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WO2020021052A2 - Utilisation d'alcools terpéniques acycliques pour améliorer l'activité antimicrobienne de la colistine - Google Patents

Utilisation d'alcools terpéniques acycliques pour améliorer l'activité antimicrobienne de la colistine Download PDF

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Publication number
WO2020021052A2
WO2020021052A2 PCT/EP2019/070153 EP2019070153W WO2020021052A2 WO 2020021052 A2 WO2020021052 A2 WO 2020021052A2 EP 2019070153 W EP2019070153 W EP 2019070153W WO 2020021052 A2 WO2020021052 A2 WO 2020021052A2
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Prior art keywords
colistin
acyclic terpene
microbial infection
terpene alcohol
mcr
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Ceased
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WO2020021052A3 (fr
Inventor
Frédéric TEWES
Chantal VALCOURT
William COUET
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Institut National de la Sante et de la Recherche Medicale INSERM
Universite de Poitiers
Centre Hospitalier Universitaire de Poitiers
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Institut National de la Sante et de la Recherche Medicale INSERM
Universite de Poitiers
Centre Hospitalier Universitaire de Poitiers
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Publication of WO2020021052A3 publication Critical patent/WO2020021052A3/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
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/51—Nanocapsules; Nanoparticles
    • A61K9/5107—Excipients; Inactive ingredients
    • A61K9/5123—Organic compounds, e.g. fats, sugars
    • 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
    • A61K31/045—Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/12—Cyclic peptides, e.g. bacitracins; Polymyxins; Gramicidins S, C; Tyrocidins A, B or C
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • 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
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

  • the present invention relates to use of acyclic terpene alcohols for enhancing the antimicrobial activity of colistin.
  • Colistin is an old polypeptide antibiotic widely used in food-producing animals, particularly in pig production as oral group treatment and metaphylaxis against Enterobacteriaceae digestive infections after weaning.
  • the use of colistin has been limited in the past because of its nephrotoxicity, however its use is nowadays recommended as a last resort for the treatment of multidrug-resistant bacteria.
  • MCR-l transferable plasmid-encoded colistin resistance gene MCR-l (Liu, Y. Y. et ai: The Lancet infectious diseases. 2016, 16(2), 161-168 )
  • MCR-l transferable plasmid-encoded colistin resistance gene
  • Non-antibiotic drugs like essential oils (EOs) could be used as additive combined to colistin as they have shown effectiveness against resistant bacteria (Cantrell, Charles L., Scott G. Franzblau, and Nikolaus H. Fischer. "Antimycobacterial plant terpenoids. " Planta medica 67.8 (2001): 685-694).
  • EOs essential oils
  • the present invention relates to use of acyclic terpene alcohols for enhancing the antimicrobial activity of colistin.
  • the present invention is defined by the claims.
  • the first object of the present invention relates to a method of enhancing the antimicrobial activity of colistin in a subject in thereof comprising administering a therapeutically effective combination of colistin and an acyclic terpene alcohol.
  • a further object of the present invention relates to a method of treating a microbial infection in a subject in need thereof comprising administering to the subject an effective amount of a combination of colistin and an acyclic terpene alcohol.
  • the term“subject” refers to any animal having a disease or condition which requires treatment with colistin.
  • the subject may be a mammal, for example a human, or may be a domestic or commercial or companion animal.
  • combination according to the present invention is suitable for use in medical treatment of humans.
  • combination according to the present invention is suitable for use veterinary treatment, including treatment of companion animals such as dogs and cats, and domestic animals such as horses, ponies, donkeys, mules, llama, alpaca, pigs, cattle and sheep, or zoo animals such as primates, felids, canids, bovids, and ungulates.
  • the subject suffers from a microbial infection.
  • the microbial infection is selected from the group consisting of bacterial wound infections, mucosal infections, enteric infections, septic conditions, and infections in airways, cerebrospinal fluid, blood, eyes or skin.
  • the microbial infection is caused by gram-negative bacteria.
  • microbial infection examples include, but are not limited to, infections caused by Gram-negative bacteria such as Bordetella pertussis, Brucella, Campylobacter infections, Escherichia coli, Haemophilus influenzae, Helicobacter pylori, Klebsiella pneumoniae, Legionella spp., Moraxella catarrhalis, Neisseria gonorrhoeae, Neisseria meningitidis, Proteus spp., Pseudomonas aeruginosa, Salmonella spp., Shigella spp., Vibrio cholera, Acinetobacter baumannii and Yersinia.
  • Gram-negative bacteria such as Bordetella pertussis, Brucella, Campylobacter infections, Escherichia coli, Haemophilus influenzae, Helicobacter pylori, Klebsiella pneumoniae, Legionella spp., Moraxella catarrhalis
  • planktonic isolated bacteria
  • biofilm communicates with host invasion and acute infections.
  • bacteria activity is high, making them aggressive for the host, but also susceptible to antibiotics and“accessible” to the host’s immune system.
  • biofilm refers to bacteria that are embedded in a self-produced matrix of extracellular polymeric substance (EPS), consisting of negatively charged polysaccharide, protein and DNA, to form a structured consortium.
  • EPS extracellular polymeric substance
  • Biofilms cause chronic infections, characterized by persistent inflammation and tissue damage, as they have increased tolerance to antibiotic and resistance to phagocytosis and other immune systems’ components.
  • Development of a biofilm is initiated by planktonic bacteria, which, when the environment changes often adhere to a biotic or abiotic surface and use cell- to-cell signaling, also referred to as quorum-sensing (QS), to coordinate gene expression in relation to population density and biofilm formation.
  • QS cell- to-cell signaling
  • the QS signal molecules regulated the formation, the sustaining and the destabilization of bio films.
  • the microbial infection is caused by multi-drug resistant gram negative bacteria, such as for example multi-drug resistant microorganism that is resistant to colistin.
  • the microbial infection is caused by colistin resistant gram negative bacteria that contain a mobile colistin resistance gene (MCR-l, MCR-2, MCR-3, MCR-4, MCR-5...) encoding for a phosphoethanolamine transferase.
  • MCR-l, MCR-2, MCR-3, MCR-4, MCR-5 mobile colistin resistance gene
  • the subject suffers from infections in airways.
  • the term“colistin” has its general meaning in the art and refers to a polymyxin antibiotic produced by certain strains of Bacillus polymyxa. Colistin is effective against gram-negative bacilli, and is particularly effective against multi-drug resistant isolates of Pseudomonas aeruginosa, Acinetobacter baumannii and Klebsiella pneumoniae. Colistin interacts with the bacterial cytoplasmic membrane, changing its permeability therefore causing leakage of the cell contents.
  • COPD chronic obstructive pulmonary disease
  • colistin sulfate salt for oral and topical use
  • colistimethate sodium salt sodium colistin methane sulphonate, colistin sulfomethate sodium
  • parenteral use shown herein
  • Methods to produce pure biologically active colistin, or a pharmaceutically acceptable salt thereof are disclosed in U.S. Pat. No. 5,767,068 and International Application WO 98/20839 which are incorporated herein in its entirety by reference.
  • acyclic terpene alcohol has its general meaning in the art and refers to any compound containing two (monoterpenes), three (sesquiterpenes) or four (diterpenes) isoprene units and an alcohol group (hydroxyl group bond to a carbon).
  • the acute oral toxicity of the acyclic terpene alcohols is likewise low, with LD50 values in rats generally greater than 2000 mg/ kg body weight, or, in the case of ocimenol, close to 2000 mg/kg body weight.
  • the acyclic terpene alcohol is selected from: farnesol, geraniol, nerol, nerolidol, phytol.
  • the acyclic terpene alcohol is farnesol.
  • farnesol has its general meaning in the art and refers to is a natural 15-carbon organic compound which is an acyclic sesquiterpene alcohol.
  • the IUPAC name of farnesol is (2E,6E) ⁇ 3,7,1 l-trimethyldodeca-2,6,l0-trien-l-ol.
  • the term comprises, in the context of the present invention, the cis/cis, the cis/trans, the trans/cis and the trans/trans isomer and mixtures of two, three or all of the stated isomers of farnesol.
  • Farnesol is produced from isoprene compounds in both plants and animals.
  • the acyclic terpene alcohol is geraniol.
  • the term “geraniol” also known as lemonol, geranyl alcohol, trans-geraniol, (E)-geraniol refers to a monoterpene with a formula of C10H18O, CAS No. 106-24-1, IUPAC name (trans)-3,7- Dimethyl-2,6-octadien- 1 -ol.
  • the term“antimicrobial activity” is defined as an activity which is capable of killing or inhibiting growth of microbial cells.
  • the term“antimicrobial” is intended to mean that there is a bactericidal and/or a bacteriostatic effect, wherein the term“bactericidal” is to be understood as capable of killing bacterial cells.
  • the term“bacteriostatic” is to be understood as capable of inhibiting bacterial growth, i.e., inhibiting growing bacterial cells.
  • the term“inhibiting growth of microbial cells” is intended to mean that the cells are in the non-growing state, i.e., that they are not able to propagate.
  • the expression "enhancing the antimicrobial activity” refers to the ability of the acyclic terpene alcohol to increase the ability of colistin to get a bactericidal and/or a bacteriostatic effect in comparison when colistin is used alone.
  • the expression also refers to the ability of the acyclic terpene alcohol to promote an antimicrobial activity of colistin at a lower concentration.
  • the acyclic terpene alcohol has the ability of restoring the minimal inhibitory concentration down to 0,5 mg/L as described in the EXAMPLE.
  • antimicrobial activity may be determined according to the procedure described in the EXAMPLE
  • treatment refers to both prophylactic or preventive treatment as well as curative or disease modifying treatment, including treatment of subject at risk of contracting the disease or suspected to have contracted the disease as well as subjects who are ill or have been diagnosed as suffering from a disease or medical condition, and includes suppression of clinical relapse.
  • the treatment may be administered to a subject having a medical disorder or who ultimately may acquire the disorder, in order to prevent, cure, delay the onset of, reduce the severity of, or ameliorate one or more symptoms of a disorder or recurring disorder, or in order to prolong the survival of a subject beyond that expected in the absence of such treatment.
  • therapeutic regimen is meant the pattern of treatment of an illness, e.g., the pattern of dosing used during therapy.
  • a therapeutic regimen may include an induction regimen and a maintenance regimen.
  • the phrase “induction regimen” or “induction period” refers to a therapeutic regimen (or the portion of a therapeutic regimen) that is used for the initial treatment of a disease.
  • the general goal of an induction regimen is to provide a high level of drug to a subject during the initial period of a treatment regimen.
  • An induction regimen may employ (in part or in whole) a "loading regimen", which may include administering a greater dose of the drug than a physician would employ during a maintenance regimen, administering a drug more frequently than a physician would administer the drug during a maintenance regimen, or both.
  • maintenance regimen refers to a therapeutic regimen (or the portion of a therapeutic regimen) that is used for the maintenance of a subject during treatment of an illness, e.g., to keep the subject in remission for long periods of time (months or years).
  • a maintenance regimen may employ continuous therapy (e.g., administering a drug at a regular intervals, e.g., weekly, monthly, yearly, etc.) or intermittent therapy (e.g., interrupted treatment, intermittent treatment, treatment at relapse, or treatment upon achievement of a particular predetermined criteria [e.g., disease manifestation, etc.]).
  • the term "therapeutically effective amount” refers to an amount effective, at dosages and for periods of time necessary, to achieve a desired therapeutic result.
  • a therapeutically effective amount of the active agent may vary according to factors such as the disease state, age, sex, and weight of the individual, and the ability of the active agent to elicit a desired response in the individual.
  • a therapeutically effective amount is also one in which any toxic or detrimental effects of the antibiotic or antibiotic portion are outweighed by the therapeutically beneficial effects.
  • the efficient dosages and dosage regimens for the active agent depend on the disease or condition to be treated and may be determined by the persons skilled in the art. A physician having ordinary skill in the art may readily determine and prescribe the effective amount of the pharmaceutical composition required.
  • a suitable dose of a composition of the present invention will be that amount of the compound, which is the lowest dose effective to produce a therapeutic effect according to a particular dosage regimen. Such an effective dose will generally depend upon the factors described above. For example, a therapeutically effective amount for therapeutic use may be measured by its ability to stabilize the progression of disease.
  • colistin is administered at a dose allowing reaching concentrations in colistin base at the site of infection between 0.25 mg/L to 4 mg/L and the acyclic terpene alcohol concentrations at the site of infection between 10 mg/L to 60 mg/L.
  • colistin and the acyclic terpene alcohol are formulated in the form of nanocapsules. In some embodiment, colistin and the acyclic terpene alcohol are administered by dry and liquid aerosol.
  • the term“nanocapsules” has its general meaning in the art and refers to particles consisting of a lipid or lipid/aqueous core that is liquid or semiliquid at room temperature, coated with a hydrophilic film.
  • room temperature means a temperature between 15 and 25° C.
  • the nanocapsules of the present invention are characterized in that they have an average particle size of less than 100 nm, preferably they have an average size between 60 nm and 90 nm, preferably between 65 nm and 85 nm.
  • the term“average size” is understood as the average diameter of the nanocapsule population, which comprises the lipophilic phase and the hydrophilic phase, which moves together in the aqueous medium.
  • the average size of these systems can be measured using standard procedures known by a person skilled in the art, and which are described, for example, in the experimental part below.
  • the nanocapsules of the present invention are characterized in that they have a negative zeta potential less than -0,5 mV when measured at pH 7 and in the presence of a ionic strength lower than 0.01 M.
  • the nanocapsules of the present invention have a zeta potential between -0,5 mV and - 2,2 mV.
  • zeta potential refers to the electrokinetic potential of a colloidal dispersion, and the magnitude of the zeta potential indicates the degree of electrostatic repulsion between adjacent, similarly charged particles in a dispersion.
  • the nanocapsules of the present invention are prepared according to well-known methods in the art and typically methods described in W02002688000, W02009001019, W02009004214; W02001064328 and Huynh, N.T. et al. : Int. J. Pharm. 2009, 379, 201-209. Typically, the formulation is based on at least three principal components: an oily phase, an aqueous phase and a nonionic surfactant.
  • the oily phase is essentially constituted of triglycerides of capric and caprylic acids known under the commercial name of Labrafac® WR 1349.
  • the hydrophilic surfactant, Solutol® HS 15 is derived from poly ethyleneglycol (PEG) and is a mixture of free PEG 660 and PEG 660 hydroxystearate.
  • the aqueous phase consists of MiliQ® water plus sodium chloride salt, NaCl.
  • Phospholipon® composed phosphatidylcholine soya bean lecithin, is used in small proportions to significantly increase LNC stability, which is especially necessary in the case of 50-100 nm LNC formulations.
  • Step I consists in mixing all the components (whose proportions vary according to the study) under magnetic stirring and heating from room temperature up to T2 temperature, above the phase-inversion temperature (PIT), to obtain a W/O emulsion. This is followed by a cooling process to the Tl temperature, below the PIT, leading to the formation of an O/W emulsion. Several temperature cycles crossing the phase-inversion zone (PIZ) between T2 and Tl are then carried out.
  • PIT phase-inversion temperature
  • the temperature before dilution is determined at the beginning of the inversion process and is defined by a temperature range that is set at 1- 3 °C from the beginning of the O/W emulsion.
  • Step II is an irreversible shock, induced by sudden dilution with cold water added to the mixture which has been maintained at the previously defined temperature. This is done to break the microemulsion system obtained in the PIZ, and leads to the formation of stable nanocapsules. Afterwards, slow magnetic stirring is applied to the suspension for 5 min. Three temperature cycles of heating and cooling at the rate of 4 °C/min are usually applied between 90 and 60 °C.
  • the nanoparticules of the present invention is be directed against biofilm and planktonic of Gram-negative bacteria.
  • FIGURES are a diagrammatic representation of FIGURES.
  • Figure 1 Colistin (base) minimum inhibitory concentration (MIC - mg/L) versus famesol (A) or geraniol (B) concentrations (mg/L) measured for E.coli J53 and the corresponding MCR-l transconjugate ( E.coli J53 MCR-1). Shaded area is a 95% confidence interval on the fitted values (lines) obtained using an Emax model (eq. 1) and the fitting values of the table 2.
  • MIC values were determined in Cation-supplemented Mueller Hinton broth using the microdilution method as required by the European Committee for Antimicrobial Susceptibility Testing (EUCAST) ( Determination of minimum inhibitory concentrations (MICs) of antibacterial agents by broth dilution.European Committee for Antimicrobial Susceptibility Testing (EUCAST) of the European Society of Clinical Microbiology and Infectious Diseases (ESCMID). First published: 26 August 2003 https://doi.Org/10.1046/j.1469-0691.2003.00790.x ).
  • Figure 2 A and B. Time kill curves obtained for E.coli J53 and E.coli J53 MCR-1 in the presence of a colistin base concentration of 1/8 of the MIC value and famesol concentration values of 10, 30, and 60 mg/L (A) or geraniol concentration values of 60, 100, and 200 mg/L (B).
  • a and B Time kill curves obtained for E.coli J53 and E.coli J53 MCR-1 in the presence of a colistin base concentration of 1/8 of the MIC value and famesol concentration values of 10, 30, and 60 mg/L (A) or geraniol concentration values of 60, 100, and 200 mg/L (B).
  • Famesol and geraniol were encapsulated in LNC.
  • the dotted horizontal line indicates the limit of quantification of the bacteria concentration
  • colistin a polypeptide antibiotic (ATB)
  • ATB polypeptide antibiotic
  • Non-antibiotic drugs like essential oils (EOs), combined to ATB have shown effectiveness against resistant bacteria [2]
  • the aim of the study was to propose an effective combination between colistin and essential oils compounds against MCR-l bacteria.
  • Two lipophilic molecules were selected (geraniol and famesol) based on the literature review, and encapsulated within lipid nanocapsules (LNCs) using a phase inversion method [3]
  • PDI mean diameter
  • a negative zeta potential -0.5, -2.2 mV
  • Table 1 Physical properties of blank LNC (without acyclic terpene alcohols) and LNC loaded with 20% (m/m) of geraniol or famesol.
  • MIC The average MIC (MIC), were calculated using equation 1, where MICo is the MIC of colistin without acyclic terpene alcohols, MIC ⁇ is the smaller colistin MIC in combination with the adjuvant (a acyclic terpene alcohol).
  • CEO is the acyclic terpene alcohol concentration (geraniol or famesol) fitted with a value of gamma (g) and EC50 is adjuvant concentration (mg/L) needed to reach half of Emax value.
  • Emax refers to the relation between the MIC of the colistin alone (MICo) and the MIC ⁇ .
  • geraniol and famesol encapsulated in LNC were both able to restore the colistin MIC down to 0.5 mg/L.
  • farnesol was more potent than geraniol as its EC50 was 2.1 mg/L, but was 35.7.4 mg/L for the geraniol.
  • Time-Kill assays have shown an enhancement of the efficacy of colistin combined with famesol against both strains ( Figure 2).
  • Figure 2 For the MCR-l strain, 60 mg/L of famesol and 1 mg/L of colistin (1/8 of the MIC) produced a bactericidal effect after 6 hours of incubation, without bacterial regrowth for up to 30 hours after incubation.
  • the sensitive strain the same bactericidal effect was obtained after 3 hours of incubation, for 60 mg/L of famesol and 0.03 lmg/L of colistin (1/8 of the MIC).
  • MCR-l E.coli allowing using low colistin concentrations, while, preventing bacterial regrowth.

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Abstract

La colistine est un ancien antibiotique polypeptidique largement utilisé chez les animaux producteurs d'aliments, en particulier dans la production de porcs en tant que traitement de groupe oral et métaphylaxie contre les infections digestives à Enterobacteriaceae après le sevrage. Chez l'homme, l'utilisation de la colistine est aujourd'hui recommandée en dernier recours pour le traitement de bactéries multirésistantes aux médicaments. Mais la découverte en 2015 d'un gène de résistance à la colistine codé par un plasmide transférable MCR-1 a soulevé un problème important de santé publique. De même, pour conserver cet antibiotique en tant qu'antibiotique de dernier recours, il serait très utile d'aborder ce mécanisme MCR-1. Les inventeurs ont étudié la diminution de la CMI (concentration minimale inhibitrice) de la colistine contre E.coli codé avec le gène MCR-1 (CMI = 8 mg/l) et son contrôle (CMI = 0,25 mg/l), en présence de concentrations croissantes d'un alcool terpénique acyclique (par exemple le farnésol ou le géraniol). Ces études montrent que l'alcool terpénique acyclique, en particulier le farnésol, est capable de restaurer l'activité de colistine contre MCR-1 E.coli, permettant d'utiliser de faibles concentrations de colistine, tout en empêchant le redéveloppement bactérien. Ainsi, la présente invention concerne l'utilisation d'alcools terpéniques acycliques pour améliorer l'activité antimicrobienne de la colistine.
PCT/EP2019/070153 2018-07-27 2019-07-26 Utilisation d'alcools terpéniques acycliques pour améliorer l'activité antimicrobienne de la colistine Ceased WO2020021052A2 (fr)

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Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1998020839A1 (fr) 1996-11-13 1998-05-22 Merck Patent Gmbh Produits de polymerisation pouvant etre resorbes biologiquement, constitues de systemes de liants durcissables par rayonnement
US5767068A (en) 1997-02-13 1998-06-16 Pathogenesis Corporation Pure biologically active colistin, its components and a colistin formulation for treatment of pulmonary infections
WO2001064328A1 (fr) 2000-03-02 2001-09-07 Mainelab Nanocapsules lipidiques, procede de preparation et utilisation comme medicament
WO2002068800A1 (fr) 2001-02-16 2002-09-06 Siemens Westinghouse Power Corporation Aube de turbine a bout aminci pre-segmente
WO2009001019A2 (fr) 2007-06-11 2008-12-31 Universite D'angers Nanocapsules a coeur lipidique liquide chargees en actifs(s) hydrosoluble(s) ou hydrodispersible(s)
WO2009004214A2 (fr) 2007-06-11 2009-01-08 Universite D'angers Procede de preparation de nanoparticules lipidiques

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1998020839A1 (fr) 1996-11-13 1998-05-22 Merck Patent Gmbh Produits de polymerisation pouvant etre resorbes biologiquement, constitues de systemes de liants durcissables par rayonnement
US5767068A (en) 1997-02-13 1998-06-16 Pathogenesis Corporation Pure biologically active colistin, its components and a colistin formulation for treatment of pulmonary infections
WO2001064328A1 (fr) 2000-03-02 2001-09-07 Mainelab Nanocapsules lipidiques, procede de preparation et utilisation comme medicament
WO2002068800A1 (fr) 2001-02-16 2002-09-06 Siemens Westinghouse Power Corporation Aube de turbine a bout aminci pre-segmente
WO2009001019A2 (fr) 2007-06-11 2008-12-31 Universite D'angers Nanocapsules a coeur lipidique liquide chargees en actifs(s) hydrosoluble(s) ou hydrodispersible(s)
WO2009004214A2 (fr) 2007-06-11 2009-01-08 Universite D'angers Procede de preparation de nanoparticules lipidiques

Non-Patent Citations (5)

* Cited by examiner, † Cited by third party
Title
CANTRELL, CHARLES L.SCOTT G. FRANZBLAUNIKOLAUS H. FISCHER: "Antimycobacterial plant terpenoids", PLANTA MEDICA, vol. 67.8, 2001, pages 685 - 694
CHEMICAL ABSTRACTS, Columbus, Ohio, US; abstract no. 106-24-1
HEMAISWARYA, S ET AL., PHYTOMEDICINE, vol. 15, no. 8, 2008, pages 639 - 652
HUYNH, N.T. ET AL., INT. J. PHARM., vol. 379, 2009, pages 201 - 209
LIU, Y. Y. ET AL., THE LANCET INFECTIOUS DISEASES, vol. 16, no. 2, 2016, pages 161 - 168

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