Triazole antifungal composition

Abstract

The present invention relates to a liquid composition comprising an azole antifungal agent and a vehicle containing a hemifluoride alkane.

Description

[Technical Field]

[0001] This invention belongs to the field of pharmacotherapy. More specifically, this invention relates to the treatment of diseases and conditions affecting the nails of humans and other mammals. [Background technology]

[0002] While many skin disorders affect the skin itself, there are also diseases and conditions related to skin appendages, particularly the nails. These are often difficult to treat due to the thick, dense nail plate, which is mainly composed of keratin, and poor absorption of therapeutic agents.

[0003] Nails are hardened structures of the keratinous region of the epidermis. They appear as sheet-like appendages covering the skin on the dorsal side of the terminal phalanges of the fingers and toes. The keratinous region of the nail is composed of hard alpha-keratin and has a distal exposed portion or nail body and a proximal hidden portion or nail root. The nail root is covered by the distal extension of the keratinous layer of the skin. This narrow nail fold is composed of soft keratin and is called the nail epithelium. Distal to the nail epithelium is the "luna" or lunula, which is a part of the keratinous region that is opaque to the underlying capillaries.

[0004] At the distal end of the nail or deep within the free edge, the keratinous region of the fingertip thickens and is often called the subungual layer. The keratinous region of the nail is attached to the underlying nail bed. The proximal portion of the nail matrix or nail bed produces hard keratin. However, further distal, the nail bed can also produce nail material. Furthermore, the outermost layer of the nail can be produced by the epithelium proximal to the nail epithelium just dorsal to the nail root. Nail growth is influenced by nutrition, hormones, and disease. Nail growth involves considerable protein synthesis, resulting in nonspecific changes in the nail in response to various local and systemic disorders.

[0005] Nails develop in the fetus as epidermal thickenings that form the nail fold, where the keratinized material of the nail grows distally undercutting the skin. In adults, it takes about six months for fingernails to form, which corresponds to a growth rate of about 2-3 mm per month. Toenails tend to grow more slowly than fingernails.

[0006] Nails are about two orders of magnitude thicker than the stratum corneum of the skin. Hard α-keratin, the main component of the stratum corneum, is a fibrous structural protein characterized by a high cysteine ​​content that readily forms thermally stable crosslinks via sulfide crosslinks. Nails have a fairly low water content, typically ranging from about 10% to 30%. Generally speaking, nails are highly resistant to the permeation of molecules such as drugs.

[0007] The primary function of nails is to protect the sensitive extremities of the fingers and toes. Fingernails also serve a scratching function. Toenails are also important for balance.

[0008] One of the most common diseases affecting the nail organs is fungal infection, also known as onychomycosis, a condition affecting approximately 20% of the adult population in the United States. Incidence is increasing worldwide. In fact, about 30% of all superficial fungal infections affect the nails. Infections can be caused by dermatophytes (tinea, onychomycosis), yeast, or other non-dermatophyte (mold) species. In paronychia, a chronic infection of the nail fold is most often caused by Candida species, but bacterial infections by Gram-negative species such as Pseudomonas can coexist. Acute paronychia (wine) caused by staphylococcal infection can also occur, and the presence of these bacterial infections affects management. Candida infiltration into the nail plate can occur in the presence of paronychia, immunocompromised states (including chronic mucocutaneous candidiasis), Raynaud's disease, or endocrine disorders.

[0009] Interestingly, nail conditions are often treated systemically rather than topically, which itself demonstrates how difficult it is to achieve therapeutic concentrations in the nails through topical administration alone. For example, onychomycosis is treated with 250 mg of oral terbinafine daily for 3–6 months, or 200 mg of itraconazole daily for 3–6 months. Even existing therapies using oral griseofulvin 10 mg / kg / day (500 mg twice daily) for 6–18 months are still recommended today. In particular, proximal nail disease or severe nail bed lesions are considered indications for systemic treatment rather than topical treatment.

[0010] There are several topical formulations of known antifungal agents for treating onychomycosis, such as nail lacquers containing cyclopirox, amorolfine, or butenafine. While there is some evidence of effectiveness, it is believed that successful topical antifungal therapy requires very long-term treatment, for example, more than a year. Some experts recommend a combination of topical and systemic treatment for better efficacy. Without appropriate treatment and patient compliance, the infection will not disappear.

[0011] There is a clear need for pharmaceutical formulations and vehicles that enable the effective treatment of fungal infections of the nails by topical administration. Therefore, an object of the present invention is to provide such improved compositions that overcome one or more drawbacks of known compositions. [Overview of the project]

[0012] The present invention relates to a novel antifungal composition for use in the treatment of fungal skin infections (mycoses), particularly fungal infections of the nails, such as the fingernails and toenails, of humans and other mammals (onychomycoses).

[0013] In a first aspect, the present invention relates to a liquid composition comprising an azole antifungal agent and a vehicle containing a hemifluoride alkane.

[0014] In a further aspect, the present invention relates to a liquid composition for use as a pharmaceutical, particularly for the treatment of fungal skin infections (mycoses) or nail fungal infections (onychomycosis), comprising an azole antifungal agent and a vehicle comprising a hydrofluoroalkane.

[0015] In yet a further aspect, the present invention relates to a liquid composition comprising an azole antifungal agent and a vehicle comprising a hydrofluoroalkane, and a kit comprising a container for holding the composition, the composition being adapted for topical administration to the skin, particularly to the nails, nail folds, nail beds, subungual skin and / or the undersurface of the nail plate of the toes and / or fingers of a subject.

BRIEF DESCRIPTION OF THE INVENTION

[0016] The present invention relates to a novel pharmaceutical composition for use as a topical formulation for administration to the skin, particularly the nails, preferably the fingernails and / or toenails of humans and other mammals. The composition comprises an effective amount of an azole antifungal agent and a liquid vehicle comprising a hydrofluoroalkane.

[0017] Thus, in a first aspect, the present invention relates to a liquid composition comprising an azole antifungal agent and a vehicle comprising a hydrofluoroalkane. In certain embodiments of the present invention, the liquid composition is a composition comprising an azole antifungal agent and a hydrofluoroalkane. Preferably, the liquid composition is a liquid pharmaceutical composition.

[0018] As used herein, a pharmaceutical composition is any composition comprising an active ingredient useful in the diagnosis, prevention, management or therapy of a disease, condition or health state, and at least one carrier or excipient. A topical formulation is a composition in a form suitable for topical administration. In the present invention, the composition is suitable for administration to the skin or nails of a subject, which subject can be human or animal. The nails of the subject, such as fingernails or toenails, may be intact, damaged, bruised, injured or otherwise affected.

[0019] In a preferred embodiment, the composition contains a triazole antifungal agent. Suitable triazole antifungal agents include the following: Efinaconazole:

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[0020]

[0020] Therefore, in a preferred embodiment, the azole antifungal agent is a triazole antifungal agent selected from albaconazole, efinaconazole, epoxyconazole, fluconazole, isabconazole, itraconazole, posaconazole, propiconazole, ravconazole, terconazole, and voriconazole. In a preferred embodiment, the triazole antifungal agent is efinaconazole.

[0021] Efinaconazole compositions are known to those skilled in the art. In the prior art compositions, efinaconazole is formulated as an aqueous solution containing 10% w / v efinaconazole. A drawback of the prior art compositions is that efinaconazole is susceptible to oxidation, particularly N-oxidation, and therefore the prior art compositions require antioxidants such as BHT.

[0022] The inventors have surprisingly found that a composition containing efinaconazole dissolved in a hemifluoride alkane exhibits improved stability against N-oxidation compared to an aqueous solution. Aliphatic double bonds are readily oxidized, and it is known that hemifluoride alkanes improve the stability of compounds having two or more aliphatic double bonds. See International Publication No. 2014 / 041071. However, the stabilization of compounds prone to N-oxidation was unexpected.

[0023] Even more surprisingly, compositions containing efinaconazole dissolved in a hemifluoride alkane were found to exhibit effective penetration into nail material and rapid action, namely rapid inhibition of the growth of representative dermatophytes.

[0024] Alkanes with hemifluoride are linear or branched alkanes in which some of their hydrogen atoms are replaced by fluorine. In preferred embodiments, the alkanes with hemifluoride (SFA) used in the present invention consist of at least one non-fluorinated hydrocarbon segment and at least one perfluorinated hydrocarbon segment. General formula F(CF2) n (CH2) mHaving one non-fluorinated hydrocarbon segment bonded to one perfluorinated hydrocarbon segment by H, or the general formula F(CF2) n (CH2) m (CF2) o SFAs having two perfluorinated hydrocarbon segments separated by one non-fluorinated hydrocarbon segment by F are particularly useful.

[0025] Another nomenclature used herein refers to the above-mentioned SFAs having two or three segments as RFRH and RFRHRF, respectively, where R F represents a perfluorinated hydrocarbon segment and R H represents a non-fluorinated segment. Alternatively, the compounds may be referred to as F n H m and F n H m F o respectively, where F means a perfluorinated hydrocarbon segment, H means a non-fluorinated segment, and n, m and o are the number of carbon atoms in each segment. For perfluoropropylpropane, for example, F3H3 is used. Further, this kind of nomenclature is usually used for compounds having linear segments. Thus, unless otherwise indicated, F3H3 should be presumed to mean 1-perfluoropropylpropane rather than 2-perfluoropropylpropane, 1-perfluoroisopropylpropane or 2-perfluoroisopropylpropane.

[0026] Preferably, the general formula F(CF2) n (CH2) m H and F(CF2) n (CH2) m (CF2) oAlkanes with fluorine have a segment size in the range of n=2 to 20 carbon atoms, i.e., n, m, and o are independently selected in the range of 2 to 20. SFAs useful in the context of the present invention are also described in European Patent Publication No. 965334, European Patent Publication No. 965329, and European Patent Publication No. 2110126, the disclosures of which are incorporated herein by reference.

[0027] Accordingly, in one embodiment, the present invention relates to the composition defined above, in which a triazole antifungal agent is dissolved in a vehicle containing a hemifluoride alkane. In some embodiments, the liquid vehicle consists of a hemifluoride alkane. In certain embodiments, the composition comprises a triazole antifungal agent dissolved in a hemifluoride alkane.

[0028] Any semi-fluorinated liquid is suitable for use in the liquid vehicle of the present invention. Preferred liquid semi-fluorinated alkanes are those of formula F(CF2) n (CH2) m H is a compound in the formula where n = 4 to 8 and m = 4 to 10. Therefore, in some embodiments of the present invention, the hemifluoride alkane is given by formula F(CF2) n (CH2) m H is a compound in the formula where n = 4 to 8 and m = 4 to 10. In a preferred embodiment, the hemifluoride alkane is selected from F4H5, F4H6, F4H8, F4H10, F6H6, F6H8, and F6H10, preferably selected from F4H8 and F6H8, and more preferably F6H8.

[0029] Liquid SFA is chemically and physiologically inert, colorless, and stable. Its typical density is 1.1–1.7 g / cm³. 3 The range is such that their surface tension can be as low as 19 mN / m. RFRH-type SFA is insoluble in water but is also somewhat amphiphilic, and the increase in lipophilicity correlates with an increase in the size of the non-fluorinated segments. Here again, in order to carry out the present invention, at least 1.2 g / cm³ 3 An SFA with a density of [value] should be selected.

[0030] The composition may comprise, or may consist solely of, a triazole antifungal agent and a liquid vehicle. The liquid vehicle may consist of a hemifluoride alkane and additional components. In some embodiments, the liquid vehicle comprises two or more hemifluoride alkanes.

[0031] Alkanes hemifluoride may be present in the composition at the following concentrations: i. Up to 70, 75, 80, 85, 90, 91, 92, 93, 94, 95, or up to 97% by volume ii. Between 60-90% by volume, 70-90% by volume, 80-90% by volume, 85-90% by volume, 65-95% by volume, 70-95% by volume, 80-95% by volume, or between 85-95% by volume iii. Approximately 65, 70, 75, 80, 85, 87, 89, 90, 91, 92, 93 or approximately 95% by volume iv. At least 60, 70, 75, 80, 85, 87, 89, 90, 92, or at least 95% by volume

[0032] In this invention, "volume %" or "%(v / v)" refers to the volume of the compound compared to the total volume of the composition. Therefore, 97 volume % of hemifluoride alkanes refers to 97 ml of hemifluoride alkanes per 100 ml of the composition.

[0033] In some embodiments, the composition comprises further hemifluoride alkanes. When the composition comprises two or more hemifluoride alkanes, it is preferable that one of the hemifluoride alkanes is a linear hemifluoride alkane and one of the hemifluoride alkanes is a branched hemifluoride alkane.

[0034] In some embodiments, the composition further comprises 2-perfluorobutylpentane or 2-perfluorohexyloctane. In some embodiments of the present invention, the composition defined above comprises 2-perfluorohexyloctane. In certain embodiments, the present invention relates to the composition defined above, preferably comprising 2-perfluorohexyloctane at concentrations below the specified amount. i. Maximum 0.25, 0.5, 0.75, 1.0, 1.5, 2.0 or 3% by volume ii. Maximum 5, 4, 3, 2, 1 or 0.5 volume% iii. Between 0.25-5 volume%, 0.25-3 volume%, 0.25-2 volume%, 0.25-1.5 volume%, or between 0.25-1.0 volume%

[0035] The composition may contain additional compounds. Preferably, the liquid vehicle contains additional compounds. In some embodiments, the composition does not contain additional pharmaceutically active compounds, and in particularly preferred embodiments, the composition does not contain additional antifungal agents, preferably the composition does not contain boron-containing antifungal agents, and more preferably the composition does not contain tababolol. In some embodiments, the composition contains additional pharmaceutically active compounds.

[0036] If the composition contains additional compounds, it is preferable that the composition further contains pharmaceutically acceptable excipients such as cosolvents, oily materials, and similar agents. In preferred embodiments of the present invention, the liquid vehicle contains a cosolvent and / or an oily material.

[0037] The co-solvent should, of course, be selected in a type, quality, and quantity that maintains the physiological tolerability of the formulation. Potentially suitable co-solvents include ethanol, acetone, ethyl acetate, isopropyl alcohol, DMF (N,N-dimethylformamide), DMSO (dimethyl sulfoxide), DMAC (N,N-dimethylacetamide), 1-methyl-2-pyrrolidone (NMP), glycerol, propylene glycol, pentylene glycol, polyethylene glycol, liquid paraffin, triglyceride oils, silicone oils (i.e., linear and cyclic silicone oils), hydrofluorocarbons, such as HFA134a and / or HFA227, as well as liquid monoglycerides or diglycerides. Among these, ethanol, isopropyl alcohol, ethyl acetate, DMF, DMAC, DMSO, and NMP are particularly preferred solvents.

[0038] In preferred embodiments, the pharmaceutical composition includes a cosolvent. In some embodiments, the cosolvent is selected from ethanol, 2-propanol, DMF (N,N-dimethylformamide), DMSO (dimethyl sulfoxide), DMAC (N,N-dimethylacetamide), and ethyl acetate, preferably the cosolvent is selected from 2-propanol, DMF, DMSO, DMAC, NMP, and mixtures thereof, and most preferably the cosolvent is 2-propanol.

[0039] Therefore, in some embodiments, the present invention relates to the above-defined composition comprising a liquid vehicle containing up to 25% by volume of a cosolvent selected from 2-propanol, DMF, DMSO, DMAC, NMP, and mixtures thereof.

[0040] In some embodiments, the composition includes an oily material. In some embodiments of the present invention, the oily material is selected from squalane, MCT, and silicone oils (i.e., linear and cyclic silicone oils).

[0041] The advantage of the presence of a co-solvent or oily material is that it increases the possibility of adjusting the solubility of the triazole antifungal agent, or the viscosity or other properties of the composition.

[0042] In preferred embodiments, the composition does not contain further components, such as stabilizers, preservatives, surfactants, co-surfactants, colorants, thickeners (viscosity improvers such as bentonite), fragrances, or substances that may be irritating to the skin.

[0043] In a more preferred embodiment, the composition does not contain one or more components selected from ethanol, 2-propanol, propylene glycol, ethyl acetate, amyl acetate, and DMSO, and more preferably, the composition does not contain one or more components selected from propylene glycol, ethyl acetate, and amyl acetate.

[0044] In a preferred embodiment, the composition does not contain water.

[0045] A further advantage of the present invention is that, as described above, the compositions defined above are suitable for stabilizing triazole antifungal agents without the need for antioxidants.

[0046] Therefore, in some embodiments, the present invention relates to compositions defined above that do not contain antioxidants, and preferably do not contain BHT, BHA, or tocopherol.

[0047] The composition is more preferably ethanol-free. In such a case, the composition should be flammable.

[0048] The compositions according to the present invention can be simpler than prior art compositions, and the number of components can be reduced. A reduction in the number of components reduces the risk of adverse effects such as skin irritation and potential allergic reactions.

[0049] The compositions according to the present invention require fewer compounds to achieve the effect compared to prior art compositions. Therefore, in some preferred embodiments, the present invention relates to compositions that do not contain one or more further components selected from the following. i. Alcohol (preferably ethanol) ii. Penetration enhancer (preferably Transktol, isopropyl myristate) iii. Chelating agent (preferably EDTA, DTPA) iv. Wetting agent or surface tension reducing agent (preferably cyclomethicone) v. pH adjuster (preferably citric acid) vi. Moisturizing agent (preferably C12-15 alkyl lactate) vii. Emulsifier (preferably diisopropyl adipate) viii.Water ix. Preservatives x. Surfactants xi. Ethanol, 2-propanol, propylene glycol, ethyl acetate, amyl acetate, and DMSO, preferably propylene glycol, ethyl acetate, amyl acetate, and DMSO (more preferably propylene glycol, ethyl acetate, and amyl acetate)

[0050] The compositions of the present invention are particularly suitable for efinaconazole due to the fact that the compositions are remarkably suitable for stabilizing efinaconazole. In preferred embodiments, the antifungal agent is efinaconazole, and the composition comprises about 2, 1, 0.5, 0.4, 0.2, 0.1, less than 0.05 or less (w / v) of efinaconazole-N-oxide.

[0051] In certain preferred embodiments, the present invention relates to a composition comprising or consisting of efinaconazole dissolved in a liquid vehicle comprising or consisting of 1-perfluorohexyloctane and a cosolvent optionally selected from 2-propanol, DMF, DMSO, DMAC, and / or NMP.

[0052] In certain preferred embodiments, the present invention relates to a composition comprising or consisting of efinaconazole dissolved in a liquid vehicle comprising or consisting of 1-perfluorohexyloctane and optionally 2-propanol.

[0053] In further embodiments, the present invention relates to a composition comprising 1-perfluorohexyloctane and fluconazole dissolved in a cosolvent optionally selected from 2-propanol, DMF, DMSO, DMAC, and / or NMP.

[0054] In certain preferred embodiments, the present invention relates to a composition comprising or comprising fluconazole dissolved in a liquid vehicle comprising or comprising 1-perfluorohexyloctane and optionally 2-propanol.

[0055] The inventors have also found that the triazole antifungal agents provided in the compositions according to the present invention can be used at substantially lower concentrations compared to the aqueous compositions of the prior art to achieve an equivalent or greater reduction or elimination of fungal symptoms.

[0056] Therefore, in some embodiments, the present invention relates to the above-defined compositions in which the antifungal agent is present at the following concentrations. i. Maximum 20, 10, 5, 2, 1.5, 1, 0.7, 0.6, 0.5, 0.4 or 0.3% (w / v) ii.0.2~10%(w / v), 0.2~5%(w / v), 0.2~3%(w / v), 0.3~1.5%(w / v), 0.3~1%(w / v), 0.4~1.5%(w / v), 0.4~1%(w / v), 0.5~1.5%(w / v), 0.5~1.0%(w / v), 0.7~1.5%(w / v), 0.7~1.0%(w / v), or 0.1~2%(w / v), or 0.1~1%(w / v) iii. Approximately 10, 5, 3, 1.5, 1, 0.9, 0.8, 0.7, 0.6, 0.5, 0.4, 0.3 or approximately 0.2% (w / v) iv. At least 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, or at least 1.5% (w / v) v. Between 0.5-2.5% (w / v), 0.75-2.25% (w / v), 1.0-2% (w / v), 1.2-1.8% (w / v), or 1.4-1.6% (w / v)

[0057] In certain embodiments, the present invention relates to a composition as defined above, comprising or consisting of about 0.5 to 2.5% (w / v) (or 0.5 to 1.0% (w / v), or 0.1 to 2% (w / v), or 0.1 to 1% (w / v), or 0.5 to 2.5% (w / v), or 0.75 to 2.25% (w / v), or 1.0 to 2% (w / v), or 1.2 to 1.8% (w / v), or 1.4 to 1.6% (w / v)) of efinaconazole dissolved in a vehicle comprising or consisting of 1-perfluorohexyloctane and 2-propanol. In further embodiments, the present invention relates to the above-defined composition comprising or consisting of efinaconazole in a maximum of about 0.5–2.5% (w / v) (or 0.5–1.0% (w / v), or 0.1–2% (w / v), or 0.1–1% (w / v), or 0.5–2.5% (w / v), or 0.75–2.25% (w / v), or 1.0–2% (w / v), or 1.2–1.8% (w / v), or 1.4–1.6% (w / v)) dissolved in a vehicle comprising or consisting of 1-perfluorohexyloctane and a cosolvent selected from 2-propanol, DMF, DMSO, DMAC, and / or NMP.

[0058] In certain embodiments, the present invention relates to the above-defined composition comprising or consisting of about 0.5 to 2.5% (w / v) (or 0.5 to 1.0% (w / v), or 0.1 to 2% (w / v), or 0.1 to 1% (w / v), or 0.5 to 2.5% (w / v), or 0.75 to 2.25% (w / v), or 1.0 to 2% (w / v), or 1.2 to 1.8% (w / v), or 1.4 to 1.6% (w / v)) of efinaconazole dissolved in a vehicle comprising or consisting of 1-perfluorohexyloctane and 2-propanol. In further embodiments, the present invention relates to the above-defined composition comprising or consisting of efinaconazole at a maximum of about 0.5–2.5% (w / v) (or 0.5–1.0% (w / v), or 0.1–2% (w / v), or 0.1–1% (w / v), or 0.5–2.5% (w / v), or 0.75–2.25% (w / v), or 1.0–2% (w / v), or 1.2–1.8% (w / v), or 1.4–1.6% (w / v)) dissolved in a vehicle comprising or consisting of 1-perfluorohexyloctane and a cosolvent selected from 2-propanol, DMF, DMSO, DMAC, and / or NMP.

[0059] In further embodiments, the composition comprises 0.1% (w / v) efinaconazole (or 0.2% (w / v), or 0.5% (w / v), or 1.0% (w / v), or 1.25% (w / v), or 1.5% (w / v), or 1.75% (w / v), or 2% (w / v), or 2.25% (w / v), or 2.5% (w / v) efinaconazole), about 90% (v / v) F6H8, and 10% (v / v) or less 2-propanol. In particular embodiments, the present invention relates to a composition comprising up to 0.7% (w / v) efinaconazole and 1-perfluorohexyloctane, or a composition comprising 0.7% (w / v) efinaconazole and 1-perfluorohexyloctane.

[0060] In one embodiment, the composition contains or comprises 1-2% (w / v) efinaconazole dissolved in a vehicle containing or comprising 1-perfluorohexyloctane and 2-propanol, and preferably the composition contains or comprises 1-2% (w / v) efinaconazole dissolved in a vehicle containing or comprising 90% (v / v) 1-perfluorohexyloctane and 10% (v / v) 2-propanol.

[0061] In certain embodiments, the composition comprises or consists of 1% (w / v) efinaconazole dissolved in a vehicle comprising or consisting of 1-perfluorohexyloctane and 2-propanol, and preferably the composition comprises or consists of 1% (w / v) efinaconazole dissolved in a vehicle comprising or consisting of 90% (v / v) 1-perfluorohexyloctane and 10% (v / v) 2-propanol.

[0062] In further embodiments, the composition comprises or consists of 2% (w / v) efinaconazole dissolved in a vehicle comprising or consisting of 1-perfluorohexyloctane and 2-propanol, preferably the composition comprises or consists of 2% (w / v) efinaconazole dissolved in a vehicle comprising or consisting of 90% (v / v) 1-perfluorohexyloctane and 10% (v / v) 2-propanol.

[0063] In further embodiments, the present invention relates to the use of the compositions, in particular to the pharmaceutically active use and applications of the compositions defined above. The compositions are particularly useful in the treatment of fungal infections of the skin (mycoses) and fungal infections of the nails (onychomycoses), and in particular the compositions of the present invention are effective in the treatment of onychomycoses of the nails, especially fingernails and / or toenails. Furthermore, the compositions are useful in the treatment of fungal infections of the eyes, and in particular the compositions of the present invention are effective in the treatment of fungal infections of the cornea (keratitis), or any other fungal infections of the eye caused by Fusarium and Aspergillus species.

[0064] In a further embodiment, the compositions of the present invention are effective in treating vaginal fungal infections, and in particular, compositions of the present invention comprising fluconazole are effective in treating candidal vulvovaginitis and vaginal yeast infections also known as vaginal candidiasis (vaginal thrush).

[0065] Accordingly, in one embodiment, the present invention relates to a composition defined above for use as a pharmaceutical. In a particular embodiment, the present invention relates to the use of a composition defined above in the manufacture of a pharmaceutical.

[0066] The pharmaceutical product is preferably a pharmaceutical product for treating fungal infections of the skin, particularly fungal infections of the fingernails or toenails. Preferably, the pharmaceutical product is a pharmaceutical product for treating onychomycosis of the fingernails or toenails.

[0067] The pharmaceutical product is preferably a pharmaceutical product for treating fungal infections of the eye, particularly fungal infections of the cornea. Preferably, the pharmaceutical product is a pharmaceutical product for treating fungal infections of the eye caused by Fusarium and Aspergillus species.

[0068] Therefore, in one embodiment, the pharmaceutical is a pharmaceutical that treats, prevents or reduces the growth of fungi that affect the skin or eyes, preferably fungi that affect the nails, such as the fingernails and / or toenails of the subject, or fungi that affect the cornea.

[0069] The main advantage of the composition according to the present invention is that, when applied to an affected nail, the composition dries in a significantly shorter time than other compositions, and therefore improves patient compliance.

[0070] Furthermore, while the efinaconazole-containing composition according to the present invention exists as an odorless liquid, commercially available efinaconazole formulations exhibit a very unpleasant, pungent odor, which also limits patient compliance.

[0071] In another embodiment, the present invention relates to compositions defined above for use in treating, preventing or reducing the growth of fungi selected from yeast (i.e., Candida albicans) or molds. Accordingly, in some embodiments, the present invention relates to compositions defined above for use in treating fungal infections of the skin, preferably for use in treating fungal infections of the nails (onychomycosis), preferably for use in treating onychomycosis of the fingernails and / or toenails.

[0072] In another embodiment, the present invention relates to compositions defined above for use in treating, preventing or reducing the growth of fungi selected from the genera Fusarium and Aspergillus. Accordingly, in some embodiments, the present invention relates to compositions defined above for use in treating fungal infections of the eye, preferably for use in treating fungal infections of the cornea (keratitis), and more preferably for use in treating fungal infections of the eye caused by the genera Fusarium and Aspergillus.

[0073] In a further embodiment, the present invention relates to a method for treating a fungal infection of the skin, preferably a method for treating nails, more preferably a method for treating onychomycosis, particularly onychomycosis of fingernails and / or toenails, comprising administering the above-defined composition to the nails.

[0074] The composition is preferably administered directly to the affected nail. The composition can be applied by any suitable method. Thus, in one embodiment, the present invention relates to the above-defined composition, which is administered topically to the nail of interest (fingernail or toenail).

[0075] In preferred embodiments, the composition is administered to the fingernails and / or toenails using a sponge applicator, dropper, brush applicator, pen, or pipette.

[0076] However, in one embodiment, the composition is not applied with a brush or brush applicator.

[0077] The composition is preferably administered topically to cover the nail, nail fold, nail bed, subungual layer and / or underside of the nail plate of the toenails and / or fingernails.

[0078] In some embodiments of the present invention, the composition is administered topically by non-contact application (without touching) to the target nail (fingernail or toenail), preferably by dropping one or more single drops of the liquid composition onto the surface of the target nail (fingernail or toenail). In certain embodiments, the composition is administered topically by dropping one or more single drops of the liquid composition onto the (central) surface of the nail, so as to cover the nail, nail fold, nail bed, subungual layer and / or underside of the nail plate of the toenail and / or fingernail. Surprisingly, the above compositions are characterized by excellent diffusion behavior, which has been found to result in easy spreading without mechanical distribution of a single drop of the composition when administered topically to the surface of the nail, e.g., fingernail or toenail, to distant areas of the nail, e.g., nail fold, nail bed, subungual layer and / or underside of the nail plate of the toenail and / or fingernail.

[0079] In some embodiments, the composition is administered topically by dropping a single drop onto the surface of the target nail (fingernail or toenail), as follows: i. Not to touch (or touch) the nail, nail fold, nail bed, subungual layer and / or underside of the nail plate of the toenails and / or fingernails, and / or ii. Do not manually distribute the composition to one or more remote areas of the toenail and / or fingernail selected from the nail fold, nail bed, subungual layer and / or the underside of the nail plate.

[0080] In a further embodiment, the present invention relates to a method for treating a fungal infection of the eye, preferably a method for treating the eye, more preferably a method for treating a fungal infection of the cornea, and in particular a method for treating keratitis caused by a fungal infection, particularly caused by Fusarium or Aspergillus species, comprising administering the above-defined composition to the eye.

[0081] The composition is preferably administered directly to the affected eye tissue, preferably to the affected cornea. The composition can also be applied topically to the affected eye tissue, such as the cornea, preferably by the use of eye drops. In one embodiment, the present invention relates to the above-defined composition, which is preferably administered topically to the eye in question (i.e., the eye surface such as the cornea and / or conjunctiva) by dropping one or more drops of the liquid composition onto the (central) surface of the affected eye, i.e., by dropping one or more drops of the liquid composition onto the surface of the cornea and / or conjunctiva.

[0082] In preferred embodiments, the composition is administered to the eye or ocular surface by the use of an eyedropper, and in particular, the composition is administered to the cornea and / or conjunctiva by one or more single drops of the liquid composition.

[0083] In further embodiments, the present invention relates to a kit comprising the composition defined above and a container for holding the composition, which is adapted for topical administration of the composition to the skin, preferably to the nail, nail fold, nail bed, subungual skin and / or underside of the nail of a target toe and / or fingernail.

[0084] In some embodiments, the present invention relates to a kit comprising the compositions defined above and instructions for use in treating fungal infections of the skin and / or nails.

[0085] In further embodiments, the present invention relates to a kit comprising the composition defined above and a container for holding the composition, which is adapted for topical administration of the composition to the eye, preferably for topical administration of the composition to the eye (or the ocular surface such as the cornea and / or conjunctiva) by one or more single drops of the liquid composition. Preferably, the container is an eyedropper adapted for dispensing a single drop of the liquid composition into the eye, preferably an eyedropper adapted for dispensing a single drop of 9-13 μl, 10-12 μl, or 11 μl of the liquid composition into the eye.

[0086] In some embodiments, the present invention relates to a kit comprising the compositions defined above and instructions for use in treating fungal infections of the eye, ophthalmic tissues and / or cornea.

[0087] In a further embodiment, the present invention relates to a composition comprising terbinafine (free base; CAS number 91161-71-6) or a pharmaceutically acceptable salt thereof (i.e., hydrochloride, CAS number 78628-80-5) and a hemifluoride alkane.

[0088] In a preferred embodiment, the composition comprises terbinafine and a hemifluoride alkane selected from the group consisting of F4H4, F4H5, F4H6, F4H8, F6H2, F6H4, F6H6, F6H8, and F6H10. In a more preferred embodiment, the hemifluoride alkane is F6H8.

[0089] The composition may optionally contain one or more pharmaceutically acceptable cosolvents, preferably selected from ethanol, 2-propanol, isopropyl myristate, DMSO, mineral oil, and squalane, and more preferably the cosolvents are selected from ethanol and 2-propanol.

[0090] The composition contains terbinafine at concentrations of 1-20 mg / ml, 1-15 mg / ml, 1-10 mg / ml, 5-15 mg / ml, 5-10 mg / ml, or 10 mg / ml.

[0091] In preferred embodiments, the pharmaceutical composition is a low-complexity composition, i.e., a composition consisting of only two components: terbinafine dissolved in a hemifluoride alkane selected from F6H8 and F4H5. More preferably, the pharmaceutical composition is a liquid solution comprising terbinafine and F6H8. A preferred pharmaceutical composition is one comprising terbinafine dissolved in F6H8 at concentrations of 1-15 mg / ml, 1-10 mg / ml, 5-15 mg / ml, 5-10 mg / ml, or 10 mg / ml.

[0092] In a more preferred embodiment, the liquid pharmaceutical composition comprises terbinafine dissolved in F6H8 and up to 10% by weight of a cosolvent selected from ethanol or 2-propanol. In this specification, the pharmaceutical composition comprises terbinafine in concentrations of 1-15 mg / ml, 1-10 mg / ml, 5-15 mg / ml, 5-10 mg / ml, or 10 mg / ml, dissolved in F6H8 and up to 10% by weight of a cosolvent selected from ethanol or 2-propanol.

[0093] Compositions containing terbinafine are particularly useful for the topical treatment of fungal infections of the skin (mycoses), nails (onychomycoses), or eyes (i.e., fungal infections of the cornea such as keratitis), and in particular the compositions of the present invention are effective for the topical treatment of onychomycoses of the nails, especially fingernails and / or toenails, or for the topical treatment of fungal infections of the cornea, especially fungal infections caused by Fusarium or Aspergillus species.

[0094] This application further relates to the following numbered items.

[0095] 1. A liquid composition comprising an azole antifungal agent and a vehicle containing a hemifluoride alkane.

[0096] 2. The composition according to item 1, wherein the azole antifungal agent is a triazole antifungal agent selected from albaconazole, efinaconazole, epoxyconazole, fluconazole, isabconazole, itraconazole, posaconazole, propiconazole, ravconazole, terconazole, and voriconazole.

[0097] 3. The composition according to item 1 or 2, wherein the antifungal agent is selected from efinaconazole or fluconazole, preferably the antifungal agent is efinaconazole, more preferably the antifungal agent is efinaconazole and it does not contain any further active ingredients, most preferably the antifungal agent is efinaconazole and it does not contain tababolol.

[0098] 4. A composition according to any one of items 1 to 3, wherein a triazole antifungal agent is dissolved in a vehicle containing a hemifluoride alkane.

[0099] 5. Alkanes with hemifluoride are given by formula F(CF2) n (CH2) m H (where n=2 to 8 and m=2 to 10 in the formula), preferably a hemifluoride alkane of formula F(CF2) n (CH2) m A composition according to any of items 1 to 4, wherein H (wherein n = 4 to 8 and m = 4 to 10 in the formula).

[0100] 6. The composition according to any one of items 1 to 5, wherein the hemifluoride alkane is selected from F4H5, F4H6, F4H8, F4H10, preferably the hemifluoride alkane is selected from F4H8 and F6H8, and more preferably the hemifluoride alkane is F6H8.

[0101] 7. A composition according to any of items 1 to 6, wherein the hemifluoride alkane is present at the following concentrations: i. Maximum 70, 75, 80, 85, 90, 91, 92, 93, 94, 95, or up to 97% (v / v) ii. Between 60~90%(v / v), 70~90%(v / v), 80~90%(v / v), 85~90%(v / v), 65~95%(v / v), 70~95%(v / v), 80~95%(v / v) or 85~95%(v / v) iii. Approximately 65, 70, 75, 80, 85, 87, 89, 90, 91, 92, 93 or approximately 95% (v / v) iv. At least 60, 70, 75, 80, 85, 87, 89, 90, 92, or at least 95% (v / v)

[0102] 8. A composition according to any one of items 1 to 7, wherein the vehicle comprises a cosolvent or an oily material.

[0103] 9. The composition according to item 8, wherein the cosolvent is selected from ethanol, 2-propanol, DMF (N,N-dimethylformamide), DMSO (dimethyl sulfoxide), DMAC (N,N-dimethylacetamide), and NMP (1-methyl-2-pyrrolidone).

[0104] 10. The composition according to item 8, wherein the oily material is selected from squalane, MCT, or silicone oil.

[0105] 11. A composition according to any of items 1 to 10, in which an antifungal agent is present at the following concentrations: i. Maximum 20, 10, 5, 2, 1, 0.7, 0.6, 0.5, 0.4 or 0.3% (w / v) ii. Between 0.2~10%(w / v), 0.2~5%(w / v), 0.2~3%(w / v), 0.3~1%(w / v), 0.4~1%(w / v), 0.5~1.0%(w / v), 0.7~1.0%(w / v) iii. Approximately 10, 5, 3, 1, 0.9, 0.8, 0.7, 0.6, 0.5, 0.4, 0.3 or approximately 0.2% (w / v) iv. At least 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, or at least 1.0% (w / v) v. Between 0.5-2.5% (w / v), 0.75-2.25% (w / v), 1.0-2% (w / v), 1.2-1.8% (w / v), or 1.4-1.6% (w / v)

[0106] 12. A composition that is not flammable, as described in any of items 1 to 11.

[0107] 13. A composition according to any one of items 1 to 12, which does not contain an antioxidant, preferably selected from BHT, BHA, and tocopherol.

[0108] 14. A composition according to any one of items 1 to 13, comprising efinaconazole and about 2, 1, 0.5, 0.4, less than 0.2 or less than 0.1% (w / v) of efinaconazole-N-oxide.

[0109] 15. A composition according to any of items 1 to 14, which does not contain one or more additional components selected from the following. i. Alcohol (preferably ethanol) ii. Penetration enhancer (preferably Transktol, isopropyl myristate) iii. Chelating agent (preferably EDTA, DTPA) iv. Wetting agent or surface tension reducing agent (preferably cyclomethicone) v. pH adjuster (preferably citric acid) vi. Moisturizing agent (preferably C12-15 alkyl lactate) vii. Emulsifier (preferably diisopropyl adipate) viii.Water ix. Preservatives x. Surfactants xi. Ethanol, 2-propanol, propylene glycol, ethyl acetate, amyl acetate, and DMSO (preferably propylene glycol, ethyl acetate, and amyl acetate)

[0110] 16. A composition according to any of items 1 to 15, which does not contain one or more further components selected from ethanol, anhydrous citric acid, butylated hydroxytoluene, C12-15 alkyl lactate, cyclomethicone, diisopropyl adipate, disodium edetate, and water.

[0111] A composition according to any one of items 1 to 16, preferably comprising 17,2-perfluorohexyloctane in the following concentrations. i. Maximum 0.25, 0.5, 0.75, 1.0, 1.5, 2.0 or maximum 3% (v / v) ii. Up to 5, 4, 3, 2, 1 or up to 0.5% (v / v), iii. Between 0.25-5%(v / v), 0.25-3%(v / v), 0.25-2%(v / v), 0.25-1.5%(v / v), or between 0.25-1.0%(v / v)

[0112] 18. A composition according to any one of items 1 to 17, comprising or consisting of efinaconazole dissolved in a vehicle comprising or consisting of 1-perfluorohexyloctane and optionally 2-propanol (or ethanol).

[0113] Preferably, a small amount of efinaconazole dissolved in a 98-99.5% (v / v) (or 99-99.5% (v / v)) vehicle containing or comprising 19.1-perfluorohexyloctane and 2-propanol, comprising or comprising about 0.1-2% (w / v), or 0.5-2% (w / v), or 1.0-2% (w / v), or 1.5-2% (w / v), or 1.75-2.0% (w / v), or 1.2-1.8% (w / v), or 1.4-1.6% (w / v), or 0.5-1.0% (w / v), A composition according to any of items 1 to 18, comprising or consisting of about 0.1-2% (w / v), or 0.5-2% (w / v), or 1.0-2% (w / v), or 1.5-2% (w / v), or 1.75-2.0% (w / v), or 1.2-1.8% (w / v), or 1.4-1.6% (w / v) (or 0.5-1.0% (w / v)) of efinaconazole dissolved in a vehicle comprising or consisting of at least 90% (v / v) of 1-perfluorohexyloctane and up to 10% (v / v) of 2-propanol.

[0114] 20. Compositions described in any of items 1 to 19, comprising or consisting of the following: i.) 1% w / v efinaconazole dissolved in a vehicle containing or consisting of at least 90% (v / v) 1-perfluorohexyloctane and up to 10% (v / v) 2-propanol. ii) 2% w / v efinaconazole dissolved in a vehicle containing or consisting of at least 90% (v / v) 1-perfluorohexyloctane and up to 10% (v / v) 2-propanol. iii) 1-2% (w / v) efinaconazole dissolved in a vehicle containing or comprising at least 90% (v / v) 1-perfluorohexyloctane and up to 10% (v / v) 2-propanol.

[0115] Preferably, a solution comprising or consisting of efinaconazole in approximately 0.1-2% (w / v), or 0.1-1% (w / v), or 1.0-2% (w / v), or 1.5-2% (w / v), or 1.75-2.0% (w / v), or 1.2-1.8% (w / v), or 1.4-1.6% (w / v), or 0.5-2.0% (w / v), dissolved in a vehicle containing or comprising 21.1-perfluorohexyloctane and ethanol, or at least 98-99.5% (v / v) (or at least 99-99.5% (v / v)), The composition according to any one of items 1 to 20, comprising or including about 0.1-2% (w / v), or 0.5-2% (w / v), or 1.0-2% (w / v), or 1.5-2% (w / v), or 1.75-2.0% (w / v), or 1.2-1.8% (w / v), or 1.4-1.6% (w / v) (or 0.5-1.0% (w / v)) of efinaconazole dissolved in a vehicle comprising or consisting of at least 98.5% (v / v) of 1-perfluorohexyloctane and up to 1.5% (v / v) of ethanol.

[0116] 22. A composition according to any one of items 1 to 21, comprising or consisting of efinaconazole in a maximum of approximately 0.5 to 2.0% (w / v), or 1.0 to 2% (w / v), or 1.5 to 2% (w / v), or 1.75 to 2.0% (w / v), or 1.2 to 1.8% (w / v), or 1.4 to 1.6% (w / v), or 0.5 to 1.0% (w / v), dissolved in a vehicle containing or comprising 1-perfluorohexyloctane, 2-propanol, and optionally one or more of DMF (N,N-dimethylformamide), DMSO (dimethyl sulfoxide), DMAC (N,N-dimethylacetamide), and NMP (1-methyl-2-pyrrolidone).

[0117] 23. A composition according to any one of items 1 to 22, comprising or consisting of efinaconazole in a maximum of approximately 0.5 to 2.0% (w / v), or 1.0 to 2% (w / v), or 1.5 to 2% (w / v), or 1.75 to 2.0% (w / v), or 1.2 to 1.8% (w / v), or 1.4 to 1.6% (w / v), or 0.5 to 1.0% (w / v), dissolved in a vehicle containing or comprising 1-perfluorohexyloctane, 2-propanol, and optionally one or more of DMF (N,N-dimethylformamide), DMSO (dimethyl sulfoxide), DMAC (N,N-dimethylacetamide), and NMP (1-methyl-2-pyrrolidone).

[0118] 24. A composition according to any one of items 1 to 23, comprising a vehicle having up to 10% (v / v) of a cosolvent selected from ethanol, 2-propanol, MCT, DMF (N,N-dimethylformamide), DMSO (dimethyl sulfoxide), DMAC (N,N-dimethylacetamide), and NMP (1-methyl-2-pyrrolidone).

[0119] A composition according to any one of items 1 to 24, comprising 25.1.5% (w / v) or less of efinaconazole, up to 85% (w / v) of 1-perfluorohexyloctane, and 15% (w / v) or less of one or more cosolvents selected from 2-propanol, DMF (N,N-dimethylformamide), DMSO (dimethyl sulfoxide), DMAC (N,N-dimethylacetamide), and NMP (1-methyl-2-pyrrolidone), preferably up to 1.5% (w / v) of efinaconazole, up to 90% (w / v) of 1-perfluorohexyloctane, and 10% (w / v) or less of one or more cosolvents selected from 2-propanol, DMF (N,N-dimethylformamide), DMSO (dimethyl sulfoxide), DMAC (N,N-dimethylformamide), and NMP (1-methyl-2-pyrrolidone).

[0120] A composition according to any one of items 1 to 25, comprising 26.1.5% (w / v) or less of efinaconazole, up to 85% (w / v) of 1-perfluorohexyloctane, and 15% (v / v) or less of one or more cosolvents selected from 2-propanol, DMF (N,N-dimethylformamide), DMSO (dimethyl sulfoxide), DMAC (N,N-dimethylacetamide), and NMP (1-methyl-2-pyrrolidone), preferably up to 1.5% (v / v) of efinaconazole, up to 90% (v / v) of 1-perfluorohexyloctane, and 10% (v / v) or less of one or more cosolvents selected from 2-propanol, DMF (N,N-dimethylformamide), DMSO (dimethyl sulfoxide), DMAC (N,N-dimethylacetamide), and NMP (1-methyl-2-pyrrolidone).

[0121] 27. A composition described in any of items 1 to 26 for use as a pharmaceutical.

[0122] 28. The composition for use described in item 27, for use in the treatment of fungal infections of the skin, preferably for use in the treatment of fungal infections of the nails (onychomycosis), more preferably for use in the treatment of onychomycosis of the fingernails and / or toenails.

[0123] 29. Compositions for use as described in items 27-28, which are administered topically to the nails of the target (fingernails or toenails).

[0124] 30. Compositions for use as described in items 27-29, administered to fingernails and / or toenails by the use of a sponge applicator, dropper, pen or pipette.

[0125] 31. Compositions for use as described in items 27-30, which are not administered by a brush applicator.

[0126] 32. Compositions for use as described in items 27-31, which are administered topically to cover the nail, nail fold, nail bed, subungual layer and / or underside of the nail plate of the toenails and / or fingernails.

[0127] 33. A composition for use according to items 27-32, which is administered topically by non-contact application to the target nail (fingernail or toenail), preferably by dropping one or more single drops of the liquid composition onto the surface of the target nail (fingernail or toenail).

[0128] 34. Compositions for use as described in items 27-33, administered topically by dropping one or more single drops of the liquid composition onto the (central) surface of the nail, so as to cover the nail, nail fold, nail bed, subungual skin and / or underside of the nail plate of the toenails and / or fingernails.

[0129] 35. The compositions for use described in items 27-33, administered topically by dropping a single drop onto the surface of the target nail (fingernail or toenail), as follows: i. Not to come into contact with the nail, nail fold, nail bed, subungual layer and / or underside of the nail plate of the toenails and / or fingernails, and / or ii. Do not manually distribute to one or more distant areas of the toenail and / or fingernail selected from the nail fold, nail bed, subungual skin and / or the underside of the nail plate. iii. Preferably, rapid drying at room temperature for less than 20 minutes, less than 10 minutes, or less than 5 minutes.

[0130] 36. The composition for use described in item 27, for use in the treatment of fungal infections of the eye, preferably for use in the treatment of fungal infections of the cornea (keratitis), more preferably for use in the treatment of fungal infections of the cornea (keratitis) caused by the genera Fusarium or Aspergillus.

[0131] 37. The composition for use according to item 36, which is preferably administered topically to the eye of interest (i.e., the ocular surface such as the cornea and / or conjunctiva) by dropping one or more drops of the liquid composition onto the (central) surface of the affected eye, and more preferably by dropping one or more drops of the liquid composition onto the surface of the cornea and / or conjunctiva.

[0132] 38. A kit comprising a composition as defined in any of items 1 to 24, and a container for holding the composition, which is adapted for topical administration of the composition to the nail, nail fold, nail bed, subungual layer and / or underside of the nail plate of a target toenail and / or fingernail.

[0133] 39. A kit comprising a composition as defined in any of items 1 to 26, and a container for holding the composition, which is adapted for topical administration of the composition to the eye or ophthalmic tissue of a target.

[0134] 40. A liquid composition comprising terbinafine or a pharmaceutically acceptable salt thereof, a hemifluoride alkane, and an optionally pharmaceutically acceptable cosolvent.

[0135] 41. The composition according to item 40, wherein the hemifluoride alkane is selected from the group consisting of F4H4, F4H5, F4H6, F4H8, F6H2, F6H4, F6H6, F6H8, and F6H10, preferably the hemifluoride alkane is selected from F4H5 and F6H8, and more preferably the hemifluoride alkane is F6H8.

[0136] 42. The composition according to either item 40 or 41, wherein terbinafine or a pharmaceutically acceptable salt thereof is present at a concentration of 1 to 20 mg / ml, preferably 1 to 10 mg / ml, and more preferably terbinafine is present at 10 mg / ml.

[0137] 43. A composition in the form of a solution, as described in any one of items 40 to 42.

[0138] 44. A composition according to any one of items 40 to 43, comprising an excipient selected from the group consisting of ethanol, 2-propanol, isopropyl myristate, DMSO, mineral oil, and squalane, and more preferably a cosolvent selected from ethanol and 2-propanol.

[0139] 45. The composition according to any one of items 40 to 44, comprising terbinafine and a hemifluoride alkane selected from F4H5 and F6H8, preferably the hemifluoride alkane being F6H8.

[0140] 46. ​​A composition according to any one of items 40 to 45, comprising terbinafine in a concentration of 1 to 15 mg / ml, 1 to 10 mg / ml, 5 to 15 mg / ml, 5 to 10 mg / ml, or 10 mg / ml dissolved in F6H8.

[0141] 47. A composition described in any one of items 40 to 46, for use in pharmaceuticals.

[0142] 48. The composition according to item 47, for use in the topical treatment of fungal infections, preferably for use in the treatment of fungal infections of the skin or nails (or eyes), more preferably for use in the treatment of onychomycosis (or fungal infections of the cornea).

[0143] 49. A method for treating a fungal infection, comprising topically administering the compositions described in items 40-46 to a subject in need thereof, preferably the compositions being topically administered to the skin or nails (or ophthalmic tissue) of the subject.

[0144] 50. The treatment method described in item 49 for the subject suffering from onychomycosis or a fungal infection of the cornea.

[0145] 51. A kit comprising a composition as defined in any of items 40-46, and a container for holding the composition, which is adapted for topical administration to the nail, nail fold, nail bed, subungual skin and / or underside of the nail plate of a target toenail and / or fingernail, or adapted for topical administration to the eye or ophthalmic tissue of a target.

[0146] The following examples are helpful in illustrating the present invention, but should not be understood as limiting the scope of the invention. (Examples) [Examples]

[0147] Preparation of efinaconazole solution in F6H8 Weigh 14 mg of efinaconazole (purity >99%) into a 5 ml glass vial; add 2 ml of F6H8 (Novaliq, purity >99%) to the vial using a pipette, seal with an aluminum crimp cap, and shake at 280 mpm for 4 hours at room temperature. The resulting 7 mg / ml composition of efinaconazole in F6H8 is present as a clear solution. [Examples]

[0148] Weigh 20 mg of efinaconazole (purity >99%) into a 5 ml glass vial. Add the required amount of cosolvent to the vial using a pipette; gently shake the vial by hand; add the required amount of F6H8 (Novaliq, purity >99%) using a pipette, close with an aluminum crimp cap, and shake at 280 mpm for 4 hours at room temperature. The resulting composition of efinaconazole in F6H8 / cosolvent is present as a clear solution.

[0149] The following compositions were prepared according to the procedures described in Examples 1 and 2 (Table 1): (Table 1: Efinaconazole composition) JPEG2026511960000012.jpg67138 [Examples]

[0150] In vitro nail penetration / inhibition model Three test products containing 0.1% to 10% efinaconazole were tested in vitro for their ability to inhibit the growth of Trichophyton interdigitale, a representative dermatophyte known to cause onychomycosis and tinea pedis in humans. (a) 0.1% efinaconazole dissolved in a mixture of F6H8 and 2-propanol (10:1 v / v%), non-aqueous (8-9), (b) 1.0% efinaconazole dissolved in a mixture of F6H8 and 2-propanol (9:1 v / v%), non-aqueous (4-7), (c) 10% efinaconazole, aqueous commercial product ("Jublia"; Bausch Health, Bridgewater, USA) (10-11).

[0151] As reference products, DMSO was used as a negative control (1), terbinafine (100 μg / ml in DMSO) as a positive control (2), and F6H8 as a vehicle control (3). Non-aqueous efinaconazole formulations (0.1% and 1%) (4-9) contained no antioxidants, were presented as colorless solutions, and showed no discoloration during the test.

[0152] In transnail permeability studies, bovine hoof sheets (BHS; 400 μm thick, 16 mm in diameter), an established in vitro substitute for human nails, were immersed in excess of three test products and three reference products for 24 hours. The BHS were then removed from the immersion bath, and all residues of the test and reference products were completely removed. The BHS were then transferred and placed on freshly plated Trichophyton interdigitale culture plates. After incubation at 28°C for 5, 7, 11, or 14 days, the inhibition regions were recorded and measured for each of the test and reference products. Details of the experiment and results are shown in Table 2 below: (Table 2) JPEG2026511960000013.jpg89138

[0153] result: The positive control (2) (terbinafine dissolved in DMSO at 100 μg / ml) and the negative (DMSO) control (1) showed the expected positive results (inhibitory region: 5.6–5.8 cm) and negative results (no inhibitory region). The vehicle control (F6H8) (3) did not produce an inhibitory region, but efinaconazole formulations (4–11), including non-aqueous formulations (0.1% and 1%) and 10% aqueous formulations, produced nearly complete to complete inhibitory regions.

[0154] Interestingly, the non-aqueous 1% efinaconazole formulation (4-7) provided comparable inhibition of Trichophyton interdigitale proliferation compared to a 10-fold higher concentration of a commercially available aqueous 10% efinaconazole formulation (Jublia) (10-11). Unexpectedly, a 100-fold lower concentration of 0.1% non-aqueous efinaconazole formulation (8-9) also achieved nearly complete inhibition of proliferation (inhibition region: 5.9 cm), comparable to or even better than the positive control (terbinafine) (2).

[0155] While not bound by theory, efinaconazole formulated in SFA (i.e., F6H8) is thought to exhibit the full antifungal activity of efinaconazole, which may be hindered by the presence of one or more excipients in commercially available Jublia formulations. Commercial efinaconazole formulations (10-11) contain the antioxidant butylated hydroxytoluene (BHT), as well as excipients such as alcohol, anhydrous citric acid, C12-15 alkyl lactate, cyclomethicone, diisopropyl adipate, disodium edetate, and purified water. Alternatively, non-aqueous efinaconazole formulations (4-9) are formulated without antioxidants and contain only two components: the hemifluoride alkane F6H8 and 2-propanol. [Examples]

[0156] In vitro death and regrowth Two test products containing 2% and 10% efinaconazole were tested in vitro for their ability to kill dermatophytes (Trichophyton interdigitale) in previously infected bovine hoof sheets and prevent dermatophyte regrowth: (a) 2.0% efinaconazole dissolved in a mixture of F6H8 and 2-propanol (9:1 v / v%), non-aqueous (14), (b) 10% efinaconazole, aqueous solution (commercial product Jublia (Bausch Health, Bridgewater, USA)) (15).

[0157] Water was used as a negative control and 7.5% povidone-iodine (Braunol, B. Braun Melsungen AG, Melsungen, Germany) as a positive control (13). The non-aqueous 2% efinaconazole preparation (14) contained no antioxidants, was presented as a colorless solution, and showed no discoloration during the test.

[0158] In transnail permeability studies, bovine hoof sheets (BHS; 400 μm thick, 16 mm in diameter), an established in vitro substitute for human nails, were first infected with the dermatophyte *Trichophyton interdigitale*. The infected BHS were then incubated for 1 hour in two test products and a reference product. The BHS were then removed from incubation. Thorough washing of the BHS ensured that the test and reference products did not remain on the surface of the BHS. After washing, the BHS were transferred to fresh culture plates and incubated at 28°C for 4 days to record the possibility of *Trichophyton interdigitale* regrowth from the BHS. Details of the experiment and results are shown in Table 3 below. (Table 3) JPEG2026511960000014.jpg35138

[0159] result: The negative control (water) showed the expected uniform lateral regrowth of Trichophyton interdigitale on the culture plate, while the positive control (7.5% povidone-iodine) only partially killed the dermatophytes in BHS, resulting in slight lateral regrowth on the culture plate.

[0160] Instead, both efinaconazole formulations, including non-aqueous SFA (2%) and aqueous (10%) formulations, effectively penetrated BHS, completely killing the dermatophytes within the BHS and thus preventing the regrowth of Trichophyton interdigital from the BHS on culture plates. This represents a key feature of the long-term effective treatment of onychomycosis and / or tinea pedis.

[0161] Interestingly, the non-aqueous 2% efinaconazole formulation (14) provided equivalent prevention of regrowth of Trichophyton interdigitale from infected BHS compared to a 5-fold higher concentration commercially available Jublia (10%) formulation (15). While not bound by theory, it is thought that the 5-fold lower concentration efinaconazole formulation (14) in SFA (i.e., F6H8) exhibits improved antifungal activity due to the improved penetration capacity of the vehicle, and further due to the absence of one or more excipients that may interfere with the penetration and / or efficacy of efinaconazole in the commercially available aqueous Jublia formulation (15). [Examples]

[0162] Discoloration and stability Certain aqueous efinaconazole formulations are known to change color over time from colorless to pale yellow to deep red or brown, which may cause patients to discontinue use. Furthermore, the clinical efficacy of the active ingredient may be reduced by oxidative changes. Therefore, non-aqueous SFA-based (i.e., F6H8) formulations (16-17) were evaluated for their visual appearance and discoloration, including under stress conditions (60°C). Details and results of the experiment are shown in Table 4 below: (Table 4) JPEG2026511960000015.jpg29138

[0163] result: The non-aqueous efinaconazole formulations in SFA (16-17) that do not contain many complex antioxidants are colorless and exist as very stable formulations. Even after storage of SFA-based efinaconazole formulations (16-17) under stress conditions (60°C), no change in appearance (color) or absorbance was apparent. [Examples]

[0164] Drying after topical application to the nails From a user's perspective, it is preferable that any antifungal formulation applied to the nail penetrates and dries rapidly, resulting in higher patient compliance. Two test products containing 1% and 10% efinaconazole were tested in vitro for their penetration rate into bovine hoof sheets (BHS). (a) 1.0% efinaconazole dissolved in a mixture of F6H8 and 2-propanol (9:1 v / v%), non-aqueous (18) (b) 10% efinaconazole, aqueous solution (commercial product Jublia (Bausch Health, Bridgewater, USA)) (19).

[0165] A bovine hoof sheet (BHS; 400 μm thick, 16 mm in diameter), an established in vitro substitute for human nails in transnail penetration studies, was placed on white paper. Three μl of each test product was then applied to the surface of the bovine hoof sheet. The amount was limited to three μl to avoid spreading across the sheet surface. The penetration rate, which represents the time it takes for the test product to completely penetrate the nail material of the BHS, was visually determined. Hereinafter, the reflection of light onto the BHS was conveniently used to determine the period / time until the test product completely penetrated or evaporated from the BHS. Details of the experiment and results are shown in Table 5 below: (Table 5) JPEG2026511960000016.jpg33140

[0166] result: The non-aqueous 1% efinaconazole formulation (18) rapidly disappeared from the surface of the BHS. After 10 minutes, only a small amount of the formulation remained, and after 20 minutes, it had completely disappeared. Interestingly, neither the residue of the drug compound nor the vehicle could be detected on the nail surface. Therefore, it was concluded that the non-aqueous efinaconazole formulation (18) had completely penetrated the nail material. Considering its high boiling point of 223°C, F6H8 is thought to provide effective penetration of efinaconazole into the nail material rather than simply evaporating.

[0167] In comparison, the commercially available aqueous efinaconazole formulation (19) appeared to remain on the BHS for a considerably longer period of time. A glossy film was observed to form on the BHS, which was visible for longer than one hour and was evident as a surface shimmer. This film felt dry to the touch. Therefore, it was concluded that at least a portion of the commercially available aqueous efinaconazole formulation (19) did not penetrate sufficiently into the nail, but dried and remained on the nail surface as a glossy film, possibly embedding some of the efinaconazole active ingredient.

[0168] In summary, it can be concluded that the non-aqueous 1% efinaconazole formulation (18) exhibits very user-friendly behavior and likely leads to higher patient compliance. Patient compliance is particularly important because topical antifungal treatment requires patients to apply the treatment for at least 9–12 months in order to be effective. [Examples]

[0169] Preparation of terbinafine solution in hemifluoride alkanes Weigh 20 mg of terbinafine (free base; purity >98%) into a 5 ml glass vial; add 2 ml of F6H8 (Novaliq, purity >99%) to the vial using a pipette, seal with an aluminum crimp cap, and shake overnight at 280 mpm at room temperature. The resulting 10 mg / ml composition of terbinafine in F6H8 is present as a clear solution.

[0170] The following compositions were prepared according to the procedure described above (Table 6): (Table 6) JPEG2026511960000017.jpg53138 [Examples]

[0171] In vitro nail penetration / inhibition model As described in Example 3, various test products containing 0.1 to 10% efinaconazole were tested in vitro to evaluate their ability to inhibit the growth of a representative dermatophyte (Trichophyton interdigitale), particularly in terms of their efficacy: a) 0.1% to 10% efinaconazole, 24-hour incubation

[0172] In a series of experiments, the effects of different concentrations of efinaconazole on inhibiting growth during longer incubation periods (24 hours) were investigated. Details and results of the experiments are shown in Table 7 below: (Table 7) JPEG2026511960000018.jpg42138

[0173] result: Considering a 24-hour incubation period, non-aqueous efinaconazole formulations provided effective inhibition of Trichophyton interdigitale growth at concentrations of approximately 0.5–2% efinaconazole. 1% and 2% non-aqueous efinaconazole formulations achieved comparable growth inhibition compared to aqueous diluted Jublia formulations, including much higher concentrations of commercially available Jublia formulations. b) 1.0% to 10% efinaconazole, 30-minute incubation.

[0174] In contrast to a), the effects of different concentrations of efinaconazole on inhibiting growth at a shorter incubation time (30 minutes) were investigated. Details and results of the experiment are shown in Table 8 below: (Table 8) JPEG2026511960000019.jpg36138

[0175] result: Considering the relatively short incubation time of 30 minutes, the 1% and 2% non-aqueous efinaconazole formulations were clearly superior to the 1% and 2% aqueous diluted Jublia formulations, as well as to much higher concentrations of commercially available Jublia formulations. While not bound by theory, this suggests that efinaconazole formulations prepared in hemifluoride alkanes penetrate the nail material much more rapidly and effectively than aqueous efinaconazole formulations. Therefore, the 1.1% and 2% non-aqueous efinaconazole formulations in hemifluoride alkanes are highly effective formulations, considering both short (30 minutes) and long (24 hours, see above) incubation times. c) 2% efinaconazole, incubation for 5 minutes to 24 hours.

[0176] In a series of experiments, a direct head-to-head comparison (2% non-aqueous efinaconazole formulation versus aqueous efinaconazole formulation was investigated over time series incubation periods ranging from 5 minutes to 24 hours. Details and results of the experiments are shown in Table 9 below: (Table 9) JPEG2026511960000020.jpg22138

[0177] result: The rapid onset of action of the non-aqueous efinaconazole formulation in a hemifluoride alkane was demonstrated in a direct comparison between the non-aqueous and aqueous 2% efinaconazole formulations. The 2% non-aqueous efinaconazole formulation was found to be significantly superior at shorter incubation times (5, 15, 30, and 60 minutes) and slightly better at longer incubation times (4 and 24 hours). Therefore, the non-aqueous efinaconazole formulation in a hemifluoride alkane is characterized by very rapid onset of action and sustained performance, which is a clear advantage compared to the aqueous efinaconazole formulation.

Claims

1. A water-free liquid composition containing efinaconazole dissolved in a vehicle containing a hemifluoride alkane.

2. The composition according to claim 1, wherein the hemifluoride alkane is selected from F4H5, F4H6, F4H8, F4H10, F6H6, F6H8, and F6H10.

3. The composition according to any one of claims 1 to 2, which does not contain any further active ingredients, optionally does not contain any further antifungal agents, and preferably does not contain tababolol.

4. The composition according to any one of claims 1 to 3, wherein the cosolvent is selected from ethanol, 2-propanol, DMF (N,N-dimethylformamide), DMSO (dimethyl sulfoxide), DMAC (N,N-dimethylacetamide), and NMP (1-methyl-2-pyrrolidone).

5. The composition according to any one of claims 1 to 4, wherein efinaconazole is present at a maximum concentration of 2% (w / v).

6. A composition according to any one of claims 1 to 5, comprising efinaconazole and less than 0.1% (w / v) of efinaconazole-N-oxide.

7. The composition according to any one of claims 1 to 6, which does not contain one or more further components selected from the following: i. Ethanol ii. Penetration enhancer selected from transktol and isopropyl myristate iii. Chelating agents selected from EDTA and DTPA. iv. Wetting agent or surface tension reducing agent selected from cyclomethicone) v. pH adjusters vi. Moisturizing agents selected from C12-15 alkyl lactates) vii. Emulsifiers selected from diisopropyl adipate) viii. water ix. Preservatives x. Surfactants xi. Propylene glycol, ethyl acetate, or amyl acetate.

8. A composition according to any one of claims 1 to 7, comprising or consisting of efinaconazole dissolved in a vehicle comprising 1-perfluorohexyloctane and optionally 2-propanol, or a vehicle comprising the same.

9. A composition according to any one of claims 1 to 8, comprising or consisting of about 0.5 to 2% (w / v) efinaconazole dissolved in a vehicle comprising or consisting of 1-perfluorohexyloctane and 2-propanol.

10. A composition according to any one of claims 1 to 9, comprising 2.0% (w / v) or less of efinaconazole, up to 90% (w / v) of 1-perfluorohexyloctane, and 10% (w / v) or less of 2-propanol, preferably comprising 2.0% (w / v) or less of efinaconazole, up to 90% (v / v) of 1-perfluorohexyloctane, and 10% (v / v) or less of 2-propanol.

11. The composition according to any one of claims 1 to 10, comprising 1% (w / v) or 2.0% (w / v) efinaconazole, up to 90% (v / v) 1-perfluorohexyloctane, and 10% (v / v) or less 2-propanol.

12. A composition according to any one of claims 1 to 11 for use as a pharmaceutical.

13. A composition for use according to claim 12, for use in the treatment of fungal infections of the skin, preferably for use in the treatment of fungal infections of the nails (onychomycosis).

14. A composition for use according to any one of claims 12 to 13, which is administered to fingernails and / or toenails by the use of a sponge applicator, dropper, pen or pipette.

15. A composition administered topically by dropping a single drop onto the surface of the target nail (fingernail or toenail), i. Not to come into contact with the nail, nail fold, nail bed, subungual layer and / or underside of the nail plate of the toenails and / or fingernails, and / or ii. Do not manually distribute to one or more remote areas of the toenail and / or fingernail selected from the nail fold, nail bed, subungual skin and / or underside of the nail plate. A composition for use according to any one of claims 12 to 14, which is administered topically.

16. A composition for use according to claim 12, for use in the treatment of fungal infections of the eye, preferably for use in the treatment of fungal infections of the cornea.

17. A kit comprising a composition as defined in any one of claims 1 to 11, and a container for holding the composition, which is adapted for topical administration of the composition to the nail, nail fold, nail bed, subungual skin and / or underside of the nail plate of a target toenail and / or fingernail.

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