“Combination of active ingredients, compositions containing it and their use to sustain and strengthen the immune system”

Summary of the Invention

Subject-matter of the present invention is a combination of active ingredients, nutraceutical and/or pharmaceutical compositions containing it and their use to support and enhance the functionality of the immune system and/or as adjuvants in counteracting the cold-related diseases.

Technical background

The immune system is constituted by a complex integrated network of chemical and cellular mediators, biological structures and processes, which have been developed in the course of the evolution, to defend the organism from the external insults that may result, for example, from trauma or infectious agents. To function properly, the immune system must be able to detect a wide variety of external "dangers" and pathogens and distinguish them from the healthy tissue of the organism it must defend.

When the immune system is less active than normal, we talk about immunodeficiency. This condition, which can be either genetic or due to diseases, caused by stress or the use of immunosuppressive drugs, can have more or less debilitating consequences depending on its severity, determining for example, in the most common cases, a greater tendency to get sick or recurrent infections.

Maintaining/enhancing a healthy immune system can be the basis of a prophylactic therapy against infections, in particular cold-related infections, which affect the entire population but, in particular and with more serious consequences, people who are less prepared to deal with them.

In addition to strictly pharmacological therapies, usually reserved for the most severe cases of immunodeficiency, various nutraceutical or phytopharmaceutical preparations are known and on the market.

A combination of nutraceutical/phytopharmaceutical active ingredients with immunomodulatory effect may act at different stages and levels of the pathogenesis of the cold-related infections. In particular, it can be useful to counteract them both at a very early stage of the infection, at the level of the colonization and penetration of the anatomical barriers by the infectious agent, and at more advanced levels such as the spread of the pathogen in the body and especially during its response to the infection (e.g., oxidative stress, inflammation).

In the field of dietary supplements, one of the best known and most pursued approaches to improve the health state of the immune system is the one related to the administration of probiotics, which are known to be able to modulate the mucosal immunity and interact with the cells of the immune system.

However, the products containing probiotics provide for a complicated development process that starts with the selection of the strains, which must be able to resist to the acids and bile, must remain viable and reproduce, adhere to the cells of the intestinal epithelium and colonize it by producing, with their metabolism, substances useful to the "host" organism and acting as antagonists for pathogenic bacteria. The formulation must also be designed to protect them and get them active and in sufficiently large numbers to the site of action. Furthermore, in some cases, these products can be inconvenient to use, many for example need to be stored in the refrigerator at temperatures between 3 and 6°C.

As concluded by a systematic review of the literature (Stephen and Avenell, J Hum Nutr Diet 2006; vol. 19, pp. 179-190), the use of multivitamin supplements with minerals for the purpose of preventing infections was also found to be partially effective in reducing episodes of infections but, significantly, only in an adult population under 65 years of age.

A further approach involves the use of products known in the phytopharmaceutical field, such as for example Echinacea or Ginseng extracts, which are traditionally known for their immunostimulating/energizing activities. However, these compounds intrinsically have some disadvantages linked to their direct natural derivation which implies a variable concentration of active ingredients inside the extract, possible interactions and side effects not always documented, dosages not exactly tabulated. Therefore, there is a need to provide novel nutraceutical combinations useful to support and strengthen the immune system that are effective and safe to use and able to overcome the disadvantages in the prior art.

Objects of the Invention

An object of the present invention is to provide a novel combination of active ingredients having immunostimulating action useful to support and enhance the function of the immune system.

Another object of the present invention is to provide a novel composition comprising said combination suitable in particular, but not only, for supporting and strengthening the immune system and/or counteracting and/or preventing the cold- related diseases.

Furthermore, a further object of the invention is the possibility of using the combination and composition subj ect of the invention, as an adjuvant in the prevention and/or treatment against the cold-related diseases.

These and other objects are achieved by the subject-matter of the present invention which provides a novel combination of nutraceutical active ingredients and a composition for the administration thereof.

Description of the invention

According to one of its aspects, subject-matter of the invention is a combination consisting of lactoferrin, N-acetylcysteine (NAC), resveratrol, vitamin D, vitamin C, Zinc, Selenium and optionally curcumin.

Lactoferrin is a natural iron-binding glycoprotein known for its ability to inhibit the bacterial growth and prevent viral infections by preventing their penetration into the host cells.

N-acetylcysteine is a molecule widely used as a mucolytic agent, it has a strong effect as an antioxidant and acts, at the intracellular level, as a precursor of glutathione.

Resveratrol, chemically 5-[2E-(4-hydroxyphenyl)-ethenyl]benzen-l,3-diol, is a natural polyphenolic molecule present in the grapevine with antioxidant action.

The term "vitamin D" denotes a group of fat-soluble secosteroids that are particularly useful for the intestinal absorption of minerals and many other biological functions. Preferably, in the combination of the invention "vitamin D" means vitamin D3, also called cholecalciferol, which is also produced by the human body starting from 7-dehydrocholesterol by the action of the UVB rays, has receptors present in every part of the body and is linked to numerous processes not only at the level of the skeleton but also of an anti-inflammatory type by reducing, for example, the production of cytokines. In the present invention, the indicated amounts of vitamin D3 refer to cholecalciferol, although in the combination and compositions of the invention said cholecalciferol may be introduced in the form of substances comprising it.

Vitamin C, also called L-ascorbic acid, is an essential micronutrient with many different functions at the level of the cellular biochemical processes and has a strong antioxidant activity. Its deficiency leads, among other problems, to a reduced ability of the immune system to respond to the infections. In the present invention, the indicated amounts of vitamin C refer to the L-ascorbic acid, although in the combination and compositions of the invention said L-ascorbic acid may be introduced in the form of substances comprising it.

Zinc and Selenium are essential minerals that become part of numerous biochemical chains within the human body. In the combination of the invention, these minerals may be present in the form of oxides, salts, esters, complexes and the like.

According to a preferred embodiment, Zinc of the combination is present in the form of Zinc oxide.

According to a preferred embodiment, Selenium is in the form of Sodium Selenite.

According to a preferred embodiment, Zinc is in the form of Zinc oxide and Selenium is in the form of Sodium Selenite.

Curcumin is a molecule that is generally extracted from turmeric, preferably Curcuma longa. For its use according to the composition of the invention, curcumin may be used in pure form or in crude extract form or in any other form. By way of example said curcumin, preferably extracted from Curcuma longa, can be used in phytosomal form, i.e., conjugated with phospholipids, advantageously with soybean phospholipids. Alternatively, said curcumin may be in the form of a hydroalcoholic extract of Turmeric, preferably of Curcuma longa. According to a preferred embodiment, the combination of the invention comprises curcumin.

All active ingredients of the composition of the invention are known and commercially available.

The combination has been found to be particularly useful and effective in supporting and strengthening the immune system and/or as an adjuvant in the prevention and/or treatment of the cold-related diseases. In fact, the combination has shown interesting immunostimulating activities thanks to the combined and synergistic action of its components, particularly when they are dosed according to the aforementioned weight ratios.

In the text of the present invention, the terms "immunostimulation", "immune system strengthening", with all synonyms for the word "strengthening", are meant be equivalent. By "immunostimulation" and derived terms, it is meant here to denote the activity of stimulating the body's own immune defenses so that it can react more promptly and effectively against the external attacks such as the infections by pathogens of any kind, such as bacteria, viruses, fungi, protozoa, etc.

By "cold-related diseases" it is meant here that class of diseases/infections determined by the presence of pathogens that affect the sense organs of the head (nose, eyes, ears), throat and lungs (at all levels) and that comprise, for example but not only, flu, cold, otitis, pharyngitis, bronchitis etc.

According to a preferred embodiment, in the combination of the invention the components are present in the following weight ratios: lactoferrin/N- acetylcysteine/resveratrol/vitamin D/vitamin C/Zinc/Selenium, 1/1-3/0.1-0.5/0.0001- 0.0005/1-4/0.001-0.05/0.0001-0.0005, preferably 1/1-2/0.1-0.3/0.0001-0.0002/1.5- 3/0.02-0.04/0.00015-0.0004, more preferably about

1/1.5/0.25/0.000125/2.5/0.0375/0.00025.

According to a preferred embodiment, in the combination of the invention the components are present in the following weight ratios: lactoferrin/N- acetylcysteine/resveratrol/vitamin D/vitamin C/Zinc/Selenium/curcumin, 1/1-3/0.1- 0.5/0.0001-0.0005/1-4/0.001-0.05/0.0001-0.0005/0.01-0.5, preferably 1/1-2/0.1- 0.3/0.0001-0.0002/1.5-3/0.02-0.04/0.00015-0.0004/0.03-0.3, more preferably about 1/1.5/0.25/0.000125/2.5/0.0375/0.00025/0.05-0.2.

In the aforementioned weight ratios, Zinc and Selenium are counted as pure elements (i.e., based on their atomic weight). Therefore, even when in the combination of the invention such elements are used in different forms, such as oxides, salts or complexes, the quantities referred to in the aforementioned weight ratios are always referred to the two elements only.

In the aforementioned weight ratios, the amounts of curcumin are always calculated on the basis of curcumin, even when used in phytosomal form or complexed in other forms.

The use of the combination as immunostimulant and/or as adjuvant in the treatment and/or prevention of the cold-related diseases is a further subject-matter of the invention.

For its use according to the invention, the combination is preferably formulated in compositions suitable for the administration by oral route, with immediate or controlled release, for example in suitable oral dosage forms, as solid dosage units, such as capsules, tablets, effervescent tablets, powders or granules, or in liquid dosage forms such as mono- or multi-dose oral solutions or suspensions. Said composition, preferably an oral composition, more preferably an oral solid composition, advantageously with immediate release, comprising the combination of the invention together with pharmaceutically acceptable excipients and carriers, is a further subject- matter of the invention.

According to a preferred embodiment, the composition of the invention comprises curcumin.

In addition to the active ingredients, the compositions of the invention may contain conventionally used excipients, for example, diluting agents, adsorbents, lubricants, glidants, sweeteners, colorants, effervescents, etc.

According to an embodiment, the combination of the invention may be administered in compositions comprising one or more pharmaceutically acceptable excipients, in daily dosages of: 100 to 300 mg lactoferrin, preferably 150 to 250, even more preferably about 200 mg;

200 to 400 mg NAC, preferably 250 to 350 mg, even more preferably about 300 mg;

20 to 100 mg resveratrol, preferably 35 to 75 mg, even more preferably about 50 mg;

10 to 40 pg vitamin D, preferably 20 to 30 pg, even more preferably about 25 pg;

250 to 1,000 mg vitamin C, preferably 350 to 650 mg, even more preferably about 500 mg;

5 to 10 mg Zinc, preferably 6 to 8 mg, even more preferably about 7.5 mg;

25 to 100 pg Selenium, preferably 35 to 65 pg, even more preferably about 50 pg.

According to an embodiment, the combination of the invention may be administered in compositions comprising one or more pharmaceutically acceptable excipients, in daily dosages of:

100 to 300 mg lactoferrin, preferably 150 to 250, even more preferably about 200 mg;

200 to 400 mg NAC, preferably 250 to 350 mg, even more preferably about 300 mg;

20 to 100 mg resveratrol, preferably 35 to 75 mg, even more preferably about 50 mg;

10 to 40 pg vitamin D, preferably 20 to 30 pg, even more preferably about 25 pg;

250 to 1,000 mg vitamin C, preferably 350 to 650 mg, even more preferably about 500 mg;

5 to 10 mg Zinc, preferably 6 to 8 mg, even more preferably about 7.5 mg;

25 to 100 pg Selenium, preferably 35 to 65 pg, even more preferably about 50 pg; 2 to 100 mg curcumin, preferably 10 to 40 mg, even more preferably about 20 mg.

If desired or necessary, e.g. if the doctor deems it useful, such daily dosages may be increased or reduced, for example also doubled.

According to a preferred embodiment, the afore stated daily dosages are taken in a single daily administration. However, if it is desired or needed, said dosages can be administered in a single dose or divided in two or more administrations, for example one, two or three daily administrations, to be taken simultaneously or at different times.

According to a preferred embodiment, the combination is in the form of oral solid compositions and packaged in capsules, sachets or tablets, if desired also effervescent tablets.

According to a preferred embodiment, the combination is in the form of oral solid compositions such as powder or granules and packaged in stick packs or sachets.

The compositions of the invention can be defined as pharmaceutical or nutraceutical compositions.

Preferably, said daily dosages or the compositions of the invention are administered on a full stomach, for example after breakfast or after lunch.

For the preparation of the preferred solid oral composition according to the invention, for example a capsule, a tablet or a granule to be packaged in sachets, it is possible to use the methods known in the art. The tablets may also be prepared by the addition of excipients which allow them to be administered after being dissolved in an aqueous vehicle, such as for example by the addition of effervescent excipients or by technologies to make them orosoluble. Capsules and tablets may also be coated with a film, which may be of cosmetic or functional type, for example to achieve a gastro- resistant form or a controlled/ sustained release.

The techniques for preparing effervescent, orosoluble dosage forms and those for applying a coating film are those known in the field of pharmaceutical technology and known to the expert in the art.

According to a preferred embodiment, the compositions of the invention are administered orally. According to a preferred embodiment, the compositions of the invention are administered in oral dosage forms, each comprising:

- 100 to 300 mg lactoferrin, preferably 150 to 250, even more preferably about 200 mg;

- 200 to 400 mg NAC, preferably 250 to 350 mg, even more preferably about 300 mg;

- 20 to 100 mg resveratrol, preferably 35 to 75 mg, even more preferably about 50 mg;

- 10 to 40 pg vitamin D, preferably 20 to 30 pg, even more preferably about 25 pg;

- 250 to 1,000 mg vitamin C, preferably 350 to 650 mg, even more preferably about 500 mg;

- 5 to 10 mg Zinc, preferably 6 to 8 mg, even more preferably about 7.5 mg;

- 25 to 100 pg Selenium, preferably 35 to 65 pg, even more preferably about 50 pg; optionally together with pharmaceutically acceptable excipients and carriers.

According to a preferred embodiment, the compositions of the invention are administered in oral dosage forms, each comprising:

- 100 to 300 mg lactoferrin, preferably 150 to 250, even more preferably about 200 mg;

- 200 to 400 mg NAC, preferably 250 to 350 mg, even more preferably about 300 mg;

- 20 to 100 mg resveratrol, preferably 35 to 75 mg, even more preferably about 50 mg;

- 10 to 40 pg vitamin D, preferably 20 to 30 pg, even more preferably about 25 pg;

- 250 to 1,000 mg vitamin C, preferably 350 to 650 mg, even more preferably about 500 mg; - 5 to 10 mg Zinc, preferably 6 to 8 mg, even more preferably about 7.5 mg;

- 25 to 100 pg Selenium, preferably 35 to 65 pg, even more preferably about 50 pg;

- 2 to 100 mg curcumin, preferably 10 to 40 mg, even more preferably about 20 mg; optionally together with pharmaceutically acceptable excipients and carriers.

Examples of compositions according to the invention are provided in the Experimental section, by way of illustration.

As mentioned, the combination of the invention is particularly recommended in clinical conditions in which a functional deficiency of the immune system is present.

In fact, thanks to its specific composition of nutrients, vitamins and minerals, it has been shown to improve the immune response, by increasing the body's defenses. The individual components carry out in a synergistic way both a preventive and protective action against the infectious (viral and bacterial) and inflammatory forms characterizing in particular the change of season and which are more frequent in elderly and weakened patients, the immune system of whom is generally deficient.

The use of the composition as described above to support and strengthen the immune system and/or as an adjuvant in the prevention and/or treatment of cold- related diseases constitutes a further subject-matter of the invention.

According to another of its aspects, a subject-matter of the invention is a method for obtaining an immunostimulant effect and/or as an adjuvant for treating and/or preventing the disorders of the cold-related diseases, comprising administering an effective dose of the combination or composition of the invention to a subject in the need thereof. By subject is meant herein to denote a mammal, preferably a human.

Although the composition of the invention itself provides the solution to the problem, if desired or needed, other substances however beneficial for the body can be added to the compositions of the present invention, provided they do not counteract the effects of the combination and composition of the invention. The invention will now be described for illustrative purpose only and in no way limiting in the Experimental Section below.

Experimental section

Example 1

Sachet of granules comprising:

Lactoferrin 200 mg;

N-acetylcysteine 300 mg;

Resveratrol 50 mg;

Vitamin D 25 pg;

Vitamin C 500 mg;

Zinc oxide 9.4 mg (corresponding to 7.5 mg Zinc);

Sodium Selenite 110 pg (corresponding to 50 pg Selenium);

Phytosomal curcumin 20 mg (of curcumin); together with conventional vehicles and excipients.

Example 2

Sachet of granules comprising:

Lactoferrin 250 mg;

N-acetylcysteine 350 mg;

Resveratrol 60 mg;

Vitamin D 40 pg;

Vitamin C 750 mg;

Zinc oxide 12.4 mg (corresponding to 10 mg Zinc);

Sodium Selenite 164 pg (corresponding to 75 pg Selenium);

Curcumin 20 mg; together with conventional vehicles and excipients.

Example 3

Hard gelatin capsule comprising:

Lactoferrin 100 mg;

N-acetylcysteine 150 mg;

Resveratrol 25 mg;

Vitamin D 12.5 pg; Vitamin C 250 mg;

Zinc oxide 12.4 mg (corresponding to 10 mg Zinc);

Sodium Selenite 110 pg (corresponding to 50 pg Selenium); Phytosomal curcumin 30 mg (of curcumin) together with conventional vehicles and excipients.

Example 4

Sachet of granules comprising:

Lactoferrin 400 mg;

N-acetylcysteine 600 mg;

Resveratrol 50 mg;

Vitamin D 50 pg;

Vitamin C 1000 mg;

Zinc oxide 18.8 mg (corresponding to 15 mg Zinc);

Sodium Selenite 220 pg (corresponding to 100 pg Selenium); Curcumin 25 mg; together with conventional vehicles and excipients. Example 5

Sachet of granules comprising:

Lactoferrin 400 mg;

N-acetylcysteine 600 mg;

Resveratrol 50 mg;

Vitamin D 50 pg;

Vitamin C 1000 mg;

Zinc oxide 18.8 mg (corresponding to 15 mg Zinc);

Sodium Selenite 220 pg (corresponding to 100 pg Selenium); together with conventional vehicles and excipients.

Example 6

Sachet of granules comprising:

Lactoferrin 250 mg;

N-acetylcysteine 350 mg;

Resveratrol 60 mg;

Vitamin D 40 pg; Vitamin C 750 mg;

Zinc oxide 12.4 mg (corresponding to 10 mg Zinc);

Sodium Selenite 164 pg (corresponding to 75 pg Selenium); together with conventional vehicles and excipients. Example 7

Hard gelatin capsule comprising:

Lactoferrin 100 mg;

N-acetylcysteine 150 mg;

Resveratrol 25 mg; Vitamin D 12.5 pg;

Vitamin C 250 mg;

Zinc oxide 12.4 mg (corresponding to 10 mg Zinc);

Sodium Selenite 110 pg (corresponding to 50 pg Selenium); together with conventional vehicles and excipients.