ANTIFUNGAL VARNISH COMPOSITION

RELATED APPLICATION

The present application gains priority from U.S. Provisional Patent Application No. 61/382,293 filed 13 September 2010, which is included by reference as if fully set forth herein.

FIELD AND BACKGROUND OF THE INVENTION

The present invention relates to the field of nail varnish compositions and more particularly, in some embodiments to antifungal nail varnish compositions for topical administration to the fingernails or toenails.

Fungal infections are probably the most common disorder of the fingernails or toenails. It has been estimated that 90% of elderly people have some degree of fungal infection of the toenails. Conditions of moisture and occlusion of the lower extremities favor fungal colonization. Pain may result from extreme deformity of the nail plate, but usually, the complaint is one of cosmetic appearance, particularly for infections of the fingernails.

The most common organisms involved in fungal infections of the nail include Trichophyton rubrum, Trichophyton mentagrophytes, Epidermophyton floccosum, Candida albicans, Microsporum persiccolor, Cephalosporium species, Aspergillus species, and Fusarium oxysporum.

Currently, fungal infections of the nail are generally treated with cream or solution compositions including an antifungal agent such as itraconazole or terbinafine. The post- treatment recurrence of such infections is high, apparently due to the inefficacy of known compositions to deliver an effective amount of antifungal agent into the nail itself.

An antifungal nail varnish composition has been disclosed in US 7,074,392.

SUMMARY OF THE INVENTION

The teachings of the present invention relate to nail varnish compositions that, in some embodiments, are useful, for example, in the treatment of fungal infections of the fingernails or toenails.

According to an aspect of some embodiments of the invention, there is provided a nail varnish composition comprising a liquid nail lacquer and at least four different plant extracts (such as essential oils and/or tinctures) selected from the group consisting of tea-tree oil, extract of Thymus, Propolis derivative, extract of calendula, extract of coneflower, extract of manuka, and extract of lemongrass.

According to an aspect of some embodiments of the invention, there is also provided a method for the preparation of a nail varnish composition comprising mixing together a liquid nail lacquer and at least four different plant extracts (such as essential oils and/or tinctures) selected from the group consisting of tea-tree oil, extract of Thymus, Propolis derivative, extract of calendula, extract of coneflower, extract of manuka, and extract of lemongrass.

In some embodiments, the nail varnish composition is useful for the treatment of a fungal infection of a nail (a toenail, a fingernail, a claw) e.g., of a non-human animal, but especially of a human. Generally, subsequent to topical administration of the nail varnish composition to a nail, the nail varnish composition forms a solid film (a varnish layer) on the nail, the solid film together with other components of the nail varnish composition together treating a fungal infection of the nail.

In some embodiments, the nail varnish composition is useful in the preparation of a composition useful for the treatment of a fungal infection of the nails. For example, in some embodiments the nail varnish composition is an intermediate and can be made into a composition useful for the treatment of a fungal infection of the nails by the addition of one or more plant extracts.

In some embodiments, the at least four plant extracts of a composition or of a method comprise at least five different plant extracts selected from the group of plant extracts.

In some embodiments, the at least four plant extracts of a composition or of a method comprise at least six different plant extracts selected from the group of plant extracts.

In some embodiments, the at least four plant extracts of a composition or of a method comprise all seven different plant extracts from the group of plant extracts.

According to an aspect of some embodiments of the invention, there is provided a use of a nail varnish composition such as described above in the treatment of a fungal infection of the nails in a subject (in some embodiments a human, in some embodiments a non-human animal) in need thereof.

According to an aspect of some embodiments of the invention, there is provided a method for the treatment of a fungal infection of the nails in a subject (in some embodiments a human, in some embodiments a non-human animal) in need thereof, comprising administering a nail varnish composition such as described above. According to an aspect of some embodiments of the invention, there is also provided a nail varnish composition useful for stripping nails comprising a liquid nail lacquer, an essential oil and a keratolytic agent. Typically, the concentration of the keratolytic agent and the concentration of the essential oil is such that the composition is effective to weaken the structural integrity of a nail to which administered to an extent greater than with keratolytic agent alone.

According to an aspect of some embodiments of the invention, there is also provided the use of two different varnish compositions in the treatment of a fungal infection of the nails in a subject in need thereof, wherein:

a first varnish composition comprising a liquid nail lacquer, an antifungal agent and substantially devoid (preferably devoid) of a keratolytic agent that is administered to skin in proximity of an infected nail; and

a second varnish composition comprising a liquid nail lacquer, an antifungal agent and a keratolytic agent at a concentration sufficient to lead to loss of the nail during a course of treatment that is administered to an infected nail concurrently with administration of the first varnish composition.

According to an aspect of some embodiments of the invention, there is also provided a method for the treatment of a fungal infection of the nails in a subject in need thereof, comprising concurrently administering two compositions:

a first varnish composition comprising a liquid nail lacquer, an antifungal agent and substantially devoid (preferably devoid) of a keratolytic agent and is administered to skin in proximity of an infected nail; and

a second varnish composition comprising a liquid nail lacquer, an antifungal agent and a keratolytic agent at a concentration sufficient to lead to loss of the nail during a course of treatment administered to an infected nail concurrently with administration of the first varnish composition.

According to an aspect of some embodiments of the invention, there is also provided a kit (suitable for use in the treatment of a fungal infection of the nails in a human and/or non-human subject) comprising two antifungal varnish compositions:

a first varnish composition comprising a liquid nail lacquer, an antifungal agent and substantially devoid (preferably devoid) of a keratolytic agent; and

a second varnish composition comprising a liquid nail lacquer, an antifungal agent and a keratolytic agent at a concentration sufficient to lead to loss of the nail during a course of treatment each of said two varnish compositions being individually administrable.

Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains. In case of conflict, the patent specification, including definitions, will control.

As used herein, the term "treating" includes curing a condition, treating a condition, preventing a condition, treating symptoms of a condition, curing symptoms of a condition, ameliorating symptoms of a condition, treating effects of a condition, ameliorating effects of a condition, and preventing results of a condition.

As used herein, the terms "comprising", "including", "having" and grammatical variants thereof are to be taken as specifying the stated features, integers, steps or components but do not preclude the addition of one or more additional features, integers, steps, components or groups thereof. These terms encompass the terms "consisting of and "consisting essentially of.

As used herein, the term "pharmaceutically acceptable" means approved by a regulatory agency of the US Federal or a US state government or listed in the U.S. Pharmacopeia or other generally recognized pharmacopeia for use in animals, and more particularly in humans. Herein, the phrase "pharmaceutically acceptable carrier" refers to an approved carrier or a diluent that does not cause significant irritation to an organism and does not abrogate the biological activity and properties of the administered conjugate.

As used herein, the term "carrier" refers to a diluent, adjuvant, excipient, or vehicle with which the therapeutic is administered.

Herein the term "excipient" refers to an inert substance added to a pharmaceutical composition to further facilitate processes and administration of the active pharmaceutical ingredients.

As used herein and especially in the priority document, the term "an extract of Propolis" and "a Propolis derivative" are interchangeable unless the context clearly dictates otherwise.

As used herein and especially in the priority document, the term "apply" and variants thereof are synonymous with "topically administer" and variants thereof unless the context clearly dictates otherwise.

As used herein, the indefinite articles "a" and "an" mean "at least one" or "one or more" unless the context clearly dictates otherwise. DESCRIPTION OF SPECIFIC EMBODIMENTS OF THE INVENTION

In some embodiments, the invention relates to nail varnish compositions that, in some embodiments, are useful, for example, in the treatment of fungal infections of the fingernails or toenails.

Some embodiments of the invention are related to the surprising and unexpected experimentally-proven result that an embodiment of a nail varnish composition described herein, substantially a mixture of plant extracts with a liquid nail lacquer, is effective in the treatment of fungal infections of the nails (fingernails, toenails, claws) and surrounding tissues.

Some embodiments of the invention are related to the surprising and unexpected experimentally-proven result that an embodiment of a nail varnish composition described herein, substantially a mixture of an essential oil and a keratolytic agent with a liquid nail lacquer damage the structural integrity of nails to an exceptional extent, allowing easy stripping thereof.

Specific embodiments of the nail varnish composition that were formulated and experimentally-proven to be effective included extract of tea tree oil, extract of Thymus (specifically, thyme oil), a Propolis derivative (specifically, Propolis tincture), extract of calendula (specifically, calendula tincture), extract of conefiower (specifically, conefiower tincture), extract of lemongrass (specifically, lemongrass oil) and in some embodiments, also extract of manuka (specifically, manuka oil).

The number of species of flowering plants on earth is estimated to be in the range of 250,000 to 400,000. In addition to flowering plants, at least 12,000 species of fern and 14,000 species of Bryophyta have been identified. From any given part of a plant (e.g., leaves, stems, fruit, flowers, roots, bark) different extracts may be extracted by different methods {inter alia, water extraction, infusion, alcoholic extraction, organic extraction, distillation, super critical fluid extraction). At least some extracts of at least some members of each of these groups have been found to, are rumored to have or are suspected as having some level of antifungal activity.

In view of the effectively infinite number of combinations of the exceedingly high number of different plant extracts having a given pharmacological activity (e.g., antifungal activity), the selection of a particular combination of plant extracts for a given use and finding that such a combination has any utility is daunting and inherently unpredictable.

Active ingredients from plant origin are complex mixtures of tens or hundreds of individual chemicals, which may exhibit antifungal activity by a variety of different mechanism. Hence, interactions between any two or more particular plant extracts may result in the antifungal effect of one such extract being reduced or neutralized by the presence of the second extract. The combination of any two or more of such active ingredients is therefore just as likely to have a lessened therapeutic effect, or even no additive therapeutic effect, as to have a simple additive effect. a priori, there is no reason to expect that any given combination of plant extracts, such as the nail varnish compositions described herein, would be safe for use, demonstrating no significant evidence of itching, burning, or other negative effect when administered in a course o f treatment .

a priori, there is no reason to expect that any given combination of plant extracts, such as the nail varnish compositions described herein, would be effective in treating a given condition such as a fungal infection of the nails.

a priori, there is no reason to expect that a given combination of plant extracts found to have some pharmaceutical activity, such as the nail varnish composition described herein, would remain effective in a complex carrier such as a liquid nail lacquer where the solubility in and release from a solid film formed by a liquid nail lacquer of each one of the plant extracts, and even the components making up each of the plant extracts, is expected to be different.

a priori, there is no reason to expect that a liquid nail lacquer to which a significant amount of different plant extracts are added retains suitable solid-film forming properties, for example, that the liquid nail lacquer remains spreadable and once administered, solidifies to form a solid film, and that a formed film has suitable properties such as a suitable thickness, sufficiently adheres to the administered surface and is not excessively frangible.

a priori, there is no reason to expect that a given combination of plant extracts found to have some pharmaceutical activity, such as the nail varnish composition described herein, would effectively penetrate into a nail to have the desired effect.

The particular combinations of plant extracts used as components in some embodiments of the nail varnish compositions described are sufficiently mixable with the liquid nail lacquer, and apparently held in and released from the solid film formed by the liquid nail lacquer to the extent that in some embodiments the nail varnish composition is effective in the treatment of fungal infections of the nails. Compositions and preparation of compositions

According to an aspect of some embodiments of the invention, there is provided a nail varnish composition comprising a liquid nail lacquer and at least four different plant extracts (such as essential oils and/or tinctures) selected from the group consisting of tea-tree oil, extract of Thymus, Propolis derivative, extract of calendula, extract of coneflower, extract of manuka and extract of lemongrass.

According to an aspect of some embodiments of the invention, there is also provided a method for the preparation of a nail varnish composition comprising mixing together a liquid nail lacquer and at least four different plant extracts (such as essential oils and/or tinctures) selected from the group consisting of tea-tree oil, extract of Thymus, Propolis derivative, extract of calendula, extract of coneflower, extract of manuka and extract of lemongrass.

In some embodiments, the nail varnish composition is useful for the treatment of a fungal infection of a nail (a toenail, a fingernail, a claw) e.g., of a non-human animal, but especially of a human. Generally, subsequent to administration of the nail varnish composition to a nail, the nail varnish composition forms a solid film on the nail, the solid film together with other components of the nail varnish composition together treating a fungal infection of the nail.

In some embodiments, the nail varnish composition is useful in the preparation of a composition useful for the treatment of a fungal infection of the nails. For example, in some embodiments the nail varnish composition is an intermediate and can be made into a composition useful for the treatment of a fungal infection of the nails by the addition of one or more plant extracts.

In some embodiments, the at least four plant extracts of a composition or of a method comprise at least five different plant extracts selected from the group of plant extracts. In some embodiments, the at least four plant extracts of a composition or of a method comprise at least six different plant extracts selected from the group of plant extracts. In some embodiments, the at least four plant extracts of a composition or of a method comprise all seven different plant extracts selected from the group of plant extracts.

In some embodiments, the plant extracts are essential oils, tinctures, or mixtures thereof.

An essential oil is a volatile mixture comprising, inter alia, esters, aldehydes, alcohols, ketones and terpenes, which can be prepared from botanical materials or plant cell biomass from cell culture. Typically, essential oils are prepared by distillation from botanical materials (e.g., steam distillation, vacuum distillation), by solvent extraction (e.g., solvent extraction, alcohol extraction, oil extraction, super critical extraction, water extraction and hot water extraction) or by expression (e.g., in a press).

Tinctures of plants are typically prepared by solvent extraction, by contacting botanical materials with a solvent, usually ethanol, although in rare cases other solvents are used, for example, vinegar, glycerol, ether and propylene glycol or combinations thereof. In some embodiments, a tincture is prepared by macerating the plant while in contact with a solvent, allowing the solvent to remain in contact with the macerated plant material for an appropriate period of time and then filtering to remove solid or particulate material in order to form a filtered extract. If desired, additional solvent is added to the filtered extract to bring to a final volume or solvent is removed (e.g., evaporated) to increase the concentration of the extracted components in the tincture.

In some embodiments, a tincture is prepared by percolating the plant with a solvent, in a percolation column. The solvent is then allowed to flow through the column, contacting the plant materials, and is collected. The collected solvent forms the extract. Percolation has the advantage of allowing a minimal volume of solvent to be used during the extraction process. The volume of solvent required can be partially controlled by the rate of fluid flow through the column, allowing for greater control over the final volume of extract. Preferably, the flow of solvent out of the column is stopped entirely during extraction, so that the efficiency of extraction is increased.

Generally, the plant extracts used in implementing the teachings herein, such as essential oils and tinctures, are commercially available and can be purchased from commercial sources. Tea tree oil

Tea tree oil, or melaleuca oil (CAS 68647-73-4) is obtained commercially from the leaves of the Melaleuca alternifolia, which is native to the northeast coast of New South Wales, Australia. Tea tree oil can also be extracted from Melaleuca dissitiflora and Melaleuca linariflora. Components of tea tree oil include terpinen-4-ol, γ-terpinine, a- terpinine, 1,8-cineole, a -terpinolene, a-terpineol, a -pinene, and p-cymene. Tea tree oil is known to have beneficial antiseptic, antibacterial, antifungal and antiviral properties when administered topically.

Tea tree oil is one member of the group of seven plant extracts for implementing the teachings herein. In some embodiments, the tea tree oil is present at a concentration of between about 0.5% and about 10%> w/w, between about 0.5%> and about 6%> w/w and even between about 1% and about 4% w/w of a composition. In some embodiments, the tea tree oil is present at a concentration of about 2% w/w of a composition.

Extract of Thymus

Thymus (thyme) is a genus of about 350 species of herbaceous plants. Thymus vulgaris is considered to have medicinal uses. For example an infusion is considered to be an antiseptic useful for treating coughing, bronchitis and throat inflammation. Thyme oil, the essential oil of Thymus vulgaris, is considered useful for topical use as an antiseptic, antibacterial, and fungicide.

An extract of Thymus is one member of the group of seven plant extracts for implementing the teachings herein. A preferred extract of Thymus for implementing the teachings herein is an extract of Thymus vulgaris, especially Thyme oil (CAS #8007-46-3), for example extracted from the leaves and flowers of Thymus vulgaris by steam distillation.

In some embodiments, the extract of Thymus, such as thyme oil, is present at a concentration of between about 0.5%> and about 10%> w/w, between about 0.5%> and about 6%> w/w and even between about 1%> and about 4%> w/w of a composition. In some embodiments, the extract of Thymus is present at a concentration of about 2% w/w of a composition.

Propolis derivatives

Propolis is a wax-like substance gathered by honey bees and used to seal small gaps in the bee hive. Practitioners of natural medicine use Propolis for the relief of various conditions, including inflammations, viral diseases, ulcers, superficial burns or scalds.

Propolis derivatives (herein also termed "extracts of Propolis") (including native

Propolis, partially purified Propolis, purified Propolis and extracts thereof) are one member of the group of seven plant extracts for implementing the teachings herein. A preferred Propolis derivative for implementing the teachings herein is Propolis tincture, for example extracted from native or purified Propolis by ethanolic extraction.

In some embodiments, the Propolis derivative, such as Propolis tincture, is present at a concentration of between about 0.5%> and about 10%> w/w, between about 0.5%> and about 6%) w/w and even between about 1%> and about 4%> w/w of a composition. In some embodiments, the Propolis derivative is present at a concentration of about 2% w/w of a composition. Extract of calendula

Calendula is a genus of about 12-20 species of annual or perennial herbaceous plants in the daisy family, Asteraceae, including Calendula arvensis, Calendula bicolor, Calendula echerleinii, Calendula lanzae, Calendula maderensis, Calendula maritime, Calendula maroccana, Calendula meuselii, Calendula officinalis, Calendula stellata, Calendula suffruticosa and Calendula tripterocarpa .

The flowers of Calendula officinalis comprise flavonol glycosides, triterpene oligoglycosides, oleanane-type triterpene glycosides, saponins, and a sesquiterpene glucoside.

Calendula extracts are considered to have anti-viral, anti-geno toxic and anti- inflammatory properties. Calendula in suspension or in tincture is used topically to treat acne, reducing inflammation, controlling bleeding and soothing irritated tissue.

Calendula extracts are one member of the group of seven plant extracts for implementing the teachings herein. A preferred calendula extract for implementing the teachings herein is Calendula tincture, for example extracted from the leaves and flowers of Calendula officinalis by ethanolic extraction.

In some embodiments, the Calendula extract, such as Calendula tincture, is present at a concentration of between about 0.5% and about 10% w/w, between about 0.5%> and about 6%) w/w and even between about 1% and about 4% w/w of a composition. In some embodiments, the Calendula extract is present at a concentration of about 2% w/w of a composition.

Extract of coneflower

Coneflower (Echinacea) is a genus of herbaceous flowering plants in the daisy family, Asteraceae. Species of Echinacea include Echinacea angustifolia (Narrow-leaf Coneflower); Echinacea atrorubens (Topeka Purple Coneflower); Echinacea laevigata (Smooth Coneflower); Echinacea pallida (Pais Purple Coneflower); Echinacea paradoxa (Yellow Coneflower); Echinacea purpurea (Eastern Purple Coneflower); Echinacea sanguinea (Sanguine purple Coneflower); Echinacea simulata (Wavyleaf Purple Coneflower); and Echinacea tennesseensis (Tennessee Coneflower).

Coneflower is popularly believed to be an immuno stimulator and antimicrobial, has been suggested to have antitumor properties and to be effective against common colds. Use of coneflower has also been documented for treatment of snakebite, anthrax, coughs, sore throat, and relief of pain. Coneflower extracts comprise phenols, alkylamides and polysaccharides. The root is considered to contain a more efficacious mixture of active chemicals than the whole plant.

Coneflower extracts are one member of the group of seven plant extracts for implementing the teachings herein. A preferred coneflower extract for implementing the teachings herein is Coneflower tincture, for example extracted from the roots of the plant by ethanolic extraction.

In some embodiments, the Coneflower extract, such as Coneflower tincture, is present at a concentration of between about 0.5% and about 5% w/w, between about 0.5%> and about 3%) w/w and even between about 0.5%> and about 2% w/w of a composition. In some embodiments, the Coneflower extract is present at a concentration of about 1% w/w of a composition.

Extract of lemongrass

Lemongrass (cymbopogon) is a genus of about 55 species of grass, widely used as a herb in Asian cuisine. Lemongrass oil is used as a pesticide and preservative, and has been shown to have anti-fungal and anti-cancer properties. The grass is also considered a diuretic, tonic and stimulant. It promotes good digestion, and a preparation of lemon grass with pepper has been used for relief of menstrual troubles and nausea. It induces perspiration, to cool the body and reduce a fever.

Species include Cymbopogon ambiguus (Australian lemon-scented grass);

(Cymbopogon bombycinus (Silky Oilgrass); Cymbopogon citratus (Lemon Grass);

Cymbopogon citriodora (West Indian lemon grass); Cymbopogon flexuosus (East Indian lemon grass); Cymbopogon martinii (Palmarosa); Cymbopogon nardus (Citronella Grass);

Cymbopogon obtectus (Silky-heads); Cymbopogon procerus; Cymbopogon proximus; Cymbopogon refractus (Barbed wire grass); Cymbopogon schoenanthus (camel grass); and

Cymbopogon winterianus (Citronella Grass).

Lemongrass extracts are one member of the group of seven plant extracts for implementing the teachings herein. A preferred lemongrass extract for implementing the teachings herein is lemongrass oil (CAS #8007-02-1).

In some embodiments, the lemongrass oil is present at a concentration of between about 0.5%) and about 10%> w/w, between about 0.5%> and about 6%> w/w and even between about 1% and about 4% w/w of a composition. In some embodiments, the lemongrass extract is present at a concentration of about 2% w/w of a composition. Extract of Manuka

Manuka (leptospermum scoparium) is a flowering plant that is typically found as a shrub (2-5 m tall) or moderately- sized tree (up to about 15 m) native to New Zealand and Southeast Australia. Kakariki parakeets chew the leaves and bark of manuka to extract materials which are then applied to the feathers during preening, apparently as an antiparasitic.

Manuka is known as a medicinal plant to Maori healers. A decoction of the leaves is allegedly useful for urinary-tract complaints as well as an antipyretic. Inhalation of the steam released during boiling of leaves is allegedly useful for relieving head colds. A decoction of the leaves and bark is topically administered to allegedly relieve muscle and joint pains. Chewing the bark is alleged to have a relaxing effect and to enhance sleep. The emollient gum is alleged to be useful in the treatment of scalds and burns. Manuka oil (CAS 219828- 87-2), is obtained by steam distillation of the biomass (especially leaves and branchlets). Folklore as well as Manuka oil sales representatives allege that the essential oil is useful for the treatment of skin and fungal infections, dandruff, cuts, scratches, acne, oily skin, rashes, body odor, insect bites and stings.

Manuka extracts are one member of the group of seven plant extracts for implementing the teachings herein. A preferred manuka extract for implementing the teachings herein is manuka oil.

In some embodiments, the manuka oil is present at a concentration of between about

0.5% and about 10%> w/w, between about 0.5%> and about 6%> w/w and even between about 1% and about 4% w/w of a composition. In some embodiments, the manuka extract is present at a concentration of about 2% w/w of a composition. erato lytic agents

According to some embodiments, a composition as described herein comprises a kerato lytic agent.

As used herein, the term "keratolytic agent" refers to an agent that reduces the structural integrity of a nail, especially by lysis of keratin, a fibrous structural protein present in nails, claws, hair and skin. Depending on the concentration, when administered to a nail, a keratolytic agent may dissolve or break down the outer layer of the nail or, at higher concentrations, may result in total loss of the nail.

In embodiments herein, use of a keratolytic agent is advantageous, presumably to increase or enable the penetration of the plant extracts into the nail to increase anti-fungal efficacy. In some embodiments, the keratolytic agent comprises a keratolytic agent selected from the group consisting of urea, sulfur, lactic acid, allantoin, resorcinol, salicylic acid, podophyllum resin, and mixtures thereof. In some embodiments, the keratolytic agent comprises urea. In some such embodiments, the keratolytic agent, especially urea is present at a concentration of between about 0.5% and about 15% w/w, between about 0.5% and about 10%) w/w and even between about 3% and about 7% w/w of a composition. In some embodiments, the keratolytic agent, especially urea, is present at a concentration of about 5% w/w of a composition.

In some embodiments, the concentration of a keratolytic agent is sufficient to lead to loss of the nail during a course of treatment, as discussed in greater detail hereinbelow. Such a concentration can be found for a specific keratolytic agent or combination of specific keratolytic agents by a person having ordinary skill in the art without undue experimentation.

In some embodiments, the concentration of a keratolytic agent is insufficient to lead to loss of the nail during the course of treatment and functions, for example, as a penetration enhancer.

In some embodiments, a composition as described herein is substantially devoid of a keratolytic agent. By "substantially devoid" is meant a concentration of keratolytic agent that is sufficiently low so as to not cause substantial damage to skin of a subject if administered thereto during the course of treatment. Such a concentration can be found for a specific keratolytic agent or combination of specific keratolytic agents by a person having ordinary skill in the art without undue experimentation. In some embodiments, a composition that is "substantially devoid of a keratolytic agent is devoid of a keratolytic agent.

According to some embodiments, a composition as described herein comprises an antioxidant to improve stability of the composition. In some embodiments, the antioxidant comprises an antioxidant selected from the group consisting of a form of vitamin E (for example, an α-, β-, γ-, or δ-tocopherol or tocotrienol, or a succinate, acetate, or nicotinate ester thereof), a carotene (β-carotene or retinol), or ubiquinol (coenzyme Q), ascorbic acid, ascorbyl palmitate, butylated hydro xyanisole, butylated hydroxytoluene, ftimaric acid, malic acid, propyl gallate, sodium ascorbate, sodium metabisulfite, or mixtures thereof. In some embodiments, the antioxidant comprises a-tocopherol succinate. In some embodiments, the tocopherol succinate is present at a concentration of between about 0.1 % and 2% w/w, between about 0.2% and about 1.5%, and even between about 0.3% and about 1% w/w of a composition. In some embodiments, the tocopherol succinate is present at a concentration of about 0.5%) w/w of a composition. In some embodiments, the liquid nail lacquer comprises a film- forming polymer and a volatile solvent.

According to some embodiments, the film-forming polymer comprises a non- degradable film-forming polymer, such as polyethylene, polypropylene, poly(ethylene-co- vinyl acetate), or a non-degradable poly(meth)acrylate (including a poly(alkyl(meth)acrylate or poly(aromatic(meth)acrylate, such as poly(aryl(meth)acrylates), poly(aralkyl (meth)acrylates), and poly(aryloxyalkyl(meth)acrylates). Examples of poly(aryl(meth)acrylates) include poly(9-anthracenyl methacrylate), poly(chlorophenylacrylate), poly(methacryloxy-2-hydroxybenzophenone), poly(methacryloxybenzotriazole), poly(naphthylacrylate) and -methacrylate), poly(4- nitrophenyl acrylate), poly(pentachloro(bromo, fluoro) acrylate) and -methacrylate), and poly(phenyl acrylate) and -methacrylate). Examples of poly(aralkyl (meth)acrylates) include poly(benzyl acrylate) and -methacrylate), poly(2-phenethyl acrylate) and - methacrylate, and poly(l-pyrenylmethyl methacrylate). Examples of poly(aryloxyalkyl (meth)acrylates) include poly(phenoxyethyl acrylate) and -methacrylate), and poly(polyethylene glycol phenyl ether acrylates) and -methacrylates with varying polyethylene glycol molecular weights.

In some embodiments, the non-degradable film forming polymer comprises a poly(ethyl acrylate, methylmethacrylate, trimethylamino ethyl methacrylate chloride) copolymer, (sold commercially as Eudragit®RS or Eudragit®RL). In some embodiments, Eudragit®RS is present at a concentration of between about 1% and about 20% w/w, between about 2%> and about 10%> w/w and even between about 3% and about 5% w/w of a composition. In some embodiments, Eudragit®RS is present at a concentration of about 4% w/w of a composition.

According to some embodiments, the volatile solvent is selected from the group consisting of a ketone, an alcohol, or a mixture thereof. In some embodiments, the volatile solvent comprises a mixture of ethanol and acetone.

According to some embodiments, the composition further comprises an excipient selected from the group consisting of a plasticizer, a release enhancer, a stabilizer and a thickener, or mixtures thereof.

In some embodiments, the plasticizer is selected from the group consisting of dibutyl sebacate, diethyl phthalate, lanolin alcohols, mineral oil, petrolatum, polyethylene glycol, propylene glycol, triacetin, triethyl citrate, or mixtures thereof.

According to some embodiments, the composition comprises a polyethylene glycol (PEG), such as PEG 100, PEG 150, PEG 200, PEG 300, PEG 400, PEG 600, PEG 800 and PEG 900 as a release enhancer and plasticizer In some embodiments, the polyethylene glycol comprises PEG-400. In some embodiments, the PEG-400 is present at a concentration of between about 0.1% and about 1% w/w, between about 0.1 % and about 0.8%> w/w and even between about 0.2%> and about 0.6%> w/w of a composition. In some embodiments, PEG-400 is present at a concentration of about 0.4% w/w of a composition.

According to some embodiments, the thickener and stabilizer comprises a non-ionic water-soluble cellulose ether. In some embodiments, the cellulose ether comprises hydro xypropylcellulose, such as that sold commercially as Klucel®HF. In some embodiments the hydroxypropylcellulose is present at a concentration of between about 0.5% and about 5% w/w, between about 0.5%> and about 4% w/w and even between about 0.5% and about 2% w/w of a composition. In some embodiments, the hydroxypropylcellulose is present at a concentration of about 1.4% w/w of a composition.

In some embodiments, the composition further comprises at least one additive selected from the group consisting of preservatives, surfactants and coloring agents which are well known in the art.

Examples of suitable preservatives include benzoic acid, benzyl alcohol, bronopol, butyl paraben, chlorbutanol, chlorocresol, cresol, ethyl paraben, methyl paraben, phenol, propyl paraben, sodium benzoate, sodium propionate, sorbic acid, or mixtures thereof.

Examples of suitable surfactants include cetrimide, sodium lauryl sulfate, docusate sodium, glyceryl monooleate, polysorbates, sorbitan esters, or mixtures thereof.

Examples of suitable coloring agents include amaranth, brilliant blue, caratenoids, carmoisine, curcumin, eosine, erythrosine, fluorescein, rhodoxantin, tetrazine, or mixtures thereof.

According to some embodiments, a composition as described herein further comprises an additional active ingredient, such as, for example, an additional antifungal agent, an antibacterial agent, an antiviral agent, an antipsoriatic agent, or mixtures thereof.

In some embodiments, the additional antifungal agent is selected from the group consisting of amphothericin B, butefanine, butoconazole, carbol-fuchsin, ciclopirox, clioquinol, clotrimazole, econazole, gentian violet, ketoconazole, miconazole, naftifme, nystatin, oxiconazole, sodium thiosulfate, terbinafme, terconazole, tolnaftate, undecylenic acid, therapeutically acceptable salts thereof, derivatives thereof, and mixtures thereof.

In some embodiments, the antibacterial agent is selected from the group consisting of bacitracin, clindamycin, erythromycin, gentamicin, mupirocin, neomycin, tetracyclines, polymyxin B, benzalkonium chloride, boric acid, hexachlorophene, iodine, iodoquinol, mafenide, mercury ammoniated, metronidazole, nitrofurazone, selenium sulfide, silver sulfadiazine, salts thereof, derivatives thereof, and mixtures thereof.

In some embodiments, the antiviral agent is selected from the group consisting of acyclovir, amantadine, cidofovir, famciclovir, foscarnet, ganciclovir, palivizumab, penciclovir, ribavirin, rimantadine, valcyclovir, salts thereof, derivatives thereof, and mixtures thereof.

In some embodiments, the antipsoriatic agent is selected from the group consisting of alclometasone, ameinonide, betamethasone, clobetasol, clocortolone, desonide, desoximetasone, diflorasone, fluocinolone, fluocinonide, flurandrenolide, halcinonide, hydrocortisone, mometasone, prednicarbate and triamcinolone, salts thereof, derivatives thereof, and mixtures thereof.

In the method of preparation of a nail varnish composition as described herein, the various components are mixed together in the appropriate amounts in an appropriate order to provide the desired nail varnish composition, formulated to form a solid film when topically administered (in the usual way) to a nail.

Upon perusal of the description herein, a person having ordinary skill in the art, for example in the field of nail varnish compositions, is able to implement the teachings herein including the method of making a nail varnish composition, including determining the appropriate amounts of the components and the order of mixing, in some cases with reference to US 7,074,392 and/or "Remington's Pharmaceutical Sciences," Mack Publishing Co., Easton, PA, latest edition, which are both incorporated by reference as if fully set forth herein.

Uses and methods of treatment of compositions

As noted above, some embodiments of a nail varnish composition as described herein are useful in the preparation of a composition useful for the treatment of a fungal infection of the nails. For example, in some embodiments the nail varnish composition is an intermediate and can be made into a composition useful for the treatment of a fungal infection of the nails by the addition of one or more plant extracts.

As noted above, some embodiments of a nail varnish composition as described herein are useful for the treatment of a fungal infection of a nail (a toenail, a fingernail, a claw) e.g., of a non-human animal, but especially of a human. Generally, subsequent to administration of the nail varnish composition to a nail, the nail varnish composition forms a solid film on the nail, the solid film together with other components of the nail varnish composition together treating a fungal infection of the nail.

Thus, according to an aspect of some embodiments of the invention, there is provided a use of a composition as described herein in the treatment of a fungal infection of the nails in a subject (human or non-human animal) in need thereof. Generally, use of a nail varnish composition in the treatment of a fungal infection comprises topical administration of the composition in liquid form to the exposed surface of a nail. The nail varnish composition forms a solid film (varnish layer) on the nail and the solid film together with other components of the nail varnish composition together treat the fungal infection of the nail.

The user, when desired, strips the layer of varnish off of the infected nail, preferably after the layer has been soaked in water, for example, subsequent to a bath or shower. Typically, stripping is performed by physical scraping, for example with a nail file or rasp. That said, it has been found that in some instances, the structural integrity of the nail is weakened to the extent that stripping can be performed with a mildly abrasive object such as cloth or a cotton ball together with a chemical varnish solvent such as acetone or ethyl acetate, as discussed below.

Subsequently, the user readministers a fresh layer of nail varnish.

Typically, the nail varnish composition is administered repeatedly (e.g., at least once every two days, at least once daily) over a course of treatment (e.g., a period of at least 5 days, a period of at least 8 days), typically until the fungal infection is cured. Eventually, a healthy nail begins to grow, which is free of any recurring fungal infection, and the initially infected portion of the nail is periodically trimmed until only healthy nail remains.

According to an aspect of some embodiments of the invention, there is also provided a method for the treatment of a fungal infection of the nails in a subject (human or non- human animal) in need thereof, comprising administering a composition as described herein. Generally, administration of the nail varnish composition comprises administration of the composition in liquid form to the exposed surface of a nail. The nail varnish composition forms a solid film on the nail and the solid film together with other components of the nail varnish composition together treat the fungal infection of the nail.

In some embodiments, the need for which a composition is used or the method applied is related to infection with at least one of Trichophython rubrum, Trichophyton mentagrophytes, Epidermophyton floccusum, Candida albicans, Microsporum persiccolor, Cephalosporium species, Aspergillus species, and Fusarium oxysporum. In some embodiments, the composition is a topical composition and administering comprises topical administration to the nails, for example, at least once a week, at least twice a week and even at least three times a week. In some embodiments, the composition is administered between 1 and 4 times per day, for example once or twice a day. Administration is for a period of from about 1 day to about 1 month, until infected nail has been trimmed away leaving only healthy nail. In some embodiments, during the course of treatment the infected portion of the nail is dissolved (e.g., is no longer present, e.g., is stripped away or washed away during treatment). Once the infected nail is dissolved, a new nail, free of fungal infection, grows.

In some embodiments, the nail varnish composition is suitable for self- administration by a patient. After administration, the volatile solvent evaporates, and a solid film is formed on the nail surface.

According to some embodiments, the method of treatment or use of the composition as described herein further comprises administration of an additional active ingredient, such as for example, an additional antifungal agent, an additional kerato lytic agent, or mixtures thereof. In some embodiments, the additional active ingredient has an additive effect with the nail varnish composition. In some embodiments, the additional active ingredient has a synergistic effect with the nail varnish composition. The additional active ingredient may be administered substantially simultaneously or sequentially, either before or after administration of the nail varnish composition.

Compositions and methods of treatment useful for stripping nails

In the art it is known that it is often useful to strip a nail infected with fungus.

Specifically, in addition to administration of an antifungal composition, infected portions of the nail are physically removed, typically with the help of a scraper, a knife, a nail file or an emery board. Such stripping is not only unpleasant but difficult due to the inherent toughness of a nail, even an infected nail.

To ease stripping of a nail, it is known to add large amounts of kerato lytic agent to an antifungal composition in order to damage the structural integrity of the nail and ease stripping thereof. For example, Agispor® nail ointment (Perrigo Israel Pharmaceuticals, Ltd.) a 1% Bifonazole ointment contains 40% by weight urea to allow nail stripping. The ointment is topically administered to the nail and covered with a bandage for a period of time. The bandage is removed and the nail stripped with a rasp. It is important to note that even though such a high concentrations of urea noticeably damages the structural integrity of the nail, the nail remains sufficiently tough to make stripping a difficult task.

As noted above, in some embodiments a nail varnish composition described herein includes no keratolytic agent.

In some embodiments, a nail varnish composition described herein includes one or more keratolytic agents, such as urea, at a concentration sufficient to act as a penetration enhancer, that is to say, sufficient to damage the structural integrity of the nail (e.g., by damaging keratin) such that one or more active ingredients more easily than otherwise penetrate into the nail even though the nail remains tough. Such use of a keratolytic agent in an antifungal nail varnish composition has been disclosed, for example, in US 7,074,392.

Some embodiments of the invention relate to the surprising and unexpected experimentally-proven result that some embodiments of a nail varnish composition described herein, substantially embodiments that include at least one essential oil and a keratolytic agent with a liquid nail lacquer damage the structural integrity of nails to an exceptional extent, allowing easy stripping thereof.

Specifically, it has been surprisingly found that when some embodiments of a nail varnish composition including at least one essential oil, at least one keratolytic agent, are used to treat a nail, the nail is quickly and easily stripped together with the varnish layer varnish , accelerating the course of treatment.

Specifically, during the removal of a previously- administered varnish layer of a composition, the structural integrity of the nail is observed to be significantly compromised (e.g., compared to equivalent use of a nail varnish composition as disclosed in US 7,074,392). The nail appears soft and thin and is easily, even inadvertently, stripped away together with the varnish layer of composition, in some instances as a powdery residue. Although stripping is typically performed using a hard abrasive object such as a rasp, nail file or emery board, in some embodiments, the structural integrity of the nail is weakened to the extent that stripping can be performed with a mildly abrasive object such as cloth or a cotton ball together with a chemical varnish solvent such as acetone or ethyl acetate. Without wishing to be held to any one theory, it is believed that the keratolytic agent (e.g., urea) and an essential oil act together, in some embodiments, synergistically, to damage the structural integrity of the nail, rendering the nail easily strippable.

Thus, according to an aspect of some embodiments of the invention, there is also provided a nail varnish composition useful for stripping nails comprising a liquid nail lacquer, an essential oil and a keratolytic agent. Typically, the concentration of the keratolytic agent and the concentration of the essential oil is such that the composition is effective to weaken the structural integrity of a nail to which administered to an extent greater than with kerato lytic agent alone, in some embodiments to a synergistically greater extent.

In some embodiments, the composition further comprises an antifungal agent. In some embodiments at least one essential oil (including some combination of essential oils) functions as the anti-fungal agent. In some embodiments, the composition comprises a nonessential oil anti-fungal agent, such as listed above.

Any essential oil (including combinations of specific essential oils) may be used. In some embodiments, the essential oil is a single essential oil. In some embodiments, the essential oil is a combination of different essential oils. In some embodiments, the essential oil is at least one essential oil selected from the group of four essential oils consisting of tea tree oil, thyme oil, lemongrass oil and manuka oil. In some embodiments, the essential oil is at least two different essential oils selected from the group of four oils. In some embodiments, the essential oil is at least three different essential oils selected from the group of four oils. In some embodiments, the essential oil is all four essential oils selected from the group of four oils.

In some such embodiments, the concentration of essential oils is not less than about 0.5%, not less than about 1%, not less than about 2%, not less than about 3%, and even not less than about 5% w/w of a composition. In some such embodiments, the concentration of essential oils is not more than about 35%, not more than about 30%, not more than about 25%o, and even not less than about 20%> w/w of a composition. In some such embodiments, the concentration of essential oils is between about 0.5%> and about 35% w/w, between about 1%) and about 30% w/w, between about 2% and about 25% w/w, and even between about 3% and about 20% w/w of a composition.

Any keratolytic agent (including combination of specific keratolytic agents) may be used. Suitable keratolytic agents include, but are not limited to, the keratolytic agents listed hereinabove, for example, the keratolytic agent of the composition comprises urea or consists of urea. The keratolytic agent may be of any suitable concentration (i.e., sufficient to cause a nail-weakening effect allowing stripping of the nail, in addition to a penetration-enhancing effect. In some such embodiments, the concentration of keratolytic agent, especially urea, is about 0.5%) and about 15% w/w, between about 0.5% and about 10% w/w and even between about 3% and about 7% w/w of a composition. In some embodiments, the keratolytic agent comprises urea, in some embodiments at a concentration of not more than about about 15% w/w. Any liquid nail lacquer may be used in implementing a nail varnish composition useful for stripping nails. In some embodiments, the nail lacquer is as described herein or as described in US 7,074,392. Methods, uses and kits using two different compositions

A challenge in treating fungal infections of the nail and similar parts of the body is recurrence. In some cases, even after an infected nail is removed and regrows, a fungal infection recurs, presumably due to the presence of the fungus in the skin surrounding the nail and nail bed. This problem is noted most often with long-term fungal infections.

It has been found that in some instances, an effective method to increase the efficacy of treatment and/or to reduce the incidence of recurrence of a fungal infection when using a composition as described herein, is to administer an anti-fungal composition not only to the nail but also to skin and other tissue surrounding the nail, for example including one or more of the hyponychium (under the distal edge of the nail), the onychodermal band, the eponychium, the cuticle, the nail walls and paronychium

It has been found that, generally, administration of a nail varnish composition including a liquid nail lacquer and a keratolytic agent (especially including an essential oil) at a concentration sufficient to lead to loss of the nail during a course of treatment is effective in treating the nail, but may cause damage to a skin surface, apparently due to the combined action of the keratolytic agent and essential oil on the skin, especially keratin making up the skin.

It has been found that a particularly effective method of treating a fungal infection of a nails by providing two varnish compositions, both comprising a liquid nail lacquer component and an antifungal agent (for example, compositions including plant extracts as described herein).

The first of the two varnish compositions is substantially devoid, preferably devoid, of a keratolytic agent, that is to say, is of a concentration of keratolytic agent that is sufficiently low so as to not cause substantial damage to skin of a subject if administered thereto during the course of treatment.

The second of the two varnish compositions further comprises a keratolytic agent, and in some embodiments also an essential oil, at a concentration sufficient to lead to loss of the nail during a course of treatment.

It has been found that in some embodiments preferred results are obtained when the first varnish composition substantially devoid of keratolytic agent is administered to skin surrounding the nail, and the second varnish composition comprising a keratolytic agent at a concentration sufficient to lead to loss of the nail during a course of treatment is concurrently administered to the nail.

It has been found that in some embodiments exceptionally preferred results are obtained when the first varnish composition substantially devoid of keratolytic agent is first administered to skin surrounding the nail, and subsequently (after a layer is formed on the administered areas) the second varnish composition comprising a keratolytic agent at a concentration sufficient to lead to loss of the nail during a course of treatment is administered to the nail. Although not wishing to be held to any one theory, it is believed that administration of the first varnish composition protects skin surrounding the nail from at least some of the negative effects of the keratolytic agent in the second varnish composition.

According to an aspect of some embodiments of the invention, there is also provided the use of two different varnish compositions in the treatment of a fungal infection of the nails in a subject (human or non-human animal) in need thereof, wherein:

a first varnish composition comprising a liquid nail lacquer, an antifungal agent and substantially devoid (preferably devoid) of a keratolytic agent that is administered to skin in proximity of an infected nail (thereby forming a varnish layer covering the skin); and

a second varnish composition comprising a liquid nail lacquer, an antifungal agent and a keratolytic agent at a concentration sufficient to lead to loss of the nail during a course of treatment that is administered to an infected nail concurrently with administration of the first varnish composition, (thereby forming a varnish layer covering the nail).

In some embodiments of the use, the two varnish compositions are administered at least once daily for a sufficient number of days to treat the fungal infection. In some embodiments, the first varnish composition is administered prior to administration of the second varnish composition.

According to an aspect of some embodiments of the invention, there is also provided a method for the treatment of a fungal infection of the nails in a subject (human or non- human animal) in need thereof, comprising concurrently administering two compositions: a first varnish composition comprising a liquid nail lacquer, an antifungal agent and substantially devoid (preferably devoid) of a keratolytic agent and is administered to skin in proximity of an infected nail (thereby forming a varnish layer covering the skin); and a second varnish composition comprising a liquid nail lacquer, an antifungal agent and a keratolytic agent at a concentration sufficient to lead to loss of the nail during a course of treatment administered to an infected nail concurrently with administration of the first varnish composition (thereby forming a varnish layer covering the nail). In some embodiments of the method, the two varnish compositions are administered at least once daily for a sufficient number of days to treat the fungal infection. In some embodiments, the first varnish composition is administered prior to administration of the second varnish composition. In some embodiments, one of the two varnish compositions is a varnish composition as described herein. In some embodiments, both of the two varnish compositions are a varnish composition as described herein.

According to an aspect of some embodiments of the invention, there is also provided a kit (suitable for use in the treatment of a fungal infection of the nails in a human and/or non-human subject) comprising two antifungal varnish compositions:

a first varnish composition comprising a liquid nail lacquer, an antifungal agent and substantially devoid (preferably devoid) of a keratolytic agent; and

a second varnish composition comprising a liquid nail lacquer, an antifungal agent and a keratolytic agent at a concentration sufficient to lead to loss of the nail during a course of treatment

each of said two varnish compositions being individually administrable.

The two varnish compositions of the kit as described above are each individually administrable, the first to a skin surface in proximity of a nail and the second to a (infected) nail, for example, each in an individual resealable bottle, each bottle provided with an appropriate applicator, such as a brush. In some embodiments, one of the two varnish compositions of the kit is a varnish composition as described herein. In some embodiments, both of the two varnish compositions of the kit are a varnish composition as described herein.

In some embodiments of the use, method or kit, at least one of the first varnish composition and the second varnish composition (that is to say, only the first composition or only the second composition or both the first and second composition) comprises an essential oil. In some such embodiments, at least one essential oil functions as the anti-fungal agent. In some such embodiments, at least one of the first varnish composition and the second varnish composition comprises a non essential-oil anti-fungal agent in addition to the essential oil. In some such embodiments, the second varnish composition comprises an essential oil at a concentration effective to assist (the keratolytic agent) in causing loss of the nail during the course of treatment. In some embodiments, one of the two varnish compositions is a varnish composition as described herein (i.e., including at least four of the seven plant extracts). In some embodiments, both of the two varnish compositions are a varnish composition as described herein (i.e., including at least four of the seven plant extracts).

In some embodiments, the need for which the two compositions are used or the method is applied or the kit is suitable for is related to infection with at least one of Trichophython rubrum, Trichophyton mentagrophytes, Epidermophyton floccusum, Candida albicans, Microsporum persiccolor, Cephalosporium species, Aspergillus species, and Fusarium oxysporum.

In some embodiments, the two compositions are topical compositions and administering comprises topical administration to the nails and skin surrounding the nails, for example, at least once a week, at least twice a week and even at least three times a week. In some embodiments, the composition is administered between 1 and 4 times per day, for example once or twice a day. Administration is for a period of from about 1 day to about 1 month, until infected nail has been trimmed away leaving only healthy nail. In some embodiments, during the course of treatment the infected portion of the nail is dissolved (e.g., is no longer present, e.g., is stripped away or washed away during treatment). Once the infected nail is dissolved, a new nail, free of fungal infection, grows.

In some embodiments, both nail varnish compositions are suitable for self- administration by a patient. After administration, the volatile solvent evaporates, and a solid film is formed on the nail surface.

Exemplary embodiments are discussed hereinbelow with reference to specific materials, methods and examples. The materials, methods and examples discussed herein are illustrative and not intended to be limiting. In some embodiments, methods and materials similar or equivalent to those described herein are used in the practice or testing of embodiments of the invention. It is to be understood that the invention is not necessarily limited in its application to the details of construction and the arrangement of the components and/or methods set forth in the following description and/or illustrated in the drawings. The invention is capable of other embodiments or of being practiced or carried out in various ways.

EXPERIMENTAL

Example 1: Exemplary embodiments of a composition

Three exemplary embodiments of a composition were prepared in accordance with the teachings herein using commercially- available ingredients. Compositions 1 and 2 include the kerato lytic agent urea. Composition 3 is substantially devoid (is devoid) of a kerato lytic agent.

The proportions of the various components of the three compositions are listed in Table 1. Wilmington, DE, USA

Klucel EF (hydroxypropylcellulose, CAS #9004- 64-2)

0 0 2.3

Hercules Incorporated. Aqualon Division,

Wilmington, DE, USA

Water 2 2 0

TABLE 1

Compositions 1, 2 and 3 were prepared as follows:

a. Ethanol, acetone and polyethylene glycol 400 (PEG 400) were mixed to a homogenous solution. Eudragit RS® and/or Eudragit® L was then added, and mixed to a homogenous mixture 1 ;

b. For compositions 1 and 2, urea was dissolved in water, with heating, and mixed with mixture 1 until homogenous;

c. Klucel HF and/or Klucel EF were added in small portions to mixture 1 and mixed until homogenous and viscous;

d. Essential oils, tinctures and tocopherol succinate were mixed to a homogenous mixture 2; e. Mixtures 1 and 2 were mixed until homogenous, and transferred to a sealed glass light- protected container.

Example 2: Treatment of fungal infection of the nails with Composition 1

Twelve otherwise healthy adult subjects, having nails of different thicknesses due to fungal infection, administered the composition of Example 1 to the nails up to twice a day, as shown in Table 2, and the number of days until the nail was dissolved was noted.

TABLE 2 Specifically, the subjects topically administered (applied) Composition 1 to the infected nail at the listed frequency using an applicator brush such as used to apply nail polish, thereby forming a varnish layer on the nail. Every day, after a bath or shower, the subjects stripped away the varnish layer using an emery board or nail file (according to individual preference). During the stripping of the varnish layer, all subjects noted that the structural integrity of the underlying nail was damaged. Specifically, all the subjects noted that during stripping of the varnish layer, at least a portion of the underlying nail had become soft and weak, and was thereby easily stripped away with no special effort, in some cases as a powdery residue. After the listed number of days, the nail had completely dissolved (i.e., only a clean nail bed was observed with no tough nail present). Further administration of composition 1 was stopped and subsequently growth of new, healthy nails later occurred in all subjects.

Example 3: Treatment of fungal infection of the nails with Composition 2

Results substantially similar to those described for Composition 1 are obtained with

Composition 2.

In further experiments, it was found that in cases of exceptionally serious and well- established fungal infections, Composition 2 was more effective than Composition 1 at treating the infection.

Example 4: Treatment of fungal infection of the nails with Composition 2 and 3

Subjects having exceptionally well-established or severe fungal infections of the nails were instructed to concurrently administer Composition 2 and Composition 3 in accordance with the teachings herein.

Specifically, on a daily basis, Composition 2 was applied and stripped together with infected portions of the nail, substantially as described above for Composition 1. However, the subjects were instructed, subsequently to stripping of a previous varnish layer of Composition 2 but prior to application of a new varnish later of Composition 2, to apply a layer of Composition 3 to the skin surfaces around the nail, including one or more of the hyponychium (under the distal edge of the nail), the onychodermal band, the eponychium, the cuticle, the nail walls and paronychium. During the course of treatment, no damage or pain of the skin where Composition 3 was applied was noted.

After the nail completely dissolves (i.e., only a clean nail bed was observed with no tough nail present), administration of both compositions was stopped and subsequently growth of new, healthy nails occured in all subjects. Subsequent to the treatment, no recurrence of infection was observed.

It is appreciated that certain features of the invention, which are, for clarity, described in the context of separate embodiments, may also be provided in combination in a single embodiment. Conversely, various features of the invention, which are, for brevity, described in the context of a single embodiment, may also be provided separately or in any suitable subcombination or as suitable in any other described embodiment of the invention. Certain features described in the context of various embodiments are not to be considered essential features of those embodiments, unless the embodiment is inoperative without those elements.

Although the invention has been described in conjunction with specific embodiments thereof, it is evident that many alternatives, modifications and variations will be apparent to those skilled in the art. Accordingly, it is intended to embrace all such alternatives, modifications and variations that fall within the spirit and broad scope of the appended claims.

Citation or identification of any reference in this application shall not be construed as an admission that such reference is available as prior art to the invention.

Section headings are used herein to ease understanding of the specification and should not be construed as necessarily limiting.