Nutraceutical compositions and their use for inducing body weight loss and / or reducing fat accumulation

Abstract

The invention relates to a nutraceutical composition for promoting weight loss in a human subject in need thereof. The nutraceutical composition is in a form suitable for oral administration and comprises, as the active ingredient, a combination of: (a) 50% to 70% w / w combination of a first apple extract containing at least 10% w / w of first chlorogenic acid apple extract; (b) 10% to 25% w / w combination of a plant extract containing capsaicinoids; (c) 5% to 20% w / w combination of an Ascophyllum nodosum extract; (d) 5% to 20% w / w combination of a plant extract containing mucilages; and (e) 1% to 10% w / w combination of a second apple extract standardised to at least 15% w / w of second phloridzin apple extract, wherein the sum of (a), (b), (c), (d), and (e) is 100%.

Description

Description Title: Nutraceutical compositions and their use for inducing body weight loss and / or reduction of fat accumulation. [Technical field. [1] The present invention relates to novel nutraceutical compositions, for oral administration, based on the combination of a first apple extract rich in chlorogenic acid, a plant extract containing capsaicinoids, a brown algae extract (Ascophyllum nodosum), a plant extract containing mucilages and a second apple extract rich in phloridzin. [2] The invention also relates to the use of these novel nutraceutical compositions, in particular as a supplement, to promote body weight loss and / or to prevent (re)gain of body weight and / or to induce a reduction in fat accumulation. [3] It relates generally to the field of dietary or nutritional compositions and methods, and more particularly to the field of compositions and methods for losing body weight. State of the art. [4] Overweight is a public health problem. It is characterized by excess fat in the body, which can be harmful to health. The most commonly used indicators to estimate excess fat in adipose tissue are the Body Mass Index (BMI) and waist circumference. BMI, expressed in kg / m 2 , is defined as the weight (in kg) divided by the square of the height (in meters) of a person. BMI estimates the degree of overweight or obesity and thus makes it possible to assess the health risks associated with it: in adults, a BMI between 18.5 kg / m 2 and 25 kg / m 2corresponds to a so-called "normal" body size, i.e. not accompanied by potential health risks. A BMI between 25 kg / m 2 and 30 kg / m 2 corresponds to overweight, and a BMI of 30 kg / m 2 and above, indicates obesity. These thresholds serve as benchmarks for individual assessment, but it is proven that the risk of chronic diseases increases progressively beyond with a BMI of approximately 22 kg / m 2Along with BMI, waist circumference measurement is also often used to assess the health risk associated with overweight and obesity, as waist circumference is strongly correlated with abdominal fat mass. It is currently accepted that the presence of excess fat inside the abdomen leads to an increased health risk (e.g., diabetes, high blood pressure, increased blood lipids, etc.). Thus, in adults, waist circumference values greater than 80 cm and 94 cm, for women and men respectively, are linked to a moderate risk of metabolic complications associated with visceral obesity. Values greater than 88 cm and 102 cm, for women and men respectively, indicate a high risk of metabolic complications. [5] Overweight is mainly caused by an energy imbalance resulting from a difference between calories consumed and those expended by the body. In general, an excessive diet of fats and / or sugars, characterized by high energy density, combined with insufficient physical activity, leads to an increase in body mass, particularly body fat mass. This increase in fat mass is mainly due to the increase in the size and number of adipocytes, which are cells specialized in storing fat in adipose tissue. When caloric intake exceeds the body's immediate energy needs, adipocytes accumulate this excess in the form of triglycerides, thus contributing to long-term weight gain. [6] Today's society promotes the appearance of overweight and obesity due to a sedentary lifestyle and diet (e.g., fast food, diets high in sugars). However, it is important to note that excess weight in overweight individuals is not always exclusively linked to a poor diet. It can also have genetic, hormonal, or even hereditary causes. In addition, certain factors such as taking certain medications (e.g., corticosteroids), stress, lack of sleep, stopping smoking, or even so-called low-grade inflammation can also play a role in the difficulty in losing weight in these overweight or obese individuals. The harmful consequences of being overweight on health are numerous and varied, including sleep disorders, altered self-esteem, recurring episodes of depression, but also metabolic disorders, cardiovascular complications, high blood pressure, digestive problems, diabetes, liver dysfunction, asthma, and increased risks of cancer. Today, there are nutritional, physical / sports, and therapeutic approaches, but they are not always effective in solving the problem of excess weight. [7] Weight management is widely recognized as a crucial element in reducing the risks associated with being overweight. From a diet, nutrition, and health perspective, it is imperative to maintain a weight considered healthy (healthy weight), generally defined as a BMI between 18.5 kg / m 2 and 25 kg / m 2 Many overweight (or obese) individuals strive to lose weight in an effort to improve their physical well-being and promote their health. [8] An effective approach to promoting weight loss in an overweight or obese person involves adopting a low-calorie diet, characterized by energy intakes lower than the body's daily needs. When a person adopts such a diet, their body begins to mobilize (or burn) fat, that is, to draw on its fat reserves to meet its daily energy needs. Adipocytes play a central role in this fat mobilization process. They release stored fatty acids in the form of triglycerides, which are then transported to muscle cells and other tissues where they undergo oxidation to produce energy. Thus, by following a low-calorie diet, the body uses its fat reserves, which contributes to weight loss and the reduction of fat mass. However, after an initial phase of weight loss, it is common to observe weight regain in individuals who have followed a low-calorie diet. This phenomenon is known as the "rebound effect" or "yo-yo effect." [9] Another approach to supporting overweight or obese people in their weight management journey is to use products such as dietary supplements. These supplements are designed to work in different ways: some can help regulate appetite, while others are formulated to positively influence fat metabolism, a process of breaking down fats in the form of triglycerides into glycerols and fatty acids, referred to as lipolysis. However, although a number of products and dietary supplements are available on the market, finding effective solutions, i.e., creating effective formulations through the combination of active ingredients, for weight loss and / or reduction of fat accumulation, remains a challenge.

[0010] In view of the above, an objective of the present invention is to provide novel nutraceutical compositions which would be effective in accelerating weight loss in a human subject.

[0011] Another objective of the present invention is to provide such nutraceutical compositions which would be effective in helping said human subject to improve or increase his carbohydrate and / or lipid metabolism.

[0012] Another object of the present invention is to provide such nutraceutical compositions which would be effective in reducing fat accumulation.

[0013] Yet another object of the present invention is to provide such nutraceutical compositions which would be effective in decreasing the weight ratio between fat mass and lean mass.

[0014] The present invention also aims to provide compositions which are of low cost and whose active ingredients are natural products, particularly simple to obtain, which do not present any undesirable effects on human health. Presentation of the invention.

[0015] The solution proposed by the invention is a nutraceutical composition presented in a form suitable for oral administration and comprising, as active agent, a combination consisting of: (a) 50% to 70% w / w combination of a first apple extract containing at least 10% w / w first apple extract 6H Chlorogenic acid, (b) 10% to 25% w / w combination of a plant extract containing capsaicinoids, (c) 5% to 20% w / pcombination of a brown algae extract (Ascophyllum nodosum), (d) 5% to 20% w / w combination of a plant extract containing mucilages, (e) 1% to 10% w / w combination of a second apple extract standardized to at least 15% w / w apple extract 6H phloridzin, the sum of (a), (b), (c), (d) and (e) being equal to 100%.

[0016] The Applicant has discovered that the nutraceutical composition according to the present invention is surprisingly effective in promoting body weight loss in a human subject in need thereof.

[0017] Tests on a three-dimensional (3D) model of human adipose tissue confirmed the effectiveness of the composition according to the invention in favorably modulating lipid and energy metabolism. In particular, the nutraceutical combination or composition comprising it in accordance with the invention stimulates thermogenesis by promoting the transformation of white adipose tissue into beige tissue (beiging), thereby increasing the body's ability to burn fat to produce heat. Transcriptomic analysis showed significant overexpression of key genes associated with thermogenesis and lipid metabolism, including CIDEA and GLUT-4, FABP4, PLN1, and leptin. These gene expression modulations are associated with improved triglyceride mobilization, a reduction in fat mass, including visceral fat, an improvement in glucose metabolism, as well as increased regulation of food intake and insulin sensitivity.

[0018] The nutraceutical composition according to the present invention can be used to obtain one or more of the following advantages: - Decrease in the weight ratio between fat mass and lean mass, - Reduction of abdominal fat accumulation, especially visceral fat, - Removal of fats (triglycerides) stored in adipocytes, fat cells which form adipose tissue, present in particular under the skin, - Maintaining or achieving a normal healthy Body Mass Index (BMI between 18.5 kg / m 2 and 25 kg / m 2 ), - Reduction of waist size, - Improvement or refinement of the silhouette, - Regulation of basal metabolism (resumption of normal basal metabolism), - Increased metabolism of carbohydrates and / or lipids, - Improved insulin sensitivity, - Reduction in the absorption of carbohydrates and lipids after their ingestion (before their storage in fat cells), - Contribution to the elimination of fats, - Reduction of serum triglycerides, - Reduction of serum LDL, - Increase in serum HDL, - Reduction of serum glucose.

[0019] Furthermore, the nutraceutical compositions according to the present invention are remarkably well tolerated by the body. They are also inexpensive, being based on plant-derived products, inexpensive and available on the market or simple to produce according to methods known to those skilled in the art.

[0020] It is worth remembering that abdominal fat includes (i) subcutaneous abdominal fat which is located just under the skin and above the abdominal muscles and can be easily felt by touch and (ii) visceral fat which is located under the abdominal muscles and is not palpable by touch. Some epidemiological studies have shown that overweight people with a BMI between 25 kg / m 2 at 30 kg / m 2 but who have a high level of visceral fat, have an increased risk of mortality compared to obese people with a lower level of visceral fat.

[0021] Chlorogenic acid is a natural compound that belongs to the hydroxycinnamic acid family. It is widely distributed in various plants, including fruits, vegetables, and green coffee beans. Chlorogenic acid has several interesting biological properties, including antioxidant activity. As an antioxidant, it helps neutralize free radicals (reactive oxygen species) in the body, which are unstable molecules that can cause oxidative stress and damage cells. By eliminating these free radicals, chlorogenic acid can help protect individuals from various diseases and contribute to their overall health. Some scientific studies report that chlorogenic acid is able to affect blood sugar levels by inhibiting certain enzymes involved in glucose metabolism and that it may have anti-inflammatory properties.

[0022] Ascophyllum nodosum is a species of brown seaweed, commonly known as knotted wrack or egg wrack. It is found in intertidal areas along the coasts of the North Atlantic Ocean, particularly in regions such as the North Atlantic and the Baltic Sea. Ascophyllum nodosum is well known for its beneficial properties and has been used for a variety of purposes. One of the notable characteristics of Ascophyllum nodosum is its rich nutritional profile. It contains a wide range of mineral salts (especially potassium) and trace elements (including chromium, zinc, selenium, manganese), vitamins (including A, C, B1, B2, B3 and B12, E), iodine, polysaccharides (including alginates, laminarin and fucoidans) and polyphenols (or phlorotannins), various amino acids and other bioactive compounds.Although primarily used as a source of alginates, Ascophyllum nodosum is also widely consumed as a food in many Asian and several European countries. Some in vitro scientific studies have demonstrated that Ascophyllum nodosum can reduce fat absorption and eliminate fat deposits. The bioactive compounds in Ascophyllum nodosum are also believed to have antioxidant, anti-inflammatory, antimicrobial, anti-diabetic, anticarcinogenic, and radioprotective properties.

[0023] Mucilages are constituents present in many plant species, primarily seeds and roots. They are composed of polysaccharides. They allow plants to retain water. Plant-derived mucilages have the ability to swell upon contact with water, taking on a viscous consistency. They are commonly used in various industries, including food, pharmaceuticals, and cosmetics.

[0024] Capsaicinoids are a group of natural compounds found in chili peppers, particularly in the fruits of plants of the genus Capsicum. These compounds are responsible for the spicy, hot sensation associated with eating chili peppers. The most well-known and most studied capsaicinoid is capsaicin. In addition to their role in providing the characteristic spiciness of chili peppers, capsaicinoids are known for their analgesic, antitumor, antioxidant, anti-inflammatory, antimicrobial, and anti-obesity properties. Capsaicinoids, particularly capsaicin, have the ability to stimulate Thermogenesis, thus promoting increased energy expenditure. Thermogenesis is an essential metabolic process in which the body generates heat to maintain its core temperature. This mechanism results in energy consumption, making it an interesting ally in the quest to burn fat and lose weight.

[0025] Phloridzin is a naturally occurring compound belonging to the dihydrochalcone class. It is found primarily in the bark and roots of apple trees (genus Malus). Phloridzin possesses several interesting biological properties, including antioxidant and anti-inflammatory activity. It has been used in the past as a pharmaceutical tool for the investigation of glucose transport. It has been shown to be effective in modulating postprandial blood glucose levels. One of the mechanisms of action described would be that phloridzin competes with simple sugars and, consequently, limits their transport in the blood, by inhibiting the Na-glucose cotransporters SGLT1 and SGLT2 (see in particular the following articles: TAKII Hiroshi, et al. “Lowering Effect of Phenolic Glycosides on the Rise in Postprandial Glucose in Mice” Biosci. Biotech. Biochem., 61 (9), 1531-1535, 1997; Thorens, B.; et al., Glucose transporters in the 21 st century. Am. J. Physiol. Endocrinol. Metab.2010, 298, E141 - E145).

[0026] However, to the Applicant's knowledge, there is currently no combination containing an apple extract standardized in chlorogenic acid, a plant extract containing capsaicinoids, an extract of Ascophyllum nodosum, a plant extract containing mucilages, an apple extract standardized in phloridzin, and even less its (non-therapeutic) use to promote body weight loss and / or reduce fat accumulation and / or to reduce the weight ratio between fat mass and lean mass, in a human subject who needs it. In other words, there is no formula containing an extract of brown algae Ascophyllum nodosum combined with other active ingredients to enhance its fat-burning properties.

[0027] Other advantageous features of the invention are listed below. Each of these features may be considered alone or in combination with the remarkable features defined above, and may be the subject, where appropriate, of one or more divisional patent applications.

[0028] In particular, the plant extract containing capsaicinoids is cayenne pepper extract.

[0029] The plant extract containing mucilages can be chosen from the group of plants consisting of mallow, marshmallow, plantain, white broth, chia, cactus, aloe vera, sage, flax seeds, psyllium and their mixtures.

[0030] Preferably, the plant extract containing mucilages is an extract of mallow leaves.

[0031] Advantageously, the combination consists of: 57.80% w / w combination of the first apple extract, 18.50% w / w combination of the plant extract containing capsaicinoids, 11.56% w / w combination of the Ascophyllum nodosum extract, 8.67% w / w combination of the plant extract containing mucilages, 3.47% w / w combination of the second apple extract.

[0032] In preferred embodiments, the nutraceutical composition according to the invention further comprises one or more additional components such as vitamins, carotenoids, mineral salts and / or trace elements, antioxidants, one or more sources of prebiotics, one or more plant extracts capable of promoting satiety and / or stimulating or increasing metabolism, amino acids, probiotic bacteria, yeasts and flavoring agents.

[0033] In preferred embodiments, the nutraceutical composition according to the invention further comprises one or more suitable excipients.

[0034] In preferred embodiments, the nutraceutical composition according to the invention is in solid or liquid form, in particular, in the form of powders, chewable tablets, effervescent tablets, capsules, granules, hard, soft or gelled candies, chewing gums, or oral solutions or suspensions.

[0035] The nutraceutical composition according to the invention can be used as a food supplement.

[0036] The nutraceutical composition according to the invention is advantageously proposed for non-therapeutic use in promoting weight loss in a human subject in need thereof.

[0037] In particular, the nutraceutical composition according to the invention is intended to reduce the accumulation of body fat, improve the destocking of fats in adipocytes, prevent weight gain, induce satiety, increase energy expenditure, and / or stimulate the metabolism of carbohydrates and lipids.

[0038] More particularly, the nutraceutical composition according to the invention is intended to stimulate thermogenesis by the activation of brown adipose tissue or by the transformation of white adipose tissue into beige tissue (beiging), in order to increase energy expenditure, reduce fat mass, including visceral fat, and / or promote the mobilization of triglycerides stored in adipocytes.

[0039] The nutraceutical composition according to the present invention can be administered in an amount providing: a) from 90 mg to 600 mg per day of the first apple extract, b) from 30 mg to 200 mg per day of the plant extract containing capsaicinoids, c) from 15 mg to 160 mg per day of the Ascophyllum nodosum extract, d) from 10 mg to 120 mg per day of the plant extract containing mucilages, e) from 5 mg to 60 mg per day of the second apple extract.

[0040] In particular, the human subject is a person with a Body Mass Index (BMI) greater than 18.5 kg / m 2 , more specifically, a BMI between 18.5 kg / m 2 and 30 kg / m 2 . More specifically, the human subject wishes to lose part of his body weight to refine his figure and / or improve his well-being.

[0041] According to another aspect, the present invention relates to a combination as defined above.

[0042] According to another aspect, the present invention relates to a use of said combination for preparing a nutraceutical composition of the invention, in particular for the preparation of a food supplement or for enriching a food product or a drink. Detailed description.

[0043] This description is given without limitation, each characteristic disclosed only in one embodiment being generalizable to other embodiments. Similarly, one or more characteristics disclosed only in one embodiment may be combined with one or more other characteristics disclosed only in another embodiment.

[0044] Definitions:

[0045] The term "weight loss" refers to a reduction in a human's body weight. Weight loss may be for the purpose of improving health, shape, and / or appearance.

[0046] By "promoting weight loss" is meant achieving a reduction in body weight in the human subject. For example, administration of a composition as described herein may result in a reduction in body weight, for example, of at least 1, 2, 3, 5, 10, 15, 20, 25, 30, 35, 40, 45 or 50% or more than 50% of body weight (as measured prior to administration of the composition to the subject, i.e., the initial body weight). In the context of the present invention, reducing body weight also encompasses maintaining the weight of a human subject and also maintaining plasma triglyceride levels achieved after the weight reduction.

[0047] By "preventing weight gain" is meant to control, arrest and / or reduce body weight gain in a human subject. By preventing weight gain, at least one or more of the following results are achieved in the human subject: reduction or maintenance of body weight and / or body mass index (BMI), and / or body fat and / or plasma triglyceride levels and / or reduction of hyperglycemia and / or hyperlipidemia and / or arrest of weight gain.

[0048] By "body shaping or improvement" is meant the process of becoming thin or thinner by a decrease (e.g., a decrease of at least 1%, 5%, 10%, 15%, 20%, 25%, 30%, 40% or 50% or more than 50%) in a human subject's body dimensions (e.g., bust, waist and / or hip measurements).

[0049] Lean body mass refers to the component of body weight that does not include fat stores. It consists primarily of muscle, bone, organs, and all non-fatty tissue in the body. Lean body mass is essential for normal body function, including muscle strength, body temperature regulation, and overall health. It is distinct from fat mass, which represents the body's stored fat reserves and plays a role in energy storage. When discussing weight management, it is often desirable to maintain or increase lean body mass while reducing fat mass to achieve a healthy body weight.

[0050] The term “nutritional product” refers to all products having a nutritional and / or physiological effect, including in particular, food supplements, foods, dietetic products, etc.

[0051] The term "nutraceutical" refers to a substance or material, whether a whole food or a component of a food, designed to be consumed by a subject and capable of conferring health benefits. Dietary supplements and natural health products are examples of nutraceuticals.

[0052] The term "nutraceutical composition" refers to a composition whose purpose is to supplement the normal diet and to constitute a concentrated source of nutrients or other substances having a nutritional or physiological effect, alone or in mixture.

[0053] The term "dietary supplement" means a product or composition that, when added to a food or ingested alone, can provide nutrients or substances with a nutritional or physiological effect (e.g., vitamins, minerals, fatty acids or amino acids, dietary fiber, antioxidants) that are missing or insufficient in an individual's normal diet. A dietary supplement may be added to a food before, during, or after the preparation of the food. It may also be ingested alone, before, during, or after a meal.

[0054] The term "standardized" is often used in the field of naturally derived nutritional products. It refers to the process of delivering a product with a specific minimum concentration of one or more plant constituents. Standardization represents the concentration level of particularly desired elements from a plant source. Methods for standardizing plant substances, including extracts of apples, Ascophyllum nodosum, mallow leaves, and chili peppers, are well known in the art. In addition, the measurement of particular plant constituents upon which standardization is based is also well known in the art.In one example, standardization of Ascophyllum nodosum, mallow leaves, and chili pepper can be performed by UV spectrophotometry, High Performance Liquid Chromatography (HPLC), or Liquid Chromatography-Mass Spectrometry (HPLC-MS), using appropriate standards.

[0055] The term "about" when used as a modifier of a numerical range or quantity means an approximation of the range or quantity, such that minor deviations from the range or quantity are within the scope of the invention. Such deviations are known in the art of manufacturing formulations having a number of different ingredients of varying weights and consistencies.

[0056] The expression "p / p C combination >> means that the percentage of the component or ingredient considered is by weight relative to the total weight of the combination according to the invention.

[0057] The expression "p / p C om P position >> means that the percentage of the component or ingredient considered is by weight relative to the total weight of the composition according to the invention.

[0058] The expression "p / p P first apple extract "means that the percentage of the component or ingredient considered is by weight relative to the total weight of the first apple extract.

[0059] The expression "p / p se “apple extract” means that the percentage of the component or ingredient considered is by weight relative to the total weight of the second apple extract.

[0060] Combination of active ingredients according to the invention:

[0061] According to the present invention, nutraceutical compositions for oral administration are provided based on a specific combination of a first apple extract standardized in chlorogenic acid, a plant extract containing capsaicinoids, an extract of Ascophyllum nodosum, a plant extract containing mucilages, and a second apple extract standardized in phloridzin. Other active ingredients may also be included in the nutraceutical compositions according to the present invention as described throughout this patent document.

[0062] The nutraceutical compositions according to the present invention have beneficial nutritional and / or biological and / or physiological effects. They have proven to be essential assets in achieving weight loss objectives.

[0063] The nutraceutical compositions according to the present innovation have proven beneficial nutritional and / or biological and / or physiological effects. They are very effective in promoting body weight loss, in particular in reducing fat accumulation. In particular, they make it possible to obtain one or more of the following effects: - Decrease in the weight ratio between fat mass and lean mass, - Reduction of abdominal fat accumulation, especially visceral fat, - Removal of fats (triglycerides) stored in adipocytes, fat cells which form adipose tissue, present in particular under the skin, - Maintaining or achieving a normal healthy Body Mass Index (BMI between 18.5 kg / m 2 and 25 kg / m 2 ), - Reduction of waist size, - Improvement or refinement of the silhouette, - Regulation of basal metabolism (resumption of normal basal metabolism), - Increased metabolism of carbohydrates and / or lipids, - Improved insulin sensitivity, - Reduction in the absorption of carbohydrates and lipids after their ingestion (before their storage in fat cells), - Contribution to the elimination of fats, - Reduction of serum triglycerides, - Reduction of serum LDL, - Increase in serum HDL, - Reduction of serum glucose.

[0064] The nutraceutical compositions according to the present invention constitute an interesting source of mucilages and alginates which help to regulate appetite and limit the absorption of calories. Alginates and mucilages have the property of swelling by absorbing water. After ingestion of the combination according to the invention or the nutraceutical composition containing it in accordance with the invention, the alginates and mucilages when present, will swell in the stomach, forming a kind of viscous gel which, on the one hand, fills the stomach, generating a satiety ballast effect, and on the other hand, captures the fats and sugars contained in the food bolus, thus limiting the absorption of calories.

[0065] The nutraceutical compositions of the present invention are further rich in polyphenolic compounds such as flavonoids like quercetin and kaempferol; phenolic acids such as salicylic acid; hydroxycinnamic acid derivatives, such as chlorogenic acid; dihydrochalcones such as phloridzin; and phlorotannins. Such polyphenolic compounds act synergistically to stimulate the production of antioxidant enzymes involved in the body's defense system against oxygen radical species (ROS) and / or the synthesis of one or more enzymes in the metabolism of xenobiotics (substances foreign to the body that are capable of interacting with the body's biological and metabolic systems). Among the antioxidant enzymes, mention may be made of superoxide dismutase (SOD) which neutralizes superoxides into oxygen and hydrogenated water and catalases (CAT) which transforms hydrogenated water into water and oxygen.The term xenobiotics refers to substances foreign to the body, such as alcohols, drugs such as antibiotics, pesticides, chemical pollutants, or other xenobiotics. Xenobiotics, often too hydrophobic to be eliminated directly by the kidneys or broken down by bile, accumulate in the body's lipids. Xenobiotic metabolism enzymes (or EMX) are responsible for facilitating their elimination by making them more hydrophilic. The metabolism of xenobiotics is broken down into 3 phases which ultimately result in the elimination of foreign substances in the bile and urine. Phase I enzymes (mainly cytochromes P450), called functionalization enzymes, essentially catalyze redox and hydrolysis reactions; phase II enzymes (glutathione-S-transferases or GST, UDP glucuronosyltransferases or UGT, or other phase II enzymes), called conjugation enzymes, catalyze transfer reactions, generally after functionalization; phase III transporters (P-glycoprotein or Pgp, multidrug resistance proteins or MRP or other transporters) transport xenobiotics and especially conjugated derivatives across membranes.

[0066] Apple extract standardized in chlorogenic acid:

[0067] The combination according to the present invention contains an apple extract which is standardized to chlorogenic acid.

[0068] The presence of the apple extract standardized in chlorogenic acid makes it possible to regulate blood sugar by inhibiting the activity of certain digestive enzymes involved in the breakdown of carbohydrates and / or to regulate or improve lipid metabolism, to reduce oxidative stress and / or to attenuate chronic low-grade inflammation linked to excess weight, thus contributing to the effectiveness of the nutraceutical compositions in accordance with the invention.

[0069] The first apple extract advantageously contains at least 10% w / w first apple extract in chlorogenic acid. It is rich in polyphenols (at least 50% by weight) including chlorogenic acid. In practice, it is in the form of a powder having a particle size of less than 2 mm, preferably less than 1 mm, preferably less than 500 μm, better still less than 250 μm. It can be obtained from apple fruit while still green (unripe) by any extraction method known to those skilled in the art (e.g. by extraction in water). It is also commercially available.

[0070] The content of the first apple extract in the combination according to the invention is advantageously from 50% to 70% w / w combination, preferably from 55% to 60% w / w combination, more preferably, approximately 57.80% w / w C combination.

[0071] Capsicum Fruit Extract:

[0072] The combination according to the present invention and the nutraceutical compositions containing it in accordance with the invention comprise a plant extract containing capsaicinoids.

[0073] Capsaicinoids are alkaloids found in chili peppers, a group of plants belonging to the Capsicum genus and the Solanaceae family. They give chili peppers their spicy effect. They are fat-soluble substances. Examples of capsaicinoids include: capsaicin (trans-8-methyl-N-vanillyl-6-Nonenamide), dihydrocapsaicin, nordihydrocapsaicin, homodihydrocapsaicin, homocapsaicin, and mixtures thereof.

[0074] The plant extract containing capsaicinoids is preferably an extract of fruits of plants of the genus Capsicum such as the species Capsicum annuum, Capsicum baccatum, Capsicum chineuse, Capsicum frutescens and Capsicum pubescens. The extract of fruits of plants of the genus Capsicum can be prepared from Capsicum fruits of a single species or from different species.

[0075] In a preferred embodiment according to the present invention, the plant extract containing capsaicinoids is an extract of cayenne pepper (Capsicum annuum). This cayenne pepper extract typically contains at least 0.2% w / w capsaicin. It is preferably standardized to at least 2% w / w capsaicin. In practice, this cayenne pepper extract is in the form of a powder (humidity level < 10%, preferably < 5%). It can be combined or mixed with one or more excipients such as maltodextrin. In practice, the particle size of the powder is less than 2 mm, preferably less than 1 mm, preferably less than 500 μm, better still less than 250 μm. The cayenne pepper extract contains, in addition to capsaicin, other capsaicinoids such as dihydrocapsaicin and nordihydrocapsaicin.

[0076] The expression "p / pchili extract" means that the percentage of capsaicin is calculated by weight relative to the total weight of the chili extract.

[0077] The present invention takes advantage of the advantageous properties of capsaicinoids, in particular capsaicin, which have antioxidant, anti-inflammatory and thermogenic activities. It also takes advantage of the properties of the other extracts present in the combination according to the invention to provide effective nutraceutical compositions to promote weight loss and / or prevent weight gain.

[0078] In the context of this innovation, capsaicinoids, particularly capsaicin, act as thermogenesis stimulators, thus promoting increased energy expenditure. Furthermore, thanks to their antioxidant and anti-inflammatory properties, they help preserve cell health and reduce inflammation, which can play a significant role in body weight management.

[0079] The content of the plant extract containing capsaicinoids in the combination according to the invention is 10% to 25% w / w C combination, preferably from 15% to 20% w / w combination, more preferably, of approximately 18.50% w / w C combination.

[0080] Ascophyllum nodosum extract (brown algae):

[0081] The combination according to the present invention comprises an extract of Ascophyllum nodosum.

[0082] In practice, the Ascophyllum nodosum extract used in the context of the present invention is implemented in the form of a powder (humidity level < 10%, preferably < 5%). It can be combined or mixed with one or more excipients such as maltodextrin. In practice, the particle size of the powder is less than 2 mm, preferably less than 1 mm, preferably less than 500 μm, better still less than 250 μm.

[0083] Ascophyllum nodosum extract can be prepared from the whole plant or any tissues and parts of the brown algae, preferably from the leaves and stems of Ascophyllum nodosum and according to techniques generally known per se (e.g. patent documents FR2914190A1, FR2837386A1, CA2541747A1, WO2014167162A1). Ascophyllum nodosum extract is also commercially available.

[0084] The Ascophyllum nodosum extract used contains a wide range of mineral salts (e.g. potassium) and trace elements (e.g. chromium, zinc, selenium, manganese), vitamins (e.g. vitamins A, C, B1, B2, B3 and B12, E), iodine, polysaccharides (e.g. alginates, laminarin and fucoidans) and polyphenols (or phlorotannins), amino acids (e.g. arginine, asparagine, glutamine) and other bioactive compounds. It is particularly rich in phlorotannins (minimum 5% w / p Ascophyiium extract in phlorotannins), the percentage of phlorotannins being expressed in chlorogenic acid equivalent relative to the dry weight of the extract) and contains between 500 ppm and 2000 ppm of iodine. As a reminder, iodine is a trace element essential for the production of thyroid hormones, which regulate various physiological processes, including metabolism.

[0085] The expression "p / p Ascophyllum nodosum extract" means that the percentage of phlorotannins is by weight relative to the total weight of the Ascophyllum nodosum extract.

[0086] The chemical composition and iodine, polyphenol and polysaccharide content of Ascophyllum nodosum extract can be determined by any analytical method known in the art (e.g. High Performance Liquid Chromatography-Mass Spectrometer (HPLC-MS), or Inductively Coupled Plasma Mass Spectrometry (ICP-MS), in particular for iodine content.

[0087] The presence of the Ascophyllum nodosum extract makes it possible to capture lipids from the food bolus, to inhibit the digestive enzymes (α-amylase, α-glucosidase) involved in the assimilation of fats and sugars, to induce the feeling of satiety, to stimulate the metabolism and oxidation of fats and to improve or strengthen the antioxidant capacities of the body, thus contributing to the effectiveness of the nutraceutical compositions in accordance with the invention.

[0088] The content of Ascophyllum nodosum extract in the combination according to the invention is advantageously 5% to 20% w / w C combination, preferably from 10% to 15% w / w combination, more preferably, of approximately 11.56% w / w C combination.

[0089] The incorporation of the Ascophyllum nodosum extract into the combination according to the invention and into the nutraceutical compositions in accordance with the present invention can be carried out by any formulation method known in the nutraceutical field.

[0090] Plant extract rich in mucilages:

[0091] The combination according to the present invention also comprises a plant extract containing mucilages.

[0092] In the context of the present invention, the mucilages play a role in inducing and / or increasing the feeling of satiety, and / or reducing appetite, and / or by reducing the absorption of carbohydrates, and / or by preventing rapid spikes in blood sugar, and / or by promoting the growth of beneficial bacteria such as beneficial lactic acid bacteria. This contributes to maintaining the balance of the intestinal microbiota (or intestinal flora) and consequently, enhances the effectiveness of the nutraceutical compositions in accordance with the invention.

[0093] When ingested, mucilages absorb water and form a gel that creates volume in the stomach and makes it easier to feel full, which can help control appetite and reduce the desire to eat more. The formation of such a gel in the stomach can also slow the absorption of nutrients, including carbohydrates. Furthermore, as polysaccharides (soluble fibers) that are indigestible by the intestine, mucilages also exert a prebiotic action by feeding the beneficial bacteria (e.g., lactic acid bacteria) present in the intestine. This promotes a healthy gut microbiota and can help reduce fat absorption and storage in the body.

[0094] In a preferred embodiment according to the invention, the plant extract containing mucilages comes from a plant selected from the group consisting of mallow, marshmallow, plantain, white broth, chia, cactus, Aloe Vera, sage, flax seeds, psyllium and mixtures thereof.

[0095] In another preferred embodiment according to the invention, the plant extract containing mucilages is an extract of mallow leaves (Malva sylvestris L.) with a 4:1 ratio, due to its high mucilage content and commercial availability. Mallow is a flowering plant belonging to the Malvaceae family. It is native to Europe, Western Asia and North Africa. It has been used in traditional medicine for various purposes. Mallow leaves contain various bioactive compounds including flavonoids, polysaccharides and mucilages. They are known for their emollient, anti-inflammatory and soothing properties. They are generally recommended for relieving sore throats, coughs and digestive discomforts such as slowed transit.

[0096] The expression "4 / 1 ratio" means that the extract has an average equivalence of 4 / 1 (1 gram of extract is on average equivalent to 4 grams of dried mallow leaves).

[0097] In practice, the mallow leaf extract used is implemented in the form of a powder (humidity level < 10%, preferably < 5%). It can be combined or mixed with one or more excipients such as maltodextrin. In practice, the particle size of the powder is less than 2 mm, preferably less than 1 mm, preferably less than 500 μm, better still less than 250 μm. It can be prepared according to extraction techniques generally known per se.

[0098] The content of plant extract containing mucilages in the combination according to the invention is advantageously 5% to 20% w / w C combination, preferably from 5% to 10% w / w combination, more preferably, of approximately 8.67% w / w C combination.

[0099] The incorporation of the plant extract containing mucilages into the combination according to the invention and into the nutraceutical compositions in accordance with the present invention can be carried out by any formulation method known in the nutraceutical fields.

[0100] Apple extract standardized in phloridzin:

[0101] The combination according to the present invention contains a second apple extract which is standardized to phloridzin.

[0102] Phloridzin-standardized apple extract exhibits multiple activities, including antioxidant activity, blood sugar regulation, and anti-inflammatory effects. It thus contributes to improving or enhancing the effectiveness of the nutraceutical compositions according to the invention.

[0103] The second apple extract advantageously contains at least 15% w / w second apple extract, preferably at least 40% w / w second apple extract, or phloridzin. In practice, it is implemented in the form of a powder (humidity level < 10%, preferably < 5%). It can be combined or mixed with one or more excipients such as maltodextrin. In practice, the particle size of the powder is less than 2 mm, preferably less than 1 mm, preferably less than 500 μm, better still less than 250 μm. It can be obtained from the skin of unripe apples by any extraction method known to those skilled in the art (e.g.: document FR2822466A1). The second apple extract is also commercially available.

[0104] The content of the second apple extract in the combination according to the invention is advantageously from 1% to 10% w / w combination, preferably from 1% to 5% w / w combination, more preferably, approximately 3.47% w / wC combination.

[0105] The incorporation of the second apple extract into the combination according to the invention and into the nutraceutical compositions in accordance with the present invention can be carried out by any formulation method known in the nutraceutical field.

[0106] A preferred combination according to the invention consists of: (a) 50% to 70% w / w combination of a first apple extract standardized to at least 10% w / w first apple extract 60 Chlorogenic acid, (b) 10% to 25% w / w combination of a plant extract containing capsaicinoids, (c) 5% to 20% w / pcombination of an extract of Ascophyllum nodosum, (d) 5% to 20% w / w combination of a plant extract containing mucilages, (e) 1% to 10% w / w combination of a second apple extract standardized to at least 15% w / w second apple extract 6H phloridzin, the sum of (a), (b), (c), (d) and (e) being equal to 100%.

[0107] In another preferred example, the combination according to the invention consists of: (ai) 55% to 60% w / w combination of a first apple extract containing at least 10% w / w first apple extract 60 Chlorogenic acid, (bi) 15% to 20% w / w combination of a plant extract containing capsaicinoids, (ci) 10% to 15% w / pcombination of an extract of Ascophyllum nodosum, (di) 5% to 10% w / w combination of a plant extract containing mucilages, (and) 1% to 5% w / wcombination of a second apple extract standardized to at least 15% w / wsecond apple extract 6H phloridzin, the sum of (ai), (bi), (ci), (di) and (et) being equal to 100%.

[0108] In yet another preferred example, the combination according to the invention consists of: 57.80% w / w combination of a first apple extract containing at least 10% w / w first apple extract 6H Chlorogenic acid, 18.50% w / w combination of a plant extract containing capsaicinoids, 1 1.56% w / pcombination of an extract of Ascophyllum nodosum, 8.67% w / w combination of a plant extract containing mucilages, 3.47% w / w combination of a second apple extract standardized to at least 15% w / w second apple extract 6H phloridzin.

[0109] Nutraceutical composition:

[0110] The combination according to the invention can be formulated in the form of a nutraceutical composition or used as such as a nutraceutical composition.

[0111] Also, the present invention also relates to a nutraceutical composition comprising, as active agent, a combination according to the present invention.

[0112] The amount of the combination according to the invention in the nutraceutical composition according to the invention can vary within wide limits, for example, from about 10% to about 95% or more, by weight relative to the total weight of the nutraceutical composition.

[0113] The nutraceutical composition in accordance with the invention may further comprise one or more suitable excipients.

[0114] By "excipient" is traditionally meant any compound or composition intended to act as a simple support or vehicle, that is to say which is not intended to have a physiological or biological activity. As examples of excipients or vehicles, mention may be made exhaustively of diluents, binders, lubricants, dispersants, antioxidants, disintegrants, anti-caking agents, colorants, preservatives, coating agents, humectants, flavorings, etc. Of course, the person skilled in the art will take care to choose the possible compounds or compositions of excipients as well as their proportions in such a way that the advantageous properties of the combination according to the invention or of the nutraceutical composition containing it in accordance with the invention are not or are not substantially altered by the envisaged addition. The excipients are well known in the nutraceutical field and are not the subject of a detailed description here.Suitable excipients or carriers are also described in the "Handbook of Pharmaceutical Excipients," Second Edition, American Pharmaceutical Association, 1994.

[0115] For the purposes of the present invention, the term "suitable" or "suitable" means that the excipient(s) are compatible with nutraceutical or food use of the composition in accordance with the invention, i.e. they are not toxic to humans when used in a nutraceutical composition.

[0116] In embodiments, the nutraceutical composition according to the invention may further comprise one or more additional components capable of promoting a complementary and / or synergistic action. The additional components may be selected from vitamins (e.g. one or more vitamins A, B1, B2, B3, B5, B6, B8, B9, B12, C, D, E and / or K), mineral salts and / or trace elements (e.g. selenium, zinc, magnesium), antioxidant agents (e.g. carotenoids, resveratrol, vitamin E), one or more sources of prebiotics (e.g. acacia fiber, chicory inulin, Fructooligosaccharides extracted from banana, wheat, asparagus or artichoke), amino acids (e.g. glutamine, aspartic acid, arginine, lysine), one or more plant extracts capable of promoting satiety (e.g. Griffonia simplicifolia extract, fenugreek extract, carob extract, konjac extract,yerba mate extract) and / or to stimulate or increase metabolism (e.g. green tea extract, guarana extract, ginseng extract, turmeric extract, pepper extract, grape seed extract, grape marc, vine leaf extract, blackcurrant seed extract, blackcurrant leaf extract, Griffonia simplicifolia extract, fenugreek extract, carob extract, konjac extract, yerba mate extract), probiotic bacteria (e.g. Lactobacillus acidophilus, Bifidobacterium lactis, Lactobacillus casei), yeasts (e.g. Saccharomyces boulardiï) and mixtures thereof.,

[0117] The concentration, in the nutraceutical composition according to the invention, of the possible additional component(s) may vary within wide limits. Of course, a person skilled in the art will take care to choose the possible additional compounds and / or their quantities, in such a way that the advantageous properties of the nutraceutical composition are not, or not substantially, impaired by the envisaged addition. By way of example, the additional component(s) may be used in a content of between 0.001% and 30% by weight relative to the total weight of the nutraceutical composition.

[0118] Process - galenic - applications:

[0119] The combination according to the invention and the nutraceutical composition containing it in accordance with the invention can be obtained by any usual formulation method known in the nutraceutical field. Their respective ingredients can be mixed, before shaping, in the order and under conditions easily determined by those skilled in the art.

[0120] In practice, before galenic formulation for oral administration, the combination according to the invention is in the form of a powder with a particle size of less than 2000 μm, preferably less than 1000 μm, preferably less than 500 μm, more preferably less than 250 μm, and with a moisture content of less than 10%, preferably less than 2.5% by weight relative to the weight of the powder.

[0121] The nutraceutical composition (or combination) according to the invention makes it possible, by its oral administration, to promote a loss of body weight, in particular to reduce the accumulation of fat, more specifically to obtain one or more of the effects or advantages mentioned above.

[0122] The combination, the nutraceutical composition and their non-therapeutic use are thus of particular interest in the nutraceutical, nutritional and food fields.

[0123] The nutraceutical composition (or combination) according to the invention may be a nutritional or food composition. It is particularly suitable for oral administration (including buccal and sublingual) with or without suitable excipient(s). It may be formulated for administration to a human subject. In this context, different galenic forms are possible, such as solid and liquid forms (e.g. syrups, gels, emulsions, drinkable ampoules).

[0124] The nutraceutical composition (or combination) according to the invention may be presented in all the galenic forms normally used for oral administration, in particular in the form of powders (e.g. compressed or loose powders, powders packaged in sachets, in particular in single-dose sachets), tablets (e.g. chewable, effervescent, gastro-resistant tablets), dragees; soft or hard capsules, gelatin capsules (e.g. gelatin capsules film-coated and / or gastro-resistant), granules, hard, soft or gelled candies, chewing gums, or aqueous or oily suspensions. The preferred forms for oral administration are powders, tablets and capsules.

[0125] In practice, the nutraceutical composition (or combination) according to the present invention is presented in a unit dosage form, such as a tablet, a capsule or a sachet.

[0126] Such galenic forms can be produced by any usual process known to those skilled in the art.

[0127] The nutraceutical composition (or combination) according to the invention may be contained in a packaging, a wrapper or a dispensing device together with instructions for use. Advantageously, the nutraceutical composition in the form of tablets or capsules is presented in a sealed packaging, which may consist of a pillbox (e.g., a polypropylene or high-density polyethylene pillbox), a plastic or aluminum bag, or a blister pack such as a PVC / PVDC blister pack, covered with an aluminum film for optimal protection.

[0128] The nutraceutical composition (or combination) according to the present invention may be intended for use as a nutritional product.

[0129] A preferred nutraceutical composition (or combination) according to the invention is a food supplement.

[0130] Preferably, the food supplement is intended to be consumed or administered orally, to provide, in a human subject, the beneficial effects for body weight management mentioned above.

[0131] The combination according to the invention or the nutraceutical composition containing it in accordance with the invention can also be used to supplement a diet (e.g.: enrich a food product or a drink) intended to help a human subject obtain the beneficial effects on body weight, and more generally on health, mentioned above.

[0132] Also, the present invention also relates to a non-therapeutic use, by oral route, of the combination according to the invention or of the The composition containing it in accordance with the invention in particular to promote weight loss and / or to prevent weight gain in human subjects.

[0133] The present invention relates in particular to the use as defined above, in which the combination in accordance with the invention is implemented within a nutraceutical composition suitable for oral administration.

[0134] The invention also relates to a method for promoting weight loss and / or preventing weight gain in a human subject, more specifically for helping said human subject to obtain the beneficial effects on body weight, and more generally on health, mentioned above. This method comprises the oral administration to a human subject of a combination according to the invention or of a nutraceutical composition containing it in accordance with the invention.

[0135] The methods according to the invention have the characteristics of non-therapeutic methods insofar as they are intended to be implemented in the human subject wishing to lose part of their body weight to improve their health and / or to refine their figure and / or for their well-being. In addition, a nutraceutical combination or composition such as, for example, a food supplement according to the invention can be used daily for several months, without a medical prescription. The present invention is therefore clearly outside the therapeutic field.

[0136] More specifically, the human subject is an individual with a Body Mass Index (BMI) greater than 18.5 kg / m 2 , in particular between 18.5 kg / m 2 and 30 kg / m 2 , more particularly between 25 kg / m 2 and 30 kg / m 2, and who may wish to lose part of their body weight, in particular by reducing their BMI and / or waist circumference by one or more percent (for example, without reducing lean mass), as well as increasing thermogenesis, in order to refine their figure and / or improve their overall well-being. Indeed, it is not uncommon for some people who currently have a healthy weight (BMI between 18.5 kg / m 2 at 25 kg / m 2 ), seek to lose additional body weight in order to improve their athletic performance and / or meet required weight classification criteria, for example, for practicing a given sport. Furthermore, other people may be motivated by achieving a more attractive body appearance.

[0137] Advantageously, the application of a method of the invention confers the advantages indicated previously as being associated with the implementation of a combination according to the invention or of a composition containing it in accordance with the invention.

[0138] The method according to the invention can be implemented by the oral administration of a combination according to the invention or of a nutraceutical composition containing it.

[0139] A method of the invention may be carried out on a daily basis, with a single administration per day or administration twice a day (e.g., once in the morning and once in the evening or twice in the morning or twice in the evening), or three times a day (e.g., once in the morning, once at noon and once in the evening) or four times a day (e.g., twice in the morning and twice in the evening).

[0140] A method according to the invention can be implemented by daily administration of a nutraceutical combination or composition formulated in solid form (e.g.: capsules, soft capsules, tablets, capsules, dragees, chewing gums (or gummies), etc.) or liquid form (e.g.: gels, emulsions, syrups, etc.) in adequate quantity and number, depending on their form.

[0141] Preferably, the combination according to the invention or the nutraceutical composition containing it in accordance with the invention is administered, orally, in an amount providing: a) from 90 mg to 600 mg per day of the first apple extract, b) from 30 mg to 200 mg per day of the plant extract containing capsaicinoids, c) from 15 mg to 160 mg per day of the Ascophyllum nodosum extract, d) from 10 mg to 120 mg per day of the plant extract containing mucilages, e) from 5 mg to 60 mg per day of the second apple extract.

[0142] This daily amount can be given either all at once or in divided doses, for example two, three or four per day.

[0143] The method according to the invention can be implemented over a period varying from one week to several weeks, or even several months. This period can moreover be repeated after periods of non-treatment, for several months or even several years. For example, the administration of a combination in accordance with the invention or of a nutraceutical composition according to the invention can be carried out at a rate of 1 or 2 times per day, generally over a prolonged period of at least 4 weeks, or even 4 to 16 weeks, including or not one or more periods of interruption or being repeated after a period of interruption.

[0144] The present invention benefits both men and women.

[0145] The invention also relates to a kit or a combination product for simultaneous, separate or spread out use over time, preferably a food supplement, comprising a first composition containing a portion of the components forming the combination according to the invention and a second composition comprising at least the other portion of the components forming the combination according to the invention. This food supplement may be formulated in such a way that the two compositions are in the same forms or in different forms, for example chosen from those mentioned above. Such a kit may in particular be presented in a single package.

[0146] The ingredients are mixed, before being shaped and in order, under conditions easily determined by those skilled in the art.

[0147] The content and nature of the ingredients used in the combination or the nutraceutical compositions containing it in accordance with the invention are adjusted by those skilled in the art, so as not to substantially affect the properties required for said combination and for said nutraceutical compositions.

[0148] Body weight loss and / or reduction of fat accumulation can be demonstrated in a number of ways, for example by: - Measuring body weight using a scale, - Determination of body mass index (BMI), - Measuring the circumference of different parts of the body, such as the waist, hips and thighs, using a perimeter measuring tape, - Measurement of the thickness of adipose tissue by ultrasound (e.g. using BodyMetrix®, a non-invasive body composition measuring device), - Body composition assessment. Techniques such as bioimpedance, hydrostatic weighing, or DEXA (dual-energy X-ray absorptiometry) can measure body composition, including fat mass, lean mass, and bone mass. These methods provide a more detailed assessment of fat loss, - Satiety assessment: monitoring food intake and satiety surveys to assess whether a person feels increased satiety, which can be an indicator of the success of a weight loss strategy, - Blood tests: these measure sugar (glucose) and lipid (HDL and LDL cholesterol, triglycerides) levels, which can reflect changes in fat metabolism associated with weight loss, - In vitro or ex vivo tests, including using appropriate cellular models such as human adipose tissue. These tests can determine fat-burning activity using cytotoxicity analysis and metabolic activity to assess general metabolic activity, using (i) secretome analysis to assess the effect of active ingredients on adipose tissue metabolism and (ii) transcriptome analysis to assess thermogenesis and adipogenesis. This study can be complemented by a lipolysis test through glycerol release analysis to assess the effect of active ingredients on fat mass reduction and lipid metabolism.In summary, in vitro and ex vivo tests on human cellular models allow the reduction of lipid accumulation in fat cells (adipocytes) to be assessed using laboratory analytical methods (e.g. ELISA (enzyme-linked immunosorbent assay), PCR (Polymerase Chain reaction), dosage of molecules such as glycerol).

[0149] The apple extracts, the Ascophyllum nodosum extract, the plant extract containing capsaicinoids and the plant extract containing mucilages used in the context of the present invention and the methods for obtaining them are well known to those skilled in the art.

[0150] In the following description and examples, value ranges labeled as "between ... and ..." include the specified lower and upper bounds.

[0151] Other features and advantages of the invention will become more apparent from the following examples, given for illustrative and non-limiting purposes. The scope of the invention should not be limited in any way by these examples. Examples:

[0152] The chemical composition of the various plant and fruit extracts used in the present invention can be determined by any known state-of-the-art analysis method (e.g. High Performance Liquid Chromatography coupled with a mass spectrometer (HPLC-MS).

[0153] The particle size of the nutraceutical composition (or its combination) and of each of its ingredients can be measured by any technique known per se, for example using a laser particle sizer or a series of standardized sieves according to the requirements of the European Pharmacopoeia 2-1-4.

[0154] Example 1: Evaluation of the effects of a combination according to the present invention on a 3D human adipose tissue model.

[0155] The Applicant conducted a study aimed at analyzing the metabolic function and transcriptomic effects of a grape marc extract alone, and of a combination containing grape marc extract according to the present invention at an equivalent dose (hereinafter combination A). This study was conducted on a classic three-dimensional (3D) human adipose tissue model.

[0156] The Applicant conducted a study aimed at evaluating the metabolic and thermogenic functions through the transcriptomic analysis of a classic model of human adipose tissue in three-dimensional (3D), in contact with an extract of Ascophyllum nodosum alone, and a combination comprising Ascophyllum nodosum according to the present invention (hereinafter combination A).

[0157] Regarding the 3D human adipose tissue used, see for example the following documents: PCT / EP2020 / 050720 and PCT / EP2021 / 069888, or the article by Dani, V., Bruni-Favier, S., Chignon-Sicard, B., Loubat, A., Doglio, A., Dani, C. et al., Regulation of Adipose Progenitor Cell Expansion in a Novel Micro-Physiological Model of Human Adipose Tissue Mimicking Fibrotic and Pro-Inflammatory Microenvironments. Cells 2022, 11(18), 2798; doi.org / 10.3390 / cells11182798.

[0158] Tested combination A contains the ingredients shown in [Table 1] below.

[0159] [Table 1]. 1) Chlorogenic acid content: >10% w / w P first apple extract- (2) Cayenne pepper extract. (3) Ascophyllum nodosum extract containing up to 1500 ppm iodine. (4) Mallow leaf extract - Ratio 4 / 1. (5) Phloridzin content > 40% w / w S second apple extract-

[0160] The 3D ex vivo human adipose tissue model used is derived from subcutaneous adipose tissue (abdominal region) specifically harvested from a healthy donor (meeting the following criteria: female, 22 < BMI < 25, age = 65 years), to ensure optimal biological relevance. As is known, this model has been developed to faithfully reproduce the characteristics and organization of human adipose tissue. Its 3D architecture provides an accurate representation of physiological conditions, allowing for in-depth exploration of the metabolic response, thermogenic function, and aspects specific to the biology of human adipose tissue. Thus, it is representative of the physiology of human adipose tissue.

[0161] Incubation period: 10 days.

[0162] Model production: Adipose tissue was mechanically dissociated to preserve the 3D structure of adipose tissue and the integrity of cell populations. The resulting tissue was maintained in EGM medium. + in 3D culture conditions at 37°C, 5% CO2, then encapsulated in LMT agarose. The EGM medium + is a proliferation medium comprising the basal medium for endothelial cell proliferation (EGM) enriched with Epidermal Growth Factor (EGF), Basic Growth Factor (FGF2), Insulin-like Growth Factor, Vascular Endothelial Growth Factor 165, ascorbic acid, heparin, and hydrocortisone. EGM+ also allows for the amplification of adipocyte stem cells without altering their ability to differentiate into adipocytes.

[0163] The doses tested: 10 pg / ml of Ascophyllum nodosum extract alone, and 86 pg / ml of combination A.

[0164] Study design: The culture conditions for each sample (negative control, Ascophyllum nodosum extract alone (hereinafter, Extract AN) as well as combination A) are presented briefly in [Table 2] below.

[0165] [Table 2]

[0166] The control group (negative control) is a model of human white adipose tissue (composed exclusively of white adipocytes that store fat), which is made competent for transformation into beige adipose tissue (containing white and beige adipocytes, which burn fat and excess energy), following stimulation. This transformation of white adipose tissue into beige adipose tissue is called beiging.

[0167] In the present study, the PreBAT model is used to test the ability of Ascophyllum nodosum extract alone and combination 1 according to the invention to stimulate beiging and therefore, the ability to induce thermogenesis (“fat-burning” action).

[0168] An XTT test (metabolic activity measurement) performed on N = 4 replicates for each sample at D10 (day 10), revealed that the tested combination A increases metabolic activity by approximately 24% compared to Ascophyllum nodosum extract alone and by approximately 28% compared to the negative control.

[0169] The expression levels of CIDEA, FABP4, PLN1, GLUT-4, PPAR-y and Leptin genes were examined at D10 by real-time quantitative polymerase chain reaction (RT-qPCR). CIDEA, FABP4, PLN1, GLUT-4, PPAR-y and Leptin genes are known to be associated with adipogenesis and thermogenesis.

[0170] It is worth recalling that adipogenesis is a complex process during which pre-adipocytic cells undergo differentiation to become mature adipocytes, specialized for lipid storage. This dynamic process is finely regulated by a network of transcription factors and cellular signals. Initially, pre-adipocytic cells undergo proliferation before undergoing morphological and biochemical changes characteristic of the transition to the mature adipocyte. As this process progresses, lipid droplets begin to accumulate in the cytoplasm of adipocytes, marking the final phase of adipogenesis.

[0171] It is also worth remembering that thermogenesis is a fundamental process within human metabolism, characterized by the ability of fat cells to burn fat to generate heat. A particularly interesting aspect of thermogenesis lies in the ability of white fat cells to evolve towards a beige adipose phenotype. Unlike white fat cells, which primarily store energy as fat, beige fat cells are specialized for heat production. This transition towards a more thermogenic phenotype is associated with an increase in energy expenditure and may contribute to the regulation of body weight.

[0172] The CIDEA (cell death-inducing DNA fragmentation factor alpha-like effector A) gene is primarily expressed in adipose tissue, where it plays a role in regulating fat cell (adipocyte) metabolism. It is associated with the regulation of thermogenesis and is also involved in lipolysis, the process of breaking down lipids stored in adipocytes to release energy.

[0173] The FABP4 (Fatty Acid-Binding Protein 4) gene encodes the protein Adipoline (an adipokine), which is primarily secreted by adipocytes and plays a crucial role in lipid metabolism, inflammation regulation, and adipocyte function. FABP4 is notably associated with fatty acid transport and the regulation of lipid homeostasis. The Adipoline protein it encodes plays a critical role in fatty acid transport. It binds to fatty acids in the cytoplasm of adipocytes, facilitating their transport and utilization for metabolic purposes. Regarding the regulation of lipid homeostasis, FABP4 is expressed throughout the adipocyte differentiation process. It participates in the regulation of this differentiation, influencing the formation and function of fat cells.

[0174] The PLN1 (Perilipin 1) gene, also known as PLIN1, encodes the protein perilipin 1. Perilipin 1 plays a crucial role in lipid metabolism, particularly in regulating the storage and release of triglycerides in fat cells. It can be regulated in response to cold, which aligns with the increased need for thermogenesis in brown or beige adipose tissue in response to lower temperatures.

[0175] The GLUT-4 (Glucose transporter type 4) gene encodes the type 4 glucose transporter, GLUT-4, which plays a critical role in the transport of glucose across cell membranes, particularly in adipocytes. The primary function of GLUT-4 is to facilitate glucose transport in response to hormonal and metabolic signals, thus significantly contributing to the regulation of carbohydrate metabolism in the body.

[0176] The PPARg gene (peroxisome proliferator-activated receptor gamma) encodes a protein that is a transcription factor involved in the regulation of metabolism, particularly in the area of adipocyte differentiation, carbohydrate metabolism, and lipogenesis (the process of lipid synthesis). PPARg promotes fat storage by influencing the differentiation of preadipocytes into mature adipocytes, making it crucial in lipid metabolism. It is also involved in the regulation of carbohydrate metabolism by influencing insulin sensitivity. Proper activation of PPARg can improve the response of cells to insulin, thus promoting efficient glucose utilization. Regarding the regulation of lipogenesis, PPARgy promotes fat accumulation by stimulating the formation of new fat cells (or adipocytes) and increasing the capacity of adipocytes to store lipids.

[0177] The Leptin gene codes for leptin, a hormone involved in regulating appetite, metabolism, and body mass. Leptin is produced by fat cells (adipocytes) and works by sending signals to the brain to indicate that the body has sufficient fat stores. As a result, it helps regulate appetite and inhibit food intake. It influences energy metabolism by stimulating energy expenditure and promoting the use of fat as an energy source.

[0178] Transcriptomic analysis revealed that the tested combination A promotes the overexpression of the examined genes CIDEA, FABP4, PLN1, GLUT-4 and Leptin and tends to inhibit the expression of the adipogenic gene PPARy.

[0179] Compared with the negative control, the increase in the expression of the genes CIDEA, FABP4, PLN1, GLUT-4 and leptin was respectively 36-fold, 1.5-fold, 25.6-fold, 12.5-fold and 2-fold.

[0180] Transcriptomic analysis also revealed that the tested combination A induced a significant increase in the expression of the CIDEA, GLUT-4 and PLN1 genes compared to the Ascophyllum nodosum extract tested alone, with respective increase factors of 18, 4 and 7.

[0181] Conclusion :

[0182] Overall, the combination of the present invention demonstrates the ability to increase energy expenditure, stimulate lipid deposition in adipocytes, and promote the burning of fats and carbohydrates in the body. These effects could be beneficial for weight management, regulation of lipid metabolism, and potentially the prevention of conditions such as overweight or obesity and associated metabolic disorders, including diabetes.

[0183] Example 2: Combination according to the invention in powder form.

[0184] By usual techniques, a combination is prepared in powder form having the composition indicated in [Table 3] below.

[0185] [Table 3]. 1) Chlorogenic acid content: >10%w / w premierex t rait de apple. (2) Cayenne pepper extract standardized to at least 0.2% w / w pepper extract in capsaicins, preferably standardized to at least 2% w / w pepper extract in capsaicins. (3) Ascophyllum nodosum extract containing up to 1500 ppm iodine. (4) Mallow leaf extract - Ratio 4 / 1. (5) Phloridzin content > 40% w / w S econ d apple extract

[0186] Example 3: Composition of a food supplement presented in tablet form.

[0187] A tablet containing 432.5 mg of the combination consisting of the first apple extract (chlorogenic acid), the plant extract containing capsaicinoids (cayenne pepper), the Ascophyllum nodosum extract, the plant extract containing mucilages (mallow leaves) and the second apple extract (Phloridzin) is prepared according to standard techniques, the respective quantities of which are shown in [Table 4] below.

[0188] [Table 4]. 1) Chlorogenic acid content: >10% w / w Pre m ie apple extract- (2) Cayenne pepper extract standardized to at least 0.2% w / w pepper extract in capsaicins, preferably standardized to at least 2% w / w pepper extract in capsaicins. (3) Ascophyllum nodosum extract containing up to 1500 ppm iodine. (4) Mallow leaf extract - Ratio 4 / 1. (5) Phloridzin content > 40% w / w S[second apple extract 89] The tablet can be prepared as follows: the first apple extract (chlorogenic acid), the plant extract containing capsaicinoids (cayenne pepper), the Ascophyllum nodosum extract, the plant extract containing mucilages (mallow leaves), the second apple extract (Phloridzin), and the excipients are in the form of powders (< 500 pm). They are independently weighed and then mixed. The mixture is then homogenized and packaged in the form of a tablet.

[0190] The tablets can then be packaged in pill boxes or in a case containing blisters and are used as food supplements (e.g. dosage: 2 tablets / day, two in the morning or two in the evening or one in the morning and one in the evening or one before the two main meals, to be swallowed with water), to promote body weight loss and / or prevent body weight gain and / or induce a reduction in fat accumulation in accordance with the invention.

Claims

Claims

1. [A nutraceutical composition for use in promoting weight loss in a human subject, which nutraceutical composition is in a form suitable for oral administration and comprises as an active agent, a combination consisting of: (a) 50% to 70% w / w combination of a first apple extract containing at least 10% w / w first apple extract 6H Chlorogenic acid, (b) 10% to 25% w / w combination of a plant extract containing capsaicinoids, (c) 5% to 20% w / pcombination of an extract of Ascophyllum nodosum, (d) 5% to 20% w / w combination of a plant extract containing mucilages, and (e) 1% to 10% w / w combination of a second apple extract standardized to at least 15% w / w second apple extract 6H phloridzin, the sum of (a), (b), (c), (d) and (e) being equal to 100%.

2. A nutraceutical composition for use according to claim 1, wherein the plant extract containing capsaicinoids is a cayenne pepper extract.

3. Nutraceutical composition for use according to claim 1 or 2, wherein the plant extract containing mucilages is selected from the group of plants consisting of mallow, marshmallow, plantain, white broth, chia, cactus, aloe vera, sage, flax seeds, psyllium and mixtures thereof.

4. Nutraceutical composition for use according to any one of claims 1 to 3, in which the plant extract containing mucilages is an extract of mallow leaves.

5. Nutraceutical composition for use according to any one of claims 1 to 4, wherein said combination consists of: 57.80% w / w combination of the first apple extract, 18.50% w / w combination of the plant extract containing capsaicinoids, 11.56% w / w combination of the Ascophyllum nodosum extract, 8.67% w / w combination of the plant extract containing mucilages, and 3.47% w / w combination of the second apple extract.

6. Nutraceutical composition for use according to any one of claims 1 to 5, further comprising one or more additional components such as vitamins, carotenoids, mineral salts and / or trace elements, antioxidants, one or more sources of prebiotics, one or more plant extracts capable of promoting satiety and / or stimulating or increasing metabolism, amino acids, probiotic bacteria, yeasts and flavoring agents.

7. A nutraceutical composition for use according to any one of claims 1 to 6, further comprising one or more suitable excipients.

8. Nutraceutical composition for use according to any one of claims 1 to 7, in solid or liquid form, in particular, in the form of powders, chewable tablets, effervescent tablets, capsules, granules, hard, soft or gelled candies, chewing gums, or oral solutions or suspensions.

9. A nutraceutical composition for use according to any one of claims 1 to 8, which is a food supplement.

10. Nutraceutical composition for use according to any one of claims 1 to 9, with a view to reducing the accumulation of body fat, improving the destocking of fats in adipocytes, preventing weight gain, inducing satiety, increasing energy expenditure, and / or stimulating the metabolism of carbohydrates and lipids.

11. Nutraceutical composition for use according to one of claims 1 to 10, intended to stimulate thermogenesis by the activation of brown adipose tissue or by the transformation of white adipose tissue into beige tissue (beiging), in order to increase energy expenditure, reduce fat mass, including visceral fat, and / or promote the mobilization of triglycerides stored in adipocytes.

12. A nutraceutical composition for use according to any one of claims 1 to 11, the human subject being a person having a Body Mass Index (BMI) greater than 18.5 kg / m 2 , in particular between 18.5 kg / m 2 and 30 kg / m 2 .

13. Nutraceutical composition for use according to any one of claims 1 to 12, the human subject wishing to lose part of their body weight to refine their figure and / or improve their well-being.

14. A combination as defined in any one of claims 1 to 5.

15. Use of the combination according to claim 14 for preparing a nutraceutical composition according to any one of claims 1 to 13, in particular for the preparation of a food supplement or for enriching a food product or a beverage.

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