WO2022168019A1 - Composition à action immunostimulante utile pour la prévention et le traitement de maladies respiratoires - Google Patents

Composition à action immunostimulante utile pour la prévention et le traitement de maladies respiratoires Download PDF

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Publication number
WO2022168019A1
WO2022168019A1 PCT/IB2022/051044 IB2022051044W WO2022168019A1 WO 2022168019 A1 WO2022168019 A1 WO 2022168019A1 IB 2022051044 W IB2022051044 W IB 2022051044W WO 2022168019 A1 WO2022168019 A1 WO 2022168019A1
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composition
extract
comprised
carica papaya
subject
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PCT/IB2022/051044
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Umberto DI MAIO
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Neilos S.r.l.
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    • 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)

Definitions

  • composition with immunostimulant action useful for the prevention and treatment of respiratory diseases Composition with immunostimulant action useful for the prevention and treatment of respiratory diseases
  • the present invention relates to a composition containing a combination or mixture of an extract of Pelargonium sidoides and of an extract of Carica papaya useful as an immune system stimulant and for the prevention and/or treatment of diseases of the respiratory tract.
  • composition is particularly effective thanks to the synergistic action of the components thereof.
  • the effectiveness of the immune system is often related to several factors such as for example stress, chronic inflammatory diseases, specific diseases that jeopardise the effectiveness of the immune system, change of seasons, sudden temperature change, etc.
  • 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 and 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.
  • 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 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 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.
  • common cold Although 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 need medical consultation. 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.
  • Rhinitis In the case of influenza, it still is 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 sustained by viruses, including Rhinoviruses, Coronaviruses, influenza and parainfluenza viruses, RSV, Coxsackie virus, ECHO 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 generally is secondary to sinusitis, deviated nasal septum, adenoid hypertrophy.
  • 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 and therefore 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).
  • sinusitis When sinusitis involves the nasal cavity, it is called rhinosinusitis.
  • 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.
  • a viral form from a bacterial form
  • antibiotics are 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.
  • 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 group A beta- haemolytic Streptococcus pyogenes 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
  • 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. 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.
  • 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 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 smoking 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 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.
  • RSV Respiratory Syncytial Virus
  • 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 should oxygen saturation be comprised between 92% and 94%, along with other clinical manifestations such as poor nutrition, dehydration, and a history of dyspnoea. Bronchiectasis
  • Bronchial dilation may be the result of a structural defect in the wall, exposure to unusual pressure, or damage to cartilage or to the 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-o, IL-8 and prostanoids. It may appear as a local or widespread obstructive process part of both lobes, also accompanied by sinusitis or asthma.
  • 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.
  • CHANIKADILUMI JAYASINGHE ET AL "Mature leaf concentrate of Sri Lankan wild type Linn, modulates nonfunctional and functional immune responses of rats", BMC COMPLEMENTARY AND ALTERNATIVE MEDICINE, BIOMED CENTRAL LTD, LONDON, UK, vol. 17, no. 1, pages 1 -14, XP021244467, is a study aimed at investigating the immune modulatory potential of a mature leaf concentrate of Carica papaya (MLCC) of cultivar Sri Lanka using non-functional and functional immunological assays.
  • MLCC Carica papaya
  • WO 2012/001337 A1 discloses a composition in the form of toothpaste or mouthwash for dental and oral hygiene, infections and inflammations, in which the active ingredients are - inter alia - an extract of Pelargonium sidoides and papain.
  • extract is used to indicate any product related to a material or herbal drug including all products derived from mechanical treatments (pulverisation, crushing, mixing and/or other methods) or from extract-based treatments (solvent extraction, distillation, and/or other specific methods) conducted on said drug or material.
  • composition containing comprising or, alternatively, consisting of an association or mixture of an extract of Pelargonium sidoides and of an extract of Carica papaya in admixture with a suitable pharmaceutically acceptable carrier.
  • composition for use as an immune system stimulant in a subject, wherein said subject is a human or animal subject.
  • compositions for use in the prevention and/or in the treatment of respiratory diseases in a subject wherein said subject is a human or animal subject (that is both in humans and animals).
  • the components of the combination according to the present invention are all known components, widely used in therapy.
  • 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.
  • 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 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.
  • TSS Tonsillopharyngitis Severity Score
  • 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.
  • Papaya ⁇ Carica papaya Linn. belongs to the family of Cactaceae and to the genus Carica which counts - therein - four species among which papaya is most cultivated and known.
  • This plant probably originates from Mexico and Costa Rica and it was subsequently exported to several tropical and sub-tropical countries.
  • the trunk of the tree can grow up to ten metres high with wide palmate lobed leaves from which the fruits - which can be green, yellow, orange or pink - grow.
  • Papaya fruits have a remarkable nutritional value thanks to their high vitamin and mineral content such as vitamin C, A, riboflavin, folate, calcium, thiamine, iron, niacin, potassium, fibres etc. Having a very low caloric content (32 kcal/100 g of ripe fruit), it is an ideal food for obese people or people who wish to keep their body weight under control. Compared to other fruits known to be used to prevent damage from free radicals, papaya has a higher carotene content. Furthermore, it contains numerous enzymes such as papain useful to help the digestion of proteins in acidic, alkaline or neutral environment.
  • Fermentation preserves the beneficial properties of the fruit and significantly modifies the composition of the extract, resulting in an increase in carbohydrates, amino acids and oligosaccharides with different degree of polymerization, consisting of monomers with a structure similar to that of p 1-3 D-glucan.
  • papaya is used above all thanks to its anti-inflammatory and immunostimulatory activity.
  • Papaya is capable of inhibiting the release of pro-inflammatory cytokines (such as TNFa, IL-1 a, IL-1 b, IL-6 and IL-8, nitric oxide and interferon gamma) in various types of cells exposed to a variety of inducing agents.
  • pro-inflammatory cytokines such as TNFa, IL-1 a, IL-1 b, IL-6 and IL-8, nitric oxide and interferon gamma
  • the composition subject of the present invention contains the combination or mixture of an extract of Pelargonium sidoides and an extract of Carica papaya in admixture 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 granules, 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 and mixtures thereof.
  • 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, solubilizers may include surfactants such as TWEEN or sodium lauryl sulfate, 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).
  • Thickeners and gelling agents may be carrageenan, pectins, starches; coating agents include, for example, waxes and derivatives; anticaking agents may include calcium or magnesium carbonate; humidifiers may include sorbitol, mannitol; sequestrants may include EDTA and 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, more preferably a composition in form of an aqueous solution, a suspension, a powder or granules, a mouth dissolvable powder, a tablet, a capsule, a pellet, even more preferably in form of mouth dissolvable powder, powder or granules for oral solution/suspension, oral solution, capsule or tablet.
  • composition subject of the present invention contains the extract of Pelargonium sidoides and extract of Carica papaya.
  • the extract of Pelargonium sidoides is present in an amount comprised from 1 mg to 2000 mg, preferably from 5 mg to 1000 mg, even more preferably from 10 mg to 500 mg.
  • the extract of Carica papaya preferably extract of fermented Carica papaya, is present in an amount comprised from 10 mg to 10000 mg, preferably from 20 mg to 7000 mg, even more preferably from 40 mg to 5000 mg.
  • said composition is in form of mouth dissolvable powder, powder or granules for oral solution/suspension, or oral solution, and it comprises (dose per dose unit):
  • Pelargonium sidoides in an amount comprised from 10 mg to 400 mg, preferably comprised from 15 mg to 200 mg, more preferably comprised from 20 mg to 120 mg;
  • - extract of Carica papaya preferably extract of fermented Carica papaya, in an amount comprised from 500 mg to 5000 mg, preferably comprised from 1000 mg to 4000 mg, more preferably comprised from 1500 mg to 3500 mg.
  • said composition is in form of capsule or tablet and it comprises (dose per dose unit):
  • Pelargonium sidoides in an amount comprised from 10 mg to 400 mg, preferably comprised from 11 mg to 200 mg, more preferably comprised from 12 mg to 80 mg;
  • - extract of Carica papaya preferably extract of fermented Carica papaya, in an amount comprised from 10 mg to 3000 mg, preferably comprised from 100 mg to 2000 mg, more preferably comprised from 200 mg to 1500 mg.
  • the composition subject of the present invention is particularly effective as an immune system stimulant.
  • 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 bronchiectasis, allowing to simultaneously obtain an antiviral effect, an antimicrobial effect and an immunomodulatory effect thanks to the synergistic action of the components thereof.
  • said respiratory disease is selected from the group consisting of: rhinitis, allergic rhinitis, nasopharyngitis or common cold, influenza, rhinosinusitis, sinusitis, pharyngitis, epiglottitis, laryngitis, bronchitis, bronchiolitis, bronchiectasis and combinations thereof.
  • composition containing the combination of an extract of Pelargonium sidoides and extract of Carica papaya in admixture with a suitable pharmaceutically acceptable carrier for use in the prevention and/or in the treatment of respiratory diseases and for the stimulation of the immune system in a subject, wherein said subject is a human or animal subject (that is both in humans and in animals).
  • the composition may be a composition for medical device, for dietary supplement, a nutraceutical, dietetic and nutritional composition, food product composition, a beverage, a nutraceutical product, a medicament, a medicated foodstuff, a pharmaceutical composition, a food for special medical purposes, a complementary feed, a complete feed, a feed intended for particular nutritional purposes or a medicated 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- o, INOS); furthermore, it is capable of stimulating mucociliary "clearance” showing to be effective in most respiratory diseases;
  • the extract of Carica papaya is one of the most potent natural antioxidants and it contributes to reducing oxidative stress which may be derived from a chronic inflammation condition or from stress and which leads to a decrease in the efficiency of the immune system.
  • 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, immunomodulatory and anti-inflammatory activity of the compositions according to the present invention and/or of the comparative compositions. Any test known in literature for evaluating the aforementioned activities may be used.
  • the antiviral activity is for example evaluated by means of various types of tests which allow to evaluate the effect of the tested compounds on the plaques of the virus, on a particular effect thereof (cytotoxicity), on some proteins fundamental for the viruses, or on particular phases of the reproduction cycle such as for example attachment, inlet, "uncoating”, replication, assembly, release etc.
  • antimicrobial activity is evaluated on the main bacterial strains belonging to the Gram positive and/or Gram-negative categories and/or other microbial species.
  • immunomodulatory activity it is preferably evaluated through scientific tests capable of detecting the stimulation/inhibition capacity of cells, cytokines or other factors involved in the immune response.
  • WBA Whole Blood Assay
  • PBMC peripheral blood mononuclear cells
  • cytokines TNF-o, IL-1, IL-4, IL-6, IL-8, IL-10, IL-17, INF-Y, COMP
  • a simple general inflammation model is the carrageenan-induced paw oedema model induced on mice or rats is used as in vivo test.
  • the injection of carrageenan into the paw of the animal determines an acute inflammatory reaction of the paw with onset of classical signs of inflammation; this reaction reaches its peak within 3 hours from inoculation.
  • This test allows to evaluate the ability of the active components of the present invention in reducing the oedema of the paw induced by the injection of carrageenan.
  • Daily doses are intended to be administered in a suitable oral dosage form and divided into one or more dosing units.
  • EXAMPLE 2 powder or granules for oral solution/suspension
  • compositions are prepared according to conventional techniques.

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Abstract

L'invention concerne une composition contenant une combinaison synergique d'un extrait de Pelargonium Sidoides et d'un extrait de Carica papaya utile en tant que stimulant du système immunitaire et pour la prévention et/ou le traitement de maladies du tractus respiratoire.
PCT/IB2022/051044 2021-02-08 2022-02-07 Composition à action immunostimulante utile pour la prévention et le traitement de maladies respiratoires WO2022168019A1 (fr)

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IT102021000002672A IT202100002672A1 (it) 2021-02-08 2021-02-08 "composizione con azione immunostimolante utile per la prevenzione e/o il trattamento di affezioni respiratorie"
IT102021000002672 2021-02-08

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Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2012001337A1 (fr) * 2010-07-01 2012-01-05 Robert Peter Taylor Composition pour la santé dentaire

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2012001337A1 (fr) * 2010-07-01 2012-01-05 Robert Peter Taylor Composition pour la santé dentaire

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
CHANIKADILUMI JAYASINGHE ET AL: "Mature leaf concentrate of Sri Lankan wild type Linn. modulates nonfunctional and functional immune responses of rats", BMC COMPLEMENTARY AND ALTERNATIVE MEDICINE, BIOMED CENTRAL LTD, LONDON, UK, vol. 17, no. 1, 26 April 2017 (2017-04-26), pages 1 - 14, XP021244467, DOI: 10.1186/S12906-017-1742-Z *
CHINSEMBU KAZHILA C ED - JOHANSEN MARIA V ET AL: "Tuberculosis and nature's pharmacy of putative anti-tuberculosis agents", ACTA TROPICA, ELSEVIER SCIENCE BV., AMSTERDAM, NL, vol. 153, 14 October 2015 (2015-10-14), pages 46 - 56, XP029304690, ISSN: 0001-706X, DOI: 10.1016/J.ACTATROPICA.2015.10.004 *
DEL-RIO-NAVARRO B E ET AL: "Immunostimulants in the prevention of respiratory infections", INTERNATIONAL JOURNAL OF BIOTECHNOLOGY, INDERSCIENCE PUBLISHERS, GB, vol. 9, no. 3-4, 1 January 2007 (2007-01-01), pages 246 - 260, XP008110251, ISSN: 0963-6048, DOI: 10.1504/IJBT.2007.014245 *

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