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US20080032994A1 - Modified azole compounds as antifungal and antibacterial agents - Google Patents

Modified azole compounds as antifungal and antibacterial agents Download PDF

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US20080032994A1
US20080032994A1 US11/591,609 US59160906A US2008032994A1 US 20080032994 A1 US20080032994 A1 US 20080032994A1 US 59160906 A US59160906 A US 59160906A US 2008032994 A1 US2008032994 A1 US 2008032994A1
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azole
alkyl
trichophyton
compound
candida
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Marcel Borgers
Maarten van Geffen
Jannie Ausma
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Barrier Therapeutics Inc
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Barrier Therapeutics Inc
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Priority to US11/591,609 priority Critical patent/US20080032994A1/en
Assigned to BARRIER THERAPEUTICS, INC. reassignment BARRIER THERAPEUTICS, INC. ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: AUSMA, JANNIE, VAN GEFFEN, MAARTEN, BORGERS, MARCEL
Priority to PCT/US2007/017251 priority patent/WO2008019030A2/fr
Priority to US12/019,942 priority patent/US20080182885A1/en
Publication of US20080032994A1 publication Critical patent/US20080032994A1/en
Priority to US12/108,262 priority patent/US8147852B2/en
Assigned to DEUTSCHE BANK TRUST COMPANY AMERICAS, AS COLLATERAL AGENT reassignment DEUTSCHE BANK TRUST COMPANY AMERICAS, AS COLLATERAL AGENT SECURITY AGREEMENT Assignors: BARRIER THERAPEUTICS, INC.
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    • C07D233/60—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms with hydrocarbon radicals, substituted by oxygen or sulfur atoms, attached to ring nitrogen atoms
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    • C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
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Definitions

  • the present invention relates to various modified azole compounds and their preparation and use as antifungal and/or antibacterial agents.
  • Candida spp. of which C. albicans accounts for approximately 50% and filamentous fungi such as Aspergillus spp. (Kremery and Barnes, 2002).
  • Mortality associated with invasive Candida ranges from around 40% (Edmond et al., 1999), while mortality associated with invasive Aspergillus approaches 100% in solid organ transplant recipients (Minari et al., 2002).
  • antifungal therapeutics antifungal therapeutics
  • the antimycotics currently in clinical use are limited either by their general ineffectiveness and inadequate pharmacological profile, including undesired drug-drug interactions and narrow activity spectrum, their fungistatic nature, or by their high overall cytotoxicity (White et al, 1998). Accordingly, there is a critical need for new antifungal compounds that could overcome these disadvantages.
  • Zhang et al. recently reported the formation of a 1:1 adduct of the antifungal azole compound miconazole nitrate with 2,6-di-tert-butyl-4-methylphenol (BHT) (Zhang et al, 2004).
  • BHT 2,6-di-tert-butyl-4-methylphenol
  • the present invention relates in part to the unexpectedly enhanced antifungal activity exhibited by this adduct as well as by adducts of BHT with other azole compounds and adducts of compounds of formula (I) other than BHT with miconazole nitrate and other azole compounds.
  • An aspect of the invention is a method of treating fungal and/or bacterial disorders comprising systemically or topically administering to a recipient in need of such treatment an effective amount of a compound of the formula (I)
  • R 1 —H, alkyl, —C(O)R 6 , —C(O)OR 6 or —S(O) n R 6 ;
  • A an azole;
  • R 6 alkyl, aryl or heteroaryl; and
  • n 1 or 2, or a pharmaceutically acceptable salt thereof.
  • Another aspect of the invention is a method of treating fungal and/or bacterial disorders comprising systemically or topically administering to a recipient in need of such treatment an effective amount of a compound or a pharmaceutically acceptable salt of the compound formed by the combination of di-tert-butyl-4-methylphenol (BHT) with an azole.
  • BHT di-tert-butyl-4-methylphenol
  • Another aspect of the invention is a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of the formula (I)
  • R 1 —H, alkyl, —C(O)R 6 , —C(O)OR 6 or —S(O) n R 6 ;
  • A an azole;
  • R 6 alkyl, aryl or heteroaryl; and
  • n 1 or 2, or a pharmaceutically acceptable salt thereof.
  • Yet another aspect of the invention is a pharmaceutical composition
  • a pharmaceutical composition comprising an adduct of BHT or a compound of formula (I) other an BHT with an azole-containing compound selected from the group consisting of miconazole, clotrimazole, econazole, fluconazole, itraconazole, ketoconazole, pramiconazole, sertaconazole, butoconazole, ravuconazole, voriconazole, posaconazole, luliconazole and pharmaceutically acceptable salts thereof.
  • an azole-containing compound selected from the group consisting of miconazole, clotrimazole, econazole, fluconazole, itraconazole, ketoconazole, pramiconazole, sertaconazole, butoconazole, ravuconazole, voriconazole, posaconazole, luliconazole and pharmaceutically acceptable salts thereof.
  • Another aspect of the invention is compound of formula (I)
  • R 1 —H, alkyl, —C(O)R 6 , —C(O)OR 6 or —S(O) n R 6 ;
  • A an azole;
  • R 6 alkyl, aryl or heteroaryl; and
  • n 1 or 2, or a pharmaceutically acceptable salt thereof, with the proviso that R 1 is not —H when R 2 and R 3 are tert-butyl, R 4 and R 5 are —H, and A is miconazole.
  • FIG. 1 depicts an exemplary embodiment of a compound of formula (I), which is the adduct miconazole nitrate and BHT.
  • FIG. 2 depicts a proposed reaction mechanism between miconazole nitrate (i.e., an exemplary azole) and BHT (i.e., an exemplary compound of formula II) to form the miconazole nitrate—BHT adduct as a salt (i.e., an exemplary compound of formula I).
  • BHT i.e., an exemplary compound of formula II
  • FIG. 3 depicts a comparison of the antifungal effect of miconazole nitrate ( ⁇ ) with the compound representing the adduct of miconazole nitrate with BHT ( ⁇ ).
  • an amount effective to or a “therapeutically effective amount” or any grammatically equivalent term refers to the amount that, when administered to an animal for treating a disease or condition, is sufficient to effect treatment for that disease or condition.
  • topical administration is used in the conventional sense to mean delivery of a topical drug or pharmacologically active agent directly to the skin or mucosa of an individual.
  • an “antifungal agent” is an agent that inhibits the growth of fungi (i.e., a fungistat) and/or kills them outright (i.e., a fungicide).
  • a “skin fungal disorder” is intended to encompass all fungal disorders that affect skin, hair, nail, oral and genital mucosa as well as internal organs and blood.
  • a “bacteria disorder” is intended to encompass any bacterial disorder, including, but not limited to those that affect skin, hair, nails, oral and genital mucosa as well as internal organs and blood.
  • the bacterial disorder is a Gram+ bacterial disorder.
  • an “adduct” is a single chemical compound formed by the combination of at least two other chemical compounds.
  • the adducts of the present invention typically exist in a salt form.
  • an “azole” is a member of a class of optionally substituted five-membered ring heterocyclic compounds containing two double bonds, a nitrogen atom and at least one other atom selected from nitrogen, sulfur and oxygen.
  • “Azole” is also used more broadly to refer to a compound that contains within its structure at least one azole moiety.
  • the term “azole” as well as the recitation of a particular azole, may include both the neutral compound and any corresponding salt.
  • the term “miconazole” as an exemplary azole may be used to refer both the neutral compound and to a salt thereof, such as miconazole nitrate.
  • rambazole refers to the compound benzothiazol-2-yl-[4-(2-ethyl-1-[1,2,4]triazol-1-yl-butyl)-phenyl]-amine, including pharmaceutically acceptable salts thereof.
  • the chemical structure of rambazole is indicated below:
  • alkyl by itself or as part of another substituent refers to, unless otherwise stated, a straight or branched chain, or cyclic hydrocarbon radical, or combination thereof, which may be fully saturated, mono- or polyunsaturated and can include di- and multivalent radicals, having the number of carbon atoms designated (i.e. C 1 -C 10 means one to ten carbons).
  • saturated hydrocarbon radicals include, but are not limited to, groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, sec-butyl, cyclohexyl, (cyclohexyl)methyl, cyclopropylmethyl, methylene, ethylene and homologs and isomers of, for example, n-pentyl, n-hexyl, n-heptyl, n-octyl, and the like.
  • An unsaturated alkyl group is one having one or more double bonds or triple bonds.
  • alkyl groups examples include, but are not limited to, vinyl, 2-propenyl, crotyl, 2-isopentenyl, 2-(butadienyl), 2,4-pentadienyl, 3-(1,4-pentadienyl), ethynyl, 1- and 3-propynyl, 3-butynyl, and the higher homologs and isomers.
  • alkyl unless otherwise noted, is also meant to include those derivatives of alkyl defined in more detail below, such as “heteroalkyl.” Alkyl groups that are limited to hydrocarbon groups are termed “homoalkyl”.
  • aryl refers to, unless otherwise stated, a polyunsaturated, optionally substituted aromatic, substituent that can be a single ring or multiple rings (preferably from 1 to 3 rings), which are fused together or linked covalently.
  • heteroaryl refers to optionally substituted aryl groups (or rings) that contain from one to four heteroatoms selected from N, O, and S, wherein the nitrogen and sulfur atoms are optionally oxidized, and the nitrogen atom(s) are optionally quaternized.
  • a heteroaryl group can be attached to the remainder of the molecule through a heteroatom.
  • Non-limiting examples of aryl and heteroaryl groups include phenyl, 1-naphthyl, 2-naphthyl, 4-biphenyl, 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 3-pyrazolyl, 2-imidazolyl, 4-imidazolyl, pyrazinyl, 2-oxazolyl, 4-oxazolyl, 2-phenyl-4-oxazolyl, 5-oxazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidyl, 4-pyrimidyl, 5-benzothiazolyl, purinyl, 2-benzimidazolyl, 5-indolyl, 1-isoquinoly
  • alkylaryl refers to include those radicals in which an aryl group is attached to an alkyl group (e.g., benzyl, phenethyl, pyridylmethyl and the like) including those alkyl groups in which a carbon atom (e.g., a methylene group) has been replaced by, for example, an oxygen atom (e.g., phenoxymethyl, 2-pyridyloxymethyl, 3-(1-naphthyloxy)propyl, and the like).
  • alkyl group substituents are generically referred to as “alkyl group substituents,” and they can be one or more of a variety of groups selected from, but not limited to: —OR′, ⁇ O, ⁇ NR′, ⁇ N—OR′, —NR′R′′, —SR′, -halogen, —SiR′R′′R′′′, —OC(O)R′, —C(O)R′, —CO 2 R′, —CONR′R′′, —OC(O)NR′R′′, —NR′′C(O)R′, —NR′—C(O)NR′′R′′′, —NR′′C(O) 2 R′, —NR—C(NR—C(NR—C(O) 2 R′, —NR—C(NR—OR′, —NR—C(NR—C(NR—C(O) 2 R′, —NR—C(NR—C(NR—C(O) 2 R′, —NR—C(NR
  • R′, R′′, R′′′ and R′′′′ each preferably independently refer to hydrogen, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, e.g., aryl substituted with 1-3 halogens, substituted or unsubstituted alkyl, alkoxy or thioalkoxy groups, or arylalkyl groups.
  • each of the R groups is independently selected as are each R′, R′′, R′′′ and R′′′′ groups when more than one of these groups is present.
  • R′ and R′′ are attached to the same nitrogen atom, they can be combined with the nitrogen atom to form a 5-, 6-, or 7-membered ring.
  • —NR′R′′ is meant to include, but not be limited to, 1-pyrrolidinyl and 4-morpholinyl.
  • alkyl is meant to include groups including carbon atoms bound to groups other than hydrogen groups, such as haloalkyl (e.g., —CF 3 and —CH 2 CF 3 ) and acyl (e.g., —C(O)CH 3 , —C(O)CF 3 , —C(O)CH 2 OCH 3 , and the like).
  • haloalkyl e.g., —CF 3 and —CH 2 CF 3
  • acyl e.g., —C(O)CH 3 , —C(O)CF 3 , —C(O)CH 2 OCH 3 , and the like.
  • substituents for the aryl and heteroaryl groups are generically referred to as “aryl group substituents.”
  • the substituents are selected from, for example: halogen, —OR′, —NR′R′′, —SR′, -halogen, —SiR′R′′R′′′, —OC(O)R′, —C(O)R′, —CO 2 R′, —CONR′R′′, —OC(O)NR′R′′, —NR′′C(O)R′, —NR′—C(O)NR′′R′′′, —NR′′C(O) 2 R′, —NR—C(NR′R′′R′′′) ⁇ NR′′′′, —NR—C(NR′R′′) ⁇ NR′′′, —S(O)R′, —S(O) 2 R′, —S(O) 2 NR′R′′, —NRSO 2 R′, —CN and —NO
  • each of the R groups is independently selected as are each R′, R′′, R′′′ and R′′′′ groups when more than one of these groups is present.
  • the symbol X represents “R” as described above.
  • Two of the substituents on adjacent atoms of the aryl or heteroaryl ring may optionally be replaced with a substituent of the formula -T-C(O)—(CRR′) q —U wherein T and U are independently —NR—, —O—, —CRR′— or a single bond, and q is an integer of from 0 to 3.
  • two of the substituents on adjacent atoms of the aryl or heteroaryl ring may optionally be replaced with a substituent of the formula -A-(CH 2 ) r —B—, wherein A and B are independently —CRR′—, —O—, —NR—, —S—, —S(O)—, —S(O) 2 —, —S(O) 2 NR′— or a single bond, and r is an integer of from 1 to 4.
  • One of the single bonds of the new ring so formed may optionally be replaced with a double bond.
  • two of the substituents on adjacent atoms of the aryl or heteroaryl ring may optionally be replaced with a substituent of the formula —(CRR′) s —X—(CR′′R′′′) d —, where s and d are independently integers of from 0 to 3, and X is —O—, —NR′—, —S—, —S(O)—, —S(O) 2 —, or —S(O) 2 NR′—.
  • the substituents R, R′, R′′ and R′′′ are preferably independently selected from hydrogen or substituted or unsubstituted (C 1 -C 6 )alkyl.
  • heteroatom refers to include oxygen (O), nitrogen (N), sulfur (S) and silicon (Si).
  • the adduct is a 1:1 combination of the compound of formula (I) with an azole.
  • the adduct is a 1:1 combination of BHT with an azole.
  • R 1 is —H.
  • R 1 is —C(O)R 6 .
  • the azole includes, but is not limited to, ketoconazole, itraconazole, pramiconazole, miconazole, metronidazole, liarozole, rambazole, benzimidazole, benzothiazole, bifonazole, butaconazole nitrate, climbazole, clotrimazole, croconazole, eberconazole, albaconazole, econazole, elubiol, fenticonazole, fluconazole, flutimazole, isoconazole, lanoconazole, neticonazole, omoconazole, oxiconazole nitrate, sertaconazole, sulconazole, tioconazole, thiazole, terconazole, posaconazole, voriconazole, ravuconazole, luliconazole and pharmaceutically acceptable salts thereof
  • the azole is selected from the group consisting of itraconazole, ketoconazole and pramiconazole. While the methods of the invention are intended to include the adduct of BHT with miconazole, this adduct is specifically excluded from the novel compounds of the invention.
  • Suitable pharmaceutical acceptable salts are those of organic or inorganic acids, including, but not limited to, hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid, acetic acid, succinic acid, oxalic acid, malic acid and the like.
  • stereochemically pure isomeric forms may be obtained by the application of known principles.
  • diastereoisomers may be separated by physical separation methods such as fractional crystallization and chromatographic techniques, and enantiomers may be separated from each other by the selective crystallization of the diastereomeric salts with optically active acids or by chiral chromatography.
  • Pure isomers may also be prepared synthetically from appropriate stereochemically pure starting materials, or by using stereospecific reactions.
  • the compounds of formula (I) are intended to include prodrugs that exhibit superior solubility and/or bioavailability properties compared to the parent compounds to which the prodrugs are converted in vivo (i.e., metabolized).
  • both the prodrug and the metabolite exhibit antifungal properties.
  • the metabolite but not the prodrug exhibits antifungal properties.
  • the prodrugs of formula (I) may be prepared by any methods known in the art.
  • the oxygen atom attached to the phenyl ring of compound serves as a means of creating prodrugs.
  • the oxygen atom forms an ester.
  • the oxygen atom forms a carbonate.
  • the oxygen atom forms an ether.
  • the compounds of formula I are prepared by combining a known azole with a phenyl derivative of formula (II) containing a benzylic hydrogen as shown below.
  • a mechanism for this coupling reaction is proposed in Zhang et al., 2004.
  • Typical skin fungal disorders that are treatable by the described adducts of BHT with azole-containing compounds include those, but are not limited to, for example, associated with Candida spp., Pityrosporum spp., Malassezia spp. and Trichophyton spp.
  • Exemplary embodiments of Candida spp. include, but are not limited to, Candida albicans, Candida tropicalis, Candida glabrata, Candida parapsiliosis, Candida guilliermondi, Candida lusitaniae and Candida krusei .
  • Exemplary embodiments of Trichophyton include, but are not limited to, Trichophyton mentagrophytes and Trichophyton rubrum .
  • Exemplary embodiments of Pityrosporum include, but are not limited to, Pityrosporum orbiculare, Pityrosporum ovale, Pityrosporum canis and Pityrosporum pachydermatis .
  • Exemplary embodiments of Malassezia include, but are not limited to, Malassezia sympodialis, Malassezia globosa, Malassezia restricta, Malassezia slooffiae, Malasseziafurfur, Malassezia obtusa and Malassezia pachydermatis.
  • Candidiasis is a common mycotic infection, especially in immunocompromised hosts, that contributes to a variety of diseases, such as, but not limited to, vaginitis, vulvovaginitis, vulvar rash, oral thrush, conjunctivitis, oropharyngeal candidiasis, endophthalmitis, diaper rash, nail infections, infections of skin folds, systemic candidiasis, oral candidiasis, gastrointestinal candidiasis and red macerated intertriginous areas.
  • diseases such as, but not limited to, vaginitis, vulvovaginitis, vulvar rash, oral thrush, conjunctivitis, oropharyngeal candidiasis, endophthalmitis, diaper rash, nail infections, infections of skin folds, systemic candidiasis, oral candidiasis, gastrointestinal candidiasis and red macerated intertriginous areas.
  • Additional diseases caused by fungi other Candida that may be treated by the compounds of the invention include, for example, Aspergillosis, Blastomycosis, Coccidioidomycosis, Cryptococcosis, Histoplasmosis, Paracoccidioidomycosis, Sporotrichosis and Zygomycosis.
  • Infections associated with gram positive bacteria such as, for example, Staphylococci and Streptococci, as well as Propionibacterium acnes are also effectively treated by the compounds of the invention.
  • Formulations for the compounds of formula (I) include, for example, solutions, ointments, salves, creams, gels, lotions, foams, dressings, shampoos, tinctures, pastes, tablets, capsules, intravenous or other parenteral formulations, muco-adhesive patches, powders and the like.
  • Anhydrous formulations may be preferred for some applications.
  • Application of the compositions of the invention may also be by aerosol, e.g., with a propellant such as nitrogen, carbon dioxide, a freon, or without a propellant such as a pump spray, drops, lotions, or a semisolid such as a thickened composition which can be applied by a swab.
  • the compounds of the invention may be applied as a transdermal patch.
  • Other suitable routes of administration include intravenous and oral applications, in, for example, solution form, of the compounds.
  • compositions of the invention include toilet waters, packs, skin milks or milky lotions.
  • Such formulations often include therapeutically inactive components such as those known in the art, such as, for example, oils, fats, waxes, surfactants, humectants, thickening agents, antioxidants, viscosity stabilizers, chelating agents, buffers, preservatives, perfumes, dyestuffs and the like.
  • additional ingredients may be incorporated in the compositions of the invention such as antiinflamatory agents, antibacterials, antifungals, disinfectants, vitamins, sunscreens, antibiotics or anti-acne agents.
  • Solid carriers include starch, lactose, dicalcium phosphate, microcrystalline cellulose, sucrose, kaolin.
  • Liquid carriers include sterile water, propylene glycol, glycerin, ethylene glycol, polyethylene glycols, lower alcohols (e.g., ethanol, propanol, isopropanol and butanol) and edible oils such as corn, peanut and sesame oils.
  • the carriers may be present in an amount of from about 5 to about 80 weight percent, such as, for example, about 10 to about 70 weight percent, such as, for example, about 15 to about 60 weight percent, such as about 15 to about 45 weight percent, such as about 15 to about 30 weight percent, such as about 15 to about 20 percent, such as about 20 to about 55 weight percent; such as about 25 to about 45 weight percent, such as, for example, about 30 to about 40 weight percent.
  • the compounds of formula (I) are present in an ointment formulation that also includes zinc oxide and a petrolatum.
  • an adduct of BHT with an azole is formulated as an ointment containing zinc oxide, white petrolatum, trihydroxystearin and optionally a fragrance.
  • compositions of the invention may also optionally include other carriers, stabilizers, preservatives or adjuvants.
  • other carriers stabilizers, preservatives or adjuvants.
  • an effective amount of the compounds of formula (I) may vary depending on the particular compound used; the mode of administration; the identity and severity of the disease state; the age, sex, weight and general physical condition of the particular recipient; and other medications that the recipient may be concurrently taking. Furthermore, it is evident that the effective frequency of administration of the combination therapy may be lowered or increased depending on the response of the treated patient and/or depending on the evaluation of the physician prescribing the therapeutic agent being used. In general, satisfactory results are obtained when the amount of the active compound used ranges from about 0.01 weight percent to about 10 weight percent, such as from about 0.01 to about 5 weight percent, and such as from about 0.05 to about 3 weight percent or from about 0.1 to about 3 weight percent.
  • Sub-doses may be formulated as unit dosage forms, for example, containing 0.001 mg to 500 mg of active ingredient per unit dosage form.
  • the effective relative amount (w/w) of BHT to the azole (with which the BHT forms an adduct) necessary for treating a fungal disease state is about 0.1% or about 0.5% or about 1% or about 5% or about 10% or about 15% or about 20% or about 25% or about 30% or about 35% or about 40% or about 45% or about 50% or about 55% or about 60% or about 65% or about 70% or about 75% or about 80% or about 85% or about 90% or about 95% or about 100%.
  • the azole is miconazole, ketoconazole, rambazole, itraconazole or pramiconazole.
  • Additional therapeutic agents that may be used in combination with the compounds of formula (I) include, but are not limited to, antimicrobial agents (e.g, amphotericin B, flucytosine, haloprogin and nystatin), anti-allergic agents (e.g., astemizole, betamethasone, carbinoxamine maleate, chlorpheniramine maleate, clemastine fumarate, dexbrompheniramine maleate, dexchlorpheniramine maleate, diphenhydramine hydrochloride, diphenylpyraline hydrochloride and trimeprazine tartrate), anti-inflammatory agents (e.g., ibuprofen, fenoprofen, ketoprofen, naproxen, diclofenac, etodolac, meclofenamate sodium phenylbutazone, indomethacin, piroxicam, sulindac and tolmetin), anti-proliferating agents (e.g., mycophenolate mo
  • sample A an ointment formulation containing miconazole nitrate, white petrolatum and zinc oxide, but no BHT
  • sample B an ointment formulation containing miconazole nitrate, white petrolatum, zinc oxide and BHT
  • the tested concentrations of Sample A and Sample B were 100%, 50%, 25%, 12.5% and 6.25%.
  • a clinical isolate of Candida albicans was subcultured and incubated at 30° C. for 24 hours.
  • An inoculum of 1 ⁇ 10 5 mL was prepared spectrophotometrically by adding the yeast to water and adjusting to 85% T on the spectrophotometer. This inoculum was diluted 1:100 in sterile distilled water for a working concentration of 1 ⁇ 10 3 CFU/mL.
  • Assessment of antifungal activity took place by two different methods. The first method involved weighing 10 mg of the Sample A and Sample B ointments, suspending them separately in 1 mL of PEG 400, and evenly spreading the resulting ointment solutions separately across the surface of a Sabouraud Dextrose Agar plate.
  • a 10 ⁇ L volume of the yeast suspension was spread across the surface of the agar to achieve confluent yeast growth.
  • the tested concentrations of Sample A and Sample B were 100%, 50%, 25%, 12.5% and 6.25%.
  • approximately 10 mg of the respective ointment solutions were added to PEG-400 volumes of 2 mL, 4 mL, 8 mL, and 16 mL respectively. Plates were incubated at 30° C. and CFU counts were performed at 48 hours post inoculation.

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US12/019,942 US20080182885A1 (en) 2006-08-03 2008-01-25 Modified Azole Compounds As Antifungal and Antibacterial Agents
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WO2012177986A2 (fr) 2011-06-22 2012-12-27 Vyome Biosciences Promédicaments antifongiques et antibactériens à base d'un conjugué
US20130231379A1 (en) * 2007-08-27 2013-09-05 Nihon Nohyaku Co., Ltd. Agent for fungal dermatitis
WO2014195872A1 (fr) 2013-06-04 2014-12-11 Vyome Biosciences Pvt. Ltd. Particules enrobées et compositions les comprenant
JP2016508492A (ja) * 2013-02-04 2016-03-22 シンジェンタ パーティシペーションズ アクチェンゲゼルシャフト 新規な殺微生物剤
EP3698793A1 (fr) 2014-01-29 2020-08-26 Vyome Therapeutics Limited Bésifloxacine pour traiter l'acné résistante

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US8883747B1 (en) 2013-10-09 2014-11-11 Craig W. Carver Topical antifungal compositions and methods of use thereof

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US20130231379A1 (en) * 2007-08-27 2013-09-05 Nihon Nohyaku Co., Ltd. Agent for fungal dermatitis
US8835479B2 (en) * 2007-08-27 2014-09-16 Nihon Nohyaku Co., Ltd. Agent for fungal dermatitis
WO2012177986A2 (fr) 2011-06-22 2012-12-27 Vyome Biosciences Promédicaments antifongiques et antibactériens à base d'un conjugué
JP2016508492A (ja) * 2013-02-04 2016-03-22 シンジェンタ パーティシペーションズ アクチェンゲゼルシャフト 新規な殺微生物剤
WO2014195872A1 (fr) 2013-06-04 2014-12-11 Vyome Biosciences Pvt. Ltd. Particules enrobées et compositions les comprenant
EP3698793A1 (fr) 2014-01-29 2020-08-26 Vyome Therapeutics Limited Bésifloxacine pour traiter l'acné résistante

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