ES2577889B1 - USE OF COFFEE HAND PRODUCTS FOR THE PREVENTION AND TREATMENT OF PATHOLOGIES THAT CONFORM THE METABOLIC SYNDROME AND ITS RISK FACTORS - Google Patents

Abstract

Use of coffee husk products for the prevention and treatment of the pathologies that make up the metabolic syndrome and its risk factors. # The present invention relates to the use of roasted coffee husk products that due to their particular composition in chlorogenic acid and caffeine, they have an important glucorregulatory and liporegulatory activity, which make them an excellent alternative for the prevention and treatment of metabolic syndrome, since they are effective simultaneously with the main pathologies that make it up and its risk factors.

Description

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USE OF COFFEE HAND PRODUCTS FOR THE PREVENTION AND TREATMENT OF PATHOLOGIES THAT CONFORM THE METABOLIC SYNDROME AND ITS RISK FACTORS

DESCRIPTION

SECTOR OF THE INVENTION

The present invention belongs to the food and pharmaceutical industry sector. More specifically, it is framed within the field of food, food supplements and pharmaceutical formulations that comprise natural coffee by-products, and that due to their lip-regulating and gluco-regulating activity are useful for the prevention and treatment of the most important pathologies that make up the metabolic syndrome and its risk factors.

STATE OF THE TECHNIQUE

Metabolic syndrome is a combination in the same individual of several risk factors, among which are dyslipidemia, hyperglycemia, insulin resistance and obesity, which share pathophysiological mechanisms and which often combine successively until degenerating. in type 2 diabetes mellitus and cardiovascular complications associated with changes in the pattern of seric lipids (Alegrla et al. 2008. Rev Esp Cardiol 61, 7, 752-64).

The treatment of the pathologies that make up the metabolic syndrome is carried out mainly through poly-pharmacological treatments that act on its risk factors, and include among other glucorregulators and liporegulators.

The goal of glucoregulatory treatments is to reduce the figures for baseline glycemia, glycosylated hemoglobin -HbA1c- (<7%) and postprandial glycemia. Among the most applicable glucorregulatory drugs are acarbose, miglitol, metformin and glitazones.

Acarbose (oligosaccharide) and miglitol (monosaccharide) are oral antidiabetics often used in the treatment of patients with type 2 diabetes mellitus, which inhibit the activity of intestinal alpha-glucosidase, effectively reduce blood sugar levels

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and are used to establish greater glycemic control over hyperglycemia, in particular with respect to postprandial hyperglycemia. However, they can cause gastrointestinal side effects such as flatulence and diarrhea.

The goal of liporegulatory treatments is to keep blood lipid levels within normal ranges (LDL <100 mg / dl, HDL> 40 mg / dl in men and> 50 mg / dl in women and triglycerides <150 mg / dl). An essential step in the treatment of dyslipidemia in patients with obesity, diabetes and metabolic syndrome is weight loss, which has been shown to cause numerous beneficial effects such as improved lipid profile. Obesity control treatments use drugs such as orlistat, which is a pancreatic lipase inhibitor that divides triglycerides into absorbable fatty acids and monoacrylic glycerol. Other liporegulatory treatments involve the administration of statins that reduce LDL levels, although they can cause liver damage, memory loss, diabetes risk and macular damage; or the administration of fibrates, particularly fenofibrate, which are considered more effective than statins for reducing triglycerides and increasing HDL, due to their PPARa agonist effect, although this drug can cause the same adverse effects as other lipid lowering agents such as liver failure. and renal, muscle toxicity and pancreatitis.

The combination of several drugs in the same subject implies an important complexity derived from the correct prescription and the possible adverse effects crossed between treatments.

On the other hand, the prevention of the pathologies that make up the metabolic syndrome and its risk factors is mainly carried out through: a) the maintenance of healthy living habits (for example with increased physical activity and with decrease in caloric intake); or b) the consumption of functional foods or nutritional supplements comprising bioactive compounds beneficial to health.

Within functional foods or nutritional supplements, a formulation is known that comprises an extract of two products that are cinnamon and coffee, rich in phenolic compounds with antioxidant activity, which according to their inventors causes a synergistic effect that could give it the ability to reduce the incidence of metabolic syndrome, associated diseases and their risk factors (WO2009018648 A1), although demonstrative examples are not included in the document in question.

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It is also known to use a flavonoid present in an extract of the rooibos plant such as aspalatine (WO2008110551 A1), which alone or in combination with another flavonoid as the routine originating in the same plant, cause a decrease in blood glucose , which is why it is considered useful for the prevention and treatment of diabetes.

Coffee raises a growing interest today due to bioactive compounds of very different nature that comprise the different parts that compose it. The coffee fruit consists of a thin outer layer or pericarp, usually green in immature fruits but then turns red-violet or deep red when ripe. The pericarp covers the pulp or outer layer of the mesocarp that is yellowish, fibrous and sweet. Following the pericarp there is a thin, translucent, viscous and highly hydrated layer of mucllago. But internally there is a small yellowish endocarp also called parchment. Finally, there is the silver skin, also known as silverskin or coffee husk, covering each hemisphere of coffee beans (endosperm) (Esquivel et al. 2012. Food Research International 46, 2, 488-495).

Moderate consumption of coffee drink is associated with potential beneficial health effects such as the reduction of plasma glucose level and the risk of type 2 diabetes (Dorea et al. 2005. British Journal of Nutrition 93, 773-782 and Ranheim et al. 2005. Molecular Nutrition & Food Research 49, 3, 274-284). Although there are indications that seem to relate the aforementioned healthy effects to the presence of certain compounds in coffee, such as chlorogenic acid, other studies such as Tuomlehto et al. (2004. JAMA 29, 10, 1213-1219) and Pereira et al. (2006. Archives of Internal Medicine 166, 12, 1311-1316) question that idea and indicate that it is not possible to establish any causal relationship.

On the other hand, Mullen et al. (2011. Journal of Agricultural and Food Chemistry 59, 8, 37543762) indicate that in addition to chlorogenic acid, other antioxidants are found in the whole coffee bean that are not roasted in combination and have the capacity to reduce the incidence of type 2 diabetes and cardiovascular risk.

The coffee husk constitutes the only by-product of the roasting process that after such treatment is either discarded or used as fuel or fertilizer (Machado et al. 2012. Biochemical Engineering Journal 60, 87-90).

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Documents are known that recommend the use of this roasted coffee husk as a functional food due to its high fiber content, low fat and reducing sugar content and marked antioxidant activity related to melanoidins formed during the process of roasting the grain (Esquivel et to 2012. Food Research International 46, 2, 488-495).

On the other hand, there are papers (Murthy et al. 2012. Food and Bioprocess Technology 5, 3, 897903) that indicate the presence of phenolic compounds in roasted coffee husk extracts obtained using an organic solvent such as isopropanol, and that present effects on the reduction of reactive oxygen species and free radicals and that according to these same authors could confer antimutagenic, anticarcinogenic, antiglycemic and antioxidant activity.

Also and within the patent literature, WO2013103465 A1 refers to improved methods for producing extracts with antioxidant substances and other health promoting compounds from coffee or by-products that include the husk and which are obtained using high pressures, higher in Any case at 2000 bar.

Finally, document WO2013004873 A1 and of which the present invention claims inventive matter, refers to a product that comes from the roasted coffee husk or that is an extract thereof and that is characterized by comprising a minimum content of chlorogenic acid and cafelna that confer antioxidant activity and that allows uses related to the prevention of physiological aging processes, pathological processes related to age or oxidative stress, and as a food preservative.

To a greater extent, subsequent studies using the coffee husk extract claimed in WO2013004873 A1, indicate that the consumption of said extract:

- allows a reduction of body fat accumulation in Caenorhabditis elegans, but without establishing any relationship with the blood lipid profile (Martinez-Saez et al. 2014. Food Chemistry 150, 227-234), and

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- It has the capacity to inhibit the in vitro formation of advanced protein glycation products also called AGEs (Mesias et al. 2014. Food Research International 62, 1120-1126). The consumption of AGEs from the diet and its in vivo training are associated with health disorders such as the complications of diabetes, atherosclerosis and Alzheimer's.

Based on the above, the search for solutions for the prevention and effective treatment of pathologies that make up the metabolic syndrome and its risk factors, through healthy natural sources, is considered of interest.

DESCRIPTION OF THE INVENTION

SHORT DESCRIPTION

The present invention relates, along different aspects, to the use of a bioactive product that is selected from,

a) roasted coffee husk, or

b) an extract of roasted coffee husk (ECCA) comprising a minimum of 80 mg of chlorogenic acid (ACG) and 985 mg of coffee (CF) per 100 g of extract,

in the preparation of a composition that is selected from a food supplement or a pharmaceutical composition and that is useful for prevention and treatment:

- of the risk factors of the pathologies that make up the metabolic syndrome and are selected from hyperglycemia, insulin resistance, dyslipidemia and obesity,

- of the pathologies that make up the metabolic syndrome and are selected from diabetes and cardiovascular pathologies associated with changes in the pattern of seric lipids, and

- of the metabolic smdrome,

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Preferably the diabetes is type 2 diabetes mellitus. Also preferably, the cardiovascular pathologies associated with changes in the pattern of seric lipids are vasculopaths.

Preferably the bioactive product is an extract of roasted coffee husk (ECCA), which comprises a minimum of 80 mg of chlorogenic acid (ACG) and 985 mg cafelna (CF) per 100 g of extract, and which is obtained by extraction with 2 volumes of water per part of husk, at a temperature of 100 ° C for a minimum of 10 minutes.

In other aspects, the invention relates to the nutritional supplement, or to the pharmaceutical composition comprising the bioactive product and which are useful for the prevention and treatment of the pathologies that make up the metabolic syndrome, its risk factors and the metabolic syndrome.

In a final aspect, the invention also refers to the use of the bioactive product as a technological adjuvant to reduce the glycemic index in a food.

DETAILED DESCRIPTION OF THE INVENTION

The technical problem that solves the present invention is the search for an alternative for the prevention and treatment of the main pathologies of a multifactorial disorder such as metabolic syndrome and its risk factors, using a natural product, in this case the product derived from the coffee husk claimed in application WO2013004873 A1 published on January 3, 2013 (originating from priority application ES2012 / 070490 dated July 4, 2011), hereinafter bioactive product of the invention.

In this document "bioactive product of the invention" is understood interchangeably:

a) roasted coffee husk, or

b) an extract of roasted coffee husk (ECCA) comprising a minimum of 80 mg of chlorogenic acid (ACG) and 985 mg cafelna (CF) per 100 g of extract.

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The roasted coffee husk in section a) is the powdered husk or the whole coffee husk of varieties such as, for example and not limited to, Arabica, Robusta or their mixtures and which have undergone a roasting process.

The roasted coffee husk extract of section b), is the product of section a) that is subjected to an extraction that can take place by enzymatic hydrolysis, cell rupture using mechanical procedures at room temperature, extraction with hot water, or extraction with the use of subcritical and / or supercritical water conditions. Preferably the extraction is carried out with:

i) 2 volumes of water per part of the husk, at a temperature of 100 ° C for a minimum of 10 minutes, or

ii) with subcritical water at temperatures between 50 and 200 ° C, maintaining a constant static extraction time of 20 minutes and a pressure between 103 and 207 psi, preferably 103 bar.

The coffee husk when in powder form is obtained with the help of a mill and using liquid nitrogen to avoid modifications of its bioactive compounds.

The present invention is based on the observation that the administration of a dose of 140 mg / kg / dla of roasted coffee husk extract comprising a minimum of 80 mg of chlorogenic acid and 985 mg cafelna per 100 g of extract during a minimum period of 35 days in a model of adult Wistar rats in which type 2 diabetes mellitus is induced simultaneously produces a glucoregulatory, hypoglycemic and antidiabetogenic effect (see examples 3.1, 3.2, 3.3, 3.5, 3.6 and 3.7), liporegulatory effect ( see examples 3.8, 3.9 and 3.10) and insulin resistance decreases (see example 3.4).

Additionally, the roasted coffee husk extract also has a hypoglycemic capacity and improves oral glucose tolerance significantly statistically in a model of healthy adult Wistar rats when co-administered with a glucose load (see example 2).

The effects outlined above, and which are based on the specificity of the composition, lay the foundations for the use of the bioactive product of the invention in the prevention and treatment of diabetes and cardiovascular pathologies associated with

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changes in the pattern of seric ilpids and their risk factors, and therefore of the metabolic syndrome.

"Metabolic syndrome" means a multifactorial disorder in which several risk factors converge that increase the probability of suffering certain pathologies such as cardiovascular diseases associated with changes in the pattern of seric lipids or diabetes mellitus. Both the pathologies and the risk factors can appear simultaneously or sequentially in the same individual and allow to identify this syndrome, in addition they are directly interrelated, in such a way that they share mechanisms of appearance and evolution and are often combined successively. Risk factors that fall within the scope of this invention are hyperglycemia, insulin resistance, dyslipidemia and obesity.

"Diabetes mellitus" or "diabetes" means a disease or condition that is generally characterized by metabolic abnormalities in the production and utilization of glucose resulting in inefficiency in maintaining blood sugar levels within the normal range. The result of these abnormalities is high blood glucose called "hyperglycemia." The two main forms of diabetes are type 1 diabetes and type 2 diabetes. Type 1 diabetes is usually the result of a failure in the pancreas that results in a lack of absolute production of insulin, the hormone that regulates the entry of glucose by the cells. Type 2 diabetes can have normal or even high levels of insulin and may result from the inability of tissues to respond appropriately to insulin. The majority of type 2 diabetic patients are resistant to insulin and have a relative insulin deficiency, which is that insulin secretion cannot compensate for the resistance of peripheral tissues to respond to insulin. Type 2 diabetic patients are often obese. Other types of glucose homeostasis disorders include glucose intolerance which is an intermediate metabolic stage between normal glucose homeostasis and diabetes. Diabetes mellitus is a multisystemic organic syndrome whose characteristic is the increase in blood glucose levels or hyperglycemia, the result of effects on the secretion of insulin, its action or both. It is a complex disease in which a global disorder of carbohydrate, fat and protein metabolism coexists. It is multifactorial due to the existence of multiple factors involved in its pathogenesis.

“Cardiovascular disease associated with changes in the pattern of seric lipids” is understood as preferably vasculopaths, initially subclinical and finally

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manifest in the form of atherothrombotic complications that occur as a result of the change in lipid metabolism associated with diabetes and metabolic smdrome.

By "hyperglycemia" is meant elevated blood glucose levels. "Insulin resistance" means high levels of insulin in the blood. "Dyslipidemia" means high levels of cholesterol (hypercholesterolemia), triglycerides (hypertriglyceridemia), low density lipoprotems (LDL-C) and low levels of high density lipoprotems (HDL-C) in plasma. By "obesity" is meant an excess of body fat that is determined based on the body mass index (BMI> 30) in metabolically healthy and diseased individuals. This concept also includes the phenotype corresponding to individuals with normal weight but metabolically obese; that is to say, they have a normal BMI but they have typical alterations of obese patients: insulin resistance, central adiposity, low cholesterol levels of high density lipoprotems (HDL-C) and high triglyceride concentrations, as well as arterial hypertension ( HTA).

Insulin resistance implies that the body's tissues become insensitive to the effects of insulin, so glucose cannot enter the cells and accumulates in the blood. Patients with type 2 diabetes mellitus and glucose intolerant suffer insulin resistance. Initially insulin resistance is moderate and glucose intolerance is asymmetric but carries a very high risk of developing type 2 diabetes in the future. Glucose intolerance can last 7-10 years before type 2 diabetes appears.

The main technical advantage of the present invention lies in the use of a bioactive product obtained from a single residual material that is the coffee husk, and which allows to act simultaneously against the pathologies that make up the metabolic syndrome and its risk factors .

Although the beneficial effects of the consumption of coffee drink on alterations such as plasma glucose level, type 2 diabetes or cardiovascular risk are known, as already indicated in the state of the art, the coffee bean is shaped by multiple parts that are characterized by comprising very diverse compounds that may or may not be bioactive.

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On the other hand, the procedures for obtaining extracts have a decisive influence on the compounds that are transferred to said extract, in such a way that the solvent used and the extraction conditions (temperature, pressure, etc.) make the extracts present compositions different, with different concentrations of the bioactive compounds and with more or less active forms of the compounds.

Finally, it is also necessary to consider that the roasting process has a dramatic effect on the composition of the different parts of the coffee and especially the coffee husk.

The results included in the examples in this document, which also show the activity of chlorogenic acid and cafelna used in isolation, affect the most beneficial effects on different risk factors and pathologies are obtained from simultaneously, only when the bioactive product of the invention is used, not being so! when chlorogenic acid is used in different doses or cafelna. Based on the foregoing, it is inferred that the effectiveness of the bioactive product of the invention probably derives from the proportion of bioactive compounds (cafelna and chlorogenic acid), but probably also from other components such as dietary fiber that are derived from its method of obtaining .

In a first aspect, the invention relates to the use of the bioactive product of the invention in the preparation of a food supplement useful for the prevention of at least one risk factor of the pathologies that make up the metabolic syndrome and that is selected from hyperglycemia , insulin resistance, dyslipidemia and obesity, or all of them simultaneously.

In the present invention, "nutritional supplement" means a product intended to complement the food and whose purpose is to increase the total dietary intake, complement it, supplement some component or prevent pathologies. In the present invention it is understood that the food supplement may have different forms of administration, including for example the Galenic form through a nutraceutical product.

"Prevention" means any action that has a direct effect on the risk factors that can trigger in any pathology, before they are effective, but also that improves the overall health status, preventing such risk factors from developing .

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In a particular embodiment of the first aspect of the invention, the nutritional supplement is additionally useful for the prevention of at least one of the pathologies that make up the metabolic syndrome, which are selected from diabetes and cardiovascular pathologies associated with changes in the pattern of Serious lipids, or both simultaneously. Preferably the pathologies are diabetes and vasculopathlas. More preferably diabetes is type 2 diabetes mellitus.

In another more particular embodiment of the first aspect of the invention, the nutritional supplement is additionally useful for the prevention of metabolic syndrome.

In a second aspect, the invention refers to the nutritional supplement, hereinafter the nutritional supplement of the invention, which comprises the bioactive product of the invention and which is useful for the prevention of the pathologies that make up the metabolic syndrome, of its risk factors and of the metabolic syndrome, as defined herein.

Additionally, the nutritional supplement of the invention may comprise at least one other active ingredient. The active ingredients included in the scope of the present invention are principles of natural or synthetic origin that increase the preventive activity of the nutritional supplement with respect to the metabolic syndrome, the pathologies that conform it or its risk factors.

The nutritional supplement of the invention can normally be consumed orally, for example in the form of tablets, capsules, granules, liquids, powders, in lyophilized form, in gel form, solutions, suspensions or any other suitable presentation form.

"Enriched food" means any combination of ingredients constituting a solid or liquid food product comprising a product enriched in chlorogenic acid and cafelna as defined according to any of sections a) and b) of the bioactive product definition of The invention, which in addition to its nutritional characteristics, has specific functions that help to improve the overall state of health and prevent the risk of contracting the metabolic syndrome, the pathologies that conform it or its risk factors

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Within the scope of the present document, the enriched food and the nutritional supplement of the invention can be used directly, or as an ingredient of another food comprising it.

In a third aspect, the invention relates to the use of the nutritional supplement of the invention or of the fortified food for the prevention of at least one of the risk factors of the pathologies that make up the metabolic syndrome and that are selected from among hyperglycemia, resistance to insulin, dyslipidemia and obesity, or all of them simultaneously.

In a particular embodiment of the third aspect of the invention, the nutritional supplement of the invention or enriched food, additionally are useful for the prevention of at least one of the pathologies that make up the metabolic syndrome, which are selected from diabetes and cardiovascular pathologies associated with changes in the pattern of seric lipids, or both simultaneously. Preferably the pathologies are diabetes and vasculopathlas. More preferably diabetes is type 2 diabetes mellitus.

In another more particular embodiment of the third aspect of the invention, the nutritional supplement of the invention or enriched food, additionally they are useful for the prevention of metabolic syndrome.

In a fourth aspect, the invention relates to the use of the bioactive product of the invention in the preparation of a pharmaceutical composition.

In a fifth aspect, the invention relates to the use of the bioactive product in the preparation of a pharmaceutical composition that is useful for the prevention and treatment of at least one of the risk factors of the pathologies that make up the metabolic syndrome and that is selected between hyperglycemia, insulin resistance, dyslipidemia and obesity, or all of them simultaneously.

In a particular embodiment of the fifth aspect of the invention, the pharmaceutical composition is additionally useful for the prevention and treatment of at least one of the pathologies that make up the metabolic syndrome, and which are selected from among diabetes and cardiovascular pathologies associated with changes in the pattern of seric lipids, or both simultaneously. Preferably the pathologies are diabetes and vasculopathlas. More preferably diabetes is type 2 diabetes mellitus.

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In another more particular embodiment of the fifth aspect of the invention, the pharmaceutical composition is additionally useful for the prevention and treatment of metabolic syndrome.

In a sixth aspect, the invention relates to a pharmaceutical composition, hereinafter pharmaceutical composition of the invention, which comprises the bioactive product of the invention for use in therapy.

Preferably the pharmaceutical composition of the invention is effective for the prevention and treatment of the metabolic syndrome, of at least one of the pathologies that make up the metabolic syndrome and that are selected from diabetes and cardiovascular pathologies associated with changes in the pattern of seric lipids. , or both simultaneously. Preferably the pathologies are diabetes and vasculopathlas. More preferably, diabetes is type 2 diabetes mellitus. Also preferably, the risk factors of the pathologies that make up the metabolic syndrome, and against which the pharmaceutical composition of the invention is effective, are selected from among hyperglycemia, insulin resistance, dyslipidemia and obesity, or are all of them simultaneously.

In particular embodiments of the sixth aspect of the invention, the pharmaceutical compositions that are included in the scope of this invention additionally use at least one pharmaceutically acceptable excipient, adjuvant and / or vehicles.

In the present invention, "excipient" is understood as an inactive substance used to incorporate the bioactive product of the invention. It can also be used to help the process by which the composition is manufactured. Examples of excipients include, but are not limited to, binders (keep the ingredients of a tablet together, such as hydroxypropyl, cellulose, xylitol, sorbitol, mannitol, etc.), diluents (fill in the contents of a tablet or capsule, such as, vegetable cellulose , dibasic calcium phosphate, safflower flower, etc.), disintegrators (compounds that expand and dissolve when they are wet causing the tablet to break when it reaches the digestive tract and release the active substances for absorption), lubricants (prevent the ingredients are grouped in lumps, such as talc, silica, etc.), coatings (protect the tablet ingredients from external agents, such as cellulose, synthetic polymers, polysaccharides, etc.), sweeteners, flavorings and dyes.

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The "vehicle" or carrier, is preferably an inert substance with the purpose of facilitating the incorporation of other compounds, allowing better dosing and administration or giving consistency and form to the pharmaceutical composition. Therefore, the vehicle is a substance that is used to dilute any of the components of the pharmaceutical composition of the present invention to a certain volume or weight; or that even without diluting these components it is able to allow a better dosage and administration or to give consistency and form to the medicine. When the presentation form is liquid, the pharmaceutically acceptable vehicle is the diluent.

The pharmaceutical composition of the invention can be administered by any appropriate route of administration, for example, oral, parenteral (subcutaneous, intraperitoneal, intravenous, intramuscular, etc.), rectal, etc.

The pharmaceutical composition of the invention may be in a pharmaceutical form of oral administration, either in solid or liquid form. Illustrative examples of pharmaceutical forms of oral administration include tablets, capsules, granules, solutions, suspensions, etc., and may contain conventional excipients, such as binders, diluents, disintegrants, lubricants, humectants, etc., and may be prepared. by conventional methods. The pharmaceutical compositions may also be adapted for parenteral administration, in the form of, for example, sterile freeze-dried solutions, suspensions or products, in the appropriate dosage form; in this case, said pharmaceutical compositions will include suitable excipients, such as buffers, surfactants, etc. In any case, the excipients will be chosen depending on the pharmaceutical form of administration selected. A review of the different pharmaceutical forms of drug administration and their preparation can be found in the book "Galenica Pharmacy Treaty", by C. Faull i Trillo, 10 Edition, 1993, Luzan 5, S.A. of Editions, or in any book of similar characteristics that exists in each country.

In further embodiments of the sixth aspect of the invention, the pharmaceutical compositions that are included in the scope of this invention comprise at least one other active ingredient. The active ingredients included in the scope of the present invention are principles of natural or synthetic origin that increase the activity of the pharmaceutical composition of the invention, preferably with respect to the treatment of metabolic syndrome pathologies, their risk factors or of metabolic syndrome.

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The scope of the present invention includes the use of the bioactive product of the invention and the pharmaceutical composition of the invention for the prevention and treatment of the pathologies that make up the metabolic syndrome of its risk factors and the metabolic syndrome, such and as defined in this document.

Also included within the scope of the present invention are any method of prevention and treatment of the pathologies that make up the metabolic syndrome, its risk factors and the metabolic syndrome, as defined herein, which consists of the administration of an effective dose of the bioactive product or the pharmaceutical composition of the invention.

In the present invention, "treatment method" means the set of means used in a subject to prevent, alleviate or cure a disease, or to eliminate or reduce the symptoms of a disease. In the present invention it is understood as " individual "or" subject "to a member of an animal species, preferably mammalian and includes, but is not limited to, a domestic animal, a primate and a human; in the context of the present invention, the individual is preferably a human being , male or female, of any race or age.

The dosage of the bioactive product, of the nutritional supplement of the invention, of the enriched food and of the pharmaceutical compositions of the invention, will vary depending on numerous factors, such as age, severity of the pathology, route of administration and dose frequency.

The characteristics of the bioactive product of the invention also allow its use as a technological aid in the preparation of food a reduced glycemic index.

Technological adjuvant means any substance that is not consumed as food in itself, if not used intentionally in the transformation of raw materials, food or its ingredients to fulfill a certain technological purpose during treatment or transformation, and can give place to the involuntary but technically unavoidable presence in the final product of residues of the substance itself or its derivatives, provided that they do not present any health risk and have no technological effect on the final product.

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In a seventh aspect, the invention relates to the use of the bioactive product of the invention as a technological adjuvant that favors a reduced glycemic index in a food.

Throughout the description and the claims the word "comprises" and its variants are not intended to exclude other technical characteristics. For the person skilled in the art, other aspects, advantages and characteristics of the invention will be derived partly from the description and partly from the practice of the invention. The following figures and examples are provided by way of illustration, and are not intended to be limiting of the present invention.

BRIEF DESCRIPTION OF THE FIGURES

Figure 1. Oral glucose tolerance test in healthy Wistar rats. Glucose was administered concurrently with chlorogenic acid, caffeine or roasted coffee husk extract. (A) Results obtained at times 30, 60, 90 and 120 minutes after oral administration of glucose together with the different treatments. (B) Detail of the results before 30 minutes. The two panels (A) and (B) show the average of the total blood glucose values (mg / dl) obtained at different analysis times ± standard error of the mean (SEM) (n = 12 per treatment) according to the Example 2. The comparison of the means was carried out using one-way ANOVA and Bonferroni test. Different letters show significant differences with p <0.05.

Figure 2. Average percentage of reduction and increase in total blood glucose levels during the 6 days after the induction of diabetes through a single dose of streptozotocin (STZ) and nicotinamide intraperitoneally in Wistar rats undergoing pretreatment with Chlorogenic acid, caffeine and roasted coffee husk extract. Percentage values were calculated using as reference the rats that were chemically induced to diabetes without prior pretreatment (control II) using the mean total blood glucose values ± the standard error of the mean (SEM) (n = 8 per treatment) according to example 3.1. The comparison of the means was carried out using one-way ANOVA and Bonferroni test. Different letters show significant differences with p <0.05.

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Figure 3. Oral glucose tolerance test in Wistar rats subjected to pretreatments with chlorogenic acid, caffeine and roasted coffee husk extract, 3 days after inducing diabetes through a single dose of streptozotocin (STZ) and nicotinamide via intraperitoneal The figure shows the values of the area under the curve (AUC) obtained by graphic representation of the blood glucose values according to example 3.2. The bars represent the mean of the AUC and the error bars the EEM (n = 8 per treatment). The comparison of the means was carried out using one-way ANOVA and Dunnett's T3 test. Different letters indicate that there are significant differences (p <0.05).

Figure 4. Antidiabetogenic effect in Wistar rats subjected to pretreatments with chlorogenic acid, caffeine and roasted coffee husk extract, after 8 days of having induced diabetes through a single dose of streptozotocin (STZ) and nicotinamide intraperitoneally. The graph shows the percentage of animals that presented permanent hyperglycemia (diabetes) in each treatment group (n = 8 per treatment) according to example 3.3 taking as diagnostic criteria permanent hyperglycemia (> 110 mg / dl fasting) and low tolerance to glucose (> 200 mg / dl at 90 and 120 min of intake).

Figure 5. In vitro inhibition capacity of ACG intestinal a-glucosidase activity and coffee roasted husk extract. The graph shows the IC50 values (mg / ml) obtained for ACG and roasted coffee husk extract according to example 3.5.

Figure 6. Effect on body weight in Wistar rats subjected to pretreatments with chlorogenic acid, caffeine and roasted coffee husk extract, after 8 days of having induced diabetes through a single dose of streptozotocin (STZ) and nicotinamide intraperitoneally . The graph shows the final weight of the animals according to example 3.6 at the end of the study. The bars represent the mean and the error bars the EEM (n = 8 per treatment). The comparison of the means was carried out using one-way ANOVA and Bonferroni test. Different letters indicate that there are significant differences (p <0.05).

Figure 7. Effect on the relative weight of the liver (liver weight / final weight) in Wistar rats subjected to pretreatments with chlorogenic acid, caffeine and roasted coffee husk extract, after 8 days of having induced diabetes through a

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single dose of streptozotocin (STZ) and nicotinamide intraperitoneally in Wistar rats. The graph shows the relative weights of the liver of the animals after supplementation with the different compounds or with the extract according to example 3.7. The bars represent the mean and the error bars the EEM (n = 8 per treatment). The comparisons of the means were carried out by one-way ANOVA and Bonferroni test. Different letters show significant differences with p <0.05.

Figure 8. Effect on plasma concentrations of total cholesterol in Wistar rats subjected to pretreatments with chlorogenic acid, caffeine and roasted coffee husk extract, after 8 days of having induced diabetes through a single dose of streptozotocin (STZ) and nicotinamide intraperitoneally in Wistar rats. The graph shows the concentrations of total cholesterol in plasma according to example 3.8. The bars represent the mean and the error bars the EEM. The comparisons of the means were carried out using one-way ANOVA and Dunnett's T3 test. Different letters show significant differences with p <0.05.

Figure 9. Effect on plasma triglyceride concentrations in Wistar rats subjected to pretreatments with chlorogenic acid, caffeine, and roasted coffee husk extract, after 8 days of having induced diabetes through a single dose of streptozotocin (STZ) and nicotinamide intraperitoneally in Wistar rats. The graph shows plasma triglyceride concentrations according to example 3.9. The bars represent the mean and the error bars the EEM. The comparisons of the means were carried out using one-way ANOVA and Dunet's T3 test. Different letters show significant differences with p <0.05.

EMBODIMENTS OF THE INVENTION

A) OBTAINING THE EXTRACT

Example 1. Obtaining the roasted coffee husk extract (ECCA)

The extract was obtained from coffee husk generated as a byproduct of roasted Arabica green coffee beans. It was prepared using 250 mg of said husk and 500 ml of water. The extraction was carried out at 100 ° C for 10 min. The extract thus obtained was centrifuged, the supernatant was collected and lyophilized to obtain powder extract. The product thus obtained was stored at room temperature in a dry place until use.

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B) TESTS IN HEALTHY RATS

Example 2. Effect on glucose tolerance of coffee components and roasted coffee husk extract in healthy Wistar rats

A group of 12 adult male Wistar rats weighing 150-200 g were used. After a fasting period of 14 hours, a single dose of the treatments detailed below was applied using a rigid nasophalangeal probe:

• glucose 2 g / kg weight (control group)

• glucose 2 g / kg weight and chlorogenic acid (ACG-1.5) 1.5 mg / kg weight

• glucose 2 g / kg weight and chlorogenic acid (ACG-10) 10 mg / kg weight

• glucose of 2 g / kg weight and cafelna (CF) 5 mg / kg weight

• 2 g / kg glucose weight and roasted coffee husk extract (ECCA) 140 mg / kg weight

Each of the 12 rats was applied sequentially to each of the previous treatments, using a 3-day wash between each treatment to ensure that the bioactive compounds were completely metabolized and avoid interference. In any case, the dose is indicated with respect to the weight in kilograms of the animal undergoing treatment.

Blood glucose concentrations (mg / dl) were determined at 0, 30, 60 and 120 min using a glucometer (FreeStyle Freedom Lite®, Abbot Laboratories) whose measurement is based on the glucose oxidase method, using a puncture in the queue. Total blood glucose levels of animals treated with ACG, CF and roasted coffee husk extract (ECCA) were lower than those detected in control animals during the 90 min after intake (see Figure 1A).

It should be noted that at 30 min of intake the total blood glucose levels of the rats treated with coffee roasted husk extract were significantly (p <0.05) lower compared to glucose levels in the control group ( see figure 1B).

The results indicate a hypoglycemic effect of roasted coffee husk extract in healthy individuals and an improvement in glucose tolerance.

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C) TESTS IN SICK RATS

Adult male Wistar rats weighing 150-200 g were used. The treatments and doses detailed below were administered using a rigid nasophalangeal tube for 35 days and a total of 8 rats per treatment:

• untreated (control group I: healthy)

• untreated (control group II: sick)

• Cafelna (CF) 5 mg / kg weight / day

• chlorogenic acid (ACG) 1.5 mg / kg weight / day

• chlorogenic acid (ACG) 10 mg / kg weight / day

• roasted coffee husk extract (ECCA) (140 mg / kg weight / dla)

In the case of the control groups, a dose of 1 ml of water was supplied. After 35 days of pretreatment, diabetes was induced by intraperitoneal injection of the agents streptozotocin (STZ) (65 mg / kg weight) and nicotinamide (250 mg / kg weight), in all groups except for control group I, continuing with the treatment for 8 more days, at which time the rats were anesthetized and saccharified.

STZ is a substance with specific cytotoxicity that destroys DD cells and causes a state of primary insulin deficiency in a dose in certain animal species such as Wistar rats and permanent diabetes (hyperglycemia) without causing damage to other organs. Nicotinamide protects animals against the cytotoxicity of STZ. The combined use of both chemical compounds allows to achieve a state of hyperglycemia and insulin resistance, just as happens in patients with type 2 diabetes mellitus.

Ketamine-xylazine was used as an anesthetic in a dose of 1 ml / kg of ketamine and 0.5 ml / kg of Xylazine intraperitoneally. The animals were kept calm for 3 min in darkness to favor the effect of anesthesia. When the animals had no reflex in the limb retraction followed by the relaxation of the abdominal muscles, the blood was extracted through a puncture in the heart that was collected in tubes with EDTA and centrifuged immediately (1800 xg for 15 min at 4 ° C) to obtain plasma samples. The liver was dissected, washed in ice-cold saline solution to remove blood, weighed and quickly frozen in liquid nitrogen. Plasma and liver were stored at -80 ° C until analysis.

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GLUCORREGULATOR AND ANTIDIABETOGENIC EFFECT

The treated rats, as indicated in section C), were monitored by the daily response of the total blood glucose levels after a 12-hour fast. The blood glucose was determined with a glucometer (FreeStyle Freedom Lite®, Abbot Laboratories) by tail puncture.

Example 3.1 Clinical response to the chemical induction of diabetes during the next 6 days

Glucose levels in diseased rats treated with ACG, CF and roasted coffee husk extract showed a different behavior than the rats subjected to the pathology-inducing chemical (control II). The clinical phase of hypoglycemia, characteristic of the model used, was not detected in any group of animals treated with coffee components and roasted coffee husk extract. Consequently, glucose levels after 24 h of disease induction were percentage higher in treated and healthy animals (control I) compared to those detected in control group II. The treatments with ACG 1.5 mg / kg and coffee husk 140 mg / kg caused a greater than 30% reduction in total blood glucose levels after 24 h of the STZ / nicotinamide injection and for the next 6 days of evolution of the disease (figure 2).

Example 3.2. Glucose tolerance 3 days after diabetes induction

Three days after the chemical induction of the pathology, an oral glucose tolerance analysis (OGTT) was carried out to confirm the diagnosis of the disease due to a decrease in the oral glucose tolerance and for this purpose it was proceeded as indicated in Example 2. The results are shown in Figure 3. On the other hand, the total blood glucose values of rats treated with a dose of ACG of 1.5 mg / kg or a dose of 140 mg / kg of husk of coffee was less than 200 mg / ml at all times tested and lower than those found in rats induced by diabetes and no disease prevention treatment was given (control II). Glucose tolerance in rats subjected to these treatments was not significantly different (p> 0.05) from that detected in animals that did not undergo chemical induction of diabetes (healthy rats).

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Example 3.3. Antidiabetogenic effect 8 days after diabetes induction

At the end of the test as described in section C), and following the diagnostic criteria of permanent hyperglycemia manifestation (> 110 mg / dl on an empty stomach) and low glucose tolerance (> 200 mg / dl at 90 and 120 min of intake) 37.5% of the animals treated with the inducing agent became ill (see figure 4). These results, expressed as a percentage, indicate a prevention of the diabetogenic effect of STZ per dose of ACG 1.5 mg / kg and roasted coffee husk extract 140 mg / kg, reducing the effectiveness of the chemical agent inducing diabetes in a 70% in both groups.

Example 3.4. Effect on insulin sensitivity indices 8 days after diabetes induction

At the end of the test as set forth in section C, plasma glucose levels were determined using a commercial kit (Spinreact, SA / SAU, Sant Esteve de Bas, Spain; Ref. 1001190) based on the method of glucose oxidase. Plasma insulin was determined by ELISA kit (Mercodia A.B, Uppsala, Sweden; Ref. 10-1250-01).

The evaluation of the homeostatic model or HOMA Insulin Resistance Index (HOMA-IR), of the function of beta cells (HOMA-P), and the Insulin Sensitivity Index (QUICKI) were calculated using the following formulas:

HOMA - IR =

, / mmo ^,. , uUL

glucose ^ —l—) xinsulin rmp

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HOMA - P =

20 x insulin i ")

glucose (mss!) _3 (5

QUICKI =

log insulin + log glucose (mg)

The calculation of the parameters for the group of diseased rats includes only those animals that meet the diagnostic criteria used in this document, that is, sustained hyperglycemia and blood glucose values in OGT> 200 mg / dl at 90 -120

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min intake and corresponding to 37.5% of the population treated with the disease-inducing agent according to example 3.3.

Table 1. Glucose, Insulin and Indices (HOMA-IR, HOMA-P and QUICKI) of the rats that took the husk extract and the sick rats of the prevention study. The mean ± SEM is represented. Statistical analysis using the t-Student test. Different letters show significant differences with p <0.05.

 Groups

 Glucose (mmol / L) Insulin (mIU / ml) HOMA-IR HOMA-P QUICKI

 Sick

 17,867 ± 2,796a 6.91 ± 0.98 8.60 ± 0.92a 9.67 ± 1.15a 0.295 ± 0.007a

 ECCA

 11,486 ± 0.388b 7.08 ± 0.91 3.30 ± 0.46b 15.87 ± 0.88b 0.321 ± 0.007b

Comparison of the results of glucose, insulin and Insulin Sensitivity Indices of the sick rats according to the diagnostic criteria indicated above and those treated with coffee roasted husk extract indicate that the extract exerts an effective glucorregulatory effect. Treatment with the extract caused a significant decrease in blood glucose levels, insulin resistance (HOMA-IR) and an improvement in pancreatic function (HOMA-P) and hormone sensitivity (QUICKI) .

Example 3.5 Ability to inhibit the activity of intestinal alpha-glucosidase

The ability to inhibit the activity of intestinal alpha-glucosidase was determined in vitro using a fluorimetric method. As a fluorogenic substrate, 4- mM 4- 4- methylunberiferone-alpha-D-glucopyranose was used and the assay was performed in a micro-method format. The enzymatic reaction was carried out in 0.1 M phosphate buffer pH 6.9 and using rat intestine alpha-glucosidase. As a reference substance, acarbose was used in a concentration range of 0.0001-25 mM which is considered the most effective inhibitor of the intestinal enzyme. The dose of roasted coffee husk extract supplied to the animals caused 100% inhibition of enzyme activity. Figure 5 shows the value of IC50 (mg / ml) for ACG and coffee roasted husk extract, respectively. Both products were effective inhibitors of enzymatic activity. In contrast, the concentrations of cafelna tested did not inhibit enzymatic activity in vitro.

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Consequently, it can be concluded that the extract can be used as a potential preventive agent of diabetes and hypoglycemic due, at least in part, to the inhibitory effect of the observed intestinal alpha-glucosidase observed.

Example 3.6. Effect on body weight

The animals were periodically weighed during the 6 weeks that the test lasted as described in section C). The results of the average body weight of each group at the end of the experiment are presented in Figure 6. A reduction in body weight was observed as a consequence of the development of the pathology. The results are in line with those described in previous studies that establish an association between body weight reduction and hyperglycemia (Lo et al. 2004. Life Science 74, 2897-908). Animals treated with roasted coffee husk extract 140 mg / kg had body weight values similar to those found in healthy individuals (control I) and significantly higher (p> 0.05) than those found in sick individuals without treatment (control I).

Example 3.7. Effect on liver weight

The relative weight of the liver was determined in proportion to the body weight to control the increase in organ weight as a result of hypertrophy due to the development of the pathology. After 6 weeks of treatment as described in section C), the organs were weighed after slaughter and their relative weight was calculated by dividing the weight of the organ (g) by the total weight of the animal at the end of the study (g). The results indicate that the treatments affect the relative weight of the liver (see figure 7) and may be due to the decrease in weight and the accumulation of triglycerides in the liver as a result of the chemically induced hyperglycemia. Values were found for healthy animals and treated with diabetes-inducing chemical agent and roasted coffee husk extract in a dose of 140 mg / kg similar (p> 0.05) and statistically lower (p <0.05) to animals patients who received no treatment. This result supports that the treatment with the extract improves or preserves the health of the animals avoiding the development of the pathology. The results are in accordance with those shown in Figure 4.

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LIPORREGULATOR EFFECT

Example 3.8. Effect on plasma cholesterol levels

For the determination of total cholesterol in plasma, a kit was used based on the enzymatic colorometric method of cholesterol esterase (Spinreact, S.A./S.A.U, Sant Esteve de Bas, Spain; Ref. 1001090). The chemical induction model of diabetes tested did not affect plasma cholesterol levels. The treatments with ACG (1.5 and 10 mg / kg, respectively) and roasted coffee husk extract significantly decreased (p <0.05) plasma cholesterol levels at the end of the experimental period as indicated in the section C) (see figure 8). The results suggest that roasted coffee husk extract has a liporegulatory potential and therefore preventive and therapeutic diseases related to dyslipidemia.

Example 3.9. Effect on plasma triglyceride levels

For the determination of triglycerides in plasma, a kit was used based on the hydrolysis of triglycerides and the subsequent determination of the released glycerol (Spinreact, S.A./S.A.U, Sant Esteve de Bas, Spain; Ref. 1001319). The chemical induction of diabetes caused a significant increase in plasma triglyceride levels in rats that received no treatment (p <0.05). The average plasma triglyceride levels found in control I (healthy) rats and treated with coffee components and coffee husk extract before and after the chemical induction of diabetes were of the same order of magnitude (p> 0.05) at end of the experimental period as indicated in section C) (see figure 9). The results suggest that roasted coffee husk extract has a preventive and therapeutic potential for hypertriglyceridemia and related pathologies. Consequently, the results described in the present example support the lip-regulating effect of coffee husk extract.

Example 3.10. Lipase inhibitor effect

The lipase inhibitory capacity of roasted coffee husk extract and its components (ACG and CF), at the concentrations tested in the in vivo study, was determined spectrophotometrically using reagents for such purposes marketed by the company Trinity Biotech (Procedure No. 805, Trinity Biotech, Jamestown, NY), according to the protocol by Girones-Vilaplana et al. (2013. International Journal

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of Food Sciences and Nutrition, 64, 897-906). The analysis revealed that the roasted coffee husk extract in the dose supplied to animals (140 mg / kg of weight) inhibited in 41.73% the activity of pancreatic lipase in vitro. The ACG at the concentrations tested (3.1 mg / ml) caused an inhibition of 30.70% of the enzymatic activity while the cafelna (1.56 mg / ml) was ineffective.

The results support that the preventive and therapeutic effect of the extract could be associated at least in part with its glucoregulatory and liporegulatory character due to its ability to inhibit the intestinal glucosidase and pancreatic lipase enzymes, respectively. On the other hand, they suggest that the particular composition of the extract is determinant of these activities. The observed effects cannot be attributed to a single compound.

Claims (9)

5 10 fifteen twenty 25 30 1.- Use of a bioactive product that is selected from a) roasted coffee husk, or b) an extract of roasted coffee husk (ECCA) comprising a minimum of 80 mg of chlorogenic acid (ACG) and 985 mg cafelna (CF) per 100 g of extract, in the elaboration of a useful composition for the prevention and treatment of at least one risk factor of the pathologies that make up the metabolic syndrome and that is selected from hyperglycemia, insulin resistance, dyslipidemia and obesity, or all of them in a way simultaneous. 2. - Use according to claim 1, characterized in that the composition is additionally useful for the prevention and treatment of at least one of the pathologies that make up the metabolic syndrome and that is selected from diabetes and cardiovascular pathologies associated with changes in the pattern of seric lipids, or both simultaneously. 3. - Use according to claim 2, characterized in that the diabetes is type 2 diabetes mellitus. 4. - Use according to any of claims 2 and 3, characterized in that the cardiovascular pathologies associated with changes in the pattern of seric lipids are vasculopaths. 5. - Use according to any of claims 1 to 4, characterized in that the composition is additionally useful for the prevention and treatment of metabolic syndrome. 6. - Use according to any one of claims 1 to 5, characterized in that the bioactive product is an extract of roasted coffee husk that is obtained by extraction with 2 volumes of water for each part of the husk, at a temperature of 100 ° C for a minimum of 10 minutes. 7. - Use according to any of claims 1 to 6, characterized in that the composition is a food supplement useful for prevention. 8. - Use according to any one of claims 1 to 6, characterized in that the composition 5 is a pharmaceutical composition useful for prevention and treatment. 9. - Use of a bioactive product as described in claim 1, as a technological aid to reduce the glycemic index in a food.