LU100105B1

LU100105B1 - Improved topical formulation

Info

Publication number: LU100105B1
Application number: LU100105A
Authority: LU
Inventors: Andrew Brown
Original assignee: Aspire Pharma Ltd
Priority date: 2017-02-20
Filing date: 2017-02-20
Publication date: 2018-10-02

Abstract

The present invention relates to a topical composition effective in the treatment of several skin disorders. The principle one being the effective treatment and prevention of miliaria (prickly heat). The principle active ingredient of the composition is a plant polyphenol (which can be a tannin, preferably a gallotannin and even more preferably tannic acid (as defined herein). Preferably the tannic acid is an extract from the plant Rumex (Dock Leaves).The present invention relates to a topical composition effective in the treatment of several skin disorders. The principle one being the effective treatment and prevention of miliaria (prickly heat). The principle active ingredient of the composition is a plant polyphenol (which can be a tannin, preferably a gallotannin and even more preferably tannic acid (as defined herein). Preferably the tannic acid is an extract from the plant Rumex (Dock Leaves).

Description

Improved topical formulation I

The present invention relates to a topical composition effective in the treatment of several skin disorders. The principle one being the effective treatment and prevention of miliaria (prickly heat). The principle active ingredient of the composition is a plant polyphenol (which can be a hydrolysable tannin, preferably a gallotannin and even more preferably tannic acid (as defined herein). Preferably the tannic acid is an extract from the plant Rumex (Dock Leaves).

Tannic acid and tannins all come under the general nomenclature of polyphenols. Traditionally these plant derived chemicals are known to be inolved in providing a defense of the plants from being eaten. It is not clear how this works but the strong ability of polyphenols to chelate proteins -thus rendering the plant of little nutritional value - is thought to be a leading reason for the presence. We are all aware of how milk when added to tea reduces its bitterness and this is due to the milk proteins chelating the tannins in tea making it less bitter. These polyphenols have good oxidising effects due to the numurous gallic acid groups present. These theories of the role of polyphenols in plants do not explain the variety of different polyphenols and their differing distribution in different plants and different parts of the plant.

Tannins are an enormous class of molecules with complex nomenclature and with terms often used interchangeably. For the purposes of this inventions we believe that the key tannins are those that are called the gallotannins and the simple gallic acid derivatives we shall call them GTs and SGADs.

Structurally perhaps the most complex group of tannins are the hydrolysable tannins (as opposed to the condensed tannins). Hydrolysable tannins are first divided into three subclasses such as simple gallic acid derivatives (SGADs), gallotannins (GTs) and ellagitannins (ETs). SGADs contain five or less galloyl groups that are most commonly esterified to either glucose (monogalloyl and pentagalloyl glucoses) or quinic acid (monogalloyl quinic acid). SGADs that contain six or more galloyl groups are defined as GTs and may further be characterized by having one or more digalloyl group. SGADs and GTs are much rarer in plants than are ETs. The diverse ETs structures described to date (>500) may be divided into six subgroups: hexahydroxydiphenoyl (HHDP) esters, dehydro-HHDP esters and their modifications, nonahydroxytriphenoyl (NHTP) esters, flavonoellagitannins, and oligomers with both varying degree of oligomerization and types of bonds between the monomers. I The ETs are not part of this invention.

The following shows the chemical structures of SGADs and GTs

However, GTs and SGADs are well known to exist in large amounts and to be extracted from the bark of certain plants commercially these are; sumac, chestnut, oak galls and oak-wood bark. This is categorised and defined in the product "tannic acid". The exact mixture of GTs and SGADs (and other tannins) in tannic acid depends upon which plant the tannic acid is extracted from. Pharmaceutical grades of tannic acid are available and pharmacopeia standards exist.

The offical monogrpah definition of tannic acis is given as "Consists of gallotannins obtained by solvent extraction from certain natural sources; the substance is not an acid in the chemical sense. The common name "Tannic acid" has been adopted to distinguish the commercial substance from other tannins, such as condensed

tannins. These specifications relate only to hydrolysable gallotannins, i.e., those which yield I gallic acid on hydrolysis. These specifications do not apply to many other kinds of tannins which occur in nature, including condensed (nonhydrolysable) tannins and hydrolysable ellagitannins. Hydrolysable gallotannins may be obtained from nutgalls, the excrescences which form on young twigs of various Que reus species, e.g., Q. infectoria; these include Chinese and Aleppo tannins. They may also be obtained from various Sumac species, e.g. Rhus corieria, R. galabra, R. thypia; these include Sicilian and American sumacs. All of these consist essentially of polydigalloyl esters of glucose. A further source of hydrolysable gallotannins is the seed pods of Tara (Caesalpinia spinosa); these tannins consist essentially of the polydigalloyl esters of quinic acid"

It is believed that the occlusion of sweat ducts is a factor in the disease miliaria which is a disease that is entirely associated with the blockage of sweat ducts and the buildup of sweat under the skin that leads to the irritation. Miliaria (also called "sweat rash" or "prickly heat") is a skin disease marked by small and itchy rashes. Miliaria is a common condition in hot and humid conditions, such as in the tropics and during the summer season in temperate climates. Although it affects people of all ages, it is especially common in children and infants due to their underdeveloped sweat glands. Journal of the American Academy of Dermatology Volume 33, Issue 5, Part 1, November 1995, Pages 729-733 describes that they think that there is a role of extracellular polysaccharide substance produced by Staphylococcus epidermidis.

Current treatments for miliaria suggested are to reduce exacerbating factors; such as exposure to heat or by cooling or by reducing the amount of exertion. Such options are not always convenient and may not be effective. Additionally, symptomatic relief such as by applying topical treatments to reduce irritation such as calamine lotion, or those that provide cooling and soothing. Caution is advised though as the underlying cause of miliaria is the blocking of the sweat glands and any preparations that increase the blocking of the sweat glands will make the miliaria worse.

However, despite some good basic research going into these skin conditions and some thoughts as above, amongst other ideas, being developed for these conditions there still exists a need for new treatments. The link between biofilm production and sweat gland blockage is suggested but not proven. However, even if the disruption of the biofilms of these bacteria is a significant factor there are no known effective disruptors of biofilms known that can be used as topical treatments. For example, Chemistry & Biology, Vol. 12, 789-796, July, 2005 tested 4509 diverse compounds but only found certain ferric salts to be effective and in Braz Oral Res., (Säo Paulo) 2013 Jan-Feb;27(l):20-5 I found that a mixture of farnesol, xylitol and lactoferrin or farnesol and xylitol had some effect in disrupting biofilms formation for endodontic treatment to prevent formation of infections. At present, there are no effective treatments known for miliaria at all. The control of atopic dermatitis and psoriasis is often associated with pharmacologically active ingredients or other topical palliative treatments that treat the symptoms of these disease. W00038646 - shows that tannic acid at very low levels has antimicrobial properties against the bacteria that cause acne and suggest its sue to attenuate the effects of other antimicrobial ingredients for treating acne. The bacteria are non-biofilm forming. However, it is not the antimicrobial effect of any ingredient that is desired - as seen in Chemistry & Biology, Vol. 12, 789-796, July, 2005 compounds that act as antibiotics were discounted. The effect desired is to disrupt the biofilm.

We have found that the plant extract from Rumex is highly effective at treating miliaria. We have found that it is the tannic acid in Rumex that is effective. We have found that it is the GTs in tannic acid that are effective in accordance with this invention. It is believed that this is due to the ability to disrupt bacteria biofilm formation or to break down bacterial films after they have been formed. The compounds that are most preferred are the GTs of formula with a central glucose molecule

The blockage of sweat ducts may also be implicated in other skin diseases but this has not been clinically proven with the benefit of any topically applied product to counteract such an effect. Suggestions as to such links are provided below. Gantz and Allen, J Clin Exp Dermatol Res 2016, discloses a theory that the exudates of certain bacteria cause the formation of biofilms and that these Staphylococcal biofilms as a likely environmental factor in the development of atopic dermatitis (eczema). Additionally, the paper also suggests that the formation of these biofilms from bacteria cause the blockage of eccrine ducts (sweat) and the blockage creates an environment factor that may be a trigger factor in atopic dermatitis. Additionally, JAMA Dermatol. 2014;150(3):260-265 also described what they think is a positive link.

I

The GTs are either polygalloyl glucoses or polygalloyl quinic acid esters with the number of galloyl moieties per molecule ranging from 2 up to 12 (with any whole number in between being contemplated as being effective). The glucose based ones are preferred. Preferably the compound additionally has at least one galloyl diester moiety and no more than six and any number in between.

The GTs are further divided into subgroups - the galloyl glucoses and the galloyl quinic acids. Either of these two subset are useful according to the invention but glucose being preferred. Within the galloyl glucoses there are a number of preferred compounds; 1-Galloyl glucose - glucogallin,

Digalloyl glucose - such as 1,6-digalloyl glucose, 2,6-digalloyl glucose & 3,6-digalloyl glucose,

Trigalloyl glucoses - such as 1,2,3-trigalloyl glucose, 1,2,3-tri-O-galloyl-ß-D-glucose, 1,2,6-Trigalloyl glucose / 1,3,6-Trigalloyl glucose

Tetragalloyl glucoses-such as 1,2,3,6-tetragalloylglucose, 1,2,3,6-tetra-O-galloyl-ß-D-glucose, 1,2,4,6-Tetragalloyl glucose and 1,2,4,6-tetra-O-galloyl-ß-D-glucose) Pentagalloyl glucose - such as 1,2,3,4,6-Pentagalloyl-glucose or 6-digalloyl-l,2,3-trigalloyl-glucose

Hexagalloyl glucose

Heptagalloyl glucose

Octagalloyl glucose

Nonagalloyl glucose

Decagalloyl glucose

Miliaria can be classified per the level at which obstruction occurs in the sweat glands.

Miliaria crystalline - the most superficial obstruction (with the most mild clinical presentation), is known as miliaria crystalline; instead of a rash the patient presents with multiple tiny blister-like lesions that look like beads of perspiration and essentially cause no symptoms. Potentially it is even this mild and untreated form that may lead to the atopic dermatitis, pruritus and psoriasis. As will be appreciated any aggravating factor on the skin that can potentially raise the heightened state of the immune system is best avoided.

Miliaria rubra - typical red spots on chest, neck and shoulders. The most commonly encountered form in which obstruction causes leakage of sweat into the deeper layers of the epidermis, provoking a local inflammatory reaction giving rise to the typical appearance of redness (hence rubra) and larger (but still only a few millimetres) blister-like lesions. This form of the illness is often accompanied by the typical symptoms - intense itching or "pins and needles" with a lack of sweating (anhidrosis) to affected areas.

Miliaria profunda - The most severe form of sometimes referred to as "wildfire" due to the rapid spread and severe burning sensations, generally occurs as a complication of repeated episodes of miliaria rubra. The obstruction is located deep in the structure of the sweat gland, causing the gland's secretions to leak between the superficial and deep layers of the skin. The rash, and associated symptoms, tend to break out within hours of an activity provoking sweating but similarly fade within hours when the stimulus for the sweating is removed. This form can be very debilitating.

The biofilm may be formed of any number of constituents but is most commonly formed of fibrin fibre and polysaccharides (often generically referred to as the glycocalyx). The biofilm is important for adhesion of the bacteria to the skin to create colonisation sites and for resistance to antimicrobial agents. Whilst the use of antibiotics would appear to be the obvious choice long term use of antibiotics on chronic skin conditions is like to lead to even more resistant strains evolving.

The compounds are preferably formulated as pure compounds. It will be appreciated that they can be used as a mixture. Also, conveniently they can be used as their raw extracted form from the plant itself such as tannic acid. It is a preferred feature of this invention that the extract is from plant genus Rumex. Rumex (commonly called dock or sorrel) covers about 200 species. It is believed that any extract from the Rumex genus is likely to be beneficial according to the invention since they contain GTs. However, preferred are the species that are commonly referred to dock or dockweed. Specific species preferred are the following R. obtusifolius and R. crispus.

I

By Active ingredient we mean 1) a plant extract of Rumex variety; or 2) tannic acid 3) or a GT as described above or 4) one or more of the following selected from; oxalic acid (or a salt thereof)and crysophanic acid (ora salt thereof).

We have found that the GTs of the invention can be synthesized. Method for the synthesis of GTs are known such as in "Gallotannins and Tannic Acid: First Chemical Syntheses and In Vitro Inhibitory Activity on Alzheimer's Amyloid ß-Peptide Aggregation" Dr. Tahiri Sylla, Prof. Laurent Pouységu, Dr. Grégory Da Costa, et al. Also certain gallotannins are available directly from specialist like Sigma -1-O-galloyl-ß-D-glucose, penta-O-galloyl-ß-D-glucose hydrate, 1,3,6-tri-O-galloyl-ß-D-glucose.

The extract of Rumex is prepared by simple plant extraction techniques to provide plant tinctures. Water alone extraction is referred although additional solvent may be added - such as chloroform or simple light petroleum's. In summary, the extraction technique comprises taking a quantity of the leaves of Rumex (such as Rumex obtusifolius - "broad leaved dock" [around 500g]) and adding water (100ml) and liquidizing the leaves in the water by the use of a blender for sufficient time that the mass of leaves is liquidised into the water (around 2 minutes). The resultant liquid is filtered to remove any insoluble elements, such as leaf mass. The tincture is then decanted. Optionally it can be clarified by gentle heating.

Therefore, we present as a feature of the inventions. Active ingredient is any compound mentioned herein.

Active ingredient for use as a topical medicament

Active ingredient for use in the treatment, or prophylaxis, of a skin condition as herein described. A method of treating a skin condition as herein described such treatment comprising applying a I medicament to the affected area comprising the Active ingredient. A topical formulation comprising an Active ingredient and at least one pharmaceutically-acceptable excipient. The Active ingredient is added to the formulation in the following preferred amounts: up to 20% w/v, 19% w/v, 18% w/v, 17% w/v, 16% w/v, 15% w/v, 14% w/v, 13% w/v, 12% w/v, 11% w/v, 10% w/v, 9% w/v, 8% w/v, 7% w/v, 6% w/v, 5% w/v, or 4% w/v. The Active ingredient is added to the formulation in the following preferred amounts: less than 40% w/v, 35% w/v, 30% w/v, 25% w/v, 20% w/v, 19% w/v, 18% w/v, 17% w/v, 16% w/v, 15% w/v, 14% w/v, 13% w/v, 12% w/v, 11% w/v, 10% w/v, 9% w/v, or 8% w/v.

The Active ingredients can be formulated in any number of standard topical formulations including without limitation. Cream (formulated as either an oil-in-water or water-in-oil), gel, ointment, foam, spray

Skin conditions that can be treated or prevented by the application of a composition according to the invention are miliaria as set out above. Additionally, we believe that the composition and active ingredients described herein will be effective due to their effect in eliminating, preventing or treating miliaria will have utility in also treating and preventing the different types of eczema; these are Atopic dermatitis, Contact dermatitis, Dyshidrotic eczema, Hand eczema, Neurodermatitis, Nummular eczema and Stasis dermatitis. In particular, we believe that there is utility in preventing or treating atopic dermatitis. Similarly, due to the development of psoriasis being associated with the blockage of sweat ducts we believe that the composition and active ingredients described herein will be effective due to their effect in eliminating, preventing or treating miliaria will have utility in also treating and preventing the different types of psoriasis; Plaque Psoriasis, Guttate Psoriasis, Inverse Psoriasis, Pustular Psoriasis and Erythrodermie Psoriasis. We believe that the composition and active ingredients will be most effective against Plaque Psoriasis.

We believe that the that the composition and active ingredients described herein may also have a role in inflammatory skin diseases (which would be largely aggravated by the blocking of the sweat ducts) and can used in treating one of more of the following: erythema, overheating, swelling, pain and limited function. Frequently symptoms can manifest themselves as the following for which can be treated or prevented; formation of edema, formation of blisters, pustules or wheals as well as

pruritus (itching). It is also possible that only one or more of these epiphenomena occur. I

Inflammatory skin diseases also include, for example, acne.

Degenerative skin diseases include, for example psoriasis, dermatitis (in particular also atopical dermatitis/neurodermitis), rosacea, urticaria (hives), actinic keratosis and eczema of the hands, including the respectively associated symptoms. And as described the use of the composition and active ingredients described herein may play a role in treating or preventing any of these conditions.

In particular, the following positive effects were observed during the application according to the invention in the case of the above-described indications or the described symptoms:

Accelerated easing of symptoms and accompanying pain-relieving action against miliaria

Effect of relieving pruritus to the extent of making it disappear (calming the skin)

Persistent pruritus-relief

Long-term cooling action/reduction of heat or burning

Anti-swelling action

Reduction of feeling of tightness

Easing of erythema

Reduction of scaling and cracked skin due to dryness

Increased elasticity of the skin (skin surface becomes more elastic and less tight)

Improved functional performance of the affected body parts (e.g. improvement of the mobility of affected joint regions, such as fingers, elbows, knees etc.)

Skin has a pleasant feel during and after application

Skin has an improved feel after application

High tolerance/Biocompatibility

In particular, during the acute treatment of pruritus (itching), most frequently as a symptom or epiphenomenon of one of the aforementioned diseases or disorders, by means of the use according to the invention preferably of layered collagen materials, the following positive effects and advantages become evident as compared with conventional treatment methods, which usually take place in the form ofcreaming treatments:

Primary Effects:

Immediate alleviation of itching to the extent of making it disappear

Calming of the skin I

Relief of the acute complaints

Reduction of the erythema which most frequently accompanies the pruritus

Skin care (optionally also by means of further skin care substances contained in the collagen material)

Secondary Effects:

The impulse to scratch is inhibited by the physical barrier by applying a protective layer on the affected regions of the skin in the form of a layered dressing; acute irritation of the skin is thus reduced, and additional mechanical damage to the skin (due to scratching) is prevented. In contrast, creams as a rule amplify the impulse to scratch oneself, because of the manual application The covered skin is given time to "relax"

Tertiary Effects:

Itching can be considered an "invisible" symptom of a disease; by applying a clearly visible product, the disease of the patient is recognized (psychological effect)

According to the invention, the use of the Active Ingredient is preferred in the treatment of psoriasis, dermatitis, neurodermitis, atopical dermatitis, rosacea, urticaria (hives), pruritus (itching), skin eczema or eczematous changes, erythema and actinic keratosis as well as of persistent inflammatory lesions after the completion of a local treatment of actinic keratosis with immunostimulants, as well as, respectively, the symptoms associated therewith.

The use of the Active Ingredient is very much preferred in the prevention of neurodermitis, atopical dermatitis, rosacea, urticaria (hives), pruritus (itching) as well as of persistent inflammatory lesions after the completion of a local treatment of actinic keratosis with immunostimulants, as well as, respectively, the symptoms associated therewith.

Formulation

The active ingredient of this invention can be added into any of these formulation types easily.

Cream - Emulsion of oil and water in approximately equal proportions. Penetrates stratum corneum I outer layer of skin well. Creams are semisolid dosage forms containing one the active ingredient dissolved in the water phase or dispersed in the oil phase.

Composition: There are four main ingredients of a cream 1: Water 2: Oil 3: Emulsifier 4: Thickening agent.

Ointment - Combines oil (80%) and water (20%).

An ointment is a homogeneous, viscous, semi-solid preparation, most commonly a greasy, thick oil (oil 80% - water 20%) with a high viscosity, that is intended for external application to the skin or mucous membranes. They are used as emollients or for the application of active ingredients to the skin for protective, therapeutic, or prophylactic purposes.

Ointments are usually very moisturizing, and good for dry skin. They have a low risk of sensitization due to having few ingredients beyond the base oil or fat, and low irritation risk. The vehicle of an ointment is known as the ointment base. The choice of a base depends upon the clinical indication for the ointment. The different types of ointment bases are: • Hydrocarbon bases, e.g. hard paraffin, soft paraffin, microcrystalline wax and ceresine • Absorption bases, e.g. wool fat, beeswax • Water soluble bases, e.g. macrogols 200, 300, 400 • Emulsifying bases, e.g. emulsifying wax, cetrimide • Vegetable oils, e.g. olive oil, coconut oil, sesame oil, almond oil and peanut oil.

The active ingredient is dispersed in the base.

Ointments are formulated using hydrophobic, hydrophilic, or water-emulsifying bases to provide preparations that are immiscible, miscible, or emulsifiable with skin secretions. They can also be derived from hydrocarbon (fatty), absorption, water-removable, or water-soluble bases.

Gels-

Gels consist of a solid three-dimensional network that spans the volume of a liquid medium and ensnares it through surface tension effects. This internal network structure may result from physical bonds (physical gels) or chemical bonds (chemical gels), as well as crystallites or other junctions that remain intact within the extending fluid. Virtually any fluid can be used as an extender including

water (hydrogels), oil, and air (aerogel). Both by weight and volume, gels are mostly fluid in I composition and thus exhibit densities similar to those of their constituent liquids.

Paste

Combines three agents - oil, water, and powder; an ointment in which a powder is suspended. In physics, a paste is a substance that behaves as a solid until a sufficiently large load or stress is applied, at which point it flows like a fluid. In rheological terms, a paste is an example of a Bingham plastic fluid. Pastes typically consist of a suspension of granular material in a background fluid. The individual grains are jammed together like sand on a beach, forming a disordered, glassy or amorphous structure, and giving pastes their solid-like character. It is this "jamming together" that gives pastes some of their most unusual properties; this causes paste to demonstrate properties of fragile matter In pharmacology, paste is basic pharmaceutical form. It consists of fatty base (e.g., petroleum jelly) and at least 25% solid substance (e.g., zinc oxide).Examples include starch pastes, toothpaste, mustard, and putty.

Spray

The active ingredients I dissolved into a suitable pharmaceutically-acceptable solution containing water, pH adjusting agents, pH buffer, and preservatives. The solution is then packaged into a suitable spray device such as those made by Aptar.

Formulation Example 40g of Eu.Ph Tannic acid (Sigma) was dissolved in 11 of water for injection. The solution was then packed aseptically in a the Aptar mult-dose EuoMist spray pump 100ml per pump.

Examples of such formulation are listed as below

Tannic Acid I available in the following grade at Sigma

Tannic acid - Source: Chinese natural gall nuts

Tannic Acid - tested according to Ph.Eur

Tannic acid, United States Pharmacopeia (USP) Reference Standard,

Plant extract 500g of broad-leaved dock (Rumex obtusifolius) was freshly picked and blended with 750g of water. I The mixture was filtered through a cloth and then centrifuged to create a clear liquid extract. The extract was refrigerated until use.

Experimental data A formulation was prepared of by mixing the plant extract into an aqueous base cream B.P. This is a standard fixed non-proprietary cream the constituents and make of which is fixed in the British Pharmacopeia - for reference we refer to the 2013 edition.

It contains Liquid Paraffin 6% w/w, White Soft Paraffin 15% w/w.

Also contains: purified water, emulsifying wax (containing cetostearyl alcohol, sodium lauryl sulfate), chlorocresol 0.1% w/w.

The patient then applies the treatment to the area of prickly heat. One area being treated and another area symmetrically opposite, where available, is non-treated. Consistently we found the formulations were effective in treating miliaria.

It is believed that other dermatological conditions will benefit from treatment with formulations of the current inventions including, but not limiting: hives, insect bites, nettle stings, rash,

By the use of the word treatment herein we also include that the formulations may also be used in prevention of any of the conditions listed herein, where applicable. Such as in preventing prickly heat by a patient susceptible to prickly heat applying the treatment to the known affected areas prior to be exposed to exacerbating factors - such as strenuous exercise or going outdoors on a very hot day.

Biofilm disruption test

Experiments can be conducted in accordance with the procedures of APMIS 115: 891-9, "Quantification of biofilm in microtiter plates: overview of testing conditions and practical recommendations for assessment of biofilm production by staphylococci" - SRDJAN STEPANOVIC et al. briefly cultures of staphylococci are inoculated into each well of a 96 well plate in an appropriate

medium using a fixed amount of bacteria per well plate and are then incubated for a period I adequate to generate an adequate biofilm. The biofilms should be all of a roughly equal size and are then washed, gently, sufficiently to remove all loose bacteria but to maintained the biofilm. The remaining bacteria are fixed through heat. The biofilm is then stained, such as with Crystal Violet, and the subjected to the test sample according to the invention at different concentration and with other excipients. Whilst not providing an absolute measurement the techniques allows excellent comparative testing.

Alternative test are available such as described in Chemistry & Biology, Vol. 12, 789-796, July, 2005 used for pseudomonas bacteria instead.

In our testing, we found that tannic acid concentration of from between 2 to 6%wt showed excellent biofilm disruption in staphylococcus especially staphylococcus epidermidis. In addition, a 2%wt solution of penta-O-galloyl-ß-D-glucose hydrate (Sigma) in waterwas also seen to be effective.

Claims

Claim

A topical formulation comprising tannic acid and at least one pharmaceutically acceptable excipient for treating or preventing heat stroke.

2. Topical formulation according to claim 1, wherein the tannic acid is extracted from the plant species Rumex.

3. A topical formulation comprising a hydrolysable tannin and at least one pharmaceutically acceptable excipient for heat block treatment or prevention.

The topical formulation of claim 3, wherein the hydrolysable tannin is a gallotannin having a glucose group and at least three galloyl groups.

5. A topical formulation comprising a gallotannin is selected from one or more of the following; Trigalloyl glucose, tetragalloyl glucose, pentagalloyl glucose, hexagalloyl glucose, heptagalloyl glucose, octagalloyl glucose, nonagalloyl glucose and decagalloyl glucose and at least one pharmaceutically acceptable excipient.

A topical formulation according to any one of claims 1 to 5, wherein the formulation is prepared as a cream, ointment, gel or spray.

The topical formulation of claim 5 for use in medical therapy.

8. Topical formulation according to claim 7 for use in the treatment of skin conditions.

9. Topical formulation according to claim 8, for use in the treatment or prevention of heat stroke.