WO2017098274A1 - Formulation - Google Patents

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Publication number
WO2017098274A1
WO2017098274A1 PCT/GB2016/053901 GB2016053901W WO2017098274A1 WO 2017098274 A1 WO2017098274 A1 WO 2017098274A1 GB 2016053901 W GB2016053901 W GB 2016053901W WO 2017098274 A1 WO2017098274 A1 WO 2017098274A1
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WIPO (PCT)
Prior art keywords
infections
colistin
zidovudine
combination
microbial infection
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PCT/GB2016/053901
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English (en)
Inventor
Professor Anthony COATES
Yanmin Hu
Original Assignee
Helperby Therapeutic Limited
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Publication of WO2017098274A1 publication Critical patent/WO2017098274A1/fr

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    • 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
    • A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
    • A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
    • A61K31/7064—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines
    • A61K31/7068—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid
    • A61K31/7072—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid having two oxo groups directly attached to the pyrimidine ring, e.g. uridine, uridylic acid, thymidine, zidovudine
    • 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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P33/00—Antiparasitic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • 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 use of zidovudine in combination with coiistin for treating microbiai infections, wherein the concentration ratio of zidovudine to co!istin is from about 8:1 to about 1 :2.
  • Zidovudine is a nucleoside analogue reverse-transcriptase inhibitor, a type of antiretroviral drug which is used for the treatment of HIV/AIDS infection.
  • ZT zidovudine
  • the antibacterial effect of zidovudine (AZT) has been demonstrated both in vitro and in vivo with experimental models of gram-negative bacteria infections (Hermann et al., Antimicrob Agents Chemther. 1992 May; 36(5): 081-1085).
  • zidovudine being active as an anti-microbial when combined with gentamicin.
  • Doleans-Jordheim A. et a! for example disclosed that zidovudine (AZT) had a bactericidal effect on some enterobacteria, yet could induce resistance in Escherichia coli (Eur J Clin Microbiol Infect Dis. 201 1 Oct;30(10): 1249-56).
  • ZT zidovudine
  • Coiistin (polymyxin E) is a polymyxin antibiotic produced by certain strains of Bacillus poiymyxa var. colistinus. Coiistin is effective against most gram-negative bacilli and is used as a polypeptide antibiotic.
  • coiistin which are available commercially: coiistin sulfate and colistimethate sodium (coiistin methanesulfonate sodium, coiistin sulfomethate sodium).
  • coiistin products which are marketed in India are Xylistin (marketed by Cipla Pharmaceuticals, Ltd., India) and Koolistin (marketed by Biocon Ltd., India).
  • Coiistin has been used in combination with rifampicin against multidrug-resistant (MDR) strains of Acinetobacter baumannii and shown to have an in vitro synergistic effect against the bacteria (Hogg et al., J Antimicrob Chemther 1998; 41 : 494-495; Motaouakkil S et al J Infect (2006) 53 274-278; Bassetti M et al J Antimicrob Chemo (2008) 61 4 7-420; Zhou A et al The AAPS J published online on 16 October 2013 DOI:10.1208/s12248-013-9537-8).
  • MDR multidrug-resistant
  • Lee JJ et al discloses the results of using a combination of coiistin and rifampicin in an in vitro model of MDR-A baumannii. Synergy was observed at some concentrations over some time periods. A mechanism is proposed whereby colistin not only self-promotes its own entry into the bacteria but thereby increases the penetration by rifampicin.
  • Tascini C et al disclose the use of the same combination in carbapenem-resistant Klebsiella pneumoniae.
  • the use of the combination in MDR- K pneumonia is proposed as having a clinical role.
  • WO 2014/147405 A1 discloses the use of zidovudine in combination with a polymyxin selected from colistin and polymyxin B for treating a microbial infection.
  • WO 2014/147405 discloses the use of zidovudine and colistin at a zidovudine to colistin ratio of 1 :4 (4 ⁇ g/ml : 16 g/ml) against log phase Klebsiella and reports a time-to-kill value of 24 hours.
  • the inventors have, however, surprisingly found that when zidovudine and colistin are used at a concentration ratio of between about 8:1 and about 1 :2, the antimicrobial activity of the combination of agents is significantly improved. Compared to the concentration ratio of zidovudine to colistin disclosed in WO 2014/147405 - namely 1 :4 - the inventors found for instance that the combinations of the present invention provide a surprisingly faster kill of microorganisms associated with a microbial infection.
  • the combinations of the invention offer the opportunity to provide improved treatment of microbial infections.
  • the combinations may therefore be used to shorten chemotherapy regimes and may result in a reduction in the emergence of microbial resistance associated with the use of such combinations.
  • the antibacterial activity of the combined agents is preferably synergistic, i.e. greater than the expected additive effect of each agent at the stated dosage level.
  • Synergy in the context of antimicrobials 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 "chequerboard" technique.
  • FICI fractional inhibitory concentration index
  • Another accepted test for ascertaining the presence or absence of synergy is to use time-kill methods where the dynamic effect of a drug combination is compared to each drug alone when assessing the effect on bacterial log or stationary-growth over time. Again, the possible results are for synergistic, additive or antagonistic effects.
  • zidovudine in combination with colistin for treating a microbial infection, wherein the concentration ratio of zidovudine to colistin is from about 8: 1 to about 1 :2.
  • a combination for use in treating a microbial infection wherein the combination comprises zidovudine and colistin, wherein the concentration ratio of zidovudine to colistin is from about 8:1 to about 1 :2.
  • a pharmaceutical composition comprising zidovudine in combination with colistin and a pharmaceutically acceptable adjuvant, diluent or carrier for treating a microbial infection, preferably for killing clinically latent microorganisms associated with a microbial infection, wherein the concentration ratio of zidovudine to colistin is from about 8:1 to about 1 :2.
  • the invention provides the use of zidovudine in combination with colistin for the manufacture of a medicament for treating a microbial infection, preferably killing clinically latent microorganisms associated with a microbial infection, wherein the concentration ratio of zidovudine to colistin is from about 8:1 to about 1 :2.
  • the invention provides a method of treating a microbial infection, preferably killing clinically latent microorganisms associated with a microbial infection which comprises administering to a mammal, including man, zidovudine and colistin wherein the concentration ratio of zidovudine to colistin is from about 8:1 to about 1 :2.
  • the term "in combination with” covers both separate and sequential administration of zidovudine and colistin.
  • the agents when the agents are administered sequentially, either the zidovudine or colistin may be administered first.
  • the agents may be administered either in the same or a different pharmaceutical composition.
  • Adjunctive therapy i.e. where one agent is used as a primary treatment and the other agent is used to assist that primary treatment, is also an embodiment of the present i nvention .
  • a product comprising zidovudine and colistin, as a combined preparation for simultaneous, separate or sequential use in treating microbial infections particularly by killing clinically latent microorganisms associated with a microbial infection, wherein the concentration ratio of zidovudine to colistin is from about 8:1 to about 1 :2.
  • 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. References herein to the treatment of a microbial infection therefore include kilting multiplying and/or clinically latent microorganisms associated with such infections. Preferably, the combinations of the present invention are used to kill clinically latent microorganisms associated with microbial infections.
  • the zidovudine and colistin are included in the combination at a specific concentration ratio, in particular, the ratio of zidovudine to colistin is from about 8:1 to about 1 :2.
  • the zidovudine to colistin concentration ratio may be about 8:1 , 7:1 , 6:1 , 5:1 , 4:1 , 3:1 , 2:1 , 1 :1 , or 1 :2.
  • the zidovudine to colistin concentration ratio is about 8: 1 or about 4: 1 or about 2: 1 or about 1 : 1 or about 1 :2.
  • the zidovudine to colistin concentration ratio is not 1 :4.
  • concentration of colistin in the combination of the present invention is up to 8 g/ml.
  • concentration of colistin in the combination is at least about 4 g/ml. For example about 4 to about 8 ⁇ g ml.
  • the zidovudine concentration is not particularly limited and will be determined by the concentration of colistin and the concentration ratio of zidovudine to colistin.
  • the ratio of zidovudine to colistin is from about 8:1 to about 1 :2, wherein the ratio is based on a colistin concentration of at least about 4 pg/ml.
  • the zidovudine to colistin concentration ratio is about 8:1 or about 4:1 , or about 2:1 or about 1 :1 or about 1 :2, wherein the ratio is based on a colistin concentration of at least about 4 g/ml.
  • kill means a loss of viability as assessed by a lack of metabolic activity.
  • clinical latent microorganism means a microorganism that is metabolically 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.
  • 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. [ 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, in addition, clinically latent microorganisms are phenotypicaliy 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).
  • microorganisms means fungi and bacteria. References herein to "microbiar, " antimicrobiaf and “antimicrobially” shall be interpreted accordingly.
  • microbiar means fungal or bacterial
  • microbial infection means any fungal or bacterial infection.
  • microbial in these contexts, means "bacterial.”
  • bacteria and derivatives thereof, such as “microbial infection” 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, saprophyticus, Staph, auricularis, Staph, capitis capitis, Staph, c. ureolyticus, Staph, caprae, Staph, cohnii cohnii, Staph, c. urealyticus, Staph, equorum, Staph, gallinarum, Staph, haemolyticus, Staph, hominis hominis, Staph, h. novobiosepticius, Staph, hyicus, Staph.
  • Staphylococci e.g. Staph, aureus, Staph, epidermidis, Staph, saprophyticus, Staph, auricularis, Staph, capitis capitis, Staph, c. ureolyticus
  • Streptococci e.g.beta-haemolytic, pyogenic streptococci (such as Strept. agalactiae, Strept. canis, Strept. dysgalactiae dysgalactiae, Strept. dysgalactiae equisimilis, Strept. equi equi, Strept. equi zooepidemicus, Strept. iniae, Strept. porcinus and Strept. pyogenes),
  • Strept. constellatus constellatus Strept. constellatus pharyngidis and Strept. intermedius
  • oral streptococci of the "mitis” alpha-haemolytic - Streptococcus "viridans", such as Strept. mitis, Strept. oralis, Strept. sanguinis, Strept. cristatus, Strept. gordonii and Strept. parasanguinis
  • "salivarius” non-haemolytic, such as Strept. salivarius and Strept. vestibularis
  • mutans teeth-surface streptococci, such as Strept. criceti, Strept. mutans, Strept ratti and Strept.
  • sobrinus groups Strept. acidominimus, Strept. bovis, Strept. faecalis, Strept. equinus, Strept. pneumoniae and Strept. suis, or Streptococci alternatively classified as Group A, B, C, D, E, G, L, P, U or V Streptococcus); Gram-negative cocci, such as Neisseria gonorrhoeae, Neisseria meningitidis. Neisseria cinerea, Neisseria elongata, Neisseria flavescens, Neisseria lactamica, Neisseria mucosa, Neisseria sicca, Neisseria subfiava and Neisseria weaver!;
  • Gram-negative cocci such as Neisseria gonorrhoeae, Neisseria meningitidis. Neisseria cinerea, Neisseria elongata, Neisseria flavescens, Neisseria lac
  • Bacillaceae such as Bacillus anthracis, Bacillus subtilis, Bacillus thuringiensis, Bacillus stearothermophilus and Bacillus cereus;
  • Enterobacteriaceae such as Escherichia coli, 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. Klebs.
  • Escherichia coli Enterobacter aerogenes, Enterobacter agglomerans and Enterobacter cloacae
  • Citrobacter such as Citrob. freundii and Citrob. divernis
  • Hafnia
  • pneumoniae Klebs. oxytoca, Klebs. ornitholytica, Klebs. planticola, Klebs. ozaenae, Klebs. terrigena, Klebs. granuiomatis (Calymmatobacterium granulomatis) and Klebs. rhinoscieromatis), Proteus (e.g. Pr. mirabiiis, Pr. rettgeri and Pr. vulgaris), Providencia (e.g. Providencia alcalifaciens, Providencia rettgeri and Providencia stuartif), Serratia (e.g.
  • Serratia marcescens and Serratia liquifaciens e.g. Yersinia enterocolitica, Yersinia pestis and Yersinia pseudotuberculosis
  • Yersinia e.g. Yersinia enterocolitica, Yersinia pestis and Yersinia pseudotuberculosis
  • Enterococci e.g. Enterococcus avium, Enterococcus casseliflavus, Enterococcus cecorum, Enterococcus dispar, Enterococcus durans, Enterococcus faecalis, Enterococcus faecium, Enterococcus flavescens, Enterococcus gallinarum, Enterococcus hirae, Enterococcus malodoratus, Enterococcus mundtii, Enterococcus pseudoavium, Enterococcus raffinosus and Enterococcus solitarius);
  • Enterococci e.g. Enterococcus avium, Enterococcus casseliflavus, Enterococcus cecorum, Enterococcus dispar, Enterococcus durans, Enterococcus faecalis, Enterococcus faecium, Enterococcus flavescens, Enter
  • Helicobacter e.g. Helicobacter pylori, Helicobacter cinaedi and Helicobacter fennelliae
  • Acinetobacter e.g. A. baumanii, A. calcoaceticus, A. haemolyticus, A. johnsonii, A. junii, A. Iwoffi and A. radioresistens
  • Pseudomonas e.g. Ps. aeruginosa, Ps. maltophilia (Stenotrophomonas maltophilia), 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
  • 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. clostridbforme, 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. ureatytt ' cum;
  • Mycobacteria e.g. Mycobacterium tuberculosis, Mycobacterium avium, Mycobacterium fortuitum, Mycobacterium marinum, Mycobacterium kansasii, Mycobacterium chelonae, Mycobacterium abscessus, Mycobacterium leprae, Mycobacterium smegmitis, Mycobacterium afncanum, Mycobacterium alvei, Mycobacterium asiaticum, Mycobacterium aurum, Mycobacterium bohemicum, Mycobacterium bovis, Mycobacterium branderi, Mycobacterium brumae, Mycobacterium celatum, Mycobacterium chubense, Mycobacterium confluentis, Mycobacterium conspicuum, Mycobacterium cookii, Mycobacterium flavescens, Mycobacterium gadtum, Mycobacterium gastri, Mycobacterium genavense, Mycobacterium gordonae,
  • Haemophilus influenzae Haemophilus ducreyi, Haemophilus aegyptius, Haemophilus parainfluenzae, Haemophilus haemolyticus and Haemophilus parahaemolyticus);
  • Actinobaciilus e.g. Actinobacillus actinomycetemcomitans, Actinobacillus equuli, Actinobacillus hominis, Actinobacillus lignieresii, Actinobacillus suis and Actinobacillus ureae
  • Actinobaciilus e.g. Actinobacillus actinomycetemcomitans, Actinobacillus equuli, Actinobacillus hominis, Actinobacillus lignieresii, Actinobacillus suis and Actinobacillus ureae
  • Actinomyces e.g. Actinomyces israelii
  • Brucella e.g. Brucella abortus, Brucella canis, Brucella melintensis and Brucella suis
  • Brucella abortus e.g. Brucella abortus, Brucella canis, Brucella melintensis and Brucella suis
  • Campylobacter e.g. Campylobacter jejuni, Campylobacter coli, Campylobacter lari and Campylobacter fetus
  • Vibrio e.g. Vibrio choierae and Vibrio parahaemolyticus, Vibrio alginolyticus, Vibrio carchariae, Vibrio fluvialis, Vibrio furnissii, Vibrio hollisae, Vibrio metschnikovii, Vibrio mimicus and Vibrio vulnificus;
  • Corynebacteriaceae e.g. Corynebacterium diphtheriae, Corynebacterium jeikeum and Corynebacterium urealyticum
  • Corynebacteriaceae e.g. Corynebacterium diphtheriae, Corynebacterium jeikeum and Corynebacterium urealyticum
  • Spirochaetaceae such as Borrelia (e.g. Borrelia recurrentis, Borrelia burgdorferi, Borrelia afzelii, Borrelia andersonii, Borrelia bissettii, Borrelia garinii, Borrelia japonica, Borrelia lusitaniae, Borrelia tanukii, Borrelia turdi, Borrelia valaisiana, Borrelia caucasica, Borrelia crocidurae, Borrelia duttoni, Borrelia graingeri, Borrelia hermsii, Borrelia hispanica, Borrelia latyschewii, Borrelia mazzottii, Borrelia parkeri, Borrelia persica, Borrelia turicatae and Borrelia venezuelensis) and Treponema ⁇ Treponema pallidum ssp.
  • Borrelia e.g. Borrelia recurrentis,
  • Pasteurella e.g. Pasteurella aerogenes, Pasteurella bettyae, Pasteurella canis, Pasteurella dagmatis, Pasteurella gallinarum, Pasteurella haemolytica, Pasteurella multocida multocida, Pasteurella multocida gallicida, Pasteurella multocida septica, Pasteurella pneumotropica and Pasteurella stomatis
  • Pasteurella e.g. Pasteurella aerogenes, Pasteurella bettyae, Pasteurella canis, Pasteurella dagmatis, Pasteurella gallinarum, Pasteurella haemolytica, Pasteurella multocida multocida, Pasteurella multocida gallicida, Pasteurella multocida septica, Pasteurella pneumotropica and Pasteurella stomatis
  • Bordetella e.g. Bordetella bronchiseptica, Bordetella hinzii, 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, Legionalla bozemanii
  • Legionalla hackeliae Legionalla israelensis, Legionalla jordanis, Legionalla lansingensis, Legionalla tongbeachae, Legionalla maceachernii, Legionalla micdadei, Legionalla oakridgensis, Legionalla pneumophila, Legionalla sainthelensi, Legionalla tucsonensis and
  • Burkholderia cepacia Burkholderia mallei and Burkholderia pseudomallei;
  • Gardnereila e.g. Gardneralla vaginalis and Gardneralla mobiluncus
  • Streptobacillus moniliformis Streptobacillus moniliformis ;
  • Fiavobacteriaceae such as Capnocytophaga (e.g. Capnocytophaga canimorsus, Capnocytophaga cynodegmt, Capnocytophaga gingivalis, Capnocytophaga granulosa, Capnocytophaga haemolytica, Capnocytophaga ochracea and Capnocytophaga sputtona); Bartonella (Bartonella bacilliformis, Bartonella clarridgeiae, Bartonella elizabethae, Bartonella henselae, Bartonella quintana and Bartonella vinsonii arupensis);
  • Capnocytophaga e.g. Capnocytophaga canimorsus, Capnocytophaga cynodegmt, Capnocytophaga gingivalis, Capnocytophaga granulosa, Capnocytophaga hae
  • Leptospira e.g. Leptospira biflexa, Leptospira borgpetersenii, Leptospira inadai, Leptospira interrogans, Leptospira kirschneri, Leptospira noguchii, Leptospira santarosai and Leptospira wellii;
  • Spirillium 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 vulgatus); Prevotella (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, Prevotella nigrescens, Prevotella oralis, Prevotella oris, Prevotella oulora, Prevotella tannerae, Prevotella venoralis and Prevotella zoogleoformans);
  • Porphyromonas e.g. Porphyromonas asaccharolytica, Porphyromonas cangingivalis, Porphyromonas canoris, Porphyromonas cansulci, Porphyromonas catoniae, Porphyromonas circumdentaria, Porphyromonas crevioricanis, Porphyromonas endodontalis, Porphyromonas gingivalis, Porphyromonas gingivicanis, Porphyromonas levii and Porphyromonas macacae);
  • Porphyromonas e.g. Porphyromonas asaccharolytica, Porphyromonas cangingivalis, Porphyromonas canoris, Porphyromonas cansulci, Porphyromonas catoniae, Porphyromonas circumdentaria, Porphyromonas crevioricanis, Porphyromonas endodontalis, Porphyromon
  • Fusobacterium e.g. F. gonadiaformans, F. mortiferum, F. naviforme, F. necrogenes, F. necrophorum necrophorum, F. necrophorum fundiliforme, F. nucleatum nucleatum, F. nucleatum fusiforme, F. nucleatum polymorphum, F. nucleatum vincentii, F. periodonticum, F. russii, F. ulcerans and F. variu );
  • Chlamydia e.g. Chlamydia trachomatis
  • Cryptosporidium e.g. C. parvum, C. hominis, C. canis, C. felis, C. meleagridis and C. muris
  • Ch!amydophila e.g. Chlamydophila abortus (Chlamydia psittaci), Chlamydophila pneumoniae ⁇ Chlamydia pneumoniae) and Chlamydophila psittaci (Chlamydia psittaci)
  • Chlamydophila abortus Chlamydia psittaci
  • Chlamydophila pneumoniae ⁇ Chlamydia pneumoniae Chlamydophila psittaci
  • Chlamydophila psittaci Chlamydophila psittaci
  • Leuconostoc e.g. Leuconostoc citreum, Leuconostoc cremoris, Leuconostoc dextranicum, Leuconostoc lactis, Leuconostoc mesenteroides and Leuconostoc pseudomesenteroides
  • Gemella e.g. Gemella bergeri, Gemella haemolysans, Gemella morbillorum and Gemella sanguinis
  • Ureaplasma e.g. Ureaplasma parvum and Ureaplasma urealyticum
  • Particular bacteria that may be treated using a combination of the invention include: Gram positive bacteria;
  • Staphylococci such as Staph, aureus (either Methicillin-sensitive (i.e. MSSA) or Methicillin-resistant (i.e. MRSA)) and Staph, epidermidis;
  • Streptococci such as Strept. agalactiae and Strept. pyogenes
  • Bacillaceae such as Bacillus anthracis
  • Enterococci such as Enterococcus faecalis and Enterococcus faecium
  • Gram negative bacteria such as Enterococcus faecalis and Enterococcus faecium
  • Enterobacteriaceae such as Escherichia co!i, Klebsiella (e.g. Klebs. pneumoniae and Klebs. oxytoca) and Proteus (e.g. Pr. mirabilis, Pr. rettgeri and Pr. vulgaris);
  • Mycobacteria such as Mycobacterium tuberculosis.
  • the bacterial infections treated by the combinations described herein are gram- negative infections.
  • the bacterium is Enterobacteriaceae, such as Escherichia coli, Klebsiella (e.g.
  • Klebs. pneumoniae and Klebs. oxytoca Enterobacter (e.g. Enterobacter cloacae and Enterobacter aerogenes), Acinetobacter (e.g. Acinetobacter baumannii and Acinetobacter baumannii-calcoaceticus species complex) and Proteus (e.g. Pr. mirabilis, Pr. rettgeri and Pr. vulgaris) or Pseudomonas (e.g. Pseudomonas aeruginosa). More preferably the bacterium is
  • Enterobacteriaceae such as Escherichia coli, Klebsiella (e.g. Klebs. pneumoniae and Klebs. oxytoca), Enterobacter, Acinetobacter or Pseudomonas.
  • E.coli and Klebsiella are E.coli and Klebsiella.
  • the bacterium is E.coli or K.pneumoniae.
  • the combination of the present invention is particularly beneficial in treating (multi)-drug- resistant ((M)DR) bacteria.
  • MDR multi-drug- resistant
  • Enterobacteriaceae 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-iactamase-1 (NDM-1) resistant Klebs. Pneumonia.
  • the microbial infection treated is an infection caused by one or more of E. coli, Klebsiella pneumoniae or one of the KES ⁇ Klebsiella, Enterobacter and Serratia) group bacteria.
  • the microbial infection treated is an infection caused by NDM-1 Klebsiella (e.g. K.pneumoniae) or E.coli.
  • the combination therapy is synergistic as compared to the administration of the combination components taken alone. It should be kept in mind that although a combination such as that claimed may initially be demonstrated to be functional in treating (M)DR strains, they can then be used in treating non-resistant strains. This is especially valuable in the context of the presently claimed combination where the primary therapy for Enterobacteriaceae, such as Escherichia coli, Klebsiella (e.g. Klebs. pneumoniae and Klebs. oxytoca) and Proteus (e.g. Pr. mirabilis, Pr. rettgeri and Pr. vulgaris) are anti-microbial drugs that are expensive due to prevailing patent protection.
  • Enterobacteriaceae such as Escherichia coli, Klebsiella (e.g. Klebs. pneumoniae and Klebs. oxytoca) and Proteus (e.g. Pr. mirabilis, Pr. rettgeri and Pr. vulgaris) are anti-microbial drugs
  • the replacement of such "ethical” drugs by a combination of "generic" antibiotics is thought to be beneficial from a therapeutic perspective as well as financial/economic perspective in times where governments are seeking to reduce the cost of healthcare.
  • 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.
  • tuberculosis e.g. pulmonary tuberculosis, non-pulmonary tuberculosis (such as tuberculosis lymph glands, genito-urinary tuberculosis, tuberculosis of bone and joints, tuberculosis meningitis) and miliary tuberculosis
  • anthrax e.g. pulmonary tuberculosis, non-pulmonary tuberculosis (such as tuberculosis lymph glands, genito-urinary tuberculosis, tuberculosis of bone and joints, tuberculosis meningitis) and miliary tuberculosis
  • anthrax e.g. pulmonary tuberculosis, non-pulmonary tuberculosis (such as tuberculosis lymph glands, genito-urinary tuberculosis, tuberculosis of bone and joints, tuberculosis meningitis
  • keratitis bacterial vaginosis, botulism, Buruli ulcer, bone and joint infections
  • bronchitis acute or chronic
  • brucellosis burn wounds, cat scratch fever, cellulitis, chancroid, cholangitis, cholecystitis, cutaneous diphtheria, cystic fibrosis, cystitis, diffuse panbronchio!itis, diphtheria, dental caries, diseases of the upper respiratory tract, eczema, empymea, endocarditis, endometritis, enteric fever, enteritis, epididymitis, epiglottitis, erysipelis, erysipelas, erysipeloid, erythrasma, eye infections, furuncles, gardnereila vaginitis, gastrointestinal infections (gastroenteritis), genital infections, gingivitis, gonorrhoea, granuloma inguina
  • references herein to zidovudine mean a compound having the following chemical structure:
  • Zidovudine has the systematic (lUPAC) name of 1-[(2R,4S,5S)-4-Azido ⁇ 5- ⁇ hydroxymethyl)oxoIan-2-yl]-5-methylpyrimidine-2,4-dione, and is available by prescription only under the trade name Retrovir®. It is also known as 3'-azido-3'-deoxythymidine.
  • references herein to colistin include colistin sulfate and colistimethate sodium (otherwise known as colistin methanesulfonate sodium or colistin sulfomethate sodium), both of which are commercially available from, for example, Sigma Aldrich Limited. References to colistin also include pharmaceutically acceptable derivatives thereof.
  • harmaceutically acceptable derivatives thereof means:
  • Suitable acid addition salts include carboxyiate salts (e.g. formate, acetate, trifluoroacetate, propionate, isobutyrate, heptanoate, decanoate, caprate, caprylate, stearate, acrylate, caproate, propiolate, ascorbate, citrate, glucuronate, glutamate, glyco!ate, a-hydroxybut rate, lactate, tartrate, phenylacetate, mandelate, phenylpropionate, phenylbutyrate, benzoate, chlorobenzoate, methylbenzoate, hydroxybenzoate, methoxybenzoate, dinitrobenzoate, o- acetoxybenzoate, salicylate, nicotinate, isonicotinate, cinnamate, oxalate, malonate, succinate, suberate, sebacate, fumarate, malate, maleate, hydroxymaleate
  • sulfonate salts e.g. benzenesuifonate, methyl-, bromo- or chloro-benzenesulfonate, xylenesulfonate, methanesulfonate, ethanesulfonate, propanesulfonate, hydroxyethanesulfonate, 1- or 2- naphthalene-sulfonate or 1 ,5-naphthalenedisulfonate salts) or sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, phosphate, monohydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate or nitrate salts, and the like.
  • sulfonate salts e.g. benzenesuifonate, methyl-, bromo- or chloro-benzenesulfonate, xylenesulfonate, methanesulf
  • Compounds for use according to the invention may be administered as the raw material but the active ingredients are preferably provided in the form of pharmaceutical compositions.
  • compositions 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
  • rectal and topical including dermal, buccal and sublingual
  • 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.
  • 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 si Edition, (2005). Suitable methods include the step of bringing into 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 99.5% (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. chewable tablets in particular for paediatric 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 excipients.
  • 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 oil-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 monolaurate, glycofurol or glycerol), oils (e.g. a mineral oil such as a liquid paraffin, natural or synthetic triglycerides such as MiglyolTM, or silicone oils such as dimethicone).
  • the dermatological vehicle employed may contain one or more components selected from the following list: a solubi!ising agent or solvent (e.g.
  • Topical formulations may also be formulated as a transdermal patch.
  • a ⁇ -cyclodextrin such as hydroxypropyl ⁇ -cyclodextrin, or an alcohol or polyo! such as ethanol, propylene glycol or glycerol
  • a thickening agent e.g. hydroxymethyl cellulose, hydroxypropyl cellulose, carboxymethyl cellulose or carbomer
  • a gelling agent e.g. a polyoxyethylene- polyoxypropylene copolymer
  • a preservative e.g. benzyl alcohol, benzalkonium chloride, chlorhexidine, chlorbutoi, a benzoate, potassium sorbate or EDTA or salt thereof
  • pH buffering agent(s) e.g. a mixture of dihydrogen phosphate and hydrogen phosphate salts, or a mixture of citric acid and a hydrogen phosphate salt.
  • Topical formulations may also be formulated as a transdermal patch.
  • Topical pharmaceutical compositions such as creams, ointments, lotions, sprays and sterile aqueous solutions or suspensions are well known in the art. Suitable methods of preparing topical pharmaceutical compositions are described, e.g. in WO9510999, US 6974585, WO2006048747, as well as in documents cited in any of these references.
  • Topical pharmaceutical 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, dermatitic skin, skin ulcers, and sites of insertion of medical equipment such as i.v.
  • 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. Methiciliin resistant S. aureus (MRSA))).
  • 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 erythematotelangiectatic rosacea, papulopustular rosacea, phymatous rosacea and ocular rosacea); erysipelas; erythrasma; ecthyma; ecthyma gangrenosum; impetigo; paronychia; cellulitis; folliculitis (including hot tub folliculitis); furuncuiosis; carbunculosis; staphylococcal scalded skin syndrome; surgical scarlet fever; streptococcal peri-anal disease; streptococcal toxic shock syndr ome; pitted keratolysis; trichomycosis axillaris; pyoderma; external canal ear infections; green nail
  • kansasii M. malmoense, M. szulgai, M, simiae, M. gordonae, M. haemophilum, M. avium, M. intraceltulare, M. chelonae (including M. abscessus) or M. fortuitum infections, swimming pool (or fish tank) granuloma, lymphadenitis and Buruli ulcer (Bairnsdale ulcer, Searles' ulcer, Kakerifu ufcer or Toro ulcer)); as well as infected eczma, burns, abrasions and skin wounds.
  • compositions 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. Where the compositions are intended for administration as two separate compositions these may be presented in the form of a twin pack.
  • Pharmaceutical 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.
  • a patient pack comprising at least one active ingredient of the combination according to the invention and an information insert containing directions on the use of the combination of the invention.
  • 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:
  • (b) antimicrobial activity against log phase bacteria In relation to (a) above, methods for determining activity against clinically latent bacteria include a determination, under conditions known to those skilled in the art (such as those described in Nature Reviews, Drug Discovery 1 , 895-910 (2002), the disclosures of which are hereby incorporated by reference), of Minimum Stationary-cidal Concentration (“MSC”) or Minimum Dormicidal Concentration (“MDC”) for a test compound.
  • MSC Minimum Stationary-cidal Concentration
  • MDC Minimum Dormicidal Concentration
  • 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 metabolically 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.
  • strain used NDM-1 Klebsiella pneumonia BAA2473
  • HT0120663 (10 mg/ml) and colistin (20 mg/ml) were obtained from the pharmacy in St George's Hospital London. The drugs were added to the 96 well plates alone or in combination. The overnight culture was diluted with nutrient broth (Oxoid) to 10 7 CFU/ml and 280 ⁇ of the culture was added to each well to make the final concentration of 300 ⁇ . Incubation of the compounds with the bacterial suspension was carried out for 24 hours. At 0, 2, 4, 6 and 24 hours, CFU counts were performed to measure the kill effects of the drug combination.
  • Figure 7 is corresponds to Figure 1 of WO 2014/147405A1 and is for comparative purposes only.
  • time-to-zero values i.e. the time for the bacteria to be completely removed/killed
  • Table 1 The time-to-zero values (i.e. the time for the bacteria to be completely removed/killed) for the specific combinations of colistin and HT0 20663 are then shown in Table 1 below.
  • concentration ratios of zidovudine and colistin improve the antimicrobial activity of the combination of agents.
  • a concentration ratio of zidovudine to colistin is used between 8:1 and 1 :2 compared with a ratio of 1 :4.

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Abstract

L'invention concerne l'utilisation de zidovudine en association avec de la colistine pour traiter une infection microbienne, le rapport de concentration de zidovudine par rapport à la colistine étant compris entre environ 8/1 et environ 1/2.
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CN114514033A (zh) * 2019-07-29 2022-05-17 赫尔普百治疗有限公司 药物开发

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WO2019211576A1 (fr) * 2018-04-30 2019-11-07 Helperby Therapeutics Limited Association comprenant de la zidovudine et un composé antimicrobien
CN112218633A (zh) * 2018-04-30 2021-01-12 赫尔普百治疗有限公司 包含齐多夫定和抗微生物化合物的组合
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CN114514033A (zh) * 2019-07-29 2022-05-17 赫尔普百治疗有限公司 药物开发

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