WO2017212233A1 - Formulation - Google Patents

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Publication number
WO2017212233A1
WO2017212233A1 PCT/GB2017/051615 GB2017051615W WO2017212233A1 WO 2017212233 A1 WO2017212233 A1 WO 2017212233A1 GB 2017051615 W GB2017051615 W GB 2017051615W WO 2017212233 A1 WO2017212233 A1 WO 2017212233A1
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WO
WIPO (PCT)
Prior art keywords
spp
peptide
aqueous
composition according
nebulisable
Prior art date
Application number
PCT/GB2017/051615
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English (en)
Inventor
Deborah O'neil
Original Assignee
Novabiotics 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 Novabiotics Limited filed Critical Novabiotics Limited
Publication of WO2017212233A1 publication Critical patent/WO2017212233A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/007—Pulmonary tract; Aromatherapy
    • A61K9/0073—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy
    • A61K9/0078—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy for inhalation via a nebulizer such as a jet nebulizer, ultrasonic nebulizer, e.g. in the form of aqueous drug solutions or dispersions

Definitions

  • the present invention relates to an aqueous nebulisabie composition comprising an antifungal peptide and water. It further relates to methods of treatment employing the composition and to use of the composition in the treatment or prevention of local and optionally systemic microbial infections.
  • Fungal infections of the lung often affect the immunocompromised and are common nosocomial infections. Due to the difficulty in administering antifungal agents in nebulised form, the treatment of fungal infections of the lung is notoriously difficult, requiring systemic agents. However, the toxicity of antifungals when used to treat a systemic infection is a cause for concern.
  • the use of direct local treatment via aerosolised/nebulised delivery is an attractive option in prevention and treatment of such infections because the drug can concentrate locally at the site of infection with minimal systemic exposure. Aspergillosis is a common life threatening condition caused by fungal infection of the lung in the immunocompromised. It presents as both a chronic and invasive local infection of the lungs and as an invasive disseminated fungal infection.
  • Antifungal agents are typically difficult to nebulise in an aqueous formulation due to being large, hydrophobic molecules. Those antifungal agents that have been nebulised tend to be in liposomal or aerosolised formulations (Le and Schiller, 2010; Castagnola et al 2007).
  • Novamycin is a known antifungal agent with a fungicidal mode of action.
  • the peptide punctures the fungal cell membrane, lysing the cell, yet has no action against mammalian cells. This mode of action makes the risk of resistance developing extremely low.
  • Novamycin is effective as a systemic drug to address disseminated infections.
  • the present Inventors have surprisingly established that the drug can be successfully nebulised in an aqueous formulation.
  • an aqueous nebulisabie composition comprising an antifungal peptide wherein the antifungal peptide is present at a concentration of 0.1 to 100 mg/ml.
  • the aqueous nebulisabie composition may comprise an antifungal peptide and water wherein the antifungal peptide is present at a concentration of 0.1 to 100 mg/ml.
  • an aqueous nebulisable formulation or composition is simple to administer in a clinical setting because it can be used with standard equipment.
  • a nebulised aqueous composition according to the disclosure.
  • a method of treating a microbial, such as a fungal, infection in a subject comprising administering to the subject an aqueous nebulisable composition according to the disclosure.
  • administration of a composition by nebuiiser allows the antifungal agent to be targeted to the site of infection (i.e. the lung) where is can work directly on the infective microbe.
  • this mode of administration is effective as a preventative or prophylactic measure.
  • an aqueous nebulisable composition for use in the treatment of a local and optionally disseminated microbial infection
  • an aqueous nebulisable composition for use in the treatment by oral (inhaled) administration once to four times per day, of a local and optionally disseminated microbial infection.
  • kit of parts comprising a composition according to the disclosure and a systemic antimicrobial agent.
  • a process of making an aqueous composition according to the disclosure comprising the step of adding an antifungal peptide to water in the amount of 0.1 to 100 mg/ml.
  • a nebuiiser comprising an aqueous composition according to the disclosure.
  • a 13 to 15 amino acid linear poly-arginine peptide and an antifungal agent In a ninth aspect there is provided a 13 to 15 amino acid linear poly-arginine peptide and an antifungal agent.
  • Figure 1 shows lung tissue burden group average in CFU/g of tissue following treatment with nebulised Novamycin at 1, 5 and lOmg/ml bidaily versus ambisome at 5mg/kg once daily further including controls.
  • Figure 2 shows a scatterplot of lung tissue burden results from figure 1 in CFU/g of tissue following treatment with nebulised Novamycin at 1, 5 and lOmg/ml bidaily versus ambisome at 5mg/kg once daily further including controls.
  • Figure 3 shows a second in vivo data set lung tissue burden group average in CFU/g of tissue following treatment with nebulised Novamycin at 1, 5 and lOmg/ml bidaily versus ambisome at 5mg/kg once daily.
  • Figure 4 shows a scatterplot of lung tissue burden results from figure 3 in CFU/g of tissue following treatment with nebulised Novamycin at 1, 5 and lOmg/ml bidaily versus ambisome at 5mg/kg once daily.
  • Figure 5 shows % survival data at various time points post infection following treatment with nebulised Novamycin at 1, 5 and lOmg/ml bidaily versus ambisome at 5mg/kg once daily further including controls.
  • Figure 6 shows the terminal Aspergillus burden following treatment with nebulised Novamycin at 1, 5 and lOmg/ml bidaily versus ambisome at 5mg/kg once daily further including controls.
  • Figure 7 shows a more spread out version of the data in figure 6, for clarity.
  • Figure 8 shows % survival data at various time points following treatment with nebulised novamycin at 1 and 5 mg/ml daily versus IV (systemic) ambisome at 5mg/kg once daily versus combination therapy of nebulised novamycin at 1 and 5 mg/ml bidaily PLUS ambisome at 5mg/kg once daily and controls.
  • Aqueous as employed herein means the composition is primarily aqueous, that is, it contains water. Typically, the composition if primarily water and active ingredient (i.e. antifungal agent). In one embodiment the composition does not contain any excipients. In one embodiment the composition consists of water and at least one antifungal agent, such as an antifungal peptide.
  • Nebulisable as employed herein means to convert a liquid into a fine spray. Typically, nebulised liquids are inhaled over a prolonged period. That is, they are not inhaled in just one or two breaths in the way an inhaler-dispensed composition would be.
  • Peptide as employed herein means a therapeutically active peptide or a salt thereof.
  • the peptide is an antifungal peptide with activity against fungal infections of the lung.
  • the term "peptide” as used herein means, in general terms, a plurality of amino acid residues joined together by peptide bonds. It is used interchangeably and means the same as polypeptide and protein.
  • the peptide is a linear peptide. That is, the peptide has free ends and is typically not a branched peptide. In one embodiment the peptide is a branched linear peptide.
  • the peptide comprises approximately 5 to 15 amino acids, such as 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15 amino acids.
  • the peptide consists of 13 to 15 amino acids, such as 14 or 15 amino acids.
  • the number of amino acid residues referred to in the ranges above does not include the histidine tag residues.
  • histidine residues at either end of the peptide are discounted when determining the numbering of amino acids in the modified peptide.
  • all amino acid residues are counted including those making up a histidine tag.
  • the peptide comprises consecutive amino acids according to the formula (I)
  • X is arginine and n is an integer between 5 and 15.
  • the peptide is a poly-arginine peptide. That is, a peptide consisting essentially of arginine residues. In one embodiment the peptide is a linear peptide consisting of 14 arginine residues or a pharmaceutically acceptable salt thereof.
  • Modified peptides also encompassed by the present invention.
  • Modified peptides as employed herein means a peptide which has 5 to 15 amino acid residues predominantly arginine further comprising: a histidine tag; and/or a fatty acid and/or a pegylated peptide.
  • the modified peptides of the present invention may be linear peptides. Modified peptides are described in WO2015150823 which is incorporated herein by reference.
  • the peptides of the invention may generally be synthetic peptides.
  • the peptides may be isolated, purified peptides or variants thereof, which can be synthesised in vitro, for example, by a solid phase peptide synthetic method, by enzyme catalysed peptide synthesis or with the aid of recombinant DNA technology.
  • individual peptides, or libraries of peptides can be made and the individual peptides or peptides from those libraries can be screened for antimicrobial activity and toxicity, including, but not limited to, antifungal, antibacterial, antiviral, antiprotozoal, anti-parasitic activity and toxicity.
  • the peptides of the invention can exist in different forms, such as free acids, free bases, esters and other prodrugs, salts and tautomers, for example, and the invention includes all variant forms of the compounds.
  • the invention encompasses the salt or pro-drug of a peptide or peptide variant of the invention.
  • the peptide of the invention may be administered in the form of a pharmaceutically acceptable salt.
  • the pharmaceutically acceptable salts of the present invention can be synthesized from the parent peptide which contains a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid or base forms of the peptide with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; generally, nonaqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitriie are preferred.
  • the invention thus includes pharmaceutically-acceptable salts of the peptide of the invention wherein the parent compound is modified by making acid or base salts thereof for example the conventional nontoxic salts or the quaternary ammonium salts which are formed, e.g., from inorganic or organic acids or bases.
  • acid addition salts include acetate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, citrate, camp ho rate, camphorsulfonate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, fumarate, glucoheptanoate, glycerophosphate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, 2- hydroxyethanesulfonate, lactate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, oxalate, palmoate, pectinate, persulfate, 3-phenylpropionate, picrate, pivalate, propionate, succinate, tartrate, thiocyan
  • Base salts include ammonium salts, alkali metal salts such as sodium and potassium salts, alkaline earth metal salts such as calcium and magnesium salts, salts with organic bases such as dicyclohexylamine salts, N-methyl-D-glutamine, and salts with amino acids such as arginine, lysine, and so forth.
  • the basic nitrogen-containing groups may be quaternized with such agents as lower a Iky I halides, such as methyl, ethyl, propyl, and butyl chloride, bromides and iodides; dialkyl sulfates like dimethyl, diethyl, dibutyl; and diamyl sulfates, long chain halides such as decyl, lauryl, myristyl and stearyl chlorides, bromides and iodides, aralkyl halides like benzyl and phenethyl bromides and others.
  • Iky I halides such as methyl, ethyl, propyl, and butyl chloride, bromides and iodides
  • dialkyl sulfates like dimethyl, diethyl, dibutyl
  • diamyl sulfates long chain halides
  • Salts of carboxyl groups of a peptide or peptide variant of the invention may be prepared in the usual manner by contacting the peptide with one or more equivalents of a desired base such as, for example, a metallic hydroxide base, e.g. sodium hydroxide; a metal carbonate or bicarbonate such as, for example, sodium carbonate or bicarbonate; or an amine base such as, for example, triethylamine, triethanolamine and the like.
  • a desired base such as, for example, a metallic hydroxide base, e.g. sodium hydroxide
  • a metal carbonate or bicarbonate such as, for example, sodium carbonate or bicarbonate
  • an amine base such as, for example, triethylamine, triethanolamine and the like.
  • the invention includes prodrugs for the active pharmaceutical species of the described peptide, for example in which one or more functional groups are protected or derivatised but can be converted in vivo to the functional group, as in the case of esters of carboxylic acids convertible in vivo to the free acid, or in the case of protected amines, to the free amino group.
  • prodrug represents in particular structures which are rapidly transformed in vivo to the parent structure, for example, by hydrolysis in blood.
  • the arginine residue is the predominant amino acid in the peptide.
  • at least 50% of the amino acid residues are arginine residues, preferably at least 60% or at least 70% or at least 80% of the amino acids in the peptide are arginine.
  • at least 90% are arginine residues.
  • all the amino acids in the peptide are arginine residues (optionally with the exception of a histidine tag).
  • the peptide may comprise amino acids other than arginine is non-predominant amounts.
  • amino acids other than arginine is non-predominant amounts.
  • histidine, ornithine and lysine could be used.
  • D and/or L amino acids consist of arginine or a combination of arginine and lysine residues except for 0, 1, or 2 substitutions to an amino acid residues other than arginine or lysine.
  • substitutions are with another cation ic amino acids selected from the group consisting of histidine, ornithine and lysine.
  • the substations are with lysine.
  • the peptide may be substituted with 0, 1, 2, 3, 4, 5, 6 or 7 substitutions provided that the arginine make up at least 60%, preferably at least 75% of the peptide.
  • the amino acids are L-amino acids.
  • At least 90%, for example at least 95% such as 97-99% or even 100%, of the amino acids in the peptide are L-amino acids.
  • the invention also includes known isomers (structural, stereo-, conformational & configurational), peptidomimetics, structural analogues of the above amino acids, and those modified either naturally (e.g. post-translational modification) or chemically, including, but not exclusively, phosphorylation, glycosylation, sulfonylation and/or hydroxylation.
  • One or more of the residues of the peptide can be exchanged for another to alter, enhance or preserve the biological activity of the peptide.
  • Such a variant can have, for example, at least about 10% of the biological activity of the corresponding non-variant peptide.
  • Conservative amino acids are often utilised, i.e. substitutions of amino acids with similar chemical and physical properties as described above.
  • conservative amino acid substitutions may involve exchanging lysine for arginine, ornithine or histidine; or exchanging arginine for lysine or isoleucine, ornithine for histidine; or exchanging one hydrophobic amino acid for another. After the substitutions are introduced, the variants are screened for biological activity.
  • the composition of the disclosure comprises approximately 0.001-500mg ml of peptide, such as approximately O.l-lOOmg/ml of peptide.
  • approximately 1-lOmg/ml preferably approximately 5mg/ml of peptide.
  • a dose of 5mg/ml bidaily provided the lowest tissue burden in in vivo studies (see figure 1).
  • composition further comprises an antifungal agent.
  • combination products that include one or more peptides of the present invention and one or more other antifungal agents, for example, polyenes such as amphotericin B, amphotericin B lipid complex (ABCD), liposomal amphotericin B (L-AMB), and liposomal nystatin, azoles and triazoles such as voriconazole, fluconazole, ketoconazole, itraconazole, pozaconazole and the like; glucan synthase inhibitors such as caspofungin, micafungin (FK463), and V-echinocandin (LY303366); griseofulvin; allylamines such as terbinafine; flucytosine or other antifungal agents, including those described herein.
  • polyenes such as amphotericin B, amphotericin B lipid complex (ABCD), liposomal amphotericin B (L-AMB), and liposomal nystatin
  • the systemic antimicrobial agent is selected from the group consisting of: polyenes such as amphotericin B, amphotericin B lipid complex (ABCD), liposomal amphotericin B (L-AMB), and liposomal nystatin, azoles and triazoles such as voriconazole, fluconazole, ketoconazole, itraconazole, pozaconazole; glucan synthase inhibitors such as caspofungin, micafungin (FK463), and V-echinocandin (LY303366); griseofulvin; allylamines such as terbinafine; flucytosine or peptides such as Novamycin.
  • polyenes such as amphotericin B, amphotericin B lipid complex (ABCD), liposomal amphotericin B (L-AMB), and liposomal nystatin
  • azoles and triazoles such as voriconazole, fluconazole
  • Novamycin as employed herein refers to 14 amino acid linear poly-arginine peptide.
  • the antimicrobial or antifungal agent is cysteamine or a derivative thereof such as cystamine.
  • the antimicrobial or antifungal agent is ambisome or amphotericin B. In one embodiment the antimicrobial or antifungal agent is caspofungin. In one embodiment the antimicrobial or antifungal agent is Novamycin.
  • Method of treating or preventing as employed herein means that a disease or condition maybe treated with the aim of curing or delaying progress the disease or condition or that the composition may be given prophylactically to prevent infection occurring or becoming established.
  • treatment relates to the effects of the peptides described herein that in imparting a benefit to patients afflicted with an (infectious) disease, including an improvement in the condition of the patient or delay in disease progression.
  • the invention provides a method of treating or preventing a fungal infection in a subject comprising administering to said subject a therapeutically effective amount of a peptide according to the invention.
  • Therapeutically effective amount as employed herein means the amount of active substance, such as antifungal agent, that is administered within the scope of sound medical judgement, is sufficient to provide a desired effect without toxicity, irritation, allergic reaction or other problem or complication commensurate with a reasonable risk/benefit ratio.
  • composition comprises a therapeutically effective amount of at least one peptide.
  • composition comprises a therapeutically effective amount of at least one antifungal agent.
  • a subject as employed herein means a human or animal subject in need of treatment with compositions of the disclosure.
  • Mammals, birds and other animals may be treated by the peptides, compositions or methods described herein.
  • Such mammals and birds include humans, dogs, cats and livestock, such as horses, cattle, sheep, goats, chickens and turkeys and the like.
  • the method of treatment further comprises simultaneous, sequential or separate administration of a systemic antimicrobial agent.
  • Simultaneous, sequential or separate administration as employed herein means that the nebulised composition and the systemic antimicrobial agent are administered at the same time, immediately one following the other or at a time spaced apart, such as several minutes to hours apart.
  • Systemic antimicrobial agent as employed herein means an antimicrobial agent which is administered such that it enters the circulatory system.
  • the method of administration may be enteral (i.e. by absorption from the intestinal tract) or parenteral (e.g. via injection, infusion or implantation).
  • antimicrobial agent is useful, inter alia, against bacteria, fungi, yeast, parasites, protozoa and viruses.
  • antimicrobial agent can be used herein to define any peptide that has microbicidal and/or microbistatic activity and encompasses, non-exclusively, any agent described as having anti-bacterial, anti-fungal, anti-mycotic, anti-parasitic, anti-protozoa I, anti-viral, anti-infectious, anti-infective and/or germicidal, algicidal, amoebicidal, microbicidal, bacterici(o)dal, fungicidal, parasiticidal, protozoacidal, protozoicidal properties.
  • the fungal infection may be an infection by one or more of the group consisting of: Candida spp., (e.g. C.albicans), Epidermophyton spp., Exophiala spp., Microsporum spp., Trichophyton spp., (e.g T.rubrum and T. interdigitale), Tinea spp., Aspergillus spp., Blastomyces spp., Blastoschizomyces spp., Coccidioides spp., Cryptococcus spp. (e.g.
  • Cryptococcus neoformans Histoplasma spp., Paracoccidiomyces spp., Sporotrix spp., Absidia spp., Cladophialophora spp., Fonsecaea spp., Phialophora spp., Lacazia spp., Arthrographis spp., Acremonium spp., Actinomadura spp., Apophysomyces spp., Emmonsia spp., Basidiobolus spp., Beauveria spp., Chrysosporium spp., Conidiobolus spp., Cunninghamella spp., Fusarium spp., Geotrichum spp., Graphium spp., Leptosphaeria spp., Malassezia spp.
  • the fungal infection is aspergillosis
  • the fungal infection is candidiasis.
  • the present invention provides a method of treating or preventing any one or more of the group consisting of: candidiasis (including OPC), aspergillosis (including bronchopulmonary aspergillosis, chronic pulmonary aspergillosis and aspergillomata), athlete's foot; basidiodiabolomycosis; blastomycosis; coccidioidomycosis cryptoccocis; basal meningitis; dermatophytosis; onchomycosis; dermatophytids; endothrix; exothrix; fungal meningitis, fungemia, histoplasmosis, mycosis, myrinogmycosis, paracoccidioidomycosis, penicilliosis, piedra, pneumocytosis, Pneumocystis, pneumonia, sporptrichosis, tinea, zeospora and zygomycosis in
  • the subject may have HIV or AIDS.
  • the peptides of the composition are potent antifungal peptides for a wide variety of pathogenic yeast and moulds.
  • the peptides of the invention may also be useful in the treatment of other conditions including, but not limited to, conditions associated with mucosal infections, for example, cystic fibrosis, gastrointestinal, urogenital, urinary (e.g kidney infection or cystitis) or respiratory infections.
  • Administration of the composition in accordance with the present disclosure may be in a single dose, in multiple doses, in a continuous or intermittent manner, depending, for example, upon the recipient's physiological condition, whether the purpose of the administration is therapeutic or prophylactic, and other factors known to skilled practitioners.
  • the administration of the composition may be essentially continuous over a pre-selected period of time or may be in a series of spaced doses. Both local and systemic administration is contemplated.
  • the composition is administered by oral administration once to four times per day. Such as once, twice, three times or four times daily.
  • a dosage of 0.1-lOOmg/ml may be administered once to four times daily for 10 to 60 minutes each dose.
  • administration by nebuliser occurs for approximately 10 to 60 minutes, such as approximately 15, 20, 25, 30, 35, 40, 45, 50 or 55 minutes.
  • 1-lOmg/ml is administered for up to 30 minutes. In one embodiment 1-lOmg/ml is administered for 20 minutes, for example by nebuliser. For example, once to four times daily, such a bidaily.
  • 5mg/ml is administered twice daily. In one embodiment the administration is for approximately 20 minutes, such as 20 minutes bidaily. In one embodiment 5mg/ml is administered for approximately 20 minutes bidaily.
  • oral administration means by nebulisation. That is, inhaled administration As employed herein oral administration refers to inhaled administration.
  • administration occurs for 1 to 30 days such as 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28 or 29 days. For example, up to 20 days. Typically, administration is for approximately 14 days.
  • administration is repeated for up to 20 days, such as for 14 days. Approximately as employed herein means ⁇ 10%.
  • Local microbial infection as employed herein means an infection that is concentrated in one location. That is, the infection is not disseminated or systemic.
  • the local infection is in the lung.
  • Disseminated microbial infection as employed herein means that an infection has extended beyond its origin or nidus and involved the circulatory system to "seed" other areas of the body.
  • compositions of the disclosure may further comprise carriers and/or diluents.
  • the carriers and/or diluents that are useful in the pharmaceutical formulations of the present invention include water and physiologically acceptable buffered saline solutions such as phosphate buffered saline solutions pH 7.0-8.0.
  • the peptides of the invention are typically administered to the respiratory tract. For administration by inhalation or insufflation.
  • Compositions of the present invention are administered in an aqueous solution when administered in an aerosol or inhaled form.
  • aerosol pharmaceutical formulations may comprise, for example, a physiologically acceptable buffered saline solution containing between about 0.001 mg/ml and about 500 mg/ml for example between 0.1 and 100 mg/ml, such as 0.5-50 mg/ml, 0.5- 20 mg/ml, 0.5-10 mg/ml, 0.5-5 mg/ml or 1-5 mg/ml of antifungal peptide specific for the indication or disease to be treated.
  • a physiologically acceptable buffered saline solution containing between about 0.001 mg/ml and about 500 mg/ml for example between 0.1 and 100 mg/ml, such as 0.5-50 mg/ml, 0.5- 20 mg/ml, 0.5-10 mg/ml, 0.5-5 mg/ml or 1-5 mg/ml of antifungal peptide specific for the indication or disease to be treated.
  • the antifungal agent is selected from the group consisting of: cysteamine, Novamycin, amphotericin B, caspofungin, pozaconazole, itraconazole and fluconazole.
  • composition further comprises inhaled cysteamine.
  • cysteamine may be administered simultaneously, sequentially or separately.
  • comprising is to be interpreted as “including”.
  • Embodiments are described herein as comprising certain features/elements. The disclosure also extends to separate embodiments consisting or consisting essentially of said features/elements.
  • Ceftriaxone, cyclosphosphamide and cortisone acetate were prepared for immunosuppression and pre-conditioning of animals at 50 mg/kg, 150 mg/kg and 175 mg/kg respectively.
  • Novamycin was prepared for twice daily nebulised dosing at 1 and 5 mg/ml, and Ambisome prepared for once daily IV dosing at 5 mg/kg.
  • Phosphate buffered saline (PBS) and Sabouraud dextrose agar containing 50 ⁇ g/ml chloramphenicol were required for fungal tissue burden.
  • mice were infected intranasally with 0.04 ml of an inoculum of 1.8 x 10 6 cfu/ml Aspergillus fumigatus A1163 (7.2 x 10 4 cfu/animal) which established a robust infection in the lungs.
  • Nebulised Novamycin was administered twice daily at 1 and 5 mg/ml alone and in combination with Ambisome IV at 5 mg/kg once daily. Additional groups included 5 mg/kg Ambisome IV once daily plus nebulised vehicle, infected but untreated controls, and treated but uninfected controls. The study lasted four days post-infection.
  • the lung tissue burden at the clinical end point of each animal was determined; following euthanasia, the lungs are removed and weighed. Lung samples are homogenised in 2 ml ice cold sterile phosphate buffered saline. Organ homogenates are quantitatively cultured following serial dilution on to Sabouraud dextrose agar containing 50 ⁇ g/ml chloramphenicol and incubated at 37°C for up to 4 days and colonies counted. In addition, serum samples and a sample of lung homogenate were taken for Galactomannan and PCR analysis. All uninfected treatment control mice survived to 96 h. Within the treatment groups two out of the eight mice treated with 5 mg/ml Novamycin + 5 mg/kg Ambisome, and one of the eight mice treated with 1 mg/kg Novamcyin + 5 mg/kg

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Abstract

La présente invention concerne une composition aqueuse d'un peptide antifongique, des méthodes de traitement utilisant la composition et des utilisations de la composition.
PCT/GB2017/051615 2016-06-07 2017-06-05 Formulation WO2017212233A1 (fr)

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Citations (4)

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Publication number Priority date Publication date Assignee Title
WO2000027363A1 (fr) * 1998-11-12 2000-05-18 Elan Pharma International Ltd. Aerosols comprenant des medicaments a nanoparticules
WO2008093060A2 (fr) * 2007-02-02 2008-08-07 Novabiotics Limited Peptides et leur utilisation
WO2015150823A1 (fr) 2014-04-02 2015-10-08 Novabiotics Limited Peptides antimicrobiens modifiés
US20160102052A1 (en) * 2014-09-22 2016-04-14 Novabiotics Limited Use of Cysteamine in Treating Infections caused by Yeasts/Moulds

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000027363A1 (fr) * 1998-11-12 2000-05-18 Elan Pharma International Ltd. Aerosols comprenant des medicaments a nanoparticules
WO2008093060A2 (fr) * 2007-02-02 2008-08-07 Novabiotics Limited Peptides et leur utilisation
WO2015150823A1 (fr) 2014-04-02 2015-10-08 Novabiotics Limited Peptides antimicrobiens modifiés
US20160102052A1 (en) * 2014-09-22 2016-04-14 Novabiotics Limited Use of Cysteamine in Treating Infections caused by Yeasts/Moulds

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