WO2017220982A1 - Combinaison comprenant de la pipérine et des polymyxines pour le traitement d'infections microbiennes - Google Patents

Combinaison comprenant de la pipérine et des polymyxines pour le traitement d'infections microbiennes Download PDF

Info

Publication number
WO2017220982A1
WO2017220982A1 PCT/GB2017/051781 GB2017051781W WO2017220982A1 WO 2017220982 A1 WO2017220982 A1 WO 2017220982A1 GB 2017051781 W GB2017051781 W GB 2017051781W WO 2017220982 A1 WO2017220982 A1 WO 2017220982A1
Authority
WO
WIPO (PCT)
Prior art keywords
infections
combination
piperine
polymyxin
colistin
Prior art date
Application number
PCT/GB2017/051781
Other languages
English (en)
Inventor
Professor Anthony COATES
Yanmin Hu
Original Assignee
Helperby Therapeutics Limited
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by Helperby Therapeutics Limited filed Critical Helperby Therapeutics Limited
Publication of WO2017220982A1 publication Critical patent/WO2017220982A1/fr

Links

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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/4525—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with oxygen as a ring hetero atom
    • 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
    • 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 the combination of piperine or a pharmaceutically acceptable derivative or stereoisomer thereof with a polymyxin selected from colistin and polymyxin B or a pharmaceutically acceptable derivative thereof, and the use of this combination for the treatment of microbial infections.
  • a polymyxin selected from colistin and polymyxin B or a pharmaceutically acceptable derivative thereof relates to the use of such combinations to kill multiplying microorganisms associated with microbial infections.
  • penicillins and cephalosporins inhibit cell wail synthesis, whereas other agents inhibit a diverse range of targets, sueh as DNA gyrase fquinolones) and protein synthesis (e.g. macroltdes, aminoglycosides, tetracyclines and oxazojidinones).
  • targets sueh as DNA gyrase fquinolones
  • protein synthesis e.g. macroltdes, aminoglycosides, tetracyclines and oxazojidinones.
  • the range of organisms against which the -antimicrobial agenis are effective varies, depending upon which organisms are heavily reliant upon the metabolic sfep(s) that is/are inhibited. Further, the effect upon bacteria can vary from a mere inhibition of growth (i.e. -a ..bacteriostatic- effect, as seen with agents such as the . tetracyclines) to full killing (i,e. a bacterici
  • Bacteria have been growing on Earth for more than 3 billion years and, in that time, have needed to respond to vast numbers of environmental stresses, It is therefore perhaps not surprising that bacteria have developed a seemingly inexhaustible variety of mechanisms by which they can respond to the metabolic stresses imposed upon them by antibiotic agents. Indeed, mechanisms by which the bacteria can generate resistance include strategies as diverse as inactivate! of the drug, modification of the site of action, modification of the permeability of the ceil wall, overproduction of the target enzyme and bypass of the inhibited steps.
  • the rate of resistance emerges to a particular agent has been observed to vary widely, depending upon factors such as the agent's mechanism of action, whether the agent's mode of killing is time- or concentration-dependent : the potency against the population of bacteria and the magnitude and duration of the available serum concentration.
  • phenotypically resistant bacteria differ from those that are genotypically resistant in that they regain their susceptibility to antimicrobials when they return to a fast-growing state ⁇ e.g. when nutrients become more readily available to them).
  • a new approach to combating the problem of bacterial resistance might be to select and develop antimicrobial agents on the basis of their ability to kill "latent" microorganisms.
  • the production of such agents would allow, amongst other things, for the shortening of chemotherapy regimes in the treatment of microbial infections, thus reducing the frequency with which genotypical resistance arises in microorganisms.
  • the present invention is based on the unexpected finding that the combination of piperine or a pharmaceutically acceptabie derivative or stereoisomer thereof, and a polymyxin selected from polymyxin B and colistin or a pharmaceutically acceptabie derivative thereof exhibit synergistic antimicrobial activity against Sog phase (i.e. multiplying) and/or clinically latent microorganisms. Particularly against log phase bacteria, in other words, the combination has a greater biological activity than the expected additive effect of each agent at the stated dosage level.
  • the surprising biological activity of the combinations of the present invention offers the opportunity to shorten chemotherapy regimens and may result in a reduction in the emergence of microbial resistance associated with the use of such combinations,
  • Synergy in the context of antimicrobial drugs is measured in a number of ways that conform to the generally accepted opinion that "synergy is .an effect greater than additive".
  • One of the ways to assess whether synergy has been observed is to use the "eheqUerboard” technique. This is a wel!-aceepfed method that leads to the generation of a value called the fractional inhibitory concentration index (FICI). Orhan et a! J. Clin.
  • the FICI value is a ratio of the sum of the MIC (Minimum Inhibitory Concentration) level Of -each individual component alone and in the mixture.
  • the combination is considered synergistic when the ⁇ FIC is ⁇ 0.5, indifferent when the ⁇ FIC is >0,5 to ⁇ 2, and antagonistic when the ⁇ FIC is >2.
  • the present invention provides a combination of piperine or a pharmaceutically acceptable derivative or stereoisomer thereof and a polymyxin selected from polymyxin B and colistin or a pharmaceutically acceptable derivative thereof.
  • the present invention provides the use of piperine or a pharmaceutically acceptable derivative or stereoisomer thereof in combination with a polymyxin selected from colistin or polymyxin B or a pharmaceutically acceptable derivative thereof, in the manufacture of a medicament for treating a microbial infection.
  • the present invention provides the combination of piperine or a pharmaceutically acceptable derivative or stereoisomer thereof and a polymyxin selected from polymyxin B and colistin or a pharmaceutically acceptable derivative thereof, for use in the treatment of a microbial infection, preferably for use in the treatment of a bacterial infection.
  • the invention provides a method of treating a microbial infection which comprises administering to a mammal, including man, piperine or a pharmaceutically acceptable derivative or stereoisomer thereof in combination with a polymyxin selected from colistin or polymyxin B or a pharmaceutically acceptable derivative thereof.
  • a pharmaceutical composition comprising piperine or a pharmaceutically acceptable derivative or stereoisomer thereof in combination with a polymyxin selected from colistin or polymyxin B or a pharmaceutically acceptable derivative thereof, and a pharmaceutically acceptable adjuvant, diluent or carrier.
  • the pharmaceutical composition is for use in the treatment of a microbial infection, preferably wherein the microbial infection is a bacterial infection.
  • the invention relates to a product comprising piperine or a pharmaceutically acceptable derivative or stereoisomer thereof in combination with a polymyxin selected from colistin or polymyxin B or a pharmaceutically acceptable derivative thereof, as a combined preparation for simultaneous, separate or sequential use in killing multiplying and/or clinically latent microorganisms associated with a microbial infection.
  • a polymyxin selected from colistin or polymyxin B or a pharmaceutically acceptable derivative thereof
  • a product comprising piperine or a pharmaceutically acceptable derivative or stereoisomer thereof in combination with a polymyxin selected from colistin or polymyxin B or a pharmaceutically acceptable derivative thereof, as a combined preparation for simultaneous, separate or sequential use in killing multiplying and/or clinically latent microorganisms associated with a microbial infection.
  • a polymyxin selected from colistin or polymyxin B or a pharmaceutically acceptable derivative thereof
  • Figure 1 is a time-kill curve (Log OFU/ml against time (hours)) tor colistin in the form of coiistsmethate sodium ai a concentration of 32 mg/mi, piperine at a concentration of 255 mg/ml and the combination of colistin (32 mg/mi) and piperine (256 mg/m!).
  • Figure 2 is : a time-kill curve (Log CFU/ral against time (hours)) for colistin in the form of coiisiimethate sodiura at a concentration of 32 mg/ml, piperine at a concenirafion of 128 mg/ml and the combination of colistin (32 mg/ral) and piperine (128 mg/mi).
  • Figure 3 is a time-kilj curve (Log CFU/m! against time (hours)) for colistin in the form of coiistiraethate sodium at a concentration of 32 mg/ml, piperine at a concentration of 64 mg/mi and the combination of colistin (32 mg/mi) and piperine ( ⁇ 4 mg/m!).
  • Figure 4 is a time-kiii curve (Log CFU/ml against time (hours)) for colistin in the form of coiisiimethate sodium at a concentration of 1 ⁇ mg/ml, piperine at a concenirafion of 258 rng/ml and the combination of colistin (16 mg/ml) and piperine (256 mg/mi).
  • the combinations of the present invention have been demonstrated to be partiGUSaffy effective against drug-fesistant bacteria, particularly drug-resistant Gram- negatsve bacteria, opening the way for said combinations to he ' administered both to drug- resistant strains and in said strains before drug-resistance is built up, Lei as a first line treatment
  • the term "in cornbinatiori with” covers both separate and sequential: administration of the piperine: and the polymyxin.
  • administration of the piperine and the polymyxin.
  • either the piperine or the polymyxin may be administered first.
  • administration is simultaneous, the piperine and polymyxin may be administered either in the same or a different pharmaceutical composition.
  • Adjunctive therapy Le. where one agent is used as a primary treatment and the other agent is used to assist that primary treatment, is aiso an embodiment of the present invention.
  • the combinations of the present invention may be used to treat microbial infections, In particular they may be used to ' kill multiplying and/or clinically latent microorganisms associated with microbial infections, preferably multiplying microorganisms associated with microbial infections, e.g. multiplying bacteria associated with Gram-negative bacterial infections.
  • References herein to the treatment of a microbial infection therefore include killing multiplying and/or clinically latent microorganisms associated with such infections.
  • kill means a loss of viability as assessed by a lack of metabolic activity.
  • clinical latent microorganism means a microorganism that is metabo!ically active but has a growth rate that is below the threshold of infectious disease expression.
  • the threshold of infectious disease expression refers to the growth rate threshold below which symptoms of infectious disease in a host are absent.
  • the metabolic activity of clinically latent microorganisms can be determined by several methods known to those skilled in the art; for example, by measuring mRNA levels in the microorganisms or by determining their rate of uridine uptake, in this respect, clinically latent microorganisms, when compared to microorganisms under logarithmic growth conditions (in vitro or in vivo), possess reduced but still significant levels of:
  • mRNA e.g. from 0.0001 to 50%, such as from 1 to 30, 5 to 25 or 10 to 20%, of the level of mRNA
  • uridine e.g. [ 3 H]uridine
  • uptake e.g. from 0.0005 to 50%, such as from 1 to 40, 15 to 35 or 20 to 30% of the level of [ 3 H]uridine uptake.
  • Clinically latent microorganisms typically possess a number of identifiable characteristics. For example, they may be viable but non-culturable; i.e. they cannot typically be detected by standard culture techniques, but are detectable and quantifiable by techniques such as broth dilution counting, microscopy, or molecular techniques such as polymerase chain reaction.
  • clinically latent microorganisms are phenotypica!ly tolerant, and as such are sensitive (in log phase) to the biostatic effects of conventional antimicrobial agents (i.e. microorganisms for which the minimum inhibitory concentration (MIC) of a conventional antimicrobial is substantially unchanged); but possess drastically decreased susceptibility to drug-induced killing (e.g. microorganisms for which, with any given conventional antimicrobial agent, the ratio of minimum microbiocidal concentration (e.g. minimum bactericidal concentration, MBC) to MIC is 10 or more).
  • conventional antimicrobial agents i.e. microorganisms for which the minimum inhibitory concentration (MIC) of a
  • microorganisms means fungi and bacteria. References herein to "microbial', “antimicrobiaf and “antimicrobially” shall be interpreted accordingly. For example, tile term “microbial” means fungal or bacterial, and “microbial infection” means any fungal or bacteria! infection.
  • one or more of the aforementioned combinations is used to treat a bacteria! infection, in particular the combinations may be used to kill clinically latent microorganisms associated with a bacterial. infection.
  • bacteria and derivatives thereof, such as “miProbia! infection”
  • the term "bacteria” includes, but is not: limited to, references to organisms (or infections due to organisms) of the following classes and specific types:
  • Gram-positive cocci, such as Staphylococci ⁇ e.g. Staph, aureus, Staph, epidermidis, Staph, sapmphyticm, Staph, auriaiiaris. Staph, capitis capitis, Staph. c ureolyticus, Staph, capraa, Staph, cohnii coivvi, Staph, c, ureaiyticus, Staph, equorum, Staph, gailinarum, Staph. haamotyticas, Staph, hominis hominis, Staph, h.
  • Staphylococci ⁇ e.g. Staph, aureus, Staph, epidermidis, Staph, sapmphyticm, Staph, auriaiiaris. Staph, capitis capitis, Staph. c ureolyticus, Staph, capraa, Stap
  • Streptococci e.g.beta-haemo:iytic, pyogenic streptococci (such as Strept, agalactiae, Stept canis, Strept dysgaiactiae dysgalactiae, Strept. clysgaiactiae equisimiiis, Strept equi equi, Strept equi zooepidemicus, Strept, iniee, Strept porcJnus and Simpt. pyogenes' ⁇ , mieroaerophilic, pyogenic streptococci (Streptococcus "miiierf, such: as Strept. anginosps, Strept.
  • Gram-negative cocci such as Neisseria gonorrhoeae, Neisseria meningitidis, Neisseria cinerea, Neisseria elongate, Neisseria flaveseens, .Neisseria iactamica, Neisseria mucosa. Neisseria sicca, Neisseria subflava and Neisseria weaver/;
  • Bacillaceae such as Baciiius anthracis, Baeii!us subtiiis, Bacillus thuringiensis, Bacillus siearothermophiius and Baci!im cereus;
  • EnterobaGteriaceae such as Escherichia, coil, Enterobacter (e.g. Enterobacter aerogenes, Enterobacter agglomerans and Enterobacter cloacae), Citrobacter ⁇ such as Citrob. freundii and Citrob. divernis), Hafnia (e.g. Hafnia alvei), Erwinia (e.g. Erwinia persicinus), Morganella morganii, Salmonella (Salmonella enterica and Salmonella typhi), Shigella (e.g. Shigella dysenteriae, Shigella flexneri, Shigella boydii and Shigella sonnei), Klebsiella (e.g.
  • Serratia marcescens and Serratia iiquifaciens include Serratia marcescens and Serratia iiquifaciens, and Yersinia (e.g. Yersinia enterocoiitica, Yersinia pestis and Yersinia pseudotuberculosis);
  • Enterococci e.g. Enterococcus avium, Enterococcus casseiiflavus, Enterococcus cecorum, Enterococcus dispar, Enterococcus durans, Enterococcus faecaiis, Enterococcus faecium, Enterococcus flavescens, Enterococcus gallinarum, Enterococcus hirae, Enterococcus matodoratus, Enterococcus mundtii, Enterococcus pseudoavium, Enterococcus raffinosus and Enterococcus sotitarius);
  • Helicobacter e.g. Helicobacter pylori, Helicobacter cinaedi and Helicobacter fennelliae
  • Acinetobacter e.g. A. baumanii, A. calcoaceticus, A. haemolyttcus, A. johnsonii, A. junii, A. Iwoffi and A. radioresistens
  • Pseudomonas e.g. Ps. aeruginosa, Ps. maltophilia [Stenotrophomonas maltophiiia), Ps. alcaligenes, Ps. chlororaphis, Ps. fluorescens, Ps. luteola. Ps. mendocina, Ps. monteilii, Ps. oryzihabitans, Ps. pertocinogena, Ps. pseudalcaligenes, Ps. putida and Ps. stutzeri);
  • Peptococcus e.g. Peptococcus niger
  • Peptostreptococcus Peptostreptococcus
  • Clostridium e.g. C. perfringens, C. difficile, C. botulinum, C. tetani, C. absonum, C. argentinense, C. baratii, C. bifermentans, C. beijerinckii, C. butyricum, C. cadaveris, C. carnis, C. celatum, C. clostridioforme, C. cochlearium, C. cocleatum, C. fallax, C. ghonii, C. glycolicum, C. haemolyticum, C. hastiforme, C. histolyticum, C. indolis, C. innocuum, C. irregulare, C.
  • leptum leptum, C. limosum, C. malenominatum, C. novyi, C. oroticum, C. paraputrificum, C. piliforme, C. putrefasciens, C. ramosum, C. septicum, C. sordelii, C. sphenoides, C. sporogenes, C. subterminale, C. symbiosum and C. tertium);
  • Mycoplasma e.g. M. pneumoniae, M. hominis, M. genitalium and M. urealyticum
  • Mycobacteria e.g. Mycobacterium tuberculosis, Mycobacterium avium, Mycobacterium fortuitum, Mycobacterium marinum, Mycobacterium kansasii, Mycobacterium chelonae, Mycobacterium abscessus, Mycobacterium leprae, Mycobacterium smegmitis, Mycobacterium africanum, Mycobacterium alvei, Mycobacterium asiaticum, Mycobacterium aurum, Mycobacterium bohemicum, Mycobacterium bovis, Mycobacterium branderi, Mycobacterium brumm, Mycobacterium DCatum, Mycobacterium ohtibense, Mycobacterium, confiuentis, Mycobacterium conspicuum, Mycobacterium cookii., Mycobacterium f!avescans, Mycobacterium gadium, Mycobacterium gastri, Mycobacterium ganavense, Mycobacterium gordonae, Mycobacter
  • Haemophilus influenzae Haemophilus ducreyi, Haemophilus aegyptius, Haemophilus paramftumzae, Haemophilus haemo!ytieus and Haemophilus par&haamotyticus) ;
  • Actinabacitius e.g. Actmobaciths actinomycetamcomitans, Actmobaciitus equuii, Actlnobacillus hominis, Actmobacillus iignieresii, Actinobacilius suis and ActinobaGiiius ureae;
  • Brucella e.g. Brucella abortus, Brucella cams, Brucella meiintensis and Brucella suis ⁇ ;
  • Campylobacter e.g. Campylobaci&r jejuni, C ' ampylobacter coll, Campylobacter lari and Campylobacter fetus
  • Listeria monocytogenes
  • Vibrio e.g. Vibrio cholerae and Vibrio parahaemolyticus, Vibrio alginolytieus, Vibrio carchariae, Vibrio fluwalis, Vibrio furnissii, Vibrio hollisae, Vibrio metschnlkovii, Vibrio mimicys mti Vibrio vulnificus);
  • CorynebacteriaGeae e.g. Gorynebacterium diphtheriae, Cotynebacterium jeikeum and Cotymhacterium ureaiyticumy
  • Spirochaeiaceae such as Borrelia (e.g. Borrelia recurrentis, Borre!ia burgdorferi, Borrelia afzell!, Borrelia andersonii, Borrelia bissettii, Borrelia garinii, Borrelia japonica, Borrelia lusitamae, Borrelia tanukii, Borrelia iurdi, Borrelia valaislana, Borrelia caucasica, Borrolia crociduraa, Borrelia duttoni; Borrelia graingerl, Borrelia hermsii, Borrelia Mspanica, Borrelia !atyschewii, Borrelia mazzottii, Borrelia parked,.
  • Borrelia e.g. Borrelia recurrentis, Borre!ia burgdorferi, Borrelia afzell!, Borrelia andersonii, Borrelia bissettii, Borrelia garini
  • Pasteurella aerogenes Pasteurella bettyae, Pasteurella canis, Pasteurella dagmatis, Pasteurella gatllnarum, Pasteurella haemolytlca, Pasteurella multocida multocida, Pasteurella multocida gallicida, Pasteurella multocida septica, Pasteurella pneumotropica and Pasteurella stomatis);
  • Bordetella e.g. Bordetella bronchiseptica, Bordetella hinzt ' i, Bordetella holmseii, Bordetella parapertussis, Bordetella pertussis and Bordetella trematum;
  • Nocardiaceae such as Nocardia (e.g. Nocardia asteroides and Nocardia brasiliensis);
  • Rickettsia e.g. Ricksettsii or Coxiella burnetii
  • Legionella e.g. Legionella anisa, Legionella birminghamensis, Legionella bozemanii, Legionella primannatiensis, Legionalla dumoffii, Legionella feeleii, Legionalla gormanii, Legionalla hackeliae, Legionalla israelensis, Legionalla jordanis, Legionalla lansingensis, Legionalla longbeachae, Legionalla maceachernii, Legionalla micdadei, Legionalla oakridgensis, Legionalla pneumophila, Legionalla sainthelensi, Legionalla tucsonensis and Legionalla wadsworthii);
  • Cyclospora cayetanensis Entamoeba histolytica; Giardia lamblia; Trichomonas vaginalis; Toxoplasma gondii; Stenotrophomonas maltophilia; Burkholderia cepacia; Burkholderia mallei and Burkholderia pseudomallei; Francisella tularensis; Gardnerella (e.g. Gardneralla vaginalis and Gardneralla mobiluncus); Streptobacillus moniliformis; Flavobacteriaceae, such as Capnocytophaga (e.g.
  • Bartonella Bartonella ⁇ Bartonella bacilliformis, Bartonella clarridgeiae, Bartonella elizabethae, Bartonella henselae, Bartonella quintana and Bartonella vinsonii arupensis);
  • Leptospira e.g. Leptospira biflexa, Leptospira borgpetersenii, Leptospira inadai, Leptospira interrogans, Leptospira kirschneri, Leptospira noguchii, Leptospira santarosai and Leptospira wellii;
  • Splegi!ium e.g. Spirillum minus
  • Baceteroides e.g. Bacteroides caccae, Bacteroides capillosus, Bacteroides coagulans, Bacteroides distasonis, Bacteroides eggerthii, Bacteroides forsythus, Bacteroides fragilis, Bacteroides merdae, Bacteroides ovatus, Bacteroides putredinis, Bacteroides pyogenes, Bacteroides splanchinicus, Bacteroides stercoris, Bacteroides tectus, Bacteroides thetaiotaomicron, Bacteroides uniformis, Bacteroides ureolyticus and Bacteroides vuigatus); Prevotelia (e.g. Bacteroides caccae, Bacteroides capillosus, Bacteroides coagulans, Bacteroides distasonis, Bacteroides eggerthii, Bacteroides forsythus, Bacteroides fragilis, Bacteroides
  • Prevotella bivia Prevotella buccae, Prevotella corporis, Prevotella dentalis (Mitsuokella dentalis), Prevotella denticola, Prevotella disiens, Prevotella enoeca, Prevotella heparinolytica, Prevotella intermedia, Prevotella loeschii, Prevotella melaninogenica, prevoteiia higrescans, Provoie!ia oralis, PreyoiBlla oris, Prevoteiia ouiora, Pr&vot@lia tannerae, Prevoteiia venoMis and Prevoteiia mogieoformansy,
  • Parphyrornonas e.g.. Porphyromonas asaccharo!yiiGa, Porphyromonas cmigingivaHs, Porphyromonas canaris, Porphyromonas cansulci, Porphyromonas catohiae, Porphyromonas circumdeptaria, Porphyromonas: creyioricaivs, Porphyromonas endodontatis, Parphyromonas gihgivalis, Porphyromonas gingivicanis, Porphyromonas levii and Porphyromonas macaoae);
  • Fusofeacterium e.g. F; gonadiaformans, F, moriiferum. F, naviforme, F. newog&nes, F. necrophorum necropharum, F, necrophorum fundiliforme, F. nUc!eaium nucleatum, F. nuclsatam fusiform®, F. nucieatum poiymorphum., F, nucleatum v/ncentii F. periedonticum, F. russii, F. ulcerans and F, varlurn ⁇ ',
  • Chlamydia e.g. Chlamydia: trachomatis
  • Gryptosporidiyrn e.g. G. parvum, C, hommis, C. caniS f C, felis, C. m&ieagridis and G. muris
  • Chlamydophiia e.g. Chlamydophiia abortus (Chlamydia ps/ifees), Chiamydaphila pneumoniae (Chlamydia pneumoniae) and CMamydophija psiiiati (Chlamydia psittaci)
  • Chlamydophiia e.g. Chlamydophia abortus (Chlamydia ps/ifees), Chiamydaphila pneumoniae (Chlamydia pneumoniae) and CMamydophija psiiiati (Chla
  • Leuconostoc e.g. LmwonostoG citreum, LeuconostoG ctemoris, Leucomsioc dextranicumi LmiGemstoG iaetis, Leuoonostoc mesmteroides and Leueonostoc psaudo.mesent&roid&s:, Gemeila (e.g. Gemeila bergeti, Gemeila haemQlysam, Gemeila morbiltotum and Gemeila sanguinis)', and Ureapiasma (e.g, Ureapiasma parvum and Ureapiasma urea!ytioum ⁇ ,.
  • Gemeila e.g. Gemeila bergeti, Gemeila haemQlysam, Gemeila morbiltotum and Gemeila sanguinis
  • Ureapiasma e.g, Ureapia
  • the bacterial infections treated by the combinations described herein are gram- negative bacteriai infections.
  • Particular Gram-negative bacteria thai may be treated using a combination of the invention include;
  • Enierobacteriaceae such as Escherichia coli, Klebsiella (e,g. Kiebs. pneumoniae and Klehs, oxytaca) and Proteus (e.g, Pr. mirahiiis, Pr. retigeri and Pr, vulgaris)',
  • Mycobacteria such as Mycobacterium tuberculosis
  • Enterobact&r e.g, Enferohacf&r chacae
  • the bacteria are ErHerobacteriaeeae, such as Escherichia ooii, Klebsiella (e.g. Kiebs. pneumoniae and Kiebs. oxytoea) and EhtemfoaGter (e.g. Enterobacfer cloacae).
  • Escherichia coli, Klebsiella and Enterobacter e.g. Escherichia coil, Kiebs, pneumoniae and EnterQb&cler cloacae.
  • the combination of the present invention is particularly beneficial in treating (rriulti)-drug- resistant ((M)DR) bacteria.
  • drug resistance most often builds up to carbapenemase i.e. carbapenemase-resistant strains and "extended spectrum ⁇ -lactamase" (ESBL) strains for example New Delhi Metallo-beta-lactamase-1 (NDM-1 ) resistant Klebs. Pneumonia, and NDM-1 E.coli.
  • the combinations of the present invention may be used to treat infections associated with any of the above-mentioned bacterial organisms, and in particular they may be used for killing multiplying and/or clinically latent microorganisms associated with such an infection, e.g. a Gram-negative bacterial infection.
  • Particular conditions which may be treated using the combination of the present invention include those which are caused by Gram-negative bacteria such as abscesses, asthma, bacilliary dysentry, bacterial conjunctivitis, bacterial keratitis, bacterial vaginosis, bone and joint infections, bronchitis (acute or chronic), brucellosis, bum wounds, cat scratch fever, cellulitis, chancroid, cholangitis, cholecystitis, cystic fibrosis, cystitis, nephritis, diffuse panbronchiolitis, dental caries, diseases of the upper respiratory tract, empymea, endocarditis, endometritis, enteric fever, enteritis, epididymitis, epiglottitis, eye infections, furuncles, gardnerella vaginitis, gastrointestinal infections (gastroenteritis), genital infections, gingivitis, gonorrhoea, granuloma inguinale
  • opthalmia neonatorum osteomyelitis
  • otitis e.g. otitis externa and otitis media
  • orchitis pancreatitis, paronychia, pelveoperitonitis, peritonitis, peritonitis with appendicitis, pharyngitis, pleural effusion, pneumonia, postoperative wound infections, postoperative gas gangrene, prostatitis, pseudo-membranous colitis, psittacosis, pyelonephritis, Q fever, rat-bite fever, Ritter's disease, salmonellosis, salpingitis, septic arthritis, septic infections, septicameia, systemic Infections, tonsillitis, trachoma, typhoid, urethritis, urinary tract infections, wound infections; or infections with, Escherichia colt, Kiebs.
  • Suitable acid addition salts include carboxylase -salts (e.g. formate, acetate, frifluoroaceiate, propionate, isobtiiyrate, heptanoafe, decanoate, caprate, eaprylate, stearate, acryiate, caproate, propio!ate, ascorbate, citrate, glucuronate, glufamate, glycolate, a-hydroxybutyrate, lactate, tartrate, phenyiacetate, mandeiate, phenyl pro pi on ate, pheny!butyrate, benzoate, chlorobenzoate, methylbenzoate, hydroxyben ⁇ oate, meihoxybenzoate, diniirobenzoate, o- acetoxybenZGate, salicylate, oiootihaie, isonicofinate, einrtamate, oxalate, matanaie, succinate,
  • haiide salts e.g. chloride, bromide or Iodide, salts
  • sulfonate salts e.g.
  • benzenesulfonate methyl-, bromo- or chlotO-benzenesuSfonate, xyienesy!fbnate, roethanesutfonate, ethanesu!fonate, propanesulfonate, bydroxyethanesuifonate, 1- or 2- naphthaiene-suifonate or 1 ,5-naphthalenedisulfonaie salts) or sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, phosphate, monobydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate or hitrate salts, and the like.
  • the poiymyxin is colistin or polymyxin B or a pfsarmaeeutically acceptable derivative thereof.
  • colistin sulfate, eolistirnethate sodium, or poiymyxin B sulfate Particularly preferred is eo!istirt, colistin sulfate or colistimethate sodium, e.g. colistin sulfate or colistimethate sodium.
  • coiistimethate sodium Coiistimethate sodium is also knowm in the ari as colistin methanesulfonate sodium or colistin sulfomethate sodium.
  • Colistin is also known as polymyxin E and is an antibiotic produced by certain strains of the bacteria Paenibacilius polymyxa. Colistin has the following chemical structure and the iUPAC chemical name
  • Colistin is available commercially as colistin sulfate and colistimethate sodium. Colistin sulfate is cationic and colistimethate sodium is anionic. Colistimethate sodium is also readily hydrolysed to a variety of methanesulfonated derivatives.
  • Piperine is the alkaloid responsible for the pungency of black pepper ⁇ Piper nigrum) and long pepper (Piper longum). Piperine has the following chemical structure and has the lUPAC Chemical name of 1
  • Piperine may exist as stereoisomers.
  • the present invention thus contemplates the use of all the stereoisomers, particularly all geometric isomers of piperine.
  • the invention contemplates the use the isomer chavicine. Chavicine is one of four diastereomeric geometric isomers of piperine and has the following structure:
  • chavicine is the alkaloid responsible for the pungency of black pepper and long pepper.
  • Compounds for use aecording to the invention may be administered as the raw materiaS but the active ingredients are preferably provided in the form of pharmaceutical compositions.
  • the active ingredients may be used either as separate formulations or as a single, combined formulation. When combined in the same formulation it will be appreciated that the two compounds must be stable and compatible with each other and the other components of the formulation.
  • Formulations of the invention include those suitable for oral, parenteral (including subcutaneous e.g. by injection or by depot tablet, Intradermal, intrathecal, intramuscular e.g. by depot and intravenous), rectal and topical ⁇ including dermal, buccal and sublingual) or in a form suitable for administration by inhalation or insufflation administration.
  • parenteral including subcutaneous e.g. by injection or by depot tablet, Intradermal, intrathecal, intramuscular e.g. by depot and intravenous
  • the most suitable route of administration may depend upon: the condition and disorder of the patient.
  • compositions of the invention are formulated for oral or topical administration, in a preferred embodiment, the composition is a cream or an ointment adapted for nasal administration, in particular for delivery to the anterior nares.
  • formulations may conveniently be presented in unit dosage form and may be prepared by any of the methods well known in the art of pharmacy e.g. as described in "Remington: The Science and Practice of Pharmacy", Lippincott Williams and Wilkins, 21 st Edition, (2005). Suitable methods include the step of bringing info association to active ingredients with a carrier which constitutes one or more excipients, In general, formulations are prepared by uniformly and intimately bringing Into association the active ingredients with liquid carriers or finely divided solid carriers or both and then, if necessary, shaping the product into the desired formulation, it will be appreciated that when the two active ingredients are administered independently, each may be administered by a different means.
  • the active ingredients When formulated with excipients, the active ingredients may be present In a concentration from 0, 1 to 98.5% (such as from 0.5 to 95%) by weight of the total mixture; conveniently from 30 to 95% for tablets and capsules and 0.01 to 50% (such as from 3 to 50%) for liquid preparations.
  • Formulations suitable for oral administration may be presented as discrete units such as capsules, cachets or tablets (e.g. chevvable tablets in particular for paediatrie administration), each containing a predetermined amount of active ingredient; as powder or granules; as a solution or suspension in an aqueous liquid or non-aqueous liquid: or as an oil-in-water liquid emulsion or water-in-oil liquid emulsion.
  • the active ingredients may also be presented a bolus, electuary or paste.
  • a tablet may be made by compression or moulding, optionally with one or more exciptents.
  • Compressed tablets may be prepared by compressing in a suitable machine the active ingredient in a free-flowing form such as a powder or granules, optionally mixed with other conventional excipients such as binding agents (e.g. syrup, acacia, gelatin, sorbitol, tragacanth, mucilage of starch, polyvinylpyrrolidone and/or hydroxymethyl cellulose), fillers (e.g. lactose, sugar, microcrystalline cellulose, maize-starch, calcium phosphate and/or sorbitol), lubricants (e.g.
  • binding agents e.g. syrup, acacia, gelatin, sorbitol, tragacanth, mucilage of starch, polyvinylpyrrolidone and/or hydroxymethyl cellulose
  • fillers e.g. lactose, sugar, microcrystalline cellulose, maize
  • Moulded tablets may be made by moulding in a suitable machine a mixture of the powdered active ingredient with an inert liquid diluent.
  • the tablets may be optionally coated or scored and may be formulated so as to provide controlled release (e.g. delayed, sustained, or pulsed release, or a combination of immediate release and controlled release) of the active ingredients.
  • the active ingredients may be incorporated into oral liquid preparations such as aqueous or oily suspensions, solutions, emulsions, syrups or elixirs.
  • Formulations containing the active ingredients may also be presented as a dry product for constitution with water or another suitable vehicle before use.
  • Such liquid preparations may contain conventional additives such as suspending agents (e.g. sorbitol syrup, methyl cellulose, glucose/sugar syrup, gelatin, hydroxymethyl cellulose, carboxymethyl cellulose, aluminium stearate gel and/or hydrogenated edible fats), emulsifying agents (e.g. lecithin, sorbitan mono-oleate and/or acacia), non-aqueous vehicles (e.g.
  • suspending agents e.g. sorbitol syrup, methyl cellulose, glucose/sugar syrup, gelatin, hydroxymethyl cellulose, carboxymethyl cellulose, aluminium stearate gel and/or hydrogenated edible fats
  • emulsifying agents
  • edible oils such as almond oil, fractionated coconut oil, oily esters, propylene glycol and/or ethyl alcohol), and preservatives (e.g. methyl or propyl p-hydroxybenzoates and/or sorbic acid).
  • Topical compositions which are useful for treating disorders of the skin or of membranes accessible by digitation (such as membrane of the mouth, vagina, cervix, anus and rectum), include creams, ointments, lotions, sprays, gels and sterile aqueous solutions or suspensions.
  • topical compositions include those in which the active ingredients are dissolved or dispersed in a dermatological vehicle known in the art (e.g. aqueous or nonaqueous gels, ointments, water-in-oil or oii-in-water emulsions).
  • Constituents of such vehicles may comprise water, aqueous buffer solutions, non-aqueous solvents (such as ethanol, isopropanol, benzyl alcohol, 2-(2-ethoxyethoxy)ethanol, propylene glycol, propylene glycol mGholaurate, glycofural or glycerol), oils (e.g. a mineral oil such as a liquid paraffin, natural or synthetic triglycerides such as Mig!yolTM, or silicone ops: such as dimethicoiie).
  • non-aqueous solvents such as ethanol, isopropanol, benzyl alcohol, 2-(2-ethoxyethoxy)ethanol, propylene glycol, propylene glycol mGholaurate, glycofural or glycerol
  • oils e.g. a mineral oil such as a liquid paraffin, natural or synthetic triglycerides such as Mig!yolTM, or silicone ops: such as dimethicoiie
  • the dermatological vehicle employed may contain one or more components selected from the following list; a spiubjjising agent or solvent (e.g. a ⁇ -cyc!odextrin, such as hydroxypropyl: p-cyc!odextrin, or an alcohol or poiyoi such as eihanol propylene glycol or glycerol); a thickening agent (e.g. hydroxyrriethy! cellulose, hydroxypropyl cellulose, carboxyrnethyl cellulose or carbomer); a gelling agent (e.g.
  • Topical formulations may also be formulated as a transdermal patch.
  • topical pharmaceutical compositions such as creams, ointments, lotions, sprays and sterile aqueous solutions or suspensioris are well known In the art. Suitable methods of preparing topical pharmaceutical compositions are described, e.g. in W095109-9-9, US 6974585, WO2006048747, as well as in documents cited in any of these references.
  • compositions according to the present Invention may be used to treat • a Variety of skin or membrane disorders, such as infections of the skin or membranes (e.g. infections- of nasal membranes, axilla, groin, perineum,; rectum, dermaiitic skin, skin ulcers, and sites of insertion of medical equipment such as i.v. needles, catheters and tracheostomy or feeding tubes) with any of the bacteria, fungi described above, (e.g. any of the Staphylococci, Streptococci.. Mycobacteria or Pseudomonas organisms mentioned hereinbefore, such as S. aureus (e.g. Methicil!in resistant S, aureus (MRSA))),
  • infections of the skin or membranes e.g. infections- of nasal membranes, axilla, groin, perineum,; rectum, dermaiitic skin, skin ulcers, and sites of insertion of medical equipment such as i.v. needles
  • Particular bacterial conditions that may be treated by topical pharmaceutical compositions of the present invention also include the skin- and membrane-related conditions disclosed hereinbefore, as well as: acne vulgaris; rosacea (including efythematotelangieetatie rosacea, papulopustular rosacea, phymatous rosacea and ocular rosacea); erysipelas; eiythrasma; ecthyma; ecthyma gangrenosum; impetigo; paronychia; cellulitis; folliculitis (including hot tub folliculitis); furunculosis; carbunculosis; staphylococcal scalded skin syndrome; surgical scarlet fever; streptococcal peri-ana!
  • simiae M. gordonae, M. haemophilum, M. avium, M. intracellulars, M. chelonae (including M. abscessus) or M. fortuitum infections, swimming pool (or fish tank) granuloma, lymphadenitis and Buru!i ulcer (Bairnsdale ulcer, Searles' ulcer, Kakerifu ulcer or Toro ulcer)); as well as infected eczema, burns, abrasions and skin wounds.
  • Combinations for use according to the invention may be presented in a pack or dispenser device which may contain one or more unit dosage forms containing the active ingredients.
  • the pack may, e.g. comprise metal or plastic foil, such as a blister pack.
  • compositions are intended for administration as two separate compositions these may be presented in the form of a twin pack.
  • compositions may also be prescribed to the patient in "patient packs" containing the whole course of treatment in a single package, usually a blister pack.
  • Patient packs have an advantage over traditional prescriptions, where a pharmacist divides a patients' supply of a pharmaceutical from a bulk supply, in that the patient always has access to the package insert contained in the patient pack, normally missing in traditional prescriptions. The inclusion of the package insert has been shown to improve patient compliance with the physician's instructions.
  • Piperine may for example be extracted from black pepper using dichloromethane. This extraction is known in the art.
  • a suitable dosage and formulation for colistin sulfate is for instance described in the product label for Colomycin® which can be found at http://www. medicines. org. uk/emc/medicine/6301/SPC/Colomvcin+Tablets/
  • a suitable dosage and formulation for colistimethate sodium is described in the product label for colistimethate sodium 1. Million I.U, Powder for Solution for Injection which can be found at Suitable dosages and formulations for the administration ⁇ 5f . pipeline are also known in the art.
  • piperine is commercially available as Bioperine®,
  • a patient pack comprising at least ' one active ing red lent of the combination according to the invention and an information insert containing directions on the use of the combination of the invention.
  • a double pack comprising in association for separate administration, an antimicrobial agent, preferably having biological activity against clinically latent microorganisms, and one or more of the compounds disc!osed herein preferably having biological activity against clinically latent microorganisms.
  • doses employed for adult human treatment will typically be in the range of 0.02 to 5000 mg per day, preferably 1 to 1500 mg per day.
  • the desired dose may conveniently be presented in a single dose or as divided doses administered at appropriate intervals, e.g. as two, three, four or more sub- doses per day.
  • Test procedures that may be employed to determine the biological (e.g. bactericidal or antimicrobial) activity of the active ingredients include those known, to persons skilled in the art for determining;
  • WO2000028074 describes a suitable method of screening compounds to determine their ability to kill clinically latent microorganisms.
  • a typical method may include the following steps:
  • the phenotypically resistant sub-population may be seen as representative of clinically latent bacteria which remain metaboltcally active in vivo and which can result in relapse or onset of disease.
  • methods for determining activity against log phase bacteria include a determination, under standard conditions ⁇ i.e. conditions known to those skilled in the art, such as those described in WO 2005014585, the disclosures of which document are hereby incorporated by reference), of Minimum Inhibitory Concentration ("MIC”) or Minimum Bactericidal Concentration (“MBC”) for a test compound. Specific examples of such methods are described below.
  • Example 1 In vitro synergistic effect of piperine (HT013018) and colistin against log phase NDM-1 Escherichia coli using the chequerboard method Growth of bacteria
  • Coiistin was in the form of colistimethate sodium.
  • the interactiGn of the combination was defined as showing synergy if the FlCI was ⁇ 0,5, no 'interaction if the F!CI was >0.S but ⁇ 4.0 and antagonism sf the FICI was >4.0.
  • the FICI was equal to 0.5 indicating that coiistin (colistsmeihate sodium) and piperine exhibited a synergistic effect againsUog phase
  • Example 2 In vitro synergistic effect of coiistin and piperine (HTQ13Q18) against log phase ND&1-1 Enimobacter cloacae using the chesquerboard method
  • the FICI was equal to 0,1875 indicating that colistin (colistimethate sodium) and piperine exhibited a synergistic effect against log phase NDM-1 Enterobacter clocae.
  • Example 3 In vitro synergistic effect of colistin and piperine (HT013018) against log phase NDM-1 Klebsiella pneumoniae using the chequerboard method
  • Piperine and colistin were obtained from commercially available sources. Colistin was in the form of colistimethate sodium.
  • the FiCI was equal to 0.15825 indicating that colistin (colistimethafe sodium) and piperine exhibited a synergistic effect against log phase NDM-1 K.pneumoniae.
  • Example 4 In vitro synergistic effect of piperine in combination with colistin against log phase NDM-1 Klebsiella Pneumoniae.
  • the objective of this example was to test the synergistic effect of piperine and colistin in combination against log phase NDM-1 Klebsiella Pneumoniae (BAA2473) by time-Kill methods over a time period of 24 hours,
  • time-kill methods are another accepted test for aseertainlng the presence or absence of synergy, and involve comparing the dynamic effect of a drug combination With each drug alone when assessing the effect on bacterial log or stationary- growth over time. The results can either show that the drug combination is synergistic, additive or antagonistic.
  • the overnight culture was diluted with nutrient broth (Oxoid) to 107 CFU/ml and 280 ⁇ ! and 290 ⁇ of the culture was added to each combination well and drug respectively, to make the final concentration of 300 ⁇ .
  • Figures 1 to 4 show that piperine at concentrations of 256, 128 and 64 mg/ml had little or no effect against NDM-1 K.pneumoniae. When used in combination with colistin, however, a significant synergistic effect can be seen.
  • Figures 1 and 2 demonstrate a complete kill of bacteria at 7 hours when piperine and colistin (colistimethate sodium) are used in combination, and
  • Figures 3 and 4 demonstrate a complete kill of bacteria after 24 hours for the combination.

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Epidemiology (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Immunology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Communicable Diseases (AREA)
  • Oncology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

La présente invention concerne une combinaison contenant de la pipérine ou un dérivé ou un stéréoisomère pharmaceutiquement acceptable de celle-ci, ainsi qu'une polymyxine sélectionnée parmi la polymyxine E et la colistine ou un dérivé pharmaceutiquement acceptable de celle-ci. La combinaison selon l'invention est particulièrement utile dans le traitement et/ou la prévention des infections microbiennes.
PCT/GB2017/051781 2016-06-22 2017-06-19 Combinaison comprenant de la pipérine et des polymyxines pour le traitement d'infections microbiennes WO2017220982A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GB1610869.8 2016-06-22
GBGB1610869.8A GB201610869D0 (en) 2016-06-22 2016-06-22 Combination

Publications (1)

Publication Number Publication Date
WO2017220982A1 true WO2017220982A1 (fr) 2017-12-28

Family

ID=56895134

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/GB2017/051781 WO2017220982A1 (fr) 2016-06-22 2017-06-19 Combinaison comprenant de la pipérine et des polymyxines pour le traitement d'infections microbiennes

Country Status (2)

Country Link
GB (1) GB201610869D0 (fr)
WO (1) WO2017220982A1 (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN116850266A (zh) * 2023-06-02 2023-10-10 大连理工大学 多粘菌素e甲磺酸钠在制备治疗三阴性乳腺癌药物中的应用

Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1995010999A1 (fr) 1993-10-22 1995-04-27 Smithkline Beecham Corporation Nouvelle composition
WO2000028074A1 (fr) 1998-11-09 2000-05-18 St. George's Enterprises Limited Procede de criblage d'agents antibacteriens
WO2004087154A1 (fr) * 2003-03-31 2004-10-14 Council Of Scientific And Industrial Research Utilisation d'extrait de cuminum cyminum et de piperine pour potentialiser la bioefficacite d'anti-infectieux
WO2005014585A1 (fr) 2003-08-08 2005-02-17 Ulysses Pharmaceutical Products Inc. Quinazolinyl nitrofuranes halogenes utilises comme agents antibacteriens
US6974585B2 (en) 2001-08-01 2005-12-13 Medlogic Global Limited Durable multi-component antibiotic formulation for topical use
WO2006048747A1 (fr) 2004-11-08 2006-05-11 Glenmark Pharmaceuticals Limited Compositions pharmaceutiques topiques contenant un compose anti-acne et un compose antibiotique
WO2014147405A1 (fr) 2013-03-22 2014-09-25 Helperby Therapeutics Limited Combinaison comprenant de la zidovudine et de la polymyxine
WO2015114340A1 (fr) * 2014-01-30 2015-08-06 Helperby Therapeutics Limited Thérapies combinatoires par zidovudine pour le traitement d'infections microbiennes

Patent Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1995010999A1 (fr) 1993-10-22 1995-04-27 Smithkline Beecham Corporation Nouvelle composition
WO2000028074A1 (fr) 1998-11-09 2000-05-18 St. George's Enterprises Limited Procede de criblage d'agents antibacteriens
US6974585B2 (en) 2001-08-01 2005-12-13 Medlogic Global Limited Durable multi-component antibiotic formulation for topical use
WO2004087154A1 (fr) * 2003-03-31 2004-10-14 Council Of Scientific And Industrial Research Utilisation d'extrait de cuminum cyminum et de piperine pour potentialiser la bioefficacite d'anti-infectieux
WO2005014585A1 (fr) 2003-08-08 2005-02-17 Ulysses Pharmaceutical Products Inc. Quinazolinyl nitrofuranes halogenes utilises comme agents antibacteriens
WO2006048747A1 (fr) 2004-11-08 2006-05-11 Glenmark Pharmaceuticals Limited Compositions pharmaceutiques topiques contenant un compose anti-acne et un compose antibiotique
WO2014147405A1 (fr) 2013-03-22 2014-09-25 Helperby Therapeutics Limited Combinaison comprenant de la zidovudine et de la polymyxine
WO2015114340A1 (fr) * 2014-01-30 2015-08-06 Helperby Therapeutics Limited Thérapies combinatoires par zidovudine pour le traitement d'infections microbiennes

Non-Patent Citations (18)

* Cited by examiner, † Cited by third party
Title
"Remington: The Science and Practice of Pharmacy, 21st Edition,", 2005, LIPPINCOTT WILLIAMS AND WILKINS
ANTIMICROB CHEMO, vol. 68, 2013, pages 374 - 384
ANTIMICROB. AGENTS CHEMOTHER., vol. 44, 2000, pages 1771 - 1777
BALAJI V ET AL: "Polymyxins: Antimicrobial susceptibility concerns and therapeutic options.", INDIAN JOURNAL OF MEDICAL MICROBIOLOGY, vol. 29, no. 3, July 2011 (2011-07-01), pages 230 - 242, XP009500107, ISSN: 1998-3646 *
FEMS MICROBIOL. LETT., vol. 202, 2001, pages 59 - 65
J BACTERIOL, vol. 182, 2000, pages 1794 - 1801
J BACTERIOL, vol. 182, 2000, pages 6358 - 6365
J BACTERIOL, vol. 183, 2001, pages 6746 - 6751
J, ANTIMICROB. CHEMOTHER.,, vol. 4, 1988, pages 395 - 404
J. BACFERIOL., vol. 179, 1997, pages 6688 - 6691
J. MED MICROBIOL.,, vol. 38, 1993, pages 197 - 202
LANCET, vol. 357, 2001, pages 1179
LANCET, vol. 358, 2001, pages 207 - 208
NATURE REVIEWS, DRUG DISCOVERY, vol. 1, 2002, pages 895 - 910
ORHAN ET AL., J. CLIN MICROBIOL., vol. 43, no. 1, 2005, pages 140
PROC. NATL. ACAD. SCI. USA, vol. 92, 1995, pages 11736 - 11740
SCIENCE, vol. 264, 1994, pages 388 - 393
TRENDS IN MICROBIOLOGY, vol. 13, 2005, pages 34 - 40

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN116850266A (zh) * 2023-06-02 2023-10-10 大连理工大学 多粘菌素e甲磺酸钠在制备治疗三阴性乳腺癌药物中的应用

Also Published As

Publication number Publication date
GB201610869D0 (en) 2016-08-03

Similar Documents

Publication Publication Date Title
EP3099298B1 (fr) Thérapies combinatoires par zidovudine pour le traitement d'infections microbiennes
US9757427B2 (en) Combination comprising zidovudine and polymyxin
EP2613774B1 (fr) Combinaison de phenoxybenzamine et de polymixine e pour traiter les infections microbiennes
US10335454B2 (en) Combination and use
EP3484587B1 (fr) Combinaison comprenant de la zidovudine et un carbapenem
EP2552440B1 (fr) Nouveau traitement combiné et utilisation associée
US20160038438A1 (en) Combination of nordihydroguaiaretic acid and an aminoglycoside
US20190111067A1 (en) Antimicrobial combinations and their use in the treatment of microbial infection
US20190328832A1 (en) Antimicrobial combinations
WO2017220982A1 (fr) Combinaison comprenant de la pipérine et des polymyxines pour le traitement d'infections microbiennes
WO2017098274A1 (fr) Formulation
US10736888B2 (en) Triple combination
EP3522875A1 (fr) Combinaison

Legal Events

Date Code Title Description
DPE1 Request for preliminary examination filed after expiration of 19th month from priority date (pct application filed from 20040101)
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 17737016

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

32PN Ep: public notification in the ep bulletin as address of the adressee cannot be established

Free format text: NOTING OF LOSS OF RIGHTS PURSUANT TO RULE 112(1) EPC (EPO FORM 1205A DATED 29/03/2019)

122 Ep: pct application non-entry in european phase

Ref document number: 17737016

Country of ref document: EP

Kind code of ref document: A1