This invention relates to the topical treatment, particularly of warts but also of corns. In this specification, the term "wart" or "warts" is taken to include verrucas, acrochordons (skin tags) and similar localised, infected epidermal growths; and the term "corn" or "corns" is taken to mean any localised, well-defined callus resulting from mechanical stress. "Self-treatment" means the treatment by an individual of the individual's own body.

Warts are commonly treated by topically freezing the growth. In order to remove the wart, it is important that the whole infected tissue region is frozen. This is conveniently accomplished by the direct or indirect application of a cryogenic agent, usually liquid nitrogen, which is effective but painful due to the extremely low temperature involved, and is not available as a self-treatment due to the practical difficulties involved in its storage and handling.

GB 2 274 588 A discloses an analgesic or anaesthetic alcoholic gel containing a concentrated plant extract and a penetration enhancer such as oleic acid or menthol, which may be applied topically prior to treatment so as to reduce the pain involved in cryogenic wart removal.

Over-the-counter topical freezing treatments are well known and disclosed, for example, in WO02/30309 Al , WO9949797, US6387090 Bl, and WO2006/093401 A2. Such systems are useful for self-treatment, providing an applicator for the direct or indirect topical application of a freezing agent such as carbon dioxide, pentafluoroethane, dimethyl ether (DME), DME / propane mix, and the like. However, such systems typically cannot achieve the intensely low temperatures of cryogenic agents such as liquid nitrogen, and as a result can be less effective in freezing the root or core region of a deeply embedded wart. The wart may thus re-grow, even after repeated treatment. Such treatments can also be painful, although typically less so than liquid nitrogen.

WO92/20308 discloses an alternative procedure for the treatment of warts, comprising the topical application of a pad containing an exothermic agent, optionally together with a keratolytic agent such as salicylic acid, so as to locally heat the wart over a period of several hours.

Corns and warts are also commonly treated by the application at ambient temperature of keratolytic, acid, caustic or vesicating agents such as salicylic acid, cantharidin and silver nitrate, which however can also be painful. Such compositions may include tissue penetrating agents, as taught for example by US 4016264, and may be applied by means of a dropper bottle or similar applicator, or via a patch, reservoir or the like, as disclosed for example by WO 2006/053223 A2 and US 5641507.

The object of the present invention is to improve the effectiveness and/or acceptability of treatments, particularly self-treatments, for warts. It is envisaged that the invention may also be useful in the treatment of corns.

In its various aspects the present invention provides a pre-treatment composition, an apparatus, a kit and a method as defined in the claims.

In each of its aspects, the invention provides a pre-treatment for sequential use prior to a subsequent treatment.

The treatment may comprise local freezing or local heating of the wart or corn, with freezing being generally quick and convenient and hence preferred. In either case the pre-treatment comprises the application of a thermal transmission agent which is absorbed by the wart or corn and acts to increase thermal transmission through the wart or corn, particularly by hydration of the wart or corn. This increases the efficacy of the subsequent treatment by ensuring that the whole tissue mass of the wart or corn is heated or cooled to the required temperature during the treatment. This is particularly advantageous in ensuring destruction of the wart by means of a relatively mild freezing agent such as commonly used in over-the-counter wart treatment systems. Older warts which are larger and contain more dry hyperkeratotic skin tissue can exhibit particularly low thermal conductivity, and so hydration of such warts prior to the application of a freezing treatment is of particular benefit.

Moreover, by increasing the rate of thermal transmission through the wart or corn, it may be possible to achieve freezing of the whole wart or corn while reducing the contact time of the subsequent freezing treatment, so as to minimise inflammation and pain in the surrounding healthy tissue.

Preferably, the thermal transmission agent is water, and the composition includes an effective amount of a tissue saturating agent and a surface acting agent which assists it to penetrate the hyperkeratotic tissue of the wart or corn. Preferably, the composition also includes an analgesic, anaesthetic or de-sensitising agent which is absorbed by the wart or corn together with the thermal transmission agent so as to reduce the pain of the subsequent treatment.

Alternatively, the treatment may comprise the application of a keratolytic, acid, caustic or vesicating agent, in which case the pre-treatment comprises an analgesic, anaesthetic or de-sensitising agent in a base comprising water with a surface acting agent, or alternatively comprising a pharmaceutically acceptable organic solvent, which is absorbed by the wart or corn so as to reduce the pain of the subsequent treatment. Preferably, the pre-treatment composition also includes a binding or gelling agent which helps the composition to adhere to the skin while it is absorbed into the wart or corn.

The pre-treatment composition may also include an anti-inflammatory agent which reduces inflammation of surrounding healthy skin tissue resulting from the treatment.

Further features and advantages will become apparent from the following description of preferred embodiments, which however is not intended to limit the scope of the invention as defined in the claims.

In a first embodiment, a method of treatment, particularly but not exclusively self- treatment, of a wart or corn comprises the steps of a) applying a pre-treatment composition to the wart or corn, the pre-treatment composition comprising a thermal transmission agent for absorption by the wart or corn so as to increase thermal transmission through the wart or corn; and then b) waiting for a first time period for the thermal transmission agent to penetrate the wart or corn so as to increase thermal transmission through the wart or corn; and then c) applying a treatment to the wart or corn, the treatment comprising one of locally freezing the wart or corn and locally heating the wart or corn.

The pre-treatment composition may include an analgesic, anaesthetic or desensitising agent.

In a second embodiment, a method of treatment, particularly but not exclusively self- treatment, of a wart or corn comprises the steps of a) applying a pre-treatment composition to the wart or corn, the pre-treatment composition comprising an analgesic, anaesthetic or de-sensitising agent incorporated (e.g. dissolved, suspended, or otherwise included) in a base comprising one of water with a surface acting agent, and a pharmaceutically acceptable organic solvent, for absorption by the wart or corn; and then b) waiting for a first time period for the pre-treatment composition to penetrate the wart or corn; and then c) applying a keratolytic, acid, caustic or vesicating agent at ambient temperature to the wart or corn.

In each embodiment, the time period at step (b) between the pre-treatment and subsequent treatment is selected to allow the thermal transmission agent to be fully absorbed so as to optimally hydrate the wart or corn and/or to allow the analgesic, anaesthetic or de-sensitising agent to temporarily anaesthetize or desensitise the tissue to be treated so as to relieve the pain of the subsequent treatment. The time period may be from a few seconds up to about thirty minutes, preferably up to no more than about five minutes. Where the thermal transmission agent or base is absorbed very rapidly and/or where the analgesic, anaesthetic or de-sensitising agent takes effect very rapidly, it may be possible to apply the treatment immediately after applying the pre-treatment. In this case, the minimum time period at step (b) will equate to the time taken by the normal user to apply the treatment, so that the user need not be aware of step (b).

Conveniently, the pre-treatment composition is contained in a first applicator adapted for precise topical application of the composition to the wart or corn. The composition can be applied directly to the wart or corn using the applicator, or alternatively can be applied to an applicator first, the applicator then being used to apply the composition to the wart or corn. The first applicator may be a dropper bottle, a pump spray, an aerosol can, a container incorporating a stylus or brush or the like, a tube, a pen-type applicator, a roller-applicator, a wipe contained in an individual sachet, a solid stick similar to lipstick, or any other applicator system suitable for the characteristics of the composition. Alternatively, the pre-treatment composition may be contained in a tube, tub, tin or the like for application by means of a suitable implement. A kit may be provided comprising the first applicator (containing the pre- treatment composition) together with a second applicator, the second applicator being adapted to deliver the treatment, and instructions for sequential use of the first and second applicators according to the method.

In accordance with the first embodiment, the second applicator preferably comprises any suitable topical freezing apparatus, e.g. a pressurised bottle having an integral or removable skin-contacting element and containing a freezing agent (such as, e.g, dimethyl ether) for topical application directly or via the skin- contacting element to the wart or corn, or for indirect application such as by cooling the skin-contacting element whereby the skin-contacting element acts as a heat exchanger for freezing the wart or corn.

Alternatively, the second applicator may comprise any suitable topical heating apparatus, for example, a patch or other skin-contacting element for applying heat from an exothermic composition for locally heating the wart or corn, such as disclosed for example by WO92/20308.

In accordance with the second embodiment, the second applicator may comprise an applicator similar to the first applicator and containing a known keratolytic, acid, caustic or vesicating agent such as salicylic acid, cantharidin, silver nitrate or the like.

The thermal transmission agent is preferably a liquid having a relatively high thermal conductivity and capable of saturating the hyperkeratotic tissue of the wart or corn. Table 1

Referring to Table 1 , it is seen that the thermal conductivity of water is higher than that of organic solvents, being twice that of glycerol and three times that of ethanol. Preferably therefore the thermal transmission agent is water.

Where the treatment comprises a freezing treatment, water is particularly preferred as the thermal transmission agent since the water absorbed by the wart or corn will advantageously be rapidly converted into ice by the treatment, the thermal conductivity of ice being several times that of liquid water. Organic solvents are less preferred for use prior to a freezing treatment, since they tend to have lower freezing points than water and can inhibit the freezing of water in the tissue of the wart or corn.

In order to ensure that the composition is rapidly frozen within the hyperkeratotic tissue by typical, relatively mild over-the-counter freezing treatments, it preferably has a freezing point of not lower than about -10 ⁰ C, more preferably not lower than about -5 °C, and most preferably not lower than about -2 ⁰ C. Thermal conductivity may still be usefully increased in such applications by pre-treatment compositions having freezing points below -10 ⁰ C, although such compositions are likely to be slower acting due to the delay in ice formation, potentially requiring a longer contact time with the freezing treatment and hence increased pain for the user. Pre-treatment compositions having a freezing point below about -25 ⁰ C are unlikely to be reasonably effective in increasing the thermal conductivity of the wart or corn when used in conjunction with an over-the- counter freezing treatment.

Since water has a higher surface tension than alcohols, where water is used as a thermal transmission agent and/or as a base for the composition, a pharmaceutically acceptable surface acting agent is included to ensure that the water penetrates the hyperkeratotic tissue of the wart or corn. The surface acting agent acts to reduce surface tension so as to allow faster penetration of the outer layers of the skin by the water and the tissue saturating agent (further discussed below), making the composition faster acting and more effective. Suitable surface acting agents include, for example, saponins, sodium lauryl sulfate, tego-betain and the like.

In some preferred embodiments, the surface acting agent is a saponin, which may be derived from a wide variety of sources including, for example, horse chestnut, quillaia saponaria, and licorice.

In other preferred embodiments, the surface acting agent is a skin-penetrating particulate carrier, most preferably non-ionic spherulites. The carrier has a dual role, functioning on the one hand as a surface acting agent to allow faster penetration of the outer layers of the skin by the water and the tissue saturating agent, and on the other hand to carry one or more ingredients, particularly an analgesic, anaesthetic, de-sensitising and/or anti-inflammatory ingredient, which is encapsulated within the carrier for delayed release into the hyperkeratotic and surrounding tissue. In yet other embodiments, a skin-penetrating particulate carrier may be used in combination with another surfactant, such as a saponin.

Preferably, where water is used as a thermal transmission agent or as a base, the composition also includes an effective amount of a tissue saturating agent, which is to say, an agent capable of locally binding the water within the hyperkeratotic tissue so as to saturate the wart or corn. This increases the amount of water retained in the hyperkeratotic tissue so that the subsequent heat or, particularly, freezing treatment is still more effective.

However, when used in a sufficiently high concentration to be effective, many tissue saturating agents also have the disadvantageous effect of lowering the freezing point of an aqueous composition, for example, to -20 ⁰ C or even lower. Examples of such potentially unsuitable agents which have a tissue saturating effect when used at relatively high concentrations include glycerol, glycerine, ethyleneglycol, polyethylene glycol, propylene glycol, propanol, isopropanol, ethanol, and other polyalcohols. Such ingredients are preferably included only in a relatively low concentration, sufficient to act as solvents for other, non-water soluble ingredients, but not high enough to disadvantageously reduce the freezing point of the composition. Such relatively low concentrations are selected according to the solubility of the ingredients of the composition, and are typically insufficient to provide effective saturation of the hyperkeratotic tissue.

The tissue saturating agent is therefore preferably one which provides little reduction (which is to say, not more than about 10 ⁰ C reduction, more preferably not more than about 5 ⁰ C reduction) or, most preferably, substantially no reduction (which is to say, only about 1 ⁰ C or 2 ⁰ C reduction) in the freezing point of the water-based composition. Suitable tissue saturating agents which do not substantially reduce the freezing point of the aqueous composition include hyaluronic acid, urea, and sugars such as, for example, trehalose, xylose, fructose, dextrose, saccharose, isomaltose, maltose, lactose, arabinose, rhamnose, galactose, etc., and sugar-like ingredients such as sugar alcohols, including for example sorbitol, mannitol, maltitol, xylitol, lactitol, etc.

By way of example, sorbitol is reported to depress the freezing point of water by less than 1 ⁰ C in aqueous solution at a concentration of 7 wt% (Robert J. Baer and Kirk A. Baldwin: Freezing Points of Bulking Agents Used in Manufacture of Low-Calorie Frozen Desserts; Journal of Dairy Science Vol. 67, No. 12, 1984). Generally, agents with higher molecular weights are preferred since they typically have less effect on the freezing point of water than do those with lower molecular weights.

In a particularly preferred embodiment, the pre-treatment composition for use prior to a freezing treatment comprises water together with an analgesic, anaesthetic or de-sensitising agent, an effective amount of a tissue saturating agent which does not substantially reduce the freezing point of the composition, and a surface acting agent which assists the water, the tissue saturating agent, and the other ingredients to penetrate into the hyperkeratotic tissue of the wart or corn. Preferably, the surface acting agent is a saponin and/or a skin-penetrating particulate carrier such as, in particular, non-ionic spherulites. Preferably, the composition also includes a binding or gelling agent, which thickens the composition and causes it to stick to the surface of the wart or corn while it is absorbed.

In alternative embodiments, the thermal transmission agent may comprise a pharmaceutically acceptable organic solvent, preferably an alcohol, which is to say, a mono-, di- or poly-alcohol, (poly-alcohols being taken to include tri- alcohols). Examples include ethanol, propanol or isopropanol, propyleneglycol, butyleneglycol, glycerine, methylpropanediol, polyethyleneglycol, ethoxydiglycol, methylic or ethylic diglycol ethers, cyclic polyols, ethoxylated or propoxylated diglycols or any mixture of these solvents.

Organic solvents advantageously have a lower surface tension than water, enabling more rapid absorption by the skin, and are also suitable solvents for many analgesic, anaesthetic or de-sensitising agents. However, they disadvantageously have both lower thermal conductivity and a lower freezing point than water, and are consequently less preferred for use as a thermal transmission agent where the subsequent treatment is a heat treatment or, in particular, a freezing treatment.

Organic solvents may advantageously be used as a base for the pre-treatment composition where the subsequent treatment comprises the application of a keratolytic, acid, caustic or vesicating agent at ambient temperature.

However, by using water as the base, the pre-treatment composition may advantageously be better adapted for dual-purpose use with a subsequent treatment or treatments which may comprise, either the application of a keratolytic, acid, caustic or vesicating agent, or a heat or freezing treatment, or any combination of these treatments. Where water is used as the base, the addition of a tissue saturating agent will retain more water and hence more of the analgesic, anaesthetic or de-sensitising agent in the tissue of the wart or corn, so that the analgesia, anaesthesia or de-sensitisation is advantageously enhanced.

Suitable anaesthetic agents include lidocaine, novocaine, benzocaine, and other known anaesthetics suitable for topical application.

Suitable agents having a mild analgesic effect include Acmella oleracea, Acmella flower extract, horse chestnut (Aesculus), grapeseed, Cheiranthus cheiri (clove), Hypericum perforatum, Vitis vinifera, tea tree oil, Glycyrrhiza glabra (licorice), glycyrrhizic acid and salts.

Suitable de-sensitising agents include those which give an impression of de- sensitising or a sensation such as of cooling, which reduces the perception of pain. One such agent is menthol, which produces a cooling sensation which can help to mask the perception of pain. Other suitable de-sensitising agents include menthol derivatives, tea tree oil, and manuca oil.

Other suitable de-sensitising agents which advantageously produce a refreshing sensation include menthyl lactate and any menthyl ester, peppermint oil, any kind of mentha, alcohol, camphor, magnesium aspartate, and cyclomethicone.

Other suitable de-sensitising agents which advantageously produce a calming and soothing sensation include allantoin and derivates, Aloe barbadensis, bisabolol, Centaurea cyanus, Echinacea pallida, Echium lycopsis oil, Zanthoxylum anatum, Hamameliis virginiana (witch hazel), jojoba oil, Butyrospermum parkii, Nymphea caerulea, Macadamia terniflora oil, Nymphea alba, Aucoumea klaineana, Citrus dulcis, Citrus grandis, Prunus persica, Rosa centifolia, Abies pectinata, Tilia platyphyllos, Helianthum (sunflower), melon, and wintergreen oil.

Tea tree oil and manuca oil advantageously provide an anti-viral, anti-microbial and anti-fungal action in addition to their cooling or de-sensitising action, while wintergreen oil advantageously contains salicylates and also exerts a keratolytic and also an analgesic effect, the keratolytic effect helping to further soften the hyperkeratotic tissues.

Many analgesic, anaesthetic or de-sensitising agents (for example, essential plant oils) are soluble in alcohol but not in water. Where water is used as a thermal transmission agent, and the composition also includes alcohol-soluble ingredients which are not soluble in water, the composition will also include an alcohol, but in a concentration sufficiently high to dissolve the alcohol-soluble ingredients but not so high as to unacceptably lower the freezing point of the composition. This ensures that the composition turns rapidly into ice within the wart or corn during the subsequent freezing treatment, which in turn is made more efficacious by the advantageously high thermal conductivity of the ice.

The constituents of the composition are selected by routine experimentation so as to obtain the required freezing point, with the optimum balance or selection between relatively more effective solvents having a disadvantageously low freezing point (such as ethanol) and relatively less effective solvents having a higher freezing point (such as propylene glycol) being determined in practice according to the nature and concentration of the non- water soluble ingredients. By way of example, in some formulations, a concentration of from about 5 wt% to about 10 wt% alcohol in water may be sufficient to dissolve the alcohol-soluble ingredients. The alcohol will have relatively little effect as a tissue-saturating agent, and so the composition preferably contains an additional tissue-saturating agent which does not substantially reduce its freezing point.

The pre-treatment composition may also include an anti-inflammatory agent such as Cucurbita pepo (pumpkin) seed extract. Calmosensine (TM) (N-acetyl-L-Tyr- L-Arg-o-hexadecyl), a soft analgesic peptide and anti-inflammatory as disclosed in WO 98/07744 is also suitable.

Advantageously, one or more of the active ingredients of the composition, and in particular the analgesic, anaesthetic or de-sensitising agent and/or the antiinflammatory agent, may be encapsulated in whole or in part into a skin- penetrating particulate carrier such as micro- or nano-scale vesicles or particles, which are adapted to rapidly penetrate the skin and thereafter to release the encapsulated active agent slowly over an extended period of, for example, from several tens of minutes to several hours. Such carriers are made from surfactants and so exert a surface action or detergent effect in a similar way to saponins or synthetic surfactants such as sodium lauryl sulphate or Tego-betain and the like. They can therefore function as the surface acting agent, as discussed above.

Suitable skin-penetrating particulate carriers include in particular non-ionic spherulites (a type of micro-capsule or microsphere), which are found to penetrate the epidermis more rapidly and effectively than ionic spherulites and are particularly preferred. Spherulite (micro-capsule) technology is disclosed for example in WO 93/19735 Al, WO 97/00623 Al, and WO 98/46199 Al. The antiinflammatory agent as well as the analgesic, anaesthetic or de-sensitising agent and/or other ingredients can be incorporated in whole or in part between multiple layers of the spherulite, so as to increase the rate and depth of penetration into the wart or corn and to provide longer lasting release of the agents into the tissue.

In particularly preferred embodiments, an anti-inflammatory agent such as Cucurbita pepo (pumpkin) seed extract or Calmosensine (TM) is incorporated into non-ionic spherulites so that it penetrates into the wart or corn and is then released slowly into the surrounding healthy skin tissue.

Other suitable skin-penetrating particulate carriers include liposomes, chylomicrons, micro particles, microcapsules or microspheres (e.g. spherulites), nano particles, nanocapsules or nanospheres, macro particles, macrocapsules or macrospheres, cyclodextrines, maltodextrine, and dextran.

In order to thicken the composition and cause it to adhere to the surface of the wart or corn after application so as to ensure a sufficient residence time for adequate absorption, the composition preferably includes a binding or gelling agent. Advantageously, the pre-treatment composition may thus comprise a soft gel. Where the primary solvent (as thermal transmission agent and/or as a base) of the composition is water, suitable water binding or gelling agents may include, for example, acrylate polymer or copolymer derivatives, carbomer, alginates, glucan and derivatives, dextran and derivatives, chitosan and derivatives, collodion, pectin, PVP (crospovidone), sclerotium gum, scleroglucan, or water-binding polysaccharides such as carob bean gum, xanthan gum, gum arabic, guar, cellulose and cellulose derivatives such as carboxymethylcellulose, ethyl cellulose, hydroxyethylcellulose and the like.

The active agents can also be absorbed into powdery inorganic polymers, talcs, bentonites, sodium or magnesium carbonate and other mineral carriers. In various embodiments, the pre-treatment composition may be formulated as a gel, cream, ointment, water-based, oil-based or other solvent-based liquid or suspension, as a gas dispensed via a spray or aerosol can, or as a powder to be mixed with water or other solvent prior to application.

Example formulations according to various embodiments of the pre-treatment composition are as follows.

Example 1

Preferred amount (wt.%) Exemplary range (wt.%)

Water 54.3 or 55.8 30 to 98

Cucurbita pepo (pumpkin) seed extract 4 0.5 to 10

Saponin 0.5 0.05 to 5

Menthyl lactate 2 0.1 to 10

Alcohol 8 0.5 to 30

{Urea 2 l to 5 or

Hyaluronic acid 0.5 0.2 to 1 }

Carbomer 0.2 0.02 to 2

Camphor 0.1 0.02 to 2

Menthol 0.2 0.02 to 2

Peppermint oil 0.2 0.02 to 2

Tea tree oil 0.05 0.02 to 2

Xanthan gum 0.05 0.01 to 2

Example 2

Preferred amount (wt.%) Exemplary range (wt.%)

Water 69,2 30 to 98

Non-ionic Spherulites 20 5 to 50

Alcohol 8 0.5 to 30

Sorbitol 2 0.1 to 20

Carbomer 0.2 0.02 to 2 Camphor 0.1 0.02 to 2

Menthol 0.2 0.02 to 2

Peppermint oil 0.2 0.02 to 2

Tea tree oil 0.05 0.02 to 2

Xanthan gum 0.05 0.01 to 2

Wherein the Non-ionic Spherulites contain:

Cucurbita pepo (pumpkin) seed extract 20 5 to 50

Glycerine 2.5 0.1 to 20 Menthyl lactate 2.5 0.1 to 10

Example 3

Preferred amount (wt.%)

Water 54.1%

Non-ionic Spherulites 20%

Alcohol 15%

Glycerine 10%

Carbomer 0.2%

Camphor 0.2%

Menthol 0.2%

Peppermint oil 0.2%

Tea tree oil 0.05%

Xanthan gum 0.05%

Wherein the Non-ionic Spherulites contain:

Cucurbita pepo (pumpkin) seed extract 20%

Glycerine 10%

Menthyl lactate 2.5%

In summary, a preferred embodiment provides a method of treatment of a wart or corn comprising the steps of applying a pre-treatment composition comprising a thermal transmission agent to the wart or corn, waiting for a first time period for the thermal transmission agent to hydrate the wart or corn, and then locally freezing or heating the wart or corn. The thermal transmission agent may be water with a surface acting agent and a tissue saturating agent, and increases the thermal conductivity of the dry tissues of the wart or corn so as to make the treatment faster and more effective. Alternatively or additionally, the pre-treatment composition may comprise an analgesic, anaesthetic or de-sensitising agent in an aqueous or organic solvent base, in which case the treatment step may comprise the application of a keratolytic, acid, caustic or vesicating agent. The pre- treatment composition is preferably contained in an applicator which may be provided as a kit including a second applicator for the subsequent treatment step.

In this specification, the term "comprise" or "comprises" is taken to be synonymous with the term "include" or "includes".