EP2908911A1 - Zusammensetzungen mit einem silbersalz von saccharoseoctasulfat und einem kaliumsalz von saccharoseoctasulfat zum schutz des schleimhautepithels - Google Patents

Zusammensetzungen mit einem silbersalz von saccharoseoctasulfat und einem kaliumsalz von saccharoseoctasulfat zum schutz des schleimhautepithels

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Publication number
EP2908911A1
EP2908911A1 EP13750887.5A EP13750887A EP2908911A1 EP 2908911 A1 EP2908911 A1 EP 2908911A1 EP 13750887 A EP13750887 A EP 13750887A EP 2908911 A1 EP2908911 A1 EP 2908911A1
Authority
EP
European Patent Office
Prior art keywords
sos
sucrose octasulfate
potassium salt
silver salt
composition
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.)
Withdrawn
Application number
EP13750887.5A
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English (en)
French (fr)
Inventor
Maria Cristina Comelli
Gabriella Calderini
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InterAlia Srl
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InterAlia Srl
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Filing date
Publication date
Application filed by InterAlia Srl filed Critical InterAlia Srl
Publication of EP2908911A1 publication Critical patent/EP2908911A1/de
Withdrawn legal-status Critical Current

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Classifications

    • 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
    • A61K31/7024—Esters of saccharides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A61K33/24—Heavy metals; Compounds thereof
    • A61K33/38—Silver; Compounds thereof
    • 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
    • A61K9/0034—Urogenital system, e.g. vagina, uterus, cervix, penis, scrotum, urethra, bladder; Personal lubricants
    • 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
    • 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
    • A61K9/0048—Eye, e.g. artificial tears
    • 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
    • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
    • A61K9/006—Oral mucosa, e.g. mucoadhesive forms, sublingual droplets; Buccal patches or films; Buccal sprays
    • 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
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/10—Antimycotics
    • 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
    • A61K9/06—Ointments; Bases therefor; Other semi-solid forms, e.g. creams, sticks, gels
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/10—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices containing or releasing inorganic materials
    • A61L2300/102—Metals or metal compounds, e.g. salts such as bicarbonates, carbonates, oxides, zeolites, silicates
    • A61L2300/104—Silver, e.g. silver sulfadiazine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/20—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices containing or releasing organic materials
    • A61L2300/23—Carbohydrates
    • A61L2300/232—Monosaccharides, disaccharides, polysaccharides, lipopolysaccharides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/40—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a specific therapeutic activity or mode of action
    • A61L2300/404—Biocides, antimicrobial agents, antiseptic agents

Definitions

  • compositions comprising a silver salt of sucrose octasulfate and a potassium salt of sucrose octasulfate for protection of mucosal epithelia
  • the present invention relates to compositions based on the association of a sucrose octasulfate silver salt [(SOS) " (Ag) + ] and of a sucrose octasulfate potassium salt [(SOS) " (K) + ] providing a synergistic antimicrobial and anti-microbial adhesion activity and to the use thereof for the achievement of an efficient protection of mucosal epithelia against infections.
  • the compositions can be particularly useful for the prevention and treatment of mucosal affections where biofilm-former microbial strains are involved.
  • Mucosal membranes are sheets of epithelial tissues covering the internal cavities of an organism; such cavities are always somehow in contact with the external environment and thus exposed to microbial contamination.
  • mucosal epithelia are naturally provided with efficient protective physico-chemical systems consisting mainly of cilia, fluids, mucous secretions, proteolytic enzymes and bacteriocins, beside the immune response.
  • protective physico-chemical systems consisting mainly of cilia, fluids, mucous secretions, proteolytic enzymes and bacteriocins, beside the immune response.
  • these defense mechanisms they are frequently affected by more or less threatening microbial infections in the course of a human life.
  • microorganisms need as an essential first step, to "stick” to the surface of the target cell in order to resist the natural defensive mechanisms of the host (Pieters RJ, Intervention with bacterial adhesion by multivalent carbohydrates, Med. Res. Rev., 2007;27:796-816). Therefore, adherence is the "key” event in a microbial infection; it allows pathogens to get a better access to nutritional sources, facilitates the delivery of toxins into the cells of the host, favours deep penetration of microbial cells into the tissue and enhances the chance for microorganisms to organize the colony in a biofilm.
  • Biofilms are aggregates of microorganisms embedded within a self-produced polymeric matrix that protects microbial cells from the environment; this is the reason why often they are resistant to antibiotic treatment. When the microbial biofilm is mature, dispersion of "planktonic" cells allows colonization of new surfaces with spreading or recurrence of infections.
  • Disruption or inhibition of pathogen attachment to host cells by anti-adherence agents is considered an innovative and interesting approach to prevention and treatment of microbial infections (Ofek I et al ., Antiadhesion therapy of bacterial diseases: prospects and problems. FEMS Immunology and Medical Microbiology 2003;38:181 -191 ). Saccharides are considered among the promising molecules for a safe anti-adhesion approach since they are neither toxic nor immunogenic (Sharon N and Ofek I., Safe as mother's milk: carbohydrates as future anti- adhesion drugs for bacterial diseases. Glycoconjugate J., 2000;17:659-664).
  • sucralfate is a disaccharide well-known for its aluminum salt (e.g. sucralfate).
  • sucralfate is widely used for the treatment of gastro-intestinal ulcers. In acidic conditions, like those encountered in the stomach, this insoluble salt forms viscous gels and, then, adheres to the gastro-intestinal mucosal surface, promoting in this manner the protection thereof.
  • sucrose octasulfate as such has been shown to potentiate the Fibroblast Growth Factor (FGF) pathway not only by binding and stabilizing FGF but also by promoting FGF receptor dimerization.
  • FGF Fibroblast Growth Factor
  • sucrose octasulfate can also contribute to mucosal wound repair, beside physical barrier protection.
  • sucrose octasulfate could be considered a chemical analog of heparin, thus, potentially competing for the binding to the same cellular receptors.
  • LMWH Low Molecular Heparin
  • the sodium salt of sucrose octasulfate can effectively inhibit in vitro only the hemagglutination induced by P.
  • sucrose octasulfate silver salt [(SOS) " (Ag) + ] as antimicrobial compound is disclosed ( ⁇ 1458733).
  • the anti-microbial activity of the [(SOS) " (Ag) + ] on Staphylococcus aureus in comparison with a silver colloidal product (Katoxyn ® ) and silver sulphadiazine and the methods of preparation thereof are described.
  • silver has long been recognized for its broad- spectrum antimicrobial activity and widely used in a large number of different pathological conditions to prevent and/or cure microbial infections.
  • 0.5% silver nitrate or 1 % silver sulfadiazine are commonly applied to fight cutaneous Gram-negative infections not effectively controlled by conventional antibiotics.
  • Other silver based compounds, mainly ionisable salts, are currently available for clinical use, such as silver citrate, silver lactate or silver picrate.
  • silver citrate has been approved as preservative for cosmetic preparations and is currently used in various products. Colloid forms of silver are also available on the market; their antimicrobial activity depends not only on the total silver content, but on the amount of provided silver ions.
  • the silver salt of sucrose octasulfate can be a useful tool to meet the need of prevention and treatment of infections, and beyond acting as an antimicrobial agent, the silver sucrose octasulfate could potentially be endowed with a tissue repair promotion property as well.
  • the inventors have now found that the potassium salt of the disaccharide sucrose octasulfate is an effective inhibitor of bacterial adhesion to mammalian fibroblasts, i.e. to cells that are structural components of mammalian tissues in their native form, and whose surface is not modified by any enzymatic treatment, differently from the previous state of the art focusing on circulating cells enzymatically treated.
  • compositions based on the association of silver salt of sucrose octasulfate [(SOS) “ (Ag) + ] and potassium salt of sucrose octasulfate [(SOS) " (K) + ] result in a stronger synergistic protection from microbial colonization of mammalian tissues, than the one exerted by each component when used alone.
  • the stronger protection comes from the synergy between the antimicrobial activity of [(SOS) " (Ag) + ] and the inhibition of microbial adhesion to mammalian cells by [(SOS) " (K) + ].
  • association of the two compounds could also act synergically in the promotion of tissue repair and this biological property can be a further advantage in the clinical management of infected wounds of mucosal epithelia.
  • the present invention relates to a composition
  • a composition comprising a silver salt of sucrose octasulfate [(SOS) " (Ag) + ] and a potassium salt of sucrose octasulfate [(SOS) " (K) + ], said composition having a combined and synergistic antimicrobial and anti-microbial adhesion biological activity against infections of mucosal epithelia, and in particular including those sustained by biofilm-forming strains.
  • compositions object of the invention provide a safe, combined biological property against infection of mucosal epithelia, which results superior to the biological properties exerted by each compound of the association when used alone, thus making the association of [(SOS) " (Ag) + ] and [(SOS) " (K) + ] suitable for use in paraphysiological and pathological conditions of mucosa epithelia, as per nasal, genital, ocular and oral mucosae.
  • the invention relates to an use of a silver salt of sucrose octasulfate and a potassium salt of sucrose octasulfate for the preparation of compositions for prevention and treatment of mucosal infections and paraphysiological and pathological conditions associated thereof, or to a method of prevention and treatment of mucosal infections and paraphysiological and pathological conditions associated thereof comprising the administration to a subject in a need thereof of a composition comprising a silver salt and a potassium salt of sucrose octasulfate.
  • the mucosal infections for which the compositions of the invention can be used are infections sustained by bacteria, yeasts and fungi occurring in nasal, genital, ocular and oral (mouth) mucosae and the paraphysiological and pathological conditions associated thereof are symptomatological mucosal inflammation/congestion states, prone to the development and recurrence of infections.
  • the prevention and treatment of symptomatological mucosal inflammation/congestion states can be achieved facilitating the tissue repair from inflammation, thus recovering from subjective complaints and objective measures of altered functionality, and regaining health related quality of life (HRQoL).
  • compositions comprising [(SOS) “ (Ag) + ] and [(SOS) “ (K) + ] could be used for providing a surface antimicrobial coating of medical devices.
  • Figure 1 shows phase contrast microscopy images obtained with a Leica DM-II IMC microscope at 100x magnification: (a) control fibroblasts treated with 2% [(SOS) " (K) + ] indicated as KSOS; (b) fibroblasts + S. aureus; (c) fibroblasts + S. aureus treated with 2% [(SOS) " (K) + ] indicated as KSOS.
  • Figure 2 shows the evaluation of barrier effects towards microbial strains colonization in S. aureus cell cultures, (a) S. aureus control cultures; (b) S.
  • aureus cultures treated with the gel comprising [(SOS) " (K) + ] 1 .0% and [(SOS) " (Ag) + ] 0.010% expressed as silver ions.
  • the present invention relates to a composition
  • a composition comprising a silver salt of sucrose octasulfate [(SOS) " (Ag) + ] and a potassium salt of sucrose octasulfate [(SOS) " (K) + ], having a combined and synergistic antimicrobial and anti-microbial adhesion biological activity against infections of mucosal epithelia, including those produced by biofilm-forming strains.
  • the composition comprises the silver salt of sucrose octasulfate [(SOS) " (Ag) + ] and the potassium salt sucrose octasulfate [(SOS) " (K) + ] in an amount comprised in a range of: [(SOS) " (Ag) + ] expressed in ppm of Ag + from 10 ppm (corresponding to 0.001 % by weight) to 200 ppm (corresponding to 0.020% by weight) and [(SOS) " (K) + ] from 0.5% to 5% by weight (expressed in g/100g).
  • the preferred amount ranges are for [(SOS) " (Ag) + ], expressed in ppm of Ag + , from 25 ppm (corresponding to 0.0025% by weight) to 100 ppm (corresponding to 0.01 % by weight) and for [(SOS) " (K) + ] from 1 .0% to 2.5 % by weight.
  • the most preferred amounts of [(SOS) " (Ag) + ] and [(SOS) " (K) + ] are respectively 0.01 % expressed as Ag + by weight and 1 .0% by weight and 0.0025% expressed as Ag + by weight and 1 .5% by weight
  • compositions according to the invention can comprise [(SOS) " (Ag) + ], expressed as Ag + , in an amount in the range from 0.001 % to 0.02 % by weight and [(SOS) " (K) + ] in an amount in the range from 0.5% to 5% by weight.
  • compositions comprising [(SOS) “ (Ag) + ], expressed as Ag + , in an amount of 0.001 % by weight and in an amount [(SOS) “ (K) + ] of 0.5% by weight and compositions comprising [(SOS) " (Ag) + ], expressed as Ag + , in an amount of 0.02% by weight and in an amount [(SOS) " (K) + ] of 5% by weight are embodiments of the present invention.
  • compositions comprising [(SOS) " (Ag) + ], expressed as Ag + , in an amount in the range from 0.0025% to 0.01 % by weight and [(SOS) " (K) + ] in an amount in the range from of 1 .0% to 2.5% by weight.
  • compositions comprising [(SOS) “ (Ag) + ], expressed as Ag + , in an amount of 0.01 % by weight and [(SOS) " (K) + ] of 1 .0% by weight and a composition comprising [(SOS) " (Ag) + ], expressed as Ag + , in an amount of 0.0025% by weight and [(SOS) " (K) + ] of 1 .5% by weight.
  • compositions of the invention further comprise excipients and/or diluents compatible with silver ions selected from polysaccharides, non-ionic surfactants, weak organic acids, highly purified vegetable extracts and amino acids.
  • compositions can be added with ingredients chemically compatible with silver, such as glycerol, propylene glycol, carbopol, non-ionic surfactants, acidic polysaccharides, lactates, citrates, purified vegetable extracts and amino acids, as an example.
  • ingredients chemically compatible with silver such as glycerol, propylene glycol, carbopol, non-ionic surfactants, acidic polysaccharides, lactates, citrates, purified vegetable extracts and amino acids, as an example.
  • the preferred polysaccharide is hyaluronic acid, being this polysaccharide highly biocompatible and having as known healing property.
  • aqueous compositions in form of hydrogels and solutions can be preferred. Solutions at different ionic strength and pH can be prepared for nasal, ocular and oral application, while hydrogel with different viscosity and pH can be prepared for nasal, oral, and vaginal treatment.
  • the pH of the composition can be adjusted using sodium hydroxide, triethanolamine, EDTA or mild organic acid as lactic or citric acid, dependent upon the intended application on specific mucosae.
  • composition according to the invention can be more various; the composition can in fact contain, according to the different and final body district of application, the two sucrose octasulfate silver and potassium salts as a such or encapsulated in nanospheres and/or microspheres based on natural, semisynthetic, synthetic polymers or entrapped in cyclodextrins to obtain a slow release delivery system.
  • compositions can be in form of liquids, semi-solids or solids, containing excipients and/or diluents of pharmaceutical or cosmetic grade (for example solutions and aqueous, non-aqueous, hydro-alcoholic suspensions, drops, gels, emulsions, creams, ovules, powder sprays, sprays with or without propellants, foams).
  • excipients and/or diluents of pharmaceutical or cosmetic grade for example solutions and aqueous, non-aqueous, hydro-alcoholic suspensions, drops, gels, emulsions, creams, ovules, powder sprays, sprays with or without propellants, foams.
  • the [(SOS) " (K) + ] and [(SOS) " (Ag) + ], as a such or encapsulated in nanospheres and/or microspheres based on natural, semisynthetic, synthetic polymers or entrapped in cyclodextrins can be loaded upon inert biocompatible systems such as films, membranes, patches and dressings acting as slow release delivery systems, or can be incorporated into biomaterials, such as for example hydrogels, membranes, sponges, or into materials dissolving rapidly in aqueous environments. They can also be applied as protective antimicrobial coating on various kinds of medical devices.
  • compositions of the invention can be in form of spray, aerosol, drops, sachets, capsules, vaginal douches, mouth washes, plain solutions, any kind of multiple or single dose and any other suitable form of delivery available for the market for the application pursued.
  • compositions of the invention can be used in the prevention and treatment of mucosal infections and paraphysiological and pathological conditions associated thereof and in particular in mucosal infections sustained by biofilm-forming strains.
  • the mucosal infections for which the compositions of the invention can be used are infections sustained by bacteria, yeasts and fungi occurring in nasal, genital, ocular and oral (mouth) mucosae and the paraphysiological and pathological conditions associated thereof are symptomatological mucosal inflammation/congestion states, prone to the development and recurrence of infections.
  • the prevention and treatment of symptomatological mucosal inflammation/ congestion states can be further achieved also facilitating the tissue repair from inflammation, thus recovering from subjective complaints and objective measures of altered functionality, and regaining health related quality of life (HRQoL).
  • compositions comprising [(SOS) " (K) + ] and [(SOS) " (Ag) + ] of the invention can be usefully employed for prevention and treatment of mucosal infections and paraphysiological and pathological conditions associated thereof selected from sinonasal diseases of different etiology, such as common seasonal affections of obstruction and congestion of the upper respiratory tract, acute, acute-post viral, recurrent and chronic rhinosinusitis, otitis, oral mucosal ulcerations and periodontitis, ocular dryness as well as other ocular conditions such as corneal abrasions or ocular infections, cold mucosal sore and infections, and vaginal bacterial vaginosis and vaginitis, including those sustained or superinfected with Candida spp.
  • sinonasal diseases of different etiology such as common seasonal affections of obstruction and congestion of the upper respiratory tract, acute, acute-post viral, recurrent and chronic rhinosinusitis, otitis, oral mu
  • composition of the invention are for preventing and treating vaginal infections and recurrences thereof, including those sustained by Candida spp, vaginal biofilm formers difficult to eradicate and responsible of fastidious vaginitis symptoms.
  • Another preferred use is prevention and treatment of obstruction and congestion of the upper respiratory tract, with or without rhinosinusitis and/or nasal polyps, irrespective whether acute, acute post-viral, recurrent or chronic, and characterized by a persistent obstructive symptomatology since at least 10 days.
  • these can be of moderate severity as per VAS>5 for one of the primary symptoms nasal congestion, nasal obstruction and rhinorrea, or a VAS>5 for one of the primary symptoms and at least one of the secondary symptoms facial pain/pressure, reduction or loss of smell, headache.
  • compositions object of the invention of said obstructive rhinopathy can facilitate the recovery of health related quality of life and nasal patency with consequent improved respiration.
  • compositions containing the two sucrose-octasulfate salts [(SOS) “ (K) + ] and [(SOS) “ (Ag) + ] are shown for exemplificative and not-limiting purposes.
  • the antimicrobial and anti-adhesive activities and the tolerability and efficacy of compositions prepared are also reported.
  • [(SOS) " (K) + ] was preliminary dose-dependently tested for its capability to inhibit the adhesion of Staphylococcus aureus to mammalian tissue cells and to interfere on mammalian cells vitality.
  • Table 1 summarizes the results of the dose-dependent inhibitory effect of [(SOS) " (K) + ] on Staphylococcus aureus adherence to murine fibroblast 3T3, with no toxic effect on plated mammalian cells vitality.
  • Figure 1 shows the images obtained by phase contrast microscopy relative to the adhesion of Staphylococcus aureus, a microorganism known for its capability to form biofilm, to mammalian tissue cells, e.g. fibroblasts, after exposure to 2% [(SOS)-(K) + ].
  • Table 2 reports the microbiological analysis at 24 (bacteria) and 48 hours (yeast), of [(SOS) " (Ag) + ] alone in aqueous solutions at several dosages, demonstrating its bacteriostatic and bactericidal activity against various kind of pathogens, with the only exclusion of Staphylococcus aureus on which [(SOS) " (Ag) + ] acted as a bacteriostatic agent only.
  • fungi and yeasts for all of the various microorganisms tested only a fungistatic effect was observed and therefore only the Minimal Inhibitory Concentration (MIC) could be determined.
  • the data relative to the yeast Candida albicans only are reported in Table 2, indicating that concentration up to 139 ppm Ag + were not fungicidal .
  • MIC Minimum Inhibitory Concentration
  • MMC Minimum Microbiocidal Concentration
  • compositions comprising the association [(SOS) “ (K) + ] and [(SOS) “ (Ag) + ] and tolerability, efficacy and anti-adhesive studies
  • sucrose octasulfate silver and potassium salts [(SOS) " (Ag) + ] and [(SOS) " (K) + ] were used to prepare compositions according to the invention with other appropriate excipients and diluents. Due to high solubility in water of the two compounds, aqueous compositions were preferentially prepared, that is hydrogels and solutions. Different concentrations of the two active compounds were incorporated within the formulations.
  • Example 1 Mild hypertonic water solution for nasal application - osmolality between 380-420 mOsm/kg
  • Example 3 Mild hypertonic water solution for mouth washing - osmolality between 380-420 mOsm/kg
  • compositions comprising [(SOS) “ (Ag) + ] in concentrations ranging from 10-200 ppm of Ag + and [(SOS) " (K) + ] in concentrations from 0.5% to 5% can be prepared without any further burden by one skilled in the art.
  • compositions of examples 1 and 2 were tested in vitro for the assessment of the cytotoxicity on cells.
  • Example 6 In vitro cytotoxicity assay on the composition of example 1
  • Example 7 In vitro cytotoxicity assay on the composition of example 2
  • HaCaT cells were exposed for 24h to scalar amounts of the gel composition, ranging from 5 to 0.15 mg/ml.
  • Cells were next tested for viability by MTT ⁇ 3-[4,5-dimethylthiazol-2yl]-2,5-diphenyl tetrazolium bromide ⁇ incubation; the absorbance of the newly formed Formazan was then measured spectrophotometrically at 550nm. An increase or a decrease in cell number results in a corresponding change in the amount of Formazan formed, indicating the degree of cytotoxicity caused by the gel composition. Data collected on the vaginal gels are reported in Table 5, confirming the optimal safety of the composition.
  • Example 8 Anti-adhesive property of the composition of example 2
  • composition of the present invention against microbial colonization was found when a thin film of the composition was applied between two layers of agar forming a sandwich-like structure, with the bottom layer being sterile and the top soft agar containing a massive microbial inoculum of biofilm-forming pathogenic strains (e.g. S. aureus). Briefly, Petri dishes of 90 mm 0 were prepared with 10 ml of Plate Count Agar (PCA) on top of which the sample was uniformly spread at the following amounts: 130 mg (corresponding to 2 mg/cm 2 ),
  • composition of the present invention can also protect mucosal epithelia from the damaging effects induced by irritant molecules.
  • the assay was performed using tridimensional epithelial units reconstituted by airlifted cultures of transformed human keratinocytes, kept for 5 days in chemically defined medium on inert polycarbonate filters; 30 mg of the gel of example 2 was applied on the mucosal surface 2 h before a 15' exposure to 5% Sodium Lauryl Sulfate (SLS).
  • SLS Sodium Lauryl Sulfate
  • the epithelial units were washed with PBS and a further amount of sample was applied.
  • Exposure to the gel was carried out for 2 and 24h at 37°C and 5% CO2.
  • the product was removed, the tissue was washed with PBS and the MTT assay was performed to evaluate cell survival.
  • an Elisa assay was performed on the culture medium 6 h and 24 h after the irritant stress to evaluate the amount of IL-1 a released by the cells. Mucosal epithelia not treated with the gel were used as controls.
  • Example 10 In vivo tolerability and efficacy of the composition of example 1
  • N 25 outpatients of both genders, aged 18-70, affected by obstructive rhinopathy of different etiology, with or without rhino-sinusitis, lasting since 10 days in advance of enrollment and therefore suggestive of ongoing bacterial super-infection.
  • To better assess the stand-alone properties of the composition in sinonasal affections neither concomitant nor previous treatment (within one week from enrollment) with local and/or systemic corticosteroid, antibiotic, decongestants and nasal saline washe
  • Nasal obstruction as well as treatment efficacy was assessed by means of: a) Patient Related Outcome Measure (PROM), administered in the form of the validated linear 0-10 cm Visual Analog Score (VAS) and the Sino-Nasal Outcome Test 22 (SNOT-22) questionnaire, a disease- related symptoms scoring method validated for chronic rhino-sinusitis, with and without polyps; and b) Anterior Active Rhinomanometry (AAR) to measure the reduced nasal patency, expressed as nasal resistance to airflow in Pascal/ml/sec (Pa/ml/s).
  • PROM Patient Related Outcome Measure
  • VAS linear 0-10 cm Visual Analog Score
  • SNOT-22 Sino-Nasal Outcome Test 22
  • AAR Anterior Active Rhinomanometry
  • Enrolled patients should have been scored for moderate disease severity due to either a VAS > 5 for two of the primary symptoms: nasal congestion, nasal obstruction and Rhinorrea, or a VAS > 5 for one of the primary symptoms above + a moderate score for at least one of the secondary symptoms: facial pain/pressure, reduction or loss of smell.
  • a VAS > 5 does impact on health related quality of life (HRQoL; ref: EPOS 2012), and the validated 22-items Sino- Nasal Outcome Tests (SNOT-22), ranging from 0 (absence of symptoms) to 5 (the highest severity degree) is commonly applied to assess treatment efficacy and surgical outcome.
  • Clinical data indicates that the composition of the present invention, i.e.
  • Thick nasal discharge 1 .28 ⁇ 1 .1 0.56 ⁇ 0.8*
  • Table 8 shows that the composition as per example 1 decreased the objectively measured airflow resistance, indicating its capability to support mucosal functional repair from nasal obstruction and/or mucosal congestion.
  • the decrease in total nasal resistance further supports the concept that the composition-induced recovery from altered airflows (respiration) related to nasal obstruction and mucosal congestion, may be due to a decongestant, antiinflammatory activity of the composition.
  • compositions based on the specific association of [(SOS) " (Ag) + ] and [(SOS) " (K) + ] are devoid of toxicity and can be beneficially used as a preventive or therapeutic method to protect mucosal epithelia in many paraphysiological and pathological conditions of, and not limited to, obstruction and congestion of the upper respiratory pathways (e.g. common seasonal affections, acute, acute non-viral, recurrent, and chronic rhinosinusitis), vaginal bacterial vaginosis and vaginitis, otitis, oral mucosal ulcerations and periodontitis, ocular dryness as well as other ocular conditions, cold sore and skin infections. Finally, they could be used as protective antimicrobial coating on the surface of medical devices.
  • obstruction and congestion of the upper respiratory pathways e.g. common seasonal affections, acute, acute non-viral, recurrent, and chronic rhinosinusitis
  • vaginal bacterial vaginosis and vaginitis o

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EP13750887.5A 2012-10-17 2013-08-22 Zusammensetzungen mit einem silbersalz von saccharoseoctasulfat und einem kaliumsalz von saccharoseoctasulfat zum schutz des schleimhautepithels Withdrawn EP2908911A1 (de)

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US201261715226P 2012-10-17 2012-10-17
PCT/EP2013/067482 WO2014060138A1 (en) 2012-10-17 2013-08-22 Compositions comprising a silver salt of sucrose octasulfate and a potassium salt of sucrose octasulfate for protection of mucosal epithelia

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ITMI20012188A1 (it) * 2001-10-19 2003-04-19 Interalta S R L Sali d'argento del saccarosio - ottosolfato

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