DESCRIPTION

The present invention relates to a nutraceutical or pharmaceutical composition for vehiculating resveratrol. Resveratrol, also defined 3,5,4'-trihydroxy-trans- stilbene, is a non-flavonoid phenolic compound with low molecular weight with reduced solubility in water. The latter is present as phytoalexin in more than different 70 plant species, acting as antimicrobial molecule produced de novo by plants, with the purpose of protecting themselves from attack by fungi and bacteria. The infection by the pathogenic microorganisms, associated to stress factors present in the plant cells, induces the expression and subsequent activation of p-coumaroyl-coenzyme A and malonyl- coenzyme A enzymes, which are involved in resveratrol synthesis reaction.

Its chemical structure is characterized by two phenolic rings linked to each other by a double styrenic bond. Depending thereupon, it is possible to distinguish in nature two different isomeric forms of resveratrol such as the cis form and the trans form.

In particular, the trans form is contained at high concentrations in the root of Polygonum cuspidatum plant, whereas both isoforms are present at different concentrations mainly in wine. In the latter case, the different concentration of an isomer with respect to the other one depends upon the type of vine, upon the environmental factors influencing the geographic area wherein the vine is cultivated and upon the wine fermentation time.

From the scientific studies performed on resveratrol it was possible to determine the beneficial effects deriving from the administration of resveratrol, which results to be an optimum ally in contrasting bacterial or viral infections as in case of the pathogenic microorganisms of the respiratory tracts, of male and female genital system, regulating the immune response, reducing the damages correlated to the cardiovascular diseases and offering protection to the nervous system.

As far as the bacterial infections are concerned, it was seen that resveratrol is particularly active in inhibiting the growth of pathogenic microorganisms, thanks to the reduced production of biofilm, decrease in the bacterial motility and destabilization of their cell membranes.

In vitro studies performed on Gram negative bacteria such as Escherichia coii and Vibrio cholerae allowed to determine a good anti-biofilm property of resveratrol with the purpose of limiting the growth of such pathogenic bacteria and the infection level of the host cells.

The antibacterial action of resveratrol is even connected to the capability of altering the motility of bacteria, mainly those flagellated as it was seen for E. coii bacterium.

Resveratrol, in fact, is capable of inhibiting the expression of genes involved in the production of flagella, by considerably limiting the bacterium capability of infecting the surrounding cells.

In addition to this, resveratrol can destabilize the integrity of the cell membranes of the pathogens, by inhibiting the action of ATP synthase and by inducing subsequently the fragmentation of the molecules of bacterial DNA.

All these mechanisms are at the basis of the protective effects deriving from taking resveratrol, in case of infections of the respiratory system. In fact, it was seen that resveratrol has a wide- spectrum bacterial activity by showing a good Minimum Inhibitory Concentration (MIC) towards Gram positive bacteria such as in case of Staphylococcus aureus, having a MIC equal to 100-200 pg/mL. For the Gram negative bacteria such as E.coll, Klebsiella pneumoniae and Pseudomonas aeruginosa the bactericidal action of resveratrol is recorded at values higher than 400 pg/mL.

Moreover, resveratrol has a strong antiviral activity which is expressed through the inhibition of some key points of the vital cycle of a virus such as replication, synthesis of proteins, gene expression and synthesis of nucleic acids.

The good antiseptic activity of resveratrol conjugates to its capability of regulating the immune response, after inflammation.

As far as the immuno-modulatory activity of resveratrol is concerned, it was seen that resveratrol is capable of stimulating the immune response, by regulating the activity of macrophages, lymphocytes T and natural killer cells (NK cells). In case of macrophages, the activation of these cells of the immune system takes place through two different mechanisms. The first mechanism provides the induction of the expression of the innate immunity receptors. In particular, resveratrol is involved in the production of receptors TRL4 by the macrophages, useful for recognizing the damage after inflammation.

The second mechanism, instead, provides an indirect control of the macrophages by resveratrol. In this specific case, resveratrol controls the expression of sirtuin 1 (SIRT1), which in turn determines the production of ICAM-1, protein useful to vehiculate the macrophages towards the inflamed region. Apart from that, it was also observed that resveratrol can control the expression of pro-inflammatory cytokines by the macrophages, by acting on the transcriptional factor NF-kb, with the purpose of limiting the production thereof.

In addition to this, resveratrol plays a fundamental role even in the activation of the cytotoxic lymphocytes T. In fact, the administration of resveratrol involves an increase in the production of interferon gamma (INF-y) involved in the production of lymphocytes T. Also in this case, the production of cytotoxic lymphocytes T is regulated by SIRT1, whose expression depends upon the presence of resveratrol.

In case of NK cells, instead, the action of resveratrol is dose-dependent. When the concentration of resveratrol is low, the production of NK cells is induced, which defend the organism from possible external threats (pathogens) or internal threats (infected cells). High concentrations of resveratrol, instead, determine a decrease in the vitality of these cells, with the purpose of inducing the apoptosis thereof.

Apart from this, the beneficial effects deriving from intaking resveratrol were observed after treatment of the cardiovascular diseases.

On this regard, the cardioprotective action of resveratrol in subjects suffering from cardiovascular problems mainly depends upon its antioxidant and anti-inflammatory activity.

The antioxidant activity of resveratrol is very important in regulating the metabolism of nitric oxide (NO).

In particular, the NO production depends upon a specific molecule called asymmetric dimethyl- arginine (ADMA), which inhibits the activity of endothelial nitric oxide synthase enzyme (eNOS). Under normal conditions, ADMA acts as substrate of the dimethyl-arginine dimethyl-amino hydrolase (DDAH) enzyme for the production of citrulline, involved in the induction of eNOS. However, when the cell is subjected to oxidative stress, DDAH enzyme is inactivated and consequently ADMA accumulates in the cell with reduction in NO production.

After intaking resveratrol, one observes the decrease in the exceeding levels of free radicals in the cells, by regulating positively the DDAH expression with consequent increase in the NO production .

The NO release favours the vasodilation process and decreases the platelet aggregation phenomenon, by preserving the morphology and functionality of the endothelium.

Such molecular mechanism was then demonstrated even through a clinical trial on subjects with cardiovascular disorders, wherein the administration of trans-resveratrol determined an improvement in the endothelial function.

In addition to this, the antioxidant activity of resveratrol also allows to inhibit the oxidation process of low-density lipoproteins (LDL) by the free radicals, thus by reducing the formation of atherosclerotic plaques. On this regard, resveratrol through the induction of SIRT1 can determine an increase in the expression of endogenous antioxidant enzymes such as superoxide dismutase, catalase and glutathione peroxidase and thus it can regulate the production of free radicals. There is also a SIRTl-independent regulatory pathway, wherein the presence of trans-resveratrol in the cell favours the translocation of the nuclear transcription factor erythoid-2 (Nrf-2) into the nucleus, responsible for the gene expression of additional endogenous antioxidant enzymes such as enzyme NAD(P)H: quinone oxidoreductase.

This experimental evidence is at the basis of the beneficial effects which resveratrol intaking can determine in patients, as it was demonstrated in different clinical trials. In particular, a considerable decrease in the levels of triglycerides and total cholesterol levels in blood was reported, apart from a decrease in LDL concentration.

The cardioprotective action derived from the administration of resveratrol also depends upon a good anti-inflammatory activity, associated to the antioxidant action.

In fact, an in-vitro study demonstrated that this phenolic compound is capable of reducing the intracellular levels of the tumour necrosis factor alpha (TNF-α), thus reducing the damages due to the inflammatory process at endothelial level.

Recently, in-vivo studies have also allowed to examine the neuroprotective activity of resveratrol, by highlighting that this phenolic compound can be useful in preventing neurological disorders such as Alzheimer, Parkinson disease and amyotropic lateral sclerosis .

The mechanisms underlying the neuroprotective action of resveratrol are substantially two.

The first mechanism is based upon the capability of resveratrol to regulate SIRT1 activation. This deacetylase is very important in the neuronal differentiation process. In presence of SIRT1, in fact, the correct growth of neurones is stimulated, thus preventing neuronal apoptosis phenomena and neurodegenerative states.

The second mechanism mainly is based upon the antioxidant activity of resveratrol. As observed for the cardiovascular diseases, even in this case, resveratrol is capable of reducing the exceeding ROS production, thus limiting the damages which can derive from oxidative stress.

The administration of resveratrol, then, reduces the lipid peroxidation phenomena by preserving the cellular integrity and the correct functionality of the genetic material. Moreover, it prevents the formation of aggregates of beta-amyloid peptides.

An accumulation of the latter, in fact, can severely damage human cognitive abilities, by involving serious damages at neurological level. The formation of these aggregates derives from the presence of ROS which influence negatively the enzymatic activity of beta and gamma secretase, enzymes involved in the digestion of amyloid beta peptide precursor.

In this case, resveratrol reduces the activity of secretases, by limiting the formation of amyloid aggregates and by preserving neurons from deterioration.

All these pieces of scientific evidence make resveratrol an optimum candidate for the treatment of different pathologies thanks to the beneficial effects deriving from its antibacterial, immuno- modulatory, antioxidant, anti-inflammatory and neuroprotective activity.

However, a limit to the use of resveratrol is determined by its poor bioavailability. In fact, it was observed that about 70% of resveratrol is absorbed by oral route and quickly metabolized and eliminated .

For this reason, the present invention relates to a technologically new formulation containing resveratrol in association with phosphatidylserine, phosphatidylcholine and starch, in particular modified starch, capable of favouring the stability of resveratrol in gastric environment, by improving the absorption thereof and the bioavailability with consequent optimization of its therapeutic effect. The present invention can optionally include even hydroxypropyl cellulose.

Hydroxypropyl cellulose is a cellulose derivative cold soluble in water.

It is considerably used in the pharmaceutical industry as binder and it is a food additive (E463) recognized as safe.

In the present invention resveratrol can be of synthetic origin (trans-resveratrol) or derived from a Polygonum cuspidatum extract.

The formulation, the present invention relates to, guarantees gastro-protection and controlled release of resveratrol thanks to the combination with the three functional excipients such as phosphatidylcholine, phosphatidylserine and starch. In particular, the starch, preferably acetylated modified starch, protects the phospholipid- resveratrol association from the gastric environment and allows the arrival thereof in high concentrations in the intestine where, thanks to the presence of phosphatidylcholine and phosphatidylserine, resveratrol is absorbed optimally.

The present invention then aims at making available a nutraceutical or pharmaceutical composition suitable to vehiculate resveratrol to improve effectiveness, safety and compliance in patients with cardiovascular system diseases, respiratory system diseases, immune system diseases, reproductive system diseases, nervous system diseases.

The scope of the invention also includes a pharmaceutical product or a food supplement comprising the nutraceutical or pharmaceutical composition according to the invention. In addition to the active principle, resveratrol and the other functional excipients, starch, phosphatidylcholine and phosphatidylserine, the pharmaceutical product or food supplement of the invention can optionally include additional active principles and functional excipients, which are easily selected by the person skilled in the art based upon the case needs. Even the selection of vehicles, excipients and/or diluents required for the formulation of the pharmaceutical product or food supplement in a suitable dosage form is within the normal abilities of the person skilled in the art.

The nutraceutical or pharmaceutical composition according to the invention is as defined in the enclosed claim 1.

Additional features and advantages of the invention are defined in the depending claims. The claims form an integral part of the present description.

Hereinafter a detailed description of some preferred embodiments of the invention is provided.

As indicated, the nutraceutical or pharmaceutical composition of the present invention comprises resveratrol as active principle and a combination of functional excipients which provide to the composition gastro-resistance property, increased resistance to degradation, controlled release and increase in bioavailability. Such combination of functional excipients includes phosphatidylcholine, phosphatidylserine and starch.

The nutraceutical or pharmaceutical composition of the invention is then particularly effective for vehiculation and supplementation of resveratrol for the prevention and/or treatment of cardiovascular system diseases, respiratory system diseases, immune system diseases, reproductive system diseases, nervous system diseases. Examples of such diseases are hypertension, hypercholesterolemia, metabolic syndrome, diabetes, obesity, flu, cold, sinusitis, pharyngitis, laryngitis, tonsillitis, tracheitis, epiglottitis, bronchitis, pneumonia, chronic obstructive pulmonary disease, male and female infertility, papilloma virus, polyomavirus, herpes virus, condyloma, molluscum contagiosum, vaginosis, vaginitis, senile dementia, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis.

The starch is an organic compound of polysaccharide nature consisting of the repetition of glucose units linked by a-glycosidic bond. It consists of two types of polymers: amylose, which generally amounts to about 20%, and amylopectin, which generally amounts to about 80%. Amylose constitutes the central portion of the starch granules, it is soluble in very hot water and it consists of glucose molecules linked by a-1,4 glycosidic bonds. Amylopectin is a polymer with a high branching level which forms the external portion of granules. The monomeric units composing it are joined, in the branching points, by a-1,6 glycosidic bonds. In nature it is formed in the green portions of the plants, to be then accumulated in the reserve organs, such as tubers, seeds and roots. Thanks to its properties and features, it has always found numerous industrial uses.

The starch is of particular importance in the food industry, which uses it as thickening agent and in the production of sweeteners such as maltitol and sorbitol. Thanks to its adhesive properties it is also used in the production of paper and glues, under form of starch mixture. In the pharmaceutical industry the starch has always been used as excipient and for the formation of coatings, thanks to its binding properties.

Although the starch is used also in its natural form, the interest of companies is mainly directed to the modified starches, that is starch molecules suitably modified to satisfy the needs of the various productive processes in which the starch is used. Such modified starches can be obtained by using as source plants which have undergone natural or induced genetic mutations and which, then, produce starches with altered features. Another strategy is that of modifying the starch, generally deriving from corn, tapioca and rice, by chemical (addition of functional groups, treatment with acids and bases), physical (gelatinization) or enzymatic (partial hydrolysis) treatments. Dextrins are an example of modified starches obtained by hydrolysis and re-polymerization. Such reactions can be implemented by simple thermal degradation or by acid catalysis. The result is the obtaining of molecules characterized by shorter chains, then partially or totally soluble in water. Examples of dextrins are cyclodextrins and maltodextrins, excipients very used in nutraceutical and pharmaceutical field.

The nutraceutical and pharmaceutical industry showed great interest in high-amylose-content modified starches (HAS, high amylose starch). A starch, in order to be defined as such, must have an amylose percentage equal to at least 50%. The high- amylose-content starch can be obtained from genetically modified plants or by enriching with amylose starches having low percentages thereof. The strategies used by different companies provide the use of HAS for the preparation of solid pharmaceutical forms or in the coating processes. HAS have several advantages with respect to other types of starch, for example a better consistence, a greater thermal stability and a greater resistance to humidity and adhesion phenomena. Different strategies were implemented to exploit most suitably the advantages of HAS. Scherer Corporation, for examples, is credited with using soft gel capsules, wherein a certain percentage of gelatine is replaced by the above-mentioned starch. The so-obtained capsules result to have a better aspect and greater resistance. Dow Chemical Company can boast the use of more uniform capsules, with greater stability in water and at high temperatures thanks to the use of hydroxyalkylated HAS. Upjohn Company boasts the use of amylose acetate phthalate as coating agent in the gastro-resistant preparations.

In the present invention two different types of starch can be used. By way of example there are mentioned: a starch of not chemically modified pregelatinized corn or a starch of acetylated pregelatinized corn with a high content of amylose which, in the specific case, can reach up to 90% by weight. The percentage of acetylic groups is comprised between 0.5% and 2.5%.

Acetylation is performed for example with acetic anhydride which guarantees to reach a percentage of acetylic groups greater than 0.5% but not higher than 2.5%. The starch pregelatinization treatment consists in dispersing the acetylated starch in water and subjecting the so-obtained dispersion to temperatures comprised between 100 and 130 degrees and to high pressures. The starch granules subjected to such procedure explode and form a gel with a humidity content comprised between 5 and 10%. Once solidified and removed, the so-obtained modified starch can be used in the processes for coating hard and soft capsules, microgranules and it guarantees to obtain a coating which results to be resistant and adequately viscous at the same time, which is capable of masking unpleasant odours and tastes and which can be used even when one wishes to obtain a gastro-resistant pharmaceutical form or with modified release. The features of the pharmaceutical form can be modulated by modifying the amount of used starch in the coating.

Tests performed by using the above-mentioned starch showed the gastro-resistant action, the humidity protection action and the capability of releasing after few minutes the active principle in intestinal environment. As indicated, additional functional excipients present in the nutraceutical or pharmaceutical composition of the invention are phosphatidylcholine and phosphatidylserine. These compounds belong to the wide class of the phospholipids. The phospholipids are molecules structurally very similar to the triglycerides. They are composed of one molecule of esterified glycerol in position 1 and 2 with fatty acids. The fatty acids entering the composition of natural phospholipids can have a length ranging from 12 and 22 carbon atoms; in position 1, generally, there is one saturated fatty acid, in position 2 there are unsaturated fatty acids; in position 3 there is one phosphate group which, in turn, is esterified with a complex molecule of various nature such as choline, serine, ethanolamine or inositol. Such molecules are the ones conferring the name to the phospholipid (phosphatidylcholine, phosphatidylserine, phosphatidylethanolamine and phosphatidylinositol) and influence the physical properties thereof since they establish if the molecule is anionic (such as phosphatidylserine) or zwitterionic (such as phosphatidylcholine) . The peculiar chemical structure makes the phospholipids amphiphilic molecules, that is molecules capable of interacting both with polar solvents and with non-polar solvents. More precisely, the carbon chains of the fatty acids represent the non-polar portion which interacts with the non-polar solvents, whereas the phospholipid head, consisting of the phosphate group and of the molecule linked thereto, represents the polar portion which interacts with water and the other polar solvents. This structural feature makes them molecules with surfactant properties which above a certain temperature, defined critical micellar concentration, aggregate by forming characteristic complexes which can vary by shape and size based upon the conditions of the environment in which they form and upon the length of chains of the fatty acids composing them. For example, if dispersed in aqueous solution, they form micelles having typical shape, with the polar heads directed outside towards the aqueous environment and the hydrophobic tails directed towards inside. If dispersed in organic solvents, they form, instead, the so-called reverse micelles, wherein the heads are directed towards inside and the tails towards the external non-polar environment. As far as the sizes are concerned, they vary based upon the length of the carbon chains of the fatty acids composing the phospholipids.

The phospholipids are molecules with a very important biological meaning, firstly since they take part in the composition of the biological membranes and, secondly, since they are involved in different complex mechanisms such as the transduction of the intracellular signals, the regulation of the intracellular concentration of some ions and the mediation of the inflammatory processes since sources of arachidonic acid. The phospholipids are interesting molecules even from the technological point of view and, then, they are used in pharmaceutical and nutraceutical field as technological adjuvants in the formulation of vehiculating systems for several active principles. Many active principles in fact can have a poor bioavailability caused by the difficulty in crossing the barriers and the biological membranes of many body districts. Phospholipids, and in particular phosphatidylcholine and phosphatidylserine, represent a valid help within the technological strategies for releasing several active principles. One of the advantages of the vehiculating systems based upon phospholipids consists in the compatibility of the phospholipids with the cellular membranes, both at mucosal level and at the skin level. Phosphatidylcholine and phosphatidylserine, then, act as enhancers of intestinal and topical absorption and such action can be ascribed to the following action mechanisms: thanks to their properties and to their structure, they can melt with the lipids of the corneous layer and of the membranes and perturb the structure thereof by allowing the passage of various substances; in contact with the intestinal fluids, they form micelles contributing to increase the absorption of the active principles of interest since they extract the lipids from the membranes and alter rheological properties, fluidity and composition of membranes by increasing permeability; the above-mentioned micelles protect the active principles from chemical and enzymatic degradation and they can be absorbed in the enterohepatic circulation of the bile salts, together with the mixed micelles of diet, and be transported in the blood circulation where they release the incorporated active principles.

The present invention then allows to obtain: - Gastro-resistance

- Increased permeability through the biological membranes

- Controlled release of resveratrol

- Increase in resveratrol bioavailability

The present invention constitutes a ready and valid intervention useful for prevention and/or treatment of cardiovascular system diseases, respiratory system diseases, immune system diseases, reproductive system diseases, nervous system diseases. Such effect is ascribed to the combined action of the substances constituting it. The starch used in the present invention, allows to protect resveratrol from acid pH of the stomach and from enzymatic degradation, by guaranteeing the controlled release at intestinal level. Phosphatidylcholine and phosphatidylserine increase resveratrol bioavailability thanks to the multi-mechanism action at the level of the intestinal mucosa.

The effectiveness of the nutraceutical or pharmaceutical composition, the present invention relates to, is evaluated by means of the experimental protocol described hereinafter.

With the purpose of evaluating the gastro- resistance a disintegration test is performed, as provided by Pharmacopoeia. A sample of the pharmaceutical form to be tested is placed in suitable instrument containing hydrochloric acid 0.1 N. The gastro-resistant pharmaceutical form, in contact with the buffer at pH 2 for two hours, does not undergo disintegration. Subsequently the sample is transferred into a buffer at pH 6.8 in which it disintegrates within ten minutes.

The gastro-resistance can be evaluated even by dissolution test by Pharmacopoeia according thereto the pharmaceutical form is put in contact with a solution 0.1 N of hydrochloric acid and to meet the assay it has to release a resveratrol amount lower than about 20% after 2 hours.

In order to evaluate the intestinal permeability an in-vitro test is performed for example on Caco-2 cells. The cells, placed in culture, are prepared by using for example a suitable growth medium (for example containing FBS, foetal bovine serum) and kept under controlled conditions (for example of 37°C, in a 5% CO ₂ and 100% humidity atmosphere). After several passages the cells are washed and pre- incubated with PBS. After treatment with the formulations of interest the collected samples are subjected to analysis to quantify resveratrol.

The effectiveness of the present invention can be evaluated by monitoring the anti-inflammatory and/or anti-oxidant activity of resveratrol formulated as claim 1 of the present invention with respect to resveratrol as such by using methods known to the person skilled in the art (for example evaluation of the inhibition of pro-inflammatory cytokines such as for example IL-6, TNF-α, evaluation of the stimulation of anti-inflammatory factors such as for example IL-10, evaluation of the inhibition activity on free radicals) in in-vitro or in-vivo models.

The nutraceutical or pharmaceutical composition of the present invention is particularly effective in the prevention and/or treatment of cardiovascular system diseases, respiratory system diseases, immune system diseases, reproductive system diseases, nervous system diseases thanks to the synergic action of its components.

As indicated previously, the nutraceutical or pharmaceutical composition of the present invention is inserted inside a pharmaceutical product or a food supplement, which is formulated in a suitable dosage form, whose composition and preparation are within the capabilities of the person skilled in the art.

In a preferred embodiment, resveratrol in the nutraceutical or pharmaceutical composition of the invention is present in an amount ranging from 0.1 to 90%, preferably from 0.5 to 80%, still more preferably from 1 to 70%, with respect to the total weight of the composition the present invention relates to.

By way of example, additional percentages of resveratrol usable in the invention composition are: 2%, 3%, 4%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 75%, or 85%.

In another preferred embodiment, the starch in the nutraceutical or pharmaceutical composition of the invention is present in an amount preferably ranging from 0.1 to 90%, more preferably from 0.5 to 80%, still more preferably from 1 to 70% with respect to the total weight of the composition the present invention relates to.

By way of example, additional percentages of starch usable in the invention composition are: 2%, 3%, 4%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 75%, or 85%.

In still another preferred embodiment, phosphatidylcholine in the nutraceutical or pharmaceutical composition of the invention is present in an amount ranging from 0.01 to 50%, preferably from 0.05 to 30%, still more preferably from 0.1 to 10% with respect to the total weight of the composition the present invention relates to.

By way of example, additional percentages of phosphatidylcholine usable in the invention composition are: 0.02%, 0.03%, 0.04%, 0.06%, 0.07%, 0.08%, 0.09%, 0.2%, 0.3%, 0.4%, 0.6%, 0.7%, 0.8%, 0.9%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 15%, 20%, 25%, 35%, 40%, or 45%.

In still another preferred embodiment, phosphatidylserine in the nutraceutical or pharmaceutical composition of the invention is present in an amount ranging from 0.01 to 50%, preferably from 0.05 to 30%, still more preferably from 0.1 to 10% with respect to the total weight of the composition the present invention relates to.

By way of example, additional percentages of phosphatidylserine usable in the invention composition are: 0.02%, 0.03%, 0.04%, 0.06%, 0.07%, 0.08%, 0.09%, 0.2%, 0.3%, 0.4%, 0.6%, 0.7%, 0.8%, 0.9%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 15%, 20%, 25%, 35%, 40%, or 45%.

All above-mentioned preferred embodiments can be combined to one another.

The pharmaceutical product or food supplement, comprising the pharmaceutical or nutraceutical composition of the invention, is formulated in a preferably oral pharmaceutical form, which can be solid, semi-solid or liquid.

By way of example a powder, an orosoluble powder, a granulate, a hard capsule, a soft-gel capsule, a tablet, a sachet, a solution, a syrup, a suspension or an emulsion are mentioned.

Hereinafter some not limiting examples of nutraceutical or pharmaceutical compositions, the present invention relates to, are provided. As indicated above, such nutraceutical or pharmaceutical compositions are formulated as pharmaceutical products or food supplements and administered in a suitable oral dosage form, in case divided into one or more dosage units, such as, for example, a capsule, a tablet or a sachet.

The following examples are provided by pure way of illustration and not limiting the scope of the invention as defined by the enclosed claims.

EXAMPLES

EXAMPLE 1

EXAMPLE 2

EXAMPLE 3

EXAMPLE 4

EXAMPLE 5

EXAMPLE 6

For the preparation of the "granular resveratrol" product it is possible to use for example the fluid bed granulation technology. Hereinafter a preparation example is provided, applied to the compositions of the Examples.

The working process consists in the following steps: a) Mixing:

The raw materials previously loaded in the granulator basket are subjected to a first mixing step on fluid bed, with process air having a determined temperature (for example 80-90°C), until obtaining a mixture having an average temperature of about 44°C. During this step one proceeds to implement a bulk homogeneous from the point of view of the composition and of the temperature, essential prerequisite for the optimum course of the subsequent granulation step. b) Granulation

The granulation step provides the insertion of an aqueous solution of a suitably selected binding or granulation agent, by direct nebulization on the bulk premixed and fluidized on fluid bed. Even in this step process air is used for example at 90°C by suitably selecting the speed for inletting the binding solution to obtain a granular product structured according to expectations (granulometry, bulk density, smoothness) and homogeneous. c) Drying

During the drying step the water content of the preformed granular product is basically brought back to the conditions of the mixture of the starting raw materials. The temperature of the process air of the granulated product at the end of the step is suitably evaluated in the pilot test step depending upon such target. d) Calibration

The semi-finished product obtained from the preceding step is transferred from the fluid bed granulator to a swinging granulator where it is calibrated through a sieve for reducing the particle size of the granules and of the agglomerates with coarser structure.

GLOSSARY

The terms used in the present description are as generally understood by the person skilled in the art, unless otherwise indicated.

Under the term "extract", in the context of the present description, any product is meant which can be traced back to a vegetable drug including all products deriving from mechanical treatments (pulverization, trituration, mixing and/or other methods) or from extractive treatments (extraction with solvent, distillation and/or other specific methods) performed on a drug.