IT202000019789A1 - MULTICOMPONENT COMPOSITION INCLUDING GANODERMA LUCIDUM EXTRACT, PANAX EXTRACT, VITAMINS, ZINC AND BACTERIA STRAINS AND ITS USE IN THE PREVENTION AND TREATMENT OF INFLUENZA SYMPTOMS AND IN INCREASING THE IMMUNE DEFENSES - Google Patents

Description

DESCRIPTION of the invention entitled:

?MULTI-COMPONENT COMPOSITION INCLUDING GANODERMA LUCIDUM EXTRACT, PANAX EXTRACT, VITAMINS, ZINC AND BACTERIA STRAINS AND ITS USE IN THE PREVENTION AND TREATMENT OF INFLUENZA SYMPTOMS AND IN INCREASING THE IMMUNE DEFENSES?.

The present invention relates to multi-component compositions comprising plant extracts, vitamins, minerals, and optionally at least one strain of bacteria and a prebiotic, capable of stimulating and/or strengthening the immune system and treating, in a preventive and/or curative way, flu symptoms and/or respiratory tract diseases, to reduce their duration, severity and the frequency. Furthermore, the present invention refers to an innovative formulation of said composition of the invention for oral use in multilayer solid form with differentiated release of the multicomponents.

The flu syndrome? a health problem? with a considerable impact from an epidemiological, clinical and economic point of view. The flu, in fact, is the first cause of absence from work, causing about 10% of all absences. The frequency with which flu symptoms arise, whether caused by bacterial or viral infection, although very different from season to season, is on average around 9% (range: 4-15%) of the general population, each year, while in the age range 0?14 years, what? the most affected, the incidence is, on average, approximately 26% (12-40%).

The typical symptoms are those affecting the respiratory system which arise suddenly, after an incubation that is generally quite short (about 1-2 days), and usually persist for 3-4 days, although they can last for one or two weeks. The therapies that can be used are various and different depending on the etiological agent that causes the flu syndrome. In general, an effective approach? to strengthen the body's immune system to counteract the onset of respiratory tract diseases, in particular those of the upper airways. This approach can be both preventive (treatment before the onset of flu symptoms) and curative (treatment at the onset of the first flu symptoms). Strengthen the immune system and prevent the onset or evolution of a flu syndrome? important, as an? untreated respiratory tract infection can? cause the onset of comorbidity? of the bacterial type, forcing the use of antibiotics and thus contributing to the establishment of the phenomenon of antibiotic resistance.

The technical problem that the present invention faces and solves? that of providing effective compositions free of side effects for use in a method of treatment, preventive and/or curative, of flu symptoms, such as for example those due to infections of the respiratory system, in particular of the upper tracts. Furthermore, the present invention faces and solves the technical problem of providing compositions for the prevention and treatment of flu states which allow the subject in need to minimize or avoid taking pharmacological therapies, in particular treatment with antibiotics. Finally, within the aforesaid technical problem, the present invention faces and solves the technical problem of providing substances useful for the prevention and/or curative treatment of flu syndromes in a single formulation and in a single dosage form and related symptoms, thus allowing? the presence of active ingredients of different nature (for example, plant extracts, vitamins, minerals, probiotics and/or prebiotics) in order to maximize the effectiveness of the product, to ensure better absorption of the components, as well as to avoid possible gastric side effects of some substances, such as for example the extract of a plant of the genus Panax, preferably Panax ginseng.

By "flu symptoms", in the context of the present invention, the following are meant: muscle and joint pain, tiredness/fatigue, cough, fever, headache, sore throat, nasal congestion, chills.

By ?respiratory system?, in the context of the present invention, we mean: the set of organs and structures which allow gaseous exchanges between the surrounding environment (load of oxygen) and the human organism (whose blood is loaded with carbon dioxide); specifically, the organs forming part of this system are: nose, pharynx, larynx, trachea, lungs, pleura, bronchi and bronchioles.

By ?upper respiratory system?, in the context of the present invention, we mean: cavity? nose, paranasal sinuses, cavity? oral, pharynx, epiglottis and larynx.

To overcome said technical problems, the Applicant, in the face of an intense research phase, provides multi-component compositions (compositions of the invention) comprising (a) an extract of Ganoderma lucidum titrated in polysaccharides, (b) an extract of a plant of the genus Panax titrated in ginsenosides, (c) at least one vitamin, (d) zinc, and, optionally, (e) a strain of bacteria belonging to the genus Bifidobacterium or Lactobacillus and (f) a prebiotic, as reported in the present description and in the combined claims.

Said compositions of the invention, when administered to a subject in need, are capable of stimulating and strengthening the immune system and, consequently, of preventing and/or treating the flu symptoms, such as for example symptoms and/or disorders of the respiratory system, in particular of the upper respiratory system.

This activity? of treatment, preventive and/or curative, of the compositions of the invention ? due to the specific and innovative combination of the active components (from (a) to (f), as defined in the present description) since, although each component has an activity immunomodulatory and/or immunostimulant, each component acts through a different mechanism of action, making the composition of the invention particularly effective in its action. Furthermore, the active components of the composition of the invention stimulate the immune system and act on physiological mechanisms in a complementary and/or synergistic way, such as to make the compositions of the invention not only effective in the treatment of flu symptoms and/or apparatus disorders respiratory, but also able to treat a wide range of these symptoms and/or disorders.

For example, the Ganoderma lucidum mushroom (or its extract) ? able to stimulate cells of the immune system (NK, T cells, dendritic cells, macrophages and lymphocytes) to produce and release cytokines and interleukins. Panax extract (e.g. Panax Ginseng) ? able to reduce the duration, the severity? and the frequency of flu symptoms and pu? effectively reduce the incidence of flu-like illnesses. Vitamin C contributes to the normal function of the immune system and its maintenance during and after intense physical effort, helps reduce tiredness and fatigue, and also contributes to normal energy-yielding metabolism and the protection of cells from oxidative stress. Daily consumption of vitamin D has preventive efficacy in reducing the risk of developing respiratory tract infections. The B vitamins complex plays a crucial role in supporting the immune system and the nervous system, participates in many biological processes and acts as a cofactor in enzymatic reactions key to the energy metabolism of the cell. A deficiency of this vitamin complex ? associated with increased levels of inflammation, caused by an elevated and unbalanced release of proinflammatory cytokines, such as TNF-?, IL-6 and IL-1?. In particular, vitamin B6 affects both the innate and adaptive immune responses; a deficiency of this vitamin causes both an inhibition of cytokine and chemokine release and a decrease in proliferation, activation, response and activity? of T lymphocytes. Similarly, a vitamin B12 deficiency? associated with an immunodeficiency caused by unresponsive T lymphocytes, generalized hypogammaglobulinaemia and an unbalanced proinflammatory cytokine release profile. Among the effects of the B vitamins the following are the most? relevant: vitamin B1 contributes to normal psychological function, normal functioning of the nervous system and normal energy metabolism; vitamin B2 and B3 contribute to the maintenance of normal mucous membranes, contribute to the protection of cells from oxidative stress and the reduction of tiredness and fatigue; vitamin B5 contributes to the reduction of tiredness and fatigue and to the maintenance of normal mental performance; vitamins B6 and B12 contribute to the well-being of the immune system, the reduction of tiredness and fatigue and normal psychological function. Zinc contributes to the normal function of the immune system (correct immune response of both innate and adaptive types), to the protection of cells from oxidative stress and has a direct antiviral action. Various strains of probiotic bacteria of the genus Bifidobacterium, such as for example the Bifidobacterium lactis BL-04<?> strain, bring benefits to the health of the host thanks, but not only, to an activity immunomodulatory (strain of immunobiotic bacteria) and the ability? to favor the balance of the intestinal flora; in particular, the Bifidobacterium Lactis strain BL-04<? > is able to modulate the innate response of the host at the nasal level and influence the replication of influenza viruses. Finally, inulin, as a prebiotic, stimulates the development and metabolic action of some bacteria that colonize the colon, especially bifidobacteria and lactobacilli, supporting the health of the intestinal microbiota; moreover, inulin carries out an action on the immune system by altering the concentration of bacterial lactic acid and, consequently, (indirectly) stimulating the action of T, NK and macrophage cells against pathogens.

Furthermore, to overcome the aforementioned technical problems, the Applicant has devised a formulation for oral use in solid form of multilayer tablet with differentiated release of the compositions of the invention (in short, formulation of the invention). Said wording? structured so as to comprise two or three or four different layers, each layer comprising different active compounds, and each layer having a variable release time in the gastro-intestinal tract of said active compounds (for example, a rapid release, an intermediate release and / or an extended release). Said formulation with differentiated release allows a better intestinal absorption of each active compound of the composition and, consequently, their greater therapeutic efficacy since: 1) in formulating the components, the preferential absorption sites of each substance have been taken into consideration at the level of gastrointestinal tract, so that the substances are mainly released in the preferential tract 2) prolongs the effectiveness of the formulation, 3) provides greater tolerability? by the body of a multi-component composition, 4) eliminates possible gastric side effects.

In fact, a differentiated release formulation of a multi-component composition allows a subject to be dosed with a pool of active compounds in a single administration, plus? easy for the subject, but at the same time not to overload the subject's organism with endogenous substances and not to have interferences in the gastrointestinal absorption of said active compounds and/or interferences between their mechanisms of action.

The compositions of the invention, showing a high safety profile, can be used by a wide category of subjects, such as adults, the elderly and sportsmen. The mixtures and compositions and formulations of the invention are easy to prepare and economically advantageous.

These aims, and others which will become clear from the detailed description which follows, are achieved by the mixtures, compositions and formulations of the present invention thanks to the technical characteristics present in the description and in the appended claims.

DETAILED DESCRIPTION OF THE INVENTION

A first aspect of the present invention relates to a mixture (in short, a mixture of the invention) which comprises or, alternatively, consists of:

(a) an extract of Ganoderma lucidum;

(b) an extract of a plant of the genus Panax;

(c) at least one vitamin;

(d) zinc; and, optionally,

(e) at least one strain of bacteria belonging to the genus Bifidobacterium or Lactobacillus (probiotic strain); and/or (f) at least one prebiotic.

In a preferred embodiment of the present invention, said mixture comprises or, alternatively, consists of:

(a) an extract of Ganoderma lucidum titrated in polysaccharides (% w/w polysaccharides: 5% to 60% or 20% to 40% or 25% to 35%);

(b) an extract of a plant of the genus Panax titrated in ginsenosides (%w/w ginsenosides: 5% to 50% or 10% to 30% or 15% to 25%), wherein said plant of the genus Panax, ? selected from the group comprising or, alternatively, consisting of: Panax ginseng, Panax notoginseng, Panax pseudoginseng, Panax quinquefolium and mixtures thereof, preferably Panax ginseng;

(c) at least one vitamin selected from the group comprising or, alternatively consisting of: (c.1) vitamin C, (c.2) vitamin D, (c.3) at least one vitamin of group B (such as B1, B2, B3 , B5, B6, B9 and/or B12) and a mixture thereof, preferably said (c) comprises or, alternatively consists of (c.1), (c.2) and (c.3);

(d) zinc selected from the group comprising or alternatively consisting of: zinc oxide, zinc bisglycinate and zinc sulfate, preferably zinc oxide; and, optionally, (e) at least one strain of bacteria belonging to the genus Bifidobacterium or Lactobacillus, preferably belonging to the species selected from the group comprising or, alternatively, consisting of Bifidobacterium lactis, Bifidobacterium breve, Lactobacillus rhamnosus, Lactobacillus helveticus, plus? preferably selected from the group comprising or alternatively consisting of: Bifidobacterium lactis BL-04<? >(SD5219), Bifidobacterium breve BR-03 (DSM 16604), Lactobacillus rhamnosus crl1505, Lactobacillus rhamnosus GG (ATCC 53103), Lactobacillus helveticus Lafti<? >L-10 (CBS 116411); and optionally,

(f) at least one prebiotic selected from the group comprising or, alternatively, consisting of: an inulin, a fructo-oligosaccharide (FOS), a galactooligosaccharide (GOS), a xylitol-oligosaccharide (XOS), plus? preferably inulin.

Preferably, said mixture of the invention comprises (a), (b), (c), (d) and (e), even more? preferably said mixture of the invention comprises (a), (b), (c), (d), (e) and (f), wherein (a), (b), (c), (d), ( e) and (f) are the active components as defined in the present description.

In the context of the present invention the terms ?titled in? and ?comprising? are synonymous terms, used interchangeably.

A second aspect of the present invention relates to a composition (in short, composition of the invention) comprising: said mixture of the invention comprising or, alternatively, consisting of (a), (b), (c), (d), and, optionally, (e) and/or (f) (according to any one of the described embodiments or aspects), and said composition further comprises at least one additive and/or excipient of acceptable pharmacological or food grade.

A third aspect of the present invention relates to a formulation (in short, formulation of the invention) in solid form of multilayer tablet (with 2 or 3 or 4 layers, preferably with 3 layers) with differentiated release comprising the mixture or composition of the invention which comprises or alternatively consists of (a), (b), (c), (d), and optionally (e) and/or (f), according to any one of the disclosed embodiments or aspects.

A fourth aspect of the present invention relates to said mixture or composition or formulation of the invention for use in a preventive and/or curative treatment method as defined in the context of the present description.

Ganoderma lucidum (Curtis) P. Karst. (synonyms: Reishi, Ling zhi) ? a saprophytic and spore-forming mushroom native to China and Japan, used in oriental medicine for various therapeutic purposes (Scientific classification: Mushroom kingdom, Basidiomycota division, Agaricomycetes class, Polyporales order, Ganodermataceae family).

In the mixture or composition or formulation of the invention (comprising (a), (b), (c), (d), and optionally (e) and/or (f), according to any of the disclosed embodiments or aspects) preferably said (a) Ganoderma lucidum extract comprises polysaccharides in a percentage by weight ranging from 5% to 60% (for example, 10%, 45% or 50%), preferably from 20% to 40% (for example example 22%, 24%, 36% or 38%), pi? preferably from 25% to 35% (e.g. 26%, 28%, 30%, 32% or 34%), based on the total weight of (a). Said polysaccharides comprise or consist of polysaccharides, linear or branched, having an average molecular weight ranging from 10 kDa (KiloDalton) to 10,000 kDa, preferably from 10 kDa to 1,000 kDa (for example, 100 kDa, 200 kDa, 500 kDa, or 800 kDa).

The polysaccharide content in Ganoderma lucidum extract can be determined by titration methods (for example titration by UV technique) and standard equipment known to the person skilled in the art.

The extract of (a) of Ganoderma lucidum comprising polysaccharides used in the present invention is preferably obtained by extraction of the mushroom (or parts of the mushroom) according to methods and equipment known to the person skilled in the art. For example, the extract of (a) pu? be obtained by an extraction step with hydroalcoholic solvent (e.g. water-ethanol mixture) to obtain an extraction liquid. Said extraction liquid is subsequently dried (for example, by spray drying or techniques known to the expert in the art) and the dry extract obtained is crushed and sieved to give a fine powder, which is finally mixed to give the Ganoderma lucidum extract comprising polysaccharides.

Panax L. (Linnaeus), also known as Ginseng, is a genus of plant native to the eastern mountainous regions, between China and Korea, known for its properties? tonic-adaptogenic of its roots (Scientific classification: kingdom Plantae, division Magnoliophyta, class Magnoliopsida, subclass Asteridae, order Apiales, family Araliaceae, subfamily Aralioidae). In the mixture or composition of the present invention, which plant of the genus Panax to obtain said extract (b) can? be used a plant belonging to a species selected from the group comprising or, alternatively, consisting of: Panax ginseng (Panax ginseng Meyer), Panax notoginseng (Panax notoginseng Chen.), Panax pseudoginseng (Panax pseudoginseng Wall.), Panax quinquefolium (Panax quinquefolium L.) and mixtures thereof.

In the mixture or composition or formulation of the invention (comprising (a), (b), (c), (d), and, optionally, (e) and/or (f), according to any of the embodiments or aspects described), preferably said (b) extract of a Panax plant, preferably Panax ginseng, comprises ginsenosides in a percentage by weight ranging from 5% to 50% (for example, 8%, 40% or 45%), preferably from 10% to 30% (for example 12%, 14%, 26% or 28%), more? preferably from 15% to 25% (e.g. 16%, 18%, 20%, 22% or 24%) with respect to the total weight of (b). The content of ginsenosides in the extract of a Panax plant, preferably Panax ginseng, can be determined by titration methods and standard equipment known to one skilled in the art; for example by HPLC or HPTLC against the reference standard.

The extract of (b) a plant of the genus Panax, preferably Panax ginseng, comprising ginsenosides used in the present invention is preferably obtained by extraction of the roots according to methods known to the person skilled in the art. For example, the extract of (b) can? be obtained from the roots of the plant by means of an extraction step with a hydroalcoholic solvent (for example water-ethanol in a ratio of about 8:1 v/v) to obtain an extraction liquid. Said extraction liquid is subsequently dried (for example, by spray drying or techniques known to the expert in the art) and the dry extract obtained, crushed and sieved to give a fine powder, which is finally mixed to give the Panax extract, preferably Panax ginseng.

The mixture or composition or formulation of the invention (comprising (a), (b), (c), (d), and, optionally, (e) and/or (f), according to any of the embodiments or aspects described), can? comprising said (a) Ganoderma lucidum extract comprising polysaccharides in a percentage by weight ranging from 5% to 60% with respect to the total weight of (a) and said (b) extract of a Panax plant, preferably Panax ginseng, comprising ginsenosides in a weight percentage ranging from 5% to 50% with respect to the total weight of (b), preferably (a) from 20% to 40% and (b) from 10% to 30%, plus? preferably (a) 25% to 35% (e.g. 30%) and (b) 15% to 25% (e.g. 20%).

In the mixture or composition or formulation of the invention (comprising (a), (b), (c), (d), and, optionally, (e) and/or (f), according to any of the embodiments or aspects described), preferably said (c) at least one vitamin comprises or, alternatively, consists of: (c.1) vitamin C (such as ascorbic acid or ascorbate), (c.2) vitamin D, preferably vitamin D3 (cholecalciferol), and (c.3) vitamins of group B comprising or, alternatively, consisting of: (c.3-i) vitamin B1, (c.3-ii) vitamin B2, (c.3-iii) vitamin B3, (c. 3-iv) vitamin B5, (c.3-v) vitamin B6, (c.3-vi) vitamin B9 (synonym: folic acid), and (c.3-vii) vitamin B12.

In the mixture or composition or formulation of the invention (comprising (a), (b), (c), (d), and, optionally, (e) and/or (f), according to any of the embodiments or aspects described), preferably said (d) zinc (zinc element) ? including as zinc oxide (ZnO, example of CAS no. 1314-13-2), zinc bisglycinate (chelated form of zinc, surrounded by amino acids; of synthetic origin), or zinc sulfate (ZnSO4, example of CAS no. 7733- 02-0).

In the mixture or composition or formulation of the invention (comprising (a), (b), (c), (d), (e) and optionally (f), according to any of the embodiments or aspects disclosed), said ( e) at least one strain of bacteria belongs to the genus Bifidobacterium or Lactobacillus, preferably belongs to the species selected from the group comprising or, alternatively, consisting of Bifidobacterium lactis, Bifidobacterium breve, Lactobacillus rhamnosus, Lactobacillus helveticus, plus? preferably ? selected from the group comprising or alternatively consisting of: Bifidobacterium lactis BL-04<? >(deposit number SD5219; also known as DGCC2908 and RB 4825) (Danisco), Bifidobacterium breve BR-03 (DSM filing number 16604) (Probiotical), Lactobacillus rhamnosus crl1505 (Sacco), Lactobacillus rhamnosus GG (ATCC filing number 53103) (Hansen), Lactobacillus helveticus Lafti<? >L-10 (CBS filing number 116411) (Lallemand), and a mixture thereof, or, alternatively, in the group comprising or, alternatively, consisting of: Bifidobacterium lactis BL-04<? >(SD5219), Bifidobacterium breve BR-03 (DSM 16604), Lactobacillus rhamnosus GG (ATCC 53103), Lactobacillus helveticus Lafti<? >L-10 (CBS 116411), and a mixture thereof (ATCC, short for American Type Culture Collection; DMS: short for Das Leibniz-Institut Deutsche Sammlung von Mikroorganismen und Zellkulturen; CBS: short for Centraalbureau voor Schimmelcultures).

Said (e) strain of bacteria belonging to the genus Bifidobacterium or Lactobacillus, preferably selected from the strains Bifidobacterium lactis BL-04<? >(SD5219) Lactobacillus rhamnosus crl1505, Lactobacillus rhamnosus GG (ATCC 53103), Lactobacillus helveticus Lafti? L-10 (CBS116114), can? be present in the mixture or composition or formulation of the invention in the form of a live and viable strain (synonym: probiotic strain) or an inactivated strain (for example, inactivated by tyndallization or gammaturation or sonication) or a derivative of the probiotic strain.

In the context of the present invention, with the term ?derived? of the probiotic strain means a parabiotic or a postbiotic, such as for example the lysates or homogenized products of the bacterial strain, the extracts or parietal fraction of the bacterial strain, the metabolites or metabolic bioproducts or exopolysaccharides (EPS) generated by the bacterial strain and /or any other product deriving from the strain of bacteria known to the person skilled in the art. Said derivatives are obtained according to methodologies and equipment known to those skilled in the art. Preferably with the term ?derived? of the bacterial strain means: the lysates or homogenized products of the bacterial strain, the extracts or the parietal fraction of the bacterial strain.

In the mixture or composition or formulation of the invention (comprising (a), (b), (c), (d), (e) and (f), according to any of the embodiments or aspects described), preferably said ( f) prebiotic? selected from the group comprising or, alternatively, consisting of: an inulin, a fructo-oligosaccharide (FOS), a galacto-oligosaccharide (GOS), a xylitol-oligosaccharide (XOS), and a mixture thereof; preferably said (f) prebiotic comprises or, alternatively, consists of an inulin (polysaccharide of vegetable nature, example of CAS nr 9005-80-5, chemical formula C6nH10n+2O5n+1).

Said mixture of the invention (included in the composition or formulation of the invention) can comprising or, alternatively, consisting of: said (a) Ganoderma lucidum extract titrated in polysaccharides (% w/w of polysaccharides: from 5% to 60% or from 20% to 40% or from 25% to 35%); said (b) extract of a Panax ginseng plant titrated in ginsenosides (%w/w of ginsenosides: from 5% to 50% or from 10% to 30% or from 15% to 25%); said (c) at least one vitamin comprising or, alternatively consisting of: (c.1) vitamin C, (c.2) vitamin D, and (c.3) at least one vitamin of group B (such as B1, B2, B3, B5, B6, B9 and/or B12); (d) zinc (zinc element), preferably wherein said zinc is selected from the group comprising or, alternatively, consisting of: zinc oxide, zinc bisglycinate and zinc sulfate, plus? preferably zinc oxide.

Said mixture of the invention (included in the composition or formulation of the invention) can comprising or, alternatively, consisting of: said (a) Ganoderma lucidum extract titrated in polysaccharides (% w/w of polysaccharides: from 5% to 60% or from 20% to 40% or from 25% to 35%); said (b) extract of a Panax ginseng plant titrated in ginsenosides (%w/w of ginsenosides: from 5% to 50% or from 10% to 30% or from 15% to 25%); said (c) at least one vitamin comprising or, alternatively consisting of: (c.1) vitamin C, (c.2) vitamin D, and (c.3) at least one vitamin of group B (such as B1, B2, B3, B5, B6, B9 and/or B12); (d) zinc (zinc element), preferably wherein said zinc is selected from the group comprising or, alternatively, consisting of: zinc oxide, zinc bisglycinate and zinc sulfate, plus? preferably zinc oxide; said (e) strain selected from the group comprising or, alternatively, consisting of: Bifidobacterium lactis BL-04<? >(SD5219), Bifidobacterium breve BR-03 (DSM 16604), Lactobacillus rhamnosus crl1505, Lactobacillus rhamnosus GG (ATCC 53103), Lactobacillus helveticus Lafti? L-10 (CBS116114) (live and viable strain (probiotic) or inactivated strain); and, optionally, said (f) prebiotic, preferably inulin.

Said mixture of the invention (included in the composition or formulation of the invention) can comprising or, alternatively, consisting of: (a) an extract of Ganoderma lucidum titrated in polysaccharides (% w/w polysaccharides: 5% to 60% or 20% to 40% or 25% to 35%); said (b) extract of a Panax ginseng plant titrated in ginsenosides (%w/w of ginsenosides: from 5% to 50% or from 10% to 30% or from 15% to 25%); called (c.1) vitamin C, (c.2) vitamin D, preferably vitamin D3, (c.3-i) vitamin B1, (c.3-ii) vitamin B2, (c.3-iii) vitamin B3 , (c.3-iv) vitamin B5, (c.3-v) vitamin B6, (c.3-vi) vitamin B9, and (c.3-vii) vitamin B12; said (d) zinc (zinc element), preferably zinc oxide; said (e) strain selected from the group comprising or, alternatively, consisting of: Bifidobacterium lactis BL-04<? >(SD5219), Bifidobacterium breve BR-03 (DSM 16604), Lactobacillus rhamnosus crl1505, Lactobacillus rhamnosus GG (ATCC 53103), Lactobacillus helveticus Lafti<? >L-10 (CBS116114) (live and viable strain (probiotic) or inactivated strain); and, optionally, said (f) prebiotic, preferably inulin.

Said mixture of the invention (included in the composition or formulation of the invention) can comprising or, alternatively, consisting of: (a) an extract of Ganoderma lucidum titrated in polysaccharides (% w/w polysaccharides: 5% to 60% or 20% to 40% or 25% to 35%); said (b) extract of a plant of the genus Panax titrated in ginsenosides (%w/w of ginsenosides: from 5% to 50% or from 10% to 30% or from 15% to 25%), in which said plant of the genus Panax, ? selected from the group comprising or, alternatively, consisting of: Panax ginseng, Panax notoginseng, Panax pseudoginseng, Panax quinquefolium and mixtures thereof, preferably Panax ginseng; called (c.1) vitamin C, (c.2) vitamin D, preferably vitamin D3, (c.3-i) vitamin B1, (c.3-ii) vitamin B2, (c.3-iii) vitamin B3 , (c.3-iv) vitamin B5, (c.3-v) vitamin B6, (c.3-vi) vitamin B9, and (c.3-vii) vitamin B12; said (d) zinc (zinc element), preferably zinc oxide; said(s) said(s) Bifidobacterium lactis strain BL-04<? >SD5219 (live and viable strain (probiotic) or inactivated strain); and, optionally, said (f) prebiotic, preferably inulin.

Preferably, said mixture of the invention (comprised in the composition or formulation of the invention) comprises or, alternatively, consists of: said (a) extract of Ganoderma lucidum comprising polysaccharides from 5% to 60% by weight, said (b) extract of a Panax ginseng plant comprising ginsenosides from 5% to 50% by weight, preferably (a) from 20% to 40% and (b) from 10% to 30%, plus? preferably (a) 25% to 35% and (b) 15% to 25%; called (c.1) vitamin C, (c.2) vitamin D, preferably vitamin D3, (c.3-i) vitamin B1, (c.3-ii) vitamin B2, (c.3-iii) vitamin B3 , (c.3-iv) vitamin B5, (c.3-v) vitamin B6, (c.3-vi) vitamin B9, and (c.3-vii) vitamin B12, (d) zinc, preferably zinc oxide , called (e) strain Bifidobacterium lactis BL04<? >SD5219 (live and viable strain (probiotic) or inactivated strain), and called (f) inulin.

According to a preferred aspect, the composition of the invention is formulated for oral (or sublingual) administration.

The dosage form of the composition of the invention can be a solid form, such as a tablet, chewable tablet, capsule, lozenge, granule or powder (granules or powder to be dissolved in water or buccal), or a semi-solid form, such as a softgel, or a liquid form, such as a solution, suspension, dispersion, emulsion or syrup; preferably the composition of? invention ? in solid form for oral use, pi? preferably in tablet form.

According to one aspect of the present invention, the composition of the invention (comprising (a), (b), (c), (d), and optionally (e) and/or (f), according to any one of the embodiments or aspects described) formulated in solid form of multilayer tablet with differentiated release (in short, formulation of the invention).

Said formulation of the invention, for example bilayer formulation, can understand:

(I) a quick release layer comprising said (a) Ganoderma lucidum extract comprising polysaccharides (% w/w polysaccharides: 5% to 60% or 20% to 40% or 25% to 35%), said ( c) at least one vitamin, preferably (c.2) vitamin D and/or (c.3) at least one vitamin of group B, and said (d) zinc (for example, zinc oxide); wherein said (I) rapid release layer breaks down and releases (a), (c) and (d) into the intestinal tract in a time ranging from 30 minutes to 120 minutes following administration of the composition to a subject, preferably ranging from 60 minutes to 120 minutes, plus? preferably ranging from 75 minutes to 105 minutes; And

(III) a sustained release layer comprising said (b) extract of a plant of the genus Panax, preferably Panax ginseng, comprising ginsenosides (%w/w ginsenosides: 5% to 50% or 10% to 30% or 15% to 25%) and, optionally, (c.1) vitamin C, in which said (III) sustained-release layer breaks down and releases (b) (and, optionally, (c.1)) into the intestinal tract in a time ranging from 180 minutes to 270 minutes following administration of the composition to said subject, preferably ranging from 180 minutes to 240 minutes, plus? preferably ranging from 180 minutes to 210 minutes.

Said formulation of the invention can? understand:

(I) a quick release layer comprising said (a) Ganoderma lucidum extract comprising polysaccharides (% w/w polysaccharides: 5% to 60% or 20% to 40% or 25% to 35%), said ( c) at least one vitamin, preferably (c.2) vitamin D and/or (c.3) at least one vitamin of group B, and said (d) zinc (for example, zinc oxide); wherein said (I) rapid release layer breaks down and releases (a), (c) and (d) into the intestinal tract in a time ranging from 30 minutes to 120 minutes following administration of the composition to a subject, preferably ranging from 60 minutes to 120 minutes, plus? preferably ranging from 75 minutes to 105 minutes; And

(II) an intermediate release layer comprising said (e) strain of bacteria belonging to the genus Bifidobacterium or Lactobacillus, preferably the strain Bifidobacterium lactis BL-04<? >SD5219, and said (f) prebiotic, preferably an inulin, in which said (II) intermediate release layer breaks down and releases (e) and (f) into the intestinal tract in a time ranging from 120 minutes to 180 minutes following the administration of the composition to said subject, preferably ranging from 120 minutes to 160 minutes, plus? preferably ranging from 120 minutes to 140 minutes; And

(III) a sustained release layer comprising said (b) extract of a plant of the genus Panax, preferably Panax ginseng, comprising ginsenosides (%w/w ginsenosides: 5% to 50% or 10% to 30% or 15% to 25%) and, optionally, (c.1) vitamin C, in which said (III) sustained-release layer breaks down and releases (b) (and, optionally, (c.1)) into the intestinal tract in a time ranging from 180 minutes to 270 minutes following administration of the composition to said subject, preferably ranging from 180 minutes to 240 minutes, plus? preferably ranging from 180 minutes to 210 minutes.

According to a preferred embodiment, said formulation of the invention of multilayer tablet with differentiated release comprises three layers, wherein said (I) rapid release layer comprises (a), (d), (c.2) and (c. 3), preferably in which said (c.3) at least one vitamin of group B? selected from the group comprising or alternatively consisting of: (c.3-i) vitamin B1, (c.3-ii) vitamin B2, (c.3-iii) vitamin B3, (c.3-iv) vitamin B5 (c.3-v), vitamin B6, (c.3-vi) vitamin B9, (c.3-vii) vitamin 12, and a mixture thereof (preferably called (c.3) is a mixture comprising (c .3-i), (c.3-ii), (c.3-iii), (c.3-iv), (c.3-v), (c.3-vi) and (c.3 -vii)); said (II) intermediate release layer comprises (e) and (f); and said (III) sustained release layer comprises (b) and (c.1).

For example, the formulation of the invention of multilayer (triple-layer) tablet with differentiated release advantageously comprises:

- said quick release layer (I) which comprises or, alternatively, consists of: the active compounds (a), (d) and, optionally, (c.2) and/or (c.3), and additives and/ or excipients of layer (I) selected from the group comprising or, alternatively, consisting of: stearate of an alkali or alkaline earth metal (for example magnesium), silicon dioxide, mono and diglycerides of fatty acids, microcrystalline cellulose, hydroxypropyl methylcellulose, flavorings natural or artificial and their mixtures;

- said intermediate release layer (II) which comprises or, alternatively, consists of: active compounds (e) and, optionally, (f) and additives and/or excipients of layer (II) selected from the group comprising or, alternatively, consisting of: phosphate buffer (e.g. dicalcium phosphate), stearate of an alkali or alkaline earth metal (e.g. magnesium), silicon dioxide, microcrystalline cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, starch or corn starch, and mixtures thereof;

- said sustained release layer (III) which comprises or, alternatively, consists of: the active compound (b) and, optionally, (c.1) and additives and/or excipients of layer (III) selected from the group comprising or, alternatively, consisting of: alkali or alkaline earth metal (e.g., magnesium) stearate, silicon dioxide, microcrystalline cellulose, hydroxypropyl methylcellulose, and mixtures thereof.

It is understood that the quantity and the weight ratios between the various additives and/or excipients of each layer of said multilayer formulation (for example, layer (I), (II) and/or (III)) will be determined and varied by the expert in the art in order to obtain the desired release time, according to methodologies known in the sector of solid formulations for oral use.

Said (b) extract of a plant of the genus Panax, preferably Panax ginseng, is advantageously inserted in the prolonged-release layer (III) as it allows to avoid release at the gastric level, which in hypersensitive subjects could cause gastric side effects, and to be mainly absorbed at the intestinal level.

Furthermore, the (vital or inactivated) probiotic bacteria strain (e) and inulin (f) are advantageously inserted in the intermediate release layer (II) as it allows them to be isolated in a dedicated layer, so the viability is increased. of the probiotic bacteria strain is not affected by the presence of other substances such as, for example, extracts of vegetable origin. The strain of bacteria present in layer (II) ? It is a gastro-resistant strain, therefore the timing of gastro-intestinal release does not affect its vitality.

Said formulation of the invention of a three-layer tablet with differentiated release can? comprising said intermediate release layer (II) in a position between (between) said quick release layer (I) and said sustained release layer (III), wherein said layers (I), (II) and (III ) are characterized in any of the forms described.

The mixture or composition or formulation of the invention can? advantageously understand for ?unit? of daily dose?, preferably in solid form (such as, for example, a bilayer or triple-layer tablet with differentiated release), the following quantities?: (a) an extract of Ganoderma lucidum titrated in polysaccharides in a percentage by weight of 5 % to 60% or from 20% to 40% or from 25% to 35% (e.g. dry extract, 30% polysaccharides), in a quantity? ranging from 10 mg to 500 mg, preferably ranging from 50 mg to 300 mg, plus? preferably ranging from 100 mg to 200 mg (for example, about 150 mg of which 45 mg of polysaccharides);

(b) an extract of a plant of the genus Panax, preferably Panax ginseng, titrated in ginsenosides in a weight percentage ranging from 5% to 50% or from 10% to 30% or from 15% to 25% (e.g. dry extract of roots, 20% ginsenosides) in a quantity? ranging from 1 mg to 300 mg, preferably ranging from 10 mg to 150 mg, plus? preferably ranging from 20 mg to 75 mg (for example, about 45 mg of which 9 mg ginsenosides);

(c) at least one vitamin according to the reference nutritional value pursuant to EU Reg. 1169/2011 (in short, VNR), preferably in which said vitamins are selected from vitamin C, vitamin D, a vitamin of group B and one of their blend;

(d) zinc (for example zinc oxide) in a quantity? as elemental zinc ranging from 1 mg to 30 mg, preferably ranging from 5 mg to 30 mg, plus? preferably ranging from 5 mg to 15 mg (e.g. 6mg, 7 mg, 8 mg, 9 mg, 10 mg, 11 mg, 12 mg, 13 mg or 14 mg; 15 mg/day is the currently maximum daily dose for an adult subject in Italy);

and, optionally, (e) a strain of bacteria belonging to the genus Bifidobacterium or Lactobacillus (preferably selected from the strains Bifidobacterium Lactis BL-04<? >SD5219, Lactobacillus rhamnosus crl1505, Lactobacillus rhamnosus GG (ATCC 53103), or Lactobacillus helveticus Lafti< ?>L-10 (CBS116114)) in a quantity? ranging from 10<7 >CFU to 10<12 >CFU, preferably from 10<9 >CFU to 10<10 >CFU, plus? preferably about 2 x 10<9 >CFU (CFU: Colony Forming Unit);

and, optionally, (f) inulin in an amount? ranging from 10 mg to 500 mg, preferably ranging from 10 mg to 350 mg, plus? preferably ranging from 50 mg to 150 mg (e.g., about 60 mg, 70 mg, 80 mg, 90 mg or 100 mg, preferably about 100 mg).

The mixture or composition or formulation of the invention can? advantageously understand for ?unit? of daily dose?, preferably in solid form (such as, for example, a bilayer or triple-layer tablet with differentiated release), the following quantities?: (a) an extract of Ganoderma lucidum titrated in polysaccharides in a percentage by weight of 5 % to 60% or from 20% to 40% or from 25% to 35% (e.g. dry extract, 30% polysaccharides), in a quantity? ranging from 10 mg to 500 mg, preferably ranging from 50 mg to 300 mg, plus? preferably ranging from 100 mg to 200 mg (for example, about 150 mg of which 45 mg of polysaccharides);

(b) an extract of a plant of the genus Panax, preferably Panax ginseng, titrated in ginsenosides in a weight percentage ranging from 5% to 50% or from 10% to 30% or from 15% to 25% (e.g. dry extract of roots, 20% ginsenosides) in a quantity? ranging from 1 mg to 300 mg, preferably ranging from 10 mg to 150 mg, plus? preferably ranging from 20 mg to 75 mg (for example, about 45 mg of which 9 mg ginsenosides);

(c.1) vitamin C in a quantity? ranging from 10 mg to 500 mg, preferably ranging from 50 mg to 300 mg, plus? preferably ranging from 100 mg to 200 mg (for example about 150-160 mg and % VNR 200); (c.2) vitamin D in a quantity? ranging from 0.5 ?g to 100 ?g, preferably ranging from 2 ?g to 50 ?g, plus? preferably ranging from 5 ?g to 30 ?g (for example, about 18-20 ?g and % VNR 360); (c.3) vitamins of group B comprising or, alternatively, consisting of: (c.3-i) vitamin B1 in an amount ranging from 0.05 mg to 30 mg, preferably ranging from 0.1 mg to 10 mg, plus? preferably ranging from 0.5 mg to 3 mg (for example, about 2.2 mg and % VNR 200); (c.3-ii) vitamin B2 in a quantity? ranging from 0.05 mg to 35 mg, preferably ranging from 0.1 mg to 10 mg, plus? preferably ranging from 1 mg to 3.5 mg (e.g., about 2.8 mg and % NRV 200); (c.3-iii) vitamin B3 in a quantity? ranging from 1 mg to 100 mg, preferably ranging from 10 mg to 50 mg, plus? preferably ranging from 20 mg to 30 mg (for example, about 24-25 mg and % NRV 150); (c.3-iv) vitamin B5 in a quantity? ranging from 0.5 mg to 50 mg, preferably ranging from 1 mg to 30 mg, plus? preferably ranging from 5 mg to 15 mg (for example, about 9-10 mg and % NRV 150); (c.3-v) vitamin B6 in a quantity? ranging from 0.05 mg to 50 mg, preferably ranging from 0.1 mg to 10 mg, plus? preferably ranging from 1 mg to 3.5 mg (e.g., about 2.8 mg and % NRV 200); (c.3-vi) vitamin B9 in a quantity? between 10 ?g and 1000 ?g, preferably between 50 ?g and 750 ?g, plus? preferably ranging from 100 ?g to 500 ?g (e.g., about 400 ?g and % NRV 200), and (c.3-vii) vitamin B12 in an amount ranging from 0.1 ?g to 50 ?g, preferably ranging from 0.5 ?g to 15 ?g, plus? preferably ranging from 1 ?g to 7 ?g (for example, about 5 ?g and % VNR 200);

(d) zinc, preferably in the form of zinc oxide, in an amount as elemental zinc ranging from 1 mg to 40 mg, preferably ranging from 1 mg to 30 mg, plus? preferably ranging from 5 mg to 15 mg (e.g. 15 mg); and, optionally, (e) a strain of bacteria belonging to the genus Bifidobacterium or Lactobacillus (preferably selected from the strains Bifidobacterium Lactis BL-04<? >SD5219, Lactobacillus rhamnosus crl1505, Lactobacillus rhamnosus GG (ATCC 53103), or Lactobacillus helveticus Lafti< ?>L-10 (CBS116114)) in a quantity? ranging from 10<7 >CFU to 10<12 >CFU, preferably from 10<9 >CFU to 10<10 >CFU, plus? preferably about 2 x 10<9 >CFU (CFU: Colony Forming Unit);

and, optionally, (f) inulin in an amount? ranging from 10 mg to 500 mg, preferably ranging from 10 mg to 350 mg, plus? preferably ranging from 50 mg to 150 mg (e.g., about 100 mg).

This ?unit? of daily dose? of the composition of? the invention can? be administered to a person in need? within 24 hours by a single dose or divided into 2, 3 or 4 doses at intervals of time from 4 hours to 12 hours, depending on the type of dosage form and the needs? of the subject. Preferably, said ?unit? of daily dose? of the composition of the invention is administered to a subject in need? once a day (for example, between meals) in the form of a bilayer or triple-layer tablet according to a described embodiment of the formulation of the present invention.

For example, a bilayer tablet with differentiated release, as a formulation of the composition of the invention (equivalent to a daily dose), comprises the following quantities: per layer:

- said (I) rapid release layer comprising: (a) an extract of Ganoderma lucidum titrated in polysaccharides in a percentage by weight from 5% to 60% or from 20% to 40% or from 25% to 35% (e.g. extract dry, about 30% polysaccharides), in a quantity? ranging from 10 mg to 500 mg, preferably ranging from 50 mg to 300 mg, plus? preferably ranging from 100 mg to 200 mg (for example, about 150 mg of which 45 mg of polysaccharides);

(d) zinc, preferably in the form of zinc oxide, in an amount as elemental zinc ranging from 1 mg to 40 mg, preferably ranging from 1 mg to 30 mg, plus? preferably ranging from 5 mg to 15 mg (e.g. about 15 mg);

(c) at least one vitamin, preferably selected from (c.2) vitamin D according to VNR and/or (c.3) vitamins of group B according to VNR; And

- said (III) sustained release layer comprising:

(b) an extract of a plant of the genus Panax, preferably Panax ginseng, titrated in ginsenosides in a weight percentage ranging from 5% to 50% or from 10% to 30% or from 15% to 25% (e.g. dry extract of roots, about 20% ginsenosides) in a quantity? ranging from 1 mg to 300 mg, preferably ranging from 10 mg to 150 mg, plus? preferably ranging from 20 mg to 75 mg (for example, about 45 mg of which 9 mg ginsenosides);

and, optionally, (c.1) vitamin C according to VNR.

For example, a triple-layer tablet with differentiated release, as a formulation of the composition of the invention (equivalent to a daily dose), comprises the following quantities: per layer:

- said (I) rapid release layer comprising: (a) an extract of Ganoderma lucidum titrated in polysaccharides in a percentage by weight from 5% to 60% or from 20% to 40% or from 25% to 35% (e.g. extract dry, about 30% polysaccharides), in a quantity? ranging from 10 mg to 500 mg, preferably ranging from 50 mg to 300 mg, plus? preferably ranging from 100 mg to 200 mg (for example, about 150 mg of which 45 mg of polysaccharides);

(d) zinc, preferably in the form of zinc oxide, in an amount as elemental zinc ranging from 1 mg to 40 mg, preferably ranging from 1 mg to 30 mg, plus? preferably ranging from 5 mg to 15 mg (e.g. about 15 mg);

(c) at least one vitamin, preferably selected from (c.2) vitamin D according to VNR and/or (c.3) vitamins of group B according to VNR; And

- said (II) intermediate release layer comprising:

(e) a strain of bacteria belonging to the genus Bifidobacterium or Lactobacillus (preferably selected from the strains Bifidobacterium Lactis BL-04<? >SD5219, Lactobacillus rhamnosus crl1505, Lactobacillus rhamnosus GG (ATCC 53103), or Lactobacillus helveticus Lafti<? >L- 10 (CBS116114)) in a quantity? ranging from 10<7 >CFU to 10<12 >CFU, preferably from 10<9 >CFU to 10<10 >CFU, plus? preferably about 2 x 10<9 >CFU;

and, optionally, (f) inulin in an amount? ranging from 10 mg to 500 mg, preferably ranging from 10 mg to 350 mg, plus? preferably ranging from 50 mg to 150 mg (e.g., about 100 mg); And

- said (III) sustained release layer comprising:

(b) an extract of a plant of the genus Panax, preferably Panax ginseng, titrated in ginsenosides in a weight percentage ranging from 5% to 50% or from 10% to 30% or from 15% to 25% (e.g. dry extract of roots, about 20% ginsenosides) in a quantity? ranging from 1 mg to 300 mg, preferably ranging from 10 mg to 150 mg, plus? preferably ranging from 20 mg to 75 mg (for example, about 45 mg of which 9 mg ginsenosides);

and, optionally, (c.1) vitamin C according to VNR.

According to a preferred example, a triple-layer tablet with differentiated release, as a formulation of the composition of the invention (equivalent to a daily dose), comprises the following quantities: per layer:

- said (I) rapid release layer comprising: (a) an extract of Ganoderma lucidum titrated in polysaccharides in a percentage by weight from 5% to 60% or from 20% to 40% or from 25% to 35% (e.g. extract dry, about 30% polysaccharides), in a quantity? ranging from 10 mg to 500 mg, preferably ranging from 50 mg to 300 mg, plus? preferably ranging from 100 mg to 200 mg (for example, about 150 mg of which 45 mg of polysaccharides);

(d) zinc, preferably in the form of zinc oxide, in an amount as elemental zinc ranging from 1 mg to 40 mg, preferably ranging from 1 mg to 30 mg, plus? preferably ranging from 5 mg to 15 mg (e.g. about 15 mg);

(c.2) vitamin D in a quantity? ranging from 0.5 ?g to 100 ?g, preferably ranging from 2 ?g to 50 ?g, plus? preferably ranging from 5 ?g to 30 ?g (for example, about 18-20 ?g and % VNR 360); (c.3) vitamins of group B comprising or, alternatively, consisting of: (c.3-i) vitamin B1 in an amount ranging from 0.05 mg to 30 mg, preferably ranging from 0.1 mg to 10 mg, plus? preferably ranging from 0.5 mg to 3 mg (for example, about 2.2 mg and % VNR 200); (c.3-ii) vitamin B2 in a quantity? ranging from 0.05 mg to 35 mg, preferably ranging from 0.1 mg to 10 mg, plus? preferably ranging from 1 mg to 3.5 mg (e.g., about 2.8 mg and % NRV 200); (c.3-iii) vitamin B3 in a quantity? ranging from 1 mg to 100 mg, preferably ranging from 10 mg to 50 mg, plus? preferably ranging from 20 mg to 30 mg (for example, about 24-25 mg and % NRV 150); (c.3-iv) vitamin B5 in a quantity? ranging from 0.5 mg to 50 mg, preferably ranging from 1 mg to 30 mg, plus? preferably ranging from 5 mg to 15 mg (for example, about 9-10 mg and % NRV 150); (c.3-v) vitamin B6 in a quantity? ranging from 0.05 mg to 50 mg, preferably ranging from 0.1 mg to 10 mg, plus? preferably ranging from 1 mg to 3.5 mg (e.g., about 2.8 mg and % NRV 200); (c.3-vi) vitamin B9 in a quantity? between 10 ?g and 1000 ?g, preferably between 50 ?g and 750 ?g, plus? preferably ranging from 100 ?g to 500 ?g (e.g., about 400 ?g and % NRV 200), and (c.3-vii) vitamin B12 in an amount ranging from 0.1 ?g to 50 ?g, preferably ranging from 0.5 ?g to 15 ?g, plus? preferably ranging from 1 ?g to 7 ?g (for example, about 5 ?g and % VNR 200); and - said (II) intermediate release layer comprising:

(e) a strain of bacteria belonging to the genus Bifidobacterium or Lactobacillus (preferably selected from the strains Bifidobacterium Lactis BL-04<? >SD5219, Lactobacillus rhamnosus crl1505, Lactobacillus rhamnosus GG (ATCC 53103), or Lactobacillus helveticus Lafti<? >L- 10 (CBS116114)) in a quantity? ranging from 10<7 >CFU to 10<12 >CFU, preferably from 10<9 >CFU to 10<10 >CFU, plus? preferably about 2 x 10<9 >CFU;

and (f) inulin in an amount? ranging from 10 mg to 500 mg, preferably ranging from 10 mg to 350 mg, plus? preferably ranging from 50 mg to 150 mg (e.g., about 100 mg); And

- said (III) sustained release layer comprising:

(b) an extract of a plant of the genus Panax, preferably Panax ginseng, titrated in ginsenosides in a weight percentage ranging from 5% to 50% or from 10% to 30% or from 15% to 25% (e.g. dry extract of roots, about 20% ginsenosides) in a quantity? ranging from 1 mg to 300 mg, preferably ranging from 10 mg to 150 mg, plus? preferably ranging from 20 mg to 75 mg (for example, about 45 mg of which 9 mg ginsenosides);

(c.1) vitamin C in a quantity? ranging from 10 mg to 500 mg, preferably ranging from 50 mg to 300 mg, plus? preferably ranging from 100 mg to 200 mg (for example about 150-160 mg and % NRV 200).

According to a further preferred example, a triple-layer tablet with differentiated release, as a formulation of the composition of the invention (equivalent to a daily dose), comprises the following quantities: per layer:

- said (I) rapid release layer comprising: (a) an extract of Ganoderma lucidum titrated in polysaccharides in a weight percentage of from 25% to 35% (e.g. dry extract, about 30% polysaccharides), in an amount ranging from 100 mg to 200 mg (for example, about 150 mg of which 45 mg are polysaccharides);

(c.2) vitamin D in a quantity? between 5 ?g and 30 ?g (for example, about 18-20 ?g and % VNR 360); (c.3) vitamins of group B comprising or, alternatively, consisting of: (c.3-i) vitamin B1 in an amount ranging from 0.5 mg to 3 mg (e.g., about 2.2 mg and % NRV 200); (c.3-ii) vitamin B2 in a quantity? ranging from 1 mg to 3.5 mg (for example, about 2.8 mg and % NRV 200); (c.3-iii) vitamin B3 in a quantity? ranging from 20 mg to 30 mg (for example, about 24-25 mg and % NRV 150); (c.3iv) vitamin B5 in a quantity? ranging from 5 mg to 15 mg (for example, about 9-10 mg and % NRV 150); (c.3-v) vitamin B6 in a quantity? ranging from 1 mg to 3.5 mg (for example, about 2.8 mg and % NRV 200); (c.3-vi) vitamin B9 in a quantity? ranging from 100 ?g to 500 ?g (e.g., about 400 ?g and % NRV 200), and (c.3-vii) vitamin B12 in an amount ranging from 1 ?g to 7 ?g (for example, about 5 ?g and % VNR 200);

(d) zinc, preferably in the form of zinc oxide, in an amount of elemental zinc ranging from 5 mg to 15 mg (e.g., about 15 mg); And

- said (II) intermediate release layer comprising:

(e) a bacterial strain selected from the Bifidobacterium Lactis BL-04<? >SD5219, Lactobacillus rhamnosus crl1505, Lactobacillus rhamnosus GG (ATCC 53103), or Lactobacillus helveticus Lafti? L-10 (CBS116114), preferably Bifidobacterium Lactis BL-04<? >SD5219, in a quantity? about 2 x 10<9 >CFU;

and (f) inulin in an amount? ranging from 50 mg to 150 mg (e.g., about 100 mg); And

- said (III) sustained release layer comprising:

(b) an extract of Panax ginseng, titrated in ginsenosides in a percentage by weight ranging from 15% to 25% (e.g. dry extract of roots, about 20% ginsenosides) in an amount ranging from 20 mg to 75 mg (for example, about 45 mg of which 9 mg ginsenosides); (c.1) vitamin C in a quantity? ranging from 100 mg to 200 mg (e.g. about 150-160 mg and % NRV 200).

Said triple-layer tablet with differentiated release can? have a thickness of 10 mm to 20 mm.

The object of the present invention is the mixture or composition of the invention (comprising (a), (b), (c), (d), and, optionally, (e) and/or (f), according to any of the forms embodiment or aspects described) and/or its multilayer formulation with differentiated release according to the invention for use as a medicament.

The object of the present invention is the mixture or composition of the invention (comprising (a), (b), (c), (d), and, optionally, (e) and/or (f), according to any of the forms embodiment or aspects described) and/or its formulation in multilayer solid form with differentiated release according to the invention for use in a method of treatment, preventive and/or curative, of flu symptoms and/or respiratory tract infection, preferably infection of the upper respiratory tract, in a subject having need?, through the administration to said subject of a quantity? therapeutically effective of the blend or composition or formulation of the present invention.

Said flu symptoms can be selected in the group comprising or, alternatively, consisting of: muscle and joint pain, asthenia/fatigue, cough, increased respiratory secretions, fever, headache, sore throat (pharyngo-laryngodynia), nasal congestion, respiratory tract congestion, dyspnoea, chills.

Said respiratory tract infections, of bacterial and/or viral origin, can be selected from the group comprising or, alternatively, consisting of: rhinitis, sinusitis, pharyngitis, tonsillitis, laryngitis, tracheitis, bronchitis, bronchiolitis, pneumonia.

The mixture or composition or formulation of the invention can? be for use in a method of preventive treatment of flu symptoms (as defined above) to avoid the onset of said flu syndromes or to mitigate their intensity? of these symptoms if they occur.

The mixture or composition or formulation of the invention can? be for use in a method of curative treatment of influenza symptoms (as defined above) either when administered to an individual as the only therapy capable of treating said influenza symptoms or when administered as an adjunct to at least one other therapy or composition capable of treat these flu symptoms.

For clarity, to achieve the object of the present invention, the active compounds of the mixture or composition of the present invention ((a), (b), (c.1), (c.2), (c.3), (d ), and, optionally, (e) and/or (f)) can also be administered separately or in groups (preferably in a time interval of 30 minutes-2-3 hours) and in any order.

Said at least one additive and/or excipient of pharmaceutical or food grade, included in the composition of the invention together with the mixture of (a), (b), (c), (d), and, optionally, (e) and/or (f), consists of a substance without activity? therapeutic suitable for pharmaceutical or alimentary use chosen among the auxiliary substances known to the expert in the field such as, for example, diluents, solvents (including water, glycerin, ethyl alcohol), solubilizers, thickeners, sweeteners, flavourings, colourings, lubricants, surfactants , antimicrobials, antioxidants, preservatives, pH stabilizing buffers, and mixtures thereof. Non-limiting examples of such substances are phosphate buffers (e.g. dicalcium phosphate), alkali or alkaline earth metal stearate (e.g. magnesium), silicon dioxide, mono and diglycerides of fatty acids, microcrystalline cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, starch or corn starch, natural or artificial flavors (for example, iron oxides).

Said composition or formulation of the invention can? be a pharmaceutical composition or formulation, a composition or formulation for medical devices (Medical Device Regulation (EU) 2017/745 (MDR)), a food supplement and/or a food for specialized medical purposes (AFMS).

With the term ?subject/s? within the scope of the present invention mammals (animals and humans), preferably human subjects, are indicated.

The term ?quantity? therapeutically effective? does it refer to the quantity? of mixture or compound or formulation that elicits the biological or medicinal response in a tissue, system or subject that is researched and defined by an expert in the art.

Unless otherwise specified, the expression mixture or composition or formulation includes a component in an amount? ?in the range from x to y? do you mean that this component can? be present in the composition in all quantities? present in said range, even if not explicit, including extremes of the range.

Examples of active components which can be used in the context of the present invention are given below.

An example of Panax ginseng extract (Meyer) which can be used in the composition of the present invention ? a Panax ginseng root extract (extraction solvent water:ethanol=8:1), HPTLC identification, comprising 10% w/w maltodextrin, 20.0% ginsenosides (HPLC), PAH hydrocarbons less than 50 ppb (GC -MS), benzo(a)pyrene ?10 ?g/kgm, sieve analysis: 100% through 80 mesh (USP39 <786>), water (KF) ?5% (Eur.Ph.7.0. [2.5.12 ]), total ash ?5% (Eur.Ph.7.0. [2.4.16]).

An example of Ganoderma lucidum (Curtis) P. Karst extract usable in the composition of the present invention ? an extract of hand-picked Ganoderma lucidum, washed, dried, cut and extracted with water and then 90% (v/v) ethanol, wherein said extract comprises about 5% maltodextrin, residual solvents: ethanol ?5000ppm, benzo(a )pyrene ppb ?10 and PAH 4 ppb ?50.

An example of zinc oxide usable in the composition of the present invention ? zinc oxide 99.7% FU (INCI name CI 77947, CAS nr 1314-13-2) obtained by the following steps: melting of zinc ingot in a furnace to give liquid zinc, evaporation of liquid zinc in a melting furnace to give gaseous zinc, oxidation by air to give zinc oxide.

An example of vitamin C which can be used in the composition of the present invention ? a coated ascorbic acid having ascorbic acid content: VC-90: 89.0%~91.0%, VC-93: 92.0%~94.0%, VC-95: 94.0%~96, 0%, VC-97: 96.0%~98.0% ?97.5%-99.3%, VC-99: 98.0%~100.0%; and a loss on drying: VC-90: ?0.40%, VC-93: ?0.20%, VC-95: ?0.20%, VC-97: ?0.20%, VC-99: ?0.20%.

An example of vitamin D usable in the composition of the present invention ? a vitamin D3 having CAS No 67-97-0, min. 90,000 IU vitamin D3/g (equivalent to 2250 ?g cholecalciferol/g), density? (bulk density) ~0.6 g/mL.

An example of vitamin B1 which can be used in the composition of the present invention ? a vitamin B1 (thiamine hydrochloride) purity 98.5-101.0% w/w (Ph.Eur. method) or 98.0-102.0% w/w (USP method), pH 2.7~3, 3 (Ph.Eur.) or 2.7~3.4 (USP), water max. 5.0% w/w (Ph.Eur., USP), sulphated ash max. 0.1% w/w (Ph.Eur.), residues on ignition max. 0.2% w/w (USP), residual solvents (USP): methanol max. 0.3% w/w and ethanol max. 0.5%.

An example of vitamin B2 which can be used in the composition of the present invention ? a vitamin B2 (riboflavin high flow 100 (HF)) having CAS No. 83-88-5. An example of vitamin B3 which can be used in the composition of the present invention ? vitamin B3 (FCC food grade niacinamide) having CAS No. 98-92-0 purity 99.0-101.0% w/w (HPLC), obtained from 3-cyanopyridine as starting material by the following steps: hydrolysis of 3-cyanopyridine on fixed bed biocatalyst to obtain a crude niacinamide solution, purification on fixed bed activated carbon, nanofiltration, evaporation and freeze-drying (spray drying).

An example of vitamin B5 usable in the composition of the present invention ? a calcium D-pantothenate having CAS No 137-08-6.

An example of vitamin B6 which can be used in the composition of the present invention ? a vitamin B6 (food grade pyridoxine hydrochloride) purity 99.0-101.0% w/w (Ph.Eur. method) or 98.0-102.0% w/w (USP method), pH 2.4~ 3.0(Ph.Eur.), chlorine (in anhydrous compound) 16.9%~17.6% w/w (USP), sulphated ash max. 0.1% w/w (Ph.Eur.), loss on drying max. 0.5% w/w (Ph.Eur.), residual solvents (Ph.Eur.): ethanol max. 0.5%.

An example of vitamin B9 which can be used in the composition of the present invention ? a vitamin B9 (folic acid) having CAS No. 59-30-3 and molecular weight 441.40, identification IR, Residue on ignition ?0.30% w/w, specific absorbance ratio 256/365 nm 2.80- 3.00, water ?8.50% w/w, titre (on anhydrous) 95.00-102.00% w/w.

An example of vitamin B12 which can be used in the composition of the present invention ? a vitamin B2 (Dry vitamin B12 0.1% GFP) having CAS No. 68-19-9.

L?inulin (example of CAS Nr 9005-80-5) ? a glucidic polymer with a lower molecular weight than starch (about 5000 Da), slightly soluble in water. ? the ?-D-fructose polymer, in which the monomers are joined by ?-2,1-glycosidic linkages.

An example of inulin usable in the composition of the present invention ? an inulin extracted from chicory roots comprising: inulin minimum 90% w/w, fructose glucose sucrestere maximum 10% w/w, average chain length 8-13 monomers, ash maximum 0.2% w/w, pH about 6( ?1), density? (tapped density) about 700 (?100) g/L.

A titration method of the polysaccharides contained in said Ganoderma lucidum extract by spectrophotometry, usable in the context of the present invention, ? performed according to the following procedure.

(I) Equipment: 721 spectrometer (or other model); (II) Reagents:

1. glucose standard solution (accurately weigh 10 mg of glucose standard for a constant dry weight at 105°C, into a 50 ml Erlenmeyer flask, add distilled water).

2. phenol, test solution (weigh 100 g of phenol, add 0.1 g of aluminum, 0.05 g of sodium bicarbonate, distill and collect the distillate at 182?C. Weigh 10 g and add distilled water 150 g in brown bottles).

(III) Process:

1) Standard curve preparation: pipette 0.00ml, 0.05ml, 0.1ml, 0.15ml, 0.2ml or 0.3ml glucose standard solution into different test tubes, add distilled water to all of them up to 2ml volume , then add Pheno 1.0ml, stir, add 5.0ml concentrated sulfuric acid, stir, then stand 5 minutes, heat to boiling for 15 minutes, and allow to cool to room temperature. Test A at 490 nm and draw the standard curve.

2) Sample preparation: Accurately weigh 0.2g of samples into the flask, add 100ml 80% ethanol, backflow 1 hour, filter, use 80% ethanol wash residue (10ml*3). Transfer to a flask using the filter paper, add 100ml distilled water, heat 1 hour, filter, use warm water to wash the residue (10ml*3). Lotion and Filtrate combined, after cooling, placed in a 250ml flask, diluted to a reserve.

3) Test the polysaccharides in the samples: take a part solution of the samples, add distilled water to volume 2ml, then add phenol 1.0ml, shake, add concentrated sulfuric acid 5ml, shake, then let stand for 5 minutes , bring to the boil for 15 minutes, leave to cool to room temperature. Test A at 490 nm.

(IV) Calculation

Cu%??Cs%?Au?Ws ?/?Wu?As ?

Cu: polysaccharide content in samples

Cs: polysaccharide content in standard

As: standard absorption ??max ?

Au: absorption of samples ??max ?

Wu: weight of samples?mg?

Ws: weight of standard?mg?

EXPERIMENTAL PART

In Table 1 ? an exemplary embodiment of the composition of the invention is reported comprising (a), (b), (c) and (d) formulated for oral use in the solid form of a bilayer tablet with differentiated release, of which a first layer (layer I ) rapid release and a second layer (layer III) extended release.

Table 1. (% w/w); *Vitamin B1 0.5-3 mg, Vitamin B2 1?3.5 mg, Vitamin B3 10?40 mg, Vitamin B5 3?15 mg, Vitamin B6 1?3.5 mg, Vitamin B9 100?500 ug, Vitamin B12 1?7 ug.

Tables 2-4 show exemplary embodiments of the composition of the invention comprising (a), (b), (c), (d), (e) and (f) formulated for oral use in solid tablet form at triple-layer with differentiated release, of which a first layer (layer I) with rapid release, a second layer (layer II) with intermediate release and a third layer (layer III) with prolonged release.

In this example, layer (II) ? disposed between the layer (I) and the layer (III).

Table 2. (% w/w); *Vitamin B1 0.5-3 mg, Vitamin B2 1?3.5 mg, Vitamin B3 10?40 mg, Vitamin B5 3?15 mg, Vitamin B6 1?3.5 mg, Vitamin B9 100?500 ug, Vitamin B12 1?7 ug.

Table 3. (% w/w); *Vitamin B1 0.5-3 mg, Vitamin B2 1?3.5 mg, Vitamin B3 20?30 mg, Vitamin B5 3?15 mg, Vitamin B6 1?3.5 mg, Vitamin B9 100?500 ug, Vitamin B12 1?7 ug. <(a)>Mg stearate, Si dioxide, mono and diglycerides of fatty acids, microcrystalline cellulose, hydroxypropyl methylcellulose, flavourings;

<(b)>Dicalcium Phosphate, Mg Stearate, Si Dioxide, Microcrystalline Cellulose, Hydroxypropyl Cellulose, Hydroxypropyl Methyl Cellulose and Maize Starch. <(c)>Mg stearate, Si dioxide, microcrystalline cellulose and hydroxypropyl methylcellulose.

Table 4. * mg/tablet: means mg of a commercial compound comprising or, alternatively, consisting of the listed ingredient.

Disintegration tests or dissolution tests of the solid formulations according to the invention (for example bilayer or triple-layer tablets according to Tables 1-4) can be carried out in order to evaluate the ability of said solid formulations to release the active components at different times and/or at different pH.

Claims (11)

1. A composition comprising a mixture comprising or alternatively consisting of: (a) an extract of Ganoderma lucidum comprising polysaccharides, (b) an extract of a plant of the genus Panax comprising ginsenosides, wherein said plant is selected from the group comprising or alternatively consisting of: Panax ginseng, Panax notoginseng, Panax pseudoginseng, Panax quinquefolium and mixtures thereof, (c) at least one vitamin selected from the group comprising or, alternatively, consisting of: (c.1) vitamin C, (c.2) vitamin D, (c.3) at least one vitamin of group B, and a mixture thereof, And (d) zinc, and, optionally, said composition further comprises at least one additive and/or excipient of food or pharmaceutical grade. 2. The composition according to claim 1, wherein said composition further comprises (e) at least one strain of bacteria belonging to the genus Bifidobacterium or Lactobacillus, preferably wherein said strain belongs to the species selected from the group comprising or, alternatively, consisting of Bifidobacterium lactis, Bifidobacterium breve, Lactobacillus rhamnosus, Lactobacillus helveticus; and, optionally, (f) at least one prebiotic, preferably wherein said prebiotic is selected from the group comprising or, alternatively, consisting of: an inulin, a fructo-oligosaccharide (FOS), a galactooligosaccharide (GOS), a xylitol-oligosaccharide (XOS), and a mixture thereof, plus? preferably inulin. 3. The composition according to claim 1 or 2, wherein said strain(s) of bacteria ? selected from the group comprising or, alternatively, consisting of: Bifidobacterium lactis BL-04<? >(SD5219), Lactobacillus rhamnosus crl1505, Lactobacillus rhamnosus GG (ATCC 53103), Lactobacillus helveticus Lafti? L-10 (CBS116114), and a mixture thereof. The composition according to any one of claims 1-3, wherein said (b) extract of a plant of the genus Panax consists of a plant of the species Panax ginseng (Meyer). 5. The composition according to any one of claims 1-4, wherein said (a) Ganoderma lucidum extract comprises polysaccharides in a percentage by weight ranging from 5% to 60%, preferably from 20% to 40%, plus ? preferably from 25% to 35%, with respect to the total weight of said (a); and/or wherein said (b) extract of a plant of the Panax genus, preferably Panax ginseng, comprises ginsenosides in a percentage by weight ranging from 5% to 50%, preferably from 10% to 30%, plus? preferably from 15% to 25%, with respect to the total weight of said (b). 6. The composition according to any one of claims 1-5, wherein said (c) at least one vitamin comprises or alternatively consists of: (c.1) vitamin C, (c.2) vitamin D, and (c. 3) at least one B group vitamin; preferably in which said (c.3) at least one vitamin of group B ? selected from the group comprising or, alternatively, consisting of: (c.3-i) vitamin B1, (c.3-ii) vitamin B2, (c.3-iii) vitamin B3, (c.3-iv) vitamin B5 , (c.3-v) vitamin B6, (c.3-vi) vitamin B9, (c.3-vii) vitamin B12, and a mixture thereof; more preferably said (c.3) at least one vitamin of group B comprises or, alternatively, consists of: (c.3-i) vitamin B1, (c.3-ii) vitamin B2, (c.3-iii) vitamin B3 , (c.3-iv) vitamin B5, (c.3-v) vitamin B6, (c.3-vi) vitamin B9, and (c.3-vii) vitamin B12. 7. The composition according to any one of claims 1-6, wherein said mixture comprises or, alternatively, consists of: - said (a) Ganoderma lucidum extract comprising polysaccharides in a percentage by weight ranging from 5% to 60%, preferably from 20% to 40%, plus? preferably from 25% to 35%, based on the total weight of (a); - said (b) Panax ginseng extract comprising ginsenosides in a percentage by weight ranging from 5% to 50%, preferably from 10% to 30%, plus? preferably from 15% to 25%, with respect to the total weight of (b); - known as (c.1) vitamin C, - known as (c.2) vitamin D, - called (c.3-i) vitamin B1, (c.3-ii) vitamin B2, (c.3-iii) vitamin B3, (c.3-iv) vitamin B5, (c.3-v) vitamin B6, (c.3-vi) vitamin B9, (c.3-vii) vitamin B12, - said (d) zinc, preferably zinc oxide, - said (e) strain ? selected from the group comprising or, alternatively, consisting of: Bifidobacterium lactis BL-04<? >(SD5219), Lactobacillus rhamnosus crl1505, Lactobacillus rhamnosus GG (ATCC 53103), Lactobacillus helveticus Lafti<? >L-10 (CBS116114), and a mixture thereof, preferably Bifidobacterium lactis BL-04<? >(SD5219) e - known as (f) inulin. 8. A solid form formulation of a multilayered, timed-release tablet, wherein said formulation comprises the mixture or composition according to any one of claims 1-7, e wherein said formulation comprises: (I) a quick release layer comprising - said (a) Ganoderma lucidum extract comprising polysaccharides, - said (c) at least one vitamin, preferably selected from the group comprising or, alternatively, consisting of: (c.2) vitamin D, (c.3) at least one vitamin of group B, and a mixture thereof, and - said (d) zinc, wherein said (I) rapid-release layer breaks down in the intestinal tract, releasing (a), (c) and (d), in a time ranging from 30 minutes to 120 minutes following administration of the composition to a subject, preferably including from 60 minutes to 120 minutes, more? preferably ranging from 75 minutes to 105 minutes; (III) a sustained-release layer comprising - said (b) extract of a plant of the genus Panax, preferably Panax ginseng, comprising ginsenosides, wherein said (III) sustained-release layer breaks down in the intestinal tract, releasing (b), in a time ranging from 180 minutes to 270 minutes following administration of the composition to said subject, preferably ranging from 180 minutes to 240 minutes, plus? preferably ranging from 180 minutes to 210 minutes. 9. The formulation in solid form of multilayer tablet with differentiated release according to claim 8, wherein said formulation further comprises (II) an intermediate release layer comprising - said (e) strain of bacteria belonging to the genus Bifidobacterium or Lactobacillus, preferably selected from the group comprising or, alternatively, consisting of: Bifidobacterium lactis BL-04<? >(SD5219), Lactobacillus rhamnosus crl1505, Lactobacillus rhamnosus GG (ATCC 53103), Lactobacillus helveticus Lafti? L-10 (CBS116114), and a mixture thereof, plus? preferably Bifidobacterium lactis BL-04<? >(SD5219); and, optionally, - said (f) prebiotic, preferably an inulin; wherein said (II) intermediate release layer breaks down in the intestinal tract, releasing (e) and (f), in a time ranging from 120 minutes to 180 minutes following the administration of the composition to said subject, preferably ranging from 120 minutes to 160 minutes, plus? preferably ranging from 120 minutes to 140 minutes. A formulation according to claim 8 or 9, wherein said (I) rapid release layer further comprising said (c.2) vitamin D, and said (c.3) at least one B vitamin; preferably in which said (c.3) at least one vitamin of group B ? selected from the group comprising or alternatively consisting of: (c.3-i) vitamin B1, (c.3-ii) vitamin B2, (c.3-iii) vitamin B3, (c.3-iv) vitamin B5 (c.3-v), vitamin B6, (c.3-vi) vitamin B9, and (c.3-vii) vitamin 12, and a mixture thereof; And wherein said (III) sustained release layer further comprising said (c.1) vitamin C. 11. The composition according to any one of claims 1-7 or the formulation according to claims 8-10 for use in a treatment method, preventive and/or curative, of at least one flu symptom and/or a respiratory tract infection; preferably for use in a method of treatment of: muscle and joint pain, asthenia/fatigue, cough, increased respiratory secretions, fever, headache, sore throat (pharyngo-laryngodynia), nasal congestion, respiratory tract congestion, dyspnoea , chills, rhinitis, sinusitis, pharyngitis, tonsillitis, laryngitis, tracheitis, bronchitis, bronchiolitis, pneumonia.