WO2004072272A1 - Compositions bactériennes - Google Patents

Compositions bactériennes Download PDF

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Publication number
WO2004072272A1
WO2004072272A1 PCT/NZ2004/000025 NZ2004000025W WO2004072272A1 WO 2004072272 A1 WO2004072272 A1 WO 2004072272A1 NZ 2004000025 W NZ2004000025 W NZ 2004000025W WO 2004072272 A1 WO2004072272 A1 WO 2004072272A1
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WIPO (PCT)
Prior art keywords
composition
salivarius
formulation
salivaricin
otitis media
Prior art date
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PCT/NZ2004/000025
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English (en)
Inventor
John Robert Tagg
Tony Martin Walls
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Blis Technologies Limited
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Publication of WO2004072272A1 publication Critical patent/WO2004072272A1/fr

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    • 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
    • A61K9/007—Pulmonary tract; Aromatherapy
    • A61K9/0073—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • A61K31/429—Thiazoles condensed with heterocyclic ring systems
    • A61K31/43—Compounds containing 4-thia-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula, e.g. penicillins, penems
    • 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
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7048—Compounds having saccharide radicals and heterocyclic rings having oxygen as a ring hetero atom, e.g. leucoglucosan, hesperidin, erythromycin, nystatin, digitoxin or digoxin
    • 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
    • A61K35/66—Microorganisms or materials therefrom
    • A61K35/74—Bacteria
    • A61K35/741—Probiotics
    • A61K35/744—Lactic acid bacteria, e.g. enterococci, pediococci, lactococci, streptococci or leuconostocs
    • 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
    • A61K38/164—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from bacteria
    • 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
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/19—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles lyophilised, i.e. freeze-dried, solutions or dispersions
    • 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
    • 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
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N1/00—Microorganisms, e.g. protozoa; Compositions thereof; Processes of propagating, maintaining or preserving microorganisms or compositions thereof; Processes of preparing or isolating a composition containing a microorganism; Culture media therefor
    • C12N1/20—Bacteria; Culture media therefor
    • C12N1/205—Bacterial isolates
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12R—INDEXING SCHEME ASSOCIATED WITH SUBCLASSES C12C - C12Q, RELATING TO MICROORGANISMS
    • C12R2001/00—Microorganisms ; Processes using microorganisms
    • C12R2001/01—Bacteria or Actinomycetales ; using bacteria or Actinomycetales
    • C12R2001/46—Streptococcus ; Enterococcus; Lactococcus

Definitions

  • This invention relates to the treatment of otitis media. More particularly, it relates to prophylactic and therapeutic treatment of patients in need of same. Also provided are compositions and organisms useful in these methods of treatment.
  • Acute otitis media is the most common bacterial infection in growing children.
  • Causative bacteria identified include S. pneumoniae, S, pyogenes, M. catarrhalis, and H. in ⁇ uenzae. It is thought that the bacteria infect the middle ear via the eustacean tube, from the nasopharynx.
  • Common approaches to treatment are use of antibiotics or insertion of tympanostomy tubes. The former approach is questionable on the grounds of antibiotic resistance, and weakening of the natural host defence system, i.e. reduction in number of normal desirable bacteria. The latter is costly and carries risks where it is performed under general anaesthesia, and can result in membrane damage. Alternate approaches to treatment have therefore been explored. These include use of normal flora in the airways to control pathogens.
  • AHS inhibitory alpha-hemolytic streptococci
  • S. mitis S. sanguis
  • S. oralis Treatment resulted in those children having fewer episodes of AOM. It appears that this result is attributable to increasing the proportion of inhibitory bacteria in the normal flora that are competitive.
  • the AHS employed in the nasal spray are also recognised human pathogens. For example, S. oralis and S. sanguis are implicated in endocarditis. S. mitis is implicated in lung infections, tooth decay, and abscesses.
  • S. salivarius is a non-pathogenic organism which meets these requirements. While S. salivarius has previously been identified in the oral cavity, the isolation of several bacteriocin producing strains from the nasopharynx is believed to be unique. Moreover, while S. salivarius with activity against S. pyogenes and S. pneumoniae have previously been identified, the strains provided by the applicant exhibit broader spectrum activity, including against the gram-negative bacteria M. catarrhalis and H. influenzae.
  • the present invention relates to a biologically pure culture of S. salivarius strain No. 30 on deposit at Deutsche Sammlung von Mikroorganism Und Zellkulturen GmbH, Brawnschweig, Germany under Accession No. DSM 14686.
  • the present invention provides an antibacterial composition which includes an organism as defined above.
  • the invention further provides a therapeutic formulation comprising an organism as defined above in combination with a diluent, carrier and/or excipient.
  • the invention provides a composition formulated for respiratory administration, the composition comprising:
  • the invention provides a therapeutic composition effective for prophylactic or therapeutic treatment of otitis media in a patient, the composition comprising:
  • the salivaricin protein is a Salivaricin A, or Salivaricin B.
  • the invention also provides a prophylactic or therapeutic method of treating a patient to at least inhibit the growth of one or more otitis media causing bacteria comprising the step of administering an effective amount of an organism or composition of the invention to said patient.
  • the bacteria are present in the nasopharynx, or oral cavity.
  • said method includes a preliminary step of pre-treating said patient to at least reduce the bacterial population present in the upper airways, or oral cavity.
  • said pre-treatment comprises the step of administering an antimicrobial or antibiotic, preferably erythromycin, orally to said individual.
  • the invention provides a method of treatment of a patient against otitis media which comprises the steps of:
  • the present invention provides novel S. salivarius strains useful in the treatment or prevention of chronic and acute sinusitis, otitis media, including secretory, chronic and particularly acute otitis media.
  • BLIS Bacteriocin-like inhibitory substance
  • S. salivarius was isolated from the oral cavity.
  • S. salivarius is not an organism commonly associated with the nasopharynx except in very young children.
  • BLIS production by S. salivarius in the nasopharynx been reported.
  • the applicant has therefore surprisingly now isolated a number of BLIS-producing strains from the nasopharynx.
  • these strains exhibit a broad spectrum of activity, including strong inhibitory activity in vitro against S. pyogenes, S. pneumoniae, M. catarrhalis and H. influenzae, the key causative bacteria in otitis media.
  • the new S. salivarius strains are also non-pathogenic and are generally recognised as non-haemolytic.
  • a preferred strain No. 30 has been deposited at Deutsche Sammlung von Mikroorganism Und Zellkulturen GmbH, Brawnschweig, Germany under Accession No. DSM 14686 on 14 December 2001. Usually, this strain has genes encoding both a Salivaricin A and Salivaricin B and is strongly inhibitory of nasopharyngeal streptococcus, as well as M. catarrhalis and H. influenzae. Two of three control subjects (but no test subjects with recurrent otitis media) had this strain in the nasopharynx, but not on the tongue. This is contrary to customary observation that S. salivarius strains preferably localise on the tongue.
  • the S. salivarius are useful in the treatment of otitis media.
  • the organisms may be formulated in a composition or therapeutic formulation which further includes a diluent, carrier and/or excipient.
  • a diluent, carrier and/or excipient included in the term "therapeutic" includes prophylactic formulations.
  • compositions and formulations are suitable for use in the treatment or prevention of microbial infections, caused by streptococcus, moraxella, and hemophilus organisms.
  • the compositions and formulations are particularly suitable for use against S. pyogenes, S. pneumoniae, M. catarrhalis and H. influenzae.
  • examples of compositions and formulations in which the organisms can be employed include orally administrable medicaments such as capsules, lozenges, syrups and gargles, and topically administrable formulations such as creams and cosmetics and respiratorally administrable medicaments. As noted above, this encompasses administration intranasally and by inhalation through the mouth. For example, nasal sprays, and nebuliser formulations.
  • One currently preferred form is a chewable or suckable lozenge.
  • compositions formulated for oral or respiratory administration which comprise one or more salivaricin proteins, and/or one or more organisms capable of expressing a salivaricin protein.
  • the proteins and organisms are effective against one or more otitis media causing bacteria.
  • respiratorally or orally formulated compositions are founded on the applicants surprising finding that they are active against otitis media causing organisms in the nasopharynx or oral cavity. Such compositions have not previously been produced.
  • S. salivarius are being administered, they are preferably provided in freeze dried form.
  • the cells may be reconstituted in liquids such as water and saline.
  • the composition will contain between about 1 x 10 4 and 1 x 10 10 colony forming units (CFU) per ml, preferably about 5 x 10 8 CFU/ l.
  • CFU colony forming units
  • these compositions will also be formulated together with an acceptable carrier.
  • the selection of the carrier will be dependent upon the formulation and mode of dispensing involved, but will in any case be a matter of routine choice for the skilled worker in this field.
  • suitable carriers may be isomalt or skim milk. Tableting aids, excipients, flavourings, and colourings may also be employed as appropriate.
  • the presently preferred orally administerable formulations are blends of freeze-dried S. salivarius with skim milk powder.
  • the formulation may also include a propellant.
  • a propellant for example, a propellant for a propellant.
  • Powders, solutions, and suspensions are also possible.
  • Optional but preferred components include non-toxic detergents or surfactants, for example, a Polysorbate.
  • Also provided by the invention is a method for at least inhibiting the growth of one or more otitis media causing bacteria as identified above. Treatment may be carried out by administering an effective amount of an organism or composition of the invention to a patient in need thereof.
  • Treatment may be prophylactic or therapeutic.
  • Therapeutic treatment encompasses preventing or reducing the severity of, or associated with the symptoms of otitis media.
  • Prophylactic treatment means treatment of a non-sufferer to prevent or at least reduce the likelihood of that individual suffering from otitis media or associated symptoms.
  • Treatment will be effected by administering the organisms, compositions, and formulations to the bacteria present in the upper respiratory tract, or oral cavity. Treatment may be repeated as required. For example, lozenges may be used three or four times a day, or as little as once a year as the need arises.
  • the new S. salivarius strains can also be used as alternatives to known S. salivarius strains in the inhibition of other bacteria on which they are known to be effective. See, for example, WO 01/27143 entitled "Lantibiotic”.
  • the new organisms may similarly be employed in the compositions and formulations identified in that specification.
  • the methods of treatment may include a step of pre-treating the patient to at least reduce the population of normal microflora including the bacteria to be inhibited, for example in the upper airways or oral cavity.
  • Pre-treatment may be effected by antibiotic administration.
  • An example of a suitable antimicrobial is clorhexidine.
  • Known antibiotics such as erythromycin, amoxycillin and phenoxymethyl penicillin may be used, particularly for oral administration to the patient.
  • the present example compares the BLIS activities against potential AOM pathogens of streptococcal isolates from the nasopharyngeal and oral microfloras of children who do or do not have recurrent AOM.
  • a nasopharyngeal swab was taken from each nostril using a sterile calcium alginate swab.
  • a catheter enclosing the swab was passed through the anterior nares to minimise contamination.
  • the tip of the swab was then pushed through the end of the catheter and rubbed against the posterior wall of the nasopharynx. Before the catheter was removed from the nose, the tip of the swab was retracted. The catheter tip was then cut off with sterile scissors before re- exposing the swab and plating the microflora sample directly onto the appropriate agar media.
  • a tongue swab was taken at the time to provide a sample for analysis of the subject's oral streptococcal population. All of the freshly inoculated agar plates were transported to the lab for incubation within two hours.
  • the nasopharyngeal specimens were plated directly onto (i) Mitis Salivarius agar (Difco Laboratories), a selective medium for streptococci and (ii) chocolate agar (Columbia Agar Base (GIBCO) plus 5% human blood, heated to lyse the erythrocytes prior to pouring into petri dishes) to provide a "total microflora" population.
  • the cultures were grown anaerobically at 35°C for 18 hours. From each Mitis Salivarius agar culture, up to five morphologically distinctive colonies were selected and plated onto blood agar (Columbia Agar Base (GIBCO) plus 5% human blood).
  • the mixed bacterial populations recovered from the tongue and the nasopharygeal swabbings were also tested by this method as a screen for BLIS activity.
  • the deferred antagonism method has been described previously. 2 It involves first incubating a 1-cm wide diametric strip of the test bacteria anaerobically at 35°C for 18 hours on the test agar plate. The streak culture is then scraped from the surface of the medium and the agar surface is sterilised by inversion for thirty minutes over a chloroform-infused cloth.
  • bacterial inhibition was considered significant if the zone of inhibition of the indicator streak growth was at least twice the width of the original test streak. Isolates significantly inhibiting the growth of either one or both of the two representative strains of each species of AOM pathogens were considered to be inhibitory to that species.
  • the indicator strains used as representative of species commonly associated with AOM were Streptococcus pneumoniae PK2 and PK34 , S. pyogenes FF22 and 71-698, Moraxella catarrhalis 4 and 22, and Haemophilus influenzae 30 and 33.
  • the S. pneumoniae, M. catarrhalis and H. influenzae indicator strains were clinical isolates taken from the middle ear of children with AOM.
  • the S. pyogenes strains were reference isolates used commonly in this laboratory as indicators of streptococcal BLIS. 2
  • the inhibitory isolates were tested to determine their BLIS P-type activity against a set of nine standard indicator strains (11-19) to enable comparison of their inhibitory activities with those of previously-studied BLIS-positive streptococci. 2
  • Salivaricin A SrtAfwd AAGACTTTGATCTCGATTTGAA; SrtArev AAACTAATTTCCAACAAGAACCA
  • Salivaricin B SalB: SalBfwd GTGAATTCTCTTCAAGAATTGACTCTT; SalBrev
  • DNA extracts from the mixed microfloras from the Mitis Salivarius tongue cultures were also tested by PCR using the salivaricin A and salivaricin B primers as a means of detecting the presence of small numbers of salivaricin-producers in the oral microbiota.
  • BLIS-producing streptococcal isolates were characterised initially on the basis of their colony appearance on Mitis Salivarius and blood agar media and on their biochemical profiles (API 20 Strep, BioMerieux, France).
  • Table 1 Number of subjects having streptococcal isolates inhibitory to strains of AOM pathogens in deferred antagonism tests on TSYCa
  • AOM species Subjects having isolates inhibitory to indicator strains of the stated species of AOM pathogens
  • Streptococcus 5 (25) 2 (13) 0.67 pneumoniae Streptococcus pyogenes 5 (25) 2 (13) 0.67 Moraxella catarrhalis 10 (50) 7 (47) 0.88 Haemophilus influenzae 2 (10) 2 (13) 0.81 Streptococcal isolates from six children (3 controls and 3 AOM group) were inhibitory to both representative strains of at least three of the species of OM pathogens (Table 2 below). Of these six inhibitory isolates, two were S. pneumoniae, one was S. pyogenes (emm-type 11) and 3 were S. salivarius. Both direct culture and PCR analysis of the extracted DNA failed to demonstrate the presence of BLIS-producing S. pyogenes or S.
  • S. salivarius strain 44 had inhibitory activity consistent with production of the bacteriocin salivaricin A, and by PCR was positive for the appropriate structural gene, salA. What appeared to be the same strain of S. salivarius was detected by PCR and was also directly isolated in culture from the tongue flora of subject 44.
  • Table 2 Detection by PCR of salivaricin A and salivaricin B structural genes in strongly- inhibitory nasopharyngeal streptococcal isolates and in samples of the tongue microflora from these subjects
  • Streptococcus pneumoniae 25* Streptococcus salivarius 30* + + + Streptococcus pyogenes 38 ⁇ Streptococcus pneumoniae 40* + Streptococcus salivarius 44 * + + +
  • S. salivarius strains positive for both type A and B salivaricins may become established relatively more readily in the nasopharyngeal microbiota than in the oral cavity when compared with S. salivarius that are positive only for type A salivaricin.
  • S. salivarius that are positive for both salivaricins appear to be relatively more commonly isolated from the nasopharyngeal microbiotas of children who are not prone to develop AOM than from children who appear susceptible to this disease.
  • S. salivarius strains isolated from the oral cavity has been well documented n ' 12 and some of these strains are strongly inhibitory to the growth of S. pyogenes.
  • strain 30 isolated from nasopharyngeal specimens has inhibitory activity not only against S. pyogenes, but also against a range of other pathogens including the gram negative M. catarrhalis and H. influenzae. Since S. salivarius is considered to be essentially non-pathogenic it may be an excellent candidate for introduction into the normal nasopharyngeal flora as protection against recurrent AOM.
  • Strain 30 was isolated from the nasopharynx of a human subject. It grows on Mitis salivarius agar at 37°C, 5% CO 2 with morphology typical of S. salivarius as follows: Colony shape and size: round, 1-2 mm in diameter
  • the API 20 Strep Identification code for the strain is 5070450, which corresponds to Streptococcus salivarius (98.4% identity). 16s rRNA Sequence Analysis with reference to the GENEBANK database established the strain to be Streptococcus salivarius (99.9% homology).
  • Biochemical characterization of S. salivarius 30 was conducted using the API 20 Strep kit (bioMerieux) and API 50 CH (bioMerieux) to investigate carbohydrate metabolism.
  • the API 50 CH results are as follows:
  • Producer typing describes the antimicrobial activity of bacteria against a set of standard indicators. The procedure was first described by Tagg and Bannister (J. Med. Microbiol. 1979; 12: 397-411).
  • S. salivarius 30 was grown as a diametric streak culture on a Blood agar + 0.1% calcium carbonate plate or Trypticase soy-yeast extract-calcium carbonate agar (Trypticase soy broth, 30; yeast extract, 20 g; calcium carbonate, 2.5 g; agar, 15 g; distilled water, 1000 ml), incubated at 37°C, 5% CO 2 for 18 h. The growth was then removed and the surface of the plate sterilised with chloroform.
  • S. salivarius 30 has a 230 P-type on Blood agar + calcium carbonate, and a 360 P-type on Trypticase soy-yeast extract-calcium carbonate agar when incubated at 37°C, 5% CO 2 in air.
  • S. salivarius 30 has a 000 P-type on Blood agar + calcium carbonate, and a 777 P-type and Trypticase soy-yeast extract-calcium carbonate agar when incubated at 37°C, anaerobically.
  • the BLIS activity of S. salivarius 30 against a set of Otitis Media pathogens was carried out using the same procedure that was first described by Tagg and Bannister (J. Med. Microbiol. 1979; 12: 397-411), except the indicator strains were as follows: OMl Streptococcus pneumoniae PK2; OM2 S. pneumoniae PK34; OM3 Streptococcus pyogenes strain FF22; OM4 S. pyogenes strain 71-698; OM5 Moraxella catarrhalis 4; OM6 M. catarrhalis 22; OM7 Haemophilus influenzae 30; OM8 H influenzae 33; OM9 Micrococcus luteus T18.
  • S. salivarius 30 has only activity against one S. pyogenes indicator when grown on BACa, while has activity against all indicators when grown on TSYE agar (Table 4).
  • compositions for use in the methods are formulated for respiratory or oral administration.
  • the compositions comprise freeze dried S. salivarius BLIS producing strains with a respiratorially acceptable adjuvant, or are formatted as lozenges.

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Abstract

L'invention concerne une culture biologiquement pure de S. salivarius, des compositions antibactériennes contenant ladite culture et son utilisation dans le traitement de l'otite moyenne.
PCT/NZ2004/000025 2003-02-14 2004-02-13 Compositions bactériennes WO2004072272A1 (fr)

Applications Claiming Priority (4)

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NZ52418503 2003-02-14
NZ524185 2003-02-14
NZ52845803 2003-09-24
NZ528458 2003-09-24

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Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005007178A1 (fr) * 2003-07-18 2005-01-27 Blis Technologies Limited Methode servant a traiter la mauvaise haleine
WO2007144334A1 (fr) * 2006-06-13 2007-12-21 Nestec S.A. Prévention et traitement d'une otite moyenne par des souches bactériennes non pathogènes
WO2011125086A1 (fr) 2010-04-07 2011-10-13 D.M.G. Italia Srl Utilisation de streptococcus salivarius dans le cadre du traitement d'infections chroniques des voies respiratoires
EP3015109A1 (fr) 2014-10-28 2016-05-04 D.M.G. Italia Srl Barrière biologique avec siméthicone pour l'utilisation dans le traitement des infections naso-pharyngo-tubal
EP3015110A1 (fr) 2014-10-28 2016-05-04 D.M.G. Italia Srl Barrière biologique avec de la cystéine pour une utilisation dans le traitement d'infections naso-pharyngo-tubales
WO2021201699A1 (fr) * 2020-04-03 2021-10-07 Blis Technologies Limited Traitement antiviral comprenant des produits probiotiques contenant du blis

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Publication number Priority date Publication date Assignee Title
US3925160A (en) * 1974-09-26 1975-12-09 Univ Creighton Method of producing an antibiotic
WO2001027143A1 (fr) * 1999-10-12 2001-04-19 Blis Technologies Limited Lantibiotique
WO2003070919A1 (fr) * 2002-02-22 2003-08-28 Blis Technologies Limited Composition antimicrobienne

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3925160A (en) * 1974-09-26 1975-12-09 Univ Creighton Method of producing an antibiotic
WO2001027143A1 (fr) * 1999-10-12 2001-04-19 Blis Technologies Limited Lantibiotique
WO2003070919A1 (fr) * 2002-02-22 2003-08-28 Blis Technologies Limited Composition antimicrobienne

Non-Patent Citations (7)

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Title
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AU2004257553C1 (en) * 2003-07-18 2011-11-10 Blis Technologies Limited Treatment of malodour
WO2007144334A1 (fr) * 2006-06-13 2007-12-21 Nestec S.A. Prévention et traitement d'une otite moyenne par des souches bactériennes non pathogènes
WO2011125086A1 (fr) 2010-04-07 2011-10-13 D.M.G. Italia Srl Utilisation de streptococcus salivarius dans le cadre du traitement d'infections chroniques des voies respiratoires
EP3015109A1 (fr) 2014-10-28 2016-05-04 D.M.G. Italia Srl Barrière biologique avec siméthicone pour l'utilisation dans le traitement des infections naso-pharyngo-tubal
EP3015110A1 (fr) 2014-10-28 2016-05-04 D.M.G. Italia Srl Barrière biologique avec de la cystéine pour une utilisation dans le traitement d'infections naso-pharyngo-tubales
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