WO2021234660A1

WO2021234660A1 - Composition for the prevention and the treatment of diseases of the respiratory tract and as a stimulant of the immune system

Info

Publication number: WO2021234660A1
Application number: PCT/IB2021/054440
Authority: WO
Inventors: Umberto DI MAIO
Original assignee: Neilos S.r.l.
Priority date: 2020-05-21
Filing date: 2021-05-21
Publication date: 2021-11-25
Also published as: EP4153205A1; IT202000011983A1

Abstract

Herein described is a composition containing a synergistic combination of an extract of Pelargonium sidoides, resveratrol and, optionally, lactoferrin for the prevention and treatment of infections of the respiratory tract and for stimulating the immune system.

Description

DESCRIPTION of the invention having the title:

“Composition for the prevention and the treatment of diseases of the respiratory tract and as a stimulant of the immune system”

DESCRIPTION

Forming an object of the present invention is a composition containing a combination or mixture comprising or, alternatively, consisting of: (a) an extract of Pelargonium sidoides ; and (b) resveratrol; optionally mixed with a suitable pharmaceutically acceptable carrier.

Furthermore, forming an object of the present invention is said composition for use in a method for the preventive or curative treatment of diseases of the respiratory tract in a subject, preferably in a mammal, more preferably in a human or in an animal.

Furthermore, forming an object of the present invention is said composition is for use as a stimulant of the immune system in a subject, preferably in a mammal, more preferably in a human being or in an animal. Furthermore, the present invention relates to a composition containing a combination of an extract of Pelargonium sidoides, resveratrol and, optionally, lactoferrin useful for the prevention and/or the treatment of diseases of the respiratory tract and for use as a stimulant of the immune system. The composition is particularly effective given that it allows to simultaneously obtain an antiviral effect, an antimicrobial effect and an immunomodulatory effect thanks to the synergistic action of the components thereof.

Background of the invention

RESPIRATORY SYSTEM AND RESPIRATORY DISEASES

The respiratory system consists of various anatomical structures useful for the proper function thereof.

As a matter of fact, it is responsible for the exchange of gases, oxygen and carbon dioxide, between tissues and the external environment, which is crucial to all the cellular processes of the organism and that is to the life thereof.

Anatomically, there are distinguished two macro-areas, which are the upper airways and the lower airways: the former consist of the nose, pharynx and associated structures, while the latter consist of larynx, trachea, bronchi and lungs, whose actual respiratory surface consists of the alveoli. This complex system of organs serves to prepare the air as it enters the lungs, through filtration against possible particulate matter, heating and humidification.

Besides turbulent precipitation, mediated by turbinates that deflect the direction of the air, particles larger than 10-15 microns can be blocked at the level of the nasal cavities, thanks to the vibrissae and the presence of mucus that trap these particles. Mucus stratifies above the periciliary liquid, into which the cilia of the epithelium cells are immersed.

Particles measuring about 10 microns arrive in the trachea, they are trapped in the mucus, and then eliminated by the ciliary movement.

Particles measuring 2-5 microns settle in the terminal bronchioles by gravitational precipitation, while those smaller than 2 microns are removed from the alveolar macrophages and moved away by the pulmonary lymphatic system.

The entire respiratory tract consists of epithelial cells that differ in type and function along the tracheobronchial tree.

Ciliated columnar cells characterise the airways from the trachea to the terminal bronchioles. The eyelashes, which have the task of moving with cleaning effect on the mucus and on possible inhaled particles, protrude from their apical surface thereof.

The goblet cells which are responsible for mucus secretion, useful to maintain the correct humidity of the epithelium and to trap particulate matter. They are present in the widest sections of the airways under the small bronchi but they were not been found in the bronchioles.

All the components of the respiratory system can be exposed to a several diseases, of different aetiology, often sustained by various pathogenic microorganisms, which - becoming preponderant in the microenvironment and on the flora normally present - determine the disease and, as a result, lead to a reduced functionality.

EXAMPLES OF DISEASES OF THE RESPIRATORY TRACT

Depending on the area of the respiratory system, there can distinguished various pathological conditions characterised by inflammation due to viruses, bacteria or fungi.

Common cold and influenza

Common cold is an acute and self-limiting infection of the upper respiratory tract that involves the nose, paranasal sinuses, pharynx, and larynx. The virus is transmitted by contact with an infected person through the air, generally by coughing, sneezing or direct contact with the virus. The incubation period is normally less than two days and symptoms usually peak between the first and third day with a duration ranging from 7 to 10 days. The most common symptoms are sore throat, rhinitis, rhinorrhoea, cough and general malaise, and the severity of the symptoms varies greatly from person to person and depending on the different infectious agents. For example, fever is usually rare in adults but very frequent in children and, in general, the incidence of common cold syndromes progressively reduces over the years. As a matter of fact, children under the age of two tend to have up to six episodes in one year, adults between two and three, and elderly people around one episode per year.

In children, this may be due to daily attendance of kindergartens, which increases the risk of infection, while for adults, stress and sleep problems may facilitate the onset of common cold.

Rhinoviruses are more involved in infections of this type. In other cases, the aetiological agent is not well known, whereas only 5% of cases are bacterial infections.

Though it is a disorder that tends to resolve alone, common cold has a very high prevalence and it can be debilitating, as it can, for example, reduce productivity at work, and interfere with other activities such as driving. Furthermore, it has a high impact on health; as a matter of fact, about 7-17% of adults and 33% of children require medical check-up. For example, in the United States, the cost of a common cold (medical examination, superinfections and medicines) was estimated at 17 billion dollars in 1997.

In the case of influenza, it is always a viral infection that deeply affects the world's population mainly between December and April. Unlike common cold, it is accompanied by fever, headache, myalgia, fatigue and loss of appetite.

Rhinitis

Rhinitis is an inflammatory process affecting the mucosa of the nasal cavities and it is distinguished in acute and chronic.

Acute rhinitis are generally borne by viruses, including Rhinoviruses, Coronaviruses, influenza and parainfluenza viruses, RSV, Coxsackie virus, ECFIO virus and adenovirus. The infection occurs through direct contact with the sick person who, in the peak of maximum infectivity (generally on the first day), has 500-1000 virions per ml of secretion, emitted by coughing and sneezing. Bacterial superinfections which lead to complications such as otitis and sinusitis are possible.

Common cold from Rhinovirus causes acute symptoms in the first 3-4 days, while coughing and other symptoms persist for 7-10 days. There is an excess of mucous secretions which are fluid and transparent, and become purulent and malodorous in case of bacterial overlap.

The chronic form of rhinitis is generally secondary to sinusitis, nasal septum deviations, hypertrophic adenoids.

Allergic rhinitis is due to the subject's exposure to substances that cause an IgE-mediated reaction, characterised by excessive production of fluids, intranasal itching, sneezing and obstruction. As a matter of fact, IgEs bind to mast cells which release large amounts of histamine, responsible for all the morbid manifestations.

Recent studies have shown that allergic rhinitis and asthma are concurrent, and they are to be considered as two manifestations of the entire respiratory tract, rather than placing one in the upper tract and the other in the lower tract of the bronchial tree. As a matter of fact, it has been observed that between 20% and 50% of patients with allergic rhinitis also have asthma, and that 30% to 90% of patients with asthma have concomitant rhinitis.

Therefore, allergic rhinitis may be a predisposing factor to the development of allergic asthma and, specifically, sensitization to aeroallergens (pollen or animal hair) it could be a significant risk factor in the combination of asthma and rhinitis.

Sinusitis

Sinusitis is the inflammation of the mucosa that coats the paranasal sinuses, bone cavities located in the facial skeleton, and that are placed in communication with the nasal fossae; therefore, the paranasal sinuses can become infected for the same causes that determine rhinitis.

Sinusitis can be distinguished into acute viral or acute bacterial (up to 4 weeks), chronic (over 12 weeks) and recurrent acute (at least 4 episodes per year with resolution).

When sinusitis involves the nasal cavity, it is called rhinosinusitis.

Generally, a healthy sinus is sterile, characterised by proper drainage of mucus and free passage of air. Ciliary abnormalities or immobility inhibit drainage resulting in sinusitis.

Predisposing factors to this disease are an immunocompromised condition, nasal septum deviation, nasal polyps, tumours, traumas and fractures, abuse of cocaine, presence of foreign bodies.

An acute viral form may be subject to bacterial superinfection. The bacteria commonly responsible for these infections are Streptococcus pneumoniae, non-typeable Haemophilus influenzae, Moraxella catarrhalis. Pseudomonas aeruginosa is most frequently present in sinusitis caused by HIV infections and cystic fibrosis. Some genera of fungi such as Candida, Aspergillus, Blastomyces, Coccidioides, Rizophus, Histoplasma and Cryptococcus may cause sinusitis in immunocompromised patients.

The signs and symptoms of acute rhinosinusitis consist of: mucopurulent discharge from the nose, nasal obstruction, congestion, facial pain, pressure on the sinuses involved, hyposmia, anosmia, fever, feeling of pressure or "plug” in the ears, pain in the teeth.

Generally, during the first 3-5 days, it is not possible to distinguish a viral form from a bacterial form, so the use of antibiotics is not recommended. If the disease persists beyond 10 days, then most likely it will be sustained by bacteria and antibiotic treatment is recommended. Chronic forms have a slower onset, longer duration and frequency. The symptoms are similar to those of the acute form with, in addition, bad breath, laryngitis, bronchitis and worsening asthma.

Sinusitis often resolves spontaneously and treatment is predominantly symptomatic. In particular, decongestant treatment serves to reduce oedema, improve drainage of excess mucus, and maintain the patency of sinus ostia. A good result can be obtained from the local application of hypertonic saline solution in the treatment of the acute bacterial form, of the recurrent acute form, in the chronic form and also in prevention.

The choice of antibiotics must instead take into account the production of beta lactamase and the presence of drug-resistant pneumococci.

Pharyngitis (pharyngotonsillitis)

This is an inflammatory process of pharynx, hypopharynx, uvula and tonsils, which is generally transmitted by direct contact with respiratory secretions. It is more frequent in paediatric age (5-15 years) and, although it is frequently self-limiting, swelling of the affected parts may result in decreased patency of the airways or in any case preclude ingestion of adequate amounts of liquids resulting in dehydration.

Infection can be sustained by viruses (such as Epstein-Barr) and bacteria; in particular beta-haemolytic Streptococcus pyogenes of group A is the most common in paediatric forms, but also Mycoplasma pneumoniae and chlamydia pneumoniae are found in adults and children. Furthermore, forms transmitted by sexual contact and sustained by Neisseria gonorrhoeae and those caused by Corynebacterium dyphtheriae (form reduced by the use of the vaccine) are to be considered.

Epiglottitis

This is an inflammation of the epiglottis, resulting from viral or bacterial infection, which causes swelling of the organ with possible obstruction of the airways.

It is mainly caused by H. influenzae type b, but also by streptococci, staphylococci or thermal trauma. It manifests itself with ear pain (in adults), dysphonia, while fever is absent up to 50% of cases and may develop in a late phase.

It is treated with antibiotics in cases where the disease is caused by bacteria, while intubation may be required in case of severe obstruction of the airways.

Laryngitis

This is an inflammation of the larynx which manifests itself with aphonia and raucousness, primarily caused by viruses, but up to 10% of cases are also caused by bacteria (including streptococci and C. dyphtheriae). Non-infectious causes may be tumours, thermal or caustic trauma, gastroesophageal reflux disease (GERD).

Laryngitis has symptoms that last 3-4 days and it is not treated with antibiotics unless bacteria are present. Bronchitis

Bronchitis is a frequent inflammation of the bronchi which manifests itself with cough, shortness of breath and chest pain. Bronchitis is distinguished in acute and chronic bronchitis. In the first case, cough lasts about three weeks and in 90% of the cases it is caused by viral infection that can occur following contact with other infected people. Predisposing risk factors may be cigarette smoke or other sources of environmental pollution. Chronic bronchitis is characterised by coughing for three months a year for at least two episodes per year, and the main trigger factors are cigarette smoke along with other genetic or environmental causes.

Unless in special cases, normally it is not treated with antibiotics but with steroidal anti-inflammatory drugs, paracetamol to compensate for any increase in temperature, and bronchodilators such as salbutamol to improve breathing.

Bronchiolitis

A frequently paediatric disease, bronchiolitis is characterised by extensive inflammation of the airways accompanied by intense production of mucus and necrosis of epithelial cells.

It is primarily caused by a viral infection, particularly by Respiratory Syncytial Virus (RSV), but also adenoviruses, influenza and parainfluenza viruses, human metapneumovirus and rhinoviruses, while the most frequently involved bacteria are of the genus Chlamydia.

In paediatric age, the main clinical manifestations are tachypnoea, shortness of breath or crackles upon auscultation, which generally follow an infection of the upper respiratory tract.

Treatment may include hospitalisation if oxygen saturation is comprised between 92% and 94%, along with other clinical manifestations such as poor nutrition, dehydration, and a history of dyspnoea.

Bronchiectasis

This is a disease characterised by an irreversible dilation of a portion of the bronchial tree in the lungs. Bronchial dilation may be the result of a structural defect in the wall, exposure to abnormal pressure, or damage to cartilage or elastic tissue following an inflammation. It involves bronchi and bronchioles where a vicious circle of infection and inflammation can be established, even with release of mediators.

Common symptoms are mucus-producing cough and chest pain. Mucus has an increased amount of elastase and TNF-a, IL-8 and prostanoids. It may appear as a local or widespread obstructive process part of both lobes, also accompanied by sinusitis or asthma.

There are various causes, for example - especially in paediatric age - infections including mycotic which leave permanent damage. Or primary ciliary dyskinesia, in which there is marked retention of secretions that are followed by infections. Cystic fibrosis, just like immunocompromisation conditions, may be predisposing factors. It was also observed that infections of the respiratory tract and bronchiectasis are present in patients with ulcerative colitis. Treatment includes the use of antimicrobials to combat infections sustained both by bacteria and fungi. Furthermore, it is particularly useful to cleanse the airways to increase the removal of secretions, using saline solutions and to keep the patient, in general, well hydrated.

WO 2019/154773 A1 discloses a pharmaceutical composition containing an extract of Pelargonium sidoides and lactoferrin, for the prevention and the treatment of diseases of the respiratory tract and for stimulating the immune system.

M. SADEKUZZAMAN ET AL: "Current and Recent Advanced Strategies for Combating Biofilms: Strategies for combating biofilm..:, COMPREHENSIVE REVIEWS IN FOOD SCIENCE AND FOOD SAFETY, vol. 14, no. 4, pages 491-509, is a review that discusses current and new advanced strategies for combating biofilms that are superior to conventional methods to address the problem relating to biofilms to improve health, food safety, and industrial processes.

ON 111 097 040 A illustrates antiviral peptides for cleansing the lungs obtained from a combination of various raw materials.

US 2019/117555 A1 illustrates a sublingual composition comprising a part of an extract of a branch, preferably from at least one resinous tree.

VAN WYK B E ET AL: " Medicinal plants of the World', 1 January 2005, MEDICINAL PLANTS OF THE WORLD: AN ILLUSTRATED SCIENTIFIC GUIDE TO IMPORTANT MEDICINAL PLANTS AND THEIR USES, TIMBER PRESS, PORTLAND, OREGON, USA, pages 38, 39, 64, 66, 69, 74, 75, 103, 104, 111, 118, 142, 173, 183, 189, 204, 228, 231, 235, 242, 24, illustrates various plants for medicinal use.

It has now been surprisingly found that a combination of an extract of Pelargonium sidoides, resveratrol and, optionally, lactoferrin is particularly useful in the prevention and in the treatment of respiratory diseases and for stimulating the immune system thanks to the synergistic action of the components thereof.

In all the above-mentioned diseases, as well as in other pathological conditions, there arises the need for active ingredients capable of significantly activating the immune system so as to effectively and rapidly combat the infection reducing the duration and severity of the symptoms.

Detailed description of the invention Thus, forming an object of the present invention is a composition containing a combination of an extract of Pelargonium sidoides, resveratrol and optionally lactoferrin for the prevention and the treatment of respiratory diseases and for stimulating the immune system both in humans and animals.

Furthermore, forming an object of the present invention is a composition containing a combination or mixture comprising or, alternatively, consisting of: (a) an extract of Pelargonium sidoides ; and (b) resveratrol; optionally mixed with a suitable pharmaceutically acceptable carrier, as defined by the characteristics of the attached claims.

Furthermore, forming an object of the present invention is said composition for use in a method for the preventive or curative treatment of diseases of the respiratory tract in a subject, preferably in a mammal, more preferably in a human being or in an animal, as defined by the characteristics of the attached claims. Furthermore, forming an object of the present invention is said composition is for use as a stimulant of the immune system in a subject, preferably in a mammal, more preferably in a human being or in an animal, as defined by the characteristics of the attached claims.

The components of the combination according to the present invention are all known components, widely used in therapy.

GLOSSARY

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

In the context of the present description, the expression "extract” is used to indicate any product related to a drug or plant matter including all products derived from mechanical treatments (pulverisation, crushing, mixing and/or other methods) and/or from extract-based treatments (solvent extraction, distillation, and/or other specific methods) conducted on said drug or plant matter.

PELARGONIUM SIDOIDES

Pelargonium sidroides is one of the most important species of the genus Pelargonium used for a long time in traditional South African medicine.

The popular use of this type of plant was aimed at respiratory infections and gastro-intestinal problems; in particular, interest in this plant species has grown increasingly due to the potential use thereof as an antitubercular agent, as a remedy for earache, common cold, tonsillitis, bronchitis, sinusitis and nasopharyngitis.

From a phytochemical point of view, numerous studies have addressed the identification of the major metabolites in plant extracts and there was observed the presence of a large number of metabolites belonging to the classes of coumarins, flavonoids, proanthocyanidins, phenolic acids and phenylpropanoids. In particular, "umckalin” and other trimethoxy-coumarins are considered as “markers" of the species Pelargonium sidoides, for example to distinguish it from the species Pelargonium reniforme in which these compounds should be absent.

The scientifically recognised effects of P. sidoides are the antibacterial, antiviral and immunomodulatory ones which have respectively been attributed to polyphenols (gallic acid) and to a combination of phenolic compounds with coumarin structure.

With regard to antibacterial and antifungal activity, a 1997 study evaluated the effect of the individual components (scopoletin, "umckalin”, 5,6,7-trimethoxy-coumarin, (+)-catechin, gallic acid and esters thereof) against Gram positive bacteria ( Staphylococcus aureus, Streptococcus pneumoniae, Streptococcus 1451) and Gram-negative bacteria ( Escherichia coli, Klebsiella pneumoniae, Proteus mirabilis, Pseudomonas aeruginosa, Haemophilus influenzae). All components except catechin showed antibacterial activity with an MIC comprised between 200 and 1000 pg/mL.

Antibacterial activity was also evaluated indirectly by evaluating the ability of an extract of Pelargonium sidoides to inhibit bacterial adhesion (streptococcus) to human epithelial cells. As regards the extract of the plant, other in vitro studies have shown the ability to increase phagocytosis, oxidative response and cell death.

Other studies have confirmed the significant immunomodulatory ability of the extracts of Pelargonium capable of stimulating, besides the macrophage activity, also the release of several cytokines crucial in immune response such as TNF-a, iNOS, IL-1, IL-10, IL-12, IL-18, interferon-a,g. This immunomodulatory action is of particular importance also considering that most of infections of the upper respiratory tract are due to viruses.

A 2011 study by Janecki et al., showed a potential role of procyanidins contained in the root of P. sidoides in inhibiting the adhesion of Streptococcus pyogenes to epithelial cells of the larynx.

Another documented activity regarding the extract of the plant lies in the ability to stimulate the mucociliary system: in two studies there was observed the ability of the extract of the plant (1, 30, 100 pg/mL) to increase mucociliary "clearance” in human nasal epithelium cell cultures.

The action of Pelargonium sidoides was evaluated in humans in approximately 20 clinical studies, most of which were randomised, double-blind and placebo-controlled. In the studies conducted, the extract revealed to be capable of reducing the severity and duration of acute bronchitis and tonsillopharyngitis, and other infections of the respiratory tract in adults and children.

For example, in a 2006 study, there were recruited 400 patients aged 6 to 18 years who randomly received 30, 60 and 90 mg of an extract of Pelargonium sidoides divided into three daily administrations or placebo for a period of 7 days. After 7 days, the authors describe an improvement in Bronchitis Severity Score (BSS) at doses of 60 and 90 mg/day and in particular cough, wheezing upon auscultation and sputum improved too. Product tolerance was comparable to placebo in the treated groups.

As regards tonsillopharyngitis, among others, a study was conducted in 143 children aged 6 to 10 years with a diagnosis of acute tonsillopharyngitis and a Tonsillopharyngitis Severity Score (TSS) > 8.

Children were administered 1 mL of an extract of P. sidroides EPs 7630 three times a day or placebo for a period of six days. In the treated group there was observed a significantly higher reduction in TSS with respect to placebo, a lower use of antipyretic drugs, without particular side effects.

In a 2007 study, the efficacy of treating cold symptoms with the extract of P. sidoides EPs 7630 was observed in 133 patients, who took it for a maximum period of ten days.

Even as regards common cold, the extract showed to be an effective treatment capable of reducing the severity and duration of symptoms with respect to placebo.

To the large number of clinical trials, which at the same time showed good efficacy and safety of use (mainly mild and transient side effects), the extract of Pelargonium sidoides is a good choice for the development of a product for the prevention and the treatment of diseases of the respiratory system.

RESVERATROL

Resveratrol is a molecule naturally produced by many plants as a form of defence against attacks by pathogens such as bacteria, fungi and viruses.

Among the various plant sources of resveratrol, the most common is Polygunum cuspidatum.

Scientific literature attributes various therapeutic properties to resveratrol: prevention of cardiovascular diseases, prevention of cancer, control of bacterial, fungal and viral infections. In the review “Resveratrol as a potential therapeutic drug for respiratory system diseases", focus is made to the efficacy of resveratrol in resolving disorders of the respiratory system. As a matter of fact, resveratrol is considered as potent anti-inflammatory, antioxidant, anti-cancer useful therefore that can be used against asthma, against inflammatory conditions, in the prevention of lung cancer, in the treatment of pulmonary hypertension, in reducing disorders such as oxidative stress and apoptotic events.

Many disorders of the respiratory system are of viral origin; this further highlights the usefulness of resveratrol in this field given that antiviral effects were reported in various studies.

There was observed in vitro and in vivo activity against Herpes (HSV-1, HSV-2) viruses, while in vitro studies have shown antiviral activity even against other strains (VZV, HCMV, EBV, HUV-1, Influenza A virus, Polyomavirus). In all cases, resveratrol showed an action on virus replication and not directly on the virus itself.

Beneficial effects of resveratrol on Herpes simplex virus are reported in several published studies: “Resveratrol inhibition of Herpes simplex virus replication", “Resveratrol suppresses nuclear factor-KB in herpes simplex virus infected cells", “Effect of topically applied resveratrol on cutaneous herpes simplex virus infection in hairless mice", “Effect of Resveratrol on herpes simplex virus vaginal infection in the mouse", while the study “Resveratrol inhibition of varicella-zooster virus replication in vitro" confirms the theory according to which resveratrol attacks the virus life cycle, while highlighting an antiviral action even with administration within 30 hours from the onset of the infection: this efficacy after a higher number of hours with respect to the one reported regarding the studies conducted on Herpes simplex virus, is likely specifically due to the diversity of the virus. The effects of resveratrol on Influenza A virus are reported in study “Inhibiton of influenza A virus replication by resveratrol' which reports a reversible dose-dependent antiviral action against Influenza A virus. The effective dose is comprised in the range from 20 micrograms/mL to 40 micrograms/mL (dose at which the virus inhibition is basically total). The efficacy of resveratrol in the treatment of Influenza A virus is confirmed in the study “In vitro antiviral effects and 3D QSAR study of Resveratrol derivate sas potent inhibitor of influenza H1N1 neuraminidase" , which besides highlighting the efficacy of resveratrol against the virus without the development of cytotoxicity, also analyses 50 derivatives of resveratrol as pertains to their intrinsic activity as well as the kinetic properties thereof: out of these 50 derivatives, a whole 35 showed inhibitory activity against the virus.

Another study that analyses the antiviral properties of resveratrol is “Effective inhibition of Mers-Cov infection by Resveratrol’ which reports that besides inhibiting the expression of nucleocapsid which is a protein essential to the replication of the Mers-CoV virus, resveratrol (used at a maximum concentration of 250 mM) also increases cell survival after virus infection. Even in this case, the mechanism of action assumed shows resveratrol affecting the virus replication cycle without directly attacking the virus itself, lowering the levels of RNA.

As previously mentioned, the effectiveness of resveratrol against the viruses places it at the centre of studies conducted in the search for natural substances that can be used to combat the main disorders of the first airways, which are almost always linked to an external insult and then lead to an inflammatory event. As a matter of fact, the study “Antioxidant and anti-inflammatory effects of resveratrol in airway disease" examines asthma (which is an inflammatory process) that can have allergens or viruses as trigger agents. This inflammatory event entails (as always) to excessive production of reactive oxygen species. Resveratrol is a useful remedy because it acts at two levels: as an anti-inflammatory and as an antioxidant (with various mechanisms: Inhibition of the production of reactive oxygen species, elimination of free radicals, stimulation of endogenous antioxidants). The anti-inflammatory efficacy of resveratrol is confirmed in the study “Resveratrol, an extract of red wine, inhibits lipopolysaccharide induced airway neutrophilia and inflammatory mediators through an NF-KB independent mechanism" in which the effect of resveratrol against LPS-induced neutrophilia is (though dose-dependent) comparable to that of the glucocorticoid "Budesonide”. Such reduction of the neutrophilia appears related to an inhibition of inflammatory mediators induced as TNF-alpha, IL-1 beta, CINC-1, PGE2 (with a mechanism yet to be clarified).

The efficacy of resveratrol, comparable to that of glucocorticoids, is confirmed in the study “Anti inflammatory and anti-asthmatic effects of resveratrol, a poliphenolic stilbene, in a mouse model of allergic asthma" where resveratrol has an anti-asthma effect similar to that of dexamethasone in rats with OVA- induced asthma. Even in this case, there is observed an inhibition of classic inflammatory mediators such as cytokines, accompanied by an inhibition of hyperresponsiveness of the airways and mucus hypersecretion. Another disorder of the first airways is the respiratory syncytial virus, which is very common in infants and young children, and which is often associated with wheezing and asthma. In the study “Resveratrol-mediated gamma interferon reduction prevents airway inflammation and airway hyperresponsiveness in respiratory syncytial virus-infected immunocompromised mice" it is shown that besides acting on asthma, resveratrol is also useful for acting specifically on the respiratory syncytial virus. Another study which analyses resveratrol in relation to various symptoms related to disorders of the first respiratory tract is “Resveratrol plus carboxymethyl-beta-glucan in infants with common cold: a randomized double-blind trial’, a double-blind, randomized, placebo-controlled study on patients aged from 0 to 6 months, where there is analysed the efficacy of an isotonic solution containing 0.05% resveratrol and 0.01% carboxymethyl-beta-glucan (3 drops per nostril, 4 times a day, for 7 days) to combat symptoms such as rhinorrhoea, sneezing and nasal congestion. The progress of the test is monitored in two ways: observation of the trend of symptoms by parents, analysis of samples taken from the nasal cavities. The results proved to be encouraging, as there was observed a significant decrease in symptoms; this is probably also due to the topical action of resveratrol, which in this way is more difficult to degrade. Another disorder of the respiratory system is pharyngitis: in the study “Resveratrol treatment inhibits acute pharyngitis in the mice model through inhibition of PGE2/CO-2 expressiorf carrageenin pharyngitis is induced in rats, subsequently treated with a dose of resveratrol 20 mg/Kg. The oedema thus treated showed a 67% reduction. Furthermore, there is observed a decrease in the expression of PGE2s and COX-2s.

LACTOFERRIN

Lactoferrin (LF), also formally known by the name lactotransferrin, is a glycoprotein capable of binding iron belonging to the family of transferrins together with serum transferrin, ovotransferrin and melanotransferrin.

Lactoferrin was isolated in 1939 from bovine milk and after several years it was discovered to be the main protein of human milk capable of binding iron. LF is produced and released from mucosal epithelial cells and neutrophils of various mammalian species including humans, bovines, horses, dogs and various rodents. Several studies have shown that such compound is involved in various physiological and protective functions such as regulation of iron absorption in the intestine, as well as having antioxidant, anti-inflammatory, antimicrobial and antitumour properties. In milk and colostrum, lactoferrin is present in a concentration of 7g/L and it is found in high concentrations even in saliva, sweat, vaginal fluids, sperm, bronchial secretions, nasal secretions, biliary secretions and in urine.

From a chemical structural point of view, lactoferrin is an 80 kDa glycosylated protein containing 700 amino acids with a high homology between the different species.

The three-dimensional structure thereof consists of a single polypeptide chain wrapped in two symmetrical lobes (lobes N and C) which are very similar to each other.

Besides iron, lactoferrin is also able to bind copper, zinc and manganese ions, and in biological fluids it can be present either in iron-free form (apo-lactoferrin) or in iron-bound form (hoi o-l actoferri n) .

Although it is a protein, scientific work reports the ability of bovine lactoferrin (approved for use in dietary supplements) to resist the passing through the gastric environment after oral administration. Although a partial digestion of the molecule is plausible, formed from this reaction are cationic peptides which show activities similar, if not superior, to the native protein like in the case of the lactoferricin peptide.

One of the main activities of lactoferrin is the antibacterial activity: as a matter of fact, this compound is very effective both against Gram positive and Gram-negative bacteria. The efficacy thereof is due to a dual mechanism of action: one dependent on the ability thereof to bind iron and an independent one. The high iron binding capacity causes a low availability of this metal, which is particularly important for some bacterial species for adhesion and proliferation. Examples of pathogens of this type are E. coli, Pseudomonas aeruginosa, Burkholderia cepacia, for which lactoferrin - by means of this mechanism - is able to reduce the adhesion to the mucous membranes and the formation of biofilm.

The other mechanism of action is linked to the ability thereof to bind the lipopolysaccharide (LPS) present in the plasma membrane of Gram-negative bacteria and the lipoteichoic acid present in the Gram-positive membrane. Receptors for the N-terminal portion of lactoferrin were identified on the surface of the bacteria. Such binding causes a structural alteration of LPS and of the lipoteichoic acid entailing an increase in the permeability of the bacterial membrane.

Lactoferrin is also endowed with a strong antiviral activity against several viruses such as Cytomegalovirus, Herpes simplex virus 1 and 2, human immunodeficiency virus (HIV), hepatitis C virus, papilloma virus. With regard to the present invention, particularly relevant are the activity against Respiratory Syncytial Virus (RSV) where it interacts with protein F, the main glycoprotein involved in cell invasion, against parainfluenza virus (PIV), where it inhibits the adhesion of the virus by preventing invasion and replication, and against Adenovirus where it binds polypeptide III responsible for the adhesion of the virus to the surface of the host cell via the integrins. Lactoferrin is particularly active even against influenza A virus where it inhibits cell death by interfering with caspase 3, which is the main virus- induced effector and it also blocks the export of viral ribonucleotides from the cell nucleus, thus preventing viral assembly in the host cell.

Lactoferrin has a significant immunomodulatory ability due both to an anti-inflammatory activity and due to the ability thereof to activate the innate and acquired immune response.

Specifically, LF interacts with surface receptors expressed by antigen presenting cells (APC) such as monocytes, macrophages, dendritic cells, neutrophils, inducing activation and migration to the site of infection. Furthermore, it increases the expression of adhesion molecules such as Betal, Beta2, ICAM-1 on the surface of monocytes, factors stimulating the synthesis of granulocytes and monocytes, extending the action thereof at the site of interest, as well as increasing the expression of glycoproteins CD80, 10 CD83, CD86 with an increase in the production of pro-inflammatory cytokines.

The antibacterial, antiviral and immunomodulatory efficacy of lactoferrin makes it a valid active ingredient to be used for the prevention and the treatment of infections of the respiratory system.

The composition subject of the present invention contains the combination of an extract of Pelargonium sidoides, resveratrol and, optionally lactoferrin, mixed with a suitable pharmaceutically acceptable carrier.

Suitable pharmaceutically acceptable carriers are those commonly known to the person skilled in the art for the preparation of pharmaceutical compositions for oral administration such as solutions, suspensions, powders, granulates, tablets, capsules, pellets.

By way of non-limiting example, such pharmaceutically acceptable carriers may consist of binders, diluents, lubricants, glidants, disaggregating agents, solubilizers (wetting agents), stabilisers, dyes, anti caking agents, emulsifiers, thickeners and gelling agents, coating agents, humidifiers, sequestrants, sweeteners.

Specifically, examples of diluents may be: magnesium carbonate, microcrystalline cellulose, starch, lactose, sucrose; the lubricants mainly used are magnesium stearate, stearic acid, sodium stearyl fumarate. Glidants may include colloidal silica, magnesium silicate, disaggregating agents may include cross-linked polyvinylpyrrolidones, sodium starch glycolate, solubilisers may include surfactants such as TWEEN or sodium lauryl sulphate, and stabilisers may include all classes of preservatives (sorbic acid and derivatives, benzoic acid and derivatives, parabens), antioxidants, (ascorbic acid and derivatives, tocopherol), acidifiers (phosphoric acid, tartaric acid). The thickeners and gelling agents may be carrageenan, pectins, starches. Coating agents include, for example, waxes and derivatives, anti-caking agents may include calcium or magnesium carbonate, humidifiers may include sorbitol, mannitol, sequestrants may include EDTAand derivatives, dyes may include aspartame, acesulfame potassium.

The composition subject of the present invention is preferably a liquid, solid or semi-solid composition for oral use, even more preferably an aqueous solution, a suspension, a syrup, a spray, a powder or granulate, a tablet, a coated tablet, a capsule, a pellet, a paste.

Forming an object of the present invention is a composition containing (that is comprising) a combination or mixture comprising or, alternatively, consisting of:

(a) an extract of Pelargonium sidoides ; and

(b) resveratrol; optionally mixed with a suitable pharmaceutically acceptable carrier.

Therefore, the composition subject of the present invention contains (a) an extract of Pelargonium sidoides and (b) resveratrol.

Preferably, resveratrol may be used as such, or as an extract of Polygunum cuspidatum.

The extract of Pelargonium sidoides (a) is preferably present in said composition in an amount comprised from 1 mg to 3000 mg, preferably from 5 mg to 2000 mg, more preferably from 10 mg to 1000 mg, even more preferably from 10 mg to 500 mg.

Resveratrol (b) is preferably present in said composition in an amount comprised from 1 mg to 3000 mg, preferably from 5 mg to 2000 mg, more preferably from 10 mg to 1000 mg, even more preferably from 10 mg to 500 mg.

Additionally to (a) and (b), the composition, combination or mixture according to the present invention preferably also comprises (c) lactoferrin as a further active component.

When present in the composition, lactoferrin is preferably present in said composition in an amount comprised from 0.1 mg to 3000 mg, preferably from 2 mg to 2000 mg, more preferably from 10 mg to 1000 mg, even more preferably from 10 mg to 700 mg. Preferably, said composition is in the form of tablet, powder or granulate, capsule, or liquid solution, wherein (the following amounts by weight referring to a dose per dosage unit):

(i) said tablet, preferably a coated tablet, comprises or, alternatively, consists of:

- extract of Pelargonium sidoides : from 10 mg to 500 mg, preferably from 15 mg to 300 mg, more preferably from 20 mg to 200 mg, even more preferably 60 mg;

- resveratrol: from 10 mg to 400 mg, preferably from 10 mg to 200 mg, more preferably from 10 mg to 50 mg, even more preferably 10 mg;

- lactoferrin: from 10 mg to 700 mg, preferably from 15 mg to 400 mg, more preferably from 20 mg to 250 mg, even more preferably 100 mg; or

(ii) said powder or granulate, preferably for oral solution/suspension, comprises or, alternatively, consists of:

- extract of Pelargonium sidoides : from 10 mg to 500 mg, preferably from 12 mg to 300 mg, more preferably from 15 mg to 160 mg, even more preferably 30 mg or 40 mg;

- resveratrol: from 10 mg to 500 mg, preferably from 11 mg to 300 mg, more preferably from 12 mg to 200 mg, even more preferably 20 mg or 50 mg;

- lactoferrin: from 10 mg to 400 mg, preferably from 10 mg to 200 mg, more preferably from 10 mg to 80 mg, even more preferably 10 mg or 20 mg; or

(iii) said capsule comprises or, alternatively, consists of:

- extract of Pelargonium sidoides : from 10 mg to 500 mg, preferably from 12 mg to 300 mg, more preferably from 15 mg to 120 mg, even more preferably 30 mg;

- resveratrol: from 10 mg to 400 mg, preferably from 11 mg to 200 mg, more preferably from 12 mg to 75 mg, even more preferably 15 mg;

- lactoferrin: from 10 mg to 400 mg, preferably from 10 mg to 200 mg, more preferably from 10 mg to 80 mg, even more preferably 10 mg; or

(iv) said liquid solution, preferably for oral use, comprises or, alternatively, consists of:

- extract of Pelargonium sidoides : from 10 mg to 500 mg, preferably from 12 mg to 300 mg, more preferably from 15 mg to 160 mg, even more preferably 40 mg; - resveratrol: from 10 mg to 500 mg, preferably from 11 mg to 300 mg, more preferably from 12 mg to 150 mg, even more preferably 20 mg;

- lactoferrin: from 10 mg to 400 mg, preferably from 11 mg to 200 mg, more preferably from 12 mg to 80 mg, even more preferably 20 mg.

Preferably, said composition is for use in a method for the preventive or curative treatment of rhinitis, allergic rhinitis, nasopharyngitis or common cold, influenza, rhinosinusitis, sinusitis, pharyngitis, epiglottitis, laryngitis, bronchitis, bronchiolitis, or bronchiectasis.

Preferably, the compositions subject of the present invention are particularly effective in the prevention and/or in the treatment of respiratory diseases, in particular in the prevention and/or in the treatment of rhinitis, allergic rhinitis, nasopharyngitis or common cold, influenza, rhinosinusitis, sinusitis, pharyngitis, epiglottitis, laryngitis, bronchitis, bronchiolitis and/or bronchiectasis, allowing to simultaneously obtain an antiviral effect, an antimicrobial effect and an immunomodulatory effect thanks to the synergistic action of the components thereof.

Furthermore, forming an object of the present invention is said composition is for use as a stimulant of the immune system in a subject, preferably in a mammal, more preferably in a human being or in an animal. Thanks to the properties of the active ingredients, preferably the composition subject of the present invention is particularly effective as a stimulant of the immune system.

Thus, forming a further object of the present invention is a composition containing the combination of an extract of Pelargonium sidoides, resveratrol and, optionally, lactoferrin mixed with a suitable pharmaceutically acceptable carrier for use in the prevention and/or in the treatment of respiratory diseases and/or for stimulating the immune system.

The composition may be a medical device composition, a dietary supplement composition, a nutraceutical, dietary and nutritional composition, a food product, a beverage, a nutraceutical, a medicament, a medicated food, a pharmaceutical composition, a food for special medical purposes or a complementary feed. Without being bound to any specific theory, the inventors believe that the synergistic effect of the combination present in the composition subject of the present invention derives from the following actions of the components of the combination:

The extract of Pelargonium sidoides has a marked antibacterial, antiviral and immunomodulatory activity thanks to the ability of the components thereof to avoid bacterial adhesion, stimulate phagocytosis and the release of various pro-inflammatory cytokines (interleukins, interferon y and TNF-a, iNOS); furthermore, it is able to stimulate mucociliary "clearance” showing to be effective in most respiratory diseases;

- resveratrol is a potent natural antioxidant and also exhibits anti-inflammatory activity linked to the inhibition of mediators such as TNF-alpha, IL-1 beta, CINC-1, PGE2. Antiviral activity is also particularly documented and it is linked to the inhibition of the virus replication cycle;

- the optional lactoferrin has an antibacterial activity with a unique mechanism of action linked to its high ability to sequester iron from bacterial cells causing the death thereof; furthermore, it is able to bind lipopolysaccharide and lipoteichoic acid, two important components of the Gram negative and positive bacteria membranes. Lactoferrin is particularly effective even against common viruses such as the influenza or common cold viruses due to the ability thereof to interfere with cell death through the inhibitory action on caspase 3. Lastly, by interacting with the surface receptors of antigen-presenting cells, it is able to induce cell activation and migration in the site of infection.

The synergistic activity of the aforementioned active ingredients can be studied by using in vitro and/or in vivo tests capable of evaluating the antiviral, antimicrobial, anti-inflammatory, antioxidant and immunomodulatory activity of the compositions according to the present invention and/or of the comparative compositions.

Any test known in the literature may be used for evaluating the antiviral, antimicrobial and immunomodulatory activity.

By way of example, the antiviral activity is evaluated for example by means of various types of tests which allow to evaluate the effect of the compounds tested on a virus, on a particular effect (cytotoxicity) thereof, on some proteins crucial to viruses, or on particular stages of the reproductive cycle such as attachment, entry, uncoating, replication, assembly, release.

Instead, antimicrobial activity is evaluated on the main bacterial strains belonging to the Gram positive and/or Gram-negative categories and/or other microbial species.

In vitro and/or in vivo assays known in the scientific literature may be used for evaluating the antioxidant activity of the composition according to the present invention. More particularly, in order to demonstrate the antioxidant efficacy of the composition according to the present invention, of particular interest for the prevention and/or the treatment of skin aging, in vitro assays such as, for example DPPH test, radical scavenging activity on nitric oxide or on peroxynitrite radical, TEAC (Total radical-trapping antioxidant parameter), FRAP (Ferric reducing-antioxidant power), HORAC (Hydroxyl 5 radical averting capacity), ORAC (Oxygen radical absorbance capacity) and the like are suitable.

In order to demonstrate the antioxidant efficacy of the composition according to the present invention, also suitable are in vivo assays consisting in determining in animals the levels of endogenous substances such as, for example, reduced glutathione, glutathione peroxidase, glutathione S-transferase, superoxide dismutase and catalase, after administration of the active agents of interest. Even the measurement of lipid peroxidation is also a valid method for the estimation of the antioxidant activity of the present composition.

In order to evaluate the anti-inflammatory efficacy of the composition according to the present invention, of particular interest for the prevention and/or the treatment of diseases of the respiratory tract, the inhibition/activation capacity of enzymes, cytokines, transcription factors or other factors involved in the inflammatory/anti-inflammatory mechanisms of the compositions according to the present invention and/or of the comparative compositions is preferably determined. In particular, in vitro assays which evaluate the ability to inhibit the release of inflammatory cytokines such as for example IL-1, IL-6 and TNF-a and/or to inhibit the expression of enzymes such as COX-2 and metal loprotease- 13 in primary cultures of cells or cell lines (for example macrophages, monocytes, chondrocytes and fibroblasts) are suitable.

The anti-inflammatory activity can be evaluated in vivo on specific animal model, for example mice or rats, by means of tests known to person skilled in the art such as carrageenan oedema in order to evaluate the anti-oedematous effect resulting from the treatment with the compositions subject of the present invention. As regards immunomodulatory activity, it is preferably evaluated by means of scientific tests capable of detecting the stimulation/inhibition capacity of cells, of cytokines or of other factors involved in the immune response.

Examples

Some non-binding examples of daily doses of the active components of the compositions subject of the present invention are provided below for illustrative purposes.

Daily doses are intended to be administered in a suitable oral dosage form and divided into one or more dosage units. EXAMPLE 1 (coated tablet)

EXAMPLE 2 (powder or granulate for oral solution/suspension)

EXAMPLE 3 (powder or granulate for oral solution/suspension)

Example 4 (capsule)

EXAMPLE 5 (bottle of liquid for oral use)

EXAMPLE 6 (spray for oral use)

Embodiments E(n) of the present invention are illustrated below:

E1. A composition containing a combination of an extract of Pelargonium sidoides and resveratrol mixed with a suitable pharmaceutically acceptable carrier.

E2. The composition according to E1, containing lactoferrin as a further active component.

E3. The composition according to any one of E1-E2, wherein resveratrol is present as an extract of Polygonum cuspidatum.

E4. The composition according to any one of E1-E3, in the form of liquid, solid or semi-solid composition for oral use.

E5. The composition according to any one of E1-E4, wherein the extract of Pelargonium sidoides is present in an amount comprised between 1 mg and 3000 mg, preferably between 5 mg and 2000 mg, even more preferably between 10 mg and 1000 mg.

E6. The composition according to any one of E1-E5, wherein resveratrol is present in an amount comprised between 1 mg and 3000 mg, preferably between 2 mg and 2000 mg, even more preferably between 10 mg and 1000 mg.

E7. The composition according to any one of E1-E6, wherein lactoferrin is present in an amount comprised between 0.1 mg and 3000 mg, preferably between 2 mg and 2000 mg, even more preferably between 10 mg and 1000 mg.

E8. The composition according to any one of E1-E7, wherein the composition is a medical device, a dietary supplement, a nutraceutical, dietetic and nutritional composition, a food product, a beverage, a nutraceutical product, a medicament, a medicated food, a pharmaceutical composition, a food for special medical purposes, a complementary feed.

E9. The composition according to any one of E1-E9, for use in the prevention or in the treatment of diseases of the respiratory tract and as a stimulant of the immune system both in humans and in animals.

E10. The composition according to E9, for use in the prevention or in the treatment of rhinitis, allergic rhinitis, nasopharyngitis or common cold, influenza, rhinosinusitis, sinusitis, pharyngitis, epiglottitis, laryngitis, bronchitis, bronchiolitis and/r bronchiectasis.

Further embodiments F(n) of the present invention are illustrated below:

F1. A composition containing a combination or mixture comprising or, alternatively, consisting of:

(a) an extract of Pelargonium sidoides ; and

F2. The composition according to F1, wherein, additionally to (a) and (b), said combination or mixture comprises:

(c) lactoferrin as a further active component.

F3. The composition according to any one of F1-F2, wherein said (b) resveratrol is present as an extract of Polygonum cuspidatum.

F4. The composition according to any one of F1-F3, wherein said (a) extract of Pelargonium sidoides is present in said composition in an amount comprised from 1 mg to 3000 mg, preferably from 5 mg to 2000 mg, more preferably from 10 mg to 1000 mg, even more preferably from 10 mg to 500 mg.

F5. The composition according to any one of F1-F4, wherein said (b) resveratrol is present in said composition in an amount comprised from 1 mg to 3000 mg, preferably from 2 mg to 2000 mg, more preferably from 10 mg to 1000 mg, even more preferably from 10 mg to 500 mg.

F6. The composition according to F2, wherein said (c) lactoferrin is present in said composition in an amount comprised from 0.1 mg to 3000 mg, preferably from 2 mg to 2000 mg, more preferably from 10 mg to 1000 mg even more preferably from 10 mg to 700 mg. F7. The composition according to any one of F1-F6, wherein said composition is in the form of liquid, solid or semi-solid composition for oral use.

F8. The composition according to any one of F1-F7, wherein said composition is in the form of a tablet, powder or granulate, capsule, or liquid solution, and wherein (the following amounts by weight referring to a dose per dosage unit):

(iii) said capsule comprises or, alternatively, consists of:

- lactoferrin: from 10 mg to 400 mg, preferably from 11 mg to 200 mg, more preferably from 12 mg to 80 mg, even more preferably 20 mg. F9. A composition according to any one of F1-F8, wherein said composition is a medical device composition, a dietary supplement composition, or a pharmaceutical composition.

F10. The composition according to any one of F1-F9, wherein said composition is for use in a method for the preventive or curative treatment of diseases of the respiratory tract in a subject, preferably in a mammal, more preferably in a human being or in an animal.

F11. The composition according to any one of F1-F9, wherein said composition is for use as a stimulant of the immune system in a subject, preferably in a mammal, more preferably in a human being or in an animal.

F12. The composition for use according to F10, wherein said composition is for use in a method for the preventive or curative treatment of rhinitis, allergic rhinitis, nasopharyngitis or common cold, influenza, rhinosinusitis, sinusitis, pharyngitis, epiglottitis, laryngitis, bronchitis, bronchiolitis, or bronchiectasis.

Claims

1. A composition containing a combination or mixture comprising or, alternatively, consisting of:

(a) an extract of Pelargonium sidoides ; and

2. The composition according to claim 1, wherein, additionally to (a) and (b), said combination or mixture comprises:

(c) lactoferrin as a further active component.

3. The composition according to any one of claims 1-2, wherein said (b) resveratrol is present as an extract of Polygonum cuspidatum.

4. The composition according to any one of claims 1-3, wherein said (a) extract of Pelargonium sidoides is present in said composition in an amount comprised from 1 mg to 3000 mg, preferably from 5 mg to 2000 mg, more preferably from 10 mg to 1000 mg, even more preferably from 10 mg to 500 mg.

5. The composition according to any one of claims 1-4, wherein said (b) resveratrol is present in said composition in an amount comprised from 1 mg to 3000 mg, preferably from 2 mg to 2000 mg, more preferably from 10 mg to 1000 mg, even more preferably from 10 mg to 500 mg.

6. The composition according to claim 2, wherein said (c) lactoferrin is present in said composition in an amount comprised from 0.1 mg to 3000 mg, preferably from 2 mg to 2000 mg, more preferably from 10 mg to 1000 mg even more preferably from 10 mg to 700 mg.

7. The composition according to any one of claims 1-6, wherein said composition is in the form of liquid, solid or semi-solid composition for oral use.

8. The composition according to any one of claims 1-7, wherein said composition is in the form of a tablet, powder or granulate, capsule, or liquid solution, and wherein (the following amounts by weight referring to a dose per dosage unit):

(i) said tablet, preferably a coated tablet, comprises or, alternatively, consists of: - extract of Pelargonium sidoides : from 10 mg to 500 mg, preferably from 15 mg to 300 mg, more preferably from 20 mg to 200 mg, even more preferably 60 mg;

- resveratrol: from 10 mg to 400 mg, more preferably from 10 mg to 200 mg, more preferably from 10 mg to 50 mg, even more preferably 10 mg;

(iii) said capsule comprises or, alternatively, consists of:

- extract of Pelargonium sidoides : from 10 mg to 500 mg, preferably from 12 mg to 300 mg, more preferably from 15 mg to 160 mg, even more preferably 40 mg;

- resveratrol: from 10 mg to 500 mg, preferably from 11 mg to 300 mg, more preferably from 12 mg to 150 mg, even more preferably 20 mg;

9. The composition according to any one of claims 1-8, wherein said composition is a medical device composition, a dietary supplement composition, or a pharmaceutical composition.

10. The composition according to any one of claims 1-9, wherein said composition is for use in a method for the preventive or curative treatment of diseases of the respiratory tract in a subject, preferably in a mammal, more preferably in a human being or in an animal.

11. The composition according to any one of claims 1-9, wherein said composition is for use as a stimulant of the immune system in a subject, preferably in a mammal, more preferably in a human being or in an animal.

12. The composition for use according to claim 10, wherein said composition is for use in a method for the preventive or curative treatment of rhinitis, allergic rhinitis, nasopharyngitis or common cold, influenza, rhinosinusitis, sinusitis, pharyngitis, epiglottitis, laryngitis, bronchitis, bronchiolitis, or bronchiectasis.