GB2518826A

GB2518826A - Composition

Info

Publication number: GB2518826A
Application number: GB1317196.2A
Authority: GB
Inventors: Thanasis Athanasiou
Original assignee: Individual
Current assignee: Individual
Priority date: 2013-09-27
Filing date: 2013-09-27
Publication date: 2015-04-08
Also published as: GB201317196D0

Abstract

A pharmaceutical composition comprises: an active pharmaceutical ingredient, preferably an antimycotic agent, suitable for treating a disease or condition of the skin; dimethyl sulfoxide (DMSO); and a humectant. Preferably the antifungal agent is capable of inactivating or killing fungi of a genus selected from the group consisting of Trichophyton, Epidermophyton, Microsporum, Aspergillus, Scopulariopsis and Candida. Preferably the antifungal agent is or comprises propolis. The humectant is preferably an ionic salt, in particular magnesium sulphate. Preferably the composition comprises 5 to 10% by weight antifungal agent; 5 to 15% by weight dimethyl sulfoxide; and 10 to 20% by weight magnesium sulfate. The composition is useful in treating a fungal infection, such as onychomycosis (fungal nail infection) selected from distal subungal onychomycosis, white superficial anychomycosis, proximal onychomycosis or candidal anychomycosis; or tinea pedis (atheletes foot).

Description

Composition

Field of the Invention

This invention relates to a pharmaceutical composition. The invention also relates to the use of the composition in the treatment of a number of conditions, particularly atthough not exclusively fungal infections such as onychomycosis (fungal nail infection).

Background to the Invention

The human nail The human nail is depicted in Fig. 1. As described in K.A. Walters and G.L. Flynn, mt. J Cosm. ScL 1983, 5, 231-246, the nail plate is the most prominent anatomical feature and in man it exists as a relatively thin (typically 0.5-1 mm) plate which exhibits a gentle convex curvature in both x and y directions when viewed from above.

The nail plate is comprised of layers of flattened, keratinized cells fused into a dense but somewhat elastic mass. These cells have their origins in the nail matrix, a living, highly proliferative epidermal tissue. The nail normally grows distally at the rate of about 0.1 mm per day and thus requires from 4 to 5 months to completely regenerate after avulsion. It has been demonstrated that growth is slowed with increasing age, by cold climatic conditions, in disease states with reduced blood flow to the body's periphery and in malnutrition, all of which indicate that proliferative events in the nail matrix are very sensitive to the local availability of nutrients.

The nail plate is surrounded on three sides and is set into a grooved epidermal invagination known as the nailfold. The folds are comprised of a typical cornified epithelium and they produce the soft keratinized nailfold flap or extension known as the eponychium or cuticle. The nail plate overlays the nail bed, a soft and normally noncornified tissue. Cells in the nail bed at the plate-nail bed interface are carried distally by the nail plate in the course of its growth. In the absence of outward pressure of the growing nail plate these cells are stationary. The nail plate is formed in the nail matrix from cells originating in both the dorsal and ventral aspects of the nail matrix. The matrix appears as a semilunar area at the proximal ventral surface of the nail groove. It may be totally recessed under the nailfold or may extend outwards from the fold as a white area called the lunula. Cell division occurs in the outermost 1* envelope of cells of the matrix on both sides of the forming nail plate. The cells push simultaneously distally and inwards towards the centre of the matrix.

Keratinization of cells takes place roughly along the matrix axis about 25% of the way out from the apex. In the keratinization process the cells undergo shape and other changes similar to those experienced by epidermal cells forming the stratum corneum and the hair. These enter the forming nail plate in tightly knit layers and about twenty-five layers of cells comprise the finished nail. The compactness of the plate is governed by dovetailing' of the cells and tight binding of the cells with numerous intercellular links. Some evidence indicates there are also perpendicularly orientated fibres of keratin in the outermost segments which contribute to the fusing together of the layers. The structure is so tightly knit that there is no cell exfoliation as occurs in stratum corneum unless pathogenic stimuli are present. Although the normal nail visually appears uniform from surface to surface there are at least two discernible macroscopic strata, with possibly a third. These are the dorsal nail plate and the intermediate nail plate with the third, sometimes observed, under-layer or ventral plate contributed by the cells of the lunula. The dorsal nail plate appears to be a harder laminate and, as mentioned, it has a perpendicularly orientated fibrous fraction which may be responsible for its unique properties. The intermediate nail plate is a softer and more flexible tissue whose extra thickness is obviously the result of more cell layers being deposited over a broader area than occurs dorsally. The ventral plate is very thin and contains only one or two layers of cells.

Onvchomycosis Onychomycosis (also known as dermatophytic onychomycosis," or "tinea unguium") means fungal infection of the nail. It is the most common disease of the nails and constitutes about a half of all nail abnormalities. This condition may affect toenails or fingernails, but toenail infections are particularly common. The prevalence of onychomycosis is about 6-8% in the adult population.

There are four classic types of onychomycosis. Distal subungual onychomycosis is the most common form of tinea ungu/um, and is usually caused by Trichophyton rubrum, which invades the nail bed and the underside of the nail plate. White superficial onychomycosis (WSO) is caused by fungal invasion of the superficial layers of the nail plate to form "white islands" on the plate. It accounts for only 10 percent of onychomycosis cases. Proximal subungual onychomycosis is fungal penetration of the newly formed nail plate through the proximal nail fold. It is the least common form of tiriea unguium in healthy people, but is found more commonly when the patient is immunocompromised. Candidal onychomycosis is Candida species invasion of the fingernails, usually occurring in persons who frequently immerse their hands in water. This normally requires the prior damage of the nail by infection or trauma.

The most common symptom of a fungal nail infection is the nail becoming thickened and discoloured: white, black, yellow or green. As the infection progresses the nail can become brittle, with pieces breaking off or coming away from the toe or finger completely. If left untreated, the skin can become inflamed and painful underneath and around the nail. There may also be white or yellow patches on the nailbed or scaly skin next to the nail. There is usually no pain or other bodily symptoms, unless the disease is severe. People with onychomycosis may experience significant psychosocial problems due to the appearance of the nail, particularly when fingers -which are always visible -rather than toenails are affected.

The causative pathogens of onychomycosis include dermatophytes, Gandida, and nondermatophytic molds. Dermatophytes are the fungi most commonly responsible for onychomycosis in the temperate western countries; while Candida and nondermatophytic moulds are more frequently involved in the tropics and subtropics with a hot and humid climate.

Trichophyton rubrum is the most common dermatophyte involved in onychomycosis.

Other dermatophytes that may be involved are T. interdigitale, Epidermophyton floccosum, 71 violaceum, Microsporurn gypseum, T. tonsurans, and T. soudanense.

Other causative pathogens include Candida and nondermatophytic moulds, in particu[ar members of the mould generation Neoscytalidium, Scopulariopsis, and Aspergillus. Candida spp. mainly cause fingernail onychomycosis in people whose hands are often submerged in water. .Scytalidium mainly affects people in the tropics, though it persists if they later move to areas of temperate climate. Other moulds more commonly affect people older than 60 years, and their presence in the nail reflects a slight weakening in the nail's ability to defend itself against fungal invasion.

Aging is the most common risk factor for onychomycosis due to diminished blood circulation1 longer exposure to fungi, and nails which grow more slowly and thicken, increasing susceptibility to infection. Nail fungus tends to affect men more often than women, and is associated with a family history of this infection. Other risk factors include perspiring heavily, being in a humid or moist environment, psoriasis, wearing socks and shoes that hinder ventilation and do not absorb perspiration, going barefoot in damp public places such as swimming pools, gyms and shower rooms, having athlete's foot (tinea pedis), minor skin or nail injury, damaged nail, or other S infection, and having diabetes, circulation problems, which may also lead to tower peripheral temperatures on hands and feet, or a weakened immune system.

The nail apparatus presents unique challenges. Penetration of active substances, regardless of whether it is from systemic or topical application is dependent upon the movement of the agent through non-viable tissues where the fungi reside. Without wishing to be bound by theory, it is believed that the most effective method of distribution through this type of environment would be through diffusion. Moisture or lipid provide the only fluid phase components in the nail apparatus that can support diffusive distribution of the agent. However, neither of these fluid phase components is in abundant concentrations within the nail plate and nail bed substrates to be exploited for effective delivery of actives. Furthermore the typical infected nail plate is usually considerably thiGkened in response to fungal activity and therefore presents a greater barrier to diffusion through the small amount of normal latent moisture in the nail.

Nail infections are usually the most difficult and challenging to treat as the nails keratinized structure acts as a physical barrier to active pharmaceutical ingredients to reach the causal pathogens that may be present on the nail surface, in the nail structure, as well as the nail-bed.

W02004/010962 describes methods and compositions for treating dermal infections, comprising the use of topical delivery vehicles, in particular organic acids such as citric acid.

Summary of the Invention

In one aspect, the invention provides a pharmaceutical composition comprising: an active pharmaceutical ingredient; dimethyl sulfoxide; and a humectant.

In one aspect, the invention provides a pharmaceutical composition comprising: an active pharmaceutical ingredient suitable for treating a disease or condition of the skin; dimethyl sulfoxide; and a humectant.

In one aspect, the invention provides a pharmaceutical composition comprising: an active pharmaceutical ingredient suitable for treating a disease or condition of the nail; dimethyl sulfoxide; and a humectant.

In one aspect, the invention provides a pharmaceutical composition comprising: an antifungal agent; dimethyl sulfoxide; and a humectant.

In another aspect, the invention provides a pharmaceutical composition, as defined above, for use in treating a disease or condition of the skin. Such diseases or conditions may be caused by, for example, bacteria, fungi, viruses or other parasites.

In another aspect, the invention provides a pharmaceutical composition, as defined above, for use in treating a disease or condition of the nail.

In another aspect, the invention provides a pharmaceutical composition, as defined above, for use in treating a fungal infection.

In another aspect, the invention provides a pharmaceutical composition, as defined above, for use in treating onychomycosis. The onychomycosis may be, for example, distal subungual onychomycosis, white superficial onychomycosis, proximal subungual onychomycosis or candidal onychornycosis.

In another aspect, the invention provides a pharmaceutical composition, as defined above, for use in treating tinea pedis (athlete's foot).

Advantages and Surprising Findings It has surprisingly been found by the present inventor that combining dimethyl sulfoxide and a humectant in a pharmaceutical composition enables greatly improved delivery of the active pharmaceutical ingredient (particularly an antifungal agent) to the desired site of activity. In particular, when the composition is used for treating nail infections such as onychomycosis, it has surprisingly been found by the present inventor that the presence of both dimethyl sulfoxide and a humectant in the composition enables greatly improved delivery of the active pharmaceutical ingredient (particularly an antifungal agent) through the nail plate to the desired site of activity.

Without wishing to be bound by any particular theory, it is believed that the dimethyl sulfoxide and humectant act synergistically to enhance the penetration of the active pharmaceutical ingredient (particularly an antifungal agent) through the nail plate and permit effective delivery of the active pharmaceutical ingredient to the desired site of activity.

In addition, and also without wishing to be bound by any particular theory, it is believed that the combination of dimethyl sulfoxide and a humectant allows the moisture and humectant that are transferred on application to the nail to hydrate the nail plate and form a diffusion gradient for the effective delivery of the active pharmaceutical ingredient to the non-viable areas of the nail apparatus.

The nail plate is hydrophilic and will readily absorb moisture into the substrate.

Therefore either exposure to moisture or, conversely, the use of agent(s) that are absorbed transdermally would create the osmotic pressure difference and transport the Iceratolytic and the antifungal agent(s) into the sub-plate matrix to act on the fungi.

Many substances do pass into the body from the outer surface of the skin and into the circulation. While from a distance it may appear impervious, at close range it is actually highly porous. The process is known as dermal absorption. Without wishing to be bound by any particular theory, it is believed that dimethyl sulfoxide may aid and at the same time be aided to reach and help dissolute other highly keratinized tissues or parts of the nail.

Brief Description of the Drawings

Fig. I illustrates the human nail; Fig. 2 illustrates the mechanisms of intracellular and transcellular absorption; Fig. 3 illustrates the nail of a patient prior to treatment with the composition of

Example I; and

Fig. 4 illustrates the nail of the same patient following treatment with the composition

of Example 1.

Detailed Description

Active Pharmaceutical Ingredient The pharmaceutical composition of the present invention contains an active pharmaceutical ingredient. In its broadest aspect, any agent capable of conferring a pharmaceutical effect may function as this ingredient.

In one embodiment, the active pharmaceutical ingredient is suitable for treating a disease or condition of the skin. In this specification the terms "skin", "dermal" or "dermal structures" are used interchangeably and refer to the elements of the integumentary system of humans and animals, including organ and cavity linings, such as pleura, dura, and pericardium, and mucous membranes and such terms. The integumentary system as it is commonly understood by those skilled in the art refers to the skin, including the epidermis and dermis, which comprise layers including stratum basale, stratum spinosum, stratum granulosum, stratum lucidum, stratum corneum, papillary layer and reticular layer. Cells which are found in these dermal structures include, but are not limited to, keratinocytes, fibroblasts, melanocytes, dendritic cells, Landerhans' cells, epithelial cells, and Merkel cells. Dermal structures include appendages such as hair, sebaceous glands, sweat glands, follicles, nerve structures, horns, hooves and nails.

In one embodiment, the active pharmaceutical ingredient is suitable for treating a disease or condition of the nail.

In one embodiment, the active pharmaceutical ingredient is capable of transdermal absorption. As illustrated in Fig. 2, intercellular skin absorption, occurs between the cells of the "stratum corneum", the outermost layer of the skin. In contrast, transcellular skin absorption involves substances actually passing through the skin cells themselves. In a preferred embodiment, the active pharmaceutical ingredient is capable of absorption through the nail, in particular the nail plate.

Examples of suitable classes of active pharmaceutical ingredient include antimicrobials (including but not limited to antibacterials, antivirals, antifungals and antiprotozoals). Examples of other possible classes of phamaceutically active substances include analgesics (painkillers), anti-inflammatories, anaesthetics, immunostimulatories, hepatoprotectives, antioxidants, antiemetics, anticancer agents, antidiabetic agents, antidepressants, anxiolytics, antipsychotics, statins and antihypertensives.

It is preferred in the present invention that the active pharmaceutical ingredient is an antimicrobial. Examples of suitable classes of antimicrobials include but are not limited to antibacterials, antivirals, antifungals and antiprotozoals.

It is particularly preferred in the present invention that the active pharmaceutical ingredient is an antifungal. Such compounds may be capable of inactivating or killing a wide range of fungi, but particularly the fungal species responsible for fungal skin and nail infections responsible for onychomycosis.

In particular, the antifungal compound is a compound capable of inactivating or killing the group of fungi known as dermatophytes. The common property of dermatophytes is that they all are capable of invading and establishing residence in the tissues associated with the skin. The principle nutrient source for dermatophytes in skin and nails is keratinized proteins. Keratin is non-viable matrix protein complexes derived from epidermal tissues. Typically dermatophytes do not invade beyond the non-viable keratinized layers. Although dermatophytes constitute 90-96% of the cases of onychomycosis, other fungi such as yeasts and moulds have also been found in association with the disease. Other causative pathogens include Candicla and nondermatophytic moulds, in particular members of the mould generation Neoscyta/idium, Scopulariopsis, and Aspergillus. Candida spp. mainly cause fingernail onychomycosis in people whose hands are often submerged in water.

In particular, the antifungal compound is a compound capable of inactivating or killing fungi of a genus selected from the group consisting of Trichophytori, Epiderrnophyton, Micmsporum, Aspergillus, Scopulariopsis and Candida.

In particular, the antifungal compound is a compound capable of inactivating or killing fungi of a species selected from the group consisting of Trichophyton rubrum, Trichophyton interdigitale, Trichophyton violaceum, Trichophyton tonsurans, Trichophyton soudanense, Trichophyton mentagrophytes, Epidermophyton.

floccosum, Microsporum gypseum, Aspergillus niger, Scopu/ariopsis brevicaulis and Can dida.

Trichophyton rubrum is the most common dermatophyte involved in onychomycosis.

Other dermatophytes that may be involved are 11 interdigitafe, Epiderrnophyton floccosum, T. violaceurn, Microsporum gypseum, T. tonsurans, and T. soudanense.

The predominate isolates from infected nails has been Tiychophyton rubrurn followed thereafter by Trichophyton mentagrophytes, Epidermophyton sp. and Microsporum sp, Non-dermatophyte moulds that are occasionally isolated include Aspergi//us niger and Scopulariopsis brevicaulis. Collectively these less frequently encountered fungi account for less than 4-5% of cases. Even less frequently encountered are yeast.

The most common yeast isolate is Candida a/b/cans which accounts for 3-4% of the total cases. C. a/b/cans onychomycosis is more frequent in women than in men, most often affecting their fingernails.

Examples of antifungal agents include those of the following classes: polyene antifungal drugs such as amphotericin B, candicidin, filipin, hamycin, natamycin, nystatin and rimocidin; azole antifungal drugs, in particular imidazoles such as bifonazole, butoconazole, clotrimazole, econazole, fenticonazole, isoconazole, ketoconazole, miconazole, omoconazole, oxiconazole, sertaconazole, sulconazole and tioconazole; triazoles such as albaconazole, fluconazole, isavuconazole, itraconazole, posaconazole, ravuconazole, terconazole and voriconazole; and thiazoles such as abafungin; allylamines such as amorolfin, butenafine, naftifine and terbinafine; echinocandins such as anidulafungin, caspofungin and micafungin; other synthetic antifurigals such as ciclopirox (ciclopirox olamine), flucytosine or 5-fluorocytosine, griseofulvin, polygodial, tolnaftate and undecylenic acid; and natural substances having antifungal properties, including propolis, oregano, allicin, citronella oil, coconut oil, lemon myrtle, menthol, neem seed oil, olive leaf, orange oil, palmarosa oil, patchouli and tea tree oil, and extracts from plants such as horopito (Pseudowintera colorata), turnip, chives, radish and garlic.

In a preferred embodiment, the antifungal is or comprises a terpene, terpenoid or terpinene. Terpenes may be classified by the number of isoprene units in the molecule; a prefix in the name indicates the number of terpene units needed to assemble the molecula When terpenes are modified chemically, such as by oxidation or rearrangement of the carbon skeleton, the resulting compounds are generally referred to as terpenoids. Examples of terpenes include monoterpenes (composed of two isoprene units and having the molecular formula C10H15) such as geraniol, limonene and terpineol; sesquiterpenes (composed of three isoprene units and having the molecular formula C15H24) including humulene, farnesenes, and farnesol; diterpenes (composed of four isoprene units and having the molecular formula C20H32) such as cafestol, kahweol, cembrene and taxadiene; sesterterpenes (composed of five isoprene units and having the molecular formula C25H40) such as geranylfarnesol; triterpenes (composed of six isoprene units) such as squalene; sesquarterpenes (composed of seven isoprene units and having the molecular formula 035H55) such as ferrugicadiol and tetraprenylcurcumene; and tetraterpenes (composed of eight isoprene units and having the molecular formula C40H64) such as lycopene, and alpha-beta-and gamma-carotene. Particular terpenes and terperioids having antifungal activity include copaene, cymene and limonene.

In a preferred embodiment, the antifungal is or comprises propolis. As described in MC. Marcucci, Apidologic, 1995, 26(2), 83-99, propolis is a natural resinous substance collected by bees from parts of plants, buds and exudates, and used by bees as a sealer for their hives.

The chemical composition of propolis varies widely depending on the flora of the area of collection, the time of collection and the inclusion of wax contaminants. A wide number of classes of chemical compounds have been isolated from propolis.

Examples of classes of compounds identified in propolis resin include: alcohols such as ethylene glycol, phenethyl alcohol and glycerol;, aldehydes; aliphatic acids, such as succinic acid, malic acid, azelaic acid, hexadecanoic acid, oleic acid, 2-hexenedioic acid, and esters of any thereof; amino acids; aromatic acids such as benzoic acid, cinnamic acid, 3,4-methylenedioxycinnamic acid, 3,4-dimethoxycinnamic acid, ferulic acid, caffeic acid, p-coumaric acid, 0-9-tetrahydrocannabinol acid, gallic acid and phoroglucinic acid; aromatic esters such as ethyl benzoate, 3-methyl-2-.butenyl isoferulate, cinnamyl cinnamate, cinnamic acid esters, benzyl ferulate, phenylethyl caffeate and ciririamyl caffeate; flavonoids, including chalcones and dihydrochalcones, flavanones, flavones and flavonols, such as pinostrobin (chalcone), pinocembrin, pinobanksin, pinobanksin 3- 0-acetate, chrysine, galangin, pinobanksin isobutanoate, naringenin, kaempferol, apigenine and quercetin; anthraquinones, such as chysophanol(1,8-dihydroxy-3-methylanthraquinone), 1,6- dihydroxy-8-methoxy-3-methylanthraquinone, emodin (1,6,8-trihydroxy-3-methylanthraquinone) and I,7-dihydroxy-3-methoxy-6-methylanthraquinone; waxes (including hydrocarbons, esters, ethers, hydroxyl and keto waxes)and waxy acids; ketones such as 5-hydroxy-1,7-diphenyl-3-heptanone and (3e,5e,7e)-6-methyl-8- (2,6,6-trimethyl-1 -cyclohexenyl)-3,5,7-octatrienone; terpenoids and related compounds such as thymol, menthol, thunbergol, pimaric acid, totarol, phytol, dehydroabietic acid, abietic acid and isopimaric acid; steroids; and sugars.

The composition of propolis from various sources is described in more detail in N. Kalogeropoulos et al; Food Chem. 2009, 116, 452-461, incorporated herein by reference.

While not wishing to be bound by theory, it is believed that a number of compounds, may be responsible for the natural antifungal activity of propolis.

In one embodiment, the antifungal active in propolis is a flavonoid. In one embodiment, the antifungal active in propolis is selected from the group consisting of pinostrobin (chalcone), pinocembrin, pinobanksin, pinobanksin 3-0-acetate, chrysine, galangin, pinobanksin isobutanoate, naririgenin, kaempferol, apigenine and quercetin. In one embodiment, the antifungal active in propolis is selected from the group consisting of pinocembrin, pinobanksin, pinobanksin 3-0-acetate, chrysin and galangin.

Without wishing to be bound by theory, it is believed that terpenoids and related compounds may be responsible for the antifungal effects of propolis. The terpenoids include monoterpenes, sesquiterpenes, diterpenes, sesterterpenes and triterpenes.

Examples of specific terpenoids and related compounds identified in propolis resin include ct-acetoxybutylenol; 13-bisabolol; I,8-cineole (eucalyptol); cc-copaene; cymene; limonene; pterostilbene; styrene; xanthorreol; xylitol; naphthalene; 4-hexanolactone; sesquiterpene alcohol; and sesquiterpene diol.

In one embodiment, the antifungal active in propolis is a terpene, terpenoid or terpenic acid. In one embodiment, the antifungal active in propolis is selected from the group consisting of thymol, menthol, thunbergol, pimaric acid, totarol, phytol, dehydroabietic acid, abietic acid, isopimaric acid, oleanolic acid and ursolic acid. In one embodiment, the antifungal active in propolis is selected from the group consisting of dehydroabietic acid, abietic acid, isopimaric acid, oleanolic acid and ursolic acid.

The proportion of the active pharmaceutical ingredient in the composition varies depending on factors such as the nature of the active ingredient, the subject and the intended use of the composition. In one embodiment, the active pharmaceutical ingredient comprises 0.01 to 99.99% by weight of the total weight of the composition In one embodiment, the active pharmaceutical ingredient comprises 0.1 to 99.9% by weight of the total weight of the composition. In one embodiment1 the active pharmaceutical ingredient comprises 5 to 95% by weight of the total weight of the composition. In one embodiment, the active pharmaceutical ingredient comprises 10 to 90% by weight of the total weight of the composition.

When the active pharmaceutical ingredient is an antifungal agent, the proportion of the antifungal agent in the composition varies depending on factors such as the nature of the antifungal agent, the subject and the intended use of the composition.

In one embodiment, the antifungal agent comprises 0.01 to 99.99% by weight of the total weight of the composition. In one embodiment, the antifungal agent comprises 0.1 to 99.9% by weight of the total weight of the composition. In one embodiment, the antifungal agent comprises I to 99% by weight of the total weight of the composition.

In one embodiment, the antifungal agent comprises 5 to 95% by weight of the total weight of the composition. In one embodiment, the antifungal agent comprises 10 to 90% by weight of the total weight of the composition. In one embodiment, the antifungal agent comprises 0.1 to 50% by weight of the total weight of the composition. In one embodiment, the antifungal agent comprises ito 25% by weight of the total weight of the composition. In one embodiment, the antifungal agent comprises 2 to 20% by weight of the total weight of the composition. In one embodiment, the antifungal agent comprises 4 to 12% by weight of the total weight of the composition. In one embodiment, the antifungal agent comprises 5 to 10% by weight of the total weight of the composition. In one embodiment, the antifungal agent comprises 6 to 8% by weight of the total weight of the composition.

When the antifungal agent is or comprises propolis, in one embodiment, the propolis comprises 2 to 20% by weight of the total weight of the composition. In one embodiment, the propolis comprises 4 to 12% by weight of the total weight of the composition. In one embodiment, the propolis comprises 5 to 10% by weight of the total weight of the composition. In one embodiment, the propolis comprises 6 to 8% by weight of the total weight of the composition.

Dimethyl sulfoxide The pharmaceutical composition of the present invention also contains dimethyl sulfoxide (DMSO). The function of the DMSO is to act both as a keratolytic and as a solvent for the active pharmaceutical ingredient. Without wishing to be bound by theory, it is believed that dimethyl sulfoxide may also act as a chemical and/or physical penetration enhancer which may aid, and at the same time be aided by, the other ingredients in the composition, to reach and help dissolve other highly keratinized tissues and parts of the nail.

The proportion of the dimethyl sulfoxide in the composition varies depending on factors such as the nature of the active pharmaceutical ingredient, the humectant and other ingredients of the composition, and the subject and the intended use of the composition. In one embodiment, the dimethyl sulfoxide comprises Ito 25% by weight of the total weight of the composition. In one embodiment, the dimethyl sulfoxide comprises 2 to 20% by weight of the total weight of the composition. In one embodiment, the dimethyl sulfoxide comprises 5 to 15% by weight of the total weight of the composition. In one embodiment, the dimethyl sulfoxide comprises 8 to 12% by weight of the total weight of the composition. In one embodiment, the dimethyl S sulfoxide comprises 9 to 11% by weight of the total weight of the composition.

Humectant The pharmaceutical composition of the present invention also contains a humectant.

A humectant is a substance that is used to keep things moist. Humectants are hygroscopic substances. Without wishing to be bound by theory, it is believed that the humectant provides molecular space for the incorporation of one or more active pharmaceutical ingredient; the humectant may also cooperate with the other ingredients of the composition to increase the penetration enhancer effect of these ingredients. The composition may include one or a mixture of two or more humectants.

Humectants typically fall into two classes: ionic salts and small molecule humectants.

In one embodiment the humectant is an ionic salt. Examples of ionic salts capable of acting as humectants include but are not limited to sodium chloride, lithium chloride, copper chloride, magnesium chloride, magnesium sulfate, manganese sulphate, aluminum sulfate, zinc sulfate, and zinc chloride. A preferred example is magnesium sulfate.

In one embodiment the humectant is a small molecule humectant. Small molecule humectants are typically molecules with one or more hydrophilic groups able to form hydrogen bonds with molecules of water. Typically, the hydrophilic groups are hydroxyl groups, but amines and carboxylic acids and esters can also be hydrophilic.

Examples of small molecule humectants include monoalcohols such as methanol, ethanol, propanol, isopropanol, and butanol; polyols such as ethylene glycol, glycerol, propylene glycol and and sugar polyols such as sorbitol, xylitol and maltitol; and hydroxy acids such as lactic acid. Other humectants include polymeric polyols like polydextrose; and polyethylene glycol (typically defined by its average molecular weight with atypical tolerance of ±10%, preferably ±5%, and which may be for example polyethylene glycol 200, polyethylene glycol 400, or polyethylene glyco! 600).

In one embodiment, the humectant used in the composition of the present invention is of sufficient low molecular size to penetrate and localize in the nail plate so that moisture attracted to the humectant will also localize in the nail. Typically, the humectant has a maximum molecular weight of about 600, in one embodiment about 500, in one embodiment about 400, in one embodiment about 300, in one embodiment about 250, in one embodiment about 200, in one embodiment about 150, in one embodiment about 125 (±5%) The proportion of the humectant in the composition varies depending on factors such as the nature of the active pharmaceutical ingredient, the other ingredients of the composition, and the subject and the intended use of the composition. In one embodiment, the humectant comprises Ito 50% by weight of the total weight of the composition. In one embodiment, the humectant comprises 2 to 35% by weight of the total weight of the composition. In one embodiment, the humectant comprises 5 to 25% by weight of the total weight of the composition. In one embodiment, the humectant comprises 10 to 20% by weight of the total weight of the composition. In one embodiment, the humectant comprises 13 to 17% by weight of the total weight of the composition.

Where the hurriectant is magnesium sulphate, the magnesium sulphate typically comprises 5 to 26% by weight of the total weight of the composition. In one embodiment, the magnesium sulphate comprises 10 to 20% by weight of the total weight of the composition. In one embodiment, the magnesium sulphate comprises 13 to 17% by weight of the total weight of the composition.

Typically, the composition comprises 5 to 15% by weight dimethyl sulfoxide and 10 to 20% by weight of the humectant. Preferably, the composition comprises 8 to 12% by weight dimethyl sulfoxide and l3to 17% by weight of the humectant. These percentages are expressed as a proportion of the total weight of the composition.

Where the humectant is magnesium sulphate, typically, the composition comprises 5 to 15% by weight dimethyl sulfoxide and 10 to 20% by weight magnesium sulphate.

Preferably, the composition comprises 8 to 12% by weight dimethyl sulfoxide and 13 to 17% by weight magnesium sulphate. These percentages are expressed as a proportion of the total weight of the composition.

Other Ingredients The pharmaceutical composition of the present invention may also contain one or more additional ingredients.

In one embodiment, the pharmaceutical composition of the present invention additionally includes water. The function of the water is to provide an aqueous phase for the formulation, especially when it is in the form of an emulsion or a cream.

Where present, the water typically comprises ito 50%, preferably 10 to 20 %, preferably 13 to 17 %, by weight of the total weight of the composition.

The water may be, for example, tap water, distilled/deionised water, or water extracted from natural materials, such as plant sources. In one embodiment, the water is distilled water. In one embodiment, the water is deionised water. In one embodiment, the water is rose water, which is the hydrosol portion of the distillate of rose petals. Where present, the rose water typically comprises 10 to 20 %, preferably 13 to 17 %, by weight of the total weight of the composition.

In one embodiment, the pharmaceutical composition of the present invention additionally includes an antiseptic. Where present, the antiseptic typically comprises 0.1 to 2 %, preferably 0.5 to 1.5%, by weight of the total weight of the composition.

The composition may include one or a mixture of two or more antiseptics. Typically, the antiseptic is boric acid.

In one embodiment, the pharmaceutical composition of the present invention additionally includes an emulsifier Where present, the emulsifier typically comprises 0.5 to 10 %, preferably ito 9 %, by weight of the total weight of the composition.

The composition may include one or a mixture of two or more emulsiflers.

Typically, the emulsifier is selected from beeswax, emulsifying wax, or a mixture thereof. Beeswax is a natural wax produced in the bee hive of honey bees of the genus Apis. It is mainly esters of fatty acids and various long chain alcohols. Its main components are palmitate, palmitoleate, and oleate esters of long-chain (30-32 carbons) aliphatic alcohols, with the ratio of triacontanyl palmitate CH3(CH2)290-CO- (CH2)14CH3 to cerotic acid CH3(CH2)24000H, the two principal components, being 6:1.

Emulsifying wax is a cosmetic emulsifying ingredient, formed by the action of a detergent (typically sodium dodecyl sulfate or polysorbates) on a wax material (either a vegetable wax of some kind or a petroleum-based wax) is treated with to cause it to make oil and water bind together into a smooth emulsion. Emulsifying Wax NE contains cetearyl alcohol (also known as cetostearyl alcohol or cetylstearyl alcohol and comprising a mixture of fatty alcohols having 16 to 18 carbon atoms, consisting predominantly of cetyl and stearyl alcohols), polyoxyethylene (20) sorbitan monostearate (polysorbate 60), polyethylene glycol-150 distearate, and polyethylene glycol 1000 stearyl ether (Steareth-20).

Alternatively, the emulsifier is behenyl TMS (a mixture of behenyltrimethylammonium methyl sulfate, cetyl alcohol and butylene glycol (available as lncroquat'TM Behenyl TMS 50 from Croda).

When the emulsifier is beeswax, it typically comprises 3 to 7 %, preferably 4 to 6 %, by weight of the total weight of the composition. When the emulsifier is emulsifying wax, it typically comprises 10 to 20 %, preferably 13 to 17 %, by weight of the total weight of the composition.

The pharmaceutical composition of the present invention may also include an oil phase. In one embodiment, the pharmaceutical composition of the present invention additionally includes mustard seed oil. The function of this ingredient is to provide an oil phase and provide skin nutrients, such as oleic acid and vitamin E (which may comprise a tocopherol, a tocotrienol, or a mixture of any thereof). Where present, the mustard seed oil typically comprises 10 to 20% preferably 13 to 17%, by weight of the total weight of the composition.

In one embodiment, the pharmaceutical composition of the present invention additionally includes tea tree oil. Tea tree oil, or melaleuca oil, is an essential oil taken from the leaves of the plant Me/aleuca alternifolia. In one embodiment, the tea tree oil is defined by international standard ISO 4730 (2004) ("Oil of Mefaleuca, Terpinen-4-ol type!!), incorporated herein by reference. Where present, the tea tree oil typically comprises 4 to 12 %, preferably 6 to 10 %, by weight of the total weight of the composition.

In one embodiment, the pharmaceutical composition of the present invention additionally includes a thickener. Thickening agents, or thickeners, are substances which increase the viscosity of a solution or liquidlsolid mixture without substantially modifying its other properties. Where present, the thickener typically comprises I to %, preferably 2 to 4 %, by weight of the total weight of the composition.

Examples of suitable thickeners include lecithin, behenyl alcohol, behenyl TMS, and cellulose gum.

In one embodiment, the thickener is lecithin. Commercially available lecithin is a mixture of phospholipids typically comprising at least 95%, such as 97%, such as 99% by weight (as a percentage of the total weight of the phospholipids) phosphatidylcholine and the balance typically comprising phosphatidylethanolamine and/or phosphosphingolipids. Where present, the lecithin typically comprises Ito %, preferably 2 to 4 %, by weight of the total weight of the composition.

In one embodiment, the pharmaceutical composition of the present invention additionally includes menthol. The function of the menthol is to act as an additional antimicrobial (particularly an antifungal). Where present, the menthol typically comprises 0. ito 2 %, preferably 1.3 to 1.7 %, by weight of the total weight of the composition.

In one embodiment, the pharmaceutical composition of the present invention additionally includes a moisturiser. A moisturiser, or emollient, is an agent capable of softening the external layers of the skin (epidermis), particularly by increasing the skin's hydration (water content) by reducing evaporation. Examples of suitable moisturisers include glycerol, amino acids, ceramides, hyaluronic acid, cholesterol, fatty acids, triglycerides, phospholipids, glycosphingolipids, urea, linoleic acid, glycosaminoglycans, mucopolysaccharide, and sodium PCA (pyrrolidone carboxylic acid), and mixtures thereof. The moisturiser may also function as an additional humectant.

In one embodiment, the moisturiser is glycerol. As noted above, the glycerol may also function as a humectant. Where present, the glycerol typically comprises 2 to 8 %, preferably 4 to 6 %, by weight of the total weight of the composition.

In one embodiment, the composition is formulated for topical delivery, particularly to the skin or nails. Examples of topical delivery vehicles include solid matrices, hydrogels, creams, gels and other solutions comprising the composition of the formulation in effective amounts to treat the intended disorders and conditions.

In one embodiment, the composition comprises: 2 to 20% by weight of the antifungal agent; to 15% by weight dimethyl sulfoxide; and to 20% by weight of the humectant; as a proportion of the total weight of the composition.

In one embodiment, the composition comprises: Sto 10% by weight of the antifungal agent; 8 to 12% by weight dimethyl sulfoxide; and 13 to 17% by weight of the humectant; as a proportion of the total weight of the composition.

In one embodiment, the composition comprises: 2 to 20% by weight of the antifungal agent; 5 to 15% by weight dimethyl sulfoxide; and to 20% by weight of magnesium sulfate; as a proportion of the total weight of the composition.

In one embodiment, the composition comprises: 5 to 10% by weight of the antifungal agent; to 15% by weight dimethyl sulfoxide; and to 20% by weight of magnesium sulfate; as a proportion of the total weight of the composition.

In one embodiment, the composition comprises: 2 to 20% by weight of the antifungal agent; to 15% by weight dimethyl sultoxide; to 20% by weight of the humectant; to 20% by weight water; 0.1 to 2% by weight of antiseptic; 0.5 to 10% by weight of emulsifier; to 20% by weight of mustard seed oil; 4 to 12% by weight of tea tree oil; 1 to 5% by weight of thickener; 0.1 to 2% by weight of menthol; and 2 to 8 % by weight of moisturiser; as a proportion of the total weight of the composition.

In one embodiment, the composition comprises: to 10% by weight of the antifungal agent: 8 to 12% by weight dimethyl sulfoxide; 13 to 17% by weight of the humectant; 13 to 17% by weight water; 0.5 to 1.5% by weight of antiseptic; ito 9 % by weight of emulsifier; to 20% by weight of mustard seed oil; 6 to 10% by weight of tea tree oil; 2 to 4%, by weight of thickener; 1,3 to 1.7% by weight of menthol; arid 4 to 6% by weight of moisturiser; as a proportion of the total weight of the composition.

In one embodiment, the composition comprises: 2 to 20% by weight of the antifungal agent; to 15% by weight dimethyl sulfoxide; to 20% by weight of magnesium sulfate; 10 to 20% by weight distilled water; 0.1 to 2% by weight of boric acid; 3 to 7% by weight of beeswax; lOto 20% by weight of emulsifying wax; 13 to 17% by weight of mustard seed oil; 4 to 12% by weight of tea tree oil; Ito 5% by weight of lecithin; 0,1 to 2% by weight of menthol; and 2 to 8% by weight of glycerol; as a proportion of the total weight of the composition.

In one embodiment, the composition comprises: to 10% by weight of the antifungal agent; 8 to 12% by weight dimethyl sulfoxide; 13 to 17% by weight of magnesium sulfate; 13 to 17% by weight distilled water; 0.5 to 1.5% by weight of boric acid; 4 to 6% by weight of beeswax; 13 to 17% by weight of emulsifying wax; 13 to 17% by weight of mustard seed oil; 6 to 10% by weight of tea tree oil; 2 to 4% by weight of lecithin; 1.3 to I.7% by weight of menthol; and 4 to 6 % by weight of glycerol; as a proportion of the total weight of the composition.

Uses and Medical Indications Depending on the nature of the active pharmaceutical ingredient, the pharmaceutical composition of the present invention may be used for treating a wide range of conditions.

In one embodiment, the pharmaceutical compositions are useful in treating microbial infections. Examples of microbial infections include those caused by bacteria1 viruses, fungi and protozoans. In one embodiment, the pharmaceutical compositions are useful in treating fungal infection.

The pharmaceutical composition of the present invention may be used for treating a disease or condition of the skin. The composition is applied to affected areas of skin or dermal structures so that the one or more active agents are delivered in an amount effective to treat altered dermal areas or prevent infection or attachment of organisms to a skin area or demial structure.

In this specification the terms "skin", "dermal" or "derrnal structures" are used interchangeably and refer to the elements of the integumentary system of humans and animals, including organ and cavity linings, such as pleura, dura, and pericardium, and mucous membranes and such terms. The integumentary system as it is commonly understood by those skilled in the art refers to the skin, including the epidermis and dermis, which comprise layers including stratum basale, stratum spinosum, stratum granulosum, stratum lucidum, stratum corneum, papillary layer and reticular layer. Cells which are found in these dermal structures include, but are not limited to, keratinocytes, fibroblasts, rnelanocytes, dendritic cells, Landerhans' cells, epithelial cells, and Merkel cells. Dermal structures include appendages such as hair, sebaceous glands, sweat glands, follicles, nerve structures, horns, hooves and nails.

In one embodiment, the pharmaceutical compositions of the present invention are useful in treating a disease or condition of the nail. In a preferred embodiment, the pharmaceutical compositions of the present invention are useful in treating onychomycosis. The onychomycosis may be, for example, distal subungual onychomycosis, white superficial onychomycosis, proximal subungual onychomycosis or candidal onychomycosis.

In one embodiment, the pharmaceutical compositions of the present invention are useful in treating tinea pedis. Tinea pedis (also known as athlete's foot, ringworm of the foot, or moccasin foot) is a fungal infection of the skin that causes scaling, flaking, and itch of affected areas, and in severe cases, swelling and amputation of the foot.

It is caused by fungi in the genus Trichophyton. Although the condition typically affects the feet, it can infect or spread to other areas of the body, including the groin, particularly areas of skin that are kept hot and moist, such as with insulation, body heat, and sweat, e.g. in a shoe, for long periods of time.

The composition may be used to treat both human and non-human subjects.

Examples of non-human subjects include companion animals such as dogs, cats, horses, rabbits, gerbils, rats, guinea pigs and hamsters, and livestock such as cows, sheep, pigs, goats and deer. Preferably the subject is a human subject.

Dosage The pharmaceutical composition of the present invention may provide a dose of, for example, between 0.01 mg and 5 g of the active ingredient. In one embodiment the composition provides a dose of between 0.05 mg and 2 g of the active ingredient. In one embodiment the composition provides a dose of between 0.1 mg and 1 g of the active ingredient. In one embodiment the composition provides a dose of between 0.5 mg and 500 mg of the active ingredient. In one embodiment the composition provides a dose of between 1 mg and 100mg of the active ingredient.

The pharmaceutical compositions of the present invention may be administered at a dosing interval selected by the doctor depending on a number of factors such as the age, sex, weight and physiological condition of the subject to be treated, In one embodiment, the compositions are administered once a day. In one embodiment, the compositions are administered twice a day. In one embodiment, the compositions are administered three times a day. In one embodiment, the compositions are administered four times a day. A number of compositions (preferably Ito 3, more preferably 1 or 2, and more preferably only one) may be administered at each dosing interval.

Exam pies Example 1 -Composition A composition of the present invention comprises the ingredients in Table 1: Component Function Grade! % by weight ________ Source Dirnethyl sulfoxide Keratolytic I solvent Ph Eur, ACS 10 Propolis Source of terpenes/ Latvia B Distilled water Aqueous phase HACCP IS Magnesium Humectant USP 15 Sulphate _________________________ _____________ ___________________ Boric Acid Antiseptic NF 1 Mustard Seed oil oil phase/skin nutrients, HACCP 14 __________________ oleic acid, vitamin E ____________ __________________ Tea Tree Oil Essential Oil __________ HACCP 6 __________ Beeswax Emulsifier _________ HACCP 5 ______ Emulsifying wax Emulsifier NF 15 Lecithin Thickener HACCP 3 Menthol Antimicrobial / antifungal Ph Eur, AP 1 _______ Glycerol Moisturizer Ph Eur, USE' 5

Table I

To form part 1 of the mixture, the propolis was dissolved in DMSO. Separately, the magnesium sulphate and boric acid were dissolved in distilled water to form pad 2 of the mixture.

To form part 3 of the mixture, mustard seed oil was firstly heated to 75°C, and beeswax was added, followed by emulsifying wax and mixed until dissolved. Tea tree oil was then added, followed by glycerol, then menthol followed by lecithin and mixing continued for 5 minutes before heating was ceased.

Parts 1 and 2 were mixed, then the mixture added to pad 3 and mixing continued for 5 minutes while cooling to form the final composition.

Example 2 -Treatment of Onychomycosis The composition of Example 1 was used to treat a patient with onychomycosis. Fig. 3 illustrates the toe nail of the patient prior to treatment.

S The composition was applied twice per day for 47 days directly to the nail, a thin coat fully covering the affected area.

Fig. 4 illustrates the toe nail of the patient after the treatment. The yellow nature of the nail provides evidence of absorption of the composition: it can easily be removed after completion of the therapy.

Example 3-Treatment of Tinea Pedia The composition of Example 1 was used to treat a patient with tinea pedia.

The composition was applied twice per day for 5 days directly to the affected area.

Claims

CLAIMS1. A pharmaceutical composition comprising: an active pharmaceutical ingredient suitable for treating a disease or condition of the skin; dimethyl sulfoxide; and a humectant.

2. A pharmaceutical composition according to claim 1, wherein the active pharmaceutical ingredient suitable for treating a disease or condition of the nail.

3. A pharmaceutical composition according to claim 1, wherein the active pharmaceutical ingredient is an antifungal agent.

4. A pharmaceutical composition according to claim 1 the wherein antifungal agent is capable of inactivating or killing dermatophytes.

5. A pharmaceutical composition according to claim 1, wherein the antifungal agent is capable of inactivating or killing fungi of a genus selected from the group consisting of Trichophyton, Epiclermophyton, Microsporum, AspergIllus, Scopulariopsis and Candida.

6. A pharmaceutical composition according to claim I wherein the antifungal agent is capable of inactivating or killing fungi of a species selected from the group consisting of Trichophyton rubrum, Trichophyton interdigifale, Trichophyton violaceum, Trichophyton tonsurans, Trichophyton soudanense, Trichophyton mentagrophytes, Epidermophyton floccosum, Microsporum gypseum, Aspergifius niger, Scopulariopsis brevicaulis and Candida alibicans.

7. A pharmaceutical composition according to any one of claims 3 to 6, wherein the antifungal agent comprises 0.01 to 99.99% by weight of the total weight of the composition.

8, A pharmaceutical composition according to any one of claims 3 to 6, wherein the antifungal agent comprises 4 to 12% by weight of the total weight of the composition.

9. A pharmaceutical composition according to any one of claims 3 to 8, wherein the antifungal is or comprises a terpene or terpenoid.

10. A pharmaceutical composition according to any one of claims 3 to 8, wherein the S antifungal is or comprises propolis.

11A pharmaceutical composition according to any one of claims ito 10, wherein the dimethyl sulfoxide comprises ito 25% by weight of the total weight of the composition. i0

12. A pharmaceutical composition according to any one of claims ito 10, wherein the dimethyl sulfoxide comprises 8 to 12% by weight of the total weight of the composition.

13. A pharmaceutical composition according to any one of claims ito 12, wherein the humectant is an ionic salt.

14. A pharmaceutical composition according to claim 13, wherein the ionic salt is selected from the group consisting of sodium chloride, lithium chloride, copper chloride, magnesium chloride, magnesium sulfate, manganese sulphate, aluminum sulfate, zinc sulfate, and zinc chloride.

15. A pharmaceutical composition according to claim 14, wherein the ionic salt is magnesium sulfate.

16. A pharmaceutical composition according to claim 15, wherein the magnesium sulfate comprises 10 to 20% by weight of the total weight of the composition.

17. A pharmaceutical composition according to claim 16, wherein the magnesium sulfate comprises 13 to 17% by weight of the total weight of the composition.

18. A pharmaceutical composition according to claim 14, comprising 5 to 15% by weight dimethyl sulfoxide and 10 to 20% by weight magnesium sulphate.

19. A pharmaceutical composition according to claim 14, comprising comprises Sto 12% by weight dimethyl sulfoxide and 13 to 17% by weight magnesium sulphate.

20. A pharmaceutical composition according to claim 1, additionally including water.

21. A pharmaceutical composition according to claim 20, wherein the water is selected from tap water, distilled water, and water extracted from plant sources.

22. A pharmaceutical composition according to claim 21, wherein the water is distilled water.

23. A pharmaceutical composition according to claim 22, wherein the distilled water comprises 10 to 20 % by weight of the total weight of the composition.

24. A pharmaceutical composition according to claim 1, additionally including an antiseptic.

25. A pharmaceutical composition according to claim 24, wherein the antiseptic comprises 0.1 to 2% by weight of the total weight of the composition.

26. A pharmaceutical composition according to claim 24 or claim 25, wherein the antiseptic is boric acid.

27. A pharmaceutical composition according to claim 1, additionally including an emulsifier.

28. A pharmaceutical composition according to claim 27, wherein the emulsifier is selected from beeswax, emulsifying wax, or a mixture thereof.

29. A pharmaceutical composition according to claim 28, wherein the emulsifier is beeswax and the beeswax comprises 3 to 7 % by weight of the total weight of the composition.

30. A pharmaceutical composition according to claim 29, wherein the emulsifier is the emulsifier is emulsifying wax, and the emulsifying wax comprises 10 to 20% by weight of the total weight of the composition.

31. A pharmaceutical composition according to claim 1, additionally including mustard seed oil.

32. A pharmaceutical composition according to claim 31, wherein the mustard seed oil comprises 10 to 20 % by weight of the total weight of the composition.

33. A pharmaceutical composition according to claim 1, additionally including tea tree oil.

34. A pharmaceutical composition according to claim 33, wherein the tea tree oil comprises 4 to 12% by weight of the total weight of the composition.

35. A pharmaceutical composition according to claim 1, additionally including a thickener.

36. A pharmaceutical composition according to claim 35, wherein the thickener comprises Ito 5 % by weight of the total weight of the composition.

37. A pharmaceutical composition according to claim 35 or claim 36, wherein the thickener is lecithin.

38. A pharmaceutical composition according to claim 1, additionally including menthol.

39. A pharmaceutical composition according to claim 38, wherein the menthol comprises 0.1 to 2 % by weight of the total weight of the composition.

40. A pharmaceutical composition according to claim 1, additionally including a moisturiser.

41. A pharmaceutical composilion according to claim 40, wherein the moisturiser is glycerol.

42. A pharmaceutical composition according to claim 41, wherein the glycerol comprises 2 to 8 % by weight of the total weight of the composition.

43. A pharmaceutical composition according to claim 1, comprising: 2 to 20% by weight of the antifungal agent; to 15% by weight dimethyl sulfoxide; and to 20% by weight of the hurnectant; as a proportion of the total weight of the composition.

44, A pharmaceutical composition according to claim 1, comprising: to 10% by weight of the antifungal agent; 8 to 12% by weight dimethyl sulfoxide; and 13 to 17% by weight of the humectant; as a proportion of the total weight of the composition.

45. A pharmaceutical composition according to claim 1, comprising: 2 to 20% by weight of the antifungal agent; to 15% by weight dimethyl sulfoxide; and to 20% by weight of magnesium sulfate; as a proportion of the total weight of the composition.

46. A pharmaceutical composition according to claim 1, comprising: to 10% by weight of the antifungal agent; to 15% by weight dimethyl sulfoxide; and to 20% by weight of magnesium sulfate; as a proportion of the total weight of the composition.

47. A pharmaceutical composition according to claim 1, comprising: 2 to 20% by weight of the antifungal agent; to 15% by weight dimethyl sulfoxide; to 20% by weight of the humectant; 10 to 20% by weight water; 0.1 to 2% by weight of antiseptic; 0.5 to 10% by weight of emulsifier; to 20% by weight of mustard seed oil; 4 to 12% by weight of tea tree oil; ito 5% by weight of thickener; 0.1 to 2% by weight of menthol; and 2 to 8 % by weight of moisturiser; as a proportion of the total weight of the composition.

48. A pharmaceutical composition according to claim 1, comprising: to 10% by weight of the antifungal agent; 6 to 12% by weight dimethyl sulfoxide; 13 to 17% by weight of the humectant; 13 to 17% by weight water; 0.5 to 1.5% by weight of antiseptic; Ito 9 % by weight of emulsifier; iOta 20% by weight of mustard seed oil; 6 to 10% by weight of tea tree oil; 2 to 4% by weight of thickener; 1.3 to 11% by weight of menthol; and 4 to 6% by weight of moisturisen as a proportion of the total weight of the composition.

49. A pharmaceutical composition according to claim 1, comprising: 2 to 20% by weight of the antifungal agent; to 15% by weight dimethyl sulfoxide; 10 to 20% by weight of magnesium sulfate; to 20% by weight distilled water; 0.1 to 2% by weight of boric acid; 3 to 7D/ by weight of beeswax; lOto 20% by weight of emulsifying wax; lSto 17% byweight of mustard seed oil; 4to 12% byweight of tea tree oil; 1 to 5% by weight of lecithin; 0.1 to 2% by weight of menthol; and 2 to 8% by weight of glycerol; as a proportion of the total weight of the composition.

50. A pharmaceutical composition according to claim 1, comprising: to 10% by weight of the antifungal agent; 8 to 12% by weight dimethyl sulfoxide; 13 to 17% by weight of magnesium sulfate; 13 to 17% by weight distilled water; 0.5 to 1.5% by weight of boric acid; 4 to 6% by weight of beeswax; 13 to 17% by weight of emulsifying wax; 13 to 17% by weight of mustard seed oil; 6 to 10% by weight of tea tree oil; 2 to 4% by weight of lecithin; 1.3 to 1.7% by weight of menthol; and 4 to 6 % by weight of glycerol; as a proportion of the total weight of the composition.

51. A pharmaceutical composition, as defined in any one of claims ito 50, for use in treating a disease or condition of the skin.

62. A pharmaceutical composition, as defined in any one of claims ito 50, for use in treating a disease or condition of the nail.

53. A pharmaceutical composition, as defined in any one of claims Ito 50, for use in treating a fungal infection.

54. A pharmaceutical composition, as defined in any one of claims ito 50, for use in treating onychomycosis.

55. The pharmaceutical composition for use according to claim 54, wherein the onychomycosis is selected from distal subungual onychomycosis, white superficial onychomycosis, proximal subungual onychomycosis or candidal onychomycosis.

56. A pharmaceutical composition, as defined in any one of claims ito 50, for use in treating tinea pedis (athlete's foot).