WO2024100615A1

WO2024100615A1 - Nutraceutical supplement for the prevention and treatment of respiratory tract infections

Info

Publication number: WO2024100615A1
Application number: PCT/IB2023/061383
Authority: WO
Inventors: Giulio TORELLO; Francesco FRATI; Carlo Cavaliere
Original assignee: Global Pharmacies Partner S.R.L. In Forma Abbreviata G.P.P. S.R.L.
Priority date: 2022-11-11
Filing date: 2023-11-10
Publication date: 2024-05-16

Abstract

Nutraceutical supplement comprising or consisting of: - lactoferrin proteins, from 3.5% to 27% by weight; - bovine colostrum, from 3.5% to 27% by weight; - zinc gluconate, containing an amount from 0.25% to 2% by weight of zinc; and - vitamin D3, from 200 IU to 4000 IU.

Description

Description of the Industrial Invention entitled:

NUTRACEUTICAL SUPPLEMENT FOR THE PREVENTION AND TREATMENT OF RESPIRATORY TRACT INFECTIONS

***

The present invention relates to a nutraceutical supplement for the prevention and treatment of respiratory tract infections, namely acute and recurrent infections in both adults and children, which effectively promotes the modulation in a physiological manner of the immune system by optimizing the immune response to the pathogens causing these infections, through direct stimulation of the nasopharyngeal tubal unit of Waldeyer's ring, namely of the upper respiratory tract with repercussions on the lower respiratory tract.

Respiratory tract infections are known to result in direct and indirect costs to patients and their families and to the health care system. Individuals with vulnerable immune systems, such as very young children, the elderly, and those with immunodeficiency, are at an increased risk of contracting respiratory tract infections that can lead to pneumonia and can also be life-threatening.

Various drugs of both the anti-inflammatory and antipyretic and antibiotic types are used in the prevention and treatment of acute and recurrent respiratory tract infections, and not infrequently even cortisone drugs are used, which are administered in conjunction with immunomodulants in prevention. Many of these drugs have significant potential side effects, and furthermore, none of the immunomodulatory products have demonstrated convincing clinical and especially immunologic efficacy in pediatric treatment.

In the prior art, some solutions consisting of immune system supplements having compositions of natural substances that have immune-stimulating properties, such as those disclosed in W02021021074706A1 and W02022016038A1, have been developed.

However, such prior art supplements for the immune system are not sufficiently effective in combating respiratory tract infections, as they act only systemically and are intended to treat the symptoms of infectious diseases. Moreover, such prior art supplements have a bioavailability and immunological efficacy that is unknown and/or unproven.

The purpose of the present invention, therefore, is to overcome the disadvantages mentioned above with reference to the prior art by enabling physiologically effective modulation of the immune system, optimizing the immune response to pathogens causing acute and recurrent respiratory tract infections in both adults and children, without producing in patients side effects, contraindications, and interactions with other drugs.

Unless otherwise indicated, weight % of components are expressed here as weight % with respect to the total weight of the supplement and/or composition, including physiologically acceptable vehicles and excipients present. It is a specific object of the present invention a nutraceutical supplement comprising or consisting of:

- lactoferrin proteins, from 3.5% to 27% by weight;

- bovine colostrum , from 3.5% to 27% by weight;

- zinc gluconate, containing an amount from 0.25% to 2% by weight of zinc; and

- vitamin D3, from 200 IU to 4000 I U. According to another aspect of the invention:

- lactoferrin proteins may be contained in lactoferrin 95% derived from cow's milk which is lactoferrin 95%, and/or

- bovine colostrum can be bovine colostrum IgG 30%, and/or

- zinc gluconate can be zinc gluconate 13%.

According to a further aspect of the invention, the nutraceutical supplement may also comprise or consist of:

- at least one flavor and/or at least one sweetener and/or at least one additive and/or one or more polyols, for the remaining percentage by weight.

According to an additional aspect of the invention, the nutraceutical supplement may also comprise or consist of:

- at least one flavor, from 1 % to 13% by weight;

- at least one sweetener, optionally sucralose, from 0.04% to 0.16% by weight;

- one or more polyols, from 26% to 90% by weight; and

- at least one additive, optionally an anti-caking additive, more optionally silicon dioxide, from 0.65% to 2.7% by weight.

According to another aspect of the invention, said one or more polyols may consist of:

- isomalt, from 19% to 80% by weight, and

- xylitol, from 6.5% to 30% by weight.

According to a further aspect of the invention:

- lactoferrin proteins can range from 3.5% to 13% by weight;

- bovine colostrum can range from 6.5% to 27% by weight;

- zinc gluconate may contain an amount of zinc ranging from 0.25% to 1 % by weight; and

- vitamin D3 can range from 200 IU to 800 IU. According to an additional aspect of the invention:

- said at least one flavor may be present in an amount from 1 % to 4% by weight;

- said at least one sweetener, optionally sucralose, may be present in an amount from 0.04% to 0.16% by weight;

- said one or more polyols may be present in an amount from 36% to 90% by weight; and

- said at least one additive, optionally an anti-caking additive, more optionally silicon dioxide, may be present in an amount from 0.65% to 2.7% by weight. According to another aspect of the invention:

- isomalt can range from 30% to 80% by weight, and

- xylitol can range from 6.5% to 27% by weight. According to a further aspect of the invention:

- lactoferrin proteins can be contained in lactoferrin 95% derived from cow's milk that is lactoferrin 95%, and lactoferrin 95% can be equal to 105.3 mg;

- bovine colostrum can be bovine colostrum IgG 30% and can be equal to 200 mg;

- zinc gluconate may be zinc gluconate 13% and can be equal to 57.7 mg;

- vitamin D3 can be vitamin D3 100,000 I U/g and can be equal to 4 mg;

- flavor can be equal to 30 mg;

- sucralose can be equal to 1 .2 mg;

- isomalt can be equal to 881.8 mg;

- silicon dioxide can be equal to 20 mg; and

- xylitol can be equal to 200 mg.

- quercetin, with an amount of active ingredient from 6.5% to 27% by weight, wherein quercetin is optionally quercetin titrated at 98% of active ingredient.

According to another aspect of the invention:

- lactoferrin proteins can range from 6.5% to 27% by weight;

- bovine colostrum can range from 3.5% to 13% by weight;

- zinc gluconate may contain an amount from 0.5% to 2% by weight of zinc;

- vitamin D3 can range from 1000 I U to 4000 IU; and

- quercetin can have an active ingredient content from 6.5% to 27% by weight.

According to a further aspect of the invention:

- said at least one flavor may be present in an amount from 3.3% to 13% by weight;

- said one or more polyols may be present in an amount from 23.5% to 66% by weight; and

- said at least one additive, optionally an anti-caking additive, more optionally silicon dioxide, may be present in an amount from 0.65% to 2.7% by weight.

According to an additional aspect of the invention:

- isomalt can range from 16% to 66% by weight, and

- xylitol can range from 7.5% to 30% by weight.

According to another aspect of the invention:

- lactoferrin proteins may be contained in lactoferrin 95% derived from cow's milk, which is lactoferrin 95%, and lactoferrin 95% ca be equal to 210.5 mg;

- bovine colostrum can be bovine colostrum IgG 30% and can be equal to 100 mg;

- zinc gluconate can be zinc gluconate 13% and can be equal to115.4 mg;

- vitamin D3 can be vitamin D3 100,000 I U/g and can be equal 20 mg;

- quercetin can be quercetin titrated at 98% of active ingredient and may be equal to 204.1 mg;

- flavor can be equal to 100 mg;

- sucralose can be equal to 1 .2 mg;

- isomalt can be equal to 500.8 mg;

- silicon dioxide can be equal to 20 mg; and

- xylitol can be equal to 228 mg.

According to a further aspect of the invention, the nutraceutical supplement can be in liquid or chewable tablet or orosoluble stick form.

According to an additional aspect of the invention, the nutraceutical supplement can be configured to interact with the immune system at the oral mucosal level up to the Waldeyer's ring.

It is also a specific object of the present invention the nutraceutical supplement previously described for use in the prevention and treatment of respiratory tract infections, wherein the nutraceutical supplement is administered to a patient treated at the oral mucosal level.

The benefits of the present invention are significant.

In fact, the nutraceutical supplement for the prevention and treatment in both adults and children of respiratory tract infections according to the invention, particularly both acute and recurrent infections, is able to provide nutrients that physiologically promote modulation in a physiological manner of the immune system through direct stimulation of the nasopharyngeal tubal unit of the Waldeyer's ring by means of a topical action guaranteed by the formation of a muco-adhesive matrix formed by the combination of its specific constituent actives with saliva and oral mucosa, increasing the duration of retention and contact of the same with the nasopharyngeal epithelium and M cells present in Waldeyer's Crypts.

In addition, lactoferrin and bovine colostrum present in the nutraceutical supplement according to the invention naturally mimic the immunomodulatory function of breast milk and its beneficial anti- infective and immunomodulatory effects important in supporting the immune system to provide protection against infection. In particular, lactoferrin proteins and immunoglobulins, or IgG, in colostrum play a direct role in pathogen clearance and immune function. Like the human milk oligosaccharides, or HMOs (Human Milk Oligosaccharides), derived from breast milk, those of lactoferrin and bovine colostrum present in the nutraceutical supplement according to the invention, when this is administered at the oral mucosal level, reduce the risk of respiratory tract infections through a topical effect.

Additionally, the components present in the nutraceutical supplement according to the invention promote the immune system's antiviral immunity action. In fact, these components act as fuels for energy generation by immune cells. In addition, vitamin D3 acts as a regulatory agent of the molecular and cellular aspects of the immune response. Additionally, vitamin D3 and zinc have specific anti-infective action. Furthermore, zinc has an action to protect the host from oxidative and inflammatory stress imposed by the immune response. In the embodiments of nutraceutical supplement according to the invention, intended for adults, which also include quercetin, this acts as an aryl hydrocarbon receptor ligand, acting to strengthen barrier function.

Thus, the nutraceutical supplement according to the invention can optimize the immune response to pathogens that cause acute and recurrent respiratory tract infections in both adults and children. In this regard, the human immune system is composed of innate immunity, i.e., nonspecific, and adaptive immunity, i.e. specific: the innate component is rapid, responding minutes to hours after infection, reacts to a wide variety of pathogens, and is important in primary protection against infection, but also has limited efficacy; the adaptive component is slow to respond, days to weeks, but it is highly specific and effective, and is activated by the innate component through the ability of monocytes, macrophages, and dendritic cells, or DCs (Dendritic Cells), to present antigen. The nutraceutical supplement according to the invention specifically promotes the innate component of the immune system, which, in turn, activates the adaptive component.

The present invention will now be described, by way of example and not limitation, according to its preferred embodiments.

In the following description, the words "equal to approximately" mean "equal to" according to usual industrial tolerances.

The nutraceutical supplement for the prevention and treatment of respiratory tract infections according to the invention comprises or consists of the following composition:

- lactoferrin proteins, from 3.5% to 27% by weight;

- bovine colostrum, from 3.5% to 27% by weight;

- zinc gluconate, containing an amount from 0.25% to 2% by weight of zinc; and

- vitamin D3, from 200 IU to 4000 IU.

In the preferred embodiments of the nutraceutical supplement according to the invention, there is that:

- lactoferrin proteins are contained in lactoferrin derived from cow's milk that is 95% lactoferrin, i.e., with a protein content not less than 95%;

- bovine colostrum is bovine colostrum IgG 30%, i.e., with a IgG content equal to 30%; and

- zinc gluconate is zinc gluconate 13%, i.e., with a zinc percentage of 13%.

The nutraceutical supplement according to the invention is preferably administered at the oral mucosal level in chewable tablets or in orosoluble sticks advantageously packaged in sachets or in liquid form. For this purpose, the nutraceutical supplement for the prevention and treatment of respiratory tract infections according to the invention also comprises or consists of:

The aforementioned components present in the nutraceutical supplement for the prevention and treatment of respiratory tract infections according to the invention have a synergistic effect, as proven by tests conducted that will be explained below.

In fact, lactoferrin is a glycoprotein capable of extremely efficiently subtracting unbound iron from body fluids and areas of inflammation, with high capacities, so as to avoid the damage produced by toxic oxygen radicals and decrease the availability of ferric ions for microorganisms invading the host. In particular, lactoferrin, which is present in milk, serum and other body fluids, has anti-infective effects, including antibacterial and antiviral effects that are effectively used in the nutraceutical supplement according to the invention for protection against respiratory viruses. In this regard, lactoferrin, as a contribution to the innate component of the immune system, inhibits the infection of cells by SARS virus and induces IFN-y as an antiviral cytokine in intestinal epithelial cells, and partially restores the deficient response of pDCs of elderly women to TLR7 stimulation. Lactoferrin is physiologically activated in an acidic environment, at the level of the oral cavity, and can be particularly activated by the acidity of saliva and/or the oral microbiota, acting as a topical immunonutraceutical already at the level of the Waldeyer's ring.

Bovine colostrum contributes to the phenomenon of passive immunity. In fact, it represents the first secretion product of the mammary gland of mammals, i.e. the first real foodstuff with which the gastrointestinal tract comes into contact, inducing a series of signals on the gastric and intestinal mucosa, modulating the expression of inflammatory genes activated following exposure to pathogens, promoting the development of lymphocytes, G- and A-type immunoglobulins, which are responsible for systemic and local surveillance, as well as the development of macrophages and cytokines. Although it has a very similar qualitative composition to human colostrum, bovine colostrum is richer in immune factors than human colostrum. In particular, its immunostimulatory action derives from its high content of G1/G2 immunoglobulins, lactoferrin antimicrobial peptides, and proline-rich polypeptides. Immunoglobulins are extremely important for the prevention and treatment of infections, and those present in the greatest amount in bovine colostrum are IgG, which increase phagocytosis against toxins and viruses. These antibodies very often are also effective against microorganisms that have become resistant to antibiotics. In this regard, ingestion of bovine colostrum influences immune function outside the gastrointestinal tract, reduces the number of Upper Respiratory Tract Infections (URTIs) and episodes of diarrhea in children, and bovine colostrum IgG binds and neutralizes human respiratory syncytial virus. Advantageously, the bovine colostrum of the nutraceutical supplement according to the invention is composed of at least 30% of IgG. In the preferred embodiment of the nutraceutical supplement according to the invention, bovine colostrum is, in addition, rich in protein, such that a 10g serving contains 6.7g of protein.

Vitamin D3 supports immunity against respiratory tract infections by acting as a topical immunomodulator, acting on the crypts of the Waldeyer's ring through its combination with lysozyme in saliva, which promotes its cleavage and activation. Notably, vitamin D3 has pleiotropic actions within the immune system and supports the activity of different cell types, as its receptors have been identified in most immune cells. In addition, vitamin D3 improves epithelial integrity and induces the synthesis of antimicrobial peptides, e.g., cathelicidin, in epithelial cells and macrophages, promotes immune cell homing in the respiratory tract. At the functional level, vitamin D3 also promotes the differentiation of monocytes into macrophages and increases phagocytosis, superoxide production, and bacterial killing by innate immune cells. Vitamin D3 also promotes antigen processing by DCs. Additionally, vitamin D3 of the nutraceutical supplement according to the invention induces C-C chemokine receptor type 10, or CCR10 (C-C chemokine receptor type 10), which is associated with homing in the respiratory tract. In addition, vitamin D3 also blocks upregulation of retinoic acid- induced intestinal markers and thus promotes homing in the respiratory tract.

Zinc supports the activity of many cells of the immune system, helps control oxidative stress and inflammation, and has specific antiviral actions including inhibition of RNA virus replication. In addition, zinc-binding metallothioneins play an important role in antiviral defense. Zinc is important in the early development of immune cells in the bone marrow and in maintaining the number of T and B lymphocytes, and it also supports the release of extracellular neutrophil traps that capture microbes. Zinc also promotes the number and function of CD4+ T lymphocytes, e.g., with the production of IL-2 and IFN-y, and supports the proliferation of CD8+ cytotoxic T lymphocytes, which enhance antiviral immune defense. Furthermore, zinc can disrupt the replication and infectivity of some respiratory viruses and prevents Acute Respiratory Distress Syndrome, or ARDS, and lung damage in COVID- 19. Additionally, zinc supplementation improves some markers of immunity, especially in the elderly or those with low zinc intake.

Since the nasopharyngeal mucosa is a densely populated environment of commensal organisms, some of which are associated with a risk of respiratory tract infections, the components of the nutraceutical supplement according to the invention, when administered at the oral-mucosal level, perform their function through direct stimulation of the immune tissues of the Waldeyer's ring, through which they have an effect on respiratory tract infections, keeping in mind the anatomy of the upper respiratory tract. The components also have local effects through the instruction of migratory cells of the immune system, and/or the induction of microbial metabolites, which may become available in the circulation and may reach distant tissues. These local effects occur before the product reaches the stomach and is digested and, in addition to immune effects, also have antiadhesive effects on ingested respiratory pathogens.

Due to their anatomical location, the immune tissues of Waldeyer's ring play a crucial role in the development of potent immune responses to respiratory pathogens.

In this regard, the immunological tissues of the head/neck area are mainly structured in tonsils, lymph nodes and lymphatic follicles. The largest area of contact between food and nasal contents and the immune system occurs in the nasopharyngeal area, i.e., in the area where the nose and mouth join. The pharynx is surrounded by a series of structured lymphoid nodules, i.e., tonsils, comprising: the lingual tonsil, nasopharyngeal tonsils or adenoids, palatine tonsils and tubal tonsils. The tonsils contain a large number of lymphoid cells consisting mainly of B cells and CD4+ T cells, which together are called Waldeyer's ring, which is also referred to as nasal mucosa-associated lymphoid tissue (MALT). The tonsils and adenoids have multiple antigen-storing crypts, which greatly increase the contact surface area between food components and the underlying cells. The reticulated epithelium lining the tonsil crypts is an antigen entry portal, specializing in the transport of antigen to the subepithelial tissue within an average of about 10 minutes after contact with the nutraceutical supplement according to the invention. The adenoids, and to a lesser extent the palatine tonsils, have epithelia with well-developed tight junctions that also contain M-like and DC cells that contribute to antigen sampling. Due to its anatomical structure and location, the Waldeyer's ring acts as a guardian of respiratory pathogens ingested from nasal secretions. Likewise, it is also exposed to nutritional components that can locally modulate immune responses to respiratory pathogens sampled in the Waldeyer's ring itself.

A significant aspect of the administration of the nutraceutical supplement according to the invention at the oral-mucosal level is the muco-adhesive matrix formed in contact with saliva and oral mucosa, which slows the passage of the active components of the nutraceutical supplement, increases the duration of retention and the contact of the same with the nasopharyngeal epithelium and Waldeyer's ring. This is promoted by the mucoadhesive effect in the oral cavity due to the specific granularity of the nutraceutical supplement according to the invention. A longer retention time increases the interaction of these components with the underlying epithelium and immune system cells. Such a muco-adhesive , i.e., colloidal, structureis is formed by combining the components of the nutraceutical supplement according to the invention, in the specific composition and amount, with lysozyme and microbiota at the level of the oral cavity. Specifically, the components thus combined stimulate the formation of oral mucus and attract it, resulting in the formation of this colloidal compound.

In addition, it should be considered that the nutraceutical supplement according to the invention acts systemically on different components of the immune system, by way of example in the bone marrow, thymus, bloodstream, and secondary lymphoid organs, and acts to influence the immune system without being absorbed systemically. By way of example, and not by way of limitation, the nutraceutical supplement according to the invention also has local actions on epithelial barrier function and/or the gut-associated lymphoid system and modulates the composition of the gut microbiota by influencing the cross-talk between the gut microbiota and the immune system. Although the latter actions are primarily focused on the gastrointestinal tract, because of the recirculation of cells from the intestinal wall to the respiratory tract, effects initiated at the intestinal level are also activated at the respiratory tract level.

The embodiments of the nutraceutical supplement according to the invention that are administered at the oral mucosal level in chewable tablets or orosoluble sticks or drops, i.e., in liquid form, have the composition comprising:

- at least one flavor, from 1 % to 13% by weight;

- at least one sweetener, optionally sucralose, from 0.04% to 0.16% by weight;

- one or more polyols, from 26% to 90% by weight; and

Optionally, said one or more polyols consist of:

- isomalt, from 19% to 80% by weight, and

- xylitol, whose chemical formula is C5H12O5, from 6.5% to 30% by weight.

The embodiments of nutraceutical supplement for the prevention and treatment of respiratory tract infections, namely acute and recurrent infections, intended for administration to children comprise or consist of the following composition:

- lactoferrin proteins, from 3.5% to 13% by weight;

- bovine colostrum, from 6.5% to 27% by weight;

- zinc gluconate, containing an amount from 0.25% to 1 % by weight of zinc; and

- vitamin D3, from 200 IU to 800 IU.

For the administration to children of the nutraceutical supplement according to the invention at the oral mucosal level in chewable tablets or orosoluble sticks or in liquid drops, the nutraceutical supplement according to the invention also comprises or consists of:

- at least one flavor and/or at least one sweetener and/or at least one additive and/or one or more polyols, for the remaining percentage by weight, wherein, optionally,

- said at least one flavor, e.g., chocolate flavor, is present in an amount from 1% to 4% by weight; - said at least one sweetener, more optionally sucralose, is present in an amounts from 0.04% to 0.16% by weight;

- said one or more polyols are present in an amount from 36% to 90% by weight; and

- said at least one additive, more optionally an anti-caking additive, even more optionally silicon dioxide, is present in an amount from 0.65% to 2.7% by weight.

Advantageously, said one or more polyols consist of:

- isomalt, from 30% to 80% by weight, and

- xylitol, for example Xylisorb® 300 available from the French company Roquette Freres, from 6.5% to 27% by weight.

The preferred embodiment of the nutraceutical supplement according to the invention for administration to children at the oral mucosal level in chewable tablets or orosoluble sticks or liquid drops consists of the following composition of 1500 mg total weight:

- lactoferrin 95%, equal to 105.3 mg;

- bovine colostrum IgG 30%, equal to 200 mg;

- zinc gluconate 13%, equal to 57.7 mg;

- vitamin D3 100,000 I U/g, equal to 4 mg;

- chocolate flavor, equal to 30 mg;

- sucralose, equal to 1 .2 mg;

- isomalt, equal to 881.8 mg;

- silicon dioxide, equal to 20 mg;

- xylitol, optionally Xylisorb® 300 available from the French company Roquette Freres, equal to 200 mg.

Advantageously, the embodiments of the nutraceutical supplement for the prevention and treatment of respiratory tract infections, namely acute and recurrent infections, intended for administration to adults also comprise or consist of:

- quercetin, with active ingredient content from 6.5% to 27% by weight.

Advantageously, quercetin is quercetin titrated at 98% of active ingredient.

The embodiments of the nutraceutical supplement for prevention and treatment of respiratory tract infections, namely acute and recurrent infections, intended for administration to adults, comprise or consist of the following composition:

- lactoferrin proteins, from 6.5% to 27% by weight;

- bovine colostrum, from 3.5% to 13% by weight;

- zinc gluconate, containing an amount from 0.5% to 2% by weight of zinc;

- vitamin D3, from 1000 I U to 4000 I U; and

- quercetin, with active ingredient content from 6.5% to 27% by weight. For the administration to adults of the nutraceutical supplement according to the invention at the oral mucosal level in chewable tablets or orosoluble sticks or in liquid drops, the nutraceutical supplement according to the invention also comprises or consists of:

- said at least one flavor is present in an amount from 3.3% to 13% by weight;

- said at least one sweetener, optionally sucralose, is present in an amount from 0.04% to 0.16% by weight;

- said one or more polyols, are present in an amount from 23.5% to 66% by weight; and

Advantageously, said one or more polyols consist of:

- isomalt, from 16% to 66% by weight, and

- xylitol, for example Xylisorb® 400 available from the French company Roquette Freres, from 7.5% to 30% by weight.

The preferred embodiment of the nutraceutical supplement according to the invention for administration to adults at the oral mucosal level in chewable tablets or orosoluble sticks or liquid drops consists of the following composition of 1500 mg total weight:

- lactoferrin 95%, equal to 210.5 mg;

- bovine colostrum IgG 30%, equal to 100 mg;

- zinc gluconate 13%, equal to 115.4 mg;

- vitamin D3 100,000 lU/g, equal to 20 mg;

- quercetin titrated at 98% of active ingredient, equal to 204.1 mg;

- flavor, equal to 100 mg;

- sucralose, equal to 1 .2 mg;

- isomalt, equal to 500.8 mg;

- silicon dioxide, equal to 20 mg;

- xylitol, optionally Xylisorb® 400 available from the French company Roquette Freres, equal to 228 mg.

Another preferred embodiment of the nutraceutical supplement according to the invention for administration to children at the oral mucosal level in liquid drops consists of the following composition, containing per milliliter of supplement:

- lactoferrin 95%, 52.63 mg (equivalent to 50 mg of lactoferrin);

- bovine colostrum IgG 30%, 30 mg; - zinc gluconate 13%, 19.23 mg (equivalent to 2.5 mg of zinc)

- vitamin D3400 I U/g; together with physiologically acceptable excipients and vehicles.

Preferably, the drop composition shown above also comprises water, sweeteners, e.g., fructose and citric acid.

The drop composition shown above can be packaged in bottles, such as bottles with dropper pipettes, for easy and safe dosing.

Unless otherwise medically indicated, the drop composition shown above may be administered at the maximum daily dose of 1 ml in children under 12 months, and at the maximum daily dose of 2 ml in children over 12 months.

As mentioned, the applicant carried out tests on the nutraceutical supplement according to the invention that proved the synergistic effect of the components present, starting from the observation that modulation of both innate and adaptive anti-infectious immune responses is activated at the level of Waldeyer's ring, that is, nutritive components can modulate immune responses similar to those elicited by normal pathogens.

Tests were conducted to explore whether the preferred embodiment of the nutraceutical supplement according to the invention, placed in contact with a major lymph node station of Waldeyer's ring, could elicit immune responses of a protective type against normal agents, namely viruses and bacteria. Specifically, the normal pathway of interaction between nutritional component and immune system in Waldeyer's ring, i.e., transit at the level of the lingual tonsil and oral mucosa, was retraced in the tests by administering the nutraceutical supplement at the oral mucosal level. Specifically, the nutraceutical supplement, before being completely swallowed, via the fornices of the mouth reaches both the oral mucosa, interfacing with the complex immune system that constitutes it, and the lingual tonsil, completely coating it.

The lingual tonsil has immune characteristics equal to the entire Waldeyer's ring, that is, of noncapsulated lymph node stations, such as Peyer's plaques, which in the component dedicated to interaction with immune substances from outside, such as germs and nutritional components, have crypts capable of retaining biological components, towards which later generate immune responses capable of conditioning anatomical areas involved in immunological and infectious phenomena.

Brief description of the Figures

Figure 1 shows schematically how the luminometric test works.

Figures 2 and 3, show the effect of exposure to increasing concentrations of a composition according to the invention on the activity of CYP2D6 and CYP3A4 enzymes, members of the cytochrome P450 family. Enzyme activity is expressed as a percentage relative to the control (vehicle only). Results are reported as mean ± standard deviation. Example 1

In order to evaluate whether the nutraceutical supplement according to the invention had immunogenic capabilities capable of activating antimicrobial responses, tests of its preferred embodiment were conducted at the Otolaryngology Clinic of the University la Sapienza in Rome, in which 13 young adult patients suffering from chronic pharyngitis, a condition in which administration of normal immune stimulants is indicated, were involved. Of these, ten patients were treated with the preferred embodiment of the nutraceutical supplement according to the invention, in the dose of 200 mg of lactoferrin protein, 400 mg of bovine colostrum, 20 mg of zinc gluconate 13% and 800IU of vitamin D3, daily for 30 days, and three control patients were treated with placebo.

In particular, the cytokines most involved in immune defense mechanisms (IF-y, IL5, TGF-p) were assayed at the level of the lingual tonsil and at the level of the oral mucosa.

Collected and assayed a suitable biological sample at TO, i.e. before treatment with the nutraceutical supplement according to the invention, and T1, i.e. after 1 month of treatment.

Sample collection was performed through brushing system using Nasal Scraping®, which is a disposable device for cytological samples, intended for qualified medical personnel, that allows, after removing excessive secretions, to proceed with the collection of a sample of cells from the most superficial layer of the mucosa, i.e., the lingual tonsil, with minimal discomfort for the patient. The biological sample collected in situ and immediately stored at a temperature of -80°C, was immediately stored in its entirety on a suitable test tube and subsequently assayed by normal ELISA method at the Immunology Laboratory at the Umberto Primo Polyclinic Hospital in Rome.

The results of these assays were collected and statistically analyzed, with regard to IF-y, TGF-p and IL5, IL 4 and IL10 assays at the level of the oral mucosa, at La Sapienza University of Rome.

Statistical analysis

Statistical analysis was performed using SPSS 20.0 software (SPSS, Chicago, IL, USA). The Kolmogorov-Smirnov test was used to assess the normality of the distribution of each continuous variable, and the Mann-Whitney test was then used to compare each variable between TO and T1; p- values of < 0.05 were considered statistically significant.

Results

Patients in the control group (group 2) showed no significant change over the 30-day follow-up period in the lingual tonsils for IFN y (20.4 ± 5.8 vs 19.7 ± 4.9 pg/mL) and TGF p (63.1 ± 20.2 vs 61.8 ± 20.1 pg/mL). mL) and in the oral mucosa (IFN y 16.8 ± 9.7 vs 16.6 ± 9.3 pg/mL; TGF p 52.2 ± 18.7 vs 52.8 ± 18.9 pg/mL). (Tables 1 and 2).

Patients in the active treatment group (group 1) showed a significant (p<0.01) change in lingual tonsils of IFN y (from 12.8 ± 6.2 at baseline to 17.3 ± 9.9 pg/mL) and TGF p (from 71.6 ± 24.4 at baseline to 101.6 ± 30.8 pg/mL) after the 30-day treatment. Similar results were evident in the oral mucosa for both IFN y (from 9.3 ± 5.9 at baseline to 12.3 ± 6.4 pg/mL) and TGF p (from 65.7 ± 15.5 at baseline to 82.2 ± 12.5 pg/mL) after 30-day treatment.

(Tables 1 and 2)

tonsil

IFN Y (pg/mL) TO T1 sig. (p)

Group 1 (treated) 12.8 ± 6.2 17.3 ± 9.9 <0.01

Group 2 (control) 20.4 ± 5.8 19.7 ± 4.9 NS (0.28)

TGF p (pg/mL) TO T1 Mr. (p)

Group 1 (treated) 71.6 ± 24.4 101.6 ± 30.8 <0.01

Group 2 (control) 63.1 ± 20.2 61.8 ± 20.1 NS (0.65)

Table 1 : Levels of IFN y and

- p in lingual tonsil samples.

Oral mucosa

IFN y (pg/mL) TO T1 sig. (p)

Group 1 (treated) 9.3 ± 5.9 12.3 ± 6.4 <0.01

Group 2 (control) 16.8 ± 9.7 16.6 ± 9.3 NS (0.11)

TGF p (pg/mL) TO T1 Mr. (p)

Group 1 (treated) 65.7 ±15.5 82.2 ±12.5 <0.01

Group 2 (control) 52.2 ±18.7 52.0 ±18.9 NS (0.18)

Table 2: Levels of IFN y and TGF p in oral mucosa samples.

None of the patients in the treated group reported significant side effects or adverse events during the follow-up period.

In summary, these results clearly show that:

IF-y, TGF-p, and IL5 in the ten patients treated with the nutraceutical supplement according to the invention increased in a statistically significant manner, both at the level of the lingual tonsil and at the level of the oral mucosa, particularly the gingiva;

IF-y, TGFp and IL5 do not increase in the three patients not treated with the nutraceutical supplement according to the invention at the level of the oral mucosa and at the level of the lingual tonsil; and

IL10 and IL4 do not increase in patients treated with the nutraceutical supplement according to the invention.

In other words, the results show a statistically significant increase <0.005 in cytokine values assayed in all ten patients treated with the nutraceutical supplement according to the invention, while there was no increase in cytokines in the three control patients. These results confirm how the nutraceutical supplement for the prevention and treatment of respiratory tract infections, namely acute and recurrent infections in both adults and children, according to the invention placed at the oral mucosal and Waldeyer's ring level is able to stimulate the immune system to produce cytokines involved in defense mechanisms against infections. Specifically, among the cytokines involved, the following are significant:

IF-y, which causes macrophage activation along with activation of Toll like receptor signals in these cells, activates numerous transcription factors such as STAT1, NF-KB and AP-1 that induce transcription of several enzymes involved in phagocytosis, such as phagocytic oxidase, inducible nitric oxide synthase and other lysosomal enzymes, promoting a stimulatory effect of anti-infective immunity; at the level of B lymphocytes, class exchange between different subclasses of IgG is promoted, stimulating CD4 T lymphocytes to differentiate into TH1 lymphocytes, inhibiting TH2 and TH17;

TGF-p, which has immunological efficacy against infectious-type diseases, and

IL5, which is able to promote the synthesis of IgA deputed to immune defenses that are also anti-infective.

In the foregoing, preferred embodiments have been described and variants of the present invention have been suggested, but it is to be understood that experts in the field may make modifications and changes without thereby departing from the relevant scope of protection as defined by the appended claims.

Claims

1 . Nutraceutical supplement comprising or consisting of: lactoferrin proteins, from 3.5% to 27% by weight; bovine colostrum, from 3.5% to 27% by weight; zinc gluconate, containing an amount from 0.25% to 2% by weight of zinc; and vitamin D3, from 200 IU to 4000 IU.

2. Nutraceutical supplement according to claim 1, wherein: lactoferrin proteins are contained in lactoferrin 95% derived from cow's milk which is lactoferrin 95%, and/or bovine colostrum is bovine colostrum IgG 30%, and/or zinc gluconate is zinc gluconate 13%.

3. Nutraceutical supplement according to claim 1 or 2, comprising or consisting also of: at least one flavor and/or at least one sweetener and/or at least one additive and/or one or more polyols, for the remaining percentage by weight.

4. Nutraceutical supplement according to claim 1 or 2, comprising or consisting also of: at least one flavor, from 1 % to 13% by weight; at least one sweetener, optionally sucralose, from 0.04% to 0.16% by weight; one or more polyols, from 26% to 90% by weight; and at least one additive, optionally an anti-caking additive, more optionally silicon dioxide, from 0.65% to 2.7% by weight.

5. Nutraceutical supplement according to claim 4, wherein said one or more polyols consist of: isomalt, from 19% to 80% by weight, and xylitol, from 6.5% to 30% by weight.

6. Nutraceutical supplement according to any one of claims 1 to 5, wherein: lactoferrin proteins range from 3.5% to 13% by weight; bovine colostrum ranges from 6.5% to 27% by weight; zinc gluconate contains an amount from 0.25% to 1% by weight of zinc; and vitamin D3 ranges from 200 IU to 800 IU.

7. Nutraceutical supplement according to claim 6, when dependent on claim 4, wherein: said at least one flavor is present in an amount from 1 % to 4% by weight; said at least one sweetener, optionally sucralose, is present in an amount from 0.04% to 0.16% by weight; said one or more polyols are present in an amount from 36% to 90% by weight; and said at least one additive, optionally an anti-caking additive, more optionally silicon dioxide, is present in an amount from 0.65% to 2.7% by weight.

8. Nutraceutical supplement according to claim 6 or 7, when dependent on claim 5, whwerein: isomalt ranges from 30% to 80% by weight, and xylitol ranges from 6.5% to 27% by weight.

9. Nutraceutical supplement according to claim 8, when dependent on claim 2, wherein: lactoferrin proteins are contained in lactoferrin 95% derived from cow's milk, which is lactoferrin 95%, and lactoferrin 95% is equal to 105.3 mg; bovine colostrum is bovine colostrum IgG 30%and is equal to 200 mg; zinc gluconate is zinc gluconate 13% and is equal to 57.7 mg; vitamin D3 is vitamin D3 100,000 I U/g and is equal to 4 mg; flavor is equal to 30 mg; sucralose is equal to1 .2 mg; isomalt is equal to 881 .8 mg; silicon dioxide is equal to 20 mg; and xylitol is equal to 200 mg.

10. Nutraceutical supplement according to any one of claims 1 to 5, also comprising or consisting of: quercetin, with active ingredient content from 6.5% to 27% by weight, wherein quercetin is optionally quercetin titrated at 98% of active ingredient.

11. Nutraceutical supplement according to claim 10, wherein: lactoferrin proteins range from 6.5% to 27% by weight; bovine colostrum ranges from 3.5% to 13% by weight; zinc gluconate contains an amount from 0.5% to 2% by weight of zinc; vitamin D3 ranges from 1000 I U to 4000 IU; and quercetin has an active ingredient content ranging from 6.5% to 27% by weight.

12. Nutraceutical supplement according to claim 11, when dependent on claim 4, wherein: said at least one flavor is present in an amount from 3.3% to 13% by weight; said at least one sweetener, optionally sucralose, is present in an amount from 0.04% to 0.16% by weight; said one or more polyols are present in an amount from 23.5% to 66% by weight; and said at least one additive, optionally an anti-caking additive, more optionally silicon dioxide, is present in an amount from 0.65% to 2.7% by weight.

13. Nutraceutical supplement according to claim 11 or 12, when dependent on claim 5, wherein: isomalt ranges from 16% to 66% by weight, and xylitol ranges from 7.5% to 30% by weight.

14. Nutraceutical supplement according to claim 13, when dependent on claim 2, wherein: lactoferrin proteins are contained in lactoferrin 95% derived from cow's milk, which is lactoferrin 95%, and lactoferrin 95% is equal to 210.5 mg; bovine colostrum is bovine colostrum IgG 30% and is equal to 100 mg; zinc gluconate is zinc gluconate 13% and is equal to115.4 mg; vitamin D3 is vitamin D3 100,000 I U/g and is equal to 20 mg; quercetin is quercetin titrated at 98% of active ingredient and is equal to 204.1 mg; flavor is equal to 100 mg; sucralose is equal to 1 .2 mg; isomalt is equal to 500.8 mg; silicon dioxide is equal to 20 mg; and xylitol is equal to 228 mg.

15. Nutraceutical supplement according to any one of claims 1 to 14 in liquid or chewable tablet or orosoluble stick form.

16. Nutraceutical supplement according to claim 1 in liquid drops having the following composition per milliliter of supplement: lactoferrin 95%, 52.63 mg (equivalent to 50 mg of lactoferrin); bovine colostrum IgG 30%, 30 mg; zinc gluconate 13%, 19.23 mg (equivalent to 2.5 mg of zinc) vitamin D3400 I U/g; physiologically acceptable excipients and vehicles.

17. Nutraceutical supplement according to any one of claims 1 to 16, configured to interact with the immune system at the oral mucosal level up to the Waldeyer's ring.

18. Nutraceutical supplement according to any one of claims 1 to 17 for use in the prevention and treatment of respiratory tract infections, wherein the nutraceutical supplement is administered to a patient treated at the oral mucosal level.