WO2019141540A1 - Composition for the treatment of diseases of the respiratory tract - Google Patents
Composition for the treatment of diseases of the respiratory tract Download PDFInfo
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- WO2019141540A1 WO2019141540A1 PCT/EP2019/050344 EP2019050344W WO2019141540A1 WO 2019141540 A1 WO2019141540 A1 WO 2019141540A1 EP 2019050344 W EP2019050344 W EP 2019050344W WO 2019141540 A1 WO2019141540 A1 WO 2019141540A1
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- 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
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
- A61K35/56—Materials from animals other than mammals
- A61K35/63—Arthropods
- A61K35/64—Insects, e.g. bees, wasps or fleas
- A61K35/644—Beeswax; Propolis; Royal jelly; Honey
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- 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
- A61K38/43—Enzymes; Proenzymes; Derivatives thereof
- A61K38/46—Hydrolases (3)
- A61K38/48—Hydrolases (3) acting on peptide bonds (3.4)
- A61K38/4873—Cysteine endopeptidases (3.4.22), e.g. stem bromelain, papain, ficin, cathepsin H
Definitions
- composition for the treatment of diseases of the respiratory tract Composition for the treatment of diseases of the respiratory tract
- the present invention relates to a composition containing an association of bromelain, an extract of Myrtus communis and honey useful for the treatment of diseases of the respiratory tract.
- the composition is particularly effective as it allows to obtain at the same time an anti-inflammatory effect and an antimicrobial effect thanks to the synergistic action of its components.
- the respiratory tract is composed of different anatomical structures that serve to the correct function thereof.
- Anatomically two macro areas which are upper and lower airways can be distinguished.
- the first ones are composed of nose, pharynx and associated structures, while the second ones are composed of larynx, trachea, bronchi and lungs, whose real respiratory surface is made by alveoli.
- This complex system of organs serves to prepare air to its entry in lungs, through the filtration from potential particulates, warming and moistening.
- At the level of nasal cavities particles bigger than 10-15 microns can be blocked, this thanks to vibrissae and to the presence of mucus that entraps these particles besides turbulence precipitation, mediated by turbinates which deviate the air direction.
- Mucus stratifies on periciliary liquid, in which are immersed the vibratile cilia of epithelial cells. Particles of about 10 microns reach the trachea, are trapped in the mucus and then eliminated by ciliary movement. Particles of 2-5 microns sediment in terminal bronchioles by gravitational precipitation, while those of dimensions less than 2 microns are removed by alveolar macrophages and moved away by lymphatic pulmonary system.
- the whole respiratory tract is composed of epithelial cells differing in type and function along the tracheobronchial tree.
- Ciliated columnar cells characterize the airways from trachea to terminal bronchioles. From their apical surface protrude cilia that have the task of moving with a cleaning effect on mucus and potentially inhaled particles.
- Globet cells have the task of secreting mucus, useful to maintain the correct moistening of the epithelium and to entrap particulate. They are present in the largest tracts of the airways under the small bronchi but they have not been found in bronchioles.
- Rhinitis allergic rhinitis and rhinopharyngitis (cold).
- Rhinitis is an inflammatory process which affects the mucosa of nasal cavities and is divided in acute and chronic.
- Acute rhinitis are generally sustained by viruses, among which Rhinovirus, Coronavirus, influenza and parainfluenza viruses, RSV, Coxsackie virus, ECHO virus and adenovirus.
- the contagion occurs by direct contact with the ill subject presenting, in the peak of maximum contagiousness (generally the first day), 500-1000 virions per ml of secrete, that emits through caught and sneezes. Bacterial superinfections are possible which lead to complications such as otitis and sinusitis.
- Rhinovirus determines an acute symptomatology in the first 3-4 days, while for 7-10 days caught and other symptoms persist. There is an excess of mucous secretions that are fluid and transparent, and become purulent and malodorous in case of bacterial superimposition.
- the chronic form is generally secondary to sinusitis, nasal septum deviations, hypertrophic adenoids.
- Allergic rhinitis is due to the exposure by the subject to substances that causes him a IgE mediated reaction, characterised by excessive production of liquids, intranasal itching, sneezes and obstructions. IgEs, in fact, bind to mast cells which release large amounts of histamine, responsible of all morbid manifestations.
- allergic rhinitis and asthma are concurrent and to be considered as two manifestations of the whole respiratory tract, rather than locate them one in the superior tract and the other in the inferior tract of the respiratory tree.
- allergic rhinitis could be a predisposing factor to the development of allergic asthma, and specifically the sensitisation to allergens (pollen or animal hair) would seem an important risk factor in the association asthma and rhinitis.
- rhinopharyngitis is identified as a mucosae inflammation of the nose and pharynges that can be due to influenza or parainfluenza viruses or cold virus such as adenoviruses.
- cold can be a triggering factor of the disease because it reduces the effectiveness of immunity processes.
- Sinusitis is the inflammation of the mucosae covering the nasal cavities, bone cavities located in the facial grouping of bones, and which are in communication with nasal cavities, and therefore can become infected for the same causes determining rhinitis.
- Sinusitis can be divided in acute viral or acute bacterial (up to 4 weeks), chronic (beyond 12 weeks) and acute recurrent (at least 4 episodes per year with resolution).
- acute viral or acute bacterial up to 4 weeks
- chronic chronic (beyond 12 weeks)
- acute recurrent at least 4 episodes per year with resolution.
- sinusitis involves the nasal cavity is called rhinosinusitis.
- a healthy sinus is sterile, characterised by suitable mucus drainage and free passage of the air. Abnormality or ciliary immobility determine the inhibition of the drainage resulting in sinusitis.
- Predisposing factors to this disease are immunocompromised state, nasal septum deviation, nasal polyps, tumours, trauma and fractures, ***e abuse, presence of foreign bodies.
- An acute viral form can be subjected to bacterial superinfection.
- Bacteria generally responsible of these infections are Streptococcus pneumoniae, nontypeable Haemophilus influenzae, Moraxella catarrhalis.
- Pseudomonas aeruginosa is more frequently present in sinusitis by HIV infection and cystic fibrosis.
- Some genera of fungi such as Candida, Aspergillus, Blastomyces, Coccidioides, Rizophus, Histoplasma and Cryptococcus can cause sinusitis in immunocompromised patients.
- Sinusitis often resolves spontaneously and the treatment is prevalently symptomatic.
- the decongestant treatment serves to reduce oedema, ameliorating the drainage of mucus in excess and maintain the patency of sinus ostia.
- a good result can be obtained from the local application of hypertonic saline solution both in the treatment of acute bacterial or acute recurrent form and chronic form and also in prevention.
- the selection of antibiotic instead has to take into consideration the production of beta-lactamase and the presence of drug resistant pneumococci.
- the infection can be sustained by viruses (such as Epstein-Barr) and bacteria, in particular beta-haemolytic Streptococcus pyogenes of group A is the most frequent in pediatric forms, but also Mycoplasma pneumoniae, Chlamydia pneumoniae are found in adults and children. Moreover, forms transmitted by sexual contact and sustained by Neisseria gonorrhoeae and those by Corynebacterium diphtheriae (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 frequent in pediatric forms, but also Mycoplasma pneumoniae, Chlamydia pneumoniae are found in adults and children.
- forms transmitted by sexual contact and sustained by Neisseria gonorrhoeae and those by Corynebacterium diphtheriae are to be considered.
- H. influenzae It is prevalently caused by type b H. influenzae, but also by streptococci, staphylococci or a thermic trauma. It manifests itself with hears pain (in adults), dysphonia, while fever is absent up to 50% of cases and can develop in a tardive phase.
- the treatment is antibiotic when bacteria are the cause of the disease, while intubation can be requested in cases of severe obstruction of the airways.
- Larynx inflammation is manifested by aphonia and hoarseness, mainly caused by viruses, but up to 10% of cases also by bacteria (streptococci and C. diphtheriae included).
- Non infective causes can be tumours, thermic or caustic trauma, gastroesophageal reflux disease (GERD).
- Laryngitis presents symptoms which last 3-4 days and, unless the presence of bacteria, antibiotics are not used. Bronchitis
- Bronchitis is a frequent inflammation of bronchi that is manifested by caught, shortness of breath and chest pain. Bronchitis is divided in acute and chronic; in the first case caught lasts about three weeks and in 90% of cases is caused by viral infection that can occur after contagion with other infected persons. Predisposing risk factors can be cigarette smoke or other sources of environmental pollution. Chronic bronchitis is characterised by caught for three months per year for at least two episodes per year and cigarette smoke together with others genetic or environmental causes are the main triggering factors. Normally, except in certain particular cases, antibiotics are not used but steroidal anti-inflammatory drugs, paracetamol in order to obviate the potential increase of temperature and bronchodilators such as salbutamol to ameliorate the respiration.
- composition containing an association of bromelain, an extract of Myrtus communis and honey for the treatment of respiratory diseases.
- the components of the association according to the present invention are all known components, widely used in therapy.
- bromelain is meant a complex natural mixture of proteolytic enzymes deriving from the Ananas comosus plant. Bromelain is notoriously known for its multiple therapeutic properties and for this reason it has been used for many years in the traditional medicine for several types of diseases. Bromelain is obtained from pineapple through different methods and for commercial use is obtained through centrifugation, ultrafiltration and lyophilisation processes. The composition varies depending on both the extraction method and the part of the plant used; in fact the concentration of proteolytic enzymes is greater in pineapple stem than in fruit.
- bromelain After oral administration bromelain reaches its maximum blood concentration after one hour and maintains its biological activity for about 6-9 hours.
- bromelain Relative to the present invention, particular attention is given to the anti-inflammatory activity of bromelain.
- the latter is due to the negative regulation of the expression of cyclooxygenase-2 (COX-2), prostaglandin E2 (PGE2) and thromboxane B2.
- COX-2 cyclooxygenase-2
- PGE2 prostaglandin E2
- bromelain in case of inflammation, is able to reduce pro-inflammatory cytokine levels such as interleukin-1 b (I L-1 b), interleukin-6 (IL-6), Tumor Necrosis Factor-a (TNF-a), interferon-Y (INT-Y) etc.
- bromelain Another interesting feature of bromelain is its ability to enhance the effectiveness of antibiotics in case of pneumonias, bronchitis, sinusitis or other types of infection. In particular it has been observed an increase of plasmatic and tissue concentrations of antibiotics such as penicillin, gentamicin, tetracycline and amoxicillin if administered concurrently with bromelain.
- bromelain represents a valid naturally occurring active ingredient for the treatment of inflammatory diseases of the respiratory tract to be used with other natural products or in conjunction with an antibiotic treatment.
- Myrtus communis In Myrtus genus three species exist among which the most important is the Myrtus communis specie.
- Myrtus, Myrtus communis is an evergreen shrub belonging to the family of Myrtaceae. This shrub comes from Mediterranean regions and Middle East zones and is distributed also in North Africa, South America and Australia.
- Myrtus Since the most ancient times, Myrtus is used in medicine and nutrition as well as in perfumery and in liquors and cosmetic industries. The mostly recognised properties thereof are of antiseptic, anti-inflammatory, mucolytic, carminative and astringent type. The numerous properties attributed to myrtus are due to several compounds present in the various parts of the plant. In particular, in the essential oil obtained from leaves a-pinene, 1 ,8-cineole, limonene, myrtenyl acetate, linalool etc. are found. Moreover leaves are rich in flavonoids such as quercetin catechins and myricetin and in oligomeric compounds such as myrtucommulone and semi-myrtucommulone.
- Myrtus leaves have a strong antibacterial activity as proved by the studies present in the literature which confirm the activity of the extract in respect of both Gram positive bacteria ( Staphylococcus aureus, Micrococcus luteus, Streptococcus pneumoniae, Streptococcus pyogenes, Listeria monocytogenes) and Gram negative bacteria (, Escherichia coli, Pseudomonas aeruginosa, etc.).
- myrtucommulone and semi-myrtucommulone leaves may be instead responsible for the anti-inflammatory activity together with the action of monoterpenes such as myrtenyl acetate, 1 ,8-cineol, a-pinene etc.
- Honey is a natural product which has been widely used for its multiple beneficial properties. Over the years honey has always maintained a central position in traditional medicine for the treatment of infections and hepatic, cardiovascular or gastro intestinal tract diseases.
- honey Physical characteristics of honey in terms of colour and taste vary depending on the derivation source and weather conditions. Types with a light yellow colour up to honey types of reddish colour and also near to black exist. Generally honey types with a lighter colour have a less strong taste compared to honey with a stronger colour.
- Form a chemical point of view honey principally contains sugars and water and, in particular, the latter represent about 95-99%. These molecules present in very high amounts are responsible of the high viscosity, adhesively and density of honey as well as of the tendency to granulate and absorb moisture from outside.
- the carbohydrates present in greater amounts are represented by fructose (between 33-38%) and glucose (between 29-31 %); others sugars that can be found in honey are maltose, sucrose etc.
- the second main component of honey is water, the content of which varies greatly depending on maturation, whether conditions, water content of the starting nectar, storage conditions but however normally it never exceeds 25% of the composition.
- the honey composition in a small part (about 0.5%), are included some acids which determine the sour taste and at the same time guarantee protection and stability against microorganism attack.
- some acids which determine the sour taste and at the same time guarantee protection and stability against microorganism attack.
- the main one is gluconic acid which derives from glucose after oxidation by a glucose oxidase.
- acetic, butyric pyruvic maleic acid etc. are also present.
- Minerals concentration can vary between 0.1 % and 1 % and potassium is present in greater amounts followed by calcium, magnesium, sodium, sulphur, phosphorus and trace quantities of zinc copper and manganese.
- Nitrogen compounds in very small amounts in honey, are thiamine, riboflavin, nicotinic acid and vitamin B6; other vitamins present are ascorbic acid and pantothenic acid.
- honey are also present a lot of enzymes such as invertase, amylase, glucose oxidase, catalase having an important role in the formation of honey.
- enzymes such as invertase, amylase, glucose oxidase, catalase having an important role in the formation of honey.
- honey polyphenolic compounds such as flavonoids are also found.
- honey its antibacterial effect is surely included documented on about 60 species of aerobic, anaerobic, Gram positive and negative bacteria.
- examples are Haemophilus influenzae, Klebsiella pneumoniae, Mycobacterium tuberculosis, Pseudomonas aeruginosa, Staphylococcus aureus etc.
- honey is suggested by the World Health Organizations (OMS) for the treatment of caught in children.
- OMS World Health Organizations
- OMS includes honey in the treatment of caught associated with upper airways infections because it is emollient, cost-effective, popular and secure.
- honey in the treatment of caught associated with upper airways infections because it is emollient, cost-effective, popular and secure.
- the high viscosity of honey and its emollient action contribute to bring relief to the throat and reduce the symptomatology of caught.
- a clinical study on children which provided for the consumption of 10 g of honey before going to sleep showed how said substance was able to reduce the frequency of caught and as a consequence children night rest confirming the OMS’s opinion.
- composition object of the present invention contains the association of bromelain, extract of Myrtus communis and honey in admixture with a suitable acceptable carrier.
- Suitable acceptable carriers are those commonly known to the man skilled in the art for the preparation of compositions for oral administration such as solutions, suspensions, powders or granulates, tablets, capsules, pellets.
- said acceptable carriers can consists of binders, diluents, lubricants, glidants, disintegrants, solubilizing (wetting) agents, stabilizers, colorants, anti-caking agents, emulsifiers, thickeners and gelling agents, coating agents, humectants, sequestrants, and sweeteners.
- diluents can be: magnesium carbonate, cellulose microcrystalline, starch, lactose, and sucrose; mainly used lubricants are magnesium stearate, stearic acid, and sodium stearyl fumarate.
- colloidal silica and magnesium silicate as disintegrants the cross-linked polyvinylpyrrolidones, and sodium starch glycolate, as solubilizing agents surfactants such as TWEEN or sodium lauryl sulphate, and as stabilizers all classes of preservatives (sorbic acid and derivatives, benzoic acid and derivatives, parabens), antioxidants (ascorbic acid and derivatives, tocopherol), and acidifying agents (phosphoric acid, tartaric acid) can be cited.
- preservatives sorbic acid and derivatives, benzoic acid and derivatives, parabens
- antioxidants ascorbic acid and derivatives, tocopherol
- acidifying agents phosphoric acid, tartaric acid
- Thickeners and gelling agents can be carrageenan, pectins, and starches
- coating agents include for example waxes and derivatives
- anti-caking agents include for example calcium or magnesium carbonate
- humectants include for example sorbitol and mannitol
- sequestrants include for example EDTA and derivatives
- sweeteners include for example aspartame, and acesulfame potassium.
- the composition object of the present invention is preferably a liquid or solid composition for oral use, still more preferably an aqueous solution, a suspension, a powder or granulate, a tablet, a capsule, and pellet.
- composition object of the present invention contains bromelain, extract of Myrtus communis and honey.
- Bromelain is present in an amount between 1 mg and 6000 mg, preferably between 20 mg and 3000 mg, still more preferably between 50 mg and 500 mg.
- the extract of Myrtus communis is present in an amount between 1 mg and 5000 mg, preferably between 10 mg and 1000 mg, still more preferably between 20 mg and 500 mg.
- Honey is present in an amount between 1 mg and 5000 mg, preferably between 20 mg and 2000 mg, still more preferably between 30 mg and 500 mg.
- compositions object of the present invention are particularly effective in the treatment of diseases of the respiratory tract, in particular in the treatment of rhinitis, allergic rhinitis, rhinopharyngitis or cold, rhinosinusitis, sinusitis, pharyngitis, epiglottitis, laryngitis and bronchitis, allowing to obtain at the same time an anti- inflammatory effect and an antimicrobial effect thanks to the synergistic actions of their components.
- Another object of the present invention is a composition containing the association of bromelain, an extract of Myrtus communis and honey in admixture with a suitable acceptable carrier for use in the treatment of diseases of the respiratory tract.
- Bromelain is an optimal anti-inflammatory agent able to reduce the levels of proinflammatory cytokines as well as the expression of cyclooxygenases, prostaglandins and bradykinin.
- the compound is able to reduce the migration and the adhesion of leucocytes in the inflammation site; moreover as confirmed by scientific studies bromelain, used in conjunction with some antibiotics, potentiates the effect thereof.
- Honey thanks to its peculiar composition (concentrated sugars, enzymes and others compounds) has a strong antibacterial activity due to both the ability to recall water dehydrating pathological cells and the presence of hydrogen peroxide and enzymes such as glucose oxidase inhibiting the growth of several microorganisms. Moreover according to some literature studies honey may also have an effect on inflammation.
- the compounds contained in myrtus Myrtus communis
- the synergic activity of the above mentioned active ingredients can be studied by in vitro and/or in vivo tests able to assess the antimicrobial and anti-inflammatory activity of the compositions according to the present invention and/or of the comparative compositions.
- antimicrobial activity is evaluated on the main bacterial strains belonging to Gram positive and/or Gram negative categories and/or other microbial species.
- anti-inflammatory activity is preferably evaluated determining the inhibition/activation activity towards enzymes, cytokines, transcription factors, or other factors involved in inflammatory/anti-inflammatory mechanisms, of the compositions according to the present invention and/or of the comparative compositions.
- daily doses of active components of the composition object of the present invention are meant to be administrated in a suitable oral dosage form and divided in one or more dosage units.
- compositions are prepared according to conventional techniques such as mixing.
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Abstract
A composition containing a synergistic association of bromelain, an extract of Myrtus communis and honey for the treatment of the respiratory tract diseases is described.
Description
“Composition for the treatment of diseases of the respiratory tract”
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DESCRIPTION
The present invention relates to a composition containing an association of bromelain, an extract of Myrtus communis and honey useful for the treatment of diseases of the respiratory tract. The composition is particularly effective as it allows to obtain at the same time an anti-inflammatory effect and an antimicrobial effect thanks to the synergistic action of its components.
Background of the invention
RESPIRATORY TRACT AND RESPIRATORY DISEASES
The respiratory tract is composed of different anatomical structures that serve to the correct function thereof.
It is, in fact, intended for the gas, oxygen and carbonic anhydride exchange, between tissues and external environment which is fundamental for all the cellular processes of the organism.
Anatomically two macro areas which are upper and lower airways can be distinguished. The first ones are composed of nose, pharynx and associated structures, while the second ones are composed of larynx, trachea, bronchi and lungs, whose real respiratory surface is made by alveoli. This complex system of organs serves to prepare air to its entry in lungs, through the filtration from potential particulates, warming and moistening. At the level of nasal cavities particles bigger than 10-15 microns can be blocked, this thanks to vibrissae and to the presence of mucus that entraps these particles besides turbulence precipitation, mediated by turbinates which deviate the air direction. Mucus stratifies on periciliary liquid, in which are immersed the vibratile cilia of epithelial cells. Particles of about 10 microns reach the trachea, are trapped in the mucus and then eliminated by ciliary movement. Particles of 2-5 microns sediment in terminal bronchioles by gravitational precipitation, while those of dimensions less than 2 microns are removed by alveolar macrophages and moved away by lymphatic pulmonary system.
The whole respiratory tract is composed of epithelial cells differing in type and function along the tracheobronchial tree. Ciliated columnar cells characterize the airways from trachea to terminal bronchioles. From their apical surface protrude cilia that have the task of moving with a cleaning effect on mucus and potentially inhaled particles. Globet cells have the task of secreting mucus, useful to maintain the correct
moistening of the epithelium and to entrap particulate. They are present in the largest tracts of the airways under the small bronchi but they have not been found in bronchioles.
All the components of the respiratory tract can be exposed to a series of diseases, of different aetiology, often sustained by different pathogenic microorganisms which, becoming preponderant in the microenvironment and on the normally present flora, determine the disease and, as a consequence, leads to a reduced functionality. EXAMPLES OF RESPIRATORY TRACT DISEASES
Depending on the area of the respiratory tract several pathological conditions can be distinguished characterised by inflammations due to viruses, bacteria or fungi.
Rhinitis, allergic rhinitis and rhinopharyngitis (cold).
Rhinitis is an inflammatory process which affects the mucosa of nasal cavities and is divided in acute and chronic. Acute rhinitis are generally sustained by viruses, among which Rhinovirus, Coronavirus, influenza and parainfluenza viruses, RSV, Coxsackie virus, ECHO virus and adenovirus. The contagion occurs by direct contact with the ill subject presenting, in the peak of maximum contagiousness (generally the first day), 500-1000 virions per ml of secrete, that emits through caught and sneezes. Bacterial superinfections are possible which lead to complications such as otitis and sinusitis. The common cold by Rhinovirus determines an acute symptomatology in the first 3-4 days, while for 7-10 days caught and other symptoms persist. There is an excess of mucous secretions that are fluid and transparent, and become purulent and malodorous in case of bacterial superimposition.
The chronic form is generally secondary to sinusitis, nasal septum deviations, hypertrophic adenoids.
Allergic rhinitis is due to the exposure by the subject to substances that causes him a IgE mediated reaction, characterised by excessive production of liquids, intranasal itching, sneezes and obstructions. IgEs, in fact, bind to mast cells which release large amounts of histamine, responsible of all morbid manifestations.
Recent studies highlighted that allergic rhinitis and asthma are concurrent and to be considered as two manifestations of the whole respiratory tract, rather than locate them one in the superior tract and the other in the inferior tract of the respiratory tree. In fact it appears that between 20% and 50% of patients with allergic rhinitis have also asthma and that from 30% to 90% of patients with asthma have concomitant rhinitis. Therefore, allergic rhinitis could be a predisposing factor to the development of allergic
asthma, and specifically the sensitisation to allergens (pollen or animal hair) would seem an important risk factor in the association asthma and rhinitis.
Instead the common cold is known as rhinopharyngitis which is identified as a mucosae inflammation of the nose and pharynges that can be due to influenza or parainfluenza viruses or cold virus such as adenoviruses. Also cold can be a triggering factor of the disease because it reduces the effectiveness of immunity processes. Sinusitis
Sinusitis is the inflammation of the mucosae covering the nasal cavities, bone cavities located in the facial grouping of bones, and which are in communication with nasal cavities, and therefore can become infected for the same causes determining rhinitis. Sinusitis can be divided in acute viral or acute bacterial (up to 4 weeks), chronic (beyond 12 weeks) and acute recurrent (at least 4 episodes per year with resolution). When sinusitis involves the nasal cavity is called rhinosinusitis. Generally, a healthy sinus is sterile, characterised by suitable mucus drainage and free passage of the air. Abnormality or ciliary immobility determine the inhibition of the drainage resulting in sinusitis. Predisposing factors to this disease are immunocompromised state, nasal septum deviation, nasal polyps, tumours, trauma and fractures, ***e abuse, presence of foreign bodies.
An acute viral form can be subjected to bacterial superinfection. Bacteria generally responsible of these infections are Streptococcus pneumoniae, nontypeable Haemophilus influenzae, Moraxella catarrhalis. Pseudomonas aeruginosa is more frequently present in sinusitis by HIV infection and cystic fibrosis. Some genera of fungi such as Candida, Aspergillus, Blastomyces, Coccidioides, Rizophus, Histoplasma and Cryptococcus can cause sinusitis in immunocompromised patients. Signs and symptoms of acute rhinosinusitis consist in: mucopurulent leaks from the nose, nasal obstruction, congestion, facial pain, pressure to the involved sinuses, hyposmia, anosmia, fever, sensation of pressure or“plug” to ears, dental pain. Generally in the first 3-5 days it is not possible to distinguish a viral form from a bacterial form, therefore the use of antibiotics is not recommended. If the disease persists beyond 10 days then it is very likely sustained by bacteria and the antibiotic treatment is indicated. Chronic forms have a slower onset, greater duration and frequency. Symptoms are similar to those of the acute form with, in addition, bad breath, laryngitis, bronchitis and asthma worsening.
Sinusitis often resolves spontaneously and the treatment is prevalently symptomatic. In particular, the decongestant treatment serves to reduce oedema, ameliorating the drainage of mucus in excess and maintain the patency of sinus ostia. A good result can be obtained from the local application of hypertonic saline solution both in the treatment of acute bacterial or acute recurrent form and chronic form and also in prevention.
The selection of antibiotic instead has to take into consideration the production of beta-lactamase and the presence of drug resistant pneumococci.
Pharyngitis (pharyngotonsillitis)
It’s an inflammatory process of pharynx, hypopharynx, uvula and tonsils, which is generally transmitted by direct contact with respiratory secretion. It is more frequent in children (5-15 years) and, although is frequently self-limiting, the swelling of the involved parts can cause a reduced patency of the airways or, anyway, preclude the ingestion of adequate amounts of liquids with consequent dehydration.
The infection can be sustained by viruses (such as Epstein-Barr) and bacteria, in particular beta-haemolytic Streptococcus pyogenes of group A is the most frequent in pediatric forms, but also Mycoplasma pneumoniae, Chlamydia pneumoniae are found in adults and children. Moreover, forms transmitted by sexual contact and sustained by Neisseria gonorrhoeae and those by Corynebacterium diphtheriae (form reduced by the use of the vaccine) are to be considered.
Epiglottitis
It is an inflammation of the epiglottis, consequent to a viral or bacterial infection, determining swelling of the organ with possible obstruction of the airways.
It is prevalently caused by type b H. influenzae, but also by streptococci, staphylococci or a thermic trauma. It manifests itself with hears pain (in adults), dysphonia, while fever is absent up to 50% of cases and can develop in a tardive phase. The treatment is antibiotic when bacteria are the cause of the disease, while intubation can be requested in cases of severe obstruction of the airways.
Laryngitis
Larynx inflammation is manifested by aphonia and hoarseness, mainly caused by viruses, but up to 10% of cases also by bacteria (streptococci and C. diphtheriae included). Non infective causes can be tumours, thermic or caustic trauma, gastroesophageal reflux disease (GERD). Laryngitis presents symptoms which last 3-4 days and, unless the presence of bacteria, antibiotics are not used.
Bronchitis
Bronchitis is a frequent inflammation of bronchi that is manifested by caught, shortness of breath and chest pain. Bronchitis is divided in acute and chronic; in the first case caught lasts about three weeks and in 90% of cases is caused by viral infection that can occur after contagion with other infected persons. Predisposing risk factors can be cigarette smoke or other sources of environmental pollution. Chronic bronchitis is characterised by caught for three months per year for at least two episodes per year and cigarette smoke together with others genetic or environmental causes are the main triggering factors. Normally, except in certain particular cases, antibiotics are not used but steroidal anti-inflammatory drugs, paracetamol in order to obviate the potential increase of temperature and bronchodilators such as salbutamol to ameliorate the respiration.
It was now surprisingly found that an association of bromelain, an extract of Myrtus communis and honey is particularly effective in the treatment of respiratory diseases thanks to the synergistic action of its components.
Detailed description of the invention
Therefore is an object of the present invention a composition containing an association of bromelain, an extract of Myrtus communis and honey for the treatment of respiratory diseases.
The components of the association according to the present invention are all known components, widely used in therapy.
BROMELAIN
With the term bromelain is meant a complex natural mixture of proteolytic enzymes deriving from the Ananas comosus plant. Bromelain is notoriously known for its multiple therapeutic properties and for this reason it has been used for many years in the traditional medicine for several types of diseases. Bromelain is obtained from pineapple through different methods and for commercial use is obtained through centrifugation, ultrafiltration and lyophilisation processes. The composition varies depending on both the extraction method and the part of the plant used; in fact the concentration of proteolytic enzymes is greater in pineapple stem than in fruit.
After oral administration bromelain reaches its maximum blood concentration after one hour and maintains its biological activity for about 6-9 hours.
Several properties are attributed to this compound such as for examples immunomodulatory, anti-inflammatory, anti-metastatic, anti-oedematous, anti-
thrombotic activity etc.
Relative to the present invention, particular attention is given to the anti-inflammatory activity of bromelain. The latter is due to the negative regulation of the expression of cyclooxygenase-2 (COX-2), prostaglandin E2 (PGE2) and thromboxane B2. Moreover bromelain, in case of inflammation, is able to reduce pro-inflammatory cytokine levels such as interleukin-1 b (I L-1 b), interleukin-6 (IL-6), Tumor Necrosis Factor-a (TNF-a), interferon-Y (INT-Y) etc.
Other studies report an inhibitory action of this compound also on brachinine in the inflammation site trough depletion of the plasmatic kallikrein system and at the same time reduced formation of fibrin by reduction of intermediates of the coagulation cascade. Experimental studies show how bromelain is able to reduce the leucocyte migration in inflamed areas and, through the removal of the surface receptors (CD128), prevent the leucocyte adhesion to the vessel in the inflamed zone.
To bromelain have been attributed also immunomodulatory activities, in fact the compound in vitro proved to be able to activate“natural killer1’ cells increase the production of TNF-a, INT-Y, IL-1 , IL-2, IL-6.
Another interesting feature of bromelain is its ability to enhance the effectiveness of antibiotics in case of pneumonias, bronchitis, sinusitis or other types of infection. In particular it has been observed an increase of plasmatic and tissue concentrations of antibiotics such as penicillin, gentamicin, tetracycline and amoxicillin if administered concurrently with bromelain.
For sinusitis, a typical inflammatory process of the airways, the activity of bromelain is certified also by clinical experimentations; from these works has emerged that 85% of patients treated with bromelain (without concurrent use of antibiotics) showed a full resolution of nasal mucosa inflammation and a resolution of respiratory difficulties in a superior way compared to placebo. Also in children, in a more recent study, the treatment with bromelain has been shown to be particularly valid in reducing the duration of symptoms and increasing the recovering speed compared to placebo. Thanks to its numerous properties, bromelain represents a valid naturally occurring active ingredient for the treatment of inflammatory diseases of the respiratory tract to be used with other natural products or in conjunction with an antibiotic treatment. MYRTUS COMMUNIS
In Myrtus genus three species exist among which the most important is the Myrtus communis specie.
Myrtus, Myrtus communis, is an evergreen shrub belonging to the family of Myrtaceae. This shrub comes from Mediterranean regions and Middle East zones and is distributed also in North Africa, South America and Australia.
Since the most ancient times, Myrtus is used in medicine and nutrition as well as in perfumery and in liquors and cosmetic industries. The mostly recognised properties thereof are of antiseptic, anti-inflammatory, mucolytic, carminative and astringent type. The numerous properties attributed to myrtus are due to several compounds present in the various parts of the plant. In particular, in the essential oil obtained from leaves a-pinene, 1 ,8-cineole, limonene, myrtenyl acetate, linalool etc. are found. Moreover leaves are rich in flavonoids such as quercetin catechins and myricetin and in oligomeric compounds such as myrtucommulone and semi-myrtucommulone. Myrtus leaves have a strong antibacterial activity as proved by the studies present in the literature which confirm the activity of the extract in respect of both Gram positive bacteria ( Staphylococcus aureus, Micrococcus luteus, Streptococcus pneumoniae, Streptococcus pyogenes, Listeria monocytogenes) and Gram negative bacteria (, Escherichia coli, Pseudomonas aeruginosa, etc.).
The presence in myrtucommulone and semi-myrtucommulone leaves may be instead responsible for the anti-inflammatory activity together with the action of monoterpenes such as myrtenyl acetate, 1 ,8-cineol, a-pinene etc.
Studies in the literature report a potent activity of myrtucommulone on the suppression of the synthesis of eicosanoids through the inhibition of cyclooxygenase- 1 (COX-1 ) and 5-lipoxygenase (5-LOX) both in vitro and in vivo. Even the essential oil of leaves revealed itself as a valid anti-inflammatory in a model of oedema by carrageenan induced on mice. In this study an oral dose of 100 mg/Kg of essential oil was able to inhibit the mouse paw oedema of about 73% almost similarly to diclofenac used as a positive control.
HONEY
Honey is a natural product which has been widely used for its multiple beneficial properties. Over the years honey has always maintained a central position in traditional medicine for the treatment of infections and hepatic, cardiovascular or gastro intestinal tract diseases.
Physical characteristics of honey in terms of colour and taste vary depending on the derivation source and weather conditions. Types with a light yellow colour up to honey types of reddish colour and also near to black exist. Generally honey types with a
lighter colour have a less strong taste compared to honey with a stronger colour. Form a chemical point of view honey principally contains sugars and water and, in particular, the latter represent about 95-99%. These molecules present in very high amounts are responsible of the high viscosity, adhesively and density of honey as well as of the tendency to granulate and absorb moisture from outside.
The carbohydrates present in greater amounts are represented by fructose (between 33-38%) and glucose (between 29-31 %); others sugars that can be found in honey are maltose, sucrose etc.
Fructooligosaccharides around 5% are also present. The second main component of honey is water, the content of which varies greatly depending on maturation, whether conditions, water content of the starting nectar, storage conditions but however normally it never exceeds 25% of the composition.
In the honey composition, in a small part (about 0.5%), are included some acids which determine the sour taste and at the same time guarantee protection and stability against microorganism attack. Among several acids the main one is gluconic acid which derives from glucose after oxidation by a glucose oxidase. Formic, acetic, butyric pyruvic maleic acid etc. are also present.
Minerals concentration can vary between 0.1 % and 1 % and potassium is present in greater amounts followed by calcium, magnesium, sodium, sulphur, phosphorus and trace quantities of zinc copper and manganese.
Nitrogen compounds, in very small amounts in honey, are thiamine, riboflavin, nicotinic acid and vitamin B6; other vitamins present are ascorbic acid and pantothenic acid.
In honey are also present a lot of enzymes such as invertase, amylase, glucose oxidase, catalase having an important role in the formation of honey. In small amounts in honey polyphenolic compounds such as flavonoids are also found.
Among the most known and documented properties of honey its antibacterial effect is surely included documented on about 60 species of aerobic, anaerobic, Gram positive and negative bacteria. Examples are Haemophilus influenzae, Klebsiella pneumoniae, Mycobacterium tuberculosis, Pseudomonas aeruginosa, Staphylococcus aureus etc.
In the literature an action of bacteriostatic or bactericidal type depending on the dose used starting from a concentration of 2% to 15% is reported. Artificial honey instead has bacteriostatic activity only in concentration between 20 and 30%.
The antimicrobial activity is mainly due to the high content in sugars which avoid the bacterial growth by the recall of water which dehydrates the pathogenic cells. Moreover, also the pH of honey between 3.2 and 4.5 and the presence of hydrogen peroxide produced by glucose oxidase contribute to the inhibition of the growth of a lot of types of microorganisms.
Thanks to the antibacterial action as well as to its lenitive and emollient ability, honey is suggested by the World Health Organizations (OMS) for the treatment of caught in children.
In fact, OMS includes honey in the treatment of caught associated with upper airways infections because it is emollient, cost-effective, popular and secure. The high viscosity of honey and its emollient action contribute to bring relief to the throat and reduce the symptomatology of caught. A clinical study on children which provided for the consumption of 10 g of honey before going to sleep showed how said substance was able to reduce the frequency of caught and as a consequence children night rest confirming the OMS’s opinion.
A similar study showed beneficial effects of honey in the treatment of cough in children using honey or dextromethorphan (widely used drug in the treatment of cough) or no treatment.
Besides the antibacterial activity, some studies report for honey also anti- inflammatory activity. In fact, the ability of honey after ingestion to reduce the concentrations of PGE2, PGF2-a and thromboxane B2 in normal individuals has been reported in the literature.
In a preferred embodiment, the composition object of the present invention contains the association of bromelain, extract of Myrtus communis and honey in admixture with a suitable acceptable carrier.
Suitable acceptable carriers are those commonly known to the man skilled in the art for the preparation of compositions for oral administration such as solutions, suspensions, powders or granulates, tablets, capsules, pellets. By way of non-limiting example, said acceptable carriers can consists of binders, diluents, lubricants, glidants, disintegrants, solubilizing (wetting) agents, stabilizers, colorants, anti-caking agents, emulsifiers, thickeners and gelling agents, coating agents, humectants, sequestrants, and sweeteners.
Specifically examples of diluents can be: magnesium carbonate, cellulose microcrystalline, starch, lactose, and sucrose; mainly used lubricants are magnesium
stearate, stearic acid, and sodium stearyl fumarate. As glidants colloidal silica and magnesium silicate, as disintegrants the cross-linked polyvinylpyrrolidones, and sodium starch glycolate, as solubilizing agents surfactants such as TWEEN or sodium lauryl sulphate, and as stabilizers all classes of preservatives (sorbic acid and derivatives, benzoic acid and derivatives, parabens), antioxidants (ascorbic acid and derivatives, tocopherol), and acidifying agents (phosphoric acid, tartaric acid) can be cited. Thickeners and gelling agents can be carrageenan, pectins, and starches, coating agents include for example waxes and derivatives, anti-caking agents include for example calcium or magnesium carbonate, humectants include for example sorbitol and mannitol, sequestrants include for example EDTA and derivatives, sweeteners include for example aspartame, and acesulfame potassium.
The composition object of the present invention is preferably a liquid or solid composition for oral use, still more preferably an aqueous solution, a suspension, a powder or granulate, a tablet, a capsule, and pellet.
The composition object of the present invention contains bromelain, extract of Myrtus communis and honey.
Bromelain is present in an amount between 1 mg and 6000 mg, preferably between 20 mg and 3000 mg, still more preferably between 50 mg and 500 mg.
The extract of Myrtus communis is present in an amount between 1 mg and 5000 mg, preferably between 10 mg and 1000 mg, still more preferably between 20 mg and 500 mg.
Honey is present in an amount between 1 mg and 5000 mg, preferably between 20 mg and 2000 mg, still more preferably between 30 mg and 500 mg.
The compositions object of the present invention are particularly effective in the treatment of diseases of the respiratory tract, in particular in the treatment of rhinitis, allergic rhinitis, rhinopharyngitis or cold, rhinosinusitis, sinusitis, pharyngitis, epiglottitis, laryngitis and bronchitis, allowing to obtain at the same time an anti- inflammatory effect and an antimicrobial effect thanks to the synergistic actions of their components.
Therefore another object of the present invention is a composition containing the association of bromelain, an extract of Myrtus communis and honey in admixture with a suitable acceptable carrier for use in the treatment of diseases of the respiratory tract.
Without being bound to a specific theory, the inventors are of the opinion that the
synergistic effect of the association present in the composition object of the present invention, derives from the following activities of the components of the association. Bromelain is an optimal anti-inflammatory agent able to reduce the levels of proinflammatory cytokines as well as the expression of cyclooxygenases, prostaglandins and bradykinin. The compound is able to reduce the migration and the adhesion of leucocytes in the inflammation site; moreover as confirmed by scientific studies bromelain, used in conjunction with some antibiotics, potentiates the effect thereof.
Honey thanks to its peculiar composition (concentrated sugars, enzymes and others compounds) has a strong antibacterial activity due to both the ability to recall water dehydrating pathological cells and the presence of hydrogen peroxide and enzymes such as glucose oxidase inhibiting the growth of several microorganisms. Moreover according to some literature studies honey may also have an effect on inflammation. The compounds contained in myrtus ( Myrtus communis) have a good broad spectrum antibacterial activity (Gram positive and negative) and some components such as myrtucommulone or some monoterpenes such as myrtenyl acetate or a-pinene have also anti-inflammatory activity.
The synergic activity of the above mentioned active ingredients can be studied by in vitro and/or in vivo tests able to assess the antimicrobial and anti-inflammatory activity of the compositions according to the present invention and/or of the comparative compositions.
For the evaluation of the antimicrobial and anti-inflammatory activity can be used any test known in the literature.
Approximately, antimicrobial activity is evaluated on the main bacterial strains belonging to Gram positive and/or Gram negative categories and/or other microbial species.
As regards the anti-inflammatory activity, is preferably evaluated determining the inhibition/activation activity towards enzymes, cytokines, transcription factors, or other factors involved in inflammatory/anti-inflammatory mechanisms, of the compositions according to the present invention and/or of the comparative compositions.
Examples
By way of example are now provided some non-binding examples of daily doses of active components of the composition object of the present invention.
Daily doses are meant to be administrated in a suitable oral dosage form and divided in one or more dosage units.
The compositions are prepared according to conventional techniques such as mixing.
Claims
1 ) A composition containing an association of bromelain, an extract of Myrtus communis and honey in admixture with a suitable acceptable carrier.
2) A composition according to claim 1 in the form of a liquid or solid composition for oral use.
3) A composition according to claim 1 or 2 wherein bromelain is present in an amount between 1 mg and 6000 mg, preferably between 20 mg and 3000 mg, still more preferably between 50 mg and 500 mg.
4) A composition according to any of the previous claims wherein the extract of Myrtus communis is present in an amount between 1 mg and 5000 mg, preferably between 10 mg and 1000 mg, still more preferably between 20 mg and 500 mg.
5) A composition according to any of the previous claims wherein honey is present in an amount between 1 mg and 5000 g, preferably between 20 mg and 2000 mg, still more preferably between 30 mg and 500 mg.
6) Composition according to any of the previous claims wherein the composition is a medical device, a food supplement, a nutraceutical, dietetic and nutritional composition, a food product, a beverage, a nutraceutical product, a medicament, a medicated food, a pharmaceutical composition or a food for special medical purposes.
7) A composition according to any of the previous claims for use in the treatment of diseases of the respiratory tract.
8) A composition according to claim 7 for use in the treatment of rhinitis, allergic rhinitis, rhinopharyngitis or cold, rhinosinusitis, sinusitis, pharyngitis, epiglottitis, laryngitis and/or bronchitis.
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CN110423835A (en) * | 2019-09-05 | 2019-11-08 | 复旦大学附属中山医院 | Primer composition for lower respiratory tract the pathogenic microorganism examination |
CN110423835B (en) * | 2019-09-05 | 2022-09-20 | 复旦大学附属中山医院 | Primer composition for detecting pathogenic microorganisms of lower respiratory tract |
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