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WO2017049105A1 - Formulations pour le traitement d'infections fongiques - Google Patents

Formulations pour le traitement d'infections fongiques Download PDF

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Publication number
WO2017049105A1
WO2017049105A1 PCT/US2016/052165 US2016052165W WO2017049105A1 WO 2017049105 A1 WO2017049105 A1 WO 2017049105A1 US 2016052165 W US2016052165 W US 2016052165W WO 2017049105 A1 WO2017049105 A1 WO 2017049105A1
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WIPO (PCT)
Prior art keywords
pharmaceutical composition
compound
added
salt
water
Prior art date
Legal status (The legal status 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 status listed.)
Ceased
Application number
PCT/US2016/052165
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English (en)
Inventor
Kenneth BARTIZAL
David Hughes
Voon ONG
Balasingam Radhakrishnan
Andreas Bernkop-Schnürch
Saskia KÖLLNER
Marie-christine LARCH
Andrew Xian Chen
Wei Lin
Julie Ann WEBB
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Cidara Therapeutics Inc
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Cidara Therapeutics Inc
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Application filed by Cidara Therapeutics Inc filed Critical Cidara Therapeutics Inc
Publication of WO2017049105A1 publication Critical patent/WO2017049105A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • 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
    • A61K9/06—Ointments; Bases therefor; Other semi-solid forms, e.g. creams, sticks, gels
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/407—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with other heterocyclic ring systems, e.g. ketorolac, physostigmine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/14—Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin

Definitions

  • VVC Vulvovaginal candidiasis
  • Echinocandins are members of a leading class of antifungal agents for the treatment of fungal infections. These compounds target the cell wall by preventing the production of ⁇ -1 ,3-glucan through inhibition of the catalytic subunit of 1 ,3-p-D-glucan synthase enzyme complex.
  • the three echinocandins approved by the U.S. Food and Drug Administration (FDA) for the treatment of invasive fungal infections (caspofungin, anidulafungin, and micafungin) are available only in intravenous formulation.
  • the limitations on the route and frequency of delivery preclude the utilization these echinocandins for, e.g., treatment of VVC.
  • VVC a leading class of antifungal agents for the treatment of fungal infections.
  • formulations of a salt of Compound 1 or a neutral form thereof.
  • Compound 1 can be a pharmaceutically acceptable salt of Compound 1 .
  • the disclosure features pharmaceutical compositions in the form of a gel, a cream, and an ointment containing a salt of
  • compositions can be used for the treatment of candidiasis (e.g., vulvovaginal candidiasis (VVC), oropharyngeal candidiasis) and/or aspergillosis (e.g., cutaneous aspergillosis).
  • candidiasis e.g., vulvovaginal candidiasis (VVC), oropharyngeal candidiasis
  • aspergillosis e.g., cutaneous aspergillosis
  • the disclosure also features methods of treating candidiasis or aspergillosis in a subject by locally administering to the subject a pharmaceutical composition containing 0.1 % to 15% (w/w) (e.g., 0.25 ⁇ 0.15, 0.5 ⁇ 0.25, 1 ⁇ 0.5, 3 ⁇ 2, 6 ⁇ 2, 8 ⁇ 2, 10 ⁇ 2, or 12 ⁇ 3% (w/w)) a salt of Compound 1 , or a neutral form thereof.
  • w/w 0.1 % to 15%
  • the disclosure features a pharmaceutical composition including 0.1 % to 1 5% (w/w) (e.g., 0.25 ⁇ 0.15, 0.5 ⁇ 0.25, 1 ⁇ 0.5, 3 ⁇ 2, 6 ⁇ 2, 8 ⁇ 2, 10 ⁇ 2, or 12 ⁇ 3% (w/w)) a salt of Compound 1 , or a neutral form thereof, in a gel carrier.
  • w/w 0.1 % to 1 5%
  • the gel carrier includes (i) about 2% to about 40% (w/w) (e.g., 5 ⁇ 3, 10 ⁇ 5, 25 ⁇ 10, or 30 ⁇ 10% (w/w)) of a gel-forming polymer and (ii) about 40% to about 99% (w/w) (e.g., 50 ⁇ 10, 60 ⁇ 10, 70 ⁇ 10, or 80 ⁇ 10% (w/w)) of water, deionized water, or buffered water.
  • w/w e.g., 5 ⁇ 3, 10 ⁇ 5, 25 ⁇ 10, or 30 ⁇ 10% (w/w)
  • w/w e.g., 50 ⁇ 10, 60 ⁇ 10, 70 ⁇ 10, or 80 ⁇ 10% (w/w)
  • the pharmaceutical composition further includes 0% to about 20% (w/w)
  • a solvent e.g., a solvent selected from the group consisting of glycerin, propylene glycol, N-methylpyrrolidone, acetone, and triacetin.
  • a solvent selected from the group consisting of glycerin, propylene glycol, N-methylpyrrolidone, acetone, and triacetin.
  • the pharmaceutical composition further includes 0% to about 20% (w/w) of a mixture of at least two solvents selected from the group consisting of glycerin, propylene glycol, N-methylpyrrolidone, acetone, and triacetin.
  • the solvent is propylene glycol.
  • the gel-forming polymer in the gel carrier is selected from the group consisting of hydroxypropyl methylcellulose, poloxamer 407, polyvinylpyrrolidone, hydroxyethyl cellulose, sodium carboxymethylcellulose, polyvinylalcohol, methylcellulose, ethylcellulose, chitosan, and hyaluronic acid.
  • the gel-forming polymer in the gel carrier is hydroxypropyl methylcellulose, poloxamer 407, polyvinylpyrrolidinone, or hydroxyethyl cellulose.
  • the salt of Compound 1 is dissolved in the gel carrier.
  • the pharmaceutical composition has a pH of 4 to 9. In some embodiments, the pharmaceutical composition has a pH of 4 to 9. In some
  • the pharmaceutical composition has a pH of 4.2 ⁇ 0.5, 4.5 ⁇ 0.5, 5.5 ⁇ 0.5, 6.5 ⁇ 0.5, 7.5 ⁇ 0.5, or 8.5 ⁇ 0.5. In some embodiments, the pharmaceutical composition has a pH of about 4.2.
  • the pharmaceutical composition further includes at least one preservative.
  • the preservative is selected from the group consisting of
  • ethylenediaminetetraacetic acid disodium dihydrate, methyl paraben, propyl paraben, benzyl alcohol, and benzoic acid.
  • the preservative is EDTA disodium dihydrate, methyl paraben, or propyl paraben.
  • the preservatives are EDTA disodium dihydrate, methyl paraben, and propyl paraben.
  • the disclosure features a pharmaceutical composition including 0.1 % to 1 5% (w/w) (e.g., 0.25 ⁇ 0.15, 0.5 ⁇ 0.25, 1 ⁇ 0.5, 3 ⁇ 2, 6 ⁇ 2, 8 ⁇ 2, 10 ⁇ 2, or 12 ⁇ 3% (w/w)) of a salt of Compound 1 , or a neutral form thereof, hydroxypropyl methylcellulose, EDTA disodium dihydrate, methyl paraben, and water.
  • w/w 0.1 % to 1 5% (w/w) (e.g., 0.25 ⁇ 0.15, 0.5 ⁇ 0.25, 1 ⁇ 0.5, 3 ⁇ 2, 6 ⁇ 2, 8 ⁇ 2, 10 ⁇ 2, or 12 ⁇ 3% (w/w)) of a salt of Compound 1 , or a neutral form thereof, hydroxypropyl methylcellulose, EDTA disodium dihydrate, methyl paraben, and water.
  • the disclosure features a pharmaceutical composition including (i) 0.1 % to 15% (w/w) of a salt of Compound 1 , or a neutral form thereof, in a gel carrier including about 2% to about 40% (w/w) of poloxamer 407 and about 40% to about 99% (w/w) of water, deionized water, or buffered water; (ii) 0% to about 20% (w/w) of propylene glycol; (iii) EDTA disodium dihydrate; (iv) methyl paraben; and (v) propyl paraben, wherein the pharmaceutical composition has a pH of about 4.2.
  • the disclosure features a pharmaceutical composition including (i) 0.1 % to 15% (w/w) of a salt of Compound 1 , or a neutral form thereof, in a gel carrier including about 2% to about 40% (w/w) of hydroxypropyl methylcellulose and about 40% to about 99% (w/w) of water, deionized water, or buffered water; (ii) EDTA disodium dihydrate; and (iii) methyl paraben, wherein the pharmaceutical composition has a pH of about 4.2.
  • the disclosure features a pharmaceutical composition including (i) 3% (w/w) of a salt of Compound 1 , or a neutral form thereof, in a gel carrier including about 1 .9% (w/w) of
  • the disclosure features a pharmaceutical composition including (i) 3% (w/w) of a salt of Compound 1 , or a neutral form thereof, in a gel carrier including about 4% (w/w) of hydroxypropyl methylcellulose and about 93% (w/w) of water, deionized water, or buffered water; (ii) about 0.1 % (w/w) of EDTA disodium dihydrate; and (iii) about 0.15% (w/w) of methyl paraben, wherein the pharmaceutical composition has a pH of about 4.5.
  • the disclosure features a pharmaceutical composition including 0.1 % to 1 5% (w/w) (e.g., 0.25 ⁇ 0.15, 0.5 ⁇ 0.25, 1 ⁇ 0.5, 3 ⁇ 2, 6 ⁇ 2, 8 ⁇ 2, 10 ⁇ 2, or 12 ⁇ 3% (w/w)) of a salt of Compound 1 , or a neutral form thereof, in an emulsion including (i) at least one emulsifiable oil; (ii) at least one emulsifying agent; and (iii) water, deionized water, or buffered water.
  • w/w e.g. 0.25 ⁇ 0.15, 0.5 ⁇ 0.25, 1 ⁇ 0.5, 3 ⁇ 2, 6 ⁇ 2, 8 ⁇ 2, 10 ⁇ 2, or 12 ⁇ 3% (w/w)
  • an emulsion including (i) at least one emulsifiable oil; (ii) at least one emulsifying agent; and (iii) water, deion
  • the emulsion includes (i) about 20% to about 70% (w/w) (e.g., 25 ⁇ 5, 30 ⁇
  • the salt of Compound 1 , or the neutral form thereof is dissolved in the emulsion. In some embodiments, the salt of Compound 1 , or the neutral form thereof, is in a particulate form in the emulsion.
  • the pharmaceutical composition of this aspect of the disclosure has a pH of 4 to 9. In some embodiments, the pharmaceutical composition has a pH of 4.5 ⁇ 0.5, 5.5 ⁇ 0.5, 6.5 ⁇ 0.5, 7.5 1 0.5, or 8.5 ⁇ 0.5.
  • the at least one emulsifiable oil includes a fatty alcohol or ester thereof.
  • the fatty alcohol or ester thereof is selected from the group consisting of cetyl alcohol, octyl dodecanol, cetearyl alcohol, and stearyl alcohol.
  • the emulsifying agent is selected from the group consisting of polysorbate 20, polysorbate 60, polysorbate 80, sorbitan monostearate, and a polyethylene glycol ether of cetyl alcohol.
  • the fatty alcohol or ester thereof is selected from the group consisting of cetyl alcohol, octyl dodecanol, cetearyl alcohol, and stearyl alcohol.
  • the emulsifying agent is selected from the group consisting of polysorbate 20, polysorbate 60, polysorbate 80, sorbitan monostearate, and a polyethylene glycol ether of cetyl alcohol.
  • the fatty alcohol or ester thereof is selected from the group consisting of cetyl alcohol, o
  • composition includes two or more emulsifying agents (e.g., emulsifying agents selected from the group consisting of of polysorbate 20, polysorbate 60, polysorbate 80, sorbitan monostearate, and a polyethylene glycol ether of cetyl alcohol).
  • emulsifying agents selected from the group consisting of of polysorbate 20, polysorbate 60, polysorbate 80, sorbitan monostearate, and a polyethylene glycol ether of cetyl alcohol.
  • the pharmaceutical composition of this aspect of the disclosure further includes from 1 % to 40% (w/w) (e.g., 3 ⁇ 2, 7 ⁇ 3, 15 ⁇ 5, 25 ⁇ 5, or 35 ⁇ 5% (w/w)) of a refatting agent.
  • w/w e.g., 3 ⁇ 2, 7 ⁇ 3, 15 ⁇ 5, 25 ⁇ 5, or 35 ⁇ 5% (w/w)
  • the refatting agent is selected from the group consisting of cetyl ester wax, petrolatum white, isopropyl myristate, decyl oleat, isohexadecane, corn oil, peanut oil, almond oil, sesame oil, olive oil, jojoba oil, soya bean oil, wool wax alcohol, paraffin, macrogol-glycerol hydroxystearate, hydrogenated castor oil, avocado oil, wheat germ oil, evening primrose oil, and shea butter.
  • the refatting agent is cetyl ester wax or petrolatum white.
  • the pharmaceutical composition of this aspect of the disclosure further includes about 5% to about 30% (w/w) (e.g., 7 ⁇ 2, 12.5 ⁇ 3.5, 20 ⁇ 5, or 25 ⁇ 5% (w/w)) of a solvent selected from the group consisting of glycerin, propylene glycol, N-methylpyrrolidone, acetone, and triacetin.
  • a solvent selected from the group consisting of glycerin, propylene glycol, N-methylpyrrolidone, acetone, and triacetin.
  • the pharmaceutical composition of this aspect of the disclosure further includes at least one preservative.
  • the preservative is selected from the group consisting of ethylenediaminetetraacetic acid (EDTA) disodium dihydrate, methyl paraben, propyl paraben, benzyl alcohol, and benzoic acid.
  • EDTA ethylenediaminetetraacetic acid
  • the preservative is benzyl alcohol or benzoic acid.
  • the preservatives are benzyl alcohol and benzoic acid.
  • the disclosure features a pharmaceutical composition including 0.1 % to 1 5% (w/w) (e.g., 0.25 ⁇ 0.15, 0.5 ⁇ 0.25, 1 ⁇ 0.5, 3 ⁇ 2, 6 ⁇ 2, 8 ⁇ 2, 10 ⁇ 2, or 12 ⁇ 3% (w/w)) of a salt of
  • Compound 1 or a neutral form thereof, at least one refatting agent selected from the group consisting of cetyl ester wax, petrolatum white, and isopropyl myristate, at least one emulsifiable oil selected from the group consisting of cetyl alcohol, octyl dodecanol, and cetearyl alcohol, at least one of emulsifying agent selected from the group consisting of sorbitan monostearate, polysorbate 60, and a polyethylene glycol ether of cetyl alcohol, and at least one preservative selected from the group consisting of benzyl alcohol and benzoic acid.
  • refatting agent selected from the group consisting of cetyl ester wax, petrolatum white, and isopropyl myristate
  • at least one emulsifiable oil selected from the group consisting of cetyl alcohol, octyl dodecanol, and cetearyl alcohol
  • emulsifying agent selected from the group consisting of
  • the pharmaceutical composition includes 0.1 % to 15% (w/w) (e.g., 0.25 ⁇ 0.15, 0.5 ⁇ 0.25, 1 ⁇ 0.5, 3 ⁇ 2, 6 ⁇ 2, 8 ⁇ 2, 10 ⁇ 2, or 12 ⁇ 3% (w/w)) of a salt of Compound 1 , or a neutral form thereof, about 6% (w/w) of cetyl ester wax, about 20% (w/w) of cetyl alcohol, about 27% (w/w) of octyl dodecanol, about 4% (w/w) of sorbitan monostearate, about 3% (w/w) of polysorbate 60, and about 2% (w/w) of benzyl alcohol.
  • w/w e.g., 0.25 ⁇ 0.15, 0.5 ⁇ 0.25, 1 ⁇ 0.5, 3 ⁇ 2, 6 ⁇ 2, 8 ⁇ 2, 10 ⁇ 2, or 12 ⁇ 3% (w/w)
  • a salt of Compound 1 or
  • the pharmaceutical composition further includes propylene glycol.
  • the disclosure features a pharmaceutical composition including 0.1 % to 1 5% (w/w) (e.g., 0.25 ⁇ 0.15, 0.5 ⁇ 0.25, 1 ⁇ 0.5, 3 ⁇ 2, 6 ⁇ 2, 8 ⁇ 2, 10 ⁇ 2, or 12 ⁇ 3% (w/w)) of a salt of Compound 1 , or a neutral form thereof, in an ointment including an oleaginous base.
  • w/w 0.1 % to 1 5% (w/w) (e.g., 0.25 ⁇ 0.15, 0.5 ⁇ 0.25, 1 ⁇ 0.5, 3 ⁇ 2, 6 ⁇ 2, 8 ⁇ 2, 10 ⁇ 2, or 12 ⁇ 3% (w/w)) of a salt of Compound 1 , or a neutral form thereof, in an ointment including an oleaginous base.
  • the oleaginous base includes a semisolid hydrocarbon. In some embodiments, the oleaginous base includes a semisolid hydrocarbon at ambient temperature. In some embodiments, the semisolid hydrocarbon is a C18-C30 hydrocarbon. In some embodiments, the semisolid hydrocarbon is selected from the group consisting of vegetable fat, animal fat, cetyl esters wax, paraffin, petrolatum white, white wax, and yellow wax. In some embodiments, the ointment includes from about 75% to about 98% (w/w) (e.g., 80 ⁇ 5, 85 ⁇ 5, 90 ⁇ 5, or 95 ⁇ 3% (w/w)) of the oleaginous base. In some embodiments, the oleaginous base is petrolatum white or cetyl ester wax.
  • the salt of Compound 1 , or the neutral form thereof is in a particulate form in the ointment.
  • the salt of Compound 1 , or the neutral form thereof, in the particulate form in the ointment is adsorbed onto a solid support.
  • the solid support is magnesium aluminum silicate, kaolin, bentonite, or attapulgite.
  • the solid support is aluminum silicate.
  • Compound 1 particles (described further herein) may be uniformly dispersed in the ointment or may be dispersed after adsorption on a solid support.
  • the salt of Compound 1 , or the neutral form thereof, in the particulate form that is adsorbed onto the solid support forms a particulate powder blend. In some embodiments, the particulate powder blend is milled to reduce particle size.
  • the pharmaceutical composition of this aspect of the disclosure further includes at least one antioxidant.
  • the antioxidant is butylated hydroxyanisole (BHA) or butylated hydroxytoluene.
  • the disclosure features a pharmaceutical composition including 0.1 % to 1 5% (w/w) (e.g., 0.25 ⁇ 0.15, 0.5 ⁇ 0.25, 1 ⁇ 0.5, 3 ⁇ 2, 6 ⁇ 2, 8 ⁇ 2, 10 ⁇ 2, or 12 ⁇ 3% (w/w)) of a salt of Compound 1 , or a neutral form thereof, magnesium aluminum silicate, petrolatum white, and butylated hydroxyanisole.
  • w/w 0.1 % to 1 5% (w/w) (e.g., 0.25 ⁇ 0.15, 0.5 ⁇ 0.25, 1 ⁇ 0.5, 3 ⁇ 2, 6 ⁇ 2, 8 ⁇ 2, 10 ⁇ 2, or 12 ⁇ 3% (w/w)
  • a salt of Compound 1 or a neutral form thereof, magnesium aluminum silicate, petrolatum white, and butylated hydroxyanisole.
  • the pharmaceutical composition includes 1 % to 10% (w/w) of a salt of Compound 1 , or a neutral form thereof, about 1 .5% to 5.5% of magnesium aluminum silicate, about 90% to 95% of petrolatum white, and optionally about 0.005 to 0.1 % of butylated hydroxyanisole.
  • the pharmaceutical composition of this aspect of the disclosure includes 6% (w/w) of a salt of Compound 1 , or a neutral form thereof, about 5.5% of magnesium aluminum silicate, about 88.8% of petrolatum white, and about 0.1 % of butylated hydroxyanisole. In some embodiments, the pharmaceutical composition of this aspect of the disclosure includes 3% (w/w) of a salt of Compound 1 , or a neutral form thereof, about 5.5% of magnesium aluminum silicate, about 91 .4% of petrolatum white, and about 0.1 % of butylated hydroxyanisole.
  • the pharmaceutical composition described herein results in the salt of Compound 1 , or the neutral form thereof, present up to 3 days following local administration to the vaginal cavity of a subject.
  • a measurable amount of Compound 1 may remain on the surface or embedded in the tissue (e.g., in the mucosal membrane) of the treatment area for three days or more.
  • the subject is a mammal. In some embodiments, the mammal is a human.
  • the disclosure features a method of treating candidiasis in a subject including locally administering to a mucosal tissue of the subject a pharmaceutical composition including 0.1 % to 15% (w/w) (e.g., 0.25 ⁇ 0.15, 0.5 ⁇ 0.25, 1 ⁇ 0.5, 3 ⁇ 2, 6 ⁇ 2, 8 ⁇ 2, 10 ⁇ 2, or 12 ⁇ 3% (w/w)) of a salt of Compound 1 , or a neutral form thereof, once or twice daily for a period of 1 to 5 days.
  • w/w e.g., 0.25 ⁇ 0.15, 0.5 ⁇ 0.25, 1 ⁇ 0.5, 3 ⁇ 2, 6 ⁇ 2, 8 ⁇ 2, 10 ⁇ 2, or 12 ⁇ 3% (w/w)
  • the candidiasis is oropharyngeal candidiasis and the locally administering includes intra-oral administration to the subject.
  • the candidiasis is vulvovaginal candidiasis and the locally administering includes intravaginal administration to the subject.
  • the disclosure features a method of treating vulvovaginal candidiasis in a subject including administering to the subject a pharmaceutical composition described herein in an amount effective to treat the vulvovaginal candidiasis, wherein the administering includes intravaginally administering and/or extravaginally administering.
  • extravaginally administering includes administering on the vulva.
  • the disclosure features a method of treating oropharyngeal candidiasis in a subject including administering to the subject a pharmaceutical composition in a gel form described herein (e.g., a pharmaceutical composition in a gel carrier) in an amount effective to treat the
  • oropharyngeal candidiasis wherein the administering includes intra-oral administering and/or topically administering in the oral cavity.
  • the locally administering includes locally administering once daily. In some embodiments, the locally administering includes locally administering twice daily. In some embodiments, the locally administering includes locally administering for four consecutive days or fewer. In some embodiments, the locally administering includes locally administering for two or three
  • the locally administering includes locally administering once weekly.
  • the disclosure features a method of treating vulvovaginal candidiasis in a subject including, on Day 1 , intravaginally administering to a mucosal tissue of the subject a
  • the method further includes, beginning on Day 1 , extravaginally administering to the external vulvar region of the subject a pharmaceutical composition including about 1 % (w/w) of a salt of Compound 1 , or a neutral form thereof, about 5.5% (w/w) magnesium aluminum silicate, petrolatum white, and butylated hydroxyanisole, wherein the pharmaceutical composition is administered once or twice daily for a period of 1 to 3 days.
  • the method further includes, beginning on Day 1 , extravaginally administering to the external vulvar region of the subject a pharmaceutical composition including about 1 % (w/w) of a salt of Compound 1 , or a neutral form thereof, about 4% (w/w) of hydroxypropyl methylcellulose, EDTA disodium dihydrate, methyl paraben, and water, deionized water, or buffered water, wherein the pharmaceutical composition has a pH of about 4.2, and wherein the pharmaceutical composition is administered once or twice daily for a period of 1 to 3 days.
  • a pharmaceutical composition including about 1 % (w/w) of a salt of Compound 1 , or a neutral form thereof, about 4% (w/w) of hydroxypropyl methylcellulose, EDTA disodium dihydrate, methyl paraben, and water, deionized water, or buffered water, wherein the pharmaceutical composition has a pH of about 4.2, and wherein the pharmaceutical composition is administered once or twice daily for a period of
  • the disclosure features a method of treating vulvovaginal candidiasis in a subject including, beginning on Day 1 , intravaginally administering to a mucosal tissue of the subject a pharmaceutical composition including 3% (w/w) of a salt of Compound 1 , or a neutral form thereof, about 4% (w/w) of hydroxypropyl methylcellulose, EDTA disodium dihydrate, methyl paraben, and water, deionized water, or buffered water, wherein the pharmaceutical composition has a pH of about 4.5, and wherein the pharmaceutical composition is administered once daily as a single dose for a period of 1 to 2 days.
  • the disclosure features a method of treating vulvovaginal candidiasis in a subject including, beginning on Day 1 , intravaginally administering to a mucosal tissue of the subject a pharmaceutical composition including 6% (w/w) of a salt of Compound 1 , or a neutral form thereof, about 4% (w/w) of hydroxypropyl methylcellulose, EDTA disodium dihydrate, methyl paraben, and water, deionized water, or buffered water, wherein the pharmaceutical composition has a pH of about 4.2, and wherein the pharmaceutical composition is administered once daily as a single dose for a period of 1 to 2 days.
  • the method further includes, beginning on Day 1 , extravaginally administering to the external vulvar region of the subject a pharmaceutical composition including about 1 % (w/w) of a salt of Compound 1 , or a neutral form thereof, about 4% (w/w) of hydroxypropyl methylcellulose, EDTA disodium dihydrate, methyl paraben, and water, deionized water, or buffered water, wherein the pharmaceutical composition has a pH of about 4.2, and wherein the pharmaceutical composition is administered once or twice daily for a period of 1 to 3 days.
  • the subject is a mammal. In some embodiments, the mammal is a human.
  • the candidiasis is caused by an antifungal drug-resistant strain of Candida. In some embodiments of the methods described herein, the candidiasis is caused by an azole-resistant strain of Candida. In some embodiments, the Candida is Candida albicans or Candida glabrata.
  • the fungal infection described herein is a Candida infection.
  • a Candida infection can be caused by a fungus in the genus Candida that is selected from the group consisting of Candida albicans, C. glabrata, C. dubliniensis, C. krusei, C. parapsilosis, C. tropicalis, C. orthopsilosis, C. guilliermondii, C. rugosa, and C. lusitaniae.
  • a Candida infection can be caused by an antifungal drug-susceptible or antifungal drug-resistant strain of fungus in the genus Candida (e.g., an antifungal drug-susceptible fungal infection or an antifungal drug- resistant fungal infection), such as an antifungal drug-susceptible or antifungal drug-resistant strain of any one of Candida albicans, C. glabrata, C. dubliniensis, C. krusei, C. parapsilosis, C. tropicalis, C.
  • Antifungal drugs include, but are not limited to, echinocandins (e.g., micafungin, caspofungin, and anidulafungin), polyene compounds (e.g., 67-121 - A, 67-121 -C, amphotericin B, arenomvcin B, aurenin, aureofungin A, aureotuscin, candidin, chinin, demethoxyrapamycin, dermostatin A, dermostatin B, DJ-400-Bi , DJ-400-B2, elizabethin, eurocidin A, eurocidin B, filipin I, filipin II, filipin III, filipin IV, fungichromin, gannibamycin, hamycin, levorin A2, lienomycin, lucensomycin, mycoheptin, mycoticin
  • a Candida infection can be caused by an azole-susceptible or azole-resistant strain of fungus in the genus Candida, such as an azole-susceptible or azole-resistant strain of any one of Candida albicans, C.
  • the disclosure features a pharmaceutical composition suitable for
  • 30-80% of Compound 1 , or the salt or neutral form thereof is released in vitro within 6 hours in simulated vaginal fluid. In some embodiments, 30-60% of Compound 1 , or the salt or neutral form thereof, is released in vitro within 6 hours in simulated vaginal fluid. In some embodiments, 60-80% of Compound 1 , or the salt or neutral form thereof, is released in vitro within 6 hours in simulated vaginal fluid.
  • 60-95% of Compound 1 , or the salt or neutral form thereof is released in vitro within 24 hours in simulated vaginal fluid. In some embodiments, 60-75% of Compound 1 , or the salt or neutral form thereof, is released in vitro within 24 hours in simulated vaginal fluid. In some embodiments, 75-95% of Compound 1 , or the salt or neutral form thereof, is released in vitro within 24 hours in simulated vaginal fluid.
  • the pharmaceutical composition of this aspect of the disclosure includes 1 % to 10% (w/w) Compound 1 , or the salt or neutral form thereof. In some embodiments, the pharmaceutical composition includes 2% to 4% (w/w) Compound 1 , or the salt or neutral form thereof.
  • the disclosure features a pharmaceutical composition suitable for
  • 0.1 -5% of Compound 1 , or the salt or neutral form thereof is released in vitro within 24 hours in simulated vaginal fluid. In some embodiments, 0.2-1 .5% of Compound 1 , or the salt or neutral form thereof, is released in vitro within 24 hours in simulated vaginal fluid.
  • the pharmaceutical composition of this aspect of the disclosure includes 1 % to 10% (w/w) Compound 1 , or the salt or neutral form thereof. In some embodiments, the
  • composition includes 2% to 4% (w/w) Compound 1 , or the salt or neutral form thereof.
  • the disclosure features a pharmaceutical composition suitable for
  • 1 -10% of Compound 1 , or the salt or neutral form thereof is released in vitro within 24 hours in in Medium 1 .
  • 2-8% of Compound 1 , or the salt or neutral form thereof is released in vitro within 24 hours in in Medium 1 .
  • 1 -4% of Compound 1 , or the salt or neutral form thereof is released in vitro within 4 hours in in Medium 1 .
  • the pharmaceutical composition of this aspect of the disclosure includes 1 % to 10% (w/w) Compound 1 , or the salt or neutral form thereof. In some embodiments, the
  • composition includes 2% to 4% (w/w) Compound 1 , or the salt or neutral form thereof.
  • the disclosure features a method of treating candidiasis in a subject including locally administering to a mucosal tissue of the subject a pharmaceutical composition described herein (e.g., a pharmaceutical composition of any one of the previous three aspects of the disclosure).
  • a pharmaceutical composition described herein e.g., a pharmaceutical composition of any one of the previous three aspects of the disclosure.
  • the candidiasis is vulvovaginal candidiasis and the locally administering includes intravaginal administration to the subject.
  • the disclosure features a method of treating vulvovaginal candidiasis in a subject including administering to the subject the pharmaceutical composition described herein (e.g., a pharmaceutical composition of any one of the previous three aspects of the disclosure) in an amount effective to treat the vulvovaginal candidiasis, wherein the administering includes intravaginally administering and/or extravaginally administering.
  • the pharmaceutical composition described herein e.g., a pharmaceutical composition of any one of the previous three aspects of the disclosure
  • the locally administering includes administering once daily or twice daily. In some embodiments, the administering includes administering for four consecutive days or fewer. In some embodiments, the administering includes administering for two or three consecutive days, in some embodiments, the administering includes administering once weekly.
  • the subject is a mammal (e.g., a human).
  • the candidiasis is caused by an antifungal drug-resistant strain of Candida. In some embodiments, the candidiasis is caused by an azole-resistant strain of Candida. In some embodiments, the Candida is Candida albicans or Candida glabrata.
  • a salt of Compound 1 refers to a salt (e.g., a pharmaceutically acceptable salt) of the compound of Formula 1 .
  • Compound 1 has a structure (below). In its salt form, the tertiary ammonium ion positive charge of Compound 1 is balanced with a negative counterion (e.g., acetate ion).
  • a neutral form includes zwitterionic forms of Compound 1 in which the compound of Formula 1 has no net positive or negative charge.
  • the zwitterion is present in a higher proportion in basic medium (e.g., pH 9) relative to a salt form of Compound 1 .
  • the term "pharmaceutically acceptable excipient” refers to carriers that are relatively inert, natural or synthetic substances used to facilitate administration or delivery of an active pharmaceutical ingredient (e.g., Compound 1 ) into drug formulation that can be used pharmaceutically for delivery to the site of action in a subject.
  • the pharmaceutically acceptable carrier must be compatible with the other ingredients (e.g., the active pharmaceutical ingredient (e.g., Compound 1 )) of the formulation and not deleterious to the subject.
  • excipients include polymers (e.g., gel-forming polymers), preservatives, antioxidants, oils (e.g., heavy oils, light oils), emulsifying agents, solvents, stabilizing agents, surfactants, surface modifiers, solubility enhancers, buffers, encapsulating agents, nonionic wetting or clarifying agents, viscosity increasing agents, bulking agents, fillers, diluents, and absorption-enhancing agents.
  • the types of excipients used in a pharmaceutical composition or formulation depends on the form of the pharmaceutical composition or formulation (e.g., in the form of a gel, cream, or ointment), as well as the mode of administration.
  • gel carrier refers to is a gel suitable for pharmaceutical compositions, such as an aqueous gel (i.e., a hydrogel), containing a gelling agent such as a gel-forming polymer.
  • a gel is a material consisting of an aqueous liquid and three-dimensional polymer networks containing gel-forming polymers that are physically associated (e.g., aggregated) within the aqueous liquid (i.e., water).
  • the term "gel-forming polymer” refers to a hydrophilic polymer that swells or expands when coming in contact with a liquid such as water, deionized water, or buffered water.
  • the gel-forming polymer may be selected from the group consisting of hydroxypropyl methylcellulose, poloxamer 407, polyvinylpyrrolidone, hydroxyethyl cellulose, sodium
  • the gel-forming polymer takes up water, deionized water, or buffered water by hydration to form a hydrogel.
  • buffered water refers to an aqueous solution typically containing a small organic molecule that prevents changes in the pH of the solution. Examples of buffered water include, but are not limited to, phosphate buffered saline (PBS) at pH 7.4, lactate buffer at pH 4.2, and water buffered with N-methylglucamine at pH 7.4.
  • preservative refers to a chemical substance or compound used to prevent the pharmaceutical composition or formulation from breaking down (i.e., decomposition, fermentation), to protect against microbial and/or viral contaminations, and/or to maintain the stability of the pharmaceutical composition or formulation. Preservatives are often effective at relatively low concentrations, soluble in the formulation, non-toxic, and stable over a wide range of pH and temperature.
  • preservatives include antimicrobial preservatives, which include, but are not limited to, antifungal agents and antibacterial agents. Examples of preservatives are described further herein.
  • antioxidant refers to a molecule that inhibits the oxidation of other molecules. Oxidation is a chemical reaction involving the loss of electrons or an increase in oxidation state. In a pharmaceutical composition or formulation, oxidation of one or more compounds in the pharmaceutical composition or formulation can cause the pharmaceutical composition or formulation to degrade, decompose, and/or become unstable, thus lose its therapeutic properties.
  • An antioxidant is added as an excipient to the pharmaceutical composition or formulation to prevent the oxidation reaction. Examples of antioxidants are described further herein.
  • emulsion refers to a mixture of two or more liquids that are normally immiscible at ambient temperature, e.g., oil and water.
  • emulsifying agent refers to a substance that stabilizes an emulsion.
  • One class of emulsifying agents is surfactants, also called surface active agents.
  • An emulsifying agent physically interacts with the different types of liquids in the emulsion (e.g., oil and water), thus stabilizing the interface between the oil and water droplets in suspension.
  • emulsifying agents include, but are not limited to, polysorbate 20, polysorbate 60, polysorbate 80, sorbitan monostearate, and a polyethylene glycol ether of cetyl alcohol.
  • emulsifiable oil refers to an oil which, when mixed with water and an emulsifying agent, forms an emulsion.
  • An emulsifiable oil may be used in a cream for local
  • emulsifiable oils include fatty alcohols or esters of fatty alcohols, which are defined herein. Other examples of emulsifiable oils are described further herein.
  • fatty alcohols or esters thereof refers to alkanols and esters thereof containing from about 6 to about 26 carbon atoms.
  • the fatty alcohols and esters thereof can be incorporated in the locally administered creams of the disclosure as an emulsifiable oil.
  • fatty alcohols or esters thereof contain from about 10 to about 20 carbon atoms.
  • Representative examples include, but are not limited to, stearyl alcohol, cetyl alcohol, cetyl stearyl alcohol, myristyl alcohol, glycerin monostearate, glyceryl stearate, PEG-100 stearate, or mixtures thereof.
  • octyldodecanol a mixture of stearyl alcohol and cetyl alcohol, may be used and the acid moiety may be supplied in a fully esterfied compound or one that is less than fully esterfied, e.g., glyceryl monostearate and glyceryl di-stearate, respectively.
  • the fatty esters for use herein can be a fatty acid (e.g., stearic acid) esterified with a lower chain alcohol such as a C1 -C12 alcohol, e.g., methyl-, ethyl-, n-propyl-, isopropyl-, and butyl-ester of stearic acid.
  • the fatty esters for use herein can also be a fatty acid esterified with a polyol. Suitable polyols include those polyols containing from two to about 10 carbon atoms and from two to six hydroxyl groups.
  • Useful polyols include, but are not limited to, sorbitol, ethylene glycol, diethylene glycol, polyethylene glycol, 1 ,2-propanediol, 1 ,3-propanediol, 1 ,2-butanediol, 1 ,3-butanediol, 2,3-butanediol, 2-ethyl-1 ,3-propanediol, 2-ethyl-2-butyl-1 ,3-propanediol, neopentyl glycol, 2,2,4-trimethyl-1 ,3-pentanediol, trimethylolpropane (TMP), pentaerythritol, and mixtures thereof.
  • TMP trimethylolpropane
  • the term "ointment” refers to a formulation formed from a viscous material, such as a viscous oil (e.g., an oil-based hydrocarbon, e.g., petrolatum white).
  • a viscous oil e.g., an oil-based hydrocarbon, e.g., petrolatum white
  • the ointment is intended for external application to the skin or mucous membranes.
  • Compound 1 particles (described further herein) may be uniformly dispersed in the ointment or may be dispersed after adsorption on a solid support.
  • an oleaginous base refers to a substantially oil-based, hydrocarbon fluid or semisolid.
  • an oleaginous base is a semisolid hydrocarbon (e.g., a semisolid hydrocarbon at ambient temperature).
  • the semisolid hydrocarbon is a C18-C30 hydrocarbon.
  • the oleaginous base serves as the carrier fluid of the ointment.
  • examples of an oleaginous base include, but are not limited to, vegetable fats, animal fats obtained from animals, cetyl esters wax, paraffin, petrolatum, white petrolatum, white wax, yellow wax, and mixtures thereof.
  • refatting agents refers to a heavy oil that can be incorporated into the topical or locally applied creams of the disclosure. Refatting agents are oil-based or wax-based substances that are highly viscous and dense.
  • a refatting agent is a thick liquid.
  • a refatting agent is a semisolid or a soft solid material, e.g., at ambient temperature. In a cream for local administration, the refatting agent increases the viscosity of the cream.
  • refatting agents include, but are not limited to, cetyl ester wax, petrolatum white, isopropyl myristate, decyl oleat, isohexadecane, corn oil, peanut oil, almond oil, sesame oil, olive oil, jojoba oil, soya bean oil, wool wax alcohol, paraffin, macrogol-glycerol hydroxystearate, hydrogenated castor oil, avocado oil, wheat germ oil, evening primrose oil, and shea butter.
  • solid support refers to a solid material used in the preparation of the ointment form of a pharmaceutical composition or formulation described herein.
  • the solid support may be in the form of a clay, e.g., smectite clay.
  • the solid support is magnesium aluminum silicate.
  • the solid support is aluminum silicate.
  • the term "about” refers to a range of values that is ⁇ 10% of specific value.
  • “about 40%” includes ⁇ 10% of 40%, or from 36% to 44%. Such a range performs the desired function or achieves the desired result.
  • “about” may refer to an amount that is within less than 10% of, within less than 5% of, within less than 1 % of, within less than 0.1 % of, and within less than 0.01 % of the stated amount.
  • the terms "effective particle size” and “particle size” are used interchangeably and refer to a mixture of particles having a distribution in which 50% of the particles are below and 50% of the particles are above a defined measurement.
  • the "effective particle size” refers to the volume- weighted median diameter as measured by a light scattering method, wherein 50% of the particles, by volume, have a smaller diameter, while 50% by volume have a larger diameter.
  • the effective particle size can be measured by conventional particle size measuring techniques well known to those skilled in the art. Such techniques include, for example, light scattering (e.g., with a Microtrac UPA 150).
  • the term "local half-life” refers to the time to eliminate half of the drug from a localized tissue of the body where the drug was initially administered.
  • the local half-life can be measured using, for example, radiolabeled Compound 1 (e.g., 14 C labeled compound) or deuterated Compound 1 to monitor the uptake and elimination of Compound 1 following local administration (see, e.g., Example 97).
  • the term "mean residence time” refers to the length of time a therapeutically effective amount of Compound 1 , or a salt or neutral form thereof, is detectable in the vaginal cavity as determined using the animal model of vulvovaginal candidiasis described in Examples 95 and 96. In some embodiments, a measurable amount of Compound 1 may remain on the surface or embedded in the tissue (e.g., in the mucosal membrane) of the treatment area for three days or more.
  • weight/weight or w/w of a specific component in the pharmaceutical composition refers to the weight of the specific component over the total weight of the pharmaceutical composition.
  • candidiasis refers to a fungal infection caused by one or more fungi in the genus Candida.
  • examples of candidiasis include, but are not limited to, oralpharyngeal candidiasis, vulvovaginal candidiasis, esophageal candidiasis, genital candidiasis, and invasive candidiasis.
  • a pharmaceutical composition described herein may be intravaginally administered (i.e., applied inside the vagina) or extravaginally administered.
  • extravaginally administering includes administering on the vulva.
  • an antifungal drug-resistant fungal infection refers to a fungal infection that is refractory to treatment with an antifungal drug.
  • an antifungal drug-resistant fungal infection is an antifungal drug-resistant Candida infection.
  • the fungus that causes the infection is resistant to treatment with one or more antifungal drugs (e.g., an antifungal drug- resistant strain of fungus (e.g., an antifungal drug-resistant strain of Candida spp.)).
  • Antifungal drugs include, but are not limited to, echinocandins, polyene compounds, flucytosine, and azole compounds.
  • Fungal infections may be caused by a fungus in the genus, e.g., Candida (e.g., Candida albicans, Candida glabrata) or Aspergillus (e.g., Aspergillus fumigatus).
  • Candida e.g., Candida albicans, Candida glabrata
  • Aspergillus e.g., Aspergillus fumigatus
  • simulated vaginal fluid refers to a standard test fluid, in some cases used to determine release of e.g., Compound 1 in a formulation, consisting of 2.6 mM MgSC , 10.0 mM KCI, 40.0 mM glucose buffered with 50 mM aqueous lactate buffer pH 4.2.
  • the term "Medium 1" refers to a test fluid used to determine the release of e.g., Compound 1 in a formulation, consisting of (N-methyl-2-pyrrolidinone and Miglyol® 812) (9:1 , v/v): Dl- H20 (v/v, 4:1 ) and 0.26% Polysorbate 80 (w/v).
  • Miglyol® 812 is a mixture of decanoyl- and octanoyl glycerides (fatty acid esters), more specifically a fractionated coconut oil comprising caprylic/capric triglyceride (CAS-No: 52622-27-2) having a fatty acid distribution of 50-60% caprylic (Ce) acid, 30-45% and capric (Cio) acid, and may have ⁇ 2% caproic (Ce), ⁇ 2% lauric acid (C12) and ⁇ 1 % myristic acid (C14:0).
  • the term "release” refers to the release of a compound from a formulation as determined using the specified in-vitro conditions and methodology set forth in Example 108 or 109.
  • the term "within" with respect to a time frame refers to the time by which an amount of compound is released into the test fluid.
  • FIG. 1 A shows antifungal activities of gel formulations of Compound 1 from Examples 9, 1 1 , and
  • FIG. 1 B shows antifungal activities of gel formulations of Compound 1 from Examples 1 1 and 13 administered twice daily in a rat vulvovaginal candidiasis model.
  • FIG. 1 C shows antifungal activities on Day 12 post-Infection of gel and ointment formulations from Examples 1 1 , 13, 64, and 67 administered once daily in a rat vulvovaginal candidiasis model.
  • FIG. 1 D shows antifungal activities on Day 5, Day 9, and Day 12 post-infection of ointment formulations from Examples 64 and 67 administered once daily in a rat vulvovaginal candidiasis model.
  • FIG 1 E shows antifungal activities on Day 5 and Day 12 post-infection of cream and ointment formulations from Examples 52, 60 and 64 administered once daily in a rat vulvovaginal candidiasis model.
  • FIG. 1 F shows antifungal activities on Day 5 and Day 12 post-infection of gel and ointment formulations from Examples 12, 18, and 64 administered once daily in a rat vulvovaginal candidiasis model.
  • FIG. 2 shows the in vitro release of Compound 1 in cream and ointment formulations from Examples 50, 58, and 62 over 24 hrs at 37 °C.
  • FIG. 3 shows the fungicidal properties of Compound 1 against C. albicans ATCC 44858.
  • FIG. 4 shows that Compound 1 in a gel formulation is highly efficacious against azole-resistant Candida albicans in a rat model of vulvovaginal candidiasis.
  • FIGS. 5A-5D show the fungicidal properties of Compound 1 and terconazole (TCZ) against azole- susceptible strain C. albicans ATCC 4458 and the fungicidal properties of Compound 1 against azole- resistant strains C. albicans DPL001 and R357.
  • TCZ terconazole
  • FIGS. 6A-6D show the fungicidal properties of Compound 1 and TCZ against azole-susceptible strain C. glabrata CG01 and the fungicidal properties of Compound 1 against azole-resistant strains C. glabrata ATCC 200918 and MMX 7070.
  • FIGS. 7A-7D show the fungicidal properties of Compound 1 and TCZ against azole-susceptible strain C. tropicalis CT02 and the fungicidal properties of Compound 1 against azole-resistant strains C. tropicalis MMX 7255 and MMX 7525.
  • FIGS. 8A-8D show the fungicidal properties of Compound 1 and TCZ against azole-susceptible strain C. parapsilosis CP02 and the fungicidal properties of Compound 1 against azole-resistant strains C. parapsilosis CP01 and MMX 7370.
  • FIGS. 9A-9B show the fungicidal properties of Compound 1 against azole-susceptible strain C. Krusei AJCC 6258 and against azole-resistant strain C. Krusei ATCC 14243.
  • FIG. 10 shows the in-vitro release profile of Compound 1 from hydroxypropyl methylcellulose (HPMC) gel formulations at 37 °C in simulated vaginal fluid.
  • HPMC hydroxypropyl methylcellulose
  • FIG. 1 1 A shows in-vitro drug release of Compound 1 from ointment formulations at 37 °C in simulated vaginal fluid.
  • FIG. 1 1 B shows in-vitro drug release of tioconazole from Tioconazole-1 ointment formulation at 37 °C in simulated vaginal fluid.
  • FIG. 12A shows in-vitro drug release profile of Compound 1 from 3 % (w/w) ointment formulations in Medium 1 at 37 S C.
  • FIG. 12B shows in-vitro drug release profile from 6.5% Tioconazole-1 in Medium 1 at 37 S C.
  • FIG. 13 shows in-vitro drug release profile from formulations compounded with variable amounts of magnesium aluminum silicate in Medium 1 at 37 S C.
  • FIG. 14 shows in-vitro drug release profile of Compound 1 from 3% ointment formulations with variable compounding in Medium 1 at 37 S C.
  • compositions in the form of a gel, a cream, and an ointment containing a salt of Compound 1 , or a neutral form thereof, described herein can be used for the treatment of candidiasis (e.g., vulvovaginal candidiasis (VVC), oropharyngeal candidiasis).
  • candidiasis e.g., vulvovaginal candidiasis (VVC), oropharyngeal candidiasis
  • the pharmaceutically composition also contains pharmaceutically acceptable excipients, which are described in detail further herein.
  • the disclosure also features methods of treating candidiasis in a subject by locally administering to the subject a pharmaceutical composition containing
  • a pharmaceutical composition described herein results in the salt of
  • Compound 1 or the neutral form thereof, present up to 3 days following local administration to the vaginal cavity of the subject.
  • a measurable amount of Compound 1 may remain on the surface or embedded in the tissue (e.g., in the mucosal membrane) of the treatment area for three days or more.
  • the type of formulation influences the size of area over which the drug is deposited.
  • the hydrophilicity and/or viscosity of the formulation influences the extent of spreading and distribution of the drug. The extent of flow and retention of the drug also depends on the type of formulation.
  • the active ingredient, a salt of Compound 1 , or a neutral form thereof, in the pharmaceutical composition penetrates into the mucosal membrane of the vagina if administered intravaginally, or penetrates into the mucosal membrane of the vulva if administered on the vulva (e.g., extravaginally administered), to inhibit and/or kill the fungi, e.g., Candida spp. (e.g., Candida albicans or Candida glabrata) causing the candidiasis.
  • Candida spp. e.g., Candida albicans or Candida glabrata
  • the pharmaceutical composition containing
  • the gel carrier may contain (i) about 2% to about 40% (w/w) a gel-forming polymer and (ii) about 40% to about 99% (w/w) of water, deionized water, or buffered water.
  • the pharmaceutical composition further includes 0.01 % to about 20% (w/w) of a solvent selected from the group consisting of glycerin, propylene glycol, N-methylpyrrolidone, acetone, and triacetin.
  • the gel-forming polymer in the gel carrier may be selected from the group consisting of hydroxypropyl methylcellulose, poloxamer 407, polyvinylpyrrolidone, hydroxyethyl cellulose, sodium carboxymethylcellulose, polyvinylalcohol, methylcellulose, ethylcellulose, chitosan, and hyaluronic acid.
  • Poloxamer 407 belongs to a class of copolymers known as poloxamers, which are non- Ionic dl-block or tri-block copolymers having a central hydrophobic chain of poiyoxypropylene flanked by hydrophiiic chains of polyoxyethylene.
  • poloxamers examples include, but are not limited to, poloxamers 101 , 105, 108, 122, 123, 124, 181 , 182, 183, 184, 185, 188, 212, 215, 21 7, 231 , 234, 235, 237, 238, 282, 284, 288, 331 , 333, 334, 335, 338, 401 , 402, 403, and 407, poloxamer 105 benzoate, and poloxamer 182 dibenzoate.
  • the gel- forming polymer is hydroxypropyl methylcellulose, poloxamer 407, po!yvinylpyrro!idinone, or hydroxyethyl cellulose.
  • the solvent n the gel carrier may be selected from the group consisting of glycerin, propylene glycol, N-methylpyrrolidone, acetone, and triacetin.
  • the salt of Compound 1 , or the neutral form thereof, is dissolved in the gel carrier.
  • the pH of the gel form of the pharmaceutically composition can be adjusted, e.g., using buffered water.
  • the pharmaceutical composition has a pH of 4 to 9 (e.g., 4.5 ⁇ 0.5).
  • the solvent n the gel carrier may be selected from the group consisting of glycerin, propylene glycol, N-methylpyrrolidone, acetone, and triacetin.
  • the salt of Compound 1 or the neutral form thereof, is dissolved in the gel carrier.
  • the pH of the gel form of the pharmaceutically composition can be adjusted, e.g., using buffered water.
  • the pharmaceutical composition has a pH of 4 to 9 (e.g., 4.5 ⁇ 0.5).
  • compositions in a gel form containing 0.1 % to 15% (w/w) of the salt of Compound 1 , or the neutral form thereof also contains other excipients, such as at least one preservative. Examples of preservatives are described further herein.
  • the disclosure features a pharmaceutical composition including 0.1 % to 15% (w/w) of a salt of Compound 1 , or a neutral form thereof, hydroxypropyl methylcellulose, EDTA disodium dihydrate, methyl paraben, and water.
  • the pharmaceutical composition containing 0.1 % to 15% (w/w) of a salt of Compound 1 , or a neutral form thereof is in an emulsion.
  • the emulsion contains (i) at least one emulsifiable oil; (ii) at least one emulsifying agent; and (iii) water, deionized water, or buffered water.
  • An emulsifiable oil is an oil which, when mixed with water and an emulsifying agent, forms an emulsion.
  • An emulsifiable oil is used in a cream form of the pharmaceutical composition described herein.
  • emulsifiable oils includes fatty alcohols or esters of fatty alcohols, which refer to alkanols and esters thereof containing from about 6 to about 26 carbon atoms. In some embodiments, fatty alcohols or esters thereof contain from about 10 to about 20 carbon atoms. Examples of fatty alcohols or esters thereof include, but are not limited to, stearyl alcohol, cetyl alcohol, cetyl stearyl alcohol, myristyl alcohol, glycerin monostearate, glyceryl stearate, PEG-100 stearate, and mixtures thereof. Octyldodecanol is a mixture of stearyl alcohol and cetyl alcohol.
  • the acid moiety of octyldodecanol may be supplied in a fully esterfied compound or one which is less than fully esterfied, e.g., glyceryl monostearate and glyceryl di-stearate, respectively.
  • the fatty esters for use herein can be a fatty acid (e.g., stearic acid) esterified with a lower chain alcohol such as a C1 -C12 alcohol, e.g., methyl-, ethyl-, n-propyl-, isopropyl-, and butyl-ester of stearic acid.
  • the fatty esters for use herein can also be a fatty acid esterified with a polyol.
  • Suitable polyols include those polyols containing from two to about 10 carbon atoms and from two to six hydroxyl groups.
  • Useful polyols include, but are not limited to, sorbitol, ethylene glycol, diethylene glycol, polyethylene glycol, 1 ,2-propanediol, 1 ,3-propanediol, 1 ,2- butanediol, 1 ,3-butanediol, 2,3-butanediol, 2-ethyl-1 ,3-propanediol, 2-ethyl-2-butyl-1 ,3-propanediol, neopentyl glycol, 2, 2, 4-trimethyl-1 ,3-pentanediol, trimethylolpropane (TMP), pentaerythritol, and mixtures thereof.
  • TMP trimethylolpropane
  • the emulsion also contains at least one emulsifying agent, which is a substance that stabilizes an emulsion.
  • emulsifying agents is surfactants, also called surface active agents.
  • An emulsifying agent physically interacts with the different types of liquids in the emulsion (e.g., oil and water), thus stabilizing the interface between the oil and water droplets in suspension.
  • emulsifying agents include, but are not limited to, polysorbate 20, polysorbate 60, polysorbate 80, sorbitan monostearate, and a polyethylene glycol ether of cetyl alcohol (also called ceteth 20).
  • the emulsion includes (i) about 20% to about 70% (w/w) of at least one emulsifiable oil; (ii) from about 1 % to about 10% (w/w) of at least one emulsifying agent; and (iii) from about 25% to about 80% (w/w) of water, deionized water, or buffered water.
  • the pharmaceutical composition containing 0.1 % to 15% (w/w) of a salt of Compound 1 , or a neutral form thereof, in an emulsion also contains from about 1 % to about 40% (w/w) of a refatting agent.
  • a refatting agent is a heavy oil that can be incorporated into the creams of the disclosure. Refatting agents are oil-based or wax-based substances that are highly viscous and dense.
  • a refatting agent is a thick liquid.
  • a refatting agent is a semi-solid or a soft solid material. In a cream, the refatting agent increases the viscosity of the cream.
  • refatting agents include, but are not limited to, cetyl ester wax, petrolatum white, isopropyl myristate, decyl oleat, isohexadecane, corn oil, peanut oil, almond oil, sesame oil, olive oil, jojoba oil, soya bean oil, wool wax alcohol, paraffin, macrogol-glycerol hydroxystearate, hydrogenated castor oil, avocado oil, wheat germ oil, evening primrose oil, and shea butter.
  • the refatting agent is cetyl ester wax or petrolatum white.
  • the pharmaceutical composition may contain about 5% to about 30% (w/w) of a solvent.
  • the solvent may be glycerin, propylene glycol, N-methylpyrrolidone, acetone, and triacetin.
  • the salt of Compound 1 , or the neutral form thereof is dissolved in the emulsion.
  • the salt of Compound 1 , or the neutral form thereof is in a particulate form in the emulsion (i.e., Compound 1 particles).
  • Compound 1 particles are described further herein.
  • the pH of the cream form of the pharmaceutically composition can be adjusted, e.g., using buffered water.
  • the pharmaceutical composition has a pH of 4 to 9 (e.g., 4.5 ⁇ 0.5).
  • the pharmaceutical composition in a cream form containing 0.1 % to 15% (w/w) of a salt of Compound 1 , or a neutral form thereof also contains other excipients, such as at least one preservative. Examples of preservatives are described further herein.
  • the disclosure features a pharmaceutical composition including 0.1 % to 15% (w/w) of a salt of Compound 1 , or a neutral form thereof, at least one refatting agent selected from the group consisting of cetyl ester wax, petrolatum white, and isopropyl myristate, at least one emulsifiable oil selected from the group consisting of cetyl alcohol, octyl dodecanol, and cetearyl alcohol, at least one of emulsifying agent selected from the group consisting of sorbitan monostearate, polysorbate 60, and a polyethylene glycol ether of cetyl alcohol, and at least one preservative selected from the group consisting of benzyl alcohol and benzoic acid.
  • the pharmaceutical composition further includes propylene glycol.
  • the pharmaceutical composition containing 0.1 % to 15% (w/w) of a salt of Compound 1 , or a neutral form thereof is in an ointment that includes an oleaginous base.
  • an oleaginous base serves as the carrier fluid of the ointment.
  • An oleaginous base is a substantially oil-based, hydrocarbon fluid or semisolid.
  • an oleaginous base is a semisolid hydrocarbon.
  • an oleaginous base is a semisolid hydrocarbon at ambient temperature.
  • the semisolid hydrocarbon is a C18-C30 hydrocarbon.
  • an oleaginous base examples include, but are not limited to, vegetable fats, animal fats obtained from animals, cetyl esters wax, paraffin, petrolatum, white petrolatum, white wax, yellow wax, and mixtures thereof.
  • the oleaginous base in the ointment form of the pharmaceutical composition is petrolatum white or cetyl ester wax.
  • the pharmaceutical composition in the ointment form includes about 75% to about 98% (w/w) of an oleaginous base.
  • the salt of Compound 1 , or the neutral form thereof is in a particulate form in the ointment (i.e., Compound 1 particles).
  • Compound 1 particles are absorbed onto a solid support.
  • the solid support may be magnesium aluminum silicate, kaolin, bentonite, attapulgite, or aluminum silicate.
  • Compound 1 particles may be uniformly dispersed in the ointment or may be dispersed after adsorption on a solid support.
  • the pharmaceutical composition in an ointment form containing 0.1 % to
  • a salt of Compound 1 or a neutral form thereof, also contains other excipients, such as at least one antioxidant. Examples of antioxidants are described further herein.
  • the disclosure features a pharmaceutical composition including 0.1 % to 15% (w/w) of a salt of Compound 1 , or a neutral form thereof, magnesium aluminum silicate, petrolatum white, and butylated hydroxyanisole.
  • a salt of Compound 1 , or a neutral form thereof is in a particulate form (i.e., Compound 1 particles, either as Compound 1 alone or in combination with a solid carrier).
  • Compound 1 particles are in the cream and ointment forms of the pharmaceutical compositions described herein.
  • Compound 1 particles may comprise particles (e.g., microparticles or nanoparticles) containing a salt of Compound 1 , or a neutral form thereof, alone or in combination with a solid carrier.
  • the particles e.g., microparticles or nanoparticles
  • compositions or formulations described herein can include Compound 1 particles having an effective average particle size of from, e.g., about 1 ⁇ to 10 ⁇ (e.g., an effective particle size of from 1 ⁇ to 9 ⁇ , from 1 ⁇ to 8 ⁇ , from 1 ⁇ to 7 ⁇ , from 1 ⁇ to 6 ⁇ , from 1 ⁇ to 5 ⁇ , from 2 ⁇ to 10 ⁇ , from 3 ⁇ to 10 ⁇ , from 4 ⁇ to 10 ⁇ , from 2 ⁇ to 7 ⁇ , or from 2 ⁇ to 6 ⁇ ).
  • Compound 1 particles may have an effective particle size of, e.g., less than about 1 ⁇ (i.e., nanoparticulate formulations).
  • Compound 1 particles may have an effective particle size of 20 nm to 1 ⁇ (e.g., an effective particle size of from 20 nm to 1 ⁇ , from 40 nm to 1 ⁇ , from 60 nm to 1 ⁇ , from 80 nm to 1 ⁇ , from 100 nm to 1 ⁇ , from 20 nm to 800 nm, from 20 nm to 700 nm, from 50 nm to 700 nm, from 40 nm to 800 nm, from 60 nm to 800 nm, from 100 nm to 800 nm, from 60 nm to 700 nm, from 60 nm to 600 nm, from 100 nm to 600 nm, from 150 nm to 800 nm, or from 150 nm to 600 nm).
  • the starting Compound 1 composition can be predominantly crystalline, predominantly amorphous, or a mixture thereof.
  • Compound 1 particles can be made by using any method known in the art for achieving the desired particle sizes.
  • Useful methods include, for example, milling, homogenization, supercritical fluid fracture, or precipitation techniques. Exemplary methods are described in U.S. Patent Nos. 4,540,602; 5,145,684; 5,518,187; 5,718,388; 5,862,999; 5,665,331 ;
  • Compound 1 is dissolved in an aqueous liquid (e.g., water) and then mixed with a solid support (e.g., a solid support as described herein, e.g., magnesium aluminum silicate, kaolin, bentonite, or attapulgite). This mixtures is dried to a dry blend. This dry blend may then be milled (see, e.g., Example 67B).
  • a solid support e.g., a solid support as described herein, e.g., magnesium aluminum silicate, kaolin, bentonite, or attapulgite.
  • Compound 1 particles are milled in order to obtain micron or submicron particles.
  • the milling process can be a dry process, e.g., a dry roller milling process, or a wet process, i.e., wet-grinding.
  • a wet-grinding process is described in U.S. Pat. Nos. 4,540,602, 5,145,684, 6,976,647 and EPO 498,482, the disclosures of which are hereby incorporated by reference.
  • the wet grinding process can be practiced in conjunction with a liquid dispersion medium and dispersing or wetting agents such as described in these publications.
  • Useful liquid dispersion media include safflower oil, ethanol, n- butanol, hexane, or glycol, among other liquids selected from known organic pharmaceutical excipients (see U.S. Patent Nos. 4,540,602 and 5,145,684), and can be present in an amount of 2.0-70%, 3-50%, or 5-25% by weight based on the total weight of the salt of Compound 1 , or the neutral form thereof, in the formulation.
  • the grinding media for the particle size reduction step can be selected from rigid media, typically spherical in shape, though non-spherical grinding media could also be used.
  • the grinding media preferably can have a mean particle size from 1 mm to about 500 ⁇ .
  • the grinding media particles can have a mean particle size from about 0.05 to about 0.6 mm. Smaller size grinding media will result in smaller size Compound 1 particles as compared to the same conditions using larger sized grinding media.
  • grinding media with higher density e.g., glass (2.6 g/cm 3 ), zirconium silicate (3.7 g/cm 3 ), and zirconium oxide (5.4 g/cm 3 ) and 95% zirconium oxide stabilized with yttrium
  • glass 2.6 g/cm 3
  • zirconium silicate 3.7 g/cm 3
  • zirconium oxide 5.4 g/cm 3
  • 95% zirconium oxide stabilized with yttrium can be utilized for more efficient milling.
  • polymeric grinding media can be used.
  • Polymeric resins suitable for use herein are chemically and physically inert, substantially free of metals, solvent and monomers, and of sufficient hardness and friability to enable them to avoid being chipped or crushed during grinding.
  • Suitable polymeric resins include, without limitation, crosslinked polystyrenes, such as polystyrene crosslinked with divinylbenzene, styrene copolymers, polycarbonates, polyacetals, such as DelrinTM, vinyl chloride polymers and copolymers, polyurethanes, polyamides,
  • TeflonTM fluoropolymers
  • high density polyethylenes polypropylenes
  • cellulose ethers and esters such as cellulose acetate, polyhydroxymethacrylate, polyhydroxyethyl acrylate, or silicone containing polymers such as polysiloxanes.
  • Suitable mills include an airjet mill, a roller mill, a ball mill, an attritor mill, a vibratory mill, a planetary mill, a sand mill and a bead mill.
  • a high energy media mill is preferred when small particles are desired.
  • the mill can contain a rotating shaft.
  • the proportions of the grinding media, the salt of Compound 1 , or the neutral form thereof, the optional liquid dispersion medium, and dispersing, wetting or other particle stabilizing agents present in the grinding vessel can vary within wide limits and depend on, for example, the size and density of the grinding media, the type of mill selected, the time of milling, etc.
  • the process can be carried out in a continuous, batch or semi-batch mode. In high energy media mills, it can be desirable to fill 80-95% of the volume of the grinding chamber with grinding media. On the other hand, in roller mills, it frequently is desirable to leave the grinding vessel up to half filled with air, the remaining volume containing the grinding media and the liquid dispersion media, if present.
  • the vessel can be completely filled with the liquid dispersion medium or an anti-foaming agent may be added to the liquid dispersion.
  • the attrition time can vary widely and depends primarily upon the mechanical means and residence conditions selected, the initial and desired final particle size, among other factors. For roller mills, processing times from several days to weeks may be required. On the other hand, milling residence times of less than about 2 hours are generally required using high energy media mills.
  • the grinding media is separated from the milled Compound 1 particulate product (in either a dry or liquid dispersion form) using conventional separation techniques, such as by filtration, or sieving through a mesh screen.
  • the grinding media can be made from beads having a size ranging from 0.05 mm to 4 mm.
  • high energy milling of the salt of Compound 1 , or the neutral form thereof, with 0.1 mm zirconium oxide balls for a milling residence time of 2 hours in batch mode can be used.
  • the milling concentration can be from about 10% to about 30% the salt of Compound 1 , or the neutral form thereof, by weight in comparison to the milling slurry weight, which can contain a wetting and/or dispersing agent to coat the initial suspension so a uniform feed rate may be applied in continuous milling mode.
  • batch milling mode is utilized with a milling media containing an agent to adjust viscosity and/or provide a wetting effect so that the salt of Compound 1 , or the neutral form thereof, is well dispersed amongst the grinding media.
  • Compound 1 particles can also be prepared by homogeneous nucleation and precipitation in the presence of a wetting agent or dispersing agent using methods analogous to those described in U.S. Patent Nos. 5,560,932 and 5,665,331 , which are specifically incorporated by reference.
  • Such a method can include the steps of: (1 ) dispersing a salt of Compound 1 , or a neutral form thereof, in a suitable liquid media; (2) adding the mixture from step (1 ) to a mixture including at least one dispersing agent or wetting agent such that at the appropriate temperature, the salt of Compound 1 , or the neutral form thereof, is dissolved; and (3) precipitating the formulation from step (2) using an appropriate anti-solvent.
  • the method can be followed by removal of any formed salt, if present, by dialysis or filtration and
  • Compound 1 particles are present in an essentially pure form and dispersed in a suitable liquid dispersion media. In this approach, Compound 1 particles are a discrete phase within the resulting mixture.
  • Useful dispersing agents, wetting agents, solvents, and anti-solvents can be experimentally determined.
  • Compound 1 particles can also be prepared by high pressure homogenization (see U.S. Patent No. 5,510,1 18). In this approach Compound 1 particles are dispersed in a liquid dispersion medium and subjected to repeated homogenization to reduce the particle size of Compound 1 particles to the desired effective average particle size. Compound 1 particles can be reduced in size in the presence of at least one or more dispersing agents or wetting agents. Alternatively, Compound 1 particles can be contacted with one or more dispersing agents or wetting agents either before or after attrition. Other materials, such as a diluent, can be added to Compound 1 /dispersing agent mixture before, during, or after the size reduction process.
  • unprocessed Compound 1 can be added to a liquid medium in which it is essentially insoluble to form a premix (i.e., about 0.1 -60% (w/w) of the salt of Compound 1 , or the neutral form thereof, and about 20-60% (w/w) dispersing agents or wetting agents).
  • the apparent viscosity of the premix suspension is preferably less than about 1000 centipoise.
  • the premix can then be transferred to a microfluidizer and circulated continuously first at low pressures, and then at maximum capacity (i.e., 3,000 to 30,000 psi) until the desired particle size reduction is achieved.
  • the resulting dispersion of Compound 1 particles can be spray coated onto a sublingual pharmaceutical formulation of the disclosure using techniques well known in the art.
  • Foaming during the particle sizing can present formulation issues and can have negative consequences for particle size reduction.
  • high levels of foam or air bubbles in the mill can cause a drastic increase in viscosity rendering the milling process inoperable.
  • Even a very low level of air presence can dramatically reduce milling efficiency causing the desired particle size unachievable. This may be due to the resultant air in the mill cushioning the milling balls and limiting grinding efficiency.
  • the air also can form a microemulsion with the milled ingredients which presents many issues with respect to the delivery of an accurate dose and palatability.
  • Addition of a small amount of simethicone is a very effective anti-foaming agent which minimizes milling variability or special handling techniques to avoid the introduction of air into the milling process.
  • Compound 1 particles can be prepared with the use of one or more wetting and/or dispersing agents, which are, e.g., adsorbed on the surface of Compound 1 particles.
  • Compound 1 particles can be contacted with wetting and/or dispersing agents either before, during or after size reduction.
  • wetting and/or dispersing agents fall into two categories: non-ionic agents and ionic agents.
  • the most common non-ionic agents are excipients which are contained in classes known as binders, fillers, surfactants and wetting agents. Limited examples of non-ionic surface stabilizers are
  • Ionic agents are typically organic molecules bearing an ionic bond such that the molecule is charged in the formulation, such as long chain sulfonic acid salts (e.g., sodium lauryl sulfate and dioctyl sodium sulfosuccinate).
  • Excipients such as wetting and dispersing agents, can be applied to the surface of Compound 1 particles via spray drying, spray granulation, or spray layering process. These procedures are well known in those skilled in the art. It is also common to add additional excipients prior to removal of solvent in the particulate suspension to aid in the dispersion of the solid composition in medium in which the solid composition will be exposed (e.g. saliva) to further prevent agglomeration and/or particle size growth of small Compound 1 particles.
  • An example of such an additional excipient is a redispersing agent.
  • Suitable redispersing agents include, without limitation, sugars, polyethylene glycols, urea and quaternary ammonium salts.
  • compositions in the form of a gel, a cream, and an ointment containing a salt of Compound 1 , or a neutral form thereof, as described herein may contain at least one preservative.
  • a preservative is a chemical substance or compound used to prevent pharmaceutical compositions described herein from breaking down (i.e., decomposition, fermentation), to protect against microbial and/or viral contaminations, and/or to maintain the stability of the pharmaceutical composition or formulation.
  • Preservatives are often effective at relatively low concentrations, soluble in the formulation, non-toxic, and stable over a wide range of pH and temperature.
  • One class of preservatives includes antimicrobial preservatives, which include, but are not limited to, antifungal agents and antibacterial agents.
  • antimicrobial preservatives include, but are not limited to, benzyl alcohol, benzoic acid, parabens (e.g., methyl paraben, propyl paraben, butyl paraben, propylene paraben), sodium benzoate, hydroxy benzoate, lactic acid, sodium propionate, propionic acid, sulfur dioxide, sorbic acid, sodium sorbate, potassium sorbate, sodium nitrite, acetic acid, and nisin.
  • Other preservatives include, but are not limited to, ethylenediaminetetraacetic acid (EDTA) disodium dihydrate, cetylpyridine chloride, glycerin, polysorbate 80, potassium sorbate, citric acid, and sodium citrate.
  • EDTA ethylenediaminetetraacetic acid
  • compositions in the form of a gel, a cream, and an ointment containing a salt of Compound 1 , or a neutral form thereof, as described herein may contain at least one antioxidant.
  • An antioxidant refers to a molecule that inhibits the oxidation of other molecules. Oxidation is a chemical reaction involving the loss of electrons or an increase in oxidation state.
  • Oxidation of one or more compounds in the pharmaceutical composition or formulation can cause the pharmaceutical composition or formulation to degrade, decompose, and/or become unstable, thus lose its therapeutic properties.
  • An antioxidant is added as an excipient to the pharmaceutical composition or formulation to prevent the oxidation reaction.
  • antioxidants include, but are not limited to, butylated hydroxyanisole, vitamin A, vitamin E, vitamin C, retinylpalmitate, and selenium.
  • the antioxidant used in a pharmaceutical composition described herein is butylated hydroxyanisole or butylated hydroxytoluene.
  • excipients may also be used, for example, inert diluents or fillers (e.g., sucrose, sorbitol, sugar, mannitol, microcrystalline cellulose, starches including potato starch, calcium carbonate, sodium chloride, lactose, calcium phosphate, calcium sulfate, or sodium phosphate); granulating and disintegrating agents (e.g., cellulose derivatives including microcrystalline cellulose, starches including potato starch, croscarmellose sodium, alginates, or alginic acid); binding agents (e.g., sucrose, glucose, sorbitol, acacia, alginic acid, sodium alginate, gelatin, starch, pregelatinized starch, microcrystalline cellulose, magnesium aluminum silicate,
  • inert diluents or fillers e.g., sucrose, sorbitol, sugar, mannitol, microcrystalline cellulose, starches including potato starch, calcium carbonate, sodium chloride
  • Other pharmaceutically acceptable excipients can be, e.g., colorants, flavoring agents, plasticizers, humectants, and buffering agents.
  • a bioadhesive agent e.g., acacia, tragacanth, carbomer, or, carboxymethyl cellulose, may be used.
  • the disclosure includes methods for treating fungal infections such as candidiasis (e.g., vulvovaginal candidiasis (VVC), oropharyngeal candidiasis) and/or aspergillosis (e.g., cutaneous aspergillosis).
  • the methods include treating fungal infections such as candidiasis (e.g., vulvovaginal candidiasis (VVC), oropharyngeal candidiasis) in a subject by locally administering to a mucosal tissue of the subject a pharmaceutical composition containing 0.1 % to 15% (w/w) a salt of Compound 1 , or a neutral form thereof, once or twice daily for a period of 1 to 5 days.
  • Compound 1 e.g., a salt of
  • Compound 1 displays long-acting pharmacokinetics with a long half-life and slow clearance and strong activities against fungal strains, e.g., Candida spp.
  • Compound 1 e.g., a salt of Compound 1 , or a neutral form thereof
  • aqueous solubility e.g., >1 00 mg/mL, pH 2-9
  • solubility in alcohol solvents e.g., >1 0 mg/mL in PEG400, ethanol, glycerol, or propylene glycol.
  • Compound 1 (e.g., a salt of Compound 1 , or a neutral form thereof) also demonstrates stability and solubility suitable for formulations, such as a gel, a cream, and an ointment.
  • echinocandin antifungals such as micafungin, caspofungin, and anidulafungin, which are unstable in formulations such as a gel, a cream, and an ointment, are only available in intravenous formulation to treat systemic Candida infections, and require daily administration for long periods of time (i.e., two weeks or more)
  • the ideal chemical and pharmacokinetic properties of Compound 1 e.g., a salt of Compound 1 , or a neutral form thereof
  • the candidiasis is oropharyngeal candidiasis and the locally administering includes intra-oral administration to the subject.
  • the candidiasis is vulvovaginal candidiasis and the locally administering includes intravaginal administering and/or extravaginally administering.
  • extravaginally administering includes administering on the vulva.
  • a pharmaceutical composition containing 0.1 % to 15% (w/w) of a salt of Compound 1 , or a neutral form thereof is administered to a subject having vulvovaginal candidiasis in an amount effective to treat the vulvovaginal candidiasis, wherein the administering includes intravaginally administering and/or extravaginally administering.
  • extravaginally administering includes administering on the vulva.
  • a pharmaceutical composition containing 0.1 % to 15% (w/w) of a salt of Compound 1 , or a neutral form thereof is administered to a subject having oropharyngeal candidiasis in an amount effective to treat the oropharyngeal candidiasis, wherein the administering includes intra-oral administering and/or topically administering in the oral cavity.
  • the pharmaceutical composition is locally administered once daily or twice daily. In some embodiments, the pharmaceutical composition is locally administered for four consecutive days or fewer (e.g., three consecutive days). In some embodiments, the
  • composition is locally administered once weekly.
  • the dosage and frequency of administration of a pharmaceutical composition described herein may be adjusted in ways consonant with these parameters.
  • the dosage may be adapted by the physician in accordance with conventional factors such as the extent of the disease and different parameters of the subject (e.g., age, weight, and medical history).
  • the timing between administrations may decrease as the medical condition improves or increase as the health of the patient declines.
  • Example 1 Gel Formulation A (10% drug concentration in 2% Poloxamer 407 gel)
  • Poloxamer 407 (0.4 g) was dissolved in 10 g of deionized water. Propylene glycol (2 g) was added with mixing. To this solution was added Compound 1 (2 g, acetate salt) followed by EDTA disodium dihydrate (0.02 g), methyl paraben (0.03 g), and propyl paraben (0.01 g). Water was then added to bring the final volume to 20 mL.
  • the indicated amount of Compound 1 represents the amount of Compound 1 excluding the salt component.
  • Example 1 B Gel Formulation A (10% drug concentration in 2% Poloxamer 407 gel, pH 4.2)
  • Poloxamer 407 (0.4 g) was dissolved in 10 g of 50 mM sodium lactate buffer, pH 4.2. Propylene glycol (2 g) was added with mixing. To this solution was added Compound 1 (2 g, acetate salt) followed by EDTA disodium dihydrate (0.02 g), methyl paraben (0.03 g), and propyl paraben (0.01 g). Water was then added to bring the final volume to 20 mL.
  • Example 2A Gel Formulation A (6% drug concentration in 2% Poloxamer 407 gel)
  • Poloxamer 407 (0.4 g) is dissolved in 10 g of deionized water. Propylene glycol (2 g) is added with mixing. To this solution is added Compound 1 (1 .2 g, acetate salt) followed by EDTA disodium dihydrate (0.02 g), methyl paraben (0.03 g), and propyl paraben (0.01 g). Water is then added to bring the final volume to 20 mL.
  • Example 2B Gel Formulation A (6% drug concentration in 2% Poloxamer 407 gel, pH 4.2)
  • Poloxamer 407 (0.4 g) is dissolved in 10 g of 50 mM sodium lactate buffer, pH 4.2. Propylene glycol (2 g) is added with mixing. To this solution is added Compound 1 (1 .2 g, acetate salt) followed by EDTA disodium dihydrate (0.02 g), methyl paraben (0.03 g), and propyl paraben (0.01 g). Water is then added to bring the final volume to 20 mL.
  • Example 3A Gel Formulation A (3% drug concentration in 2% Poloxamer 407 gel)
  • Poloxamer 407 (0.4 g) is dissolved in 10 g of deionized water. Propylene glycol (2 g) is added with mixing. To this solution is added Compound 1 (0.6 g, acetate salt) followed by EDTA disodium dihydrate (0.02 g), methyl paraben (0.03 g), and propyl paraben (0.01 g). Water is then added to bring the final volume to 20 mL.
  • Example 3B Gel Formulation A (3% drug concentration in 2% Poloxamer 407 gel, pH 4.2)
  • Poloxamer 407 (0.4 g) is dissolved in 10 g of 50 mM sodium lactate buffer, pH 4.2. Propylene glycol (2 g) is added with mixing. To this solution is added Compound 1 (0.6 g, acetate salt) followed by EDTA disodium dihydrate (0.02 g), methyl paraben (0.03 g), and propyl paraben (0.01 g). Water is then added to bring the final volume to 20 mL.
  • Example 4A Gel Formulation A (1 % drug concentration in 2% Poloxamer 407 gel)
  • Poloxamer 407 (0.4 g) was dissolved in 10 g of deionized water. Propylene glycol (2 g) was added with mixing. To this solution was added Compound 1 (0.2 g, acetate salt) followed by EDTA disodium dihydrate (0.02 g), methyl paraben (0.03 g), and propyl paraben (0.01 g). Water was then added to bring the final volume to 20 mL.
  • Example 4B Gel Formulation A (1 % drug concentration in 2% Poloxamer 407 gel, pH 4.2)
  • Poloxamer 407 (0.4 g) was dissolved in 10 g of 50 mM sodium lactate buffer, pH 4.2. Propylene glycol (2 g) was added with mixing. To this solution was added Compound 1 (0.2 g, acetate salt) followed by EDTA disodium dihydrate (0.02 g), methyl paraben (0.03 g), and propyl paraben (0.01 g). Water was then added to bring the final volume to 20 mL.
  • Example 5A Gel Formulation A (10% drug concentration in 4% Poloxamer 407 gel)
  • Poloxamer 407 (0.8 g) is dissolved in 10 g of deionized water. Propylene glycol (2 g) is added with mixing. To this solution is added Compound 1 (2 g, acetate salt) followed by EDTA disodium dihydrate (0.02 g), methyl paraben (0.03 g), and propyl paraben (0.01 g). Water is then added to bring the final volume to 20 mL.
  • Example 5B. Gel Formulation A (10% drug concentration in 4% Poloxamer 407 gel, pH 4.2)
  • Poloxamer 407 (0.8 g) is dissolved in 10 g of 50 mM sodium lactate buffer, pH 4.2. Propylene glycol (2 g) is added with mixing. To this solution is added Compound 1 (2 g, acetate salt) followed by EDTA disodium dihydrate (0.02 g), methyl paraben (0.03 g), and propyl paraben (0.01 g). Water is then added to bring the final volume to 20 mL.
  • Example 6A Gel Formulation A (6% drug concentration in 4% Poloxamer 407 gel)
  • Poloxamer 407 (0.8 g) is dissolved in 10 g of deionized water. Propylene glycol (2 g) is added with mixing. To this solution is added Compound 1 (1 .2 g, acetate salt) followed by EDTA disodium dihydrate (0.02 g), methyl paraben (0.03 g), and propyl paraben (0.01 g). Water is then added to bring the final volume to 20 mL.
  • Example 6B Gel Formulation A (6% drug concentration in 4% Poloxamer 407 gel, pH 4.2)
  • Poloxamer 407 (0.8 g) is dissolved in 10 g of 50 mM sodium lactate buffer, pH 4.2. Propylene glycol (2 g) is added with mixing. To this solution is added Compound 1 (1 .2 g, acetate salt) followed by EDTA disodium dihydrate (0.02 g), methyl paraben (0.03 g), and propyl paraben (0.01 g). Water is then added to bring the final volume to 20 mL.
  • Poloxamer 407 (0.8 g) is dissolved in 10 g of deionized water. Propylene glycol (2 g) is added with mixing. To this solution is added Compound 1 (0.6 g, acetate salt) followed by EDTA disodium dihydrate (0.02 g), methyl paraben (0.03 g), and propyl paraben (0.01 g). Water is then added to bring the final volume to 20 mL.
  • Example 7B Gel Formulation A (3% drug concentration in 4% Poloxamer 407 gel, pH 4.2)
  • Poloxamer 407 (0.8 g) is dissolved in 10 g of 50 mM sodium lactate buffer, pH 4.2. Propylene glycol (2 g) is added with mixing. To this solution is added Compound 1 (0.6 g, acetate salt) followed by EDTA disodium dihydrate (0.02 g), methyl paraben (0.03 g), and propyl paraben (0.01 g). Water is then added to bring the final volume to 20 mL.
  • Example 8A Gel Formulation A (1 % drug concentration in 4% Poloxamer 407 gel)
  • Poloxamer 407 (0.8 g) is dissolved in 10 g of deionized water. Propylene glycol (2 g) is added with mixing. To this solution is added Compound 1 (0.2 g, acetate salt) followed by EDTA disodium dihydrate (0.02 g), methyl paraben (0.03 g), and propyl paraben (0.01 g). Water is then added to bring the final volume to 20 mL.
  • Example 8B Gel Formulation A (1 % drug concentration in 4% Poloxamer 407 gel, pH 4.2)
  • Poloxamer 407 (0.8 g) is dissolved in 10 g of 50 mM sodium lactate buffer, pH 4.2. Propylene glycol (2 g) is added with mixing. To this solution is added Compound 1 (0.2 g, acetate salt) followed by EDTA disodium dihydrate (0.02 g), methyl paraben (0.03 g), and propyl paraben (0.01 g). Water is then added to bring the final volume to 20 mL.
  • Example 9A Gel Formulation B (10% drug concentration in 2% hydroxypropyl methylcellulose gel)
  • Hydroxypropyl methylcellulose (0.4 g) was dissolved in 10 g of 50 mM sodium lactate buffer, pH 4.2. To this solution was added Compound 1 (2 g, acetate salt) followed by EDTA disodium dihydrate (0.02 g) and methyl paraben (0.03 g), water was then added to bring the final volume to 20 mL.
  • Example 10A Gel Formulation B (6% drug concentration in 2% hydroxypropyl methylcellulose gel)
  • Hydroxypropyl methylcellulose (0.4 g) was dissolved in 10 g of deionized water. To this solution was added Compound 1 (1 .2 g, acetate salt) followed by EDTA disodium dihydrate (0.02 g) and methyl paraben (0.03 g), water was then added to bring the final volume to 20 mL.
  • Example 10B Gel Formulation B (6% drug concentration in 2% hydroxypropyl methylcellulose gel, pH 4.2)
  • Hydroxypropyl methylcellulose (0.4 g) was dissolved in 10 g of 50 mM sodium lactate buffer, pH 4.2. To this solution was added Compound 1 (1 .2 g, acetate salt) followed by EDTA disodium dihydrate (0.02 g) and methyl paraben (0.03 g), water was then added to bring the final volume to 20 mL.
  • Hydroxypropyl methylcellulose (0.4 g) was dissolved in 10 g of deionized water. To this solution was added Compound 1 (0.6 g, acetate salt) followed by EDTA disodium dihydrate (0.02 g) and methyl paraben (0.03 g), water was then added to bring the final volume to 20 mL.
  • Hydroxypropyl methylcellulose (0.2 g) was dissolved in 10 g of 50 mM sodium lactate buffer, pH 8.
  • Example 13A Gel Formulation B (1 % drug concentration in 2% hydroxypropyl methylcellulose gel)
  • Hydroxypropyl methylcellulose (0.4 g) was dissolved in 10 g of deionized water. To this solution was added Compound 1 (0.2 g, acetate salt) followed by EDTA disodium dihydrate (0.02 g) and methyl paraben (0.03 g). Water was then added to bring the final volume to 20 mL.
  • Example 13B Gel Formulation B (0.3% drug concentration in 2% hydroxypropyl methylcellulose gel)
  • Hydroxypropyl methylcellulose (0.4 g) was dissolved in 10 g of deionized water. To this solution was added Compound 1 (0.06 g, acetate salt) followed by EDTA disodium dihydrate (0.02 g) and methyl paraben (0.03 g). Water was then added to bring the final volume to 20 mL.
  • Example 14A Gel Formulation B (1 % drug concentration in 2% hydroxypropyl methylcellulose gel, pH 4.2)
  • Hydroxypropyl methylcellulose (0.2 g) was dissolved in 10 g of 50 mM sodium lactate buffer, pH 8.
  • Example 14B Gel Formulation B (0.3% drug concentration in 2% hydroxypropyl methylcellulose gel, pH 4.2)
  • Hydroxypropyl methylcellulose (0.8 g) is dissolved in 10 g of deionized water. To this solution is added Compound 1 (2 g, acetate salt) followed by EDTA disodium dihydrate (0.02 g) and methyl paraben (0.03 g). Water is then added to bring the final volume to 20 mL.
  • Example 15B Gel Formulation B (10% drug concentration in 4% hydroxypropyl methylcellulose gel, pH 4.2)
  • Hydroxypropyl methylcellulose (0.8 g) is dissolved in 10 g of 50 mM sodium lactate buffer, pH 4.2. To this solution is added Compound 1 (2 g, acetate salt) followed by EDTA disodium dihydrate (0.02 g) and methyl paraben (0.03 g). Water is then added to bring the final volume to 20 mL.
  • Example 16A Gel Formulation B (6% drug concentration in 4% hydroxypropyl methylcellulose gel)
  • Hydroxypropyl methylcellulose (0.8 g) was dissolved in 18 g of 50 mM lactate buffer, pH 4.2. To this solution was added Compound 1 (1 .2 g, acetate salt) followed by EDTA disodium dihydrate (0.02 g) and methyl paraben (0.03 g). Lactate buffer (50 mM, pH 4.2) was then added to bring the final volume to 20 ml_.
  • Example 17 Gel Formulation B (3% drug concentration in 4% hydroxypropyl methylcellulose gel) Hydroxypropyl methylcellulose (0.8 g) was dissolved in 10 g of deionized water. To this solution was added Compound 1 (0.6 g, acetate salt) followed by EDTA disodium dihydrate (0.02 g) and methyl paraben (0.03 g). Water was then added to bring the final volume to 20 mL.
  • Hydroxypropyl methylcellulose (0.4 g) was dissolved in 9.5 g of 50 mM sodium lactate buffer, pH 4.5. To this solution was added Compound 1 (0.3 g, acetate salt), methyl paraben (0.015 g), and EDTA disodium dihydrate (0.01 g). The solution was stirred until dissolution was complete. Sodium lactate buffer (50 mM, pH 4.2) was then added to bring the final volume to 10 mL.
  • Example 19A Gel Formulation B (1 % drug concentration in 4% hydroxypropyl methylcellulose gel)
  • Hydroxypropyl methylcellulose (0.8 g) was dissolved in 10 g of deionized water. To this solution was added Compound 1 (0.2 g, acetate salt) followed by EDTA disodium dihydrate (0.02 g) and methyl paraben (0.03 g). Water was then added to bring the final volume to 20 mL.
  • Example 19B Gel Formulation B (1 % drug concentration in 4% hydroxypropyl methylcellulose gel, pH 4.2)
  • Hydroxypropyl methylcellulose (0.8 g) was dissolved in 18 g of 50 mM lactate buffer, pH 4.2. To this solution was added Compound 1 (0.2 g, acetate salt) followed by EDTA disodium dihydrate (0.02 g) and methyl paraben (0.03 g). Sodium lactate buffer (50 mM, pH 4.2) was then added to bring the final volume to 20 mL.
  • Example 19C Gel Formulation B (0.3% drug concentration in 4% hydroxypropyl methylcellulose gel)
  • Hydroxypropyl methylcellulose (0.8 g) was dissolved in 18 g of 50 mM lactate buffer, pH 4.2. To this solution was added Compound 1 (0.06 g, acetate salt) followed by EDTA disodium dihydrate (0.02 g) and methyl paraben (0.03 g). Sodium lactate buffer (50 mM, pH 4.2) was then added to bring the final volume to 20 mL.
  • Example 20A Gel Formulation B (1 % drug concentration in 4% hydroxypropyl methylcellulose gel, pH 4.2)
  • Hydroxypropyl methylcellulose (0.4 g) was dissolved in 10 g of 50 mM sodium lactate buffer, pH
  • Example 20B Gel Formulation B (0.3% drug concentration in 4% hydroxypropyl methylcellulose gel, pH 4.2)
  • Hydroxyethyl cellulose (0.5 g) was dissolved in 10 g of 50 mM sodium lactate buffer at pH 4.2. To this solution was added Compound 1 (0.1 g, acetate salt) which was stirred until dissolution was complete.
  • Hydroxyethyl cellulose (0.5 g) was dissolved in 10 g of 50 mM sodium lactate buffer at pH 4.2. To this solution was added Compound 1 (0.3 g, acetate salt) which was stirred until dissolution was complete.
  • Example 27 Gel Formulation D (1% drug concentration in 5% hydroxyethyl cellulose, pH 7.4)
  • Hydroxyethyl cellulose (0.5 g) was dissolved in 10 g of 50 mM N-methylglucamine buffer at pH 7.4. To this solution was added Compound 1 (0.1 g, acetate salt) which was stirred until dissolution was complete.
  • Example 28 Gel Formulation D (3% drug concentration in 5% hydroxyethyl cellulose, pH 7.4)
  • Hydroxyethyl cellulose (0.5 g) was dissolved in 10 g of 50 mM N-methylglucamine buffer at pH 7.4. To this solution was added Compound 1 (0.3 g, acetate salt) which was stirred until dissolution was complete.
  • Example 29 Gel Formulation D (1% drug concentration in 2% hydroxyethyl cellulose (Natrosol®), pH 4.2)
  • Hydroxyethyl cellulose (Natrosol®)(0.2 g) was dissolved in 10 g of 50 mM sodium lactate buffer at pH 4.2. To this solution was added Compound 1 (0.1 g, acetate salt) which was stirred until dissolution was complete.
  • Example 30 Gel Formulation D (3% drug concentration in 2% hydroxyethyl cellulose (Natrosol®), pH 4.2)
  • Hydroxyethyl cellulose (Natrosol®)(0.2 g) was dissolved in 10 g of 50 mM sodium lactate buffer at pH 4.2. To this solution was added Compound 1 (0.3 g, acetate salt) which was stirred until dissolution was complete.
  • Example 31 Gel Formulation D (1% drug concentration in 2% hydroxyethyl cellulose (Natrosol®), pH 7.4)
  • Hydroxyethyl cellulose (Natrosol®)(0.2 g) was dissolved in 10 g of 50 mM N-methylglucamine buffer at pH 7.4. To this solution was added Compound 1 (0.3 g, acetate salt) which was stirred until dissolution was complete.
  • Example 33 Cream formulation A (10% drug concentration)
  • Example 35 Cream formulation A (3% drug concentration)
  • Example 36 Cream formulation A (1 % drug concentration)
  • the mixture in the second falcon tube was added to the first falcon tube.
  • the second falcon tube was rinsed with 893 mg of deionized water to ensure the transfer was complete.
  • Deionized water was added to bring the total weight to 5 g .
  • the mixture was vigorously mixed then cooled to room temperature to obtain a white cream.
  • Example 38 Cream formulation B (1 % drug concentration)
  • Example 40 Cream formulation B (3% drug concentration)
  • vial 2 The mixture in vial 2 was added to the warm contents of vial 1 .
  • Vial 2 was rinsed with a small amount of deionized water to ensure that Compound 1 was completely transferred.
  • Deionized water was added to a total weight of 5 g and the contents were vigorously mixed for about 2 minutes. After cooling to room temperature, a white semi-solid was obtained.
  • Example 43 Cream formulation C, 6 % drug concentration
  • Example 44 Cream formulation C, 3 % drug concentration
  • Example 45 Cream formulation C, 1 % drug concentration
  • Example 46 Cream formulation D, 10% drug concentration
  • Example 47 Cream formulation D, 6% drug concentration
  • Example 48 Cream formulation D, 3% drug concentration
  • Example 49 Cream formulation D, 1% drug concentration
  • Example 50 Cream formulation E (10% drug concentration)
  • Example 53 Cream formulation E, 1 % drug concentration
  • Example 54 Cream formulation F (10 % drug concentration)
  • Example 55 Cream formulation F (6 % drug concentration)
  • Example 57 Cream formulation F (1 % drug concentration)
  • Example 60 Cream Formulation G (3 % drug concentration)
  • Example 61 Cream Formulation G (1 % drug concentration)
  • Example 62 Ointment Formulation H (10% drug concentration, 5.5% Magnesium aluminum silicate)
  • This material was warmed in a water bath set at 50 ⁇ 5°C until petrolatum white became a less viscous semi-solid.
  • the solids from the first beaker and 1 mg BHA were added slowly to the petrolatum white in beaker 2 with good mixing. After a homogeneous mixture was obtained, the mixture was cooled to room temperature to obtain a tan semi-solid.
  • Example 63 Ointment Formulation H (6 % drug concentration, 5.5% Magnesium aluminum silicate)
  • Example 64 Ointment Formulation H (3 % drug concentration, 5.5% Magnesium aluminum silicate)
  • Example 66A Ointment Formulation H (3 % drug concentration, 1.5% Magnesium aluminum silicate)
  • Example 66B Ointment Formulation H (3 % drug concentration, 0% Magnesium aluminum silicate)
  • Example 66C Ointment Formulation H (3 % drug concentration, 1 % Magnesium aluminum silicate)
  • Example 66D Ointment Formulation H (3 % drug concentration, 7.5% Magnesium aluminum silicate)
  • Example 67 A. Ointment Formulation H (1 % drug concentration, 5.5% Magnesium aluminum silicate)
  • Example 67B Ointment Formulation H (3 % drug concentration, 5.5% Magnesium aluminum silicate, milled powder blend)
  • Example 68 Ointment Formulation H (1 % drug concentration, 3% Magnesium aluminum silicate)
  • Example 69 Ointment Formulation H (1 % drug concentration, 1.5% Magnesium aluminum silicate)
  • Example 70 Ointment Formulation H (1 % drug concentration, 0.75% Magnesium aluminum silicate)
  • This material is warmed in a water bath set at 50 ⁇ 5°C until petrolatum white become a less viscous semi-solid.
  • the solids from the first beaker and 1 mg BHA are added slowly to the petrolatum white in beaker 2 with good mixing. After a homogeneous mixture is obtained, the mixture is cooled to room temperature.
  • Example 72 Ointment Formulation J (3 % drug concentration, 5.5% kaolin)
  • Example 75 Ointment Formulation J (1 % drug concentration, 5.5% kaolin)
  • Example 76 Ointment Formulation J (1 % drug concentration, 3% kaolin)
  • Example 77 Ointment Formulation J (1 % drug concentration, 1.5% kaolin)
  • Example 78 Ointment Formulation J (1 % drug concentration, 0.75% kaolin)
  • Example 82 Ointment Formulation K (3 % drug concentration, 1.5% bentonite)
  • Example 83 Ointment Formulation K (1 % drug concentration, 5.5% bentonite)
  • Example 84 Ointment Formulation K (1 % drug concentration, 3% bentonite)
  • Example 85 Ointment Formulation K (1 % drug concentration, 1.5% bentonite)
  • Example 87 Ointment Formulation L (6 % drug concentration, 5.5% attapulgite)
  • Example 88 Ointment Formulation L (3 % drug concentration, 5.5% attapulgite)
  • Example 89 Ointment Formulation L (3 % drug concentration, 3% attapulgite)
  • Example 90 Ointment Formulation L (3 % drug concentration, 1.5% attapulgite)
  • Example 91 Ointment Formulation L (1 % drug concentration, 5.5% attapulgite)
  • Example 93 Ointment Formulation L (1 % drug concentration, 1.5% attapulgite)
  • Example 94 Ointment Formulation L (1 % drug concentration, 0.75% attapulgite)
  • Compound 1 The mean vaginal exposures (and standard deviations SD) for Compound 1 , as measured in vaginal lavage fluid concentrations, are shown in Table 1 . Significant concentrations of Compound 1 persisted out to at least 72 hours, which indicates that the mean residence time of Compound 1 in the vagina or on the vulva of the vagina is at least 72 hours.
  • Example 96 Compound 1 Levels in Vaginal Lavage Fluid from Rats
  • the local half-life of Compound 1 in various formulations may be determined by measuring the amount or concentration of Compound 1 that remains inside the vagina or on the vulva of a rat at various time points after Compound 1 was administered, and comparing the remaining amount or concentration of Compound 1 at each time point to the initial, administered amount or concentration of Compound 1 .
  • Vaginal lavage samples as described in Examples 95 and 96, may be used.
  • the local half-life of Compound 1 is time it takes for the remaining amount or concentration of Compound 1 to reach half of the initial, administered amount or concentration of Compound 1 .
  • the amount or concentration of Compound 1 that remains inside the tissue of the vagina may also be measured. This measurement determines the local half-life of Compound 1 that has already penetrated the surface of the skin and reached the underlying mucosal membrane.
  • vaginal lavage samples instead of using vaginal lavage samples as described in Examples 95 and 96, after the rats were sacrificed, vagina cavity tissue or vulva tissue of the rats may be processed to extract Compound 1 .
  • Various techniques that can be used to extract organic compounds from tissues are known in the art. Extracted Compound 1 from different time points can then be analyzed by LC-MS/MS.
  • Compound 1 may take a period of time (e.g., minutes to a few hours) to penetrate the surface of the tissue to get to the underlying mucosal membrane.
  • the initial amount or concentration of Compound 1 inside the vaginal cavity tissue or vulva tissue may be low.
  • the amount or concentration of Compound 1 inside the vaginal cavity tissue or vulva tissue may peak as time progresses, then slowly decrease as Compound 1 is eliminated from the body.
  • the local half-life of Compound 1 inside the vaginal cavity tissue or vulva tissue is the time it takes for the amount or concentration of Compound 1 to decrease to half of the amount or concentration of Compound 1 at the peak.
  • Estrogen supplementation was supplied by subcutaneous administration of 17p-estradiol at a dose of 10 mg/kg 3 days before infection and subsequently maintained by subcutaneous administration at a dose of 4 mg/kg weekly throughout the experiment. Animals were immunosuppressed with dexamethasone added to the drinking water at a final concentration of 2 mg/L. Immunosuppressive treatment was started 3 days before infection and maintained throughout the experiment.
  • Infected animals were then randomly distributed into twelve groups of 4 each. Antifungal therapy was started 48 hours after infection. Groups of 4 rats each were treated orally or intravaginally with vehicle, a standard drug (fluconazole, terconazole, or miconazole), and test article, once daily (QD) or twice daily (BID) for 3 consecutive days. The animals were euthanized by CO2 asphyxiation on Day 5 (12 hr after the last treatment), Day 7, Day 9, or Day 12. Vaginal lavage was performed and fungal burden (log CFU/mL of lavage fluid) was measured.
  • Fluconazole was administered orally once daily (QD) at either 10 mg/kg or 20 mg/kg; miconazole 2% was applied intravaginally, twice daily (BID); terconazole 0.8% was applied intravaginally once daily (QD); and test article (formulation from Examples 9, 1 1 , 13, 52, 60, 64, or 67) was applied intravaginally once or twice daily as noted. Vehicle controls were administered either once or twice daily.
  • FIG. 1 A shows the antifungal activities on Day 5 and Day 7 post-infection of gel formulations from Examples 9, 1 1 , and 13 administered once daily in the rat vulvovaginal candidiasis model.
  • Fluconazole was dosed at 20 mg/kg. As can be seen in FIG. 1 A, once daily (qd) application of
  • FIG. 1 B further shows the antifungal activities on Day 5, Day 7, Day 9, and Day 12 post-infection of gel formulations from Examples 1 1 and 13 administered twice daily in the rat vulvovaginal candidiasis model. Twice daily (bid) application of Compound 1 gel eliminated detectable fungal counts ( ⁇ LOD (limit of detection)) (FIG. 1 B).
  • FIG. 1 C shows the antifungal activities on Day 12 post-infection of formulations from Examples 1 1 and 13 (gel) and Examples 64 and 67 (ointment) administered once daily in the rat vulvovaginal candidiasis model.
  • FIG. 1 B shows the antifungal activities on Day 5, Day 7, Day 9, and Day 12 post-infection of gel formulations from Examples 1 1 and 13 administered twice daily in the rat vulvovaginal candidiasis model. Twice daily (bid) application of Compound 1 gel eliminated detectable fungal counts ( ⁇ LOD (limit of detection)) (FIG. 1 B).
  • FIG. 1 C shows the antifung
  • FIG. 1 D shows the antifungal activities on Day 5, Day 9, and Day 12 post-infection of ointment formulations from Examples 64 and 67 administered once daily in the rat vulvovaginal candidiasis model.
  • Ointment forms of Compound 1 (Examples 64 and 67) were compared to miconazole cream (bid) and oral fluconazole at 20 mg/kg (qd).
  • FIG. 1 D shows that ointment formulations of Compound 1 showed prolonged efficacy after once daily (qd) dosing.
  • FIG 1 E further shows antifungal activities on Day 5 and Day 12 post-infection of cream and ointment formulations from Examples 52, 60, and 64 administered once daily in the rat vulvovaginal candidiasis model.
  • FIG. 1 D shows the antifungal activities on Day 5, Day 9, and Day 12 post-infection of ointment formulations from Examples 64 and 67 administered once daily in the rat vulvovaginal candidiasis
  • Example 99 In Vitro Release Rates of Cream and Ointment Formulations from Examples 50, 58 and 62
  • the wells were covered with a 500 ⁇ nylon mesh, placed in the vessel, and 200 mL of SVF1 (similar vaginal fluid, pH 4.9) was added.
  • the dissolution apparatus water bath was set at 37 ⁇ 1 °C and the peddle rotation speed was set at 1 00 rpm.
  • Example 62 Aliquots were taken from the cylinder (sample volume: 1 .0 mL) for HPLC assay at 0.5, 1 , 2, 3, 6, 9, 12, 16, 20, and 24 hrs to determine the concentration of Compound 1 that was released into solution. The results as shown in FIG. 2 demonstrate that the ointment formulation of Example 62 gave the slowest release.
  • FIG. 3 further shows the fungicidal properties of Compound 1 against ATCC 44858.
  • Example 12 Moderately viscous gel with rapid Compound 1 release
  • Example 18 (highly viscous gel with intermediate Compound 1 release), and Example 64 (ointment with slow Compound 1 release) were evaluated in a rat model of VVC.
  • vaginal infection with C. albicans ATCC 44858 was established in oophorohysterectomized and immunosuppressed female rats.
  • Estrogen levels in each animal were regulated by subcutaneous (SC) administration of 17p-estradiol at 10 mg/kg 3 days before infection (Day -3) and subsequently maintained at 4 mg/kg SC weekly during the study. Animals were immunosuppressed with dexamethasone (added to drinking water with a final concentration at 2 mg/L) 3 days before infection until the end of study.
  • the animals were intravaginally inoculated with C. albicans followed by treatment with Compound 1 or relevant positive controls starting 48 hours (Day 2) post-infection for 3 days.
  • the rats including untreated group) were sacrificed at selected time points starting the day after the last dose (Day 5) or 8 days after the last dose (Day 12) after infection, and C. albicans CFU counts in lavage fluid were determined.
  • a decrease of ⁇ 99% ( ⁇ 2-log) in the C. albicans counts of treated animals compared to the untreated group was considered significant antifungal activity.
  • Compound 1 concentrations in lavage samples were higher in the more viscous/slower release formulations and, as expected, Day 5 concentrations were higher than Day 12 concentrations. Prolonged exposure, for example slower release, may be beneficial for the treatment of VVC.
  • Tioconocazole-1 ointment had appreciable levels of drug present at Days 5 and 12, but were 1 .5-fold to 14-fold below the levels observed with Compound 1 ointment.
  • Single use, pre-filled, ready-to-use applicator is filled to deliver 4 g of semisolid Example 63, 6% ointment, and is administered intravaginally to the subject as a single dose on Day 1 .
  • the 6% ointment contains 240 mg of Compound 1 in 4 g of ointment.
  • a multiuse tube is filled to deliver approximately 4 g of Example 67A, 1 % external ointment, for application to the external vulvar region by the subject up to twice per day over 72 hours for symptomatic relief.
  • the 1 % ointment contains 40 mg of Compound 1 in 4 g of ointment.
  • Single use, pre-filled, ready-to-use applicator is filled to deliver 4 g of gel with Example 18 vaginal gel (3%, 120 mg) and the gel is administered intravaginally to the subject as a single dose on Day 1 and Day 2.
  • the 3% gel contains 120 mg of Compound 1 in 4 g of gel.
  • a multiuse tube is filled to deliver approximately 4 g of Example 19B, external gel (1 %), and the gel is applied by the subject to the external vulvar region up to twice per day over 72 hours for symptomatic relief.
  • the 1 % gel contains 40 mg of Compound 1 in 4 g of gel.
  • Single use, pre-filled, ready-to-use applicator is filled to deliver 4 g of semisolid with Example 16B vaginal gel (6%, 240 mg) and the gel is administered intravaginally to the subject as a single dose on Day 1 .
  • the 6% gel contains 240 mg of Compound 1 in 4 g of gel.
  • a multiuse tube is filled to deliver approximately 4 g of Example 19B, external gel (1 %), and the gel is applied by the subject to the external vulvar region up to twice per day over 72 hours for symptomatic relief.
  • the 1 % gel contains 40 mg of Compound 1 in 4 g of gel.
  • Example 105 Human Dosing Regimen for Intravaginal Ointment and External Gel
  • Example 63 vaginal ointment (6%, 240 mg) is administered intravaginally to the subject as a single dose on Day 1 .
  • a multiuse tube is filled to deliver approximately 4 g of Example 19B external gel (1 %) and the gel is applied by the subject to the external vulvar region up to twice per day over 72 hours for symptomatic relief.
  • the 1 % gel contains 40 mg of Compound 1 in 4 g of gel.
  • Example 106 Compound 1 Gel Formulation is Highly Efficacious against Azole-Resistant Candida albicans in a Rat Model of Vulvovaginal Candidiasis
  • dexamethasone applied in drinking water (2 mg/L) three days before challenge and throughout the study.
  • anesthetized rats were inoculated intravaginally with C. albicans (10 7 CFU) in PBS. All treatments began 48 hour after challenge.
  • Compound 1 3% gel from Example 18 or 2% miconazole cream or nystatin cream were administered intravaginally at 0.1 mL/rat once daily for three days.
  • Oral fluconazole was also administered at 20 mg/kg once daily for three days.
  • Rats were sacrificed at two different time points after treatment end (days 5 and 12 corresponding to 1 and 8 days after treatment end) followed by vaginal lavage. C. albicans counts were measured in lavage fluid and also in excised vaginal tissue.
  • results at days 5 and 12 are shown in FIG. 4.
  • oral fluconazole showed minimal ( ⁇ 1 log-fold) reduction in vaginal CFU against the azole-resistant strain of C. albicans as expected.
  • Topical administration of miconazole cream showed a >2 log-fold reduction in vaginal CFU one day after treatment end that was short-lived, as vaginal CFU rebounded a week later.
  • Nystatin cream showed >2 log-fold reduction in vaginal CFU one day after treatment end that persisted through a week later.
  • Compound 1 showed the greatest efficacy of the agents tested as vaginal CFUs were below the limit of detection (3.8 log-fold reduction) from one day after treatment end and remained >3 log-fold lower for a week after treatment end.
  • Example 107 Time-Kill Kinetics of Compound 1 for Azole-Susceptible and -Resistant Candida spp. at pH 4 in Vagina-Simulative Medium
  • the echinocandin class of antifungal agents has not been considered for treatment of VVC because currently available echinocandins are limited to IV administration.
  • This study investigated the killing kinetics of the novel echinocandin, Compound 1 , which is in development as a topical formulation, against Candida spp., including azole-S and -R strains, in conditions and at concentrations relevant to topical treatment of VVC.
  • Candida spp. including C. albicans, C. glabrata, C. tropicalis, C. parapsilosis and C. krusei
  • Time-kill assays used a starting inoculum of mid-10 5 colony-forming units (CFU)/ml_ in 10 mL of vagina-simulative medium (VSM) at pH 4.0.
  • Cidality was defined as a ⁇ 3-log reduction in CFU.
  • Fungicidal activity was defined as a ⁇ 3-log reduction in CFU from the starting assay inoculum.
  • Compound 1 achieved cidality or near-cidality by 72 h for all strains in a strongly dose-dependent fashion, albeit to a lesser extent for C. tropicalis.
  • the most rapid killing for Compound 1 occurred for the two C. krusei strains where cidality was achieved at all concentrations ⁇ 24 h.
  • Dose-dependent activity was also observed for TCZ. Even though TCZ was only tested against FLU-S strains, cidality was not achieved for any strain at any time point and typically only the highest concentrations resulted in CFU reductions.
  • 5A-5D, 6A-6D, 7A-7D, 8A-8D, and 9A-9B show the fungicidal properties of Compound 1 and TCZ against azole-S and azole-R strains of 5 Candida spp. (C. albicans, C. glabrata, C. tropicalis, C. parapsilosis and C. krusei).
  • Tables 4-8 summarize the log-fold changes in CFU for each of the 5 Candida spp. (C. albicans, C. glabrata, C. tropicalis, C. parapsilosis, and C. krusei).
  • Compound 1 a novel echinocandin in development for topical administration, demonstrates potent activity against all major Candida spp. etiological agents of VVC, including azole-R strains, in i vitro time-kill assays performed under conditions relevant to the treatment of VVC.
  • the activity of Compound 1 was more potent than that of TCZ for all strains evaluated.
  • examples 13B, 14B, 19C, 19D on a flat-bottomed glass vial and covering it with 5 mL of simulated vaginal fluid consisting of 2.6 mM MgSC , 10.0 mM KCI, 40.0 mM glucose buffered with 50 mM aqueous lactate buffer pH 4.2.
  • the samples were incubated at 37 °C while shaking at 200 rpm over 24 h on a Heidolph Viramax 100 apparatus. Aliquots of 50 ⁇ were withdrawn at time points 0, 0.5, 1 , 2, 4, 6 and 24 h and replaced with an equal volume of release medium pre-equilibrated to temperature.
  • Example 109 Comparison of In-Vitro Drug Release of Commercial VVC Ointment Formulation (Tioconazole-1) vs. Compound 1 Ointment
  • Compound 1 from ointment formulations Approximately 100 ⁇ of the ointment formulations were placed in flat-bottomed glass vials and covered with 1 ml of simulated vaginal fluid containing 2.6 mM MgS04, 10.0 mM KCI, 40.0 mM glucose buffered with 50 mM aqueous lactate buffer pH 4.2. The samples were incubated at 37 °C while shaking at 200 rpm over 24 h on a Heidolph Viramax 100 apparatus. Aliquots of 50 ⁇ were withdrawn at time points 0, 0.5, 1 , 2, 4, 6 and 24 h and replaced with an equal volume of release medium pre-equilibrated to temperature.
  • FIG. 1 1 A Compound 1
  • FIG. 1 1 B Tioconazole- 1
  • Compound 1 approximately 1 % drug is released over 24 hours for the 1 % formulation and 0.5% release from the 3% formulation.
  • Tioconazole drug release was 8.4% drug over 24 hours.
  • Compound 1 drug release of a 3% ointment formulation is presented in FIG. 12A (3 replicates), indicating about 7% drug is released in Medium 1 over 48 hours at 37 5 C.
  • Experimental conditions are as follows: Ointment formulations (0.6 g of the ointment, 3 replicates) were placed into six stainless steel sample wells with a wide opening of a Vankel VK7000 dissolution apparatus. The wells were covered with a 500 ⁇ nylon mesh, placed in the vessel, and 200 mL of Medium 1 was added. The dissolution apparatus water bath was set at 37 ⁇ 1 °C and the paddle rotation speed was set at 150 rpm.
  • FIG. 12B drug release data from Tioconazole-1 , 6.5 % (w/w) (sold under the brand name Vagistat-1 ) are presented in FIG. 12B, which show drug release of 70-80% over 48 hours at 37 5 C.
  • Example 110 In Vitro Drug Release Studies - Evaluation of Magnesium Aluminum Silicate Level ln-vitro drug release studies were conducted to evaluate the effect of magnesium aluminum silicate levels, ranging from 0% to 7.5% (w/w) in petrolatum white, on in vitro drug release kinetics.
  • compositions studied are provided in Table 9. Compound 1 concentration was 3% in all cases.
  • Example 66B had the most rapid release of approximately 8% over 48 hours at 37 S C.
  • the other three formulations had similar release rates of 4-5% over 48 hours (FIG. 13).
  • the formulation of Example 64 had a unique release rate, with a rapid release of 2% over the first 3 hours followed by a slower release. 2155 Example 111. In Vitro Drug Release Studies - Evaluation of Magnesium Aluminum Silicate
  • milling was conducted with a planetary micromill, model Pulverisette 7, set at 250 rpm for 5 minutes.
  • the particle size distributions of the milled samples were 2165 analyzed by Malvern Mastersizer 2000.
  • the release profile shown in FIG. 14 indicates that compounding all materials at once, avoiding 2175 the dry blending, affords the most rapid release (example 66E). Milling of the dry blend resulted in

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Abstract

La présente invention concerne des compositions pharmaceutiques sous la forme de gel, de crème et d'onguent contenant un sel du Composé 1, ou une forme neutre de ce dernier. Les compositions pharmaceutiques peuvent être utilisées pour le traitement de candidoses (par exemple, la candidose vulvovaginale (VVC)). L'invention concerne également des méthodes de traitement de candidoses chez le patient par administration locale au patient d'une composition pharmaceutique contenant entre 0,1 % et 15 % (poids/poids) d'un sel du Composé 1, ou une forme neutre de ce dernier.
PCT/US2016/052165 2015-09-16 2016-09-16 Formulations pour le traitement d'infections fongiques Ceased WO2017049105A1 (fr)

Applications Claiming Priority (8)

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