Anti-fat-accumulation and Anti-cellulite combination

Abstract

The invention relates to a combination containing: (a) at least 40% w / wcombination of a Coleus forskohlii extract, (b) at least 1% w / wcombination of a proanthocyanidins-rich apple extract, (c) at least 4% w / wcombination of a grape pomace extract, (d) at least 20% w / wcombination of a phloretin powder, the sum of (a), (b), (c) and (d) being equal to 100%.

Description

DescriptionTitle: Anti-fat accumulation and anti-cellulite combination. Technical field. [1] The present invention relates to a combination containing a Coleus forskohlii extract, an apple extract rich in proanthocyanidins, a grape marc extract and a phloretin powder. [2] The invention also relates to a nutraceutical or topical composition containing said combination as an active agent. [3] The invention also relates to the use of said combination or said nutraceutical or topical composition, for promoting the metabolism of lipids and / or carbohydrates, and / or for reducing the accumulation of body or skin fat and / or for preventing and / or treating cellulite. [4] The technical field of the present invention is that of the use of plant extracts having beneficial properties for the body, in particular for regulating fat metabolism and / or preventing and / or treating cellulite.State of the art. [5] Body fat accumulation is a major public health problem. It is associated with an increased risk of disorders, such as overweight and obesity. It is also associated with skin conditions, such as cellulite. [6] Fat (lipid) metabolism is the process by which lipids (fats) are absorbed, used, and stored by the body. It is regulated by a number of factors, including hormones, diet, and physical activity. [7] To regulate fat accumulation, it is important to maintain a healthy lipid metabolism. This can be done by adopting a healthy lifestyle, which includes a balanced diet and regular physical activity. and a healthy weight, that is, a body weight corresponding to a body mass index (BMI) between 18.5 and 25. According to the World Health Organization (WHO), a BMI below 18.5 is considered underweight, and a BMI above 25 is considered overweight or obese.[8] However, there is a need for products or compositions that better regulate fat metabolism. These products or compositions that could be beneficial for those seeking to lose weight or maintain a healthy weight. They could also be used to improve and / or treat cellulite.[9] Cellulite is a condition characterized by uneven skin covered with bumps and dimples, leaving the skin with a texture resembling an orange peel. It is a common condition that primarily affects post-pubescent females and a majority of them (approximately 90%).It is usually seen in areas of the body with higher fat storage, such as the thighs, buttocks, abdomen, and sometimes the upper arms. Cellulite is not specific to overweight people, although increased adiposity (fat accumulation) exacerbates it.

[0010] There are three types of cellulite: fatty cellulite, aqueous cellulite and fibrous cellulite.

[0011] Adipose cellulite is primarily caused by excessive accumulation of subcutaneous fat. It gives the skin a bumpy, dimpled appearance. It is only visible when the skin is pinched between the finger and index finger (hereinafter referred to as the pinch test). It is not painful.

[0012] Watery cellulite is linked to excessive water retention in the skin tissue. It gives the skin a sagging and swollen appearance. It is barely visible and appears slightly bumpy when tested with a pinch test. It is generally due to venous or lymphatic circulation problems.

[0013] Fibrous cellulite is the most advanced form of cellulite, resulting from a prolonged presence of this condition in the affected area. It is characterized by the development of fibrous connective tissue under the skin, resulting in the formation of nodules or bands, which gives a granular texture to the affected area. It feels firm to the touch and may cause a painful pinch test.

[0014] It is important to emphasize that cellulite is not a disease. It is described as a normal physiological condition in post-pubertal women that maximizes fat retention to ensure adequate caloric availability for pregnancy and lactation. However, it poses an aesthetic problem and can even cause considerable distress to those affected. Therefore, there is a need to find effective methods to combat cellulite.

[0015] The specific structure of the skin influences the appearance of cellulite. Beneath the skin's surface, adipose tissue, rich in fat cells (adipocytes), is anchored by trabeculae of fibrous connective tissue, above the dermis and below the anterior fascia of the muscle. These trabeculae, also called septa, are composed primarily of collagen fibers.

[0016] The trabeculae (or septa) help maintain (i) the structural integrity of the skin; (ii) the passage of nerve fibers and blood vessels to ensure the supply of oxygen and nutrients to the skin cells; and (iii) the passage of lymphatic vessels whose function is to drain lymph (a fluid containing water, various white blood cells, antibodies, nutrients, bacteria, toxins, as well as cellular and metabolic waste products), to the lymph nodes and then to the bloodstream. In addition, the trabeculae of fibrous connective tissue compartmentalize the fat cells into fat pockets. When the number and size of fat cells increase through the processes of adipogenesis and lipogenesis, the fat pockets swell and push against the skin, which is pulled inward by the trabeculae of fibrous connective tissue.The skin then deforms, creating bumps and dimples that give the characteristic appearance of cellulite. Additionally, as the fat pockets increase in volume, they put pressure on the surrounding blood and lymphatic vessels, hindering the flow of oxygen and nutrients to the cells. skin on one side, and disrupting the normal circulation of lymph on the other. This inability to effectively drain elements of the lymph, such as interstitial fluids, toxins and waste, leads to their accumulation and the formation of edema (water retention). This situation leads to asphyxiation of the cells of the surrounding tissues, disrupting the synthesis of collagen by dermal fibroblasts. In addition, it causes chronic low-grade inflammation, which in turn triggers the release of pro-inflammatory cytokines. This leads to the activation of pathways involved in the increase in the production of reactive oxygen species (ROS), thus creating a state of oxidative stress. Similarly, a high level of oxidative stress can stimulate the production of inflammatory cytokines.

[0017] Adipogenesis is a process of cellular differentiation during which preadipocytes become adipocytes. The first early differentiation gives rise to young adipocytes which, after late differentiation, give rise to mature adipocytes.

[0018] Lipogenesis refers to the set of biochemical processes involved in the biosynthesis of triglycerides and fatty acids and their storage in adipocytes. Lipogenesis is a metabolic pathway that occurs from dietary triglycerides, fatty acids, and other non-lipid precursors such as dietary carbohydrates or other excess substrates in the diet.

[0019] Furthermore, it is important to note that the configuration of the hypodermal tissue is not the same in women as in men. In women, the trabeculae framing the fat pockets are oriented in a parallel manner, perpendicular to the surface of the skin, whereas in men, these trabeculae have an oblique orientation. This difference explains why cellulite is generally a feminine manifestation. Indeed, in women, when the fat pockets increase in volume, they easily protrude into the dermis, causing the formation of bumps and dimples on the surface of the skin. In men, the oblique orientation of the Trabeculae of fibrous connective tissue prevent or limit deformation of the skin in the event of excessive development of fat cells.

[0020] The exact causes of cellulite are not fully understood, but most scientists agree that it involves localized hypertrophy (increase in volume) of fat cells, impaired microcirculation, dysregulated collagen synthesis, persistent low-grade inflammation, and oxidative stress.

[0021] The prevalence of cellulite has led to numerous treatment attempts.

[0022] Cellulite treatment strategies are currently based mainly on medical-aesthetic methods, such as manual or mechanical massage techniques, invasive treatments such as mesotherapy, liposuction or subcision, and non-invasive treatments such as acoustic wave therapy or radiofrequency and / or laser. Although these medical-aesthetic methods achieve satisfactory results, they are expensive, cumbersome and restrictive.

[0023] The prior art also proposes anti-cellulite preparations based on plant extracts that are used topically on the skin. While current topical preparations can help improve skin texture and reduce the appearance of cellulite, they nevertheless have disadvantages related to local application. By definition, topical preparations act locally on the areas of skin to be treated, where they can be unevenly distributed, and require repeated and lengthy applications. Furthermore, they can in some cases cause skin side effects, or even discomfort.

[0024] Alternatively, there are also oral compositions for the treatment of cellulite. Unlike topical preparations, oral compositions offer the advantage of acting from within the body to exert a cellulite-improving effect. Indeed, the metabolites and other active ingredients are particularly distributed in the skin via the blood circulation. However, no oral composition proposed so far has been sufficiently effective in treating cellulite.

[0025] In view of the above and due to the increasing demand for new oral administration products and the attraction of consumers for products of natural origin, there is a need for new products that can stimulate lipid (fat) metabolism and / or reduce the accumulation of body fat and / or improve or treat cellulite. Presentation of the invention.

[0026] The present invention is based on the discovery that a combination containing a Coleus forskohlii extract, an apple extract rich in proanthocyanidins, a grape marc extract and a phloretin powder has several beneficial effects. This combination makes it possible in particular to reduce the accumulation of body fat and / or to prevent and / or treat cellulite, whether adipose, aqueous and / or fibrous.

[0027] In particular, the combination has demonstrated its ability to perform at least one of the following activities: - Stimulate the expression of the Adiponectin (ADIPOQ), LYVE-1 and MSCA1 genes, which promotes metabolic regulation, lymphangiogenesis and improved adipose tissue homeostasis; - Inhibit the expression of the INHBA (Activin A) gene, helping to attenuate inflammatory and fibrotic processes in adipose tissue; - Reduce the secretion of the pro-inflammatory cytokine IL-6, helping to reduce inflammation in adipose tissue; - Reduce the amount of fibrillar collagen, reflecting enhanced anti-fibrotic activity; - Reduce the size of adipocytes, contributing to a significant improvement in the morphology and metabolic functions of adipose tissue.

[0028] In addition, this combination has proven to be more effective than grape marc extract used alone in reducing cellulite and improving the quality of adipose tissue. It is distinguished by excellent tolerance for the body, presenting no adverse effects on human health. In addition, it is inexpensive, based on affordable ingredients, widely available on the market or easy to produce using processes well known to those skilled in the art.

[0029] The apple is a fruit produced by an apple tree, which is a tree belonging to the Rosaceae family, genus Malus, more specifically the species Malus Pumula and Malus Domestica. The apple represents a rich source of polyphenols, including flavonoids such as anthocyanidins and anthocyanins, proanthocyanidins, flavan-3-ols (e.g., catechin, epicatechin), and phenolic acids such as hydroxycinnamic acids, including chlorogenic acid. Apple skin or peel reportedly contains more than twice as many polyphenols as apple flesh. The polyphenols found in apples are relatively effective antioxidants. They have also demonstrated numerous biological effects in the prevention of various chronic diseases, including cardiovascular disease, diabetes, cancer, and neurodegenerative diseases.In particular, apple polyphenols may help alleviate type II diabetes through various mechanisms such as inhibition of digestive enzymes that metabolize carbohydrates, such as α-glucosidase and α-amylase (see for example the article: Barbosa, ACL, et al., 2010).

[0030] It is worth remembering here that antioxidants generally get their name from their ability to slow down or prevent the oxidation of other chemicals caused by free radicals. These chemicals can be biomolecules such as proteins, nucleic acids, carbohydrates, and lipids. Free radicals include reactive oxygen species (ROS), such as hydroxyl radicals (HO•), peroxyls (HOO•, ROO•), and superoxide ions (O2•−), which tend to form in cells and can cause cellular and tissue damage if not neutralized by antioxidants. In addition, an excess of free radicals can lead to a state of oxidative stress in the body. This phenomenon can negatively impact many aspects of health by affecting various tissues, including adipose tissue and Skin tissue. In adipose tissue, excess free radicals can disrupt metabolic balance, impacting fat regulation in the body. This disruption may play a role in the development of cellulite. In skin tissue, oxidative stress induced by free radicals can damage collagen and elastin fibers, which are essential for maintaining skin firmness and elasticity. However, when these fibers are affected by oxidative stress, they can lose their strength and natural elasticity. Sagging skin can be a contributing factor to the appearance of cellulite.

[0031] Coleus forskohlii, also known as Indian Coleus, is a perennial plant belonging to the large Lamiaceae family and historically used in Ayurvedic medicine to treat various conditions, including inflammatory diseases, hypertension, respiratory disorders, obesity, and asthma. Its roots contain an active substance called forskolin (7β-acetoxy-8,13-epoxy-1α,6β,9α-trihydroxylabd-14-en-11-one; CAS Number: 66575-29-9) which is a potent activator of adenylate cyclase, an enzyme that increases cyclic adenosine monophosphate (cAMP) in cells. cAMP is an essential intracellular messenger in the lipolysis (fat breakdown) mechanism. An increase in cAMP promotes the breakdown of fats in fat cells and their use as fuel in the body, which can lead to increased thermogenesis and loss of body fat.Research (in vivo) has shown that forskolin can optimize body composition by increasing lean mass and metabolic activity.

[0032] Grape marc (called in English "grape marc" or "grape pomace") is a residual product obtained from the fruits (grapes) of the vine, a plant of the genus Vitis (botanical family: Vitaceae). Typically, grape marc consists of the solid part resulting from the pressing or crushing of grape bunches, i.e., the skins, seeds and possibly stalks. It represents approximately 20 to 30% of the weight of grapes used to make wine or grape juice. Grape marc is a particularly rich source of polyphenolic compounds (5 to 10% by weight). These polyphenolic compounds include anthocyanins, flavonoids including flavanols (e.g., catechins) and flavonols (e.g., quercetin), phenolic acids such as hydroxycinnamic acid and gallic acid, stilbenes including resveratrol, and tannins. These polyphenolic compounds are known for their broad spectrum of biological activities, including antioxidant, anti-inflammatory, anticancer, antimicrobial, antithrombotic, cardioprotective, and vasodilatory properties. Grape pomace phenolic compounds have also shown significant inhibitory activities, particularly in limiting dietary fat absorption and fat accumulation in adipose tissue (see, for example, the following articles: Hogan S., et al., 2010; Yunoki K., et al., 2008).Grape pomace is also an important source of dietary fiber, which accounts for approximately 30% to 60% of the dry weight of grape pomace. These dietary fibers include soluble and insoluble fibers, such as cellulose and hemicellulose. In addition, grape pomace contains mono- and polyunsaturated fatty acids, essential minerals (e.g., calcium, iron, potassium, manganese, and zinc), vitamins (e.g., vitamins C and E), and a range of other health-promoting compounds. The phytochemical composition of grape pomace is influenced by various factors, including grape variety, weather conditions, terroir, and the ripeness of the grapes. For example, it is common to find that red grapes generally have a higher content of anthocyanins (a subgroup of flavonoids) compared to white grapes.

[0033] Phloretin [2',4',6'-trihydroxy-3-(4-hydroxyphenyl)-propiophenone; CAS No. 60-82-2] is a naturally occurring polyphenolic compound that belongs to a special family of flavonoids called dihydrochalcones and is present in many fruits and vegetables, especially in apple leaves (Malus sp., Rosaceae). Phloretin has numerous biological activities such as antioxidant, anti-inflammatory, antidiabetic, anti-obesity, antitumor, antimicrobial, hepatoprotective, and cardioprotective.

[0034] To the Applicant's knowledge, there is currently no combination comprising a Coleus forskohlii extract, a grape marc extract, an apple extract rich in proanthocyanidins and a phloretin powder, and even less its use with a view to promoting the metabolism of lipids and carbohydrates and / or reducing the accumulation of fat and / or preventing and / or slowing down the formation of cellulite or reducing cellulite already present.

[0035] Thus, according to one aspect of the invention, there is provided a combination containing:(a) at least 40% w / w combination of an extract of Coleus forskohlii,(b) at least 1% w / w combination of an apple extract rich in proanthocyanidins, (c) at least 4% w / w combination of a grape marc extract, (d) at least 20% w / w combination of a phloretin powder,the sum of (a), (b), (c) and (d) being equal to 100%.

[0036] 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:

[0037] In particular, the extract of Coleus forskohlii is present in a content of 45 to 70% w / w combination.

[0038] The apple extract may contain at least 50% w / w apple extract, preferably at least 90% w / w apple extract of proanthocyanidins.

[0039] Preferably, the apple extract rich in proanthocyanidins is present in the combination according to the invention in a content of 2 to 9% w / w combination.

[0040] The grape marc extract may be present in the combination according to the invention in a content of 4 to 20% w / w combination.

[0041] Preferably, the content of phloretin powder is 20 to 40% w / w combination.

[0042] More particularly, the combination according to the invention contains: (a') from 45 to 70% w / w combination of Coleus forskohlii root extract, (b') from 2 to 9% w / w combination of apple extract rich in proanthocyanidins, (c') from 4 to 20% w / w combination of grape marc extract, (d') from 20 to 40% w / w combination of phloretin powder, the sum of (a'), (b'), (c') and (d') being equal to 100%.

[0043] More particularly, the combination according to the invention contains: 58.39% w / w combination of Coleus forskohlii root, 3.65% w / w combination of apple extract rich in proanthocyanidins, 8.76% w / w combination of grape marc extract, 29.20% w / w combination of phloretin powder.

[0044] According to another aspect, the invention provides a nutraceutical or topical composition comprising, as active agent, a combination according to the present invention.

[0045] The nutraceutical or topical composition according to the present invention may further comprise one or more excipients.

[0046] The nutraceutical or topical composition according to the present invention may further comprise 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 stimulating the metabolism of lipids and / or carbohydrates and / or promoting blood circulation, amino acids, probiotic bacteria and / or yeasts.

[0047] Preferably, the nutraceutical composition according to the present invention is presented in a form suitable for oral administration, in particular, in the form of powders, tablets, capsules, granules, candies, chewing gum, or aqueous or oily suspensions.

[0048] In particular, the nutraceutical composition according to the present invention is a food supplement.

[0049] Preferably, the topical composition according to the present invention is presented in a form suitable for topical administration, in particular, in the form of creams, milks, ointments, lotions, serums, gels, pastes, mousses, sticks, aerosols

[0050] Advantageously, the combination according to the present invention, or the nutraceutical or topical composition in accordance with the invention is intended for use in reducing the accumulation of body or skin fat and / or in preventing and / or treating cellulite. Detailed description.

[0051] This description is given without limitation, each feature disclosed only in one embodiment being generalizable to the other embodiments presented herein or in the summary of the invention presented previously. Similarly, one or more features disclosed only in one embodiment may be combined with one or more other features disclosed only in another embodiment.

[0052] The present invention is based on the discovery that a combination containing a Coleus forskohlii extract, an apple extract rich in proanthocyanidins, a grape marc extract and a phloretin powder, has several beneficial effects and in particular makes it possible to reduce the accumulation of body fat and / or to prevent and / or treat cellulite, the cellulite being able to be adipose, aqueous and / or fibrous.

[0053] With regard to cellulite and without wishing to be bound by a theoretical explanation and without excluding other modes of action, the inventor believes that the combination according to the present invention or the nutraceutical composition or topical composition containing it in accordance with the invention acts to prevent or slow down the formation of cellulite and to reduce cellulite already present via one or more modes of action, in particular protection against oxidative stress, reduction of inflammation, regulation of lipid and carbohydrate metabolism, inhibition of fat accumulation in fat cells (adipocytes), inhibition of differentiation, proliferation or hypertrophy of fat cells, stimulation of blood circulation, including microcirculation which is often impaired in areas affected by cellulite, and stimulation of collagen synthesis.

[0054] Indeed, the extracts of Coleus forskohlii, grape and apple marc and phloretin powder provide the combination according to the present invention with beneficial properties for preventing or slowing down the formation of cellulite and reducing cellulite already present, in particular: - antioxidant properties which can help protect cells and tissues (e.g. subcutaneous tissue) from the harmful effects of free radicals derived from oxygen, stimulate the immune system and promote the production of collagen and elastin, which help keep the skin firm and elastic, which can prevent or reduce the appearance of cellulite; - anti-inflammatory properties which help to reduce inflammation, including in areas affected by cellulite; - vasodilator properties which can stimulate and / or improve blood flow, particularly at the level of microcirculation.This action promotes the oxygenation of cells and tissues, including subcutaneous tissue, as well as the evacuation of toxins, cellular waste and fats through the lymphatic system. This dual benefit helps improve the quality and appearance of the skin, particularly in areas affected by cellulite; - lipid and carbohydrate metabolism regulating properties (e.g. lowering triglycerides and cholesterol) which can support metabolism while helping to limit the accumulation of fat in adipose tissue; - anti-adipogenic properties which help to regulate and / or inhibit adipogenesis and / or lipogenesis, thus slowing the differentiation, proliferation and / or increase in the size of adipocytes; - lymphangiogenic properties which stimulate the growth of new lymphatic vessels, thus contributing to the improvement of the lymphatic network.This promotes efficient drainage of lymph elements, such as interstitial fluids, and thus helps maintain tissue homeostasis; - anti-fibrotic properties that prevent or limit excessive scar tissue formation, thus helping to alleviate fibrosis. including fibrosis of adipose tissue, and potentially to prevent fibrous cellulite.

[0055] On the other hand, the combination according to the present invention can be used in a composition of the food supplement type. It is chemically stable and easy to formulate for oral administration.

[0056] Definitions:

[0057] The term "cellulite" means one or more of the conditions selected from the group consisting of fibrous cellulite, adipose cellulite and aqueous cellulite.

[0058] The term "prevent" and its derivatives, for example "prevention", encompass all preventive measures aimed at reducing the risk of the appearance of signs, delaying their appearance and reducing the incidence of the condition in question.

[0059] The term "improve" and its derivatives, such as "enhancement," encompass the reduction of signs, the slowing of the progression of signs, and the possibility of a complete cure.

[0060] The term "treat" and its derivatives, for example "treatment," encompass the reversal, alleviation, and / or inhibition of the progression of the condition to which the term treat or any of its derivatives is applicable.

[0061] The term "polyphenols" refers to a very large family of molecules, widespread in the plant world, generally characterized by the presence of one or more aromatic hydrocarbon rings, each carrying one or more hydroxyl groups. Polyphenols are divided into subfamilies such as: (i) flavonoids, which include, for example, flavanols, flavones, flavonols or anthocyanidins (ii), phenolic acids such as hydroxycinnamic acids; stilbenoids (including resveratrol) and lignans.

[0062] The term "proanthocyanidins" refers to polyphenolic compounds consisting of flavan-3-ol units (catechin or epicatechin) linked together by carbon-carbon bonds of the 4→8 or 4→6 type. Proanthocyanidins, also called condensed tannins, proanthocyanidins Oligomeric proanthocyanidins (OPCs) or procyanidins are present in many plants such as apples, plums and grape seeds. Proanthocyanidins are natural glycosidase inhibitors and are distinguished by their antioxidant activity, which can be 20 to 50 times higher than that of vitamins C and E. They are of great interest in the fields of nutrition and medicine due to their many beneficial properties, including antioxidant, anti-inflammatory, vasodilatory, anti-allergic, antibacterial, antiviral, antitumor and chemopreventive properties. They help protect the body's cells and tissues from free radicals. They are particularly beneficial for the cardiovascular system because they help protect and strengthen the components of the vessel wall, including microvessels, thus contributing to better venous circulation.

[0063] The term "nutraceutical" refers to a substance or material, whether a whole food or a component of a food, intended for consumption by a subject and capable of conferring health benefits. Dietary supplements and natural health products are examples of nutraceuticals.

[0064] 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 combination.

[0065] The term “nutritional product” refers to all products having a nutritional and / or physiological effect, including in particular, food supplements, foods, dietetic products, etc.

[0066] The term "dietary supplement" refers to a product or composition that enhances a food by its addition. A dietary supplement can be added to a food before, during, or after the preparation of said food. However, a dietary supplement can also be ingested alone, either before, during, or after a meal, or between meals.

[0067] The term "topical composition" refers to a composition formulated for topical administration. The term "topical administration" refers to application to the skin, particularly to the area of skin affected by cellulite.

[0068] The term "dry extract" refers to an extract without extraction solvent or containing only non-significant traces of it.

[0069] 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 phloretin powder and extracts of apples, Coleus forskohlii, and grape pomace, 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.Typically, standardization of plant extracts such as Coleus forskohlii extract, apple extract, grape pomace extract, and phloretin powder is performed by UV spectrophotometry, high-performance liquid chromatography (HPLC), or liquid chromatography-mass spectrometry (HPLC-MS), using appropriate standards.

[0070] 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.

[0071] The expression "p / pcombination" 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.

[0072] The expression “p / pcomposition” 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.

[0073] The expression "w / papple extract" means that the percentage of the component considered is by weight relative to the total weight of the apple extract.

[0074] Combination of active ingredients according to the invention

[0075] The combination of active ingredients according to the invention contains an extract of Coleusforskohlii, an apple extract rich in proanthocyanidins, a grape marc extract and a phloretin powder.

[0076] Coleus forskohlii extract:

[0077] Coleus forskohlii extract works in concert with phloretin, apple extract, and grape pomace extract to reduce body fat accumulation and prevent and / or treat cellulite. It helps stimulate fat metabolism and promote the breakdown of fat in fat cells and their use as fuel in the body. In addition, it works simultaneously to reduce oxidative stress and inflammation associated with cellulite.

[0078] For the purposes of the present invention, the term "Coleus forskohlii extract" means, in particular, a dry extract of Coleus forskohlii containing forskolin (CAS number: 66575-29-9) produced by an extraction process from the root of Coleus forskohlii.

[0079] Preferably, the Coleus forskohlii extract contains at least 10% by weight of forskolin relative to the total weight of the dry extract.

[0080] The Coleus forskohlii extract can be prepared by various extraction processes known to those skilled in the art, involving steps of grinding the roots of Coleus forskohlii, solid / liquid extraction, for example in a Soxhlet extractor using one or more suitable solvents such as toluene, hexane, ether, ethanol, methanol, ethyl acetate, acetone, dichloromethane, chloroform and mixtures thereof, separation of the soluble and insoluble phases by filtration, concentration and drying, and, where appropriate, mixing with a matrix (e.g., dextrin and / or maltodextrin), sieving and packaging.

[0081] Examples of solid / liquid extraction include maceration, infusion, decoction, extraction using Soxhlet extractors, microwave-assisted extraction, ultrasound-assisted extraction, supercritical fluid extraction (e.g. CO2 + dipropylene glycol). Solid / liquid extraction leads to the recovery of metabolites, including forskolin, contained in the roots of Coleus forskohlii.

[0082] As a solvent, any solvent normally used for plant extraction may be suitable. It is particularly preferred to use as a solvent one or more solvents chosen from toluene, hexane, cyclohexane, ether, a C1-C4 alcohol such as methanol, ethanol, and isopropanol, a C1-C4 ketone such as acetone and methyl ethyl ketone, a C1-C6 ester such as ethyl acetate, isopropyl acetate and butyl acetate, and chloroform or dichloromethane.

[0083] The extraction can be carried out at room temperature or at a higher temperature, for example at reflux of the extraction solvent used.

[0084] The extraction process advantageously includes a filtration step aimed at separating the liquid phase from the exhausted plant material (roots of Coleus forskohlii).

[0085] The extraction and filtration cycle can be repeated several times in order to deplete the plant material (Coleus forskohlii roots) of substances that have an affinity for the extraction solvent.

[0086] Typically, the extraction process may be completed by a step of partial or total removal of the extraction solvent or solvent mixture. A concentrated extract free of a significant amount of solvents or a dry residue may thus be obtained by removing all of the extraction solvent or solvent mixture. Alternatively, the product of the extraction step may be freeze-dried or atomized to be in the form of a powder.

[0087] Examples of Coleus forskohlii extraction processes can be found in the following articles: Pritee Singh and MA Suryanarayana, 2019; and Haritha Kanne, et al., 2015).

[0088] In practice, the extract of Coleus forskohlii is presented in powder form, in particular with a particle size of less than 1000 µm, preferably less than 600 µm, preferably less than 250 µm, and with a water content of less than 10%, preferably less than 5% by weight relative to the weight of the powder.

[0089] Advantageously, the extract of Coleus forskohlii is present in the combination in a content of at least 40% w / w combination, preferably from 45% to 70% w / w combination.

[0090] Apple extract:

[0091] The combination according to the present invention contains an apple extract concentrated in proanthocyanidins, which enriches and strengthens the antioxidant and anti-inflammatory properties of Coleus forskohlii extract, grape pomace extract and phloretin powder. This apple extract also has the ability to inhibit digestive enzymes such as lipases, α-glucosidase and α-amylase, responsible for the breakdown of fats and carbohydrates. This inhibition slows down the breakdown of nutrients, thus reducing the absorption of calories by the body, which can help limit fat deposits in the body. In addition, it has vasodilatory properties that can promote the improvement of blood flow, including at the level of microcirculation, often compromised in areas affected by cellulite.

[0092] For the purposes of the invention, the term "apple" means the apple fruit of the botanical genus Malus (Botanical Family: Rosaceae), for example of a species of Malus selected from the group consisting of: Malus domestica, Maluspumila, Malus sieversii, Malus sylvestris, and combinations thereof. The apple fruit may be ripe or immature (still green). More particularly, the apple fruit is immature.

[0093] For the purposes of the invention, the term "apple extract" means an extract obtained from apple fruit. This may be, for example, an extract of apple fruit or of apple fruit skin. In particular, the apple extract is (or comprises) an extract of apple fruit skin.

[0094] The apple extract is rich in proanthocyanidins such as procyanidins B1 (CAS number: 20315-25-7) and B2 (CAS number 29106-49-8). Advantageously, the apple extract used contains at least 50% w / p apple extract of proanthocyanidins. Most preferably, the apple extract contains at least 90% w / p apple extract of proanthocyanidins.

[0095] The apple extract may also comprise other polyphenolic compounds, including polyphenolic acids such as chlorogenic acid and / or dihydrochalcones including phloridzin and / or other proanthocyanidins having a chain length of 2 to 12 monomer units, for example 2 to 8 monomers.

[0096] Proanthocyanidin-rich apple extracts may be prepared from apple fruit or its peels by any of the extraction methods known to those skilled in the art (see for example patent documents US20050010040A1, EP0657169A1 and EP2579886A1, or the following article: Asma, U. et al., 2023).

[0097] The apple extract rich in proanthocyanidins used is preferably in powder form, in particular with a particle size of less than 1000 µm, preferably less than 600 µm, preferably less than 250 µm, and a water content of less than 10%, preferably less than 5% by weight relative to the weight of the powder.

[0098] Advantageously, the combination of the invention comprises at least 1% w / w combination, preferably from 2% to 9% w / w combination of apple extract rich in proanthocyanidins.

[0099] Grape marc extract:

[0100] The combination according to the present invention contains a grape marc extract.

[0101] For the purposes of the invention, the term "grape" means the fruit of the vine of the genus Vitis (botanical family: Vitaceae), for example of a species of Vitis selected from the group consisting of: Vitis vinifera, Vitis labrusca, Vitisriparia, Vitis rotundifolia, Vitis rupestris, Vitis aestivalis, Vitis mustangensis and combinations thereof.

[0102] For the purposes of the invention, the term "grape marc" means the residual product, in particular the skin (or film), seeds, and possibly the stalks, resulting from the operation of pressing or crushing the fruits of the vine of the genus Vitis, for example of at least one species of Vitis selected from the group consisting of: Vitis vinifera, Vitis labrusca, Vitis riparia, Vitis rotundifolia, Vitis rupestris, Vitis aestivalis, Vitis mustangensis. Typically, grape marc represents approximately 20 to 30% of the weight of the grapes used to make wine or grape juice.

[0103] The grape marc may be one or more red grape marcs, one or more white grape marcs or mixtures thereof. The grape marc may be derived from any type of grape variety known to those skilled in the art. Non-limiting examples of grape varieties include Merlot, Syrah, Tannat, Mourvèdre, Cabernet-Sauvignon, Cabernet-Franc, Grenache, Chardonnay, Pinot Noir and Sauvignon. Preferably, the grape marc is one or more red grape marcs.

[0104] By “grape marc extract” within the meaning of the invention a product obtained from grape marc (skins, seeds, and possibly stalks) recovered after separation of the liquid part (juice or must) of the grape.

[0105] According to a first embodiment, the grape marc extract is dehydrated (raw) grape marc presented in powder form. It can be obtained by any known process, for example by recovering at least one grape marc after separation from the juice or grape must, freezing and drying, for example by freeze-drying, then grinding-sieving the dried grape marc(s) (See for example the article by Solari-Godiño, A. et al., 2017).

[0106] Grape pomace extract is an excellent source of polyphenols and dietary fiber, as previously mentioned. It helps improve cellulite through one or more mechanisms. Its polyphenolic compounds, such as flavonoids, phenolic acids, and resveratrol, have the ability to reduce oxidative stress and inflammation, particularly those associated with cellulite. Indeed, these compounds may act by neutralizing free radicals responsible for oxidative stress and modulating inflammatory pathways, thus helping to prevent cellular damage and mitigate unwanted inflammatory responses in the body, particularly in areas affected by cellulite.Furthermore, due to their inhibitory activities, such polyphenolic compounds have the potential to limit the absorption of dietary fat and prevent excessive fat accumulation in adipose tissue, which helps prevent the formation of cellulite and / or reduce existing cellulite. Furthermore, thanks to its high dietary fiber content (at least 30% by weight), grape pomace extract may help regulate blood sugar and carbohydrate metabolism. These dietary fibers have the ability to slow the digestion and absorption of carbohydrates, thus preventing blood sugar spikes after meals. By limiting the amount of carbohydrates available to be stored as fat in fat cells (adipocytes), grape pomace extract may help prevent fat accumulation and avoid unwanted body weight gain and / or induce body weight loss.Additionally, this ability to moderate glycemic response may also be beneficial in preventing cellulite formation and / or reducing existing cellulite. By minimizing blood sugar fluctuations, grape pomace extract helps limit excessive fat storage in adipocytes.

[0107] According to a second embodiment, the grape marc extract is an extract concentrated in polyphenols potentially present in grape marc (hereinafter, polyphenolic grape marc extract).

[0108] Advantageously, the polyphenolic extract of grape marc is in powder form. It can be obtained from one or more grape marcs by extraction with one or more solvents, according to the methods for extracting grape skins or seeds known per se (see for example patent documents FR3002453A1, US6544581B1, WO2014013122, WO2017013299A1). As a solvent, any solvent usually used for extracting grape seeds or skins may be suitable. It is particularly preferred to use water and / or alcohols, such as methanol or ethanol, as the solvent.

[0109] Preferably, the polyphenolic extract of grape marc used contains, relative to the total weight of the dry extract, at least 50% by weight of polyphenols including at least 20% of proanthocyanidins. It may, if necessary, be associated or mixed with one or more excipients such as dextrin and / or maltodextrin.

[0110] The dehydrated (raw) grape marc powder or the polyphenolic extract of grape marc generally has a particle size of less than 1000 µm, preferably less than 600 µm, preferably less than 250 µm, and a water content of less than 10% by weight relative to the weight of the powder.

[0111] Advantageously, the combination of the invention comprises at least 4% w / w combination, preferably from 4 to 20% w / w combination of grape marc extract.

[0112] Phloretin:

[0113] Phloretin has anti-adipogenic, antioxidant, and anti-inflammatory properties. It helps limit fat accumulation and / or the growth of fat cells that cause cellulite. In addition, it also helps reduce oxidative stress and inflammation associated with cellulite.

[0114] For the purposes of the present invention, the term "phloretin powder" means, in particular, an extract containing phloretin and produced by an extraction process from the apple tree (e.g., the fruit, leaves, peels of the fruit). The phloretin powder may be extracted from the fruit (apple), either whole or part of the fruit. Typically, the phloretin powder is obtained from apple leaves and / or peels.

[0115] Apple tree and apple fruit (Malus species) are as defined in the case of proanthocyanidin-rich apple extract.

[0116] Examples of phloretin extraction processes can be found in the article by Nakhate KT, et al., 2022.

[0117] In practice, the phloretin powder has a particle size of less than 1000 µm, preferably less than 600 µm, preferably less than 250 µm. The moisture content of the phloretin powder may be less than 10%, preferably less than 5% by weight relative to the weight of the powder.

[0118] The phloretin powder suitable for the invention is an apple extract standardized to contain at least 90% phloretin, preferably at least 98% phloretin. It is commercially available.

[0119] Advantageously, the phloretin powder is present in the combination in a content of at least 20% w / w combination, preferably from 20% to 40% w / w combination.

[0120] A preferred combination according to the invention comprises: (a') from 45 to 70% w / p combination of Coleus forskohlii root extract, (b') from 2 to 9% w / p combination of proanthocyanidin-rich apple extract, (c') from 4 to 20% w / p combination of grape marc extract, (d') from 20 to 40% w / p combination of phloretin powder, the sum of (a'), (b'), (c') and (d') being equal to 100%.

[0121] Yet another example of a preferred combination according to the invention comprises: 58.39% w / w combination of Coleus forskohlii root, 3.65% w / w combination of proanthocyanidin-rich apple extract, 8.76% w / w combination of grape pomace extract, 29.20% w / w combination of phloretin powder.

[0122] Nutraceutical composition – Topical composition:

[0123] The combination according to the invention can be formulated in the form of a nutraceutical composition (for oral administration) or a topical composition (for topical administration). Thus, according to one embodiment, the The present invention also relates to a nutraceutical composition comprising, as active agent, a combination according to the present invention. According to another embodiment, the present invention also relates to a topical composition comprising, as active agent, a combination according to the present invention.

[0124] The amount of the combination according to the invention may vary within wide limits, such as for example from 0.01% to 99.99% by weight relative to the total weight of the nutraceutical composition or the topical composition. In embodiments, the amount of the combination is at least 10% by weight relative to the total weight of the nutraceutical composition or the topical composition.

[0125] The nutraceutical composition or the topical composition in accordance with the invention may further comprise one or more suitable excipients or vehicles.

[0126] By "excipient" or "vehicles" is traditionally meant any compound or composition intended to act as a simple support or vehicle, i.e. which is not intended to have a physiological or biological activity. Examples of excipients or vehicles include, but are not limited to, diluents, binders, lubricants, dispersants, antioxidants, disintegrants, anti-caking agents, colorants, preservatives, coating agents, humectants, flavorings, etc. The excipient(s) or vehicle(s) may also consist of or include aqueous solvents, non-aqueous solvents (e.g. alcohols, oils, waxes, etc.), hydroalcoholic solvents (e.g. water-glycerin).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 vehicles are also described in the work entitled. "Handbook of Pharmaceutical Excipients," Second edition, American Pharmaceutical Association, 1994.

[0127] For the purposes of the present invention, the term "suitable" or "suitable" means that the excipient(s) (or vehicle) are compatible with nutraceutical or topical use of the composition in accordance with the invention, i.e. they are not toxic to humans when used in a nutraceutical or topical composition.

[0128] In embodiments, the nutraceutical composition according to the invention may further comprise one or more additional components that can promote 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, etc.), 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), one or more amino acids (e.g., glutamine, aspartic acid, arginine, lysine, etc.), one or more plant extracts capable of stimulating the metabolism of lipids and / or carbohydrates and / or promoting blood circulation (e.g. green tea extract, guarana extract, ginseng extract, turmeric extract, pepper extract, grape seed extract, vine leaf extract, blackcurrant seed extract, blackcurrant leaf extract, Griffonia simplicifolia extract, fenugreek extract, carob extract, konjac extract, yerba mate extract, etc.), probiotic bacteria (e.g. Lactobacillus acidophilus, Bifidobacterium lactis, Lactobacillus casei, etc.), yeasts (e.g. Saccharomyces boulardii) and mixtures thereof.

[0129] The concentration, in the nutraceutical composition or in the topical 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 composition nutraceutical or topical composition are not, or not substantially, altered by the intended addition. For 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 or topical composition.

[0130] Process – galenic – applications:

[0131] The combination according to the invention and the nutraceutical composition, or the topical composition, containing it in accordance with the invention can be obtained by any usual formulation method known in the nutraceutical or cosmetic fields. Their respective ingredients can be mixed, before shaping, in the order and under conditions easily determined by a person skilled in the art.

[0132] In practice, before galenic formulation, the combination according to the invention is generally in the form of a powder with a particle size of less than 2000 µm, preferably less than 1000 µm, preferably less than 600 µm, more preferably less than 250 µm, and with a humidity level of less than 10%, preferably less than 2.5% by weight relative to the weight of the powder.

[0133] When the combination is formulated as a topical composition, it may be in any of the galenic forms normally used for topical application to the skin, including an aqueous, hydroalcoholic, or oily solution; an oil-in-water, water-in-oil, or multiple emulsions. It may be more or less fluid and have the appearance of a cream, milk, ointment, lotion, serum, gel, paste, or mousse. It may also be in solid form, such as a stick, or applied to the skin in aerosol form.

[0134] When the combination is formulated as a nutraceutical composition, it 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 dose sachets), tablets (e.g. chewable, effervescent, gastro-resistant tablets), dragees; soft or hard capsules, gelatin capsules (e.g. film-coated and / or gastro-resistant capsules), granules, hard, soft or gelatinous candies, chewing gums, or aqueous or oily suspensions. The preferred forms for oral administration are powders, tablets and gelatin capsules.

[0135] Such galenic forms can be produced by any usual process known to those skilled in the art.

[0136] Preferably, the nutraceutical composition according to the present invention is presented in a unit dosage form, such as a tablet, a capsule or a sachet.

[0137] When the nutraceutical composition according to the present invention is in unit dosage form, each unit dosage form may contain the combination according to the invention in an amount containing: from 75 mg to 150 mg of Coleus forskohlii extract, from 5 mg to 30 mg of grape marc extract, from 2.5 mg to 15 mg of proanthocyanidin-rich apple extract, from 25 mg to 75 mg of phloretin powder.

[0138] The nutraceutical or topical composition according to the invention may be contained in a packaging, a wrapper or a dispensing device together with instructions for use. In particular, the nutraceutical composition in the form of tablets or capsules may be 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, in particular, a PVC / PVDC blister pack (cell), covered with an aluminum film for optimal protection.

[0139] The nutraceutical composition according to the present invention can be dedicated to use as a nutritional product.

[0140] A preferred nutraceutical composition according to the invention is a food supplement.

[0141] Advantageously, the food supplement is intended to be consumed or administered orally, to provide, in a human subject, beneficial effects against cellulite and / or the accumulation of body or skin fat.

[0142] 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 an individual obtain the expected beneficial effects, namely: reduce the accumulation of body fat, and / or prevent and / or treat cellulite.

[0143] Also, the present invention also relates to a non-therapeutic use, orally and / or topically, of the combination according to the invention (in the form of a nutraceutical composition and / or a topical composition) for regulating the metabolism of lipids and / or carbohydrates; and / or for reducing and / or inhibiting the accumulation of interstitial fluids; and / or for limiting and / or inhibiting the expansion of adipocytes; and / or for reducing and / or inhibiting adipocyte differentiation; and / or for stimulating lymphangiogenesis; and / or for reducing the accumulation of body or skin fat; and / or for preventing the formation of cellulite and / or for reducing existing cellulite. The present invention relates in particular to the uses as defined above, in which the combination in accordance with the invention is implemented within a nutraceutical composition or a topical composition.

[0144] The invention also relates to a non-therapeutic method for regulating lipid and / or carbohydrate metabolism; and / or for decreasing and / or inhibiting the accumulation of interstitial fluids; and / or for limiting and / or inhibiting the expansion of adipocytes; and / or for decreasing and / or inhibiting adipocyte differentiation; and / or for stimulating lymphangiogenesis; and / or for reducing the accumulation of body or skin fat; and / or for preventing the formation of cellulite and / or for reducing existing cellulite, in a human subject. In one embodiment, the non-therapeutic method according to the present invention comprises administering by oral administration to the human subject of a nutraceutical composition in accordance with the invention. In another embodiment, the non-therapeutic method according to the present invention involves the topical administration to the human subject of a topical composition in accordance with the invention. In yet another embodiment, the non-therapeutic method according to the present invention comprises both the oral administration to the human subject of a nutraceutical composition in accordance with the invention and the topical administration to said human subject of a topical composition in accordance with the invention. The oral and topical administration allows for a synergistic approach, exploiting the respective advantages of these modes of administration. The joint adoption of oral and topical administration favors a synergistic approach, exploiting the respective advantages of these two modes of administration.The combination of these modes of administration provides a synergy that can optimize the overall effectiveness of combating the accumulation of body or skin fat and / or cellulite, acting in a complementary manner to achieve more significant results. Advantageously, the application of at least one method of the invention provides the advantages indicated above as being associated with the implementation of a combination according to the invention or a nutraceutical or topical composition containing it in accordance with the invention.

[0145] A method according to the invention can be implemented by daily administration (once, twice or more than twice) of a nutraceutical combination or composition, formulated for example in solid form (e.g. powders, capsules, soft capsules, tablets, capsules, dragees, chewing gums, etc.) or liquid form (e.g. gels, emulsions, syrups, etc.) in an adequate quantity and number, depending on their form. and / or a topical composition formulated for example in the form of a cream, milk, ointment, lotion, serum, gel, paste or mousse, or in the form of a stick or aerosol.

[0146] 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 also be repeated after periods of non- treatment, for several months or even several years. For example, when the nutraceutical composition according to the present invention is in a unit dosage form, as mentioned above, the administration of this nutraceutical composition can be carried out at a rate of, for example, 1 to 4 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.

[0147] This invention benefits both women and men.

[0148] The combination according to the invention and the compositions in accordance with the invention may comprise all or only part of the daily dose.

[0149] 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 and same packaging.

[0150] The ingredients are mixed, before being shaped and in order, under conditions easily determined by those skilled in the art.

[0151] The content and nature of the ingredients used in the combination or nutraceutical composition, or the topical composition, 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 or topical compositions.

[0152] Coleus forskohlii root extract, concentrated apple extract proanthocyanidins, grape pomace extract and phloretin powder used in the context of the present invention and the methods enabling them to be obtained are well known to those skilled in the art. Such extracts can each be associated or mixed with one or more excipients such as dextrin and / or maltodextrin.

[0153] The chemical composition of the various plant and fruit extracts used in the present invention can be determined by any analytical method known in the art, for example by high performance liquid chromatography (HPLC) optionally coupled to a mass spectrometer (MS).

[0154] The particle size of the combination and each of its ingredients can be measured by any technique known per se. For example, using a laser particle size analyzer or a series of standardized sieves according to the requirements of the European Pharmacopoeia 2-1-4.

[0155] In the following description and examples, value ranges labeled as "between ... and ..." include the specified lower and upper bounds.

[0156] The effect of preventing and / or reducing cellulite can be demonstrated in different ways, for example by: - In vitro and ex vivo tests, in particular by using appropriate cellular models such as human adipose tissue. Ex vivo models are unique tissue models, because they are derived directly from donors and keep in culture, the 3D structure as well as all the functions of the native tissue. They are therefore representative of the physiology of human adipose tissue. These tests can determine the fibrotic activity of the adipose tissue in contact with the combination of the present invention. The fibrotic activity can be carried out through the analysis of cytotoxicity, metabolic activity or even transcriptome and secretome. The analysis of cytotoxicity and metabolic activity makes it possible to determine the stability of the combination formula on adipose tissue.Secretome analysis allows to evaluate the effect of the combination on metabolism and fibrotic response of adipose tissues. Transcriptome analysis allows to evaluate adipogenesis at the level of the lymphatic network and to evaluate the reduction of the fibrotic phenotype. -The tests can also be supplemented by qualitative / quantitative imaging analyses allowing to observe the lymphatic network, the size and number of adipocytes as well as the extracellular matrix, with an evaluation of fibrosis on the structure of the adipose tissue before and after incubation. -In vitro and ex vivo tests on human cellular models can be carried out using analytical methods in the laboratory (e.g.: Immunofluorescence, ELISA (enzyme-linked immunosorbent assay), PCR (Polymerase Chain reaction).

[0157] 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:

[0158] The phloretin powder and the extracts of Coleus forskohlii root, proanthocyanidin-rich apple, and grape pomace used in the examples below each have a particle size of less than 600 microns and are all commercially available.

[0159] Example 1: Evaluation of the effects of a combination according to the present invention on a 3D human adipose tissue model.

[0160] 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 (see for example the following documents: PCT / EP2020 / 050720 or Dani, V, et al.; 2022).

[0161] Combination A tested contains the ingredients shown in [Table 1] below.

[0162] [Table 1]. Ingredients Quantity (% w / w combination ) Coleus forskohlii root extract 58.4%Apple extract rich in 3.6% proanthocyanidinsGrape marc extract 8.8%Phloretin powder 29.2%

[0163] The ex vivo three-dimensional (3D) 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 and aspects specific to the biology of human adipose tissue. Thus, it is representative of the physiology of human adipose tissue.

[0164] The combination was suspended in 5 ml of culture medium.

[0165] The doses tested: 30 µg / ml of grape marc extract alone and 341µg / ml of combination A.

[0166] Incubation period: 7 days.

[0167] Model production: Adipose tissue was mechanically dissociated to preserve the 3D structure of the adipose tissue and the integrity of the cell populations. The resulting tissue was maintained in EGM-Plus medium (EBM basal medium + EGM supplements) under 3D culture conditions at 37°C, 5% CO 2, then encapsulated in LMT agarose.

[0168] Study plan:

[0169] The culture conditions for each sample (healthy control without fibrosis, fibrotic control, anti-fibrotic molecule control, grape marc alone as well as the combination) are presented briefly in [Table 2] below.

[0170] [Table 2]. Group No. Type Culture conditions 1 Healthy control Medium 2 Fibrotic control Medium + TGF-β1 dose 5 ng / ml (fibrotic stimuli- (untreated) fibrotic) 3 Anti-fibrotic control Medium + TGF-β1 dose 5 ng / ml (fibrotic stimuli- fibrotic) + SB431542 dose 5µM (anti-fibrotic) 4 Grape marc Medium + TGF-β1 dose 5 ng / ml (fibrotic stimuli) + Grape marc 30 µg / ml 5 Combination Medium + TGF-β1 dose 5 ng / ml (fibrotic stimuli) + Combination 341 µg / ml

[0171] The number of replicates (N) per sample performed for each analysis is presented in [Table 3] below.

[0172] [Table 3]. Analysis No. Transcriptome Analysis Binding in secretome group Activity (RNA extraction PFA 4% for metabolic (ELISA IL-6) at D7, RT-qPCR imaging (XXT D7) subsequent 1N = 4 N = 4 N = 4 N = 12 N = 4 N = 4 N = 13 N = 4 N = 4 N = 4 N = 14 N = 4 N = 4 N = 15 N = 4 N = 4 N = 4 N = 1

[0173] Timeline of the study:

[0174] After model production, pre-treatment was performed with the addition of compounds with TGF-β1 in order to create a fibrotic model. Renewal by addition of compounds with TGF-β1 was performed on D0, D3 and D6. On D7, the supernatant was recovered for XTT analysis, RNA lysis for transcriptomic study, secretome analysis and fixation for imaging analyses.

[0175] The synopsis of the study is presented in [Table 4] below.

[0176] [Table 4]. Type of analysis Procedures Objective ACTIVITY XTT test on n=4 Evaluation of general metabolic activity in adipose tissues. ACTION Transcriptome on D7 on n=4 Evaluation of the ANTICELLULITE network replicates / condition (RNA by RT-lymphatic and qPCR) through a set of 5 known genes / markers of fibrotic phenotype reduction, simulating the TRANSCRIPTOME literature: ADIPOQ cellulite.(adiponectin), LEP (leptin), INHBA (activin A), MSCA1, LYVE-1 VISUALIZATION -Adipocyte size (Oil Red O staining): visualization and measurement of the effect of active ingredients on ex vivo models. OF THE ACTION OF THE ANTI-CELLULITE ACTION OF active ingredients on the fibrotic context. -Cell matrix labeling (immunofluorescence labeling for Laminin): visualization of the effect of active ingredients on the matrix of fibrotic adipose tissue. -SHG microscopy: visualization of the reduction in compaction of collagen fibers following exposure to active ingredients. ELISA action analysis on n=4 replicates / condition Evaluation of the effect of anti-cellulite: for IL-6 secretion at the end of the active ingredients on the fibrotic response Secretome incubation period R ésultats :

[0178] An XTT (metabolic activity measurement) test (after 9 days of treatment) revealed that the tested combination A increased metabolic activity by approximately 13% compared to grape marc alone.

[0179] The expression levels of adiponectin markers, INHBA (activin A), MSCA1, LYVE-1 and IL-6 were examined at the same time period, by real-time quantitative polymerase chain reaction (RT-qPCR).

[0180] Adiponectin, a hormone mainly secreted by adipocytes, plays a critical role in the metabolic regulation of carbohydrates and lipids. As a key mediator between adipose tissue, liver and muscle, it exerts notable positive effects on metabolism. Its ability to promote insulin sensitivity, regulate inflammation and modulate fatty acid oxidation makes it a central player in metabolic balance. By promoting balanced growth of adipocytes, adiponectin promotes healthy expansion of adipose tissue.Plasma adiponectin levels, which are generally higher in healthy individuals, tend to decrease in those affected by obesity or metabolic disorders. Beyond its metabolic role, adiponectin is also distinguished by its ability to stimulate the production of antioxidant enzymes, thus helping to strengthen the body's natural defenses against oxidative stress. In addition, it exhibits an anti-inflammatory action, protecting tissues, including adipose tissue, from the harmful effects of fibrosis and inflammation.

[0181] An increase in Adiponectin expression is correlated with a favorable metabolic health status, stimulation of Lymphangiogenesis (expansion of the lymphatic network) and a reduction in adipose and aqueous cellulite.

[0182] MSCA1 (Mesenchymal Stem Cell Antigen 1), is a protein expressed by adipogenic progenitors of adipose tissue, decreased in inflammatory and fibrotic conditions.Activation of the MSCA1 marker suggests a reduction in fibrous cellulite.

[0183] INHBA (Inhibin Subunit Beta A) is a gene that codes for the beta A subunit of activin, a protein better known as activin A. This protein is expressed by fibrogenic progenitors in response to stimulation by pro-inflammatory cytokines, themselves produced by macrophages that invade adipose tissue. It is a characteristic marker of pro-inflammatory fibroblasts, whose proliferation increases in inflammatory and fibrotic conditions, without differentiation into adipocytes. Induction of the INHBA marker is at the origin of a deregulation of adipose tissue homeostasis, thus promoting the transition to a fibrotic state.Furthermore, an increase in the expression of the MSCA1 marker and at the same time a decrease in the expression of the INHBA (Activin A) marker suggest an anti-fibrotic effect, and consequently, a reduction in fibrous cellulite and an improvement in adipose tissue homeostasis with a balance between fibroblast-like and adipocyte-like cellular progenitors towards a healthy adipose tissue condition.

[0184] LYVE-1 (Lymphatic Vessel Endothelial Hyaluronan Receptor 1), a protein encoded by a gene of the same name, plays a key role in the regulation of lymphatic vessels and the composition of interstitial fluid. This protein acts as a specific receptor for hyaluronic acid, a macromolecule involved in water retention in tissues. When the LYVE-1 gene is functioning optimally, it actively participates in the elimination of hyaluronic acid, thus helping to maintain tissue water balance.An improvement in LYVE-1 gene expression indicates an optimization of lymphangiogenesis (growth of the lymphatic network) and / or the transport of interstitial fluid through the lymphatic network, thus suggesting a potential effect of reducing aqueous cellulite.

[0185] IL-6: pro-inflammatory cytokine produced in response to various inflammatory and fibrotic stimuli. Role in the emergence of cellulite. It also contributes to a deregulation of metabolic homeostasis (contributes to insulin resistance and metabolic disorders linked to weight gain)

[0186] Laminin: protein of the extracellular matrix of many tissues, including adipose tissue, playing a role in structural support and in the phenomena of cell migration and adhesion. In response to various inflammatory and fibrotic stimuli (in the context of cellulite, overweight, etc.), an alteration of the laminin mesh (compaction, heterogeneous distribution) is often observed.

[0187] Transcriptomic analysis revealed that the tested combination A promotes the activation of the examined markers Adiponectin, LYVE-1 and MSCA1 and inhibits the expression of INHBA (Activin A).

[0188] Transcriptomic analysis also revealed that the tested combination induces a 47% increase in the expression of adiponectin compared to grape marc tested alone.

[0189] Secretome analysis revealed that the tested combination A promotes the decrease in the secretion of the pro-inflammatory cytokine IL-6 on human adipose tissue models by -88% compared to grape marc alone.

[0190] By stimulating the expression of Adiponectin (a molecule beneficial for metabolism and the promotion of lymphangiogenesis), by increasing the general metabolic activity of adipose tissue and by decreasing the secretion of the pro-inflammatory cytokine IL-6, combination A could have a better efficacy in reducing the cellulite phenotype compared to grape marc alone.

[0191] Combination A allows to reestablish a homogeneous distribution of Laminin, with a signal that surrounds the adipocytes.

[0192] Combination A also allows to reduce the presence of fibrillar collagen by approximately 60% compared to grape marc alone (at equivalent dose)

[0193] - Under the conditions of the study, combination A shows its superiority over grape marc as an anti-fibrotic active, which suggests a better capacity as a product for the reduction of cellulite.

[0194] Imaging analysis revealed the decrease in adipocyte size for combination A.

[0195] Combination A induces a reduction in adipocyte size of approximately 30% compared to grape marc alone at equivalent dose.

[0196] Conclusion:

[0197] Overall, the combination described in the present invention demonstrates the ability to improve lipid and carbohydrate metabolism, stimulate lymphangiogenesis with an improvement in the lymphatic network, induce an improvement in adipose tissue homeostasis by balancing fibroblast and adipocyte-like cellular progenitors toward a healthy adipose tissue condition, cause an anti-fibrotic effect, decrease the presence and amount of fibrotic fibrillar collagen, improve the structure of Laminin, and finally, decrease adipocyte size. These different effects could be beneficial for the regulation of lipid and carbohydrate metabolism, the management of interstitial fluid accumulation, and the reduction of cellulite (adipose, aqueous, or fibrous cellulite).

[0198] Example 2: Nutraceutical composition in powder form.

[0199] A nutraceutical composition was prepared in powder form, then packaged in a sachet (e.g., stick), by mixing the ingredients shown in [Table 5] below.

[0200] [Table 5]. Ingredients Quantity (per sachet) Coleus forskohlii root extract from 75 mg to 150 mg Apple extract rich in proanthocyanidins from 2.5 mg to 15 mg Grape marc extract from 5 mg to 30 mg Phloretin powder from 25 mg to 75 mg

[0203] Recommended dosages for reducing fat accumulation and for the prevention and / or treatment of cellulite: 2 doses (sachets) per day (midday and / or evening) to be mixed with a glass of water (approximately 200 mL) and taken before meal(s).

[0204] Example 3: Nutraceutical composition in tablet form.

[0205] A nutraceutical composition in tablet form was prepared, comprising the combination shown in [Table 6] below.

[0206] [Table 6].Ingredients Quantity (per tablet) Coleus forskohlii root extract 100 mg Apple extract rich in 6.25 mg proanthocyanidins Grape pomace extract 15 mg Phloretin powder 50 mg

[0208] This nutraceutical composition, in tablet form, also includes conventional excipients including flavorings.

[0209] Recommended dosages for the reduction of fat accumulation and for the prevention or treatment of cellulite: 2 tablets per day (midday or evening) to be taken with a glass of water, 30 minutes before meals.

[0210] Bibliographic references: Asma, U.; Morozova, K.; Ferrentino, G.; Scampicchio, M. Apples and Apple By-Products: Antioxidant Properties and Food Applications. Antioxidants 2023, 12, 1456.Barbosa, ACL, Pinto, MDS, Sarkar, D., Ankolekar, C., Greene, D., and Shetty, K. (2010). Varietal influences on antihyperglycemia properties of freshly harvested apples using in vitro assay models. J.Med. Food 13, 1313–1323. doi: 10.1089 / jmf.2009.0273.Csilla Zsuzsanna Dávid, Judit Hohmann, Andrea Vasas. Chemistry and Pharmacology of Cyperaceae Stilbenoids: A Review. Molecules 2021, 26 (9),794. 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. Haritha Kanne, Narayan Pandurang Burte, V. Prasanna, and Ravi Gujjula.,Extraction and elemental analysis of Coleus forskohlii extract, PharmacognosyResearch, 2015; 7; 237-241.Hogan S, Canning C, Sun S, Sun X, Zhou K. Effects of grape pomace antioxidant extract on oxidative stress and inflammation in diet induced obesemice. Journal of Agricultural and Food Chemistry. 2010;58(21):11250–11256.Nakhate KT, Badwaik H, Choudhary R, Sakure K, Agrawal YO, Sharma C, Ojha S, Goyal SN. Therapeutic Potential and Pharmaceutical Development of a Multitargeted Flavonoid Phloretin. Nutrients.2022 Sep 2;14(17):3638. doi: 10.3390 / nu14173638. PMID: 36079895; PMCID: PMC9460114. Pritee Singh and M.A. Suryanarayana, Effect of Solvents and ExtractionMethods on Forskolin Content from Coleus forskholii Roots, Indian Journal ofPharmaceutical Sciences; 2019, 1136-1140. Solari-Godiño A., Lindo-Rojas I. & Pandia-Estrada S.| (2017) Determination of phenolic compounds and evaluation of antioxidant capacity of two grapes residues (Vitis vinifera) of varieties dried: Quebranta (red) and Torontel (white), Cogent Food & Agriculture, 3:1, 1361599, DOI: 10.1080 / 23311932.2017.1361599. Valeria Marinelli, Lucia Padalino, Amalia Conte , Matteo Alessandro Del Nobile and Karlis Briviba. Red Grape Marc Flour as Food Ingredient in Durum Wheat Spaghetti: Nutritional Evaluation and Bioaccessibility of Bioactive Compounds; Food Science and Technology Research, 2018, 24 (6), 1093–1100. Yu, J., & Ahmedna, M. (2013). Functional components of grape pomace: Their composition, biological properties and potential applications. International Journal of Food Science and Technology 2013, 48, 221–237.Yunoki K, Sasaki G, Tokuji Y, et al. Effect of dietary wine pomace extract and. oleanolic acid on plasma lipids in rats fed high-fat diet and its DNA microarrayanalysis. Journal of Agricultural and Food Chemistry. 2008;56(24):12052–12058.

Claims

Claims [Revendication 1] Combinaison contenant : (a) au moins 40% p / pcombinaison d’un extrait du Coleus forskohlii, (b) at least 1% w / w combination of an apple extract rich in proanthocyanidins, (c) at least 4% w / w combinaison from an extract of grape marc, ( d) au moins 20% p / pcombinaison d’une poudre de phlorétine, the sum of (a), (b), (c) and (d) being equal to 100%. [Revendication 2] Combinaison selon la revendication 1, caractérisée en ce que l’extrait du Coleus forskohlii est présent en une teneur de 45 à 70% p / pcombination. [Revendication 3] Combinaison selon la revendication 1 ou 2, caractérisée en ce que l’extrait de pommes contient au moins 50 % en p / pextrait de pomme, de preferably at least 90% w / w apple extract of proanthocyanidins. [Revendication 4] Combinaison selon l’une quelconque des revendications 1 à 3, caractérisée en ce que l’extrait de pomme riche en proanthocyanidines est présent en une teneur de 2 à 9% p / pcombinaison. [Revendication 5] Combinaison selon l’une quelconque des revendications 1 à 4, caractérisée en ce que l’extrait de marc de raisin est présent en une teneur de 4 à 20% p / pcombinaison. [Revendication 6] Combinaison selon l’une quelconque des revendications 1 à 5, caractérisée en ce que la poudre de phlorétine est présente en une teneur de 20 à 40 % p / pcombinaison. [Revendication 7] Combinaison selon l’une quelconque des revendications 1 to 6, characterized in that it contains: (a') from 45 to 70% w / w combinaison Coleus forskohlii root extract, (b') 2 to 9% w / w combination of proanthocyanidin-rich apple extract, (c') 4 to 20% w / w combination of grape marc extract, (d') 20 to 40% w / w combinaison phloretin powder, the sum of (a'), (b'), (c') and (d') being equal to 100%. [Revendication 8] Combinaison selon l’une quelconque des revendications 1 à 7, caractérisée en ce qu’elle contient : 58.39% w / w combinaisonof Coleus forskohlii root, 8.76% w / pcombination of grape pomace extract, 3.65% w / pcombination of apple extract rich in proanthocyanidins, 29.20% w / pcombination of phloretin powder. [Revendication 9] Composition nutraceutique ou topique, caractérisée en which comprises, as active agent, a combination according to any one of claims 1 to 8. [Revendication 10] Composition nutraceutique ou topique selon la claim 9, characterized in that it further comprises one or more excipients. [Revendication 11] Composition nutraceutique ou topique selon la revendication 9 ou 10, caractérisée en ce qu’elle comprend en outre un ou several 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 stimulating the metabolism of lipids and / or carbohydrates and / or promoting blood circulation, amino acids, probiotic bacteria and / or yeasts. [Revendication 12] Composition nutraceutique selon l'une quelconque des revendications 9 à 11, caractérisée en ce qu’elle est présentée sous uneform suitable for oral administration, in particular, in the form of powders, tablets, capsules, granules, candies, chewing gum, or aqueous or oily suspensions. [Revendication 13] Composition nutraceutique selon l'une quelconque des revendications 9 à 12, qui est un complément alimentaire. [Revendication 14] Composition topique selon l'une quelconque des revendications 9 à 11, caractérisée en ce qu’elle est présentée sous une form suitable for topical administration, in particular, in the form of creams, milks, ointments, lotions, serums, gels, pastes, mousses, sticks, aerosols. [Revendication 15] Combinaison selon l’une quelconque des revendications 1 to 8, or the nutraceutical composition according to any one of the r evendications 9 à 13, ou la composition topique l'une quelconque des revendications 9 à 11 ou 14, pour une utilisation pour favoriser le métabolisme de lipides et / ou de glucides, et / ou pour réduire l'accumulation de body or skin fat, and / or to prevent and / or treat cellulite.