WO2018204506A1 - Méthodes de traitement d'infections fongiques - Google Patents

Méthodes de traitement d'infections fongiques Download PDF

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WO2018204506A1
WO2018204506A1 PCT/US2018/030670 US2018030670W WO2018204506A1 WO 2018204506 A1 WO2018204506 A1 WO 2018204506A1 US 2018030670 W US2018030670 W US 2018030670W WO 2018204506 A1 WO2018204506 A1 WO 2018204506A1
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composition
alkyl
csa
candida
treatment composition
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PCT/US2018/030670
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English (en)
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Carl GENBERG
Chad S. BEUS
Paul B. Savage
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Genberg Carl
Beus Chad S
Savage Paul B
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Priority claimed from US15/585,632 external-priority patent/US10238665B2/en
Application filed by Genberg Carl, Beus Chad S, Savage Paul B filed Critical Genberg Carl
Publication of WO2018204506A1 publication Critical patent/WO2018204506A1/fr

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    • 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
    • A61P31/10—Antimycotics
    • 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
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids

Definitions

  • CSAs Cationic steroidal antimicrobials
  • formulations thereof for treating certain diseases and symptoms, such as fungal infections, and prevent fungal infections or colonization when implanting medical devices.
  • Candida auris is a pathogenic yeast which is capable of entering the bloodstream of an affected individual and spreading throughout the body to cause serious invasive infections.
  • Candida auris is often non-responsive to commonly used antifungal drugs.
  • Candida auris infections are often associated with long-term care in a healthcare facility. Patients who have undergone recent surgery, who have been under intensive care for long periods of time, who have received a venous catheter, who are diabetic, who have open wounds, and/or who have previously received antibiotics or antifungal medications are among those at highest risk of developing a Candida auris infection.
  • kits comprising such compositions and instructions on such methods are also contemplated herein.
  • the patient is not immunocompromised.
  • the patient is immunocompromised.
  • the patient is infected with Human Immunodeficiency Virus (HIV).
  • HIV Human Immunodeficiency Virus
  • the fungal infection is caused by one or more fungi selected from the group consisting of Epidermophyton floccosum, Trichophyton rubrum, Trichophyton mentagrophytes, the Microsporum genera, the Trychophyton genera, Candida auris, Candida albicans, Candida lusitaniae, Candida kruseii, Candida glabrata, Candida parapsilosis, Candida tropicalis, Candida guilliermondii, Cryptococcus neoformans, Trichophyton tonsurans, Microsporum canis, Epidermophyton floccosum, Histoplasma capsulatum, blastomyces, Cryptoccus neoformans, Pneumocystis jiroveci, Cocidioides immitis, Aspergillus fumigatus, Aspergillus niger, Penicillium genera, and Cladosporium genera.
  • fungi selected from the group consisting of Epidermophyton floccosum, Trich
  • the fungal infection is resistant to one or more antifungal agents selected from the group consisting of terbinafine, amphotericin B, candicidin, filipin, hamycin, nystatin, rimocidin, bifonazole, butoconazole, clotrimazole, econazole, fenticonazole, isoconazole, ketoconazole, luliconazole, miconazole, omoconazole, oxiconazole, sertaconazole, sulconazole, tioconazole, albaconazole, fluconazole, isavuconazole, itraconazole, psoaconazole, ravuconazole, terconazole, voriconazole, abafungin, amorolfin, butenafine, naftifine, anidulafungin, caspofungin, micafungin, ciclopi
  • the fungal infection is a skin infection.
  • the skin infection is Athlete's Foot.
  • the fungal infection is caused by one or more fungi selected from from the group consisting of Epidermophyton floccosum, Trichophyton rubrum, or Trichophyton mentagrophytes.
  • the skin infection is ringworm.
  • the skin infection is ringworm caused by one or more fungi from the Microsporum or Trichophyton genera.
  • the skin infection is Tinea curis (jock itch).
  • the skin infection is caused by one or more fungi from the group consisting of Trichphyton rubrum, Candida albicans, Trichophyton mentagrophytes, and Epidermophyton floccosum.
  • the fungal infection is fungal meningitis. In some embodiments, the fungal infection is a lung infection. In some embodiments, the lung infection is pneumonia.
  • the patient has a chronic lung disease.
  • the chronic lung disease is associated with cystic fibrosis.
  • the lung infection is caused by one or more fungi from the group consisting of Candida albicans, Aspergillus funigatus, Histoplasma capsulatum, blastomyces, Cryptoccus neoformans, Pneumocystis jiroveci, and Cocidioides immitis.
  • the infection is an eye infection.
  • the fungal infection is nail fungus (e.g., affecting a toenail, fingernail, or analogous structure in a non-human animal).
  • the nail fungus, or onychomycosis may be caused by dermatophytes, Candida, and nondermatophytic molds. Dermatophytes are the fungi most commonly responsible for onychomycosis in the temperate western countries. While Candida and nondermatophytic molds are more frequently involved in the tropics and subtropics with a hot and humid climate, Trichophyton rubrum is the most common dermatophyte involved in onychomycosis.
  • Trichophyton interdigitale Other dermatophytes that may be involved are Trichophyton interdigitale, Epidermophyton floccosum, Trichophyton violaceum, Microsporum gypseum, Trichophyton tonsurans, and Trichophyton soudanense.
  • Trichophyton mentagrophytes for Trichophyton interdigitale.
  • Candida and nondermatophytic molds in particular members of the mold genera Scytalidium (name recently changed to Neoscytalidium), Scopulariopsis, and Aspergillus.
  • Candida spp. mainly causes fingernail onychomycosis in people whose hands are often submerged in water.
  • Scytalidium mainly affects people in the tropics, though it persists if they later move to areas of temperate climate.
  • Other molds more commonly affect people older than 60 years, and their presence in the nail reflects a slight weakening in the nail's ability to defend itself against fungal invasion.
  • nail fungus can be treated by topical application of a topical composition on the nail surface and/or inserted or injected to the nail bed beneath the nail.
  • the topical composition may include an appropriate liquid or gel carrier, one or more CSA compounds, and optionally other adjuvents.
  • the carrier can a liquid carrier selected so as to penetrate beyond the nail surface and at least partially toward the nail bed.
  • an antifungal composition comprising one or more CSA compounds is utilized to therapeutically or prophylactically treat or prevent an infection associated with Candida auris.
  • a treatment composition is configured for application to an open wound, surgical site, catheter (e.g., venous catheter) insertion site, or other such wound.
  • a treatment composition is configured as a wash, spray, gel, paste, or other formulation suitable for application to an open wound, surgical site, catheter insertion site, or other site of potential fungal infection. Such embodiments may be particularly useful for treating or preventing a Candida auris infection.
  • an antifungal composition comprising one or more CSA compounds is applied to a medical device to prevent fungal colonization of the medical device and/or fungal infections at the medical implant site.
  • medical devices to which the treatment composition may be applied include devices which are implanted into a subject's tissues, deployed at a puncture or wound site, positioned for feeding or withdrawing material from a body cavity, or are otherwise associated with a patient/subject in such a way that biological compatibility is of concern (e.g., because fungal infection and/or fouling of the device can result).
  • the antifungal composition may be applied to a catheter (e.g., a venous catheter), intravenous needle, intravenous line, oral care device (e.g., dentures, dental implant), intrauterine device (IUD), feeder tube, drain, prosthesis component (e.g., voice prosthesis), peristaltic pump, tympsanostomy tube, tracheotomy tube, endotracheal tube, joint prosthesis, dialysis access graft, or cardiac graft.
  • a catheter e.g., a venous catheter
  • intravenous needle e.g., intravenous line
  • oral care device e.g., dentures, dental implant
  • intrauterine device IUD
  • feeder tube e.g., drain
  • prosthesis component e.g., voice prosthesis
  • peristaltic pump e.g., tympsanostomy tube, tracheotomy tube, endotracheal tube, joint prosthesis, dialysis
  • the CSA or a pharmaceutically acceptable salt thereof, is selected from the compound of Formula IV:
  • the CSA compound, or pharmaceutically acceptable salt thereof has a free base structure selected from the group of:
  • the CSA is not CSA-13. In some embodiments, the CSA is CSA-131, which has been found to be unexpectedly superior to CSA-13 in treating fungal infections.
  • the pharmaceutically acceptable salt is a hydrochloride salt. In some embodiments, the pharmaceutically acceptable salt is a mono-hydrochloride salt, a dihydrochloride salt, a trihydrochloride salt, or a tetrahydrochloride salt. In some embodiments, the pharmaceutically acceptable salt is a sulfuric acid addition salt or sulfonic acid addition salt. In some embodiments, the sulfonic acid addition salt is a disulfonic acid addition salt. In some embodiments, the sulfonic acid addition salt is a 1,5-naphthalenedisulfonic acid ( DSA) addition salt (e.g., of CSA-131).
  • DSA 1,5-naphthalenedisulfonic acid
  • the CSA is selected by measuring a biomarker or subjecting a sample from the patient to a companion diagnostic device in the patient.
  • the biomarker is a cellular response to the CSA or the companion diagnostic device measures a cellular response to the CSA.
  • the cellular response is a change in mRNA levels associated with fungal infection.
  • the patient is a mammal.
  • the mammal is a human.
  • at least one CSA is administered with at least one non-CSA therapeutic agent.
  • the non-CSA therapeutic agent is selected from the group consisting of an antifungal agent, an antibiotic, a nonsteroidal anti-inflammatory agent, an antiviral agent, an antiretroviral agent, an antipyretic, an antiemetic, an immunomodulator, a chemotherapeutic agent, an antihistamine, an opioid receptor agonist, an anti-cholinergic, and a beta2-adrenoreceptor agonist.
  • two or more CSAs are co-administered.
  • administration of the CSA is selected from the group consisting of topical application (via topical spray, wash, cream, paste, gel), inhalation, intravenous injection, subcutaneous injection, intraperitoneal injection, depot injection, intramuscular injection, transdermal patch, ear drops, and eye drops.
  • one or more CSAs are administered in a pharmaceutically acceptable formulation.
  • kits for treating a fungal infection comprising (a) one or more CSAs, and (b) instructions for administering one or more CSAs such that the fungal infection is treated.
  • a method comprises identifying a patient in need of treatment and administering a therapeutically effective amount of at least one cationic steroid antimicrobial (CSA), or a pharmaceutically acceptable salt thereof. Kits comprising such compositions and instructions on such methods are also contemplated herein.
  • CSA cationic steroid antimicrobial
  • Non-limiting examples of fungal infections that may be prevented or treated as disclosed herein include, for example, skin infections, Athlete's Foot, ringworm, Tinea curis (jock itch), fungal meningitis, lung infections, pneumonia, chronic lung disease, lung conditions associated with cystic fibrosis, eye infections, and nail fungus.
  • a Candida auris infection is treated and/or prevented.
  • Cationic sterioidal antimicrobial (“CSA”) compounds which are also known as “ceragenin” compounds (or “ceragenins”), are synthetically produced small molecule chemical compounds that include a sterol backbone having various charged groups (e.g., amine, guanidine, and/or other groups capable of exhibiting cationic properties under biological conditions) attached to the backbone.
  • the backbone can be used to orient the cationic groups on one face, or plane, of the sterol backbone.
  • CSA compound refers to the type or structure of the CSA
  • CSA molecule refers to the CSAs themselves when used in a treatment composition or medical implant.
  • CSAs are cationic and amphiphilic, based upon the functional groups attached to the backbone. They are facially amphiphilic with a hydrophobic face and a polycationic face.
  • anti-microbial agents e.g., anti-bacterials, anti-fungals, and anti-virals
  • CSA compounds described herein may also act to sensitize microbes to other types of antimicrobials.
  • concentrations of the CSA compound below the corresponding minimum bacteriostatic concentration CSAs have been shown to cause bacteria or fungi to become more susceptible to other antibiotics or antifungal agents, respectively, by increasing membrane permeability of the bacteria or fungi.
  • the charged groups are responsible for disrupting the bacterial or fungal cellular membrane, and without the charged groups, the CSA compound cannot disrupt the membrane to cause cell death or sensitization.
  • Example of CSA compounds have a chemical structure of Formula I as shown below.
  • the R groups of Formula I can have a variety of different functionalities, thus providing a given ceragenin compound with specific, different properties.
  • the sterol backbone can be formed of 5-member and/or 6-member rings, so that p, q, m, and n may independently be 1 (providing a 6-member ring) or 0 (providing a 5-member ring).
  • the CSAs of Formula I are of two types: (1) CSA compounds having cationic groups linked to the sterol backbone with hydrolysable linkages and (2) CSA compounds having cationic groups linked to the sterol backbone with non-hydrolysable linkages.
  • one type of hydrolysable linkage is an ester linkage
  • one type of non- hydrolysable linkage is an ether linkage.
  • CSA compounds of the first type can be "inactivated" by hydrolysis of the linkages coupling the cationic groups to the sterol backbone, whereas CSA compounds of the second type are more resistant to degradation and inactivation.
  • R 3 , R7, or R12 may independently include a cationic moiety attached to the Formula I structure via a hydrolysable (e.g., an ester) or non-hydrolizable (e.g., an ether) linkage.
  • a tail moiety may be attached to Formula I at Ri 8 .
  • the tail moiety may be charged, uncharged, polar, non-polar, hydrophobic, or amphipathic, for example, and can thereby be selected to adjust the properties of the CSA and/or to provide desired characteristics.
  • the anti-microbial activity of the CSA compounds can be affected by the orientation of the substituent groups attached to the backbone structure.
  • the substituent groups attached to the backbone structure are oriented on a single face of the CSA compound. Accordingly, each of R 3 , R7, and R12 may be positioned on a single face of Formula I.
  • Ri 8 may also be positioned on the same single face of Formula I.
  • the CSA or a pharmaceutically acceptable salt thereof, is selected from the compound of Formula IV:
  • the free base structure of the CSA compound, or pharmaceutically acceptable salt, of Formula (III) is:
  • the free base structure of the CSA compound or pharmaceutically acceptable salt, of Formula (III) is:
  • the free base structure of the CSA compound pharmaceutically acceptable salt, of Formula (III) is:
  • the free base structure of the CSA compound, pharmaceutically acceptable salt, of Formula (III) is:
  • the free base structure of the CSA compound, pharmaceutically acceptable salt, of Formula (III) is:
  • the free base structure of the CSA compound, pharmaceutically acceptable salt, of Formula (III) is:
  • the free base structure of the CSA compound, pharmaceutically acceptable salt, of Formula (III) is:
  • the free base structure of the CSA compound, or pharmaceutically acceptable salt, of Formula (III) is:
  • the free base structure of the CSA compound, or pharmaceutically acceptable salt, of Formula (III) is:
  • the free base structure of the CSA compound, or pharmaceutically acceptable salt, of Formula (III) is:
  • the free base structure of the CSA compound, or pharmaceutically acceptable salt, of Formula (III) is:
  • the free base structure of the CSA compound, or pharmaceutically acceptable salt, of Formula (III) is:
  • the method of therapeutically or prophylactically treating a fungal infection comprises identifying a patient in need of treatment, and administering a therapeutically effective amount of at least one cationic steroid antimicrobial (CSA), or a pharmaceutically acceptable salt thereof, to a patient in need thereof.
  • CSA cationic steroid antimicrobial
  • the patient is not immunocompromised.
  • the patient is immunocompromised.
  • the patient is infected with Human Immunodeficiency Virus.
  • the fungal infection is caused by one or more fungi selected from the group consisting of Epidermophyton floccosum, Trichophyton rubrum, Trichophyton mentagrophytes, the Microsporum genera, the Trychophyton genera, Candida auris, Candida albicans, Candida lusitaniae, Candida kruseii, Candida glabrata, Candida parapsilosis, Candida tropicalis, Candida guilliermondii, Cryptococcus neoformans, Trichophyton tonsurans, Microsporum canis, Epidermophyton floccosum, Histoplasma capsulatum, blastomyces, Cryptoccus neoformans, Pneumocystis jiroveci, Cocidioides immitis, Aspergillus fumigatus, Aspergillus niger, Penicillium genera, and Cladosporium genera.
  • fungi selected from the group consisting of Epidermophyton floccosum, Trich
  • the fungal infection is resistant to one or more antifungal agents selected from the group consisting of terbinafine, amphotericin B, candicidin, filipin, hamycin, nystatin, rimocidin, bifonazole, butoconazole, clotrimazole, econazole, fenticonazole, isoconazole, ketoconazole, luliconazole, miconazole, omoconazole, oxiconazole, sertaconazole, sulconazole, tioconazole, albaconazole, fluconazole, isavuconazole, itraconazole, psoaconazole, ravuconazole, terconazole, voriconazole, abafungin, amorolfin, butenafine, naftifine, anidulafungin, caspofungin, micafungin, ciclopi
  • the fungal infection is a skin infection.
  • the skin infection is Athletes' Foot.
  • the fungal infection is caused by one or more fungi from the group consisting of Epidermophyton floccosum, Trichophyton rubrum, or Trichophyton mentagrophytes .
  • the skin infection is ringworm.
  • the skin infection is ringworm caused by one or more fungi from the Microsporum or Trichophyton genera.
  • the skin infection is Tinea curis (jock itch).
  • the skin infection is caused by one or more fungi from the group consisting of Trichphyton rubrum, Candida albicans, Trichophyton mentagrophytes, and Epidermophyton floccosum.
  • the fungal infection is fungal meningitis. In some embodiments, the fungal infection is a lung infection. In some embodiments, the lung infection is pneumonia.
  • the patient has a chronic lung disease.
  • the chronic lung disease is associated with cystic fibrosis.
  • the lung infection is caused by one or more fungi from the group consisting of Candida albicans, Aspergillus funigatus, Histoplasma capsulatum, blastomyces, Cryptoccus neoformans, Pneumocystis jiroveci, and Cocidioides immitis.
  • the infection is an eye infection.
  • the fungal infection is nail fungus (e.g., affecting a toenail, fingernail, or analogous structure in a non-human animal).
  • the nail fungus, or onychomycosis may be caused by dermatophytes, Candida, and nondermatophytic molds. Dermatophytes are the fungi most commonly responsible for onychomycosis in the temperate western countries; while Candida and nondermatophytic molds are more frequently involved in the tropics and subtropics with a hot and humid climate. Trichophyton rubrum is the most common dermatophyte involved in onychomycosis.
  • Trichophyton interdigitale Other dermatophytes that may be involved are Trichophyton interdigitale, Epidermophyton floccosum, Trichophyton violaceum, Microsporum gypseum, Trichophyton tonsurans, and Trichophyton soudanense.
  • Trichophyton mentagrophytes for Trichophyton interdigitale.
  • Candida and nondermatophytic molds include Candida and nondermatophytic molds, in particular members of the mold generation Scytalidium (name recently changed to Neoscytalidium), Scopulariopsis, and Aspergillus.
  • Candida spp. mainly cause fingernail onychomycosis in people whose hands are often submerged in water.
  • Scytalidium mainly affects people in the tropics, though it persists if they later move to areas of temperate climate.
  • Other molds more commonly affect people older than 60 years, and their presence in the nail reflects a slight weakening in the nail's ability to defend itself against fungal invasion.
  • nail fungus can be treated by topical application of a topical composition of the nail surface and/or inserted or injected to the nail bed under the nail.
  • the topical composition may include an appropriate liquid or gel carrier, one or more CSA compounds, and optionally other adjuvents.
  • the carrier can a liquid carrier selected so as to penetrate beyond the nail surface and at least partially toward the nail bed.
  • an antifungal composition comprising one or more CSA compounds is utilized to treat or prevent an infection associated with Candida auris.
  • a treatment composition is configured for application to an open wound, surgical site, catheter (e.g., venous catheter) insertion site, or other such wound.
  • a treatment composition is configured as a wash, spray, gel, paste, or other formulation suitable for application to an open wound, surgical site, catheter insertion site, or other site of potential fungal infection. Such embodiments may be particularly useful for treating or preventing a Candida auris infection.
  • an antifungal composition comprising one or more CSA compounds is applied to a medical device to prevent fungal colonization of the medical device and/or fungal infections at the medical implant site.
  • medical devices to which the treatment composition may be applied include devices which are implanted into a subject's tissues, deployed at a puncture or wound site, positioned for feeding or withdrawing material from a body cavity, or are otherwise associated with a patient/subject in such a way that biological compatibility is of concern (e.g., because fungal infection and/or fouling of the device can result).
  • the antifungal composition may be applied to a catheter (e.g., a venous catheter), intravenous needle, intravenous line, oral care device (e.g., dentures, dental implant), intrauterine device (IUD), feeder tube, drain, prosthesis component (e.g., voice prosthesis), peristaltic pump, tympsanostomy tube, tracheotomy tube, endotracheal tube, joint prosthesis, dialysis access graft, or cardiac graft.
  • a catheter e.g., a venous catheter
  • intravenous needle e.g., intravenous line
  • oral care device e.g., dentures, dental implant
  • intrauterine device IUD
  • feeder tube e.g., drain
  • prosthesis component e.g., voice prosthesis
  • peristaltic pump e.g., tympsanostomy tube, tracheotomy tube, endotracheal tube, joint prosthesis, dialysis
  • compound 1-A is converted to the mesylate, compound 1-B using known conditions.
  • Treatment of compound 1-B with a secondary amine, such as HNR1R2 results in the formation of compound 1-C, whose azido functional groups are reduced with hydrogen gas in the presence of a suitable catalyst to afford compound 1-D.
  • Suitable catalysts include Palladium on Carbon and Lindlar catalyst.
  • the reagent HNR1R2 is not particularly limited under this reaction scheme. For example, when Ri is hydrogen and R 2 is a C 8 -alkyl, CSA-13 is obtained from the synthesis. When Ri is hydrogen and R 2 is a Ci6-alkyl, CSA-92 is obtained from the synthesis. When Ri and R 2 are both Cs-alkyl, CSA-90 is obtained from the synthesis.
  • CSA 8 and CSA 13 were dissolved in dimethyl sulfoxide (DMSO) to create stock solutions. These solutions were applied to fungal isolates to determine the minimum inhibitory concentration (MIC) for each CSA.
  • DMSO dimethyl sulfoxide
  • An antifungal agent is serially diluted two-fold in a desired medium to produce ten concentrations of the antifungal under investigation.
  • the range used is chosen to include achievable serum levels of the drug.
  • a standardized inoculum of either yeast cells or conidia is diluted in an equal volume of the desired medium.
  • the yeast or conidia inoculum is incubated in the serially diluted drug wells at 35° C. Two wells are used as controls.
  • the negative control well has only media and serves as a sterility control.
  • the positive control well has the standardized inoculum with no drug, and is used to compare with the amount of growth in the drug wells.
  • Testing is reported as an MIC, or minimum inhibitory concentration in ⁇ g/ml. This number represents the concentration at which the organism's growth in inhibited 50% from the control well for yeasts, and 80% for dermatophytes and certain filamentous fungi/antifungal combinations. Amphotericin B readings are taken at 100% inhibition.
  • CFU colony forming units or yeast cells
  • Antifungal susceptibility testing gives a numerical result expressed in ⁇ g/ml indicating an in vitro MIC, or minimum inhibitory concentration, of the drug being investigated.
  • the Clinical and Laboratory Standards Institute (CLSI) has provided guidelines for standardized microdilution broth testing (CLSI M27-A2 for yeasts and CLSI M38-A for filamentous molds), which is followed in the above procedure.
  • CLSI has also published guidelines for interpretation of MIC results based on clinical correlation studies for yeasts.
  • Penicillium sp. 1 Penicillium sp. 1 0.5
  • the antifungal effectiveness of CSA-131 was tested against 100 Candida auris isolates.
  • the C auris isolates were from all over the world and covered known C auris clades.
  • CSA-131 showed activity against all C. auris among this collection, with all isolates falling into one of two possible MIC values. The activity across the 4 clades was comparable. The MIC50 value for this compound is not impacted by individual isolate status as echinocandin- or fluconazole-resistant. Results are shown in Tables 3 through 7. The results show that CSA-131 is expected to be particularly effective in therapeutically or prophylactically treating or preventing Candida auris infections and/or preventing colonization by Candida auris of medical devices, such as when implanted in a patient.
  • Table 3 MIC data for 100 C. auris isolates
  • Table 5 MIC values ⁇ g/ml) for 100 C auris isolates by clade
  • Table 7 MIC data for isolates with elevated echinocandin MICs
  • CSA compounds according to Formula I are shown below in Formulas II and III, wherein Formula III differs from Formula II by omitting R15 and the ring carbon to which it is attached.
  • the R groups shown in the Formulae can have a variety of different structures.
  • CSA compounds, and a variety of different R groups, useful in accordance with the present disclosure are disclosed in U.S. Patent Nos. 6,350,738, 6,486,148, 6,767,904, 7,598,234, 7,754,705, 8 975,310 and 9,434,759, which are incorporated herein by reference.
  • R 3 , R7, and R12 may independently include a cationic moiety (e.g., amino or guanidino groups) bonded to the steroid backbone structure via a non-hydrolysable or hydrolysable linkage.
  • a cationic moiety e.g., amino or guanidino groups
  • the linkage is preferably non-hydrolysable under conditions of sterilization and storage, and physiological conditions.
  • Such cationic functional groups e.g., amino or guanidino groups
  • a tail moiety may be attached to the backbone structures at Ris.
  • the tail moiety may have variable chain length or size and may be charged, uncharged, polar, non-polar, hydrophobic, amphipathic, and the like.
  • the tail moiety may, for example, be configured to alter the hydrophobicity/hydrophilicity of the ceragenin compound.
  • CSA compounds of the present disclosure having different degrees of hydrophobicity/ hydrophilicity may, for example, have different rates of uptake into different target microbes.
  • each of fused rings A, B, C, and D may be independently saturated, or may be fully or partially unsaturated, provided that at least two of A, B, C, and D are saturated, wherein rings A, B, C, and D form a ring system.
  • Other ring systems can also be used, e.g., 5-member fused rings and/or compounds with backbones having a combination of 5- and 6-membered rings;
  • Ri through R 4 , R 6 , R7 , R11 , R12, R15, Ri6, and Ris are independently selected from the group consisting of hydrogen, hydroxyl, alkyl, hydroxyalkyl, alkyloxyalkyl, alkylcarboxyalkyl, alkylaminoalkyl, alkylaminoalkylamino, alkylaminoalkylamino-alkylamino, aminoalkyl, aryl, arylaminoalkyl, haloalkyl, alkenyl, alkynyl, oxo, a linking group attached to a second steroid, aminoalkyloxy, aminoalkyloxyalkyl, aminoalkylcarboxy, aminoalkylaminocarbonyl, aminoalkylcarboxamido, di(alkyl)aminoalkyl, H2N-HC(Q5)-C(0)-0-, H 2 N-HC(Q 5 )-C(0)-N(H)-, azi
  • R5, R 8 , R9, Rio, Ri3, Ri4 and Ri 8 are independently deleted when one of rings A, B, C, or D is unsaturated so as to complete the valency of the carbon atom at that site, or R5, R 8 , R9, Rio, Ri3, and R14 are independently selected from the group consisting of hydrogen, hydroxyl, alkyl, hydroxyalkyl, alkyloxyalkyl, aminoalkyl, aryl, haloalkyl, alkenyl, alkynyl, oxo, a linking group attached to a second steroid, aminoalkyloxy, aminoalkylcarboxy, aminoalkylaminocarbonyl, di(alkyl)aminoalkyl, H 2 N-HC(Q 5 )-C(0)-0-, H 2 N-HC(Q 5 )-C(0)- N(H)-, azidoalkyloxy, cyanoalkyloxy, P.G.-HN-HC(Q5)-C(0)-
  • At least one, and sometimes two or three of R1-4, R 6 , R7, R11, R12, Ri5, Ri6, Ri7, and Ri 8 are independently selected from the group consisting of aminoalkyl, aminoalkyloxy, alkylcarboxyalkyl, alkylaminoalkylamino, alkylaminoalkyl-aminoalkylamino, aminoalkylcarboxy, arylaminoalkyl, aminoalkyl oxyaminoalkylamino-carbonyl, aminoalkylaminocarbonyl, aminoalkyl-carboxyamido, a quaternary ammonium alkylcarboxy, di(alkyl)aminoalkyl, H 2 N-HC(Q 5 )-C(0)-0-, H 2 N-HC(Q 5 )-C(0)-N(H)-, azidoalkyloxy, cyanoalkyloxy, P.G.-HN-HC(Q5)
  • Ri through R 4 , R 6 , R7 , R11 , R12, R15, Ri6, and Ri 8 are independently selected from the group consisting of hydrogen, hydroxyl, (C1-C22) alkyl, (Ci- C22) hydroxyalkyl, (C1-C22) alkyloxy-(Ci-C 2 2) alkyl, (C1-C22) alkylcarboxy-(Ci-C 2 2) alkyl, (Ci- C22) alkylamino-(Ci-C 22 ) alkyl, (C1-C22) alkylamino-(Ci-C 22 ) alkylamino, (C1-C22) alkylamino- (C1-C22) alkylamino- (C1-C22) alkylamino, (C1-C22) aminoalkyl, aryl, arylamino-(Ci-C 22 ) alkyl, (C1-C1-C
  • R.5, R 8 , R9, Rio, Ri3, Ri4 and Rn are independently deleted when one of rings A, B, C, or D is unsaturated so as to complete the valency of the carbon atom at that site, or R 5 , R 8 , Rs>, Rio, Ri3, and R14 are independently selected from the group consisting of hydrogen, hydroxyl, (C1-C22) alkyl, (C1-C22) hydroxyalkyl, (C1-C22) alkyloxy-(Ci-C 2 2) alkyl, (C1-C22) aminoalkyl, aryl, (C1-C22) haloalkyl, (C 2 -C 6 ) alkenyl, (C 2 -C 6 ) alkynyl, oxo, a linking group attached to a second steroid, (C1-C22) aminoalkyloxy, (C1-C22) aminoalkylcarboxy, (C1-C22) aminoalkylamino
  • R1-4, R5 , R7 , R11, R12, R15, R1 ⁇ 2, Rn, and Ri 8 are independently selected from the group consisting of (C1-C22) aminoalkyl, (C1-C22) aminoalkyloxy, (C1-C22) alkylcarboxy-(Ci-C22) alkyl, (C1-C22) alkylamino-(Ci-C22) alkylamino, (C1-C22) alkylamino-(Ci-C22) alkylamino (C1-C22) alkylamino, (C1-C22) aminoalkylcarboxy, arylamino (C1-C22) alkyl, (C1-C22) aminoalkyloxy (C1-C22) aminoalkylaminocarbonyl, (C1-C22) aminoalkylaminocarbonyl, (C1-C22) aminoalkylcarboxyamido
  • Ri through R 4 , R 6 , R7 , R11 , R12, R15, Ri6, and Ri 8 are independently selected from the group consisting of hydrogen, hydroxyl, (Ci-Ci 8 ) alkyl, (Ci- Cis) hydroxyalkyl, (Ci-Cis) alkyloxy-(Ci-Ci 8 ) alkyl, (Ci-Cis) alkylcarboxy-(Ci-Ci 8 ) alkyl, (Ci- Ci 8 ) alkylamino-(Ci-Ci 8 )alkyl, (Ci-Ci 8 ) alkylamino-(Ci-Ci 8 ) alkylamino, (Ci-Ci 8 ) alkylamino- (Ci-Ci 8 ) alkylamino- (Ci-Ci 8 ) alkylamino, (Ci-Ci 8 ) aminoalkyl, aryl, arylamin
  • R5, R 8 , R9, Rio, Ri3, Ri4 and R17 are independently deleted when one of rings A, B, C, or D is unsaturated so as to complete the valency of the carbon atom at that site, or R5, R 8 , R9, Rio, Ri3, and R14 are independently selected from the group consisting of hydrogen, hydroxyl, (Ci-Cis) alkyl, (Ci-Cis) hydroxyalkyl, (Ci-Cis) alkyloxy-(Ci-Ci 8 ) alkyl, (Ci-Cis) alkylcarboxy- (Ci-Ci 8 ) alkyl, (Ci-Cis) alkylamino-(Ci-Ci8)alkyl, (Ci-Cis) alkylamino-(Ci-Ci8) alkylamino, (Ci-Ci 8 ) alkylamino-(Ci-Ci8) alkylamino- (Ci-Cis) alkylamino, (
  • R1-4, R6 , R7 , R11, R12, R15, R1 ⁇ 2, R17, and Ri 8 are independently selected from the group consisting of of hydrogen, hydroxyl, an unsubstituted (Ci-Ci 8 ) alkyl, unsubstituted (Ci-Ci 8 ) hydroxyalkyl, unsubstituted (Ci-Ci 8 ) alkyloxy-(Ci-Ci 8 ) alkyl, unsubstituted (Ci-Ci 8 ) alkylcarboxy-(Ci-Ci 8 ) alkyl, unsubstituted (Ci-Ci 8 ) alkylamino- (Ci-Ci 8 )alkyl, unsubstituted (Ci-Ci 8 ) alkylamino-(Ci-Ci 8 ) alkylamino, unsubstituted (Ci-Ci 8 ) alkylamino-(Ci-Ci 8
  • R3, R7, R12, and Ri 8 are independently selected from the group consisting of hydrogen, an unsubstituted (Ci-Ci 8 ) alkyl, unsubstituted (Ci-Ci 8 ) hydroxyalkyl, unsubstituted (Ci-Ci 8 ) alkyloxy-(Ci-Ci 8 ) alkyl, unsubstituted (Ci-Ci 8 ) alkylcarboxy-(Ci-Ci 8 ) alkyl, unsubstituted (Ci-Ci 8 ) alkylamino-(Ci-Ci 8 )alkyl, unsubstituted (Ci-Ci 8 ) alkylamino-(Ci- Ci 8 ) alkylamino, unsubstituted (Ci-Ci 8 ) alkylamino-(Ci-Ci 8 ) alkylamino- (Ci-Ci 8 ) alkylamino- (Ci
  • Ri, R 2 , R 4 , R5, R5, R 8 , R9, Rio, R11, R13, R14, R15, Ri6, and R17 are independently selected from the group consisting of hydrogen and unsubstituted (Ci-C 6 ) alkyl.
  • R 3 , R7, R12, and Ri 8 are independently selected from the group consisting of hydrogen, an unsubstituted (Ci-C 6 ) alkyl, unsubstituted (Ci-C 6 ) hydroxyalkyl, unsubstituted (Ci-Ci 6 ) alkyl oxy-(Ci-C5) alkyl, unsubstituted (Ci-Ci 6 ) alkylcarboxy-(Ci-C5) alkyl, unsubstituted (Ci-Ci 6 ) alkylamino-(Ci-C5)alkyl, (Ci-Ci 6 ) alkylamino-(Ci-C5) alkylamino, unsubstituted (Ci-Ci 6 ) alkylamino-(Ci-Ci6) alkylamino-(Ci-C5) alkylamino, an unsubstituted (Ci-Ci 6 )
  • Ri, R 2 , R 4 , R5, R5, R 8 , Rio, R11, R14, Ri6, and R17 are each hydrogen; and R9 and Ri 3 are each methyl.
  • R 3 , R7, R12, and Ri 8 are independently selected from the group consisting of aminoalkyloxy; aminoalkylcarboxy; alkyl aminoalkyl; alkoxycarbonylalkyl; alkylcarbonylalkyl; di(alkyl)aminoalkyl; alkylcarboxyalkyl; and hydroxyalkyl.
  • R 3 , R7, and R12 are independently selected from the group consisting of aminoalkyloxy and aminoalkylcarboxy; and Ri 8 is selected from the group consisting of alkylaminoalkyl; alkoxycarbonylalkyl; alkylcarbonyloxyalkyl; di(alkyl)aminoalkyl; alkylaminoalkyl; alkyoxycarbonylalkyl; alkylcarboxyalkyl; and hydroxyalkyl.
  • R 3 , R7, and R12 are the same.
  • R 3 , R7, and R12 are aminoalkyloxy.
  • Ri 8 is alkylaminoalkyl.
  • Ri 8 is alkoxycarbonylalkyl.
  • Ri 8 is di(alkyl)aminoalkyl.
  • Ri 8 is alkylcarboxyalkyl.
  • Ri 8 is hydroxyalkyl
  • R 3 , R7, and R12 are aminoalkylcarboxy.
  • R 3 , R7, R12 and Ri 8 are independently selected from the group consisting of aminoalkyloxy; aminoalkylcarboxy; alkylaminoalkyl; di-(alkyl)aminoalkyl; alkoxycarbonylalkyl; and alkylcarboxyalkyl.
  • R 3 , R7, and R12 are independently selected from the group consisting of aminoalkyloxy and aminoalkylcarboxy, and wherein Ri 8 is selected from the group consisting of alkylaminoalkyl; di-(alkyl)aminoalkyl; alkoxycarbonylalkyl; and alkylcarboxyalkyl .
  • R 3 , R7, and R12 are independently selected from the group consisting of aminoalkyloxy and aminoalkylcarboxy, and wherein Ri 8 is selected from the group consisting of alkylaminoalkyl; di-(alkyl)aminoalkyl; and alkoxycarbonylalkyl.
  • R 3 , R7, R12, and Ri 8 are independently selected from the group consisting of amino-C 3 -alkyloxy; amino-C 3 -alkyl-carboxy; Cs-alkylamino-Cs-alkyl; C12- alkylamino-C5-alkyl; Cn-alkylamino-Cs-alkyl; Ci6-alkylamino-C5-alkyl; di-(C5-alkyl)amino-C5- alkyl; C6-alkoxy-carbonyl-C4-alkyl; C 8 -alkoxy-carbonyl-C4-alkyl; Cio-alkoxy-carbonyl-C4- alkyl; C6-alkyl-carboxy-C4-alkyl; C 8 -alkyl-carboxy-C4-alkyl; and Cio-alkyl-carboxy-C4-alkyl.
  • R 3 , R7, R12, and Ri 8 are independently selected from the group consisting of amino-C 3 -alkyloxy; amino-C 3 -alkyl-carboxy; Cs-alkylamino-Cs-alkyl; C12- alkylamino-C5-alkyl; Cn-alkylamino-Cs-alkyl; Ci6-alkylamino-C5-alkyl; di-(C5-alkyl)amino-C5- alkyl; C6-alkoxy-carbonyl-C4-alkyl; C 8 -alkoxy-carbonyl-C4-alkyl; and Cio-alkoxy-carbonyl-C4- alkyl.
  • R 3 , R7, and R12 are independently selected from the group consisting of amino-C 3 -alkyloxy or amino-C 3 -alkyl-carboxy
  • Ri 8 is selected from the group consisting of Cs-alkylamino-Cs-alkyl; Co-alkylamino-Cs-alkyl; Cn-alkylamino-Cs- alkyl; Ci6-alkylamino-C5-alkyl; di-(C5-alkyl)amino-C5-alkyl; C6-alkoxy-carbonyl-C4-alkyl; C 8 - alkoxy-carbonyl-C4-alkyl; Cio-alkoxy-carbonyl-C4-alkyl; C6-alkyl-carboxy-C4-alkyl; C 8 -alkyl- carboxy-C4-alkyl; and Cio-alkyl-carboxy-C
  • R 3 , R7, and R12 are independently selected from the group consisting of amino-C 3 -alkyloxy or amino-C 3 -alkyl-carboxy
  • Ri 8 is selected from the group consisting of Cs-alkylamino-Cs-alkyl; Co-alkylamino-Cs-alkyl; C 13 -alkylamino-C 5 - alkyl; Ci6-alkylamino-C5-alkyl; di-(C5-alkyl)amino-C5-alkyl; C6-alkoxy-carbonyl-C4-alkyl; C 8 - alkoxy-carbonyl-C4-alkyl; and Cio-alkoxy-carbonyl-C4-alkyl.
  • R 3 , R7, R12, and Ri 8 are independently selected from the group consisting of amino-C 3 -alkyloxy; amino-C 3 -alkyl-carboxy; amino-C2-alkylcarboxy; C 8 - alkylamino-C5-alkyl; C 8 -alkoxy-carbonyl-C4-alkyl; Cio-alkoxy-carbonyl-C4-alkyl; C 8 -alkyl- carbonyl-C4-alkyl; di-(C5-alkyl)amino-C5-alkyl; Cn-alkylamino-Cs-alkyl; C 6 -alkoxy-carbonyl- C4-alkyl; C6-alkyl-carboxy-C4-alkyl; Ci6-alkylamino-C5-alkyl; Co-alkylamino-Cs-alkyl; and hydroxy(C5)alkyl
  • Ri 8 is selected from the group consisting of C 8 -alkylamino- C 5 -alkyl or C 8 -alkoxy-carbonyl-C4-alkyl. [0102] In some embodiments, at least Ris can have the following structure:
  • R20 is omitted or alkyl, alkenyl, alkynyl, or aryl
  • R21 and R22 are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, or aryl, provided that at least one of R21 and R22 is not hydrogen.
  • R21 and R22 are independently selected from the group consisting of hydrogen, C1-C24 alkyl, C2-C24 alkenyl, C2-C24 alkynyl, C 6 or C10 aryl, 5 to 10 membered heteroaryl, 5 to 10 membered heterocyclyl, C7-13 aralkyl, (5 to 10 membered heteroaryl)-Ci-C6 alkyl, C3-10 carbocyclyl, C4-10 (carbocyclyl)alkyl, (5 to 10 membered heterocyclyl)-Ci-C 6 alkyl, amido, and a suitable amine protecting group, provided that at least one of R21 and R22 is not hydrogen.
  • one or more of rings A, B, C, and D are heterocyclic.
  • rings A, B, C, and D are non-heterocyclic.
  • the CSA compound is a compound of Formula IV, which is a subset of Formula III, or salt thereof having a steroidal backbone:
  • R3, R7, R12 and Ris can be any of the constituents for these groups listed above for Formulas I, II and III.
  • R3, R7, and R12 are independently selected from the group consisting of hydrogen, an unsubstituted (C1-C22) alkyl, unsubstituted (C1-C22) hydroxyalkyl, unsubstituted (C1-C22) alkyl oxy-(Ci-C22) alkyl, unsubstituted (C1-C22) alkylcarboxy-(Ci-C22) alkyl, unsubstituted (C1-C22) alkylamino-(Ci-C22)alkyl, unsubstituted (Ci- C22) alkylamino-(Ci-C22) alkylamino, unsubstituted (C1-C22) alkylamino-(Ci-C22) alkylamino, unsubstituted (C1-
  • R 3 , R7, and R12 are independently selected from the group consisting of hydrogen, an unsubstituted (Ci-C 6 ) alkyl, unsubstituted (Ci-C 6 ) hydroxyalkyl, unsubstituted (Ci-Ci 6 ) alkyl oxy-(Ci-C5) alkyl, unsubstituted (Ci-Ci 6 ) alkylcarboxy-(Ci-C5) alkyl, unsubstituted (Ci-Ci 6 ) alkylamino-(Ci-C5)alkyl, unsubstituted (Ci-Ci 6 ) alkylamino-(Ci- C5) alkylamino, unsubstituted (Ci-Ci 6 ) alkylamino-(Ci-Ci6) alkylamino-(Ci-C5) alkylamino, an unsubstituted (Ci-Ci)
  • R 3 , R7, and R12 are independently selected from the group consisting of aminoalkyloxy; aminoalkylcarboxy; alkyl aminoalkyl; alkoxycarbonylalkyl; alkylcarbonylalkyl; di(alkyl)aminoalkyl; alkylcarboxyalkyl; and hydroxyalkyl.
  • R 3 , R7, and R12 are independently selected from the group consisting of aminoalkyloxy and aminoalkylcarboxy; and Ri 8 is selected from the group consisting of alkylaminoalkyl; alkoxycarbonylalkyl; alkylcarbonyloxyalkyl; di(alkyl)aminoalkyl; alkylaminoalkyl; alkyoxycarbonylalkyl; alkylcarboxyalkyl; and hydroxyalkyl.
  • R 3 , R7, and R12 are the same. In some embodiments, R 3 , R7, and R12 are aminoalkyloxy. In some embodiments, R 3 , R7, and R12 are aminoalkylcarboxy.
  • R 3 , R7, and R12 are independently selected from the group consisting of amino-C 3 -alkyloxy; amino-C 3 -alkyl-carboxy; Cs-alkylamino-Cs-alkyl; C 8 -alkoxy- carbonyl-C4-alkyl; C 8 -alkyl-carbonyl-C4-alkyl; di-(C5-alkyl)amino-C5-alkyl; C 13 -alkylamino-C 5 - alkyl; C6-alkoxy-carbonyl-C4-alkyl; C6-alkyl-carboxy-C4-alkyl; and Ci6-alkylamino-C5-alkyl.
  • CSA compounds as disclosed herein can be a compound of Formula I, Formula II, Formula III, Formula IV, or salts thereof wherein at least Ri 8 of the steroidal backbone includes amide functionality in which the carbonyl group of the amide is positioned between the amido nitrogen of the amide and fused ring D of the steroidal backbone.
  • Ri 8 of the steroidal backbone includes amide functionality in which the carbonyl group of the amide is positioned between the amido nitrogen of the amide and fused ring D of the steroidal backbone.
  • one or more of R 3 , R7, or R12 may include a guanidine group as a cationic functional group and may be bonded to the steroid backbone by an ether linkage.
  • one or more of R 3 , R7, or R12 may be a guanidinoalkyloxy group.
  • the alkyl portion is defined as with the embodiments described above.
  • the alkyl portion is a straight chain with 3 carbon atoms, and therefore one or more of R 3 , R7, or R12 may be a guanidinopropyloxy group.
  • cationic functional groups may be utilized, and that the cationic functional groups may be bonded to the steroid backbone through a variety of other tethers or linkages.
  • the cationic functional groups may be bonded to the steroid backbone by an ester linkage.
  • the cationic functional groups may be bonded to the steroid backbone by an amide linkage.
  • R 3 , R7, or R12 may be an aminoalkylcarbonylamino (i.e. aminoalkylcarboxamido) or guanidinoalkylcarbonylamino (i.e.
  • the tethers may be of varying lengths.
  • the length between the steroid backbone and the cationic functional group e.g., amino or guanidino group
  • the length between the steroid backbone and the cationic functional group may be between 1 and 15 atoms or even more than 15 atoms. In other embodiments, the length may be between 1 and 8 atoms. In a preferred embodiment, the length of the tether is between two and four atoms. In other embodiments, there is no tether, such that the cationic functional group is bonded directly to the steroid backbone.
  • R 3 , R7, or R12 may include one variation of cationic functional group while one or more of another of R 3 , R7, or R12 of the same compound may include a different variation of cationic functional group.
  • two or more of R 3 , R7, or R12 may include the same cationic functional group, or all of R 3 , R7, or R12 may include the same cationic functional group (in embodiments where all of R 3 , R7, or R12 are cationic functional groups).
  • one or more cationic functional groups are disposed at R 3 , R7, or R12
  • R 3 , R7, or R12 may not be cationic functional groups and/or one or more cationic functional groups may be disposed at other locations of the steroid backbone.
  • one or more cationic functional groups may be disposed at Ri, R 2 , R3, R4, R5, R7, R11, R12, R15, Ri6, Ri7, and/or Ri 8 .
  • salts are optionally prepared as salts.
  • the term "salt” as used herein is a broad term, and is to be given its ordinary and customary meaning to a skilled artisan (and is not to be limited to a special or customized meaning), and refers without limitation to a salt of a compound.
  • the salt is an acid addition salt of the compound. Salts can be obtained by reacting a compound with inorganic acids such as hydrohalic acid (e.g., hydrochloric acid or hydrobromic acid), sulfuric acid, nitric acid, and phosphoric acid.
  • hydrohalic acid e.g., hydrochloric acid or hydrobromic acid
  • sulfuric acid e.g., nitric acid, and phosphoric acid.
  • Salts can also be obtained by reacting a compound with an organic acid such as aliphatic or aromatic carboxylic or sulfonic acids, for example formic acid, acetic acid, propionic acid, glycolic acid, pyruvic acid, malonic acid, maleic acid, fumaric acid, trifluoroacetic acid, benzoic acid, cinnamic acid, mandelic acid, succinic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, nicotinic acid, methanesulfonic acid, ethanesulfonic acid, p-toluensulfonic acid, salicylic acid, stearic acid, muconic acid, butyric acid, phenylacetic acid, phenylbutyric acid, valproic acid, 1,2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 2-naphthalenesulfonic acid
  • Salts can also be obtained by reacting a compound with a base to form a salt such as an ammonium salt, an alkali metal salt, such as a lithium, sodium or a potassium salt, an alkaline earth metal salt, such as a calcium, magnesium or aluminum salt, a salt of organic bases such as dicyclohexylamine, N- methyl-D-glucamine, tris(hydroxymethyl)methyl amine, C1-C7 alkylamine, cyclohexylamine, dicyclohexylamine, triethanolamine, ethylenediamine, ethanolamine, diethanolamine, triethanolamine, tromethamine, and salts with amino acids such as arginine and lysine; or a salt of an inorganic base, such as aluminum hydroxide, calcium hydroxide, potassium hydroxide, sodium carbonate, sodium hydroxide, or the like.
  • a salt of an inorganic base such as aluminum hydroxide, calcium hydroxide, potassium hydroxide, sodium carbonate, sodium
  • a CSA compound represented by the chemical structure of its free base also includes any salt thereof (e.g., in which one or more amine groups have been protonated).
  • the compounds and compositions disclosed herein are optionally prepared as pharmaceutically acceptable salts.
  • pharmaceutically acceptable salt as used herein is a broad term, and is to be given its ordinary and customary meaning to a skilled artisan (and is not to be limited to a special or customized meaning), and refers without limitation to a salt of a compound that does not cause significant irritation to an organism to which it is administered and does not abrogate the biological activity and properties of the compound.
  • the salt is an acid addition salt of the compound.
  • Pharmaceutical salts can be obtained by reacting a compound with inorganic acids such as hydrohalic acid (e.g., hydrochloric acid or hydrobromic acid), sulfuric acid, nitric acid, and phosphoric acid.
  • Pharmaceutical salts can also be obtained by reacting a compound with an organic acid such as aliphatic or aromatic carboxylic or sulfonic acids, for example formic acid, acetic acid, propionic acid, glycolic acid, pyruvic acid, malonic acid, maleic acid, fumaric acid, trifluoroacetic acid, benzoic acid, cinnamic acid, mandelic acid, succinic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, nicotinic acid, methanesulfonic acid, ethanesulfonic acid, p- toluensulfonic acid, salicylic acid, stearic acid, muconic acid, butyric acid, phenylacetic acid,
  • Pharmaceutical salts can also be obtained by reacting a compound with a base to form a salt such as an ammonium salt, an alkali metal salt, such as a lithium, sodium or a potassium salt, an alkaline earth metal salt, such as a calcium, magnesium or aluminum salt, a salt of organic bases such as dicyclohexylamine, N-methyl-D-glucamine, tris(hydroxymethyl)methylamine, C1-C7 alkylamine, cyclohexylamine, dicyclohexylamine, triethanolamine, ethylenediamine, ethanolamine, diethanolamine, triethanolamine, tromethamine, and salts with amino acids such as arginine and lysine; or a salt of an inorganic base, such as aluminum hydroxide, calcium hydroxide, potassium hydroxide, sodium carbonate, sodium hydroxide, or the like.
  • a salt of organic bases such as dicyclohexylamine, N-methyl-D-glucamine, tris(hydroxymethyl
  • the pharmaceutically acceptable salt is a hydrochloride salt. In some embodiments, the pharmaceutically acceptable salt is a mono-hydrochloride salt, a di- hydrochloride salt, a tri-hydrochloride salt, or a tetra-hydrochloride salt. In some embodiments, the pharmaceutically acceptable salt is a sulfate salt. In other embodiments, the pharmaceutically acceptable salt is a monosulfate salt. In other embodiments, the pharmaceutically acceptable salt is a 1,5-dinapthalenesulphonic acid salt. In other embodiments, the pharmaceutically acceptable salt is a 1,5-naphthalenedisulfonic acid salt. B. Pharmaceutical Compositions
  • compositions described herein may be useful, inter alia, for treating or preventing a bone disease and/or a broken bone.
  • a pharmaceutical composition is any composition that may be administered in vitro or in vivo or both to a subject in order to treat or ameliorate a condition.
  • a pharmaceutical composition may be administered in vivo.
  • a subject may include one or more cells or tissues, or organisms.
  • the subject is an animal.
  • the animal is a mammal.
  • the mammal may be a human or primate in some embodiments.
  • a mammal includes any mammal, such as by way of non-limiting example, cattle, pigs, sheep, goats, horses, camels, buffalo, cats, dogs, rats, mice, and humans.
  • the terms “pharmaceutically acceptable” and “physiologically acceptable” mean a biologically compatible formulation, gaseous, liquid or solid, or mixture thereof, which is suitable for one or more routes of administration, in vivo delivery, or contact.
  • a formulation is compatible in that it does not destroy activity of an active ingredient therein (e.g., a CSA), or induce adverse side effects that far outweigh any prophylactic or therapeutic effect or benefit.
  • the pharmaceutical compositions may be formulated with pharmaceutically acceptable excipients such as carriers, solvents, stabilizers, adjuvants, diluents, etc., depending upon the particular mode of administration and dosage form.
  • the pharmaceutical compositions should generally be formulated to achieve a physiologically compatible pH, and may range from a pH of about 3 to a pH of about 11, preferably about pH 3 to about pH 7, depending on the formulation and route of administration. In alternative embodiments, it may be preferred that the pH is adjusted to a range from about pH 5.0 to about pH 8. More particularly, the pharmaceutical compositions may comprise a therapeutically or prophylactically effective amount of at least one compound as described herein, together with one or more pharmaceutically acceptable excipients.
  • the pharmaceutical compositions may comprise a combination of the compounds described herein, or may include a second active ingredient useful in the treatment or prevention of bacterial infection (e.g., anti -bacterial or antimicrobial agents).
  • a second active ingredient useful in the treatment or prevention of bacterial infection e.g., anti -bacterial or antimicrobial agents.
  • Formulations e.g., for parenteral or oral administration, are most typically solids, liquid solutions, emulsions or suspensions, while inhalable formulations for pulmonary administration are generally liquids or powders, with powder formulations being generally preferred.
  • a preferred pharmaceutical composition may also be formulated as a lyophilized solid that is reconstituted with a physiologically compatible solvent prior to administration.
  • Alternative pharmaceutical compositions may be formulated as syrups, creams, ointments, tablets, and the like.
  • compositions may contain one or more excipients.
  • Pharmaceutically acceptable excipients are determined in part by the particular composition being administered, as well as by the particular method used to administer the composition. Accordingly, there exists a wide variety of suitable formulations of pharmaceutical compositions (see, e.g., Remington's Pharmaceutical Sciences).
  • Suitable excipients may be carrier molecules that include large, slowly metabolized macromolecules such as proteins, polysaccharides, polylactic acids, polyglycolic acids, polymeric amino acids, amino acid copolymers, and inactive virus particles.
  • Other exemplary excipients include antioxidants such as ascorbic acid; chelating agents such as EDTA; carbohydrates such as dextrin, hydroxyalkylcellulose, hydroxyalkylmethylcellulose, stearic acid; liquids such as oils, water, saline, glycerol and ethanol; wetting or emulsifying agents; pH buffering substances; and the like. Liposomes are also included within the definition of pharmaceutically acceptable excipients.
  • compositions described herein may be formulated in any form suitable for the intended method of administration.
  • tablets, troches, lozenges, aqueous or oil suspensions, non-aqueous solutions, dispersible powders or granules (including micronized particles or nanoparticles), emulsions, hard or soft capsules, syrups or elixirs may be prepared.
  • Compositions intended for oral use may be prepared according to any method known to the art for the manufacture of pharmaceutical compositions, and such compositions may contain one or more agents including sweetening agents, flavoring agents, coloring agents and preserving agents, in order to provide a palatable preparation.
  • compositions particularly suitable for use in conjunction with tablets include, for example, inert diluents, such as celluloses, calcium or sodium carbonate, lactose, calcium or sodium phosphate; disintegrating agents, such as cross-linked povidone, maize starch, or alginic acid; binding agents, such as povidone, starch, gelatin or acacia; and lubricating agents, such as magnesium stearate, stearic acid or talc.
  • Tablets may be uncoated or may be coated by known techniques including microencapsulation to delay disintegration and adsorption in the gastrointestinal tract and thereby provide a sustained action over a longer period.
  • a time delay material such as glyceryl monostearate or glyceryl distearate alone or with a wax may be employed.
  • Formulations for oral use may be also presented as hard gelatin capsules where the active ingredient is mixed with an inert solid diluent, for example celluloses, lactose, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with nonaqueous or oil medium, such as glycerin, propylene glycol, polyethylene glycol, peanut oil, liquid paraffin or olive oil.
  • an inert solid diluent for example celluloses, lactose, calcium phosphate or kaolin
  • nonaqueous or oil medium such as glycerin, propylene glycol, polyethylene glycol, peanut oil, liquid paraffin or olive oil.
  • compositions may be formulated as suspensions comprising a compound of the embodiments in admixture with at least one pharmaceutically acceptable excipient suitable for the manufacture of a suspension.
  • compositions may be formulated as dispersible powders and granules suitable for preparation of a suspension by the addition of suitable excipients.
  • Excipients suitable for use in connection with suspensions include suspending agents, such as sodium carboxymethylcellulose, methylcellulose, hydroxypropyl methylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth, gum acacia, dispersing or wetting agents such as a naturally occurring phosphatide (e.g., lecithin), a condensation product of an alkylene oxide with a fatty acid (e.g., polyoxyethylene stearate), a condensation product of ethylene oxide with a long chain aliphatic alcohol (e.g., heptadecaethyleneoxycethanol), a condensation product of ethylene oxide with a partial ester derived from a fatty acid and a hexitol anhydride (e.g., polyoxyethylene sorbitan monooleate); polysaccharides and polysaccharide-like compounds (e.g.
  • dextran sulfate dextran sulfate
  • glycoaminoglycans and glycosaminoglycan-like compounds e.g., hyaluronic acid
  • thickening agents such as carbomer, beeswax, hard paraffin or cetyl alcohol.
  • the suspensions may also contain one or more preservatives such as acetic acid, methyl and/or n-propyl p-hydroxy-benzoate; one or more coloring agents; one or more flavoring agents; and one or more sweetening agents such as sucrose or saccharin.
  • the pharmaceutical compositions may also be in the form of oil-in water emulsions.
  • the oily phase may be a vegetable oil, such as olive oil or arachis oil, a mineral oil, such as liquid paraffin, or a mixture of these.
  • Suitable emulsifying agents include naturally occurring gums, such as gum acacia and gum tragacanth; naturally occurring phosphatides, such as soybean lecithin, esters or partial esters derived from fatty acids; hexitol anhydrides, such as sorbitan monooleate; and condensation products of these partial esters with ethylene oxide, such as polyoxyethylene sorbitan monooleate.
  • the emulsion may also contain sweetening and flavoring agents.
  • Syrups and elixirs may be formulated with sweetening agents, such as glycerol, sorbitol or sucrose. Such formulations may also contain a demulcent, a preservative, a flavoring or a coloring agent.
  • sweetening agents such as glycerol, sorbitol or sucrose.
  • Such formulations may also contain a demulcent, a preservative, a flavoring or a coloring agent.
  • the pharmaceutical compositions may be in the form of a sterile injectable preparation, such as a sterile injectable aqueous emulsion or oleaginous suspension.
  • a sterile injectable preparation such as a sterile injectable aqueous emulsion or oleaginous suspension.
  • This emulsion or suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents which have been mentioned above.
  • the sterile injectable preparation may also be a sterile injectable solution or suspension in a nontoxic parenterally acceptable diluent or solvent, such as a solution in 1,2-propane-diol.
  • the sterile injectable preparation may also be prepared as a lyophilized powder.
  • acceptable vehicles and solvents that may be employed are water, Ringer's solution, and isotonic sodium chloride solution.
  • sterile fixed oils may be employed as a solvent or suspending medium.
  • any bland fixed oil may be employed including synthetic mono- or diglycerides.
  • fatty acids such as oleic acid may likewise be used in the preparation of injectables.
  • a pharmaceutically acceptable salt of a compound described herein may be dissolved in an aqueous solution of an organic or inorganic acid, such as 0.3 M solution of succinic acid, or more preferably, citric acid. If a soluble salt form is not available, the compound may be dissolved in a suitable co-solvent or combination of co-solvents. Examples of suitable co- solvents include alcohol, propylene glycol, polyethylene glycol 300, polysorbate 80, glycerin and the like in concentrations ranging from about 0 to about 60% of the total volume. In one embodiment, the active compound is dissolved in DMSO and diluted with water.
  • the pharmaceutical composition may also be in the form of a solution of a salt form of the active ingredient in an appropriate aqueous vehicle, such as water or isotonic saline or dextrose solution.
  • an appropriate aqueous vehicle such as water or isotonic saline or dextrose solution.
  • compounds which have been modified by substitutions or additions of chemical or biochemical moieties which make them more suitable for delivery e.g., increase solubility, bioactivity, palatability, decrease adverse reactions, etc.
  • esterification e.g., glycosylation, PEGylation, and complexation.
  • compositions can be prepared, however, by complexing the therapeutic with a biochemical moiety to improve such undesirable properties.
  • Proteins are a particular biochemical moiety that may be complexed with a CSA for administration in a wide variety of applications.
  • one or more CSAs are complexed with a protein for the treatment of infection.
  • one or more CSAs are complexed with a protein to increase the CSA's half-life.
  • one or more CSAs are complexed with a protein to decrease the CSA's toxicity.
  • Albumin is a particularly preferred protein for complexation with a CSA.
  • the albumin is fat-free albumin.
  • the biochemical moiety for complexation can be added to the pharmaceutical composition as 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 10, 20, 50, or 100 weight equivalents, or a range bounded by any two of the aforementioned numbers, or about any of the numbers.
  • the weight ratio of albumin to CSA is about 18: 1 or less, such as about 9: 1 or less.
  • the CSA is coated with albumin.
  • non-biochemical compounds can be added to the pharmaceutical compositions to reduce the toxicity of the therapeutic and/or improve the half- life. Suitable amounts and ratios of an additive that can improve toxicity can be determined via a cellular assay.
  • toxicity reducing compounds can be added to the pharmaceutical composition as 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 10, 20, 50, or 100 weight equivalents, or a range bounded by any two of the aforementioned numbers, or about any of the numbers.
  • the toxicity reducing compound is a cocoamphodi acetate such as Miranol® (disodium cocoamphodi acetate).
  • the toxicity reducing compound is an amphoteric surfactant. In some embodiments, the toxicity reducing compound is a surfactant. In other embodiments, the molar ratio of cocoamphodi acetate to CSA is between about 8: 1 and 1 : 1, preferably about 4: 1. In some embodiments, the toxicity reducing compound is allantoin.
  • the compounds described herein may be formulated for oral administration in a lipid-based formulation suitable for low solubility compounds.
  • Lipid-based formulations can generally enhance the oral bioavailability of such compounds.
  • a pharmaceutical composition comprises a therapeutically or prophylactically effective amount of a compound described herein, together with at least one pharmaceutically acceptable excipient selected from the group consisting of- medium chain fatty acids or propylene glycol esters thereof (e.g., propylene glycol esters of edible fatty acids such as caprylic and capric fatty acids) and pharmaceutically acceptable surfactants such as polyoxyl 40 hydrogenated castor oil.
  • cyclodextrins may be added as aqueous solubility enhancers.
  • Preferred cyclodextrins include hydroxypropyl, hydroxyethyl, glucosyl, maltosyl and maltotriosyl derivatives of ⁇ -, ⁇ -, and ⁇ -cyclodextrin.
  • a particularly preferred cyclodextrin solubility enhancer is hydroxypropyl-o-cyclodextrin (BPBC), which may be added to any of the above-described compositions to further improve the aqueous solubility characteristics of the compounds of the embodiments.
  • BPBC hydroxypropyl-o-cyclodextrin
  • the composition comprises about 0.1% to about 20% hydroxypropyl-o-cyclodextrin, more preferably about 1% to about 15%) hydroxypropyl-o-cyclodextrin, and even more preferably from about 2.5% to about 10%) hydroxypropyl-o-cyclodextrin.
  • the amount of solubility enhancer employed will depend on the amount of the compound of the embodiments in the composition.
  • a CSA comprises a multimer (e.g., a dimer, trimer, tetramer, or higher order polymer).
  • the CSAs can be incorporated into pharmaceutical compositions or formulations. Such pharmaceutical compositions/formulations are useful for administration to a subject, in vivo or ex vivo.
  • Pharmaceutical compositions and formulations include carriers or excipients for administration to a subject.
  • Such formulations include solvents (aqueous or non-aqueous), solutions (aqueous or non-aqueous), emulsions (e.g., oil-in-water or water-in-oil), suspensions, syrups, elixirs, dispersion and suspension media, coatings, isotonic and absorption promoting or delaying agents, compatible with pharmaceutical administration or in vivo contact or delivery.
  • Aqueous and non-aqueous solvents, solutions and suspensions may include suspending agents and thickening agents.
  • Such pharmaceutically acceptable carriers include tablets (coated or uncoated), capsules (hard or soft), microbeads, powder, granules and crystals.
  • Supplementary active compounds e.g., preservatives, antibacterial, antiviral and antifungal agents
  • Cosolvents and adjuvants may be added to the formulation.
  • cosolvents contain hydroxyl groups or other polar groups, for example, alcohols, such as isopropyl alcohol; glycols, such as propylene glycol, polyethyleneglycol, polypropylene glycol, glycol ether; glycerol; polyoxy ethylene alcohols and polyoxy ethylene fatty acid esters.
  • Adjuvants include, for example, surfactants such as, soya lecithin and oleic acid; sorbitan esters such as sorbitan trioleate; and polyvinylpyrrolidone.
  • a pharmaceutical composition and/or formulation contains a total amount of the active ingredient(s) sufficient to achieve an intended therapeutic effect.
  • the term "packaging material" refers to a physical structure housing one or more components of the kit.
  • the packaging material can maintain the components sterilely, and can be made of material commonly used for such purposes (e.g., paper, corrugated fiber, glass, plastic, foil, ampules, vials, tubes, etc.).
  • a kit can contain a plurality of components, e.g., two or more compounds alone or in combination with an osteogenesis agent or treatment or drug, optionally sterile.
  • a kit optionally includes a label or insert including a description of the components (type, amounts, doses, etc.), instructions for use in vitro, in vivo, or ex vivo, and any other components therein.
  • Labels or inserts include "printed matter," e.g., paper or cardboard, or separate or affixed to a component, a kit or packing material (e.g., a box), or attached to an ampule, tube or vial containing a kit component.
  • Labels or inserts can additionally include a computer readable medium, such as a disk (e.g., floppy diskette, hard disk, ZIP disk), optical disk such as CD- or DVD -ROM/RAM, DVD, MP3, magnetic tape, or an electrical storage media such as RAM and ROM or hybrids of these such as magnetic/optical storage media, FLASH media or memory type cards.
  • a computer readable medium such as a disk (e.g., floppy diskette, hard disk, ZIP disk), optical disk such as CD- or DVD -ROM/RAM, DVD, MP3, magnetic tape, or an electrical storage media such as RAM and ROM or hybrids of these such as magnetic/optical storage media, FLASH media or memory type cards.
  • compositions may be administered in numerous ways.
  • administration may mean simply applying the compositions to a bone directly.
  • administration may be enteral, parenteral, or topical.
  • exemplary routes of administration for contact or in vivo delivery which a compound can optionally be formulated include inhalation, respiration, intubation, intrapulmonary instillation, oral (buccal, sublingual, mucosal), intrapulmonary, rectal, vaginal, intrauterine, intradermal, topical, dermal, parenteral (e.g., subcutaneous, intramuscular, intravenous, intradermal, intraocular, intratracheal and epidural), intranasal, intrathecal, intraarticular, intracavity, transdermal, iontophoretic, ophthalmic, optical (e.g., corneal), intraglandular, intraorgan, and/or intralymphatic.
  • parenteral e.g., subcutaneous, intramuscular, intravenous, intradermal, intraocular, intratracheal and epidural
  • parenteral e.g., subcutaneous, intramuscular, intravenous, intradermal, intraocular, intratracheal and epid
  • the delivery forms can be homogeneous, e.g., forms in which the composition is in solution, or heterogeneous, e.g., forms in which the composition is contained within liposomes or microspheres.
  • the forms can produce an immediate effect, and can alternatively, or additionally, produce an extended effect.
  • liposomes, or microspheres, or other similar means of providing an extended release of the composition can be used to extend the period during which the composition is exposed to the targeted area; non-encapsulated compositions can also be provided for an immediate effect.
  • the composition or method includes administering a CSA from a pharmaceutically acceptable device(s) such as bandages, surgical dressings, gauzes, adhesive strips, surgical staples, clips, hemostats, intrauterine devices, sutures, trocars, catheters, tubes, and implants.
  • a pharmaceutically acceptable device(s) such as bandages, surgical dressings, gauzes, adhesive strips, surgical staples, clips, hemostats, intrauterine devices, sutures, trocars, catheters, tubes, and implants.
  • the implant is a pill, pellet, rod, screw, wafer, disc, and/or tablet.
  • the devices can deliver the composition to a targeted area for a desired period of time.
  • the composition may be incorporated into a medical device coating.
  • the coating contains 0.1 weight %, 1 weight %, 5 weight %, 10 weight %, 15 weight %, 20 weight %, 25 weight %, 50 weight %, about any of the aforementioned numbers, and/or a range bounded by any two of the aforementioned numbers.
  • Devices according to the disclosure can be prepared according to known methods, and can include, or be made from, polymeric material.
  • the polymeric material will be an absorbable material and in other instances, a non-absorbable material, or in other instances a resorbable material.
  • Devices can, of course, include absorbable, non-absorbable, resorbable materials, and combinations thereof.
  • Absorbable materials can be synthetic materials and non-synthetic materials.
  • Absorbable synthetic materials include, but are not limited to, cellulosic polymers, glycolic acid polymers, methacrylate polymers, ethylene vinyl acetate polymers, ethylene vinyl alcohol copolymers, polycaptrolactam, polyacetate, copolymers of lactide and glycolide, polydioxanone, polyglactin, poliglecaprone, polyglyconate, polygluconate, and combinations thereof.
  • Absorbable non-synthetic materials include, but are not limited to, catgut, cargile membrane, fascia lata, gelatin, collagen, and combinations thereof.
  • Nonabsorbable synthetic materials include, but are not limited to nylons, rayons, polyesters, polyolefins, and combinations thereof.
  • Non-absorbable non-synthetic materials include, but are not limited to, silk, dermal silk, cotton, linen, and combinations thereof.
  • a CSA gel or ointment can be impregnated into a bandage or wound dressing for delivery of the CSA to a targeted location.
  • an implantable absorbable device can be loaded with a CSA material and release the CSA from the device over a desired period.
  • Sustained or controlled release formulations, compositions, or devices can be used.
  • a desired period of delivery can be, for example, at least about 2, 3, 6, 10, 12, 18, or 24 hours, or 1, 2, 4, 8, 12, 20, or 30 days, or 1, 2, 3, 4, 5, 6, or more months, and any value in between.
  • the physical form used to deliver the CSA is not critical and the choice or design of such devices is well within the level of skill of one in the art.
  • the vehicles or carriers may also include humectants or moisturizers to maintain a desired moisture level in the treated area.
  • humectants or moisturizers to maintain a desired moisture level in the treated area.
  • drugs such as anesthetics or antibiotics, which provide other desired effects. Again, the possibilities are unlimited and are left to the practitioner.
  • the composition may comprise a second CSA for purposes for which CSAs are known to serve.
  • co-administration means concurrently or administering one substance followed by beginning the administration of a second substance within 24 hours, 20 hours, 16 hours, 12 hours, 8 hours, 4 hours, 1 hour, 30 minutes, 15 minutes, 5 minutes, 1 minute, a range bounded by any two of the aforementioned numbers, and/or about any of the aforementioned numbers.
  • one or more CSAs are co-administered. In other embodiments, the co-administration of CSAs accounts for their therapeutic benefit. In some embodiments, co-administration is concurrent.
  • non-CSA agents are administered to the patient.
  • the non-CSA agents are co-administered.
  • agents include, but are not limited to, a regulatory agency approved antifungal agent.
  • the regulatory agency is the Food and Drug Administration (FDA).
  • the non-CSA agent is selected from the group consisting of antifungal agent, an antibiotic, a non-steroidal anti-inflammatory agent, an anti-viral agent, an anti-retroviral agent, an anti-pyretic, an anti-emetic, an immunomodulator, a chemotherapeutic agent, an anti-histamine, an opioid receptor agonist, an anti-cholinergic, and a beta2- adrenoreceptor agonist.
  • Such agents are known in the art, for example, ketoconazole, linezolid, ibuprofen, rifampicin, acyclovir, aspirin, dolasetron, interferon, cisplatin, diphenhydramine, morphine, atropine, and albuterol.
  • a companion diagnostic is an in vitro diagnostic test or device that provides information that is essential for the safe and effective use of a corresponding therapeutic product. Such tests or devices can identify patients likely to be at risk for adverse reactions as a result of treatment with a particular therapeutic product. Such tests or devices can also monitor responsiveness to treatment (or estimate responsiveness to possible treatments). Such monitoring may include schedule, dose, discontinuation, or combinations of therapeutic agents.
  • the CSA is selected by measuring a biomarker in the patient.
  • the term biomarker includes, but is not limited to, genetic regulation, protein levels, RNA levels, blood and/or tissue cultures, and cellular responses such as cytotoxicity.
  • one or more CSAs are selected by subjecting a sample from the patient to a companion diagnostic device.
  • the sample is a tissue sample. In other embodiments, the tissue sample is from the fungi to be treated.
  • the formulations may, for convenience, be prepared or provided as a unit dosage form. Preparation techniques include bringing into association the active ingredient (e.g., CSA) and a pharmaceutical carrier(s) or excipient(s). In general, formulations are prepared by uniformly and intimately associating the active ingredient with liquid carriers or finely divided solid carriers or both, and then, if necessary, shaping the product. For example, a tablet may be made by compression or molding.
  • active ingredient e.g., CSA
  • a pharmaceutical carrier(s) or excipient(s) e.g., CSA
  • formulations are prepared by uniformly and intimately associating the active ingredient with liquid carriers or finely divided solid carriers or both, and then, if necessary, shaping the product.
  • a tablet may be made by compression or molding.
  • Compressed tablets may be prepared by compressing, in a suitable machine, an active ingredient (e.g., a CSA) in a free-flowing form such as a powder or granules, optionally mixed with a binder, lubricant, inert diluent, preservative, surface-active or dispersing agent. Molded tablets may be produced by molding, in a suitable apparatus, a mixture of powdered compound (e.g., CSA) moistened with an inert liquid diluent. The tablets may optionally be coated or scored and may be formulated so as to provide a slow or controlled release of the active ingredient therein.
  • an active ingredient e.g., a CSA
  • a free-flowing form such as a powder or granules, optionally mixed with a binder, lubricant, inert diluent, preservative, surface-active or dispersing agent.
  • Molded tablets may be produced by molding, in a suitable apparatus
  • Compounds e.g., CSAs
  • a "unit dosage form” as used herein refers to a physically discrete unit suited as unitary dosages for the subject to be treated; each unit containing a predetermined quantity of compound optionally in association with a pharmaceutical carrier (excipient, diluent, vehicle or filling agent) which, when administered in one or more doses, is calculated to produce a desired effect (e.g., prophylactic or therapeutic effect or benefit).
  • Unit dosage forms can contain a daily dose or unit, daily sub-dose, or an appropriate fraction thereof, of an administered compound (e.g., CSA).
  • Unit dosage forms also include, for example, capsules, troches, cachets, lozenges, tablets, ampules and vials, which may include a composition in a freeze-dried or lyophilized state; a sterile liquid carrier, for example, can be added prior to administration or delivery in vivo.
  • Unit dosage forms additionally include, for example, ampules and vials with liquid compositions disposed therein.
  • Unit dosage forms further include compounds for transdermal administration, such as "patches" that contact with the epidermis of the subject for an extended or brief period of time.
  • the individual unit dosage forms can be included in multi-dose kits or containers. Pharmaceutical formulations can be packaged in single or multiple unit dosage forms for ease of administration and uniformity of dosage.
  • Compounds can be administered in accordance with the methods at any frequency as a single bolus or multiple dose e.g., one, two, three, four, five, or more times hourly, daily, weekly, monthly, or annually or between about 1 to 10 days, weeks, months, or for as long as appropriate.
  • Exemplary frequencies are typically from 1-7 times, 1-5 times, 1-3 times, 2-times or once, daily, weekly or monthly. Timing of contact, administration ex vivo or in vivo delivery can be dictated by the infection, pathogenesis, symptom, pathology or adverse side effect to be treated.
  • an amount can be administered to the subject substantially contemporaneously with, or within about 1-60 minutes or hours of the onset of a symptom or adverse side effect, pathogenesis, or vaccination.
  • Long-acting pharmaceutical compositions may be administered twice a day, once a day, once every two days, three times a week, twice a week, every 3 to 4 days, or every week depending on half-life and clearance rate of the particular formulation.
  • a pharmaceutical composition contains an amount of a compound as described herein that is selected for administration to a patient on a schedule selected from: twice a day, once a day, once every two days, three times a week, twice a week, and once a week.
  • Localized delivery is also contemplated, including but not limited to delivery techniques in which the compound is implanted, injected, infused, or otherwise locally delivered. Localized delivery is characterized by higher concentrations of drug at the site of desired action (e.g., the tumor or organ to be treated) versus systemic concentrations of the drug.
  • Well-known localized delivery forms can be used, including long-acting injections; infusion directly into the site of action; depot delivery forms; controlled or sustained delivery compositions; transdermal patches; infusion pumps; and the like.
  • the CSA can further be incorporated into a biodegradable or bioerodible material or be put into or on a medical device.
  • Doses may vary depending upon whether the treatment is therapeutic or prophylactic, the onset, progression, severity, frequency, duration, probability of or susceptibility of the symptom, the type pathogenesis to which treatment is directed, clinical endpoint desired, previous, simultaneous or subsequent treatments, general health, age, gender or race of the subject, bioavailability, potential adverse systemic, regional or local side effects, the presence of other disorders or diseases in the subject, and other factors that will be appreciated by the skilled artisan (e.g., medical or familial history). Dose amount, frequency or duration may be increased or reduced, as indicated by the clinical outcome desired, status of the infection, symptom or pathology, any adverse side effects of the treatment or therapy.
  • treatment includes preventing a disease, ameliorating symptoms, slowing disease progression, reversing damage, or curing a disease.
  • the dosage may range broadly, depending upon the desired effects and the therapeutic indication. Alternatively dosages may be based and calculated upon the surface area of the patient, as understood by those of skill in the art. Although the exact dosage will be determined on a drug-by-drug basis, in most cases, some generalizations regarding the dosage can be made.
  • the systemic daily dosage regimen for an adult human patient may be, for example, an oral dose of between 0.01 mg and 3000 mg of the active ingredient, preferably between 1 mg and 700 mg, e.g. 5 to 200 mg.
  • the dosage may be a single one or a series of two or more given in the course of one or more days, as is needed by the subject.
  • the compounds will be administered for a period of continuous therapy, for example for a week or more, or for months or years. Doses tailored for particular types of fungal infections, or particular patients can be selected based, in part, on the GI50, TGI, and LC50 values set forth in the Examples that follow.
  • human dosages for compounds have been established for at least some condition, those same dosages may be used, or dosages that are between about 0.1% and 500%, more preferably between about 25% and 250% of the established human dosage.
  • a suitable human dosage can be inferred from ED50 or ID50 values, or other appropriate values derived from in vitro or in vivo studies, as qualified by toxicity studies and efficacy studies in animals.
  • dosages may be calculated as the free base.
  • the compounds disclosed herein in certain situations it may be necessary to administer the compounds disclosed herein in amounts that exceed, or even far exceed, the above-stated, preferred dosage range in order to effectively and aggressively treat particularly aggressive diseases or conditions.
  • Dosage amount and interval may be adjusted individually to provide plasma levels of the active moiety which are sufficient to maintain the modulating effects, or minimal effective concentration (MEC).
  • therapeutic dosages may result in plasma levels of 0.05 ⁇ g/mL, 0.1 ⁇ g/mL, 0.5 ⁇ g/mL, 1 ⁇ g/mL, 5 ⁇ g/mL, 10 ⁇ g/mL, 15 ⁇ g/mL, 20 ⁇ g/mL, 25 ⁇ g/mL, 30 ⁇ g/mL, 35 ⁇ g/mL, 40 ⁇ g/mL, 45 ⁇ g/mL, 50 ⁇ g/mL, 55 ⁇ g/mL, 60 ⁇ g/mL, 65 ⁇ g/mL, 70 ⁇ g/mL, 75 ⁇ g/mL, 80 ⁇ g/mL, 85 ⁇ g/mL, 90 ⁇ g/mL, 95 ⁇ g/mL, 100 ⁇ g/mL, a range bounded by
  • the therapeutic dose is sufficient to establish plasma levels in the range of about 0.1 ⁇ g/mL to about 10 ⁇ g/mL. In other embodiments, the therapeutic dose is sufficient to establish plasma levels in the range of 1 ⁇ g/mL to 20 ⁇ g/mL.
  • the MEC will vary for each compound but can be estimated from in vitro data. Dosages necessary to achieve the MEC will depend on individual characteristics and route of administration. However, HPLC assays or bioassays can be used to determine plasma concentrations. Dosage intervals can also be determined using MEC value. Compositions should be administered using a regimen which maintains plasma levels above the MEC for 10-90% of the time, preferably between 30-90% and most preferably between 50-90%. In cases of local administration or selective uptake, the effective local concentration of the drug may not be related to plasma concentration.
  • Compounds disclosed herein can be evaluated for efficacy and toxicity using known methods.
  • the toxicology of a particular compound, or of a subset of the compounds, sharing certain chemical moieties may be established by determining in vitro toxicity towards a cell line, such as a mammalian, and preferably human, cell line. The results of such studies are often predictive of toxicity in animals, such as mammals, or more specifically, humans.
  • the toxicity of particular compounds in an animal model such as mice, rats, rabbits, or monkeys, may be determined using known methods.
  • the efficacy of a particular compound may be established using several recognized methods, such as in vitro methods, animal models, or human clinical trials. When selecting a model to determine efficacy, the skilled artisan can be guided by the state of the art to choose an appropriate model, dose, route of administration and/or regime.
  • the methods of the embodiments also include the use of a compound or compounds as described herein together with one or more additional therapeutic agents for the treatment of disease conditions.
  • the combination of active ingredients may be: (1) co-formulated and administered or delivered simultaneously in a combined formulation; (2) delivered by alternation or in parallel as separate formulations; or (3) by any other combination therapy regimen known in the art.
  • the methods described herein may comprise administering or delivering the active ingredients sequentially, e.g., in separate solution, emulsion, suspension, tablets, pills or capsules, or by different injections in separate syringes.
  • an effective dosage of each active ingredient is administered sequentially, i.e., serially
  • simultaneous therapy effective dosages of two or more active ingredients are administered together.
  • Various sequences of intermittent combination therapy may also be used.

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Abstract

L'invention concerne des compositions et des méthodes de traitement d'infections fongiques chez un patient, qui consistent à identifier un patient nécessitant un tel traitement et à lui administrer une quantité thérapeutiquement efficace d'au moins un antimicrobien stéroïdien cationique (ASC) ou d'un sel pharmaceutiquement acceptable de ce dernier. Des kits comprenant ces compositions et des instructions relatives à ces méthodes selon l'invention sont également décrits. Les compositions et les méthodes sont utiles dans le traitement d'infections fongiques provoquées par Candida auris et pour empêcher la colonisation de dispositifs médicaux par des champignons, tels que Candida auris.
PCT/US2018/030670 2017-05-03 2018-05-02 Méthodes de traitement d'infections fongiques WO2018204506A1 (fr)

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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9180132B2 (en) * 2010-03-04 2015-11-10 The Trustees Of The University Of Pennsylvania Antimicrobial cationic steroids and methods of use
US20150374719A1 (en) * 2014-06-26 2015-12-31 Brigham Young University Methods for treating fungal infections

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9180132B2 (en) * 2010-03-04 2015-11-10 The Trustees Of The University Of Pennsylvania Antimicrobial cationic steroids and methods of use
US20150374719A1 (en) * 2014-06-26 2015-12-31 Brigham Young University Methods for treating fungal infections

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