ce que la bactérie et/ou levure probiotique est choisie parmi les bactéries et/ou levures du genre Lactobacillus, Lactobaciilus, Bifidobacterium, Bacillus, Streptococcus, Saccharomyces, Enterococcus, Clostridium, Lactococcus et Escherichia. [Claim 4] Composition according to one of the preceding claims, characterized in that the probiotic bacterium and/or yeast is chosen from bacteria and/or yeasts of the genus Lactobacillus, Lactobacilus, Bifidobacterium, Bacillus, Streptococcus, Saccharomyces, Enterococcus, Clostridium , Lactococcus and Escherichia.
[Revendication 5] Composition selon l'une des revendications précédentes, caractérisée en ce que la bactérie probiotique et/ou levure probiotique est morte, inactivée, semi-inactivée ou vivante. [Claim 5] Composition according to one of the preceding claims, characterized in that the probiotic bacterium and/or probiotic yeast is dead, inactivated, semi-inactivated or alive.
[Revendication 6] Composition selon l'une des revendications précédentes, caractérisée en ce que la composition comprend également au moins un prébiotique choisi parmi l'inuline, les oligosaccharides, FOS, GOS, CLA (conjugated linoleic acid), PUFA (polyunsaturated fatty acid), MOS (mannan-oligo-saccharide) et XOS (xylo-oligo-saccharide). [Claim 6] Composition according to one of the preceding claims, characterized in that the composition also comprises at least one prebiotic chosen from inulin, oligosaccharides, FOS, GOS, CLA (conjugated linoleic acid), PUFA (polyunsaturated fatty acid ), MOS (mannan-oligo-saccharide) and XOS (xylo-oligo-saccharide).
[Revendication 7] Composition selon l'une des revendications précédentes, caractérisée en ce que la composition est encapsulée ou microencapsulée dans un support alimentaire choisi parmi une maltodextrine, une gomme arabique, une huile hydrogénée ou non hydrogénée, une cire, des alginates, de l'amidon, des protéines hydrolysées ou non, de la
phosphatidylcholine, des phospholipides, du galactomannane, des émulsifiants choisis parmi la pectine ou polyricinoléate de polyglycérol et des fibres choisies parmi la polydextrose, la HPMC et la cellulose. [Claim 7] Composition according to one of the preceding claims, characterized in that the composition is encapsulated or microencapsulated in a food carrier chosen from maltodextrin, gum arabic, hydrogenated or non-hydrogenated oil, wax, alginates, starch, hydrolyzed or non-hydrolyzed proteins, phosphatidylcholine, phospholipids, galactomannan, emulsifiers chosen from pectin or polyglycerol polyricinoleate and fibers chosen from polydextrose, HPMC and cellulose.
[Revendication 8] Composition selon l'une des revendications précédentes, caractérisée en ce qu'elle se présente sous forme de poudre, de gélule, de comprimé, de capsule, d'une solution, d'une suspension, d'une émulsion ou d'une gomme à mâcher. [Claim 8] Composition according to one of the preceding claims, characterized in that it is in the form of a powder, capsule, tablet, capsule, solution, suspension, emulsion or of chewing gum.
[Revendication 9] Composition selon l'une des revendications précédentes, caractérisée en ce que la composition est un produit alimentaire se présentant sous forme de produits laitiers, purées, céréales, produits céréaliers et boissons. [Claim 9] Composition according to one of the preceding claims, characterized in that the composition is a food product in the form of dairy products, purées, cereals, cereal products and beverages.
[Revendication 10] Composition selon l'une des revendications 1 à 9, pour son utilisation en tant que médicament pour l'Homme ou l'animal. [Claim 10] Composition according to one of Claims 1 to 9, for its use as a medicament for humans or animals.
[Revendication 11] Composition pour son utilisation selon la revendication précédente, dans la neuroprotection, l'amélioration des fonctions cognitives et/ou de la mémoire et/ou des fonctions exécutives, l'atténuation du déclin cognitif. [Claim 11] Composition for its use according to the preceding claim, in neuroprotection, improvement of cognitive functions and/or memory and/or executive functions, alleviation of cognitive decline.
[Revendication 12] Composition pour son utilisation selon l'une des revendications 10 ou 11, dans la prévention et/ou le traitement des pathologies associées au déclin cognitif. [Claim 12] Composition for its use according to one of Claims 10 or 11, in the prevention and/or treatment of pathologies associated with cognitive decline.
[Revendication 13] Composition pour son utilisation selon la revendication précédente, dans la prévention et/ou le traitement : a. des maladies neurodégénératives telles que la maladie d'Alzheimer, et/ou la maladie de Parkinson, et/ou la maladie de Huntington, et/ou les maladies du motoneurone et/ou la dégénérescence maculaire liée à l'âge (DM LA), b. du déclin cognitif pathologique et/ou de la démence et/ou de la dépression et /ou de l'anxiété et/ou de la schizophrénie et/ou du retard mental et/ou du syndrome de dysfonctionnement cognitif (CDS). [Claim 13] Composition for its use according to the preceding claim, in the prevention and/or treatment: a. neurodegenerative diseases such as Alzheimer's disease, and/or Parkinson's disease, and/or Huntington's disease, and/or motor neuron diseases and/or age-related macular degeneration (AMD), b. pathological cognitive decline and/or dementia and/or depression and/or anxiety and/or schizophrenia and/or mental retardation and/or cognitive dysfunction syndrome (CDS).
[Revendication 14] Utilisation non thérapeutique d'une composition selon l'une des revendications 1 à 9 chez l'Homme ou l'animal sain, pour améliorer les fonctions cognitives et/ou les fonctions exécutives, et/ou pour limiter le déclin cognitif normal lié à l'âge.
[Claim 14] Non-therapeutic use of a composition according to one of Claims 1 to 9 in humans or healthy animals, to improve cognitive functions and/or executive functions, and/or to limit cognitive decline age-related normal.
[Revendication 15] Utilisation non thérapeutique selon la revendication précédente, pour améliorer la mémoire et/ou l'attention et/ou la concentration et/ou la vivacité et/ou la vigilance et/ou l'apprentissage et/ou l'intelligence et/ou le langage et/ou l'humeur et/ou le stress et/ou l'anxiété et/ou le sommeil. [Claim 15] Non-therapeutic use according to the preceding claim, for improving memory and/or attention and/or concentration and/or alertness and/or alertness and/or learning and/or intelligence and /or language and/or mood and/or stress and/or anxiety and/or sleep.
[Revendication 16] Utilisation non thérapeutique selon la revendication 14 ou 15, caractérisée en ce que ladite composition est délivrée à une quantité permettant de fournir à l'Homme ou l'animal sain : au moins 100 pg par kg de poids corporel de catéchines et/ou d'épicatéchines, au moins 0,05 pg par kg de poids corporel d'acide férulique. [Claim 16] Non-therapeutic use according to Claim 14 or 15, characterized in that the said composition is delivered in an amount making it possible to provide healthy humans or animals with: at least 100 pg per kg of body weight of catechins and /or epicatechins, at least 0.05 µg per kg body weight of ferulic acid.
[Revendication 17] Utilisation non thérapeutique selon la revendication précédente, caractérisé en ce que ladite composition est délivrée à une quantité permettant de fournir à l'Homme ou l'animal sain : au moins 10 pg par kg de poids corporel de resvératrol, au moins 0,2 pg par kg de poids corporel de quercétine et/ou glycosides quercétines, et au moins 1 pg par kg de poids corporel d'anthocyanidines.
[Claim 17] Non-therapeutic use according to the preceding claim, characterized in that the said composition is delivered in an amount making it possible to provide healthy humans or animals with: at least 10 pg per kg of body weight of resveratrol, at least 0.2 µg per kg body weight of quercetin and/or quercetin glycosides, and at least 1 µg per kg body weight of anthocyanidins.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| FR2007796A FR3112686B3 (en) | 2020-07-24 | 2020-07-24 | Composition comprising a mixture of Vitis vinifera and Vaccinium angustifolium extracts and probiotics to improve cognitive functions |
| FRFR2007796 | 2020-07-24 |
Publications (2)
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|---|---|
| WO2022018281A2 true WO2022018281A2 (en) | 2022-01-27 |
| WO2022018281A3 WO2022018281A3 (en) | 2022-03-10 |
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| PCT/EP2021/070733 WO2022018281A2 (en) | 2020-07-24 | 2021-07-23 | Composition comprising a mixture of extracts of vitis vinifera and vaccinium angustifolium and probiotics to improve cognitive function |
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| AU (1) | AU2021107611A4 (en) |
| DK (1) | DK202100060U3 (en) |
| FR (1) | FR3112686B3 (en) |
| PL (1) | PL438609A1 (en) |
| WO (1) | WO2022018281A2 (en) |
Cited By (2)
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|---|---|---|---|---|
| CN115300532A (en) * | 2022-09-20 | 2022-11-08 | 中加健康工程研究院(合肥)有限公司 | Probiotics capable of improving cognitive ability of Alzheimer's disease and preparation method thereof |
| WO2023144289A1 (en) * | 2022-01-28 | 2023-08-03 | Activ'inside | Use of a mixture of flavanols to increase the concentration of the active form of vitamin d, calcitriol |
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| FR3146578A1 (en) * | 2023-03-14 | 2024-09-20 | Laboratoire D'innovation Cosmetique Et Dermatologique | NEW ASSOCIATION BASED ON PROBIOTICS, COMPOSITIONS CONTAINING IT AND ITS USES |
Citations (1)
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| FR3042712A1 (en) | 2015-10-27 | 2017-04-28 | Activ'inside | SPECIAL NUTRITIONAL OR THERAPEUTIC AGENT COMPRISING A MIXTURE OF GRAPE AND BLUEBERRY |
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| FR2899768B1 (en) * | 2006-04-14 | 2008-06-20 | Juva Sante Soc Par Actions Sim | ANTIOXIDANT FOOD SUPPLEMENT COMPRISING OLIGOPROANTHOCYANIDES, GAMMA-TOCOPHEROL, CATECHINS AND BIFLAVANES, CARNOSIC ACID AND CARNOSOL |
| EP2710901A1 (en) * | 2012-09-20 | 2014-03-26 | Symrise AG | Dietary supplement compositions |
| CN108601372A (en) * | 2015-10-27 | 2018-09-28 | 特种宠物食品公司 | Synergistically effective antioxidant compositions for pets |
| WO2017155898A1 (en) * | 2016-03-07 | 2017-09-14 | Nature's Sunshine Products, Inc. | Methods and compositions to improve weight loss and cardiometabolic health beyond diet and exercise |
| CN107334025A (en) * | 2017-08-08 | 2017-11-10 | 安徽永骏生物科技有限公司 | A kind of blueberry fermented beverage |
| FR3088540B1 (en) * | 2018-11-21 | 2023-05-12 | Activinside | SINGLE USE OF A COMPOSITION comprising a SPECIFIC blend of GRAPE EXTRACT AND BLUEBERRY EXTRACT |
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- 2021-07-26 DK DKBA202100060U patent/DK202100060U3/en active IP Right Grant
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Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| FR3042712A1 (en) | 2015-10-27 | 2017-04-28 | Activ'inside | SPECIAL NUTRITIONAL OR THERAPEUTIC AGENT COMPRISING A MIXTURE OF GRAPE AND BLUEBERRY |
Non-Patent Citations (13)
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2023144289A1 (en) * | 2022-01-28 | 2023-08-03 | Activ'inside | Use of a mixture of flavanols to increase the concentration of the active form of vitamin d, calcitriol |
| FR3132221A1 (en) * | 2022-01-28 | 2023-08-04 | Activ'inside | Use of a mixture of flavanols to increase the concentration of the active form of vitamin D, calcitriol. |
| CN115300532A (en) * | 2022-09-20 | 2022-11-08 | 中加健康工程研究院(合肥)有限公司 | Probiotics capable of improving cognitive ability of Alzheimer's disease and preparation method thereof |
| CN115300532B (en) * | 2022-09-20 | 2023-10-20 | 中加健康工程研究院(合肥)有限公司 | Probiotic agent with Alzheimer disease cognitive ability improving function and preparation method thereof |
Also Published As
| Publication number | Publication date |
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| FR3112686A3 (en) | 2022-01-28 |
| AU2021107611A4 (en) | 2022-01-06 |
| DK202100060U3 (en) | 2021-10-26 |
| FR3112686B3 (en) | 2022-07-29 |
| PL438609A1 (en) | 2022-01-31 |
| WO2022018281A3 (en) | 2022-03-10 |
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