WO2014048888A1 - Acide dihydroférulique et/ou acide dihydrocaféique destinés à être utilisés dans le traitement de maladies métaboliques - Google Patents

Acide dihydroférulique et/ou acide dihydrocaféique destinés à être utilisés dans le traitement de maladies métaboliques Download PDF

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Publication number
WO2014048888A1
WO2014048888A1 PCT/EP2013/069765 EP2013069765W WO2014048888A1 WO 2014048888 A1 WO2014048888 A1 WO 2014048888A1 EP 2013069765 W EP2013069765 W EP 2013069765W WO 2014048888 A1 WO2014048888 A1 WO 2014048888A1
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formula
compound
coffee
sample
food
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PCT/EP2013/069765
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English (en)
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Corinne BRENNER
Christian Darimont-Nicolau
Mathieu Renouf
Ornella AVANTI NIGRO
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Nestec S.A.
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Publication of WO2014048888A1 publication Critical patent/WO2014048888A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/192—Carboxylic acids, e.g. valproic acid having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid 
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23K—FODDER
    • A23K20/00—Accessory food factors for animal feeding-stuffs
    • A23K20/10—Organic substances
    • A23K20/105—Aliphatic or alicyclic compounds
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23K—FODDER
    • A23K50/00—Feeding-stuffs specially adapted for particular animals
    • A23K50/20—Feeding-stuffs specially adapted for particular animals for horses
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23K—FODDER
    • A23K50/00—Feeding-stuffs specially adapted for particular animals
    • A23K50/40—Feeding-stuffs specially adapted for particular animals for carnivorous animals, e.g. cats or dogs
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
    • A23L2/00—Non-alcoholic beverages; Dry compositions or concentrates therefor; Their preparation
    • A23L2/52—Adding ingredients
    • A23L2/68—Acidifying substances
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
    • A23L33/105—Plant extracts, their artificial duplicates or their derivatives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
    • A23V2002/00—Food compositions, function of food ingredients or processes for food or foodstuffs

Definitions

  • Dihydroferulic acid and/or dihydrocaffeic acid for use in the treatment of metabolic diseases
  • the present invention relates to compositions comprising dihydroferulic acid (DHFA) and/or dihydrocaffeic acid (DHCA) for use in the treatment of metabolic diseases such as type 2 diabetes.
  • the invention relates to food ingredients and food products comprising dihydroferulic acid and/or dihydrocaffeic acid.
  • an improved prevention and/or treatment of type 2 diabetes would be advantageous, and in particular a more efficient and/or reliable treatment comprising e.g. coffee or grain constituents would be advantageous.
  • an object of the present invention relates to the provision of chlorogenic acids and their metabolites which inhibit hepatic gluconeogenesis.
  • composition comprising a compound of the formula I for use as a medicament:
  • Another aspect of the present invention relates to a composition comprising a compound of the Formula I for use in the treatment or prevention of metabolic diseases.
  • Yet another aspect of the present invention is to provide a composition comprising a compound of the Formula I for use in the treatment or prevention of type 2 diabetes in a subject.
  • Still another aspect of the present invention is to provide a food ingredient comprising a compound of the Formula I.
  • Yet another aspect relates to a process for enriching or providing a food ingredient with a compound of the Formula I, said method comprising
  • FIG 1 shows the metabolic fate of chlorogenic acids in humans.
  • coffee provides a major dietary source of chlorogenic acids.
  • Chlorogenic acids are extensively metabolized following coffee ingestion, with some compounds being absorbed in the stomach/duodenum, while others are absorbed in the small or large intestine.
  • Figure 2 shows the metabolic fate of chlorogenic acids in humans.
  • coffee provides a major dietary source of chlorogenic acids.
  • Chlorogenic acids are extensively metabolized following coffee ingestion, with some compounds being absorbed in the stomach/duodenum, while others are absorbed in the small or large intestine.
  • Figure 2 shows the metabolic fate of chlorogenic acids in humans.
  • FIG. 2 shows the Effect of chlorogenic acids on hepatic gluconeogenesis.
  • H4IIE rat hepatoma cells were incubated for 6 hours in glucose production media (DMEM without glucose, 20 mM lactate, 2 mM pyruvate) with or without chlorogenic acids at indicated concentrations. 10 mM of metformin was included as a control to inhibit gluconeogenesis.
  • Figure 3 shows the effect of free phenolic acids (caffeic acid (CA) or ferulic acid (FA)) on hepatic gluconeogenesis.
  • H4IIE rat hepatoma cells were incubated for 6 hours in glucose production media (DMEM without glucose, 20 mM lactate, 2 mM pyruvate) with or without phenolic acids at indicated concentrations. 10 mM of metformin was included as a control to inhibit gluconeogenesis. Results are expressed as means (+/- SEM) from at least three different experiments, each done in duplicate. For each experiment, data were first normalised before pooling .
  • Figure 4 shows the effect of proposed colonic metabolites on hepatic
  • Figure 5 shows the effect of sulfated forms of caffeic acids on hepatic
  • H4IIE rat hepatoma cells were incubated for 6 hours in glucose production media (DMEM without glucose, 20 mM lactate, 2 mM pyruvate) with or without compounds at indicated concentrations. 10 mM of metformin was included as a control to inhibit gluconeogenesis. Results are expressed as means (+/- SEM) from at least three different experiments, each done in duplicate. For each experiment, data were first normalised before pooling . */**/*** p ⁇
  • Figure 6 shows the effect of sulfated forms of ferulic acids on hepatic
  • H4IIE rat hepatoma cells were incubated for 6 hours in glucose production media (DMEM without glucose, 20 mM lactate, 2 mM pyruvate) with or without compounds at indicated concentrations. 10 mM of metformin was included as a control to inhibit gluconeogenesis. Results are expressed as means (+ SEM) from at least three different experiments, each done in duplicate. For each experiment, data were first normalised before pooling. */**/*** p ⁇
  • Figure 7 shows the effect of methylated forms of ferulic acids on hepatic gluconeogenesis.
  • H4IIE rat hepatoma cells were incubated for 6 hours in glucose production media (DMEM without glucose, 20 mM lactate, 2 mM pyruvate) with or without compounds at indicated concentrations. 10 mM of metformin was included as a control to inhibit gluconeogenesis. Results are expressed as means (+ SEM) from at least three different experiments, each done in duplicate. For each experiment, data were first normalised before pooling. */**/*** p ⁇
  • Figure 8-10 shows the plasma kinetics of different coffee metabolites after ingestion of low dose (0.5% instant soluble coffee; 2g soluble coffee in 400ml_ water), medium dose (1% instant soluble coffee; 4g soluble coffee in 400ml_ water) and high dose (2% instant soluble coffee; 8g soluble coffee in 400ml_ water).
  • Figure 11 shows a schematic overview of how DHCA and DHFA may be
  • an aspect of the present invention relates to a composition
  • a composition comprising a compound of the formula I for use as a medicament:
  • DHFA and DHCA are naturally occurring metabolites of coffee which may be produced by the gut microbiota after coffee consumption. This is in contrast to the synthetic drug metformin.
  • DHFA and DHCA show anti-hyperglycaemic effect through inhibition of the gluconeogenesis (Example 4). 3) High plasma levels of DHFA and DHCA have been observed after coffee consumption, which is not the case for other similar metabolites (example 6).
  • Tautomers are isomers (structural isomers) of organic compounds that readily interconvert by a chemical reaction called tautomerization. This reaction commonly results in the formal migration of a hydrogen atom or proton, accompanied by a switch of a single bond and adjacent double bond. The concept of tautomerizations is called tautomerism. Because of the rapid interconversion, tautomers are generally considered to be the same chemical compound .
  • the compounds according to the invention may be enantiomers, diastereomers, as well as tautemers of the compounds according to the invention.
  • the compounds are enantiomers, diastereomers, or tautemers of the compounds according to the invention.
  • the compound is of the formula I is
  • DHFA dihydroferuiic acid
  • the compound is dihydrocaffeic acid (DHCA), illustrated by Formula III:
  • the compounds according to the present invention may find different medical uses.
  • another aspect of the present invention relates to a compound of the Formula I for use in the treatment or prevention of metabolic diseases.
  • Type 2 diabetes is also a metabolic disease.
  • the invention relates to a composition comprising a compound of the Formula I for use in the treatment or prevention of type 2 diabetes in a subject.
  • the presented data show that compounds of the formula I (and formula II and III) may inhibit
  • gluconeogenesis as a cause for fasting hyperglycemia.
  • the invention relates to a composition comprising a compound of the Formula I for use in the treatment or prevention of fasting hyperglycemia in a subject.
  • Fasting hyperglycemia is defined as a blood sugar greater than 130 mg/dl (milligrams per deciliter) after fasting for at least 8 hours.
  • the compounds according to the invention may function through inhibition of gluconeogenesis.
  • an aspect relates to a composition comprising a compound of the Formula I for use in the inhibition of gluconeogenesis in a subject.
  • the gluconeogenesis is hepatic gluconeogenesis.
  • Gluconeogenesis is a metabolic pathway that results in the generation of glucose from non-carbohydrate carbon substrates such as lactate, glycerol, and glucogenic amino acids.
  • the compounds (or composition) according to the present invention are metabolites of compounds present in food products and food ingredients, such ingredients may be enriched with the compounds according to the present invention.
  • the composition forms part of a food
  • composition forms part of a food product.
  • the composition according to the present invention may be part of different food products.
  • the food product is selected from the group consisting of beverages, petfoods, and food supplements.
  • the beverage is selected from the group consisting of coffee, such as green coffee, tea, milk products, such as skimmed milk and infant milk formulations.
  • the food or beverage product may be any food or beverage product known in the art.
  • the food or beverage product is a coffee beverage; pure soluble coffee; a soft drink; a dietary supplement; a dairy product; a cereal product; a fruit or vegetable juice product; or a confectionary product, such as a chocolate product, e.g. a chocolate drink.
  • a soluble coffee product may be produced by concentrating and drying the extract of the invention. Before drying, the extract may be mixed with coffee extract that has not been treated to transform chlorogenic acids, e.g. extract of roasted coffee beans, green coffee beans, or both. Methods for producing a soluble coffee product from a coffee extract are well known in the art.
  • the beans to be extracted may have been subjected to stripping to remove volatile aromas before extraction, e.g. as described in EP-A-1078576.
  • the volatile aromas may then be added back to the extract after the treatment to hydrolyse chlorogenic acids, e.g . after drying, to produce an aromatised soluble coffee product.
  • a soluble coffee product produced from a coffee extract of the invention may be sold as such, or may e.g. be mixed with a creamer and/or sweetener and sold to prepare a coffee beverage comprising creamer and/or sweetener, e.g. cappuccino or cafe latte.
  • the compositions according to the present invention may also find use in petfoods.
  • the petfood is selected from the group consisting of kibbles and pellets.
  • Examples of food supplements according to the present invention are capsules and pills.
  • compositions according to the present invention are to be provided to a subject.
  • the subject is a mammal, such as a human, a cat, a dog or a horse.
  • the compounds according to the present invention are metabolites of constituents present in e.g. coffee or grains.
  • the compounds according to the present invention are not naturally present in food product but are metabolites which may be formed after consumption e.g . by the gut microbiota.
  • an aspect of the present invention relates to a food ingredient comprising a compound of the Formula I.
  • the invention relates to a food ingredient enriched with a compound of the Formula I. Such ingredient may find medical use as described above.
  • the specific concentration of the compounds of formula I may vary in the food ingredient.
  • the level of the compound of the Formula I is in the range 0.0001 ⁇ - 100 ⁇ , such as 0.001 ⁇ - 10 ⁇ , such as 0.01 ⁇ - 10 ⁇ , or such as 0.1 ⁇ - 10 ⁇ .
  • the compounds according to present invention which may form part of a food ingredient may be provided by different methods.
  • at least part of the compound of the Formula I is chemically and/or enzymatically produced .
  • Figure 11 illustrates how such compounds may be enzymatically produced from a natural source.
  • the food ingredient according to the present invention may form part of a food product.
  • the invention relates to a food product comprising the food ingredient according to the present invention.
  • the invention relates to a composite food product, wherein at least one part of the composite food products comprises the food ingredient according to the present invention. This may be the case where a food product is constituted of multiple independent parts (composite), where e.g. only one of the parts comprises the food ingredient according to the invention.
  • an aspect of the present invention relates to a process for enriching or providing a food ingredient with a compound of the Formula I, said method comprising
  • Figure 11 shows a schematic overview of how DHCA and DHFA may be
  • coffee such as 5-CQA is present in the sample and the enzymes are esterase and a reductase and the enriched product comprises DHCA.
  • part of the sample may be modified to DHFA by the addition of 0- methyltransferase.
  • the enzymes may be added sequentially or simultaneously as illustrated in figure 11.
  • whole grains such as wheat grains and/or ferulic acid is present in the sample and the enzymes are carbohydrase (such as xylanase), feruloyl esterase and reductase and the enriched product comprises DHFA.
  • carbohydrase is xylanase.
  • the sample may be a natural source such as grains or coffee.
  • the sample is provided from a natural source.
  • the natural source is whole grain, such as wheat grain or coffee, such as green coffee, roasted coffee or a polyphenol extract.
  • whole grain such as wheat grain or coffee, such as green coffee, roasted coffee or a polyphenol extract.
  • sample the natural source is selected from the group consisting of blackberry, raspberry, black currant, strawberry, blueberry, kiwi, cherry, plum, aubergine, apple, pear, chicory, artichoke, potato, corn flour, flour: wheat, rice, oat, cider, and coffee. All these sources are known to comprise chlorogenic acids.
  • the sample may be pre-treated before enzymatic treatment.
  • the sample is pre-treated before enzymatic treatment.
  • the pre-treatment is
  • the metabolites according to the present invention may be processed by the gut flora after consumption of a food product comprising precursors.
  • Such microorganisms may be used to process e.g. coffee by providing the relevant enzymes required to produce the compounds according to the present invention.
  • the enzymatic steps are performed by micro-organisms.
  • the micro-organisms are selected from the group consisting of bacteria, yeast, and fungi.
  • the process according to the present application may comprise further steps.
  • the food ingredient enriched in a compound of the Formula I is mixed or assembled with a food product, thereby providing a food product enriched in a compound of the Formula I.
  • the wording "assembling" relates to the situation where the food product and food ingredient are not mixed, but instead assembled, e.g . in the case the ingredient is a topping or part of a layered product.
  • the food ingredient according to the present invention may be produced by a process according to the present invention.
  • an aspect relates to a food ingredient obtainable by a process according to the present invention.
  • the invention relates to a food product obtainable by a process according to the present invention It should be noted that embodiments and features described in the context of one of the aspects of the present invention also apply to the other aspects of the invention .
  • the aim of this study was to investigate the inhibitory activity of coffee-derived compounds, as well as their metabolites, on hepatic gluconeogenesis.
  • Chlorogenic acids are the second major components in coffee after caffeine, accounting for 6-10% of dry matter. They are a family of esters which are formed by the linkage of a hydroxycinnamate (e.g. CA, FA) to a quinic acid .
  • the hydroxycinnamate can be attached to a 3-, 4- or 5-position of the quinic moiety and depending on the hydroxycinnamate, the resulting structure is called caffeoylquinic acid (CQA) or feruloylquinic acid (FQA), respectively ( Figure 1, (1)).
  • CQA caffeoylquinic acid
  • FQA feruloylquinic acid
  • the different isoforms of CQAs and FQAs can be detected in human plasma as early as 30 minutes and up to 1 hour following coffee consumption, with a maximal plasma concentration (Cmax) of approximately 50 nM (example 6).
  • H4IIE cells ATCC, ref. CLR-1548
  • a cellular bioassay was established according to a method described by Okamoto with some modifications. Briefly, H4IIE cells pre-cultured at high density were seeded into a 12-well plate at a density of 3 x 105 cells/cm2 and cultured for 24 h in EMEM supplemented with 10% FCS. Thereafter, cells were washed three times with PBS, followed by pre-incubation in phenol red-free DMEM containing 1 g/L glucose for another 16 h. The assay was started by exchanging the medium for glucose-free DMEM in the presence or absence of gluconeogenesis-inducing substrates (2 mM sodium pyruvate and 20 mM lactate). Coffee compounds were added at different concentrations (1 ⁇ , 5 ⁇ , 10 ⁇ ) and tested in duplicate. 10 mM of metformin was included as a positive control for inhibition of
  • CA Caffeic acid
  • FA Ferulic acid
  • DHCA Dihydroferulic acid
  • DHFA Dihydrocaffeic acid
  • Results are expressed as means ⁇ SEM from at least three independent experiments, whereby each experiment was done in duplicate. For each experiment, data were separately normalised to untreated, pyruvate/lactate- stimulated control cells before pooling . Statistical analysis was performed using a one-way ANOVA with Dunnetts multiple comparison, whereby pyruvate/lactate- stimulated cells pre-treated with test compounds were compared to untreated cells that were only stimulated with the pyruvate/lactate mixture.
  • Phenolic acid equivalents such as CA and FA can be detected in human plasma where they peak at approximately one hour following coffee ingestion (example 6). Results
  • CA Caffeic acid
  • FA ferulic acid
  • DHCA and DHFA significantly inhibited gluconeogenesis at all concentrations tested. Importantly, these metabolites are already effective at their observed physiological concentration around 1 ⁇ (20-25% inhibition) which stands in contrast to the previous compounds tested (see example 6).
  • DHCA and DHFA have a glucose-suppressing effect.
  • chlorogenic acids and their derivatives are subjected to phase II metabolism which leads to sulfated, methylated or glucuronidated structures.
  • CA and FA/DHFA were included in the analysis.
  • the inhibitory potential of CA/DHCA and FA/DHFA was removed upon conjugation, with the exception of CA-3-O-sulfate, which still had a minor effect (20% inhibition) on gluconeogenesis at a concentration of 10 ⁇ .
  • Plasma levels of different coffee metabolites were measured after consumption of different doses of soluble coffee Plasma levels of different Coffee doses.
  • Low dose 0.5% coffee in 400 ml
  • medium dose 1% coffee in 400 ml
  • high dose 2% coffee in 400 ml (figures 8-10).
  • Example 2 demonstrates that the chlorogenic acids 5-CQA, 3-FQA and 4-FQA have a moderate effect on gluconeogenesis, with 5-CQA having the strongest effect. However, despite being major components in coffee, only trace amounts of CQAs and FQAs appear in the circulation following coffee consumption. Example 6 shows that these isomers can reach concentrations of up to around 50 nM in human plasma following ingestion of 400 ml of 2% soluble instant coffee (figure 8).
  • Example 6 When investigating the potential of the phenolic acids CA and FA to inhibit glucose production (example 3), a significant effect at concentrations above 5 ⁇ was observed . However, as for chlorogenic acids, this concentration were not of physiological relevance since the measured plasma level after coffee intake is much lower (Example 6 and figure 9). The most interesting finding of this study is that the colonic metabolites DHCA and DHFA inhibit gluconeogenesis at concentrations of > 1 ⁇ (example 4). Notably, Example 6 demonstrates that these compounds are present in human plasma in much higher concentration than the parent compounds. Indeed, plasma levels of DHCA and DHFA can be as high as approximately 1 ⁇ following coffee

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Abstract

La présente invention concerne une composition, comprenant un composé de formule I, destinée à être utilisée comme médicament, dans laquelle R1 représente méthyle ou hydrogène et dans laquelle R2 représente méthyle ou hydrogène. L'invention concerne en outre des ingrédients alimentaires et des produits alimentaires comprenant un composé de formule I. L'invention concerne également des procédés de production des composés de formule I.
PCT/EP2013/069765 2012-09-28 2013-09-24 Acide dihydroférulique et/ou acide dihydrocaféique destinés à être utilisés dans le traitement de maladies métaboliques WO2014048888A1 (fr)

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Cited By (7)

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WO2016016101A1 (fr) * 2014-08-01 2016-02-04 Illycaffe' Spa Café laurina torréfié, son procédé de préparation, et utilisation pour prévenir le syndrome métabolique
JP2016079186A (ja) * 2014-10-21 2016-05-16 丸善製薬株式会社 皮膚化粧料、頭髪化粧料および飲食品
WO2016162227A1 (fr) 2015-04-09 2016-10-13 Nestec S.A. Procédé de formation d'un acide dihydroférulique
JP6236185B1 (ja) * 2016-09-27 2017-11-22 丸善製薬株式会社 脳の機能改善剤および脳の機能改善用飲食品
WO2022239837A1 (fr) * 2021-05-12 2022-11-17 丸善製薬株式会社 Composition orale, produit cosmétique pour la peau et produit cosmétique capillaire
WO2023218868A1 (fr) * 2022-05-13 2023-11-16 丸善製薬株式会社 Activateur de nerf sympathique et composition pour l'activation de nerf sympathique
WO2024074495A1 (fr) * 2022-10-04 2024-04-11 Cysbio Aps Procédé d'inhibition de la prolifération d'un phytopathogène sur des plantes et compositions utilisées à cet effet

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WO2008022974A2 (fr) * 2006-08-18 2008-02-28 Centre National De La Recherche Scientifique (Cnrs) Composition antidiabetique contenant de l'acide chicorique et/ou l'un de ses metabolites
WO2008112368A2 (fr) * 2007-02-08 2008-09-18 Emisphere Technologies, Inc. Agents de distribution d'acide phénylalkylcarboxylique
WO2008150212A1 (fr) * 2007-06-08 2008-12-11 Probi Ab Procédé pour modifier du polyphénol contenant des matériaux végétaux et utilisations médicales du polyphénol modifié contenant des matériaux végétaux
FR2951085A1 (fr) * 2009-10-09 2011-04-15 Inst Substances Vegetales Utilisation de composes phenoliques pour la deglycation des proteines

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