EP4236930A1 - Composition for use in the prevention and treatment of diseases of the respiratory system - Google Patents
Composition for use in the prevention and treatment of diseases of the respiratory systemInfo
- Publication number
- EP4236930A1 EP4236930A1 EP21814876.5A EP21814876A EP4236930A1 EP 4236930 A1 EP4236930 A1 EP 4236930A1 EP 21814876 A EP21814876 A EP 21814876A EP 4236930 A1 EP4236930 A1 EP 4236930A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- composition
- comprised
- nasal
- salt
- preferably comprised
- 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
Links
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- BAQAVOSOZGMPRM-QBMZZYIRSA-N sucralose Chemical compound O[C@@H]1[C@@H](O)[C@@H](Cl)[C@@H](CO)O[C@@H]1O[C@@]1(CCl)[C@@H](O)[C@H](O)[C@@H](CCl)O1 BAQAVOSOZGMPRM-QBMZZYIRSA-N 0.000 description 1
- 235000019408 sucralose Nutrition 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 230000008093 supporting effect Effects 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 230000008961 swelling Effects 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 230000009885 systemic effect Effects 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- BHTRKEVKTKCXOH-LBSADWJPSA-N tauroursodeoxycholic acid Chemical compound C([C@H]1C[C@@H]2O)[C@H](O)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H]([C@@H](CCC(=O)NCCS(O)(=O)=O)C)[C@@]2(C)CC1 BHTRKEVKTKCXOH-LBSADWJPSA-N 0.000 description 1
- YMBCJWGVCUEGHA-UHFFFAOYSA-M tetraethylammonium chloride Chemical compound [Cl-].CC[N+](CC)(CC)CC YMBCJWGVCUEGHA-UHFFFAOYSA-M 0.000 description 1
- 239000002562 thickening agent Substances 0.000 description 1
- 229940113082 thymine Drugs 0.000 description 1
- 230000036962 time dependent Effects 0.000 description 1
- OGIDPMRJRNCKJF-UHFFFAOYSA-N titanium oxide Inorganic materials [Ti]=O OGIDPMRJRNCKJF-UHFFFAOYSA-N 0.000 description 1
- 206010044008 tonsillitis Diseases 0.000 description 1
- 230000005945 translocation Effects 0.000 description 1
- 210000004881 tumor cell Anatomy 0.000 description 1
- 231100000397 ulcer Toxicity 0.000 description 1
- 241001529453 unidentified herpesvirus Species 0.000 description 1
- 230000004218 vascular function Effects 0.000 description 1
- 230000006442 vascular tone Effects 0.000 description 1
- 230000001457 vasomotor Effects 0.000 description 1
- 239000002699 waste material Substances 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
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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
- A61K31/095—Sulfur, selenium, or tellurium compounds, e.g. thiols
- A61K31/10—Sulfides; Sulfoxides; Sulfones
-
- 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
- A61K31/13—Amines
- A61K31/155—Amidines (), e.g. guanidine (H2N—C(=NH)—NH2), isourea (N=C(OH)—NH2), isothiourea (—N=C(SH)—NH2)
-
- 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
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/715—Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
- A61K31/726—Glycosaminoglycans, i.e. mucopolysaccharides
- A61K31/728—Hyaluronic acid
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0043—Nose
-
- 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
- A61P11/04—Drugs for disorders of the respiratory system for throat disorders
Definitions
- composition for use in the prevention and treatment of diseases of the respiratory system “Composition for use in the prevention and treatment of diseases of the respiratory system ”
- the present invention relates to a composition
- a composition comprising hyaluronic acid or a salt thereof, chlorhexidine or a salt thereof, and methylsulfonylmethane (MSM) useful in the prevention and/or in the treatment of diseases associated with the respiratory system.
- MSM methylsulfonylmethane
- composition comprising a combination or mixture of: (a) hyaluronic acid or a salt thereof, (b) chlorhexidine or a salt thereof, and (c) methylsulfonylmethane (MSM).
- composition for use in a method for the prevention or treatment of diseases of the respiratory system, or symptoms related to said diseases, in a mammal, wherein said mammal is a human being or an animal.
- the combination is particularly effective thanks to the synergistic action of the components thereof.
- the respiratory system is the set of organs and tissues that allow the breathing process.
- Respiration consists of assimilating the oxygen inspired with air and the simultaneous ejection of the carbon dioxide generated by cellular activity and representing a waste product.
- the main anatomical elements of the respiratory system are: the nose with the cavities thereof, the mouth, the pharynx, the nasopharynx, the larynx, the trachea, the bronchi, the bronchioles, the lungs and the muscles of respiration, muscles of the diaphragm and intercostal muscles.
- the respiratory system can be divided into two main components: the upper respiratory tract (or upper airways) and the lower respiratory tract (or lower airways).
- the upper respiratory tract includes the nose with the nasal cavities thereof, the mouth, the pharynx, the nasopharynx and the larynx; the lower respiratory tract instead includes the trachea, the bronchi, the bronchioles, the lungs and the muscles of respiration, muscles of the diaphragm and intercostal muscles.
- Diseases affecting the respiratory system may be of the following types: obstructive, restrictive, vascular or infectious/environmental.
- the most common diseases of the airways are cold, sinusitis and pharyngitis. Cold is a viral disease.
- the most common agents are rhinovirus, human parainfluenza virus, respiratory syncytial virus, adenovirus, echovirus and coxsackievirus.
- Symptoms include nasal secretion, nasal obstruction and throat irritation, usually associated with low-intensity fever, malaise, sneezing and nasal secretions that could become purulent.
- Symptoms are not specific and not characteristic of any agent.
- the standard duration of symptoms is about 7 days.
- the common cold in children resolves alone in most cases.
- the use of antibiotics is potentially harmful, because it increases the risk of colonisation with resistant organisms. This can lead to subsequent antibiotic-resistant bacterial infections.
- Cough occurs in 60-80% of common colds, symptoms usually last 2-7 days. Patients usually improve within 10 days, but sometimes cough and nasal secretions may persist for 2 weeks or more.
- Sinusitis consists of inflammation of the mucosal lining of one or more paranasal sinuses. It can be caused by infections or non-infectious causes such as allergies. In children it manifests itself as complication of a common cold where there is a congestion of the nasal mucous membranes and the paranasal sinuses, leading to rhinosinusitis.
- Viral rhinosinusitis is 20-200 times more common than bacterial sinusitis. Sinusitis is classified according to the duration of symptoms in acute sinusitis (up to 3 weeks), subacute sinusitis (3-10 weeks) and chronic sinusitis (>10 weeks).
- Sinusitis manifests itself when a viral agent in the upper respiratory airways produces inflammation of the mucous membranes which leads to obstruction of the sinuses. This in turn leads to the entrapment of liquids into the sinus cavities and to the proliferation of the normal bacterial flora of the upper respiratory airways.
- S. pneumoniae H. influenzae
- M. catarrhalis S.aureus
- S. pyogenes J it should be pointed out that most of the rhinosinusitises are viral and, therefore, about 60% resolve spontaneously without antimicrobial therapy.
- the symptoms can be sinus morbidity, pain in the teeth, headache and high fever.
- Rhinorrhoea is mostly purulent, but it can also be serous or aqueous. Other indicators of sinusitis are the presence of severe symptoms during an episode of respiratory infection. These include high fever > about 39°C, persistent fever, periorbital swelling, and facial pain. Pharyngitis is an inflammatory disease of the mucous membranes of the throat and the underlying structures.
- Pharyngitis is divided into two categories: symptomatic nasal disease (nasopharyngitis) and disease without nasal involvement (pharyngitis or tonsillopharyngitis).
- Nasopharyngitis is almost always of viral aetiology, while pharyngitis without nasal signs has various aetiology signs including bacteria, viruses, fungi and other infectious agents.
- Adenoviruses are the most common agents that trigger the nasopharyngitis; other viruses are flu, parainfluenza and enteroviruses.
- Bacterial agents that cause pharyngitis include Streptococcus pyogenes, H. influenzae, C. diphtheriae and N. meningitidis.
- Group A streptococci cause about 15% of bacterial pharyngitis and about 1-2 out of 10 patients with sore throat. Infection in most of the other cases can therefore be attributed to viruses.
- Symptoms of pharyngitis comprise: inflammation of the pharynx, characterised by erythema, exudate or ulcer, pharyngeal pain, dysphagia and fever, while rhinorrhoea, cough, raucousness, conjunctivitis and diarrhoea suggest a viral aetiology.
- Pharyngitis in paediatric age is of viral type, whereas pharyngitis of bacterial type is rarely not due to streptococcus.
- IT MI20 111 005 A1 discloses ophthalmic formulations containing tauroursodeoxycholic acid with an antioxidant, protective and anti-degenerative action for ocular tissues, in particular for the retina.
- US 10 398 723 B1 discloses a composition comprising hyaluronan and methylsulfonylmethane, wherein said composition is useful for the attenuation and/or prevention of inflammation and/or pain.
- US 2008/102107 A1 discloses compositions suitable for use in the treatment of pain and swelling of an affected joint of an animal, particularly a human being.
- WO 2019/077521 A1 discloses a composition comprising or, alternatively, consisting of an effective amount of a mixture comprising hyaluronic acid and methylsulfonylmethane (MSM) to be used as an antiinflammatory agent.
- MSM methylsulfonylmethane
- WU YAN ET AL "The study on Chlorhexidine acetate against pathogens bacteria of acute and chronic pharyngitis in vitro", ZHONGGUO KANGSHENGSU ZAZHI, vol. 36, no. 9, 2011, pages 712-715, is a study conducted to evaluate the antibacterial activity of different concentrations of chlorhexidine acetate against different pathogens of pharyngitis.
- the combination subject of the present invention consists of a combination of hyaluronic acid or a salt thereof, chlorhexidine or a salt thereof, and methylsulfonylmethane (MSM).
- composition comprising an association or a combination or a mixture comprising or, alternatively, consisting of: (a) hyaluronic acid or a salt thereof, (b) chlorhexidine or a salt thereof, and (c) methylsulfonylmethane (MSM), having the characteristics as defined in the attached claims.
- MSM methylsulfonylmethane
- Hyaluronic acid is a carbohydrate, specifically a mucopolysaccharide, consisting of dimers of N- acetyl-glucosamine and glucuronic acid, present in all living organisms.
- the biological functions it carries out are: maintenance of the elasto-viscosity of the liquid in the connective tissue, control of tissue hydration, supramolecular assembly of proteoglycans in the cellular matrix, receptor-mediated role in cell detachment, mitosis and inflammation.
- hyaluronic acid Besides reducing nerve impulses and neuronal sensitivity to pain, hyaluronic acid also reduces the production and activity of pro-inflammatory molecules. These functions are carried out in the scavenger activity against reactive free radicals derived from oxygen and the inhibition of the immune complex adherence to polymorphonuclear cells, the inhibition of leukocyte and macrophage migration and fibroblast proliferation.
- Hyaluronic acid plays a significant role in the airways, acting as a component of many extracellular matrices. It can be found in connective tissue, respiratory epithelium, nasal and tracheobronchial mucosa, airway secretions and serous glandular cells.
- Hyaluronic acid acts by lubricating the airways, it repairs damaged tissues, it remodels and modulates the inflammatory response.
- HA is present in high concentrations at the laryngeal muscle level and in the subepithelium at the glottis level, where it can facilitate mucosal movements. It has been assumed that the abundance of HA in the subglottic region may be involved in the control of vascular leakage and in the formation of oedemas. At the level of the nasal mucosa, HA is involved in modulating the activity of substances, such as for example (ET-I), which plays a role in regulating vasomotor tone and glandular secretion at serum and mucous membrane levels. Furthermore, it has recently been reported that depolymerisation of HA during inflammatory responses may be directly involved in the induction of mucus hypersecretion.
- the result of the trial showed an improvement in patients treated with hyaluronic acid, in the condition of hypertrophy and nasal secretions.
- a group of patients is treated with 9 mg of HA in 3 ml of saline solution, in form of spray, per day plus 100 pig of mometasone furoate spray per day while another group was treated with 6 ml of a saline solution plus 100 pig of mometasone furoate and desloratadine 5 mg through the oral route.
- patients in the treatment group were found to have significantly fewer nasal neutrophils, also experienced significant improvement in nasal symptoms (sneezing, rhinorrhoea, and nasal congestion), and they showed a decrease in endoscopic evidence of nasal exudate.
- intranasal ointment containing lysine hyaluronate, thymine and sodium chloride (LHT) was used in 48 patients with allergic, non-allergic and mixed rhinitis, among whom 12 patients also took 100 pig/day of intranasal mometasone furoate and rupatadine fumarate through the oral route.
- LHT administered through the intranasal route was found to significantly reduce the number of patients with symptoms, the number of intranasal inflammatory cells and the endoscopic characteristics of decreasing the nasal value with respect to the baseline level with respect to the control group (intranasal isotonic saline solution plus intranasal corticosteroid and oral antihistamine).
- HA administered through the topical route has also been successfully used to treat chronic rhinosinusitis with or without nasal polyps.
- One study involved a cohort of patients with chronic rhinosinusitis with nasal polyposis. Patients treated with mometasone furoate nasal spray 400 pig/day and HA 9 mg diluted in 2 ml isotonic saline solution, atomised or non-atomised, show a significant improvement in nasal symptoms, in endoscopic aspect, in rhinomanometry and in eliminating saccharin with respect to the baseline and with respect to patients who receive placebo.
- patients in the treatment group use steroids administered through the oral route less often with respect to the control group.
- a treatment with atomised HA significantly reduced ostium-meatal oedema and secretion and it improved the quality of life of 21 adults with chronic rhinosinusitis and nasal polyposis, while no improvement was observed in 18 patients treated with placebo.
- hyaluronic acid reveals activity inhibiting the formation of biofilm.
- Biofilm consists of a complex microbial community protected by a self-produced polymer matrix consisting of polysaccharides, nucleic acid and proteins. Biofilms adhere firmly to the surfaces of many materials used in a clinical environment. This is particularly relevant for airway infections, when biofilms are formed on tracheostomy, endotracheal and tympanostomy tubes, sinus drains, stents, valves, ossicular prosthesis and cochlear implants, but it is also a problem with orthopaedic prostheses, dental implants, catheters and heart valves.
- biofilms in chronic infections are well-known: 65-80% of microbial infections, including almost all chronic infections, involve bacterial biofilms.
- the main biofilm producing bacteria responsible for respiratory infections are Streptococcus pneumoniae, S. pyogenes, Haemophilus influenzae and Pseudomonas aeruginosa.
- This activity was evaluated in vitro on the Hep-2 cell line, infected by various bacterial species including S. aureus, H. influenzae and M. catarrhalis.
- the cells were treated with a 0.3% HA solution, then diluted to 50%, thus showing interference with bacterial adhesion to the cell as well as a modest antibiotic activity.
- Chlorhexidine is a biguanide, consisting of two chloro-guanidine chains linked by hexamethylene chains.
- the substance is colourless, odourless, bitter-tasting and insoluble in water, which covalently binds the proteins of the skin and of the mucosa, thus ensuring a long duration of action and poor systemic absorption.
- Chlorhexidine is absorbed by the phosphorylated component of proteins of the bacterial wall. Binding with microbial proteins triggers lysis of the cytoplasmic membrane, at bacteriostatic concentrations, while in bactericidal amounts chlorhexidine forms an irreversible bond with adenosine triphosphate and nucleic acids, precipitating them.
- chlorhexidine Besides having bacteriostatic, bactericidal, fungicidal activity and activity against some viral species, chlorhexidine also has a greater affinity for the bacterial wall of Gram positive (+) bacteria.
- the topical application of antiseptic in the oral cavity exerts the antimicrobial activity thereof through electrostatic binding with the oral mucous membranes.
- Chlorhexidine effectively acts on the dental biofilm which produces enzymes that degrade fibronectin.
- the antimicrobial activity of chlorhexidine was tested on various cell lines including rabbit kidney cells and human foreskin fibroblasts. Each cell line was associated with a viral strain, particularly, the flu virus was inoculated into the cell line in the Madin Darby canine kidney, and the human parainfluenza virus on the African green monkey kidney cell line. Antiviral activity was compared to a placebo and monitored over time, monitored between 30 seconds after treatment, up to the subsequent 15 minutes.
- the test result showed a significant time-dependent decrease in viral growth.
- the inhibition of human parainfluenza virus changes from 59% after 30 seconds up to 99% after 15 minutes, while the flu virus decreases by 93% after 30 seconds up to 98% after 15 minutes.
- test result showed a decrease in symptoms, significantly greater in the treated group with respect to the control group, showing the effectiveness thereof in combating this type of infections.
- the antimicrobial activity of chlorhexidine against some microbial species is also tested in this study.
- a 0.5% solution of chlorhexidine in 50% of alcohol and subsequently a 1% solution are inoculated into a culture broth containing Micrococcus pyogenes, a bacterium responsible for some respiratory diseases, and compared with a control broth.
- the test result showed the absence of bacteria in the media treated with chlorhexidine.
- the test was conducted on a cohort of volunteers, taking the bacterial strain through a pharyngeal swab, in particular from the tonsils.
- the presence of p-haemolytic streptococcus was evaluated through a swab and subsequently 2 tablets of 0.2% chlorhexidine were administered to one group of patients 5 times a day for one week, while another group received placebo.
- the result showed the presence of p-haemolytic streptococcus in only a small part of patients treated with chlorhexidine, and showing the efficacy thereof.
- Methylsulfonylmethane or more simply MSM is an organosulfide, an organic compound containing sulphur.
- the nutraceutical properties of methylsulfonylmethane derive from the sulphur content thereof in a bioavailable form, thanks to the presence of an organic component which facilitates the absorption thereof.
- MSM has various pharmacological activities including anti-inflammatory and antioxidant action.
- MSM inhibits the transcriptional activity of NF-kB, preventing the degradation of the inhibitor of this molecule. Furthermore, MSM showed to block the phosphorylation of the p65 subunit at serine-536.
- regulatory cascade of NK-kB is a pro-inflammatory signalling mechanism, responsible for activating gene expression cytokines, chemokines and adhesion molecules.
- the inhibitory effect of MSM on NF-KB results in a decrease in mRNA regulation for interleukin (IL)- 1, IL-6 and (TNF-a). Furthermore, IL-1 and TNF-a are inhibited in a dose-dependent manner.
- MSM may also decrease the expression of inducible nitric oxide synthase (INOS) and cyclooxygenase-2 (COX-2) by suppressing NF-KB; thus, reducing the production of vasodilator agents such as nitric oxide (NO) and prostanoids. Not only does NO modulate the vascular tone, but it also regulates mast cell activation. Therefore, MSM may indirectly play an inhibitory role on mast cells. Decreasing cytokines and vasodilator agents, allows to inhibit the flow and recruitment of immune cells to sites of inflammation. MSM negatively affects the expression of the NLRP3 inflammasome, decreasing the production and transcription of NF-KB and blocking the ROS activation signal.
- IOS inducible nitric oxide synthase
- COX-2 cyclooxygenase-2
- the MSM affects the activation of at least four types of transcription factors: NF-KB, signal transducers and activators of transcription (STATs), p53 and Nrf2. By mediating these transcription factors, MSM can regulate the balance between ROS and antioxidant enzymes.
- MSM can inhibit the transcriptional activity of NF-KB and therefore reduce the expression of enzymes and cytokines involved in the production of ROS.
- the down-regulation of COX-2 and INOS reduces the amount of superoxide radicals and of (NO), respectively.
- MSM suppresses expression of cytokines such as TNF-o, which may reduce any ROS generated at mitochondrial level. Decreases in cytokine expression may also be involved in reduced paracrine signalling and activation of other transcription factors.
- MSM has been shown to suppress the expression or activity of STAT transcription factors in a given number of tumour cell lines in vitro.
- the janus kinase (Jak)ZSTAT signalling pathway is involved in the regulation of apoptosis, differentiation and proliferation-related genes, which generate ROS as a necessary signalling component.
- Signalling through the Jak/STAT pathway may also be inhibited by reduced cytokine expression.
- the reduction of the Jak/STAT pathway may further decrease ROS synthesis by decreasing the expression of oxidase and B cell lymphoma 2 (Bcl-2).
- P53 shows a dichotomic oxidative function depending on levels of intracellular ROS, it exerts an antioxidant action at low levels of intracellular ROS and pro-oxidative activities at high levels of ROS.
- the antioxidant function of p53 stimulates scavenging enzymes such as sestrin, glutathione peroxidase (GPx) and aldehyde dehydrogenase (ALDH).
- GPx glutathione peroxidase
- ADH aldehyde dehydrogenase
- the pro-oxidative function of p53 stimulates oxidase, and at the same time suppresses antioxidant genes.
- Murine neuroblastoma cells cultured with the human immunodeficiency virus type 1 transactivating the regulatory protein (HIV-1 Tat) showed reduced nuclear translocation of Nrf2; however, inserting into the MSM culture medium allowed to resume the translocation of Nrf2 to the nucleus at regular levels.
- Nrf2 is well documented for the association thereof with antioxidant enzymes including glutamate-cysteine ligase (GCL), superoxide dismutase (SOD), catalase (CAT), peroxiredoxin (Prdx), GPx, glutathione S-transferase (GST), and others.
- GCL glutamate-cysteine ligase
- SOD superoxide dismutase
- CAT catalase
- Prdx peroxiredoxin
- GST glutathione S-transferase
- Stress can trigger an acute response by the innate immune system and a resulting adaptive immune response if the stress factor is pathogenic.
- MSM plays a crucial role in supporting the immune response. Through mechanisms such as those mentioned above, MSM modulates the immune response through the link between oxidative stress and inflammation.
- MSM has been shown to reduce IL-6, which is involved in the maintenance of chronic inflammation.
- MSM histamine release from mast cells is inhibited by DMSO2; however, the effects of MSM on histamine release remain unknown. Previous studies show that MSM has an inhibitory role on vascular function. Other in vitro studies demonstrate that MSM has the ability to dampen the expression of vasodilating agents such as nitric oxide (NO) and prostanoids. A reduction of NO protects macrophages against NO stimulated apoptosis.
- NO nitric oxide
- MSM may provide other immune modulatory effects linked to cell cycle and cell death.
- MSM does not chemically neutralise ROS in stimulated neutrophils but it instead suppresses mitochondrial generation of superoxide, hydrogen peroxide, and hypochlorous acid. Furthermore, MSM is able to restore the reduced glutathione (GSH)/oxidised glutathione (GSSG) ratio to normal levels, decrease the production of NO, and reduce the production of neuronal ROS following exposure to HIV-1 Tat.
- Animal studies using MSM as primary treatment for experimentally induced lesions show reductions in malondialdehyde (MDA), GSSG, myeloperoxidase (MPO), NO, carbon monoxide (CO) and increase in GSH, CAT, SOD and GPx.
- MDA malondialdehyde
- MPO myeloperoxidase
- CO carbon monoxide
- a clinical trial was conducted to test anti-inflammatory activity in patients with allergic rhinitis.
- the cohort of patients was treated with capsules of 650 mg of MSM 4 times a day, two in the morning and two in the afternoon, for 30 days.
- the group of patients non-responsive to the therapy continued for another 14 days, doubling the treatment dose.
- MSM seems to be well tolerated and safe.
- a series of toxicity studies was conducted on various animal species, including rats, mice and dogs. In a preliminary toxicity study report, there was reported a single mortality in a female rat to which there was administered an oral aqueous dose of 15.4 g/kg after two days; however, the post-mortem necroscopic examination did not reveal any serious disease.
- compositions subject of the present invention consists of a combination of hyaluronic acid or a salt thereof, chlorhexidine or a salt thereof and methylsulfonylmethane (MSM) for the prevention and/or treatment of diseases of the respiratory system both in humans and animals.
- MSM methylsulfonylmethane
- composition comprising an association or a combination or a mixture comprising or, alternatively, consisting of: (a) hyaluronic acid or a salt thereof, (b) chlorhexidine or a salt thereof, (c) methylsulfonylmethane (MSM) and optionally food or pharmaceutical grade additives or excipients.
- MSM methylsulfonylmethane
- composition for use in a method for the prevention or treatment of diseases of the respiratory system, or symptoms related to said diseases, in a mammal, wherein said mammal is a human being or an animal.
- said (a) is preferably sodium hyaluronate.
- said (b) is preferably chlorhexidine digluconate.
- diseases in particular are preferably selected from the group comprising or, alternatively, consisting of: rhinitis, allergic rhinitis, nasopharyngitis, cold, cough, nasal congestion, accumulation of nasal mucus, flu, rhinosinusitis, sinusitis, pharyngitis, epiglottitis, laryngitis, tracheitis, bronchitis, bronchiolitis and bronchiectasis.
- hyaluronic acid or a salt thereof is present in an amount comprised from 0.001% to 30%, preferably in an amount comprised from 0.005% to 20%, more preferably in an amount comprised from 0.01% to 10%, even more preferably comprised from 0.02% to 2%, on the total weight or volume of the composition
- chlorhexidine or a salt thereof is present in an amount comprised from 0.01% to 40%, preferably in an amount comprised from 0.05% to 30%, more preferably in an amount comprised from 0.1% to 20%, even more preferably comprised from 0.1% and 3%, on the total weight or volume of the composition
- methylsulfonylmethane (MSM) is present in an amount comprised from 0.05% to 35%, preferably in an amount comprised from 0.1% to 25%, more preferably comprised from 0.5% to 15%, even more preferably comprised from 0.5% to 5%, on the total weight or volume of the composition.
- the dosage form may preferably be a pharmaceutical composition or a medical device or a cosmetic or food supplement a food for special medical purposes or a dietary supplement, a food for special medical purposes or a complementary feed including the aforementioned active ingredients mixed to each other. More preferably, said composition is a medical device composition, a pharmaceutical composition, or a food for special medical purposes.
- the preferred route of administration is nasal, topical, inhalation, oral.
- composition is preferably for topical, nasal, oral or inhalation use.
- the pharmaceutical forms which can be used according to the present invention will preferably be nasal sprays, vials for nasal instillation, vials for inhalation through aerosol, nasal drops, nasal creams, nasal ointments or other pharmaceutical forms suitable for nasal, topical, inhalation, oral administration. More preferably, said composition is in liquid form for topical nasal use, preferably nasal spray, liquid form for nasal instillation, nasal cream, nasal ointment, or in liquid form for inhalation through aerosol.
- said composition is selected from the following (A), (B) or (C):
- composition is a spray for nasal application and wherein, with respect to a total weight or volume of said composition:
- the hyaluronic acid or a salt thereof is in an amount comprised from 0.03% to 1%, preferably comprised from 0.04% to 0.5%;
- the chlorhexidine or a salt thereof is present in an amount comprised from 0.12% to 2%, preferably comprised from 0. 13% to 1 %;
- the methylsulfonylmethane (MSM) is present in an amount comprised from 0.5% to 3%, preferably comprised from 0.5% to 2%; or
- composition is in liquid form for nasal instillation and wherein, with respect to a total weight or volume of said composition:
- the hyaluronic acid or a salt thereof is in an amount comprised from 0.02% to 1%, preferably comprised from 0.02% to 0.2%;
- the chlorhexidine or a salt thereof is present in an amount comprised from 0.13% to 1%, preferably comprised from 0. 15% to 0.5%;
- the methylsulfonylmethane (MSM) is present in an amount comprised from 0.5% to 3%, preferably comprised from 0.8% to 2%; or
- composition is in liquid form for inhalation through aerosol and wherein, with respect to a total weight or volume of said composition:
- the hyaluronic acid or a salt thereof is in an amount comprised from 0.02% to 1%, preferably comprised from 0.02% to 0.2%;
- the chlorhexidine or a salt thereof is present in an amount comprised from 0.05% to 3%, preferably comprised from 0.05% to 0.1 %;
- the methylsulfonylmethane (MSM) is present in an amount comprised from 0.1% to 5%, preferably comprised from 0. 15% to 2%.
- Suitable excipients may be selected from those normally known in the state of the art and include, but are not limited to: diluents (e.g. dibasic calcium phosphate, lactose, microcrystalline cellulose and cellulose derivatives), thickeners (for example gums, hydroxypropyl methylcellulose and other cellulose derivatives), sweeteners (for example sorbitols, mannitol and other polyols, acesulfame K, aspartame, cyclamates, saccharin, sucralose), lubricants (for example magnesium stearate, stearic acid, waxes), dispersants, surfactants (for example sodium lauryl sulfate and polysorbates), flavour enhancement agents, adsorbents (for example silica gel, talc, starch, bentonite, kaolin), glidants and antiadherents (for example talc, colloidal silica, corn starch, silicon dioxide), colorants (for
- Example 1 spray for nasal application
- Example 3 drops for nasal application
- Example 4 vials for nasal instillation
- Example 5 solution for inhalation application through aerosol EXPERIMENTAL PART
- the experimental groups differ in the group treated with single substance, group treated with combination of substances and control group.
- 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 attachment, inlet, "uncoating”, replication, assembly, release etc.
- Antimicrobial activity is evaluated on the main bacterial strains belonging to the categories of Gram positive and/or Gram negative and/or other microbial species.
- In vitro assays such as for example broth-dilution (the sensitivity of the microorganism is evaluated based on the growth or non-growth thereof in a culture medium at different concentrations of the sample) and diffusion into agar (where a standardised concentration of the sample is applied in a bacterial broth-culture and the diffusivity of the sample in the medium is calculated) are suitable to demonstrate the antibacterial efficacy of the composition according to the present invention.
- In vitro assays which evaluate the ability to inhibit the release of inflammatory cytokines such as IL-1, IL-6 and TNF-o and to inhibit the expression of enzymes such as COX-2 and IL-1 p-induced metalloprotease- 13 in primary cultures of human cells (for example macrophages, chondrocytes, fibroblasts or others) are suitable to demonstrate the anti-inflammatory efficacy of the composition according to the present invention.
- immunomodulating 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.
- In vitro assays such as for example DPPH tests, radical scavenging activity on nitric oxide or peroxynitrite radical, TEAC (total radical-trapping antioxidant parameter), FRAP (ferric reducing-antioxidant power), HORAC (hydroxyl radical averting capacity), ORAC (oxygen radical absorbance capacity) tests and the like, are suitable to demonstrate the antioxidant efficacy of the composition according to the present invention.
- the antioxidant activity can also be evaluated by means of cell tests known to the person skilled in the art.
- An experimental protocol for evaluating the efficacy of the composition subject of the present invention provides for the following activities:
- a composition comprising a combination of hyaluronic acid or a salt thereof, chlorhexidine or a salt thereof, and methylsulfonylmethane (MSM).
- composition according to E1 wherein hyaluronic acid or a salt thereof is present in an amount comprised between 0.001% and 30%, more preferably in an amount comprised between 0.005% and 20%, even more preferably in an amount comprised between 0.01% and 10% on the total weight or volume of the composition.
- MSM methylsulfonylmethane
- composition according to any one of E1-E4, wherein the composition is a medical device, a cosmetic, a dietary supplement, a nutraceutical, dietetic and nutritional composition, a food product, a beverage, a nutraceutical, a medicament, a medicated food, a pharmaceutical composition, a food for special medical purposes, a complementary feed.
- E6 Composition according to any one of E1-E5 effective in the prevention and/or in the treatment of diseases of the respiratory system and related symptoms both in humans and animals.
- E7 Composition according to any one of E1-E6, wherein diseases associated with the respiratory system are: rhinitis, allergic rhinitis, nasopharyngitis or cold, cough, nasal congestion, accumulation of nasal mucus, flu, rhinosinusitis, sinusitis, pharyngitis, epiglottitis, laryngitis, tracheitis, bronchitis, bronchiolitis and bronchiectasis.
- composition comprising an association or a combination or a mixture comprising or, alternatively, consisting of:
- methylsulfonylmethane MSM
- optionally food or pharmaceutical grade additives or excipients optionally food or pharmaceutical grade additives or excipients.
- composition according to F2 wherein, with respect to a total weight or volume of said composition:
- the hyaluronic acid or a salt thereof is in an amount comprised from 0.001% to 30%, preferably comprised from 0.005% to 20%, more preferably comprised from 0.01% to 10%, even more preferably comprised from 0.02% to 2%;
- the chlorhexidine or a salt thereof is present in an amount comprised from 0.01% to 40%, preferably comprised from 0.05% to 30%, more preferably comprised from 0.1% to 20%, even more preferably comprised from 0. 1 % to 3%;
- the methylsulfonylmethane (MSM) is present in an amount comprised from 0.05% to 35%, preferably comprised from 0.1% to 25%, more preferably comprised from 0.5% to 15%, even more preferably comprised from 0.5% to 5%.
- composition according to F3 wherein said composition is in liquid form for topical nasal use, preferably nasal spray, liquid form for nasal instillation, nasal cream, nasal ointment, or in liquid form for inhalation through aerosol.
- composition is a spray for nasal application and wherein, with respect to a total weight or volume of said composition: (a) the hyaluronic acid or a salt thereof is in an amount comprised from 0.03% to 1%, preferably comprised from 0.04% to 0.5%;
- the chlorhexidine or a salt thereof is present in an amount comprised from 0.12% to 2%, preferably comprised from 0. 13% to 1 %;
- the methylsulfonylmethane (MSM) is present in an amount comprised from 0.5% to 3%, preferably comprised from 0.5% to 2%; or
- composition is in liquid form for nasal instillation and wherein, with respect to a total weight or volume of said composition:
- the hyaluronic acid or a salt thereof is in an amount comprised from 0.02% to 1%, preferably comprised from 0.02% to 0.2%;
- the chlorhexidine or a salt thereof is present in an amount comprised from 0.13% to 1%, preferably comprised from 0. 15% to 0.5%;
- the methylsulfonylmethane (MSM) is present in an amount comprised from 0.5% to 3%, preferably comprised from 0.8% to 2%; or
- composition is in liquid form for inhalation through aerosol and wherein, with respect to a total weight or volume of said composition:
- the hyaluronic acid or a salt thereof is in an amount comprised from 0.02% to 1%, preferably comprised from 0.02% to 0.2%;
- the chlorhexidine or a salt thereof is present in an amount comprised from 0.05% to 3%, preferably comprised from 0.05% to 0.1 %;
- the methylsulfonylmethane (MSM) is present in an amount comprised from 0.1% to 5%, preferably comprised from 0. 15% to 2%.
- F6 The composition according to any one of F1-F5, wherein said (a) is sodium hyaluronate.
- F7 The composition according to any one of F1-F6, wherein said (b) is chlorhexidine digluconate.
- F8 The composition according to any one of F1-F7, wherein the composition is a medical device composition, a pharmaceutical composition, or a food for special medical purposes.
- F9 The composition according to any one of F1-F8, wherein said composition is for use in a method for the prevention or treatment of diseases of the respiratory system, or symptoms related to said diseases, in a mammal, wherein said mammal is a human being or an animal.
- composition for use according to F9 wherein said diseases of the respiratory system are selected from the group comprising or, alternatively, consisting of: rhinitis, allergic rhinitis, nasopharyngitis or cold, cough, nasal congestion, accumulation of nasal mucus, flu, rhinosinusitis, sinusitis, pharyngitis, epiglottitis, laryngitis, tracheitis, bronchitis, bronchiolitis and bronchiectasis.
- diseases of the respiratory system are selected from the group comprising or, alternatively, consisting of: rhinitis, allergic rhinitis, nasopharyngitis or cold, cough, nasal congestion, accumulation of nasal mucus, flu, rhinosinusitis, sinusitis, pharyngitis, epiglottitis, laryngitis, tracheitis, bronchitis, bronchiolitis and bronchiectasis.
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IT102020000025963A IT202000025963A1 (it) | 2020-11-02 | 2020-11-02 | “composizione per la prevenzione e il trattamento di affezioni dell’apparato respiratorio” |
PCT/IB2021/060124 WO2022091067A1 (en) | 2020-11-02 | 2021-11-02 | Composition for use in the prevention and treatment of diseases of the respiratory system |
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EP4236930A1 true EP4236930A1 (en) | 2023-09-06 |
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EP21814876.5A Pending EP4236930A1 (en) | 2020-11-02 | 2021-11-02 | Composition for use in the prevention and treatment of diseases of the respiratory system |
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EP (1) | EP4236930A1 (it) |
IT (1) | IT202000025963A1 (it) |
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US20080102107A1 (en) * | 2005-12-16 | 2008-05-01 | Valex Pharmaceuticals, Llc | Compositions and methods for transdermal joint pain therapy |
ITMI20111005A1 (it) * | 2011-06-01 | 2012-12-02 | Bruschettini Srl | Composizioni oftalmiche ad azione antiossidante, protettiva e antidegenerativa per i tessuti oculari |
US10398723B1 (en) * | 2015-02-23 | 2019-09-03 | Viscos, LLC | Hyaluronan-containing composition and use thereof for mitigation and/or prevention of inflammation and/or pain |
DE202016100357U1 (de) * | 2016-01-27 | 2016-03-09 | Peter Sommer | Pharmazeutische Zubereitung und deren Verwendung bei viralen, entzündlichen Erkrankungen der oberen Atemwege |
IT201700117361A1 (it) * | 2017-10-17 | 2019-04-17 | Alfakjn S R L | Composizione liquida per uso come antiinfiammatorio |
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