WO2016097450A1 - Use of products of the husk of coffee for the prevention and treatment of the diseases that form the metabolic syndrome and the risk factors thereof - Google Patents

Use of products of the husk of coffee for the prevention and treatment of the diseases that form the metabolic syndrome and the risk factors thereof Download PDF

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WO2016097450A1
WO2016097450A1 PCT/ES2015/070915 ES2015070915W WO2016097450A1 WO 2016097450 A1 WO2016097450 A1 WO 2016097450A1 ES 2015070915 W ES2015070915 W ES 2015070915W WO 2016097450 A1 WO2016097450 A1 WO 2016097450A1
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diabetes
prevention
treatment
metabolic syndrome
extract
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PCT/ES2015/070915
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Spanish (es)
French (fr)
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María Dolores DEL CASTILLO BILBAO
Beatriz FERNÁNDEZ GÓMEZ
Mónica ULLATE ARTIZ
María Dolores MESA GARCÍA
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Consejo Superior De Investigaciones Científicas (Csic)
Universidad De Granada
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/185—Magnoliopsida (dicotyledons)
    • A61K36/74—Rubiaceae (Madder family)

Definitions

  • 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 which, due to their liporregulatory and glucoregulatory activity, are useful for the prevention and treatment of the most important pathologies that make up the metabolic syndrome and its risk factors.
  • the metabolic syndrome is a conjunction in the same individual of several risk factors, among which are dyslipidemia, hyperglycemia, insulin resistance and obesity, which share pathophysiological mechanisms and that are often combined successively until degenerating in type 2 diabetes mellitus and cardiovascular complications associated with changes in the serum lipid pattern (Alegr ⁇ a et al. 2008. Rev Esp Carcf / o / 61, 7, 752-64).
  • the treatment of the pathologies that make up the metabolic syndrome is mainly carried out through poly-pharmacological treatments that act on its risk factors, and include among other glucorregulators and liporegulators.
  • Acarbose (oligosaccharide) and miglitol (monosaccharide) are oral antidiabetics often used in the treatment of patients with type 2 diabetes mellitus, which inhibit Intestinal alpha-glucosidase activity effectively reduces blood sugar levels and is used to establish greater glycemic control over hyperglycemia, particularly with respect to postprandial hyperglycemia.
  • Intestinal alpha-glucosidase activity effectively reduces blood sugar levels and is used to establish greater glycemic control over hyperglycemia, particularly with respect to postprandial hyperglycemia.
  • 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.
  • 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.
  • Coffee is 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 mucilage. More internally there is a small yellowish endocarp also called parchment.
  • silver skin also known as silverskin or coffee husk, covering each hemisphere of coffee beans (endosperm) (Esquivel et al. 2012.
  • Mullen et al. 2011. Journal of Agricultural and Food Chemistry 59, 8, 3754-3762 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 diabetes Type 2 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 a fuel or fertilizer (Machado et al. 2012. Biochemical Engineering Journal 60, 87-90).
  • 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 higher pressures, higher in Any case at 2000 bar.
  • WO2013004873 A1 and of which the present invention claims inventive material 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 caffeine that confer antioxidant activity and that allows related uses, with the prevention of physiological aging, of pathological processes related to age or oxidative stress, and as a food preservative.
  • the present invention relates, in different aspects, to the use of a bioactive product that is selected from, a) roasted coffee husk, or b) a roasted coffee husk extract (ECCA) comprising a minimum of 80 mg of chlorogenic acid (ACG) and 985 mg of caffeine (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 that are selected from hyperglycemia, insulin resistance, dyslipidemia and obesity,
  • ECCA roasted coffee husk extract
  • ACG chlorogenic acid
  • CF caffeine
  • the diabetes is type 2 diabetes mellitus.
  • the cardiovascular pathologies associated with changes in the serum lipid pattern are vasculopathies.
  • the bioactive product is a roasted coffee husk extract (ECCA), which comprises a minimum of 80 mg of chlorogenic acid (ACG) and 985 mg of caffeine (CF) per 100 g of extract, and which is obtained by extraction with 2 volumes of water for each part of husk, at a temperature of 100 ° C for a minimum of 10 minutes.
  • ECCA roasted coffee husk extract
  • 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.
  • the invention also relates to the use of the bioactive product as a technological adjuvant to reduce the glycemic index in a food.
  • bioactive product of the invention is understood interchangeably: a) the roasted coffee husk, or b) a roasted coffee husk extract (ECCA) comprising a minimum of 80 mg of chlorogenic acid (ACG) and 985 mg caffeine (CF) per 100 g of extract.
  • ECCA roasted coffee husk extract
  • 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.
  • the extraction is carried out with: i) 2 volumes of water for each part of the scale, 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 / day of roasted coffee husk extract comprising a minimum of 80 mg of chlorogenic acid and 985 mg of caffeine 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).
  • the roasted coffee husk extract also has a hypoglycemic and improved ability to orally tolerate glucose in a statistically significant way in a model of healthy adult Wistar rats when co-administered with a glucose load (see example 2).
  • Cardiovascular disease associated with changes in the pattern of serum lipids is understood to be preferably vasculopathies, initially subclinical and finally manifested in the form of botanical disorders that occur as a result of the change in lipid metabolism associated with diabetes. and metabolic syndrome.
  • Heyperglycemia means high blood glucose levels.
  • Insulin resistance means high levels of insulin in the blood.
  • Dyslipidemia means high levels of cholesterol (hypercholesterolemia), triglycerides (hypertriglyceridemia), low density lipoproteins (LDL-C) and low levels of high density lipoproteins (HDL-C) in plasma.
  • 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.
  • the nutritional supplement is additionally useful for the prevention of metabolic syndrome.
  • the invention relates 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.
  • the enriched food and the nutritional supplement of the invention can be used directly, or as an ingredient of another food comprising it.
  • 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.
  • the nutritional supplement of the invention or the 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 serum lipids, or both simultaneously.
  • the pathologies are diabetes and vasculopathies. More preferably diabetes is type 2 diabetes mellitus.
  • the nutritional supplement of the invention or the fortified food are additionally useful for the prevention of metabolic syndrome.
  • 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 diabetes and cardiovascular pathologies associated with changes in the serum lipid pattern, or both simultaneously.
  • the pathologies are diabetes and vasculopathies. More preferably diabetes is type 2 diabetes mellitus.
  • the pharmaceutical composition is additionally useful for the prevention and treatment of metabolic syndrome.
  • the “carrier” or carrier is preferably an inert substance in order to facilitate the incorporation of other compounds, allow better dosing and administration or give consistency and form to the pharmaceutical composition. Therefore, the carrier is a substance that is used to dilute any of the components of the pharmaceutical composition of the present invention to a given volume or weight; or that even undiluted said components is capable of allowing a better dosage and administration or give consistency and form to the medicine.
  • the pharmaceutically acceptable carrier 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 for 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 can also be adapted for parenteral administration, in the form of, for example, sterile lyophilized solutions, suspensions or products, in the appropriate dosage form; in this case, said pharmaceutical compositions will include suitable excipients, such as buffers, surfactants, etc.
  • the excipients will be chosen based 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 "Treaty of Pharmacy Galenica", by C. Faul ⁇ i Trillo, 10 Edition, 1993, Luzán 5, S.A. of Editions, or in any book of similar characteristics that exists in each country.
  • the pharmaceutical compositions that fall within the scope of this invention comprise at least one other active ingredient.
  • the active ingredients that are 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 the pathologies of the metabolic syndrome, its risk factors or of metabolic syndrome.
  • bioactive product of the invention and the pharmaceutical composition of the invention for prevention and prevention are included in the scope of the present invention. treatment of the pathologies that make up the metabolic syndrome of its risk factors and metabolic syndrome, as defined herein.
  • treatment method is understood as 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.
  • subject means a member of an animal species, preferably a mammal, 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, male or female, of any race or age.
  • the characteristics of the bioactive product of the invention also allow a reduced glycemic index to be used as a technological aid in food preparation.
  • FIG. 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.
  • FIG. 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 coffee roasted husk extract according to example 3.5.
  • FIG. 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 intraperitoneal nicotinamide .
  • FIG. 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.
  • EMBODIMENTS OF THE INVENTION A) OBTAINING THE EXTRACT Example 1.
  • ECCA roasted coffee husk extract
  • 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 performed 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.
  • Each of the 12 rats was sequentially applied 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.
  • 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, by 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 1 A). 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 1 B).
  • STZ is a substance with specific cytotoxicity that destroys 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.
  • the blood was extracted by means of 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.
  • Glucose levels in sick 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 induction of the disease 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 the induction of diabetes
  • an oral glucose tolerance test (OGTT) was performed to confirm the diagnosis of the disease due to a decrease in the oral glucose tolerance and for this purpose, the procedure was performed as indicated in Example 2. The results are shown in Figure 3.
  • the total blood glucose values of rats treated with an ACG dose 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).
  • Example 3.3 Antidiabetogenic effect 8 days after the induction of diabetes At the end of the trial as described in section C), and following the diagnostic criteria for the manifestation of permanent hyperglycemia (> 110 mg / dl on an empty stomach) and low tolerance to glucose (> 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).
  • results which are expressed as a percentage, indicate a prevention of the diabetogenic effect of STZ by a dose of 1.5 mg / kg ACG 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
  • Plasma glucose levels were determined using a commercial kit (Spinreact, SA / SAU, Sant Esteve de Bas, Spain; Ref. 1001 190) based on the glucose oxidase method.
  • the Plasma insulin was determined by ELISA kit (Mercodia AB, Uppsala, Sweden; Ref. 10-1250-01).
  • HOMA-IR homeostatic model
  • beta cell function beta- ⁇
  • insulin sensitivity index QUICKI
  • the calculation of the parameters for the group of diseased rats includes only those animals that meet the diagnostic criteria of diabetes used in this document, that is, sustained hyperglycemia and blood glucose values in OGTT> 200 mg / dl at 90 -120 min of intake and corresponding to 37.5% of the population treated with the disease-inducing agent according to example 3.3.
  • the ability to inhibit intestinal alpha-glucosidase activity was determined in vitro using a fluorimetric method.
  • a fluorogenic substrate 0.2 mM 4- methylunberiferone-alpha-D-glucopyranoside was used and the assay was performed in micro-method format.
  • the enzymatic reaction was carried out in 0.1 M phosphate buffer pH 6.9 and using rat intestine alpha-glucosidase.
  • 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 caffeine tested did not inhibit enzyme activity in vitro.
  • 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.
  • 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.
  • 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 weight loss and the accumulation of triglycerides in the liver as a result of chemically induced hyperglycemia.
  • triglycerides in plasma For the determination of triglycerides in plasma, a kit was used based on the hydrolysis of triglycerides and the subsequent determination of glycerol released (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 the 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 the coffee husk extract.

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Abstract

The invention relates to the use of products of the husk of toasted coffee, which, as a result of their particular composition of chlorogenic acid and caffeine, provide an important glucoregulatory and liporegulatory activity, which convert same into an excellent alternative for the prevention and treatment of the metabolic syndrome, given that they are effective simultaneously against the main diseases that form same and the risk factors thereof.

Description

USO DE PRODUCTOS DE LA CASCARILLA DE CAFÉ PARA LA PREVENCIÓN Y TRATAMIENTO DE LAS PATOLOGÍAS QUE CONFORMAN EL SÍNDROME METABÓLICO Y DE SUS FACTORES DE RIESGO DESCRIPCIÓN  USE OF COFFEE HAND PRODUCTS FOR THE PREVENTION AND TREATMENT OF PATHOLOGIES THAT CONFORM THE METABOLIC SYNDROME AND ITS RISK FACTORS DESCRIPTION
SECTOR DE LA INVENCION SECTOR OF THE INVENTION
La presente invención pertenece al sector de la industria alimentaria y farmacéutica. Más concretamente, se enmarca dentro del campo de los alimentos, de los suplementos alimenticios y de las formulaciones farmacéuticas que comprenden subproductos naturales del café, y que por su actividad liporreguladora y glucorreguladora son útiles para la prevención y tratamiento de las patologías más importantes que conforman el síndrome metabólico y de sus factores de riesgo. 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 which, due to their liporregulatory and glucoregulatory activity, are useful for the prevention and treatment of the most important pathologies that make up the metabolic syndrome and its risk factors.
ESTADO DE LA TECNICA STATE OF THE TECHNIQUE
El síndrome metabólico es una conjunción en un mismo individuo de diversos factores de riesgo, entre los que se encuentran la dislipidemia, la hiperglucemia, la resistencia a la insulina y la obesidad, que comparten mecanismos patofisiológicos y que con frecuencia se van combinando sucesivamente hasta degenerar en diabetes mellitus tipo 2 y complicaciones cardiovasculares asociadas a cambios en el patrón de los lípidos séricos (Alegría et al. 2008. Rev Esp Carcf/o/ 61 , 7, 752-64). El tratamiento de las patologías que conforman el síndrome metabólico se lleva a cabo fundamentalmente a través de tratamientos poli-farmacológicos que actúan sobre sus factores de riesgo, e incluyen entre otros glucorreguladores y liporreguladores. The metabolic syndrome is a conjunction in the same individual of several risk factors, among which are dyslipidemia, hyperglycemia, insulin resistance and obesity, which share pathophysiological mechanisms and that are often combined successively until degenerating in type 2 diabetes mellitus and cardiovascular complications associated with changes in the serum lipid pattern (Alegría et al. 2008. Rev Esp Carcf / o / 61, 7, 752-64). The treatment of the pathologies that make up the metabolic syndrome is mainly carried out through poly-pharmacological treatments that act on its risk factors, and include among other glucorregulators and liporegulators.
El objetivo de los tratamientos glucorreguladores es reducir las cifras de la glucemia basal, la hemoglobina glucosilada -HbA1 c- (< 7%) y la glucemia postprandial. Entre los fármacos glucorreguladores más aplicables destacan la acarbosa, el miglitol, la metformina y las glitazonas. The goal of glucoregulatory treatments is to reduce the levels of basal glycemia, glycosylated hemoglobin -HbA1 c- (<7%) and postprandial glycemia. The most applicable glucorregulatory drugs include acarbose, miglitol, metformin and glitazones.
La acarbosa (oligosacárido) y el miglitol (monosacárido) son antidiabéticos orales de uso frecuente en el tratamiento de pacientes con diabetes mellitus tipo 2, que inhiben la actividad de la alfa-glucosidasa intestinal, reducen de manera efectiva los niveles de azúcar en sangre y se utilizan para establecer un mayor control glucémico sobre la hiperglucemia, en particular con respecto a la hiperglucemia postprandial. Sin embargo, pueden provocar efectos secundarios gastrointestinales tales como flatulencia y diarrea. Acarbose (oligosaccharide) and miglitol (monosaccharide) are oral antidiabetics often used in the treatment of patients with type 2 diabetes mellitus, which inhibit Intestinal alpha-glucosidase activity effectively reduces blood sugar levels and is used to establish greater glycemic control over hyperglycemia, particularly with respect to postprandial hyperglycemia. However, they can cause gastrointestinal side effects such as flatulence and diarrhea.
El objetivo de los tratamiento liporreguladores es mantener los niveles de lípidos en sangre dentro de los rangos de normalidad (LDL < 100 mg/dl, HDL > 40 mg/dl en hombres y > 50 mg/dl en mujeres y triglicéridos < 150 mg/dl). Un paso esencial en el tratamiento de la dislipidemia en pacientes con obesidad, diabetes y síndrome metabólico es la pérdida de peso, que ha demostrado causar numerosos efectos beneficiosos tales como la mejora del perfil lipídico. Los tratamientos para el control de la obesidad utilizan fármacos como el orlistat que es un inhibidor de la lipasa pancreática que divide triglicéridos en ácidos grasos y monoacilglicerol absorbibles. Otros tratamientos liporreguladores conllevan la administración de estatinas que reducen las cifras de LDL, aunque pueden causar daño hepático, pérdida de memoria, riesgo de diabetes y daño macular; o la administración de fibratos, particularmente el fenofibrato, que se consideran más eficaces que las estatinas para reducir los triglicéridos y aumentar las HDL, debido a su efecto agonista PPARa, aunque este fármaco puede causar los mismos efectos adversos que otros hipolipemiantes tales como fallo hepático y renal, toxicidad muscular y pancreatitis. 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 lip-regulating 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.
La combinación de varios fármacos en un mismo sujeto implica una importante complejidad derivada de la correcta prescripción y de los posibles efectos adversos cruzados entre tratamientos. 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.
Por otra parte, la prevención de las patologías que conforman el síndrome metabólico y de sus factores de riesgo se lleva a cabo fundamentalmente a través de: a) el mantenimiento de hábitos de vida saludable (por ejemplo con aumento de la actividad física y con disminución en la ingesta calórica); o b) el consumo de alimentos funcionales o suplementos alimenticios que comprenden compuestos bioactivos beneficiosos para la salud. 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 lifestyle habits (for example, with increased physical activity and decreased in caloric intake); or b) the consumption of functional foods or nutritional supplements comprising bioactive compounds beneficial to health.
Dentro de los alimentos funcionales o suplementos alimenticios, es conocida una formulación que comprende un extracto de dos productos que son la canela y el café, rica en compuestos fenólicos con actividad antioxidante, que según sus inventores provoca un efecto sinérgico que podría dotarlo de capacidad para reducir la incidencia del síndrome metabólico, de las enfermedades asociadas y de sus factores de riesgo (WO2009018648 A1), aunque en el documento en cuestión no se incluyen ejemplos demostrativos. Within functional foods or nutritional supplements, a formulation comprising an extract of two products that are cinnamon and coffee is known, 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 in the document in question Demonstrative examples are not included.
También es conocido el uso de un flavonoide presente en un extracto de la planta de rooibos como la aspalatina (WO2008110551 A1), que solo o combinado con otro flavonoide como la rutina con procedencia en la misma planta, provocan una disminución de la glucosa en sangre, motivo por el cual se considera útil para la prevención y tratamiento de la diabetes. It is also known to use a flavonoid present in an extract of the rooibos plant such as aspalatine (WO2008110551 A1), which alone or combined 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.
El café suscita un interés creciente en la actualidad debido a los compuestos bioactivos de muy distinta naturaleza que comprenden las distintas partes que lo componen. El fruto del café consiste en una capa fina exterior o pericarpio, usualmente verde en frutos inmaduros pero que luego se torna rojo-violeta o rojo intenso cuando madura. El pericarpio cubre la pulpa o la capa externa del mesocarpio que es amarillento, fibroso y dulce. A continuación del pericarpio hay una capa delgada, traslucida, viscosa y muy hidratada de mucílago. Más internamente hay un pequeño endocarpio amarillento también llamado pergamino. Finalmente, se encuentra la piel de plata, también conocida por silverskin o cascarilla de café, cubriendo cada hemisferio de los granos de café (endospermo) (Esquivel et al. 2012. Food Research International 46, 2, 488-495). Al consumo moderado de la bebida de café se le asocian potenciales efectos beneficiosos sobre la salud tales como la reducción del nivel de glucosa en plasma y del riesgo de diabetes tipo 2 (Dorea et al. 2005. British Journal of Nutrition 93, 773-782 y Ranheim et al. 2005. Molecular Nutrition & Food Research 49, 3, 274-284). Aunque hay indicios que parecen relacionar los anteriormente indicados efectos saludables con la presencia de determinados compuestos en el café, como el ácido clorogénico, otros estudios como el de Tuomlehto et al. (2004. JAMA 29, 10, 1213-1219) y Pereira et al. (2006. Archives of Interna! Medicine 166, 12, 131 1-1316) cuestionan dicha idea e indican que no es posible establecer ninguna relación causal. Por su parte, Mullen et al. (2011. Journal of Agricultural and Food Chemistry 59, 8, 3754-3762) indican que adicionalmente al ácido clorogénico, en el grano de café entero no sometido a tostado se encuentran otros antioxidantes que de forma combinada presentan capacidad para reducir la incidencia de diabetes tipo 2 y el riesgo cardiovascular. Coffee is 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 mucilage. More 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 Interna! Medicine 166, 12, 131 1-1316) question this idea and indicate that it is not possible to establish a causal relationship. On the other hand, Mullen et al. (2011. Journal of Agricultural and Food Chemistry 59, 8, 3754-3762) 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 diabetes Type 2 and cardiovascular risk.
La cascarilla de café constituye el único subproducto del proceso de tostado que tras dicho tratamiento o bien se desecha o bien se utiliza como combustible o fertilizante (Machado et al. 2012. Biochemical Engineering Journal 60, 87-90). The coffee husk constitutes the only by-product of the roasting process that after such treatment is either discarded or used as a fuel or fertilizer (Machado et al. 2012. Biochemical Engineering Journal 60, 87-90).
Se conocen documentos que recomiendan el uso de esta cascarilla de café tostado como alimento funcional debido a su alto contenido en fibra, bajo contenido en grasas y azúcares reductores y marcada actividad antioxidante relacionada con las melanoidinas formadas durante el proceso de tostado del grano (Esquivel et al. 2012. Food Research International 46, 2, 488-495). 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 the melanoidins formed during the process of roasting the grain (Esquivel et to 2012. Food Research International 46, 2, 488-495).
Por otra parte, hay trabajos (Murthy et al. 2012. Food and Bioprocess Technology 5, 3, 897-903) que señalan la presencia de compuestos fenólicos en extractos de la cascarilla de café tostado obtenidos usando un disolvente orgánico como el isopropanol, y que presentan efectos en la reducción de las especies reactivas de oxígeno y los radicales libres y que según estos mismos autores podrían conferirle actividad antimutagénica, anticarcinogénica, antiglucémica y antioxidante. On the other hand, there are papers (Murthy et al. 2012. Food and Bioprocess Technology 5, 3, 897-903) that indicate the presence of phenolic compounds in roasted coffee husk extracts obtained using an organic solvent such as isopropanol, and that have 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.
También y dentro de la literatura patente, el documento WO2013103465 A1 se refiere a métodos mejorados para producir extractos con sustancias antioxidantes y otros compuestos promotores de la salud a partir del café o subproductos que incluyen la cascarilla y que se obtienen utilizando presiones elevadas, superiores en todo caso a 2000 bar. Finalmente, el documento WO2013004873 A1 y del que la presente invención reivindica materia inventiva, se refiere a un producto que procede de la cascarilla del café tostado o que es un extracto del mismo y que se caracteriza por comprender unos contenidos mínimos de ácido clorogénico y de cafeína que le confieren actividad antioxidante y que le permite usos relacionados, con la prevención de procesos de envejecimiento fisiológico, de procesos patológicos relacionados con la edad o el estrés oxidativo, y como conservante alimentario. 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 higher pressures, higher in Any case at 2000 bar. Finally, WO2013004873 A1 and of which the present invention claims inventive material, 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 caffeine that confer antioxidant activity and that allows related uses, with the prevention of physiological aging, of pathological processes related to age or oxidative stress, and as a food preservative.
A mayor abundamiento, estudios posteriores que utilizan el extracto de cascarilla de café que se reivindica en el documento WO2013004873 A1 , indican que el consumo de dicho extracto: To a greater extent, subsequent studies using the coffee husk extract claimed in WO2013004873 A1, indicate that the consumption of said extract:
- permite una reducción de la acumulación de grasa corporal en Caenorhabditis elegans, pero sin establecer ninguna relación con el perfil de lípidos sanguíneo (Martinez-Saez et al. 2014. Food Chemistry 150, 227-234), y - 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
- presenta capacidad para inhibir la formación in vitro de productos avanzados de la glicación de proteínas también denominados AGEs (Mesías et al. 2014. Food Research International 62, 1120-1 126). El consumo de AGEs de la dieta y su formación in vivo se asocian con desordenes de la salud como las complicaciones de la diabetes, la ateroesclerosis y Alzheimer. - It has the capacity to inhibit the in vitro formation of advanced protein glycation products also called AGEs (Messiah et al. 2014. Food Research International 62, 1120-1 126). The consumption of AGEs from the diet and its in vivo training are associated with health disorders such as complications of diabetes, atherosclerosis and Alzheimer's.
En base a lo anterior, se considera de interés la búsqueda de soluciones para la prevención y el tratamiento efectivos de las patologías que conforman el síndrome metabólico y de sus factores de riesgo, a través de fuentes naturales saludables. Based on the above, it is considered of interest to find solutions for the effective prevention and treatment of the pathologies that make up the metabolic syndrome and its risk factors, through healthy natural sources.
DESCRIPCIÓN DE LA INVENCION DESCRIPTION OF THE INVENTION
BREVE DESCRIPCIÓN La presente invención se refiere, a lo largo de diferentes aspectos, al uso de un producto bioactivo que se selecciona de entre, a) cascarilla tostada del café, o b) un extracto de cascarilla tostada de café (ECCA) que comprende un mínimo de 80 mg de ácido clorogénico (ACG) y 985 mg cafeína (CF) por cada 100 g de extracto, en la elaboración de una composición que se selecciona de entre un suplemento alimenticio o una composición farmacéutica y que es útil para la prevención y tratamiento: - de los factores de riesgo de las patologías que conforman el síndrome metabólico y que se seleccionan de entre hiperglucemia, resistencia a la insulina, dislipidemia y obesidad, BRIEF DESCRIPTION The present invention relates, in different aspects, to the use of a bioactive product that is selected from, a) roasted coffee husk, or b) a roasted coffee husk extract (ECCA) comprising a minimum of 80 mg of chlorogenic acid (ACG) and 985 mg of caffeine (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 that are selected from hyperglycemia, insulin resistance, dyslipidemia and obesity,
- de las patologías que conforman el síndrome metabólico y que se seleccionan de entre diabetes y patologías cardiovasculares asociadas a cambios en el patrón de los lípidos séricos, y - del síndrome metabólico, - of the pathologies that make up the metabolic syndrome and that are selected from diabetes and cardiovascular pathologies associated with changes in the serum lipid pattern, and - of the metabolic syndrome,
Preferentemente la diabetes es diabetes mellitus tipo 2. También preferentemente, las patologías cardiovasculares asociadas a cambios en el patrón de los lípidos séricos, son vasculopatías. Preferably the diabetes is type 2 diabetes mellitus. Also preferably, the cardiovascular pathologies associated with changes in the serum lipid pattern are vasculopathies.
Preferentemente el producto bioactivo es un extracto de cascarilla tostada de café (ECCA), que comprende un mínimo de 80 mg de ácido clorogénico (ACG) y 985 mg cafeína (CF) por cada 100 g de extracto, y que se obtiene por extracción con 2 volúmenes de agua por cada parte de cascarilla, a una temperatura de 100 °C durante un mínimo de 10 minutos. Preferably the bioactive product is a roasted coffee husk extract (ECCA), which comprises a minimum of 80 mg of chlorogenic acid (ACG) and 985 mg of caffeine (CF) per 100 g of extract, and which is obtained by extraction with 2 volumes of water for each part of husk, at a temperature of 100 ° C for a minimum of 10 minutes.
En otros aspectos, la invención se refiere al suplemento alimenticio, o a la composición farmacéutica que comprende al producto bioactivo y que son útiles para la prevención y tratamiento de las patologías que conforman el síndrome metabólico, de sus factores de riesgo y del síndrome metabólico. 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.
En un último aspecto, la invención también se refiere al uso del producto bioactivo como coadyuvante tecnológico para reducir el índice glucémico en un alimento. DESCRIPCION DETALLADA DE LA INVENCION In a final aspect, the invention also relates to the use of the bioactive product as a technological adjuvant to reduce the glycemic index in a food. DETAILED DESCRIPTION OF THE INVENTION
El problema técnico que resuelve la presente invención es la búsqueda de una alternativa para la prevención y tratamiento de las principales patologías de un desorden multifactorial como el síndrome metabólico y de sus factores de riesgo, utilizando un producto natural, en este caso el producto derivado de la cascarilla del café que se reivindica en la solicitud WO2013004873 A1 publicada con fecha 3 de enero de 2013 (con origen en la solicitud de prioridad ES2012/070490 de fecha 4 de julio 2011), en adelante producto bioactivo de la invención. En el presente documento por "producto bioactivo de la invención" se entiende indistintamente: a) la cascarilla tostada del café, o b) un extracto de cascarilla tostada de café (ECCA) que comprende un mínimo de 80 mg de ácido clorogénico (ACG) y 985 mg cafeína (CF) por cada 100 g de extracto. 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 husk of coffee claimed in application WO2013004873 A1 published on January 3, 2013 (originating from priority application ES2012 / 070490 dated July 4, 2011), hereinafter referred to as the bioactive product of the invention. In this document, "bioactive product of the invention" is understood interchangeably: a) the roasted coffee husk, or b) a roasted coffee husk extract (ECCA) comprising a minimum of 80 mg of chlorogenic acid (ACG) and 985 mg caffeine (CF) per 100 g of extract.
La cascarilla tostada del café del apartado a) es la cascarilla en polvo o la cascarilla de café entera de variedades como, por ejemplo y sin limitarse, Arábica, Robusta o sus mezclas y que han sufrido un proceso de tostado. 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.
El extracto de cascarilla tostada de café del apartado b), es el producto del apartado a) que se somete a una extracción que puede tener lugar mediante hidrólisis enzimática, ruptura celular empleando procedimientos mecánicos a temperatura ambiente, extracción con agua caliente, o extracción con el empleo de condiciones de agua subcrítica y/o supercrítica. Preferentemente la extracción se lleva a cabo con: i) 2 volúmenes de agua por cada parte de cascarilla, a una temperatura de 100°C durante un mínimo de 10 minutos, o ii) con agua subcrítica a temperaturas comprendidas entre 50 y 200°C, manteniendo un tiempo de extracción estático constante de 20 minutos y una presión de entre 103 y 207 psi, preferentemente 103 bar. 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 for each part of the scale, 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.
La cascarilla de café cuando está en forma de polvo se obtiene con ayuda de un molino y empleando nitrógeno líquido para evitar modificaciones de sus compuestos bioactivos. La presente invención se basa en la observación de que la administración de una dosis de 140 mg/kg/día de extracto de cascarilla tostada de café que comprende un mínimo de 80 mg de ácido clorogénico y 985 mg cafeína por cada 100 g de extracto durante un período mínimo de 35 días en un modelo de ratas Wistar adultas en las que se induce diabetes mellitus tipo 2, produce simultáneamente efecto glucorregulador, hipoglucemiante y antidiabetogénico (ver ejemplos 3.1 , 3.2, 3.3, 3.5, 3.6 y 3.7), efecto liporregulador (ver ejemplos 3.8, 3.9 y 3.10) y disminuye la resistencia a la insulina (ver ejemplo 3.4). Adicionalmente, el extracto de cascarilla tostada de café también presenta capacidad hipoglucemiante y mejoradora de la tolerancia oral a la glucosa de forma significativamente estadística en un modelo de ratas Wistar adultas sanas cuando se administra conjuntamente con una carga de glucosa (ver ejemplo 2). Los efectos anteriormente reseñados, y que tienen su base en la especificidad de la composición, sientan las bases para el uso del producto bioactivo de la invención en la prevención y tratamiento de la diabetes y de patologías cardiovasculares asociadas a cambios en el patrón de los lípidos séricos y de sus factores de riesgo, y por ende del síndrome metabólico. 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 / day of roasted coffee husk extract comprising a minimum of 80 mg of chlorogenic acid and 985 mg of caffeine 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 and improved ability to orally tolerate glucose in a statistically significant way in a model of healthy adult Wistar rats when co-administered with a glucose load (see example 2). The effects described 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 changes in the lipid pattern serum and its risk factors, and hence the metabolic syndrome.
Por "síndrome metabólico" se entiende un desorden multifactorial en el que confluyen varios factores de riesgo que aumentan la probabilidad de padecer determinadas patologías como enfermedades cardiovasculares asociadas a cambios en el patrón de los lípidos séricos o diabetes mellitus. Tanto las patologías como los factores de riesgo pueden aparecer de forma simultánea o secuencial en un mismo individuo y permiten identificar este síndrome, además están directamente interrelacionadas, de tal modo que comparten mecanismos de aparición y evolución y con frecuencia se van combinando sucesivamente. Factores de riesgo que se incluyen dentro del ámbito de esta invención son, hiperglucemia, resistencia a la insulina, dislipidemia y obesidad. "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 serum 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.
Se entiende por "diabetes mellitus" o "diabetes" una enfermedad o afección que se caracteriza generalmente por anomalías metabólicas en la producción y utilización de glucosa que resulta en la ineficacia para mantener los niveles de azúcar en sangre dentro del rango de normalidad. El resultado de estas anomalías es glucosa en sangre elevada que se denomina "hiperglucemia." Las dos formas principales de diabetes son diabetes tipo 1 y diabetes tipo 2. La diabetes tipo 1 es generalmente el resultado de un fallo en el páncreas que deriva en una falta de producción absoluta de insulina, la hormona que regula la entrada de la glucosa por las células. La diabetes tipo 2 puede presentar niveles normales o incluso elevados de insulina y puede ser resultado de la incapacidad de los tejidos para responder de forma apropiada a la insulina. La mayoría de los pacientes diabéticos tipo 2 son resistentes a la insulina y tienen una deficiencia relativa de insulina, que consiste en que la secreción de insulina no puede compensar la resistencia de los tejidos periféricos a responder a la insulina. Los pacientes diabéticos tipo 2, con frecuencia, son obesos. Otros tipos de trastornos de la homeostasis de la glucosa incluyen intolerancia a la glucosa que es una etapa metabólica intermedia entre la homeostasis de la glucosa normal y la diabetes. La diabetes mellitus es un síndrome orgánico multisistémico que tiene como característica el aumento de los niveles de glucosa en sangre o hiperglucemia, resultado de efectos en la secreción de insulina, en su acción o ambos. Se trata de una compleja enfermedad en la que coexiste un trastorno global del metabolismo de los carbohidratos, grasas y proteínas. Es multifactorial por la existencia de múltiples factores implicados en su patogénesis. "Diabetes mellitus" or "diabetes" is understood as a disease or condition that is generally characterized by metabolic abnormalities in the production and use 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 generally 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 into 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. Most 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 insulin secretion, its action or both. It is a complex disease in which a global disorder of the metabolism of carbohydrates, fats and proteins coexists. It is multifactorial due to the existence of multiple factors involved in its pathogenesis.
Se entiende por "enfermedad cardiovascular asociada a cambios en el patrón de los lípidos séricos" preferentemente a las vasculopatías, inicialmente subclínicas y finalmente manifiestas en forma de complicaciones ate rotrom boticas que tienen lugar como consecuencia del cambio del metabolismo de los lípidos asociado a la diabetes y síndrome metabólico. Por "hiperglucemia" se entiende niveles elevados de glucosa en sangre. Por "resistencia a la insulina" se entiende niveles elevados de insulina en sangre. Por "dislipidemia" se entiende elevados niveles de colesterol (hipercolesterolemia), triglicéridos (hipertrigliceridemia), lipoproteínas de baja densidad (LDL-C) y bajos niveles de lipoproteínas de alta densidad (HDL-C) en plasma. Por "obesidad" se entiende un exceso de adiposidad corporal que se determina en base al índice de masa corporal (IMC >30) en individuos metabólicamente sanos y enfermos. Se incluye además en este concepto al fenotipo correspondiente a individuos con peso normal pero metabólicamente obesos; es decir, tienen un IMC normal pero presentan alteraciones típicas de los pacientes obesos: resistencia a la insulina, adiposidad central, bajas cifras de colesterol de las lipoproteínas de alta densidad (HDL-C) y elevadas concentraciones de triglicéridos, así como hipertensión arterial (HTA). "Cardiovascular disease associated with changes in the pattern of serum lipids" is understood to be preferably vasculopathies, initially subclinical and finally manifested in the form of botanical disorders that occur as a result of the change in lipid metabolism associated with diabetes. and metabolic syndrome. "Hyperglycemia" means high blood glucose levels. "Insulin resistance" means high levels of insulin in the blood. "Dyslipidemia" means high levels of cholesterol (hypercholesterolemia), triglycerides (hypertriglyceridemia), low density lipoproteins (LDL-C) and low levels of high density lipoproteins (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 present typical alterations of obese patients: insulin resistance, adiposity central, low cholesterol levels of high density lipoproteins (HDL-C) and high concentrations of triglycerides, as well as arterial hypertension (AHT).
La resistencia a la insulina implica que los tejidos del cuerpo se vuelven insensibles a los efectos de la insulina, por lo que la glucosa no puede entrar en las células y se acumula en sangre. Los pacientes con diabetes mellitus tipo 2 y los intolerantes a la glucosa sufren resistencia a la insulina. Inicialmente la resistencia a la insulina es moderada y la intolerancia a la glucosa es asimétrica pero conlleva un riesgo muy alto de desarrollar diabetes tipo 2 en el futuro. La intolerancia a la glucosa puede durar 7- 10 años antes de que aparezca la diabetes tipo 2. 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.
La principal ventaja técnica de la presente invención estriba en la utilización de un producto bioactivo obtenido a partir de un único material residual que es la cascarilla de café, y que permite actuar simultáneamente frente a las patologías que conforman el síndrome metabólico y sus factores de riesgo. 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 simultaneous action against the pathologies that make up the metabolic syndrome and its risk factors .
Aunque son conocidos los efectos beneficiosos del consumo de la bebida del café sobre alteraciones como el nivel de glucosa en plasma, la diabetes tipo 2 o el riesgo cardiovascular, como ya se ha indicado en el estado de la técnica, el grano de café está conformado por múltiples partes que se caracterizan por comprender muy diversos compuestos que pueden ser o no ser bioactivos. 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 prior art, the coffee bean is shaped by multiple parts that are characterized by comprising very diverse compounds that may or may not be bioactive.
Por otra parte, los procedimientos de obtención de extractos influyen de forma determinante sobre los compuestos que se trasladan a dicho extracto, de tal modo que el solvente utilizado y las condiciones de extracción (temperatura, presión, etc.) hacen que los extractos presenten composiciones diferentes, con distintas concentraciones de los compuestos bioactivos y con formas más o menos activas de los compuestos. 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.
Finalmente, es también necesario considerar que el proceso de tostado tiene un efecto dramático en la composición de las diferentes partes del café y especialmente de la cascarilla de café. 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.
Los resultados que se incluyen en los ejemplos de este documento, en los que se muestra también la actividad del ácido clorogénico y de la cafeína utilizados de forma aislada, inciden en que los efectos más beneficiosos sobre los distintos factores de riesgo y patologías se obtienen de forma simultánea, únicamente cuando se utiliza el producto bioactivo de la invención, no siendo así cuando se utiliza el ácido clorogénico en distintas dosis o la cafeína. En base a lo anterior se infiere que la efectividad del producto bioactivo de la invención probablemente se derive de la proporción de compuestos bioactivos (cafeína y ácido clorogénico), pero probablemente también de otros componentes como la fibra dietética que se derivan de su procedimiento de obtención. The results included in the examples in this document, which also show the activity of chlorogenic acid and caffeine used in isolation, affect the most beneficial effects on the various factors of Risk and pathologies are obtained simultaneously, only when the bioactive product of the invention is used, but not when chlorogenic acid is used in different doses or caffeine. 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 (caffeine and chlorogenic acid), but probably also from other components such as dietary fiber that are derived from its process of obtaining .
En un primer aspecto, la invención se refiere al uso del producto bioactivo de la invención en la elaboración de un suplemento alimenticio útil para la prevención de al menos un factor de riesgo de las patologías que conforman el síndrome metabólico y que se selecciona de entre hiperglucemia, resistencia a la insulina, dislipidemia y obesidad, o de todos ellos de forma simultánea. En la presente invención, por "suplemento alimenticio" se entiende un producto destinado a complementar la alimentación y cuya finalidad es incrementar la ingesta dietética total, complementarla, suplir algún componente o prevenir patologías. En la presente invención se entiende que el suplemento alimenticio puede presentar distintas formas de administración, incluyendo por ejemplo la forma galénica a través de un producto nutracéútico. 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.
Por "prevención" se entiende cualquier actuación que tenga un efecto directo sobre los factores de riesgo que pueden desencadenar en alguna patología, antes de que sean efectivos, pero también que mejore el estado de salud global, evitando que dichos factores de riesgo lleguen a desarrollarse. "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 .
En una realización particular del primer aspecto de la invención, el suplemento alimenticio adicionalmente es útil para la prevención de al menos una de las patologías que conforman el síndrome metabólico, que se seleccionan de entre diabetes y patologías cardiovasculares asociadas a cambios en el patrón de los lípidos séricos, o de ambas de forma simultánea. Preferentemente las patologías son diabetes y vasculopatías. Más preferentemente la diabetes es diabetes mellitus tipo 2.  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 among diabetes and cardiovascular pathologies associated with changes in the pattern of serum lipids, or both simultaneously. Preferably the pathologies are diabetes and vasculopathies. More preferably diabetes is type 2 diabetes mellitus.
En otra realización más particular del primer aspecto de la invención, el suplemento alimenticio adicionalmente es útil para la prevención del síndrome metabólico. En un segundo aspecto, la invención se refiere al suplemento alimenticio, en adelante suplemento alimenticio de la invención, que comprende al producto bioactivo de la invención y que es útil para la prevención de las patologías que conforman el síndrome metabólico, de sus factores de riesgo y del síndrome metabólico, tal y como se define en el presente documento. 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 relates 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.
Adicionalmente, el suplemento alimenticio de la invención puede comprender al menos otro principio activo. Los principios activos que se incluyen en el ámbito de la presente invención son principios de origen natural o sintético que incrementan la actividad preventiva del suplemento alimenticio con respecto al síndrome metabólico, a las patologías que lo conforman o a sus factores de riesgo. Additionally, the nutritional supplement of the invention may comprise at least one other active ingredient. The active principles that are 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.
El suplemento alimenticio de la invención se puede consumir normalmente por vía oral, por ejemplo en forma de comprimidos, cápsulas, granulados, líquidos, polvos, en forma liofilizada, en forma de gel, soluciones, suspensiones o cualquier otra forma de presentación adecuada. The food 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 form of presentation.
Por "alimento enriquecido" se entiende cualquier combinación de ingredientes constitutiva de un producto alimentario sólido o líquido que comprende un producto enriquecido en ácido clorogénico y cafeína tal y como se define según cualquiera de los apartados a) y b) de la definición de producto bioactivo de la invención, que adicionalmente a sus características nutricionales, tiene funciones específicas que ayudan a mejorar el estado de salud global y prevenir el riesgo de contraer el síndrome metabólico, las patologías que lo conforman o sus factores de riesgo "Enriched food" means any combination of ingredients constituting a solid or liquid food product comprising a product enriched in chlorogenic acid and caffeine 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 comprise it or its risk factors
En el ámbito del presente documento, el alimento enriquecido y el suplemento alimenticio de la invención se pueden utilizar directamente, o como ingrediente de otro alimento que lo comprende. En un tercer aspecto, la invención se refiere al uso del suplemento alimenticio de la invención o del alimento enriquecido para la prevención de al menos uno de los factores de riesgo de las patologías que conforman el síndrome metabólico y que se seleccionan de entre hiperglucemia, resistencia a la insulina, dislipidemia y obesidad, o de todos ellos de forma simultánea. En una realización particular de tercer aspecto de la invención, el suplemento alimenticio de la invención o el alimento enriquecido, adicionalmente son útiles para la prevención de al menos una de las patologías que conforman el síndrome metabólico, que se seleccionan de entre diabetes y patologías cardiovasculares asociada a cambios en el patrón de los lípidos séricos, o de ambas de forma simultánea. Preferentemente las patologías son diabetes y vasculopatías. Más preferentemente la diabetes es diabetes mellitus tipo 2. 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 the 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 serum lipids, or both simultaneously. Preferably the pathologies are diabetes and vasculopathies. More preferably diabetes is type 2 diabetes mellitus.
En otra realización más particular del tercer aspecto de la invención, el suplemento alimenticio de la invención o el alimento enriquecido, adicionalmente son útiles para la prevención del síndrome metabólico. In another more particular embodiment of the third aspect of the invention, the nutritional supplement of the invention or the fortified food, are additionally useful for the prevention of metabolic syndrome.
En un cuarto aspecto, la invención se refiere al uso del producto bioactivo de la invención en la elaboración de una composición farmacéutica. In a fourth aspect, the invention relates to the use of the bioactive product of the invention in the preparation of a pharmaceutical composition.
En un quinto aspecto, la invención se refiere al uso del producto bioactivo en la elaboración de una composición farmacéutica que es útil para la prevención y tratamiento de al menos uno de los factores de riesgo de las patologías que conforman el síndrome metabólico y que se selecciona de entre hiperglucemia, resistencia a la insulina, dislipidemia y obesidad, o de todos ellos de forma simultánea. 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.
En una realización particular del quinto aspecto de la invención, la composición farmacéutica adicionalmente es útil para la prevención y tratamiento de al menos una de las patologías que conforman el síndrome metabólico, y que se seleccionan de entre diabetes y patologías cardiovasculares asociadas a cambios en el patrón de los lípidos séricos, o de ambas de forma simultánea. Preferentemente las patologías son diabetes y vasculopatías. Más preferentemente la diabetes es diabetes mellitus tipo 2. En otra realización más particular del quinto aspecto de la invención, la composición farmacéutica adicionalmente es útil para la prevención y tratamiento del síndrome metabólico. 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 diabetes and cardiovascular pathologies associated with changes in the serum lipid pattern, or both simultaneously. Preferably the pathologies are diabetes and vasculopathies. More preferably diabetes is type 2 diabetes mellitus. 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.
En un sexto aspecto, la invención se refiere a una composición farmacéutica, en adelante composición farmacéutica de la invención, que comprende el producto bioactivo de la invención para su uso en terapia. Preferentemente la composición farmacéutica de la invención es eficaz para la prevención y tratamiento del síndrome metabólico, de al menos una de las patologías que conforman el síndrome metabólico y que se seleccionan de entre diabetes y patologías cardiovasculares asociada a cambios en el patrón de los lípidos séricos, o de ambas de forma simultánea. Preferentemente las patologías son diabetes y vasculopatías. Más preferentemente la diabetes es diabetes mellitus tipo 2. También preferentemente, los factores de riesgo de las patologías que conforman el síndrome metabólico, y contra las que es efectiva la composición farmacéutica de la invención, se seleccionan de entre hiperglucemia, resistencia a la insulina, dislipidemia y obesidad, o son todos ellos de forma simultánea. In a sixth aspect, the invention relates to a pharmaceutical composition, hereinafter pharmaceutical composition of the invention, comprising 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 serum lipid pattern. , or both simultaneously. Preferably the pathologies are diabetes and vasculopathies. 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.
En realizaciones particulares del sexto aspecto de la invención, las composiciones farmacéuticas que se incluyen en el ámbito de esta invención adicionalmente utilizan al menos un excipiente, un adyuvante y/o vehículos farmacéuticamente aceptables. In particular embodiments of the sixth aspect of the invention, pharmaceutical compositions that fall within the scope of this invention additionally use at least one pharmaceutically acceptable excipient, adjuvant and / or vehicles.
En la presente invención se entiende por "excipiente" a una sustancia inactiva usada para incorporar el producto bioactivo de la invención. Además puede ser usado para ayudar al proceso mediante el cual la composición es manufacturada. Ejemplos de excipientes incluyen sin limitar a, aglutinantes (mantienen los ingredientes de una tableta unidos, tales como hidroxipropil, celulosa, xilitol, sorbitol, manitol, etc.), diluyentes (rellenan el contenido de una pastilla o cápsula, tales como, celulosa vegetal, fosfato cálcico dibásico, flor de cártamo, etc.), desintegradores (compuestos que se expanden y disuelven cuando se les moja causando que la tableta se rompa cuando llegue al tracto digestivo y libere los principio activos para su absorción), lubrificantes (previenen que los ingredientes se agrupen en terrones, tales como talco, sílica, etc.), recubridores (protegen a los ingredientes de la tableta de los agentes externos, tales como celulosa, polímeros sintéticos, polisacáridos, etc.), edulcorantes, saborizantes y colorantes. El "vehículo" o portador, es preferiblemente una sustancia inerte con la finalidad de facilitar la incorporación de otros compuestos, permitir una mejor dosificación y administración o dar consistencia y forma a la composición farmacéutica. Por tanto, el vehículo es una sustancia que se emplea para diluir cualquiera de los componentes de la composición farmacéutica de la presente invención hasta un volumen o peso determinado; o bien que aún sin diluir dichos componentes es capaz de permitir una mejor dosificación y administración o dar consistencia y forma al medicamento. Cuando la forma de presentación es líquida, el vehículo farmacéuticamente aceptable es el diluyente. La composición farmacéutica de la invención se puede administrar por cualquier vía de administración apropiada, por ejemplo, oral, parenteral (subcutánea, intraperitoneal, intravenosa, intramuscular, etc.), rectal, etc. 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 into 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. The "carrier" or carrier, is preferably an inert substance in order to facilitate the incorporation of other compounds, allow better dosing and administration or give consistency and form to the pharmaceutical composition. Therefore, the carrier is a substance that is used to dilute any of the components of the pharmaceutical composition of the present invention to a given volume or weight; or that even undiluted said components is capable of allowing a better dosage and administration or give consistency and form to the medicine. When the form of presentation is liquid, the pharmaceutically acceptable carrier 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.
La composición farmacéutica de la invención puede estar en una forma farmacéutica de administración por vía oral, bien en forma sólida o líquida. Ejemplos ilustrativos de formas farmacéuticas de administración por vía oral incluyen comprimidos, cápsulas, granulados, soluciones, suspensiones, etc., y pueden contener los excipientes convencionales, tales como aglutinantes, diluyentes, desintegrantes, lubrificantes, humectantes, etc., y pueden ser preparadas por métodos convencionales. Las composiciones farmacéuticas también pueden ser adaptadas para su administración parenteral, en forma de, por ejemplo, soluciones, suspensiones o productos liofilizados, estériles, en la forma de dosificación apropiada; en este caso, dichas composiciones farmacéuticas incluirán los excipientes adecuados, tales como tampones, tensoactivos, etc. En cualquier caso, los excipientes se elegirán en función de la forma farmacéutica de administración seleccionada. Una revisión de las distintas formas farmacéuticas de administración de fármacos y de su preparación puede encontrarse en el libro "Tratado de Farmacia Galénica", de C. Faulí i Trillo, 10 Edición, 1993, Luzán 5, S.A. de Ediciones, o en cualquier libro de similares características que exista en cada país. The pharmaceutical composition of the invention may be in a pharmaceutical form for 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 can also be adapted for parenteral administration, in the form of, for example, sterile lyophilized 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 based 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 "Treaty of Pharmacy Galenica", by C. Faulí i Trillo, 10 Edition, 1993, Luzán 5, S.A. of Editions, or in any book of similar characteristics that exists in each country.
En realizaciones adicionales del sexto aspecto de la invención, las composiciones farmacéuticas que se incluyen en el ámbito de esta invención comprenden al menos otro principio activo. Los principios activos que se incluyen en el ámbito de la presente invención son principios de origen natural o sintético que incrementan la actividad de la composición farmacéutica de la invención, preferentemente con respecto al tratamiento de las patologías del síndrome metabólico, de sus factores de riesgo o del síndrome metabólico. In further embodiments of the sixth aspect of the invention, the pharmaceutical compositions that fall within the scope of this invention comprise at least one other active ingredient. The active ingredients that are 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 the pathologies of the metabolic syndrome, its risk factors or of metabolic syndrome.
En el ámbito de la presente invención se incluye el uso del producto bioactivo de la invención y de la composición farmacéutica de la invención para la prevención y tratamiento de las patologías que conforman el síndrome metabólico de sus factores de riesgo y del síndrome metabólico, tal y como se define en el presente documento. The use of the bioactive product of the invention and the pharmaceutical composition of the invention for prevention and prevention are included in the scope of the present invention. treatment of the pathologies that make up the metabolic syndrome of its risk factors and metabolic syndrome, as defined herein.
También se incluye dentro del ámbito de la presente invención cualquier método de prevención y tratamiento de las patologías que conforman el síndrome metabólico, de sus factores de riesgo y del síndrome metabólico, tal y como se define en el presente documento, que consiste en la administración de una dosis efectiva del producto bioactivo o de la composición farmacéutica de la invención. En la presente invención se entiende por "método de tratamiento" al conjunto de medios que se emplean en un sujeto para prevenir, aliviar o curar una enfermedad, o para eliminar o disminuir los síntomas de una enfermedad. En la presente invención se entiende por "individuo" o "sujeto" a un miembro de una especie animal, preferentemente mamífero e incluye, pero no se limita a, un animal doméstico, un primate y un humano; en el contexto de la presente invención, el individuo es preferiblemente un ser humano, masculino o femenino, de cualquier raza o edad. 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 of the pharmaceutical composition of the invention. In the present invention, "treatment method" is understood as 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, "individual" or "subject" means a member of an animal species, preferably a mammal, 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, male or female, of any race or age.
La dosificación del producto bioactivo, del suplemento alimenticio de la invención, del alimento enriquecido y de las composiciones farmacéuticas de la invención, variará dependiendo de numerosos factores, como la edad, severidad de la patología, vía de administración y frecuencia de la dosis. The dosage of the bioactive product, of the nutritional supplement of the invention, of the fortified 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.
Las características del producto bioactivo de la invención también permiten su utilización como coadyuvante tecnológico en la preparación de alimentos un reducido índice glucémico. The characteristics of the bioactive product of the invention also allow a reduced glycemic index to be used as a technological aid in food preparation.
Se entiende por coadyuvante tecnológico toda sustancia que no se consuma como alimento en sí misma, si no que se utilice intencionadamente en la transformación de materias primas, alimentos o sus ingredientes para cumplir un determinado propósito tecnológico durante el tratamiento o la transformación, y pueda dar lugar a la presencia involuntaria, pero técnicamente inevitable, en el producto final de residuos de la propia sustancia o de sus derivados, a condición de que no presenten ningún riesgo para la salud y no tengan ningún efecto tecnológico en el producto final. En un séptimo aspecto, la invención se refiere al uso del producto bioactivo de la invención como coadyuvante tecnológico que favorece un reducido índice glucémico en un alimento. A lo largo de la descripción y de las reivindicaciones la palabra "comprende" y sus variantes no pretenden excluir otras características técnicas. Para el experto en la materia, otros aspectos, ventajas y características de la invención se desprenderán en parte de la descripción y en parte de la práctica de la invención. Las siguientes figuras y ejemplos se proporcionan a modo de ilustración, y no se pretende que sean limitativos de la presente invención. 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. 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.
BREVE DESCRIPCIÓN DE LAS FIGURAS BRIEF DESCRIPTION OF THE FIGURES
Figura 1. Prueba de tolerancia oral a la glucosa en ratas Wistar sanas. La glucosa se administró de forma simultánea con ácido clorogénico, cafeína o extracto de cascarilla tostada de café. (A) Resultados obtenidos a los tiempos 30, 60, 90 y 120 minutos posteriores a la administración oral de glucosa conjuntamente con los distintos tratamientos. (B) Detalle de los resultados anteriores a los 30 minutos. Los dos paneles (A) y (B) muestran la media de los valores de glucosa en sangre total (mg/dl) obtenidos a diferentes tiempos de análisis ± error estándar de la media (EEM) (n=12 por tratamiento) según el ejemplo 2. La comparación de las medias se llevó a cabo mediante ANOVA de una vía y prueba de Bonferroni. Letras distintas muestran diferencias significativas con p <0,05. Figure 1. Oral glucose tolerance test in healthy Wistar rats. Glucose was administered simultaneously 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.
Figura 2. Porcentaje promedio de reducción y aumento de los niveles de glucosa en sangre total durante los 6 días posteriores a la inducción de diabetes a través de una dosis única de streptozotocina (STZ) y nicotinamida por vía intraperitoneal en ratas Wistar sometidas a pretratamientos con ácido clorogénico, cafeína y extracto de cascarilla tostada de café. Los valores de los porcentajes se calcularon empleando como referencia las ratas a las que se les indujo químicamente diabetes sin habérseles aplicado pretratamiento previo (control II) utilizando la media de los valores de glucosa en sangre total ± el error estándar de la media (EEM) (n=8 por tratamiento) según el ejemplo 3.1. La comparación de las medias se llevó a cabo mediante ANOVA de una vía y prueba de Bonferroni. Letras distintas muestran diferencias significativas con p <0,05. Figura 3. Prueba de tolerancia oral a la glucosa en ratas Wistar sometidas a pretratamientos con ácido clorogénico, cafeína y extracto de cascarilla tostada de café, 3 días después de inducirles diabetes a través de una dosis única de streptozotocina (STZ) y nicotinamida por vía intraperitoneal. La figura muestra los valores del área bajo la curva (AUC) obtenidos por representación gráfica de los valores de glucosa en sangre total según el ejemplo 3.2. Las barras representan la media del AUC y las barras de error el EEM (n=8 por tratamiento). La comparación de las medias se llevó a cabo mediante ANOVA de una vía y prueba T3 de Dunnett. Letras distintas indican que existen diferencias significativas (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 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. 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 route 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).
Figura 4. Efecto antidiabetogénico en ratas Wistar sometidas a pretratamientos con ácido clorogénico, cafeína y extracto de cascarilla tostada de café, tras 8 días de haberse inducido la diabetes a través de una dosis única de streptozotocina (STZ) y nicotinamida por vía intraperitoneal. La gráfica muestra el porcentaje de animales que presentaron hiperglucemia permanente (diabetes) en cada grupo de tratamiento (n=8 por tratamiento) según el ejemplo 3.3 tomando como criterios diagnósticos hiperglucemia permanente (>1 10 mg/dl en ayunas) y baja tolerancia a la glucosa (>200 mg/dl a las 90 y 120 min de ingesta). 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 (> 1 10 mg / dl fasting) and low tolerance to glucose (> 200 mg / dl at 90 and 120 min of intake).
Figura 5. Capacidad de inhibición in vitro de la actividad de la a-glucosidasa intestinal del ACG y el extracto de cascarilla tostada de café. La gráfica muestra los valores de IC50 (mg/ml) obtenidos para ACG y extracto de cascarilla tostada de café según el ejemplo 3.5. 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 coffee roasted husk extract according to example 3.5.
Figura 6. Efecto sobre el peso corporal en ratas Wistar sometidas a pretratamientos con ácido clorogénico, cafeína y extracto de cascarilla tostada de café, tras 8 días de haberse inducido diabetes a través de una dosis única de streptozotocina (STZ) y nicotinamida por vía intraperitoneal. La gráfica muestra el peso final de los animales según el ejemplo 3.6 al final del estudio. Las barras representan la media y las barras de error el EEM (n=8 por tratamiento). La comparación de las medias se llevó a cabo mediante ANOVA de una vía y prueba de Bonferroni. Letras distintas indican que existen diferencias significativas (p< 0,05). Figura 7. Efecto sobre el peso relativo del hígado (peso hígado/peso final) en ratas Wistar sometidas a pretratamientos con ácido clorogénico, cafeína y extracto de cascarilla tostada de café, tras 8 días de haber inducido diabetes a través de una dosis única de streptozotocina (STZ) y nicotinamida por vía intraperitoneal en ratas Wistar. La gráfica muestra los pesos relativos del hígado de los animales tras la suplementación con los distintos compuestos o con el extracto según el ejemplo 3.7. Las barras representan la media y las barras de error el EEM (n=8 por tratamiento). Las comparaciones de las medias se llevaron a cabo mediante ANOVA de una vía y prueba de Bonferroni. Letras distintas muestran diferencias significativas con p <0,05. 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 intraperitoneal nicotinamide . 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 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 using one-way ANOVA and Bonferroni test. Different letters show significant differences with p <0.05.
Figura 8. Efecto sobre las concentraciones plasmáticas de colesterol total en ratas Wistar sometidas a pretratamientos con ácido clorogénico, cafeína y extracto de cascarilla tostada de café, tras 8 días de haberse inducido diabetes a través de una dosis única de streptozotocina (STZ) y nicotinamida por vía intraperitoneal en ratas Wistar. La gráfica muestra las concentraciones de colesterol total en plasma según el ejemplo 3.8. Las barras representan la media y las barras de error el EEM. Las comparaciones de las medias se llevaron a cabo mediante ANOVA de una vía y prueba T3 de Dunnett. Letras distintas muestran diferencias significativas con 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.
Figura 9. Efecto sobre las concentraciones plasmáticas de triglicéridos en ratas Wistar sometidas a pretratamientos con ácido clorogénico, cafeína, y extracto de cascarilla tostada de café, tras 8 días de haberse inducido diabetes a través de una dosis única de streptozotocina (STZ) y nicotinamida por vía intraperitoneal en ratas Wistar. La gráfica muestra las concentraciones de triglicéridos en plasma según el ejemplo 3.9. Las barras representan la media y las barras de error la EEM. Las comparaciones de las medias se llevaron a cabo mediante ANOVA de una vía y pruebaT3 de Dunet. Letras distintas muestran diferencias significativas con 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.
MODOS DE REALIZACIÓN DE LA INVENCIÓN A) OBTENCIÓN DEL EXTRACTO Ejemplo 1. Obtención del extracto de cascarilla tostada de café (ECCA) El extracto se obtuvo a partir de cascarilla de café generada como subproducto del tostado de granos de café verde Arábica. Se preparó empleando 250 mg de dicha cascarilla y 500 mi de agua. La extracción se realizó a 100 °C durante 10 min. El extracto así obtenido se centrifugó, se colectó el sobrenadante y se liofilizó para obtener extracto en polvo. El producto así obtenido se almacenó a temperatura ambiente en un lugar seco hasta su uso. 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 performed 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.
B) ENSAYOS EN RATAS SANAS B) TESTS IN HEALTHY RATS
Ejemplo 2. Efecto sobre la tolerancia a la glucosa de los componentes del café y el extracto de cascarilla tostada de café en ratas Wistar sanas Example 2. Effect on glucose tolerance of coffee components and roasted coffee husk extract in healthy Wistar rats
Se empleó un grupo de 12 ratas macho Wistar adultas de entre 150-200 g de peso. Tras un periodo de ayuno de 14 horas se les aplicó una única dosis de los tratamientos que se detallan a continuación empleando una sonda nasofaríngea rígida:A group of 12 adult Wistar male 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 nasopharyngeal catheter:
• glucosa 2 g/kg peso (grupo control) • glucose 2 g / kg weight (control group)
• glucosa 2 g/kg peso y ácido clorogénico (ACG-1 ,5) 1 ,5 mg/kg peso  • glucose 2 g / kg weight and chlorogenic acid (ACG-1, 5) 1.5 mg / kg weight
• glucosa 2 g/kg peso y ácido clorogénico (ACG-10) 10 mg/kg peso  • glucose 2 g / kg weight and chlorogenic acid (ACG-10) 10 mg / kg weight
· glucosa de 2 g/kg peso y cafeína (CF) 5 mg/kg peso  Glucose of 2 g / kg weight and caffeine (CF) 5 mg / kg weight
• glucosa de 2 g/kg peso y extracto de cascarilla tostada de café (ECCA) 140 mg/kg peso  • 2 g / kg glucose weight and roasted coffee husk extract (ECCA) 140 mg / kg weight
A cada una de las 12 ratas se les aplicó de forma secuencial cada uno de los tratamientos anteriores, empleando un lavado de 3 días entre cada tratamiento para garantizar que se metabolizaran totalmente los compuestos bioactivos y evitar interferencias. En todo caso, la dosis se indica con respecto al peso en kilogramos del animal sometido a tratamiento. Las concentraciones de glucosa en sangre (mg/dl) se determinaron a los 0, 30, 60 y 120 min usando un glucómetro (FreeStyle Freedom Lite®, Abbot Laboratories) cuya medición se basa en el método de la glucosa oxidasa, mediante una punción en la cola. Los niveles de glucosa en sangre total de los animales tratados con ACG, CF y extracto de cascarilla tostada de café (ECCA) fueron menores que los detectados en animales control durante los 90 min después de la ingesta (ver figura 1 A). Cabe destacar que a los 30 min de ingesta los niveles de glucosa en sangre total de las ratas tratadas con extracto de cascarilla tostada de café fueron significativamente (p<0,05) más bajos en comparación con los niveles de glucosa en el grupo control (ver figura 1 B). Each of the 12 rats was sequentially applied 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, by 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 1 A). 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 1 B).
Los resultados indican un efecto hipoglucemiante del extracto de cascarilla tostada de café en individuos sanos y una mejora de la tolerancia a la glucosa. C) ENSAYOS EN RATAS ENFERMAS The results indicate a hypoglycemic effect of roasted coffee husk extract in healthy individuals and an improvement in glucose tolerance. C) TESTS IN SICK RATS
Se emplearon ratas macho Wistar adultas de entre 150-200 g de peso. Los tratamientos y dosis que se detallan a continuación fueron administrados empleando una sonda nasofaríngea rígida durante 35 días y un total de 8 ratas por tratamiento: Adult male Wistar rats weighing 150-200 g were used. The treatments and doses detailed below were administered using a rigid nasopharyngeal catheter for 35 days and a total of 8 rats per treatment:
• no tratadas (grupo control I: sanas) • untreated (control group I: healthy)
• no tratadas (grupo control II: enfermas)  • untreated (control group II: sick)
• cafeína (CF) 5 mg/kg peso/día  • caffeine (CF) 5 mg / kg weight / day
• ácido clorogénico (ACG) 1 ,5 mg/kg peso/día  • chlorogenic acid (ACG) 1.5 mg / kg weight / day
· ácido clorogénico (ACG) 10 mg/kg peso/día  Chlorogenic acid (ACG) 10 mg / kg weight / day
• extracto de cascarilla tostada de café (ECCA) (140 mg/kg peso/día)  • roasted coffee husk extract (ECCA) (140 mg / kg weight / day)
En el caso de los grupos control se suministró una dosis de 1 mi de agua. Después de los 35 días de pretratamiento se indujo la diabetes por inyección intraperitoneal de los agentes estreptozotocina (STZ) (65 mg/kg peso) y nicotinamida (250 mg/kg de peso), en todos los grupos a excepción del grupo control I, continuándose con el tratamiento durante 8 días más, momento en cual las ratas fueron anestesiadas y sacarificadas. 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 the control group I, continuing with the treatment for 8 more days, at which time the rats were anesthetized and saccharified.
La STZ es una sustancia con citotoxicidad específica que destruye células y causa un estado de deficiencia primaria de insulina en una dosis en ciertas especies animales como las ratas Wistar y diabetes permanente (hiperglucemia) sin causar daños en otros órganos. La nicotinamida protege a los animales contra la citotoxicidad de la STZ. El uso combinado de ambos compuestos químicos permite lograr un estado de hiperglucemia y resistencia a la insulina, del mismo modo que sucede en pacientes con diabetes mellitus tipo 2. Se empleó como anestésico ketamina-xilacina en una dosis de 1 ml/kg de ketamina y 0,5 ml/kg de Xilacina por vía intraperitoneal. Los animales se mantuvieron tranquilos durante 3 min en oscuridad para favorecer el efecto de la anestesia. Cuando los animales no presentaban reflejo en la retracción de la extremidad seguida de la relajación de los músculos abdominales, se les extrajo la sangre mediante una punción en el corazón que se recogió en tubos con EDTA y se centrifugó inmediatamente (1800 x g durante 15 min a 4 °C) para obtener muestras de plasma. El hígado se diseccionó, se lavó en solución salina enfriada con hielo para eliminar la sangre, se pesó y se congeló rápidamente en nitrógeno líquido. El plasma y el hígado se conservaron a -80 °C hasta su análisis. STZ is a substance with specific cytotoxicity that destroys 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 by means of 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.
EFECTO GLUCORREGULADOR Y ANTIDIABETOGÉNICO Las ratas tratadas tal y como se indica en el apartado C), fueron objeto de un seguimiento de la respuesta clínica mediante análisis diario de los niveles de glucosa en sangre total después de un ayuno de 12 h. La determinación de la glucosa en sangre se realizó con un glucómetro (FreeStyle Freedom Lite®, Abbot Laboratories) mediante punción en la cola. GLUCORREGULATOR AND ANTIDIABETOGENIC EFFECT Rats treated as indicated in section C) were monitored for clinical response by daily analysis of blood glucose levels after a 12-hour fast. Blood glucose was determined with a glucometer (FreeStyle Freedom Lite®, Abbot Laboratories) by tail puncture.
Ejemplo 3.1. Respuesta clínica a la inducción química de la diabetes durante los 6 días posteriores Example 3.1 Clinical response to the chemical induction of diabetes during the next 6 days
Los niveles de glucosa en ratas enfermas tratadas con ACG, CF y extracto de cascarilla tostada de café mostraron un comportamiento distinto que las ratas sometidas al agente químico inductor de la patología (control II). No se detectó la fase clínica de hipoglucemia, característica del modelo empleado, en ningún grupo de animales tratados con componentes del café y extracto de cascarilla tostada de café. En consecuencia los niveles de glucosa tras 24 h de inducción de la enfermedad fueron porcentualmente más elevados en los animales tratados y sanos (control I) comparativamente a los detectados en el grupo control II. Los tratamientos con ACG 1 ,5 mg/kg y cascarilla de café 140 mg/kg causaron una reducción mayor del 30 % de los niveles de glucosa en sangre total después de 24 h de la inyección de STZ/nicotinamida y durante los 6 días siguientes de evolución de la enfermedad (figura 2). Ejemplo 3.2. Tolerancia a la glucosa a los 3 días de la inducción de la diabetes Glucose levels in sick 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 induction of the disease 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 the induction of diabetes
A los tres días de inducción química de la patología se realizó un análisis de tolerancia oral a la glucosa (PTGO) para confirmar el diagnóstico de la enfermedad por disminución de la tolerancia a la glucosa oral y para ello se procedió tal y como se indica en el ejemplo 2. Los resultados se muestran en la figura 3. Por otra parte, los valores de glucosa en sangre total de ratas tratadas con una dosis de ACG de 1 ,5 mg/kg o una dosis de 140 mg/kg de cascarilla de café fueron inferiores a los 200 mg/ml en todos los tiempos ensayados y más bajos que los encontrados en las ratas a las que se les indujo la diabetes y no se les suministró ningún tratamiento de prevención de la enfermedad (control II). La tolerancia de la glucosa en las ratas sometidas a estos tratamientos no fue significativamente distinta (p>0,05) a la detectada en los animales que no se sometieron a inducción química de la diabetes (ratas sanas). Three days after the chemical induction of the pathology, an oral glucose tolerance test (OGTT) was performed to confirm the diagnosis of the disease due to a decrease in the oral glucose tolerance and for this purpose, the procedure was performed 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 an ACG dose 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).
Ejemplo 3.3. Efecto antidiabetogénico 8 días después de la inducción de la diabetes Al finalizar el ensayo tal y como se expone en el apartado C), y siguiendo los criterios diagnósticos de manifestación de hiperglucemia permanente (>110 mg/dl en ayunas) y baja tolerancia a la glucosa (>200 mg/dl a las 90 y 120 min de ingesta) el 37,5% de los animales tratados con el agente inductor enfermaron (ver figura 4). Estos resultados que se expresan como porcentaje indican una prevención del efecto diabetogénico de la STZ por dosis de ACG 1 ,5 mg/kg y extracto de cascarilla tostada de café 140 mg/kg, reduciendo la efectividad del agente químico inductor de la diabetes en un 70% en ambos grupos. Example 3.3. Antidiabetogenic effect 8 days after the induction of diabetes At the end of the trial as described in section C), and following the diagnostic criteria for the manifestation of permanent hyperglycemia (> 110 mg / dl on an empty stomach) and low tolerance to glucose (> 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, which are expressed as a percentage, indicate a prevention of the diabetogenic effect of STZ by a dose of 1.5 mg / kg ACG and roasted coffee husk extract 140 mg / kg, reducing the effectiveness of the chemical agent inducing diabetes in a 70% in both groups.
Ejemplo 3.4. Efecto sobre los índices de sensibilidad a la insulina 8 días después de la inducción de la diabetes Example 3.4. Effect on insulin sensitivity indices 8 days after diabetes induction
Al finalizar el ensayo tal y como se expone en el apartado C, los niveles de glucosa en plasma se determinaron utilizando un kit comercial (Spinreact, S.A./S.A.U, Sant Esteve de Bas, España; Ref. 1001 190) que se basa en el método de la glucosa oxidasa. La insulina en plasma se determinó por kit ELISA (Mercodia A.B, Uppsala, Sweden; Ref. 10-1250-01). At the end of the test as set out in section C, plasma glucose levels were determined using a commercial kit (Spinreact, SA / SAU, Sant Esteve de Bas, Spain; Ref. 1001 190) based on the glucose oxidase method. The Plasma insulin was determined by ELISA kit (Mercodia AB, Uppsala, Sweden; Ref. 10-1250-01).
La evaluación del modelo homeostático o índice HOMA de resistencia a la insulina (HOMA-IR), de la función de las células beta (ΗΟΜΑ-β), y el índice de sensibilidad a la insulina (QUICKI) se calcularon empleando las siguientes fórmulas: glucosa Evaluation of the homeostatic model or HOMA insulin resistance index (HOMA-IR), beta cell function (beta-β), and insulin sensitivity index (QUICKI) were calculated using the following formulas: glucose
HOMA - IR = vmn Li°^ x insulina (^ ) HOMA - IR = v mn L i ° ^ x insulin (^)
22,5  22.5
20 x insulina (^¡ ) 20 x insulin (^ ¡)
HOMA— β =  HOMA— β =
glucosa (~¡~-)— 3,5 glucose ( ~ ¡ ~ -) - 3,5
QUICKI =QUICKI =
Figure imgf000025_0001
Figure imgf000025_0001
El cálculo de los parámetros para el grupo de ratas enfermas incluye sólo aquellos animales que se ajustan a los criterios diagnóstico de diabetes utilizados en este documento, es decir, hiperglucemia sostenida y valores de glucosa en sangre en PTGO > 200 mg/dl a los 90-120 min de ingesta y que se corresponden con el 37,5% de la población tratada con el agente inductor de la enfermedad según el ejemplo 3.3. The calculation of the parameters for the group of diseased rats includes only those animals that meet the diagnostic criteria of diabetes used in this document, that is, sustained hyperglycemia and blood glucose values in OGTT> 200 mg / dl at 90 -120 min of intake and corresponding to 37.5% of the population treated with the disease-inducing agent according to example 3.3.
Tabla 1. Glucosa, Insulina e índices (HOMA-IR, ΗΟΜΑ-β y QUICKI) de las ratas que tomaron el extracto de cascarilla y las ratas enfermas del estudio de prevención. Se representan la media ± EEM. Análisis estadístico mediante la prueba t-Student. Letras diferentes muestran diferencias significativas con p<0,05. Table 1. Glucose, Insulin and indices (HOMA-IR, ΗΟΜΑ-β 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.
Glucosa Insulina Glucose Insulin
Grupos HOMA-IR ΗΟΜΑ-β QUICKI  HOMA-IR ΗΟΜΑ-β QUICKI groups
(mmol/L) (mlU/ml)  (mmol / L) (mlU / ml)
Enfermas 17,867±2,796a 6,91 ±0,98 8,60±0,92a 9,67±1 ,15a 0,295±0,007a Patients 17,867 ± 2,796 to 6.91 ± 0.98 8.60 ± 0.92 to 9.67 ± 1, 15 to 0.295 ± 0.007 a
ECCA 1 1 ,486±0,388b 7,08±0,91 3,30±0,46b 15,87±0,88b 0,321±0,007b ECCA 1 1, 486 ± 0.388 b 7.08 ± 0.91 3.30 ± 0.46 b 15.87 ± 0.88 b 0.321 ± 0.007 b
La comparación de los resultados de glucosa, insulina e índices de sensibilidad a la insulina de las ratas enfermas según los criterios diagnósticos anteriormente indicados y las tratadas con extracto de cascarilla tostada de café indican que el extracto ejerce un efecto glucorregulador efectivo. El tratamiento con el extracto causó una disminución significativa de los niveles de glucosa en sangre, de la resistencia a la insulina (HOMA-IR) y una mejora de la función pancreática (HOMA- β) y de la sensibilidad a la hormona (QUICKI). Comparison of the results of glucose, insulin and insulin sensitivity indices of diseased rats according to the diagnostic criteria indicated above. and those treated with roasted coffee husk extract indicate that the extract exerts an effective glucoregulatory effect. Treatment with the extract caused a significant decrease in blood glucose levels, insulin resistance (HOMA-IR) and an improvement in pancreatic function (HOMA-β) and hormone sensitivity (QUICKI) .
Ejemplo 3.5. Capacidad para inhibir la actividad de la alfa-glucosidasa intestinal Example 3.5 Ability to inhibit the activity of intestinal alpha-glucosidase
La capacidad para inhibir la actividad de la alfa-glucosidasa intestinal se determinó in vitro empleando un método fluorimétrico. Como sustrato fluorogénico se empleó 4- metilunberiferona- alfa-D-glucopiranosa 0,2 mM y el ensayo se realizó en formato de micro-método. La reacción enzimática se llevó a cabo en tampón fosfato 0, 1 M pH 6,9 y empleando alfa-glucosidasa de intestino de rata. Como sustancia de referencia se utilizó acarbosa en un rango de concentración de 0,0001 - 25 mM que es considerado el inhibidor más efectivo de la enzima intestinal. La dosis de extracto de cascarilla tostada de café suministrada a los animales causó un 100% de inhibición de la actividad de la enzima. La figura 5 muestra el valor de IC50 (mg/ml) para ACG y extracto de cascarilla tostada de café, respectivamente. Ambos productos resultaron efectivos inhibidores de la actividad enzimática. Por el contrario, las concentraciones de cafeína ensayadas no inhibieron la actividad enzimática in vitro. The ability to inhibit intestinal alpha-glucosidase activity was determined in vitro using a fluorimetric method. As a fluorogenic substrate, 0.2 mM 4- methylunberiferone-alpha-D-glucopyranoside was used and the assay was performed in 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 caffeine tested did not inhibit enzyme activity in vitro.
En consecuencia, puede concluirse que el extracto puede utilizarse como potencial agente preventivo de la diabetes e hipoglucemiante debido, al menos en parte, al efecto inhibidor de la alfa-glucosidasa intestinal observado. 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.
Ejemplo 3.6. Efecto sobre el peso corporal Example 3.6. Effect on body weight
Los animales se pesaron periódicamente durante las 6 semanas que duró el ensayo según se describe en el apartado C). Los resultados del peso corporal medio de cada grupo al final del experimento se presentan en la figura 6. Se observó una reducción en el peso corporal como consecuencia del desarrollo de la patología. Los resultados están en línea con los descritos en estudios previos que establecen una asociación entre la reducción del peso corporal y la hiperglucemia (Lo et al. 2004. Life Science 74, 2897-908). Los animales tratados con extracto de cascarilla tostada de café 140 mg/kg presentaron valores de peso corporal similares a los encontrados en individuos sanos (control I) y significativamente superiores (p>0,05) a los encontrados en individuos enfermos sin tratamiento (control I). 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 coffee roasted 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).
Ejemplo 3.7. Efecto sobre el peso del hígado Example 3.7. Effect on liver weight
Se determinó el peso relativo del hígado en proporción al peso corporal para controlar el aumento del peso del órgano como consecuencia de hipertrofia debida al desarrollo de la patología. Tras las 6 semanas de tratamiento tal y como se describe en el apartado C), los órganos se pesaron tras el sacrificio y se calculó el peso relativo de los mismos dividiendo el peso del órgano (g) por el peso total del animal al final del estudio (g). Los resultados indican que los tratamientos afectan al peso relativo del hígado (ver figura 7) y pueden deberse a la disminución de peso y a la acumulación de triglicéridos en hígado como consecuencia de la hiperglucemia que se ha inducido químicamente. Se encontraron valores para animales sanos y tratados con agente químico inductor de diabetes y extracto de cascarilla tostada de café en una dosis de 140 mg/kg similares (p>0,05) y estadísticamente inferiores (p<0,05) a los animales enfermos que no recibieron ningún tratamiento. Este resultado apoya que el tratamiento con el extracto mejora o preserva la salud de los animales evitando el desarrollo de la patología. Los resultados están de acuerdo con los que se muestran en la figura 4. 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 weight loss and the accumulation of triglycerides in the liver as a result of chemically induced hyperglycemia. Values were found for healthy animals and treated with chemical agent inducing diabetes and roasted coffee husk extract at a dose of 140 mg / kg similar (p> 0.05) and statistically lower (p <0.05) to animals patients who did not receive any 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.
EFECTO LIPORREGULADOR LIPORREGULATOR EFFECT
Ejemplo 3.8. Efecto sobre los niveles plasmáticos de colesterol Example 3.8. Effect on plasma cholesterol levels
Para la determinación de colesterol total en plasma se empleó un kit basado en el método colorométrico enzimático de la colesterol esterasa (Spinreact, S.A./S.A.U, Sant Esteve de Bas, España; Ref. 1001090). El modelo de inducción química de diabetes ensayado no afectó los niveles plasmáticos de colesterol. Los tratamientos con ACG (1 ,5 y 10 mg/kg, respectivamente) y extracto de cascarilla tostada de café disminuyeron significativamente (p<0,05) los niveles de colesterol plasmático al final del período experimental tal y como se indica en el apartado C) (ver figura 8). Los resultados sugieren que el extracto de cascarilla tostada de café presenta un potencial liporregulador y por tanto preventivo y terapéutico de enfermedades relacionadas con la dislipidemia. Ejemplo 3.9. Efecto sobre los niveles plasmáticos de triglicéridos A kit based on the enzymatic colorometric method of cholesterol esterase (Spinreact, SA / SAU, Sant Esteve de Bas, Spain; Ref. 1001090) was used to determine total cholesterol in plasma. 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
Para la determinación de triglicéridos en plasma se empleó un kit basado en la hidrólisis de los triglicéridos y la posterior determinación del glicerol liberado (Spinreact, S.A./S.A.U, Sant Esteve de Bas, España; Ref. 1001319). La inducción química de la diabetes causó un incremento significativo de los niveles de triglicéridos plasmáticos en las ratas que no recibieron ningún tratamiento (p<0,05). Los niveles plasmáticos medios de triglicéridos encontrados en ratas control I (sanas) y tratadas con componentes de café y extracto de cascarilla de café antes y después de la inducción química de la diabetes fueron del mismo orden de magnitud (p>0,05) al final del período experimental tal y como se indica en el apartado C) (ver figura 9). Los resultados sugieren que el extracto de cascarilla tostada de café presenta un potencial preventivo y terapéutico de la hipertrigliceridemia y de las patologías relacionadas. En consecuencia, los resultados que se describen en el presente ejemplo apoyan el efecto liporregulador del extracto de cascarilla de café. For the determination of triglycerides in plasma, a kit was used based on the hydrolysis of triglycerides and the subsequent determination of glycerol released (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 the 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 the coffee husk extract.
Ejemplo 3.10. Efecto inhibidor de lipasa Example 3.10. Lipase inhibitor effect
La capacidad inhibidora de lipasa del extracto de cascarilla tostada de café y sus componentes (ACG y CF), en las concentraciones ensayadas en el estudio in vivo, se determinó espectrofotométricamente empleando los reactivos para tales fines comercializados por la empresa Trinity Biotech (Procedure No. 805, Trinity Biotech, Jamestown, NY), según el protocolo por Gironés-Vilaplana et al. (2013. International Journal of Food Sciences and Nutrition, 64, 897-906). El análisis reveló que el extracto de cascarilla tostada de café en la dosis suministrada a los animales (140 mg/kg de peso) inhibió en un 41 ,73% la actividad de la lipasa pancréatica in vitro. El ACG en las concentraciones ensayadas (3, 1 mg/ml) causó una inhibición del 30,70% de la actividad enzimática mientras que la cafeína (1 ,56 mg/ml) resultó inefectiva. Los resultados apoyan que el efecto preventivo y terapéutico del extracto podría asociarse al menos en parte a su carácter glucorregulador y liporregulador debido a su capacidad para inhibir las enzimas glucosidasa intestinal y lipasa pancréatica, respectivamente. Por otra parte, sugieren que la composición particular del extracto es determinante de estas actividades. No se puede atribuir los efectos observados a un único compuesto. 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 the reagents for such purposes marketed by Trinity Biotech (Procedure No. 805, Trinity Biotech, Jamestown, NY), according to the protocol by Gironés-Vilaplana et al. (2013. International Journal of Food Sciences and Nutrition, 64, 897-906). The analysis revealed that the roasted coffee husk extract in the dose supplied to the animals (140 mg / kg of weight) inhibited in 41.7% the activity of pancreatic lipase in vitro. ACG at the concentrations tested (3.1 mg / ml) caused a 30.70% inhibition of enzyme activity while caffeine (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 glucorregulatory and liporegulatory character due to its ability to inhibit the enzymes intestinal glucosidase and pancreatic lipase, 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

REIVINDICACIONES
1.- Uso de un producto bioactivo que se selecciona de entre 1.- Use of a bioactive product that is selected from
a) cascarilla tostada del café, o b) un extracto de cascarilla tostada de café (ECCA) que comprende un mínimo de 80 mg de ácido clorogénico (ACG) y 985 mg cafeína (CF) por cada 100 g de extracto, en la elaboración de una composición útil para la prevención y tratamiento de al menos un factor de riesgo de las patologías que conforman el síndrome metabólico y que se selecciona de entre hiperglucemia, resistencia a la insulina, dislipidemia y obesidad, o de todos ellos de forma simultánea. a) roasted coffee husk, or b) an roasted coffee husk extract (ECCA) comprising a minimum of 80 mg of chlorogenic acid (ACG) and 985 mg of caffeine (CF) per 100 g of extract, in the preparation of a composition useful 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 simultaneously.
2.- Uso según la reivindicación 1 , caracterizado por que la composición es, adicionalmente, útil para la prevención y tratamiento de al menos una de las patologías que conforman el síndrome metabólico y que se selecciona de entre diabetes y patologías cardiovasculares asociadas a cambios en el patrón de los lípidos séricos, o de ambas de forma simultánea. 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 is selected from diabetes and cardiovascular pathologies associated with changes in the pattern of serum lipids, or both simultaneously.
3. - Uso según la reivindicación 2, caracterizado por que la diabetes es diabetes mellitus tipo 2. 3. - Use according to claim 2, characterized in that the diabetes is type 2 diabetes mellitus.
4. - Uso según cualquiera de las reivindicaciones 2 y 3, caracterizado por que las patologías cardiovasculares asociadas a cambios en el patrón de los lípidos séricos son vasculopatías. 4. - Use according to any of claims 2 and 3, characterized in that the cardiovascular pathologies associated with changes in the serum lipid pattern are vasculopathies.
5. - Uso según cualquiera de las reivindicaciones 1 a 4, caracterizado por que la composición es, adicionalmente, útil para la prevención y tratamiento del síndrome metabólico. 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. - Uso según cualquiera de las reivindicaciones 1 a 5, caracterizado por que el producto bioactivo es un extracto de cascarilla tostada de café que se obtiene por extracción con 2 volúmenes de agua por cada parte de cascarilla, a una temperatura de 100 °C durante un mínimo de 10 minutos. 6. - Use according to any 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 husk, at a temperature of 100 ° C for a minimum of 10 minutes.
7. - Uso según cualquiera de las reivindicaciones 1 a 6, caracterizado por que la composición es un suplemento alimenticio útil para la prevención. 7. - Use according to any of claims 1 to 6, characterized in that the composition is a nutritional supplement useful for prevention.
8. - Uso según cualquiera de las reivindicaciones 1 a 6, caracterizado por que la composición es una composición farmacéutica útil para la prevención y tratamiento. 8. - Use according to any of claims 1 to 6, characterized in that the composition is a pharmaceutical composition useful for prevention and treatment.
9.- Uso de un producto bioactivo tal y como se describe en la reivindicación 1 , como coadyuvante tecnológico para reducir el índice glucémico en un alimento. 9. Use of a bioactive product as described in claim 1, as a technological adjuvant to reduce the glycemic index in a food.
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