EP4153205A1 - Composition pour la prévention et le traitement de maladies du tractus respiratoire et en tant que stimulant du système immunitaire - Google Patents

Composition pour la prévention et le traitement de maladies du tractus respiratoire et en tant que stimulant du système immunitaire

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Publication number
EP4153205A1
EP4153205A1 EP21733540.5A EP21733540A EP4153205A1 EP 4153205 A1 EP4153205 A1 EP 4153205A1 EP 21733540 A EP21733540 A EP 21733540A EP 4153205 A1 EP4153205 A1 EP 4153205A1
Authority
EP
European Patent Office
Prior art keywords
composition
resveratrol
extract
lactoferrin
composition according
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
EP21733540.5A
Other languages
German (de)
English (en)
Inventor
Umberto DI MAIO
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Neilos SRL
Original Assignee
Neilos SRL
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Neilos SRL filed Critical Neilos SRL
Publication of EP4153205A1 publication Critical patent/EP4153205A1/fr
Pending legal-status Critical Current

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/045—Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates
    • A61K31/05—Phenols
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/185—Magnoliopsida (dicotyledons)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/185—Magnoliopsida (dicotyledons)
    • A61K36/70—Polygonaceae (Buckwheat family), e.g. spineflower or dock
    • A61K36/704—Polygonum, e.g. knotweed
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/40—Transferrins, e.g. lactoferrins, ovotransferrins
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/02—Nasal agents, e.g. decongestants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/10—Expectorants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/12—Mucolytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/14—Antitussive agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/04—Immunostimulants

Definitions

  • composition for the prevention and the treatment of diseases of the respiratory tract and as a stimulant of the immune system Composition for the prevention and the treatment of diseases of the respiratory tract and as a stimulant of the immune system
  • 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.
  • 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.
  • 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.
  • 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.
  • the respiratory system consists of various anatomical structures useful for the proper function 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • influenza 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 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.
  • Rhinovirus 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.
  • IgEs bind to mast cells which release large amounts of histamine, responsible for all the morbid manifestations.
  • 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 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).
  • 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.
  • Sinusitis often resolves spontaneously and treatment is predominantly symptomatic.
  • 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.
  • antibiotics must instead take into account the production of beta lactamase and the presence of drug-resistant pneumococci.
  • 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.
  • viruses such as Epstein-Barr
  • 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.
  • forms transmitted by sexual contact and sustained by Neisseria gonorrhoeae and those caused by Corynebacterium dyphtheriae are to be considered.
  • H. influenzae type b H. influenzae type b
  • 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.
  • 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.
  • bronchiolitis is characterised by extensive inflammation of the airways accompanied by intense production of mucus and necrosis of epithelial cells.
  • RSV Respiratory Syncytial Virus
  • 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.
  • 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.
  • Mucus-producing cough and chest pain 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.
  • 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.
  • 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.
  • 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.
  • compositions 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.
  • 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.
  • 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 sidroides is one of the most important species of the genus Pelargonium used for a long time in traditional South African medicine.
  • 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.
  • 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.
  • Pelargonium sidoides 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.
  • BSS Bronchitis Severity Score
  • 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.
  • the extract showed to be an effective treatment capable of reducing the severity and duration of symptoms with respect to placebo.
  • 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 is a molecule naturally produced by many plants as a form of defence against attacks by pathogens such as bacteria, fungi and viruses.
  • 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.
  • 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.
  • 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).
  • Lactoferrin 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.
  • 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.
  • 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.
  • 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) .
  • 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.
  • lactoferrin 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.
  • 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.
  • LPS lipopolysaccharide
  • 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.
  • viruses such as Cytomegalovirus, Herpes simplex virus 1 and 2, human immunodeficiency virus (HIV), hepatitis C virus, papilloma virus.
  • HIV human immunodeficiency virus
  • hepatitis C virus hepatitis C virus
  • papilloma virus 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.
  • 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.
  • APC antigen presenting cells
  • 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.
  • lactoferrin makes it a valid active ingredient to be used for the prevention and the treatment of infections of the respiratory system.
  • 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.
  • 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.
  • 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.
  • 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:
  • composition subject of the present invention contains (a) an extract of Pelargonium sidoides and (b) resveratrol.
  • 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.
  • composition, combination or mixture according to the present invention preferably also comprises (c) lactoferrin as a further active component.
  • 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.
  • 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):
  • said tablet preferably a coated tablet, comprises or, alternatively, consists 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
  • said powder or granulate preferably for oral solution/suspension, comprises or, alternatively, consists 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
  • said capsule comprises or, alternatively, consists 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
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • test known in the literature may be used for evaluating the antiviral, antimicrobial and immunomodulatory activity.
  • 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.
  • 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 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
  • 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.
  • 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 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.
  • 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.
  • EXAMPLE 1 coated tablet
  • EXAMPLE 2 powder or granulate for oral solution/suspension
  • EXAMPLE 5 (bottle of liquid for oral use)
  • EXAMPLE 6 (spray for oral use)
  • Embodiments E(n) of the present invention are illustrated below:
  • composition according to E1 containing lactoferrin as a further active component.
  • 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.
  • 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.
  • 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.
  • composition containing a combination or mixture comprising or, alternatively, consisting of:
  • composition according to F1 wherein, additionally to (a) and (b), said combination or mixture comprises:
  • 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):
  • said tablet preferably a coated tablet, comprises or, alternatively, consists 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
  • said powder or granulate preferably for oral solution/suspension, comprises or, alternatively, consists 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
  • said capsule comprises or, alternatively, consists 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
  • 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;
  • 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.
  • 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.

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Abstract

L'invention concerne une composition contenant une combinaison synergique d'un extrait de Pelargonium sidoides, le resvératrol et, éventuellement, de la lactoferrine pour la prévention et le traitement d'infections des voies respiratoires et pour stimuler le système immunitaire.
EP21733540.5A 2020-05-21 2021-05-21 Composition pour la prévention et le traitement de maladies du tractus respiratoire et en tant que stimulant du système immunitaire Pending EP4153205A1 (fr)

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IT102020000011983A IT202000011983A1 (it) 2020-05-21 2020-05-21 Composizione per la prevenzione e il trattamento delle affezioni delle vie respiratorie e come stimolante del sistema immunitario
PCT/IB2021/054440 WO2021234660A1 (fr) 2020-05-21 2021-05-21 Composition pour la prévention et le traitement de maladies du tractus respiratoire et en tant que stimulant du système immunitaire

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EP4153205A1 true EP4153205A1 (fr) 2023-03-29

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EP3426273B1 (fr) * 2016-03-11 2021-04-21 Harmonic Pharma Compositions sublinguales comprenant des extraits naturels et leurs utilisations
IT201800002457A1 (it) * 2018-02-07 2019-08-07 Neilos S R L Composizione per la prevenzione e il trattamento delle affezioni delle vie respiratorie
CN111097040A (zh) * 2020-02-19 2020-05-05 苟春虎 抗病毒清肺肽

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