GB2465633A - Anti-acne formulation - Google Patents

Abstract

Anti-acne formulation containing: (i) a polyoxyalkylene-based solubilising agent; (ii) an organic solvent; and (iii) a thickening agent, together with one or more anti-acne actives selected from (a) bismuth salts; (b) copper salts; (c) antibiotics; (d) halogenated salicylanilides; and mixtures thereof. The formulation may be applied topically. It may additionally include a dialkyl sulphosuccinate (DAS) or derivative thereof. Also provided is such a formulation for use in the treatment of acne, and its use to control the growth of a propionibacterium. Further provided is an antibacterial or anti-acne formulation containing one or more anti-acne actives selected from (a) to (d) above, together with a DAS or derivative thereof.

Description

Formulations

Field of the invention

This invention relates to anti-acne formulations, and to the use of certain combinations of compounds as anti-acne agents.

Background to the invention

A range of different compounds are known for use as anti-acne agents, two of the most common being salicylic acid and benzoyl peroxide.

Because acne is an extremely common condition, and a cause of significant distress to those suffering from it, there is always a need to find new and preferably more effective anti-acne treatments.

It has now surprisingly been found that certain new combinations of materials can be effective as anti-acne agents.

Statements of the invention

According to a first aspect of the present invention there is provided an anti-acne formulation containing: (i) a polyoxyalkylene-based solubilising agent; (ii) an organic solvent, in particular an alcohol; and (iii) a thickening agent; together with one or more anti-acne actives selected from the following: (a) bismuth salts; (b) copper salts; (c) antibiotics; (d) halogenated salicylanilides; and mixtures thereof The formulation suitably also contains water. In particular, it may be in the form of an aqueous gel. In an embodiment of the invention, the formulation is a gel which may for example have a viscosity of from 25,000 to 300,000 cps, or from 50,000 to 200,000 cps.

The formulation may additionally contain a dialkyl sulphosuccinate (DAS) or derivative thereof The antibiotic (c), if present, may in particular be selected from chloramphenicol, trimethoprim and mixtures thereof It has surprisingly been found that the combination of components (i) to (iii), in is particular in the presence of water, can be effective as an anti-acne agent. The combination has been found for example, as illustrated in Example 1 below, to be effective in the treatment of non-inflamed acne lesions. It is particularly surprising that the components (i) to (iii), which are conventionally used as excipients for other active agents, can themselves be active against acne.

The presence of the additional anti-acne active(s) (a) to (d) can serve to improve the overall efficacy of the formulation, in some cases by providing antibacterial activity against propionibacteria, the key pathogens implicated in inflammatory acne. Thus formulations according to the invention may be able to target both inflammatory and non-inflammatory aspects of the condition.

At the same time, the activity contributed by the components (i) to (iii) can make it possible to reduce the concentration of the additional anti-acne active(s) needed in the formulation whilst still retaining acceptable efficacy overall. This can be of particular value where the additional anti-acne active is or includes an antibiotic, helping to reduce the risk of the targeted micro-organisms developing antibiotic resistance and also to reduce the risk of undesirable side effects and/or allergic reactions which can accompany the administration of certain types of antibiotic.

In a formulation according to the invention, the solubilising agent (i) is polyoxyalkylene-based, for example polyoxyethylene (polyethylene glyco 1, PEG)-based. It may comprise a derivative of a polyoxyalkylene, for example an ether or more particularly an ester. It may for example be selected from (a) polyalkoxylated esters, other than polyalkoxylated sorbitan esters and (b) polyalkoxylated alkyl ethers.

More particularly it may be selected from (a) polyethoxylated esters, other than polyethoxylated sorbitan esters and (b) polyethoxylated alkyl ethers. It is suitably nonionic.

A polyalkoxylated ester may be a polyalkoxylated fatty acid ester. The fatty acid component may be a C10 to C20 group or a C12 to C18 group, for example stearic acid (C18) or 12-hydroxystearic acid. It may in particular be a hydroxyl-substituted fatty acid group. Suitable such solubilising agents are commercially available as MyrjTM 45 (PEG 400-monostearate) and Solutol� HS 15 (PEG-15-hydroxystearate, also known as PEG 660 1 2-hydroxystearate and Macrogol-15 -hydroxystearate).

Solutol� HS 15 is a nonionic solubilising agent available from BASF AG. It consists primarily ofpolyglycol mono-and di-esters of 12-hydroxystearic acid (the lipophilic part of the molecule) and of about 30 % of free polyethylene glycol (the hydrophilic part). It is prepared by reacting 15 moles of ethylene oxide with one mole of 12-hydroxystearic acid.

Solubilisers of this general type are known for use in injectable and in cases oral pharmaceutical formulations, but have not previously been widely used in, or recommended for use in, formulations intended for topical application.

A polyalkoxylated ester may be a polyalkoxylated glyceryl ester (also known as a polyalkoxylated glyceride), which is a glyceride ester of a polyalkylene glycol (typically PEG). It may contain mono-, di-or tri-glycerides, partial glycerides or mixtures thereof. It may for example be formed by esterification of a polyalkylene glycol with a glyceride oil of an appropriate chain length. The glyceride components may for example contain from 6 to 20 or from 8 to 18 carbon atoms. Suitable such solubilising agents are commercially available as GlyceroxTM and LabrasolTM.

GlyceroxTM esters, for example, are PEG-based products which are commercially available from Croda Inc in a number of grades reflecting the molecular weight of the PEG, for example PEG-6, PEG-7, PEG-8 (L8) and PEG-15 (L15). Of these, the PEG- 6 version may be preferred. GlyceroxTM esters are sold for use as emollients, for example in bath products, skin cleansers and shampoos, and as solubilisers, superfatting agents, dispersing agents and emulsifiers. LabrasolTM is a mixture of caprylic and capric glycerides of PEG-8 and is commercially available from Gattefosse, France. It is an excipient used to formulate lipophilic drugs for both oral and topical delivery. In particular it is used as a solubiliser/bioavailability enhancer for oral formulations, and can be used in self emulsifying lipidic formulations (SELFs) as a surfactant.

A glyceride solubilising agent may for example be GlyceroxTM 767 (polyoxyethylene (6) glyceryl monocaprylate/caprate, a mixture of caprylic and capric glycerides of PEG-6) or GlyceroxTM HE, which is a PEG-7 glyceryl cocoate. It may be a LabrasolTM solubilising agent.

A polyalkoxylated alkyl ether may be a polyalkoxylated ether of a fatty alcohol such as a C12 to C20 or C14 to C20 alcohol, for example cetyl (C16), stearyl (C18) or oleyl (C18:i).

It may in particular be a polyethoxylated alkyl ether, also known as a macrogol ether.

Suitable such solubilising agents are commercially available as BrijTM 97 (PEG-monooleyl ether) and CremophorTM A 25 (a mixture of stearic and cetyl ethers).

In general, the polyalkylene glycol element of a solubilising agent used in the present invention may have any appropriate molecular weight.

The solubilising agent (i) may in particular be a polyethoxylated ester, more particularly a fatty acid ester or a polyethoxylated glyceride. It may be a polyethoxylated glyceride. Solutol� HS 15, GlyceroxTM 767 and LabrasolTM have been found to be suitable solubilising agents for use in the present invention.

The organic solvent (ii) used in the formulation of the invention is suitably an alcohol, for example methanol, ethanol, isopropanol or phenoxyethanol. It may be selected from methanol, ethanol, isopropanol and mixtures thereof, preferably from methanol, ethanol and mixtures thereof. In an embodiment of the invention the organic solvent is ethanol.

The thickening agent (iii) may be any thickening agent suitable for topical application.

It is suitably a gelling agent. It may in particular be a cellulose-based thickening agent such as ethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose or a carboxymethyl cellulose. Such agents may be used in the form of a (preferably pharmaceutically acceptable) salt such as for instance the sodium salt. The thickening agent may be a polymeric thickening agent such as a carbomer, which will typically be a homopolymer of acrylic acid, cross-linked with an allyl ether.

A preferred thickening agent is hydroxyethyl cellulose. Another preferred thickening agent is hydroxypropyl cellulose. Thus, the thickening agent may be for example a KlucelTM thickener such as KlucelTM HF, which is a hydroxypropyl cellulose thickener commercially available from Hercules, USA.

The solubilising agent is preferably present at a concentration of 2 or 5 or 8 or 10 % w/w or greater, more preferably 15 % w/w or greater. It may be present at a concentration of up to 50 % w/w, suitably up to 40 or 35 or 30 or 25 % w/w. Its concentration may for example be from 2 to 40 % w/w or from 10 to 30 % w/w or from 15 to 25 % w/w, such as about 20 % w/w.

The organic solvent is preferably present at a concentration of 10 % w/w or greater, more preferably 15 or 17 % w/w or greater. It may be present at a concentration of up to 40 or 30 % w/w, suitably up to 25 % w/w. Its concentration may for example be from 10 to 30 % w/w or from 15 to 25 or 30 % w/w, such as about 20 % w/w or in cases 30 % w/w.

The thickening agent is preferably present at a concentration of 0.2 % w/w or greater, more preferably 0.5 % w/w or greater. It may be present at a concentration of up to 5 % w/w, suitably up to 3 % w/w. Its concentration may for example be from 0.5 to 5 % w/w or from 0.5 to 3 % w/w, such as from 1 to 2 % w/w or from 1 to 1.8 % w/w or from 1.2to 1.6%w/w.

The balance of the formulation, allowing also for the component(s) (a) to (d) and for the DAS or derivative if present, may be water.

Thus according to a preferred embodiment, the invention provides an anti-acne formulation which contains: (i) from 2 to 40 % w/w (or from 10 to 30 % w/w) of a polyoxyalkylene-based solubilising agent; (ii) from 10 to 30 % w/w of an organic solvent, in particular an alcohol; (iii) from 0.5 to 5 % w/w of a thickening agent; one or more anti-acne actives selected from (a) bismuth salts, (b) copper salts, (c) antibiotics, (d) halogenated salicylanilides, and mixtures thereof; and optionally (iv) the balance water.

In the context of the present invention the term "bismuth salt" includes bismuth (III) and (V) salts. Preferably a bismuth salt used in a formulation according to the invention is a bismuth (III) salt.

Certain bismuth salts are already recognised as antibacterial agents, for instance in WO-96/37228 which describes their use in wound treatment compositions together with wound healing agents. EP-1 702 621 discloses antimicrobial combinations of thiol-containing complexing agents and bismuth salts: these compositions can be used, for example, as surface disinfectants, topical pharmaceuticals and antimicrobial soaps, such as to treat microbial skin conditions. WO-O1/00151 also describes combining a pyrithione with a metal ion source, which can be a bismuth salt, in a topical antimicrobial formulation in particular for antiftingal and anti-dandruff use.

In WO-2008/035085, bismuth salts are shown to be active against propionibacteria, and thus to be of use in the treatment of acne. Bismuth salts have not however, to our knowledge, been combined with the components (i) to (iii) above for the treatment of acne.

In a formulation according to the invention, a bismuth salt may for instance be selected from bismuth carboxylates, bismuth halides, bismuth sulphadiazine, bismuth sulphate, bismuth nitrate, bismuth subnitrate, bismuth carbonate, bismuth subcarbonate, bismuth oxide, bismuth oxychloride, bismuth hydroxide, bismuth phosphate, bismuth aluminate, bismuth tribromophenate, bismuth thiol, bismuth peptides, bismuth salts of quino lines and their derivatives (eg, bismuth hydroxyquino lines), bismuth pyrithione and other bismuth salts of pyridine thio ls, bismuth amino acid salts such as the glycinate, tripotassium dicitrato bismuthate, and mixtures thereof Generally speaking the bismuth salt may be either organic or inorganic. It may be a basic bismuth salt (bismuth subsalt) such as the subsalts referred to above.

Suitable bismuth carboxylates include the salicylate, subsalicylate, lactate, citrate, subcitrate, ascorbate, acetate, dipropylacetate, tartrate, sodium tartrate, gluconate, subgallate, benzoate, laurate, myristate, palmitate, propionate, stearate, undecylenate, aspirinate, neodecanoate and ricinoleate. Of these, basic bismuth salicylate (bismuth subsalicylate) and bismuth citrate may be preferred.

Suitable halides include bismuth chloride, bismuth bromide and bismuth iodide.

Preferred bismuth salts may be selected from bismuth halides (in particular bismuth chloride), bismuth nitrates and bismuth carboxylates. More preferred bismuth salts may be selected from bismuth subsalicylate, bismuth salicylate, bismuth subgallate, bismuth subcitrate, bismuth citrate, bismuth acetate, bismuth nitrate and bismuth subnitrate. Yet more preferably the bismuth salt may be selected from bismuth subsalicylate, bismuth citrate and bismuth subnitrate, or from bismuth subsalicylate and bismuth subnitrate, or from bismuth subsalicylate and bismuth citrate. A particularly preferred bismuth salt is bismuth subsalicylate.

The bismuth salt may be used in an at least partially hydrated form, and may thus be formulated in the presence of an aqueous solvent. Alternatively it may be used in the form of a lipid-soluble salt, suitably in the presence of an organic solvent.

A formulation according to the invention may contain more than one bismuth salt.

The concentration of the bismuth salt in the formulation might suitably be 0.05 or 0.1 % w/v or greater, preferably 0.3 or 0.5 or 1 % w/v or greater. Its concentration might be up to 5 % w/v, preferably up to 3 % w/v, more preferably up to 2 or 1 % w/v, such as from 0.5 to 5 % w/v or from 0.5 to 3 % w/v or from 1 to 2 % w/v.

In the context of the present invention the term "copper salt" includes copper (I), (II) and (III) salts. Preferably the copper salt in a formulation according to the invention is a copper (I) (cuprous) or copper (II) (cupric) salt, more preferably a copper (II) salt.

Certain copper salts are already recognised as antimicrobial agents, including in anti-acne formulations -see for example US-2005/0 123620 which refers to (although does not exemplify) the use of various polyvalent metal compounds, including copper salts, in the topical treatment of acne and warts; US-6,294, 186 which describes a topical antimicrobial composition for the treatment of acne containing a benzoic acid analogue and a metal salt which can be a copper salt such as a halide, sulphate or salicylate; and EP-1 437 124 which describes a topical anti-acne formulation containing a hydroxyacid, a copper salt such as a sulphate or pidolate, a zinc salt, an algae extract and a haloalkynyl carbamate. In WO-2007/09660 1, copper salts are shown to be active against propionibacteria, and thus to be of use in the treatment of acne. Copper salts have not however, to our knowledge, been combined with the components (i) to (iii) above for the treatment of acne.

In a formulation according to the invention, a copper salt may be selected for instance from copper carboxylates, copper halides, copper sulphadiazine, copper usnate, copper sulphate (in particular the pentahydrate), copper nitrate, copper carbonate, copper oxide, copper oxychloride, copper hydroxide, copper peptides, copper amino acid salts (eg, copper glutamate, copper aspartate and copper glycinate), copper silicates, copper salts of quino lines -especially hydroxyquino lines -and their derivatives (eg, the copper salt of 8-hydroxyquinoline), copper pyrithione and other copper salts of pyridine thiols, and mixtures thereof.

In an embodiment of the invention, the copper salt is a salt of a pyridine thiol, which may for example be a 2-pyridine thiol, 3-pyridine thiol or 4-pyridine thiol, in particular a 2-or 4-pyridine thiol. Such a pyridine thiol may be present in the form of a salt or other derivative, for instance a pyridine thiol oxide or hydroxide. Preferably the copper salt is a salt of a pyrithione (ie, an N-oxide pyridine thiol) or tautomer or derivative thereof In particular it may be copper-2-pyridinethiol-1-oxide.

A pyrithione may be present in the form of a pyrithione derivative, eg, a molecular and/or ionic complex containing the pyrithione group, such as for example a pyrithione salt or a dimer, oligomer or polymer containing a pyrithione or pyrithione salt monomer (for example, dipyrithione, also known as di-2-pyridinedisulphide-1,1'-dioxide).

Generally speaking the copper salt may be either organic or inorganic.

Suitable copper carboxylates include lactate, citrate, ascorbate, acetate, gluconate, laurate, myristate, palmitate, salicylate, aspirinate, stearate, succinate, tartrate, undecylenate, neodecanoate and ricino leate.

Suitable halides include copper chloride, copper bromide and copper iodide, preferably the cupric halide (CuHal2) in each case.

In an embodiment of the invention, the copper salt (b) is copper usnate. In other embodiments, the copper salt may be selected from copper sulphate (in particular the pentahydrate), copper carboxylates (in particular copper aspirinate or copper salicylate), copper pyrithione, copper silicate, the copper salt of 8-hydroxyquinoline, copper gluconate, copper chloride, copper hydroxide and copper acetate, again preferably in the form of the copper (II) salt in each case. In another embodiment, the copper salt is selected from copper sulphate, copper gluconate, copper salicylate and copper usnate. In a yet further embodiment the copper salt is selected from copper sulphate and copper usnate.

The copper salt may be used in an at least partially hydrated form, and may thus be formulated in the presence of an aqueous solvent. Alternatively it may be used in the form of a lipid-soluble salt, suitably in the presence of an organic solvent.

A formulation according to the invention may contain more than one copper salt.

The concentration of the copper salt in the formulation might suitably be 0.01 % w/v or greater, preferably 0.1 % w/v or greater. Its concentration might be up to 10 % w/v, preferably up to 2 % w/v, such as from 0.1 to 1 % w/v.

In the context of the present invention, an antibiotic may generally be defined as a substance, produced by or derived from a micro-organism, which destroys or inhibits the growth of another micro-organism such as a bacterial or fungal organism. An antibiotic will generally have one main cellular target which is not found in eukaryotic cells. In the present context an antibiotic may be either synthetic, semi-synthetic or naturally occurring; it may for instance be a synthetic or semi-synthetic analogue of a naturally occurring antibiotic.

An antibiotic used in a formulation according to the present invention may be of the "cidal" or the "static" type, ie, it may serve either to destroy a micro-organism or to inhibit its growth and/or reproduction. It may for example be selected from lincosamides such as clindamycin and lincomycin; macrolides (eg, erythromycin); folate pathway inhibitors such as dapsone or trimethoprim; tetracyclines (eg, oxytetracycline, minocycline, doxycycline, lymecycline, tetracycline or chlortetracycline); azalides (eg, azithrornycin); phenicols such as chloramphenicol; fusidic acid (a fusidane); and mixtures thereof.

An antibiotic (c) used in a formulation according to the present invention may in particular be selected from phenicols such as chloramphenicol; folate pathway inhibitors such as dapsone or trimethoprim; lincosamides such as clindamycin; macro lides such as erythromycin; tetracyclines; and mixtures thereof.

The antibiotic may be selected from phenicols such as chloramphenicol; folate pathway inhibitors such as dapsone or trimethoprim; and mixtures thereof. In an embodiment of the invention, the antibiotic (c) is chloramphenicol, a compound which is already well known for use in the topical treatment of acne (see Fraser NB, Main RA, Stewart TW, Thronton EJ, "Treatment of acne vulgaris comparing two similar lotion formulations, one with (Actinac') and one without chloramphenico 1", Curr Med Res Opin 1980; 6: 46 1-5; also Fluhr JW, Gloor M, Merkel W et al, Arzneinmittelforschung 1998; 48: 188-96). In another embodiment, the antibiotic (c) is trimethoprim, which has been described as an anti-acne agent for both oral delivery (see Cunliffe WJ, Aldana OL, Goulden VO et al, "Trimethoprim: a relatively safe and successful third-line treatment for acne vulgaris", Br. J. Dermatol., 1999, 141: 757-8) and topical delivery (see CN-1483408).

A formulation according to the invention may contain more than one antibiotic.

For use in the present invention, an antibiotic may be in the form of a salt or other derivative. A "derivative" of an antibiotic may be a pharmaceutically acceptable derivative. It may be for example a salt, ester, complex or solvate or a so-called "pro drug" form or protected form which reverts to an active form of the relevant compound at an appropriate time on or after administration. The antibiotic trimethoprim, for example, may be used in the form either of its free base or of a suitable salt such as a carboxylate, in particular the lactate salt. Clindamycin may be used in the form of a phosphate salt. A tetracycline antibiotic may be used in the form of a hydrochloride salt.

The concentration of an antibiotic (c) used in a formulation according to the invention will vary according to the nature of the antibiotic, but might typically range from 0.01 to 5 % w!v, such as from 0.025 to 5 % w/v. It may be from 0.1 to 5 or 2 % w/v, such asfromO.25to2%w/v.

The anti-acne active (d), if present in a formulation according to the invention, is a halogenated salicylanilide. Salicylanilides are also known as 2-hydroxy-N-phenylbenzamides or 2-hydroxybenzanilides. They have the following basic structure:

QOH

Specific known halogenated salicylanilides include: ClosantelTM (CAS #: 57808-65-8), which is a halogenated salicylanilide also known as N-[5 -chloro-4-[(4-chlorophenyl)cyanomethyl] -2-methylphenyl] -2-hydroxy-3,5-di-iodobenzamide, and is used as a veterinary anthelmintic. This is a broad spectrum antiparasitic agent used against several species and developmental stages of trematodes, nematodes and arthropods. The anti- trematode activity of closantel is mainly used against liver fluke. Its anti-nematode and anti-arthropod activity are especially used against species which feed on blood or plasma. The drug is widely used in sheep and cattle and can be used either parenterally (s.c. or i.m.) or orally for both prophylactic and therapeutic purposes. It is available as drench, bolus and injectable formulations. Closantel has also been combined with mebendazole and several other benzimidazoles in drench formulations for sheep and with levamisole in a bolus for cattle.

* Niclosamide, which is another halogenated salicylanilide and is also known as 5 -chloro-N-(2-chloro-4-nitrophenyl)-2-hydroxybenzamide. It is used as a veterinary anthelmintic against cestodes, and its ethanolamine salt is also known for use as a molluscicide.

* Rafoxanide (3 -chloro-4'-(p-chlorophenoxy)-3,5 -diiodosalicylanilide), which is known for veterinary use as a fasciolicide and anthelmintic.

* Oxyclozanide (3,3,5,5,6-pentachloro-2'-hydroxysalicylanilide), which again is known for veterinary use as an anthelmintic, primarily against trematodes.

Halogenated salicylanilides are known for use as anthelmintics, and also in certain contexts as antimicrobial agents (in particular the brominated salicylanilides such as dibromsalan, metabromsalan and tribromsalan). They have not however been used to treat acne.

In the context of the present invention, a halogenated salicylanilide is substituted at either or both of its phenyl rings with one or more halo groups, for instance selected from fluoro, chloro, bromo and iodo groups. In cases it may be preferred, however, for the salicylanilide not to be substituted with any bromo groups; in this case a halo substituent may be selected from fluoro, chloro and iodo, in particular chloro and iodo.

In an embodiment of the invention, the salicylanilide is substituted with two or more halo groups, for example three or more.

The salicylanilide may also be substituted, at either or both of its phenyl rings, with one or more substituents selected from hydroxyl, nitro, cyano, phenoxy, optionally substituted C1-C4 alkyl (in particular methyl) and ether groups -OR. In an ether group -OR, R may be selected for example from optionally substituted C1-C4 alkyl and Substituents for substituted Ci-C4 alkyl groups may be selected for example from cyano (-CN), halo, hydroxyl, nitro, Ci-C4 alkyl and optionally substituted phenyl, in particular cyano and optionally substituted phenyl. A halogenated salicylanilide may for example be substituted with one or more (suitably one) trifluoromethyl groups.

Substituents for substituted phenyl groups may be selected for example from cyano, halo, hydroxyl, nitro, C1-C4 alkyl and optionally substituted phenyl, in particular halo and C1-C4 alkyl, more particularly halo.

A salicylanilide used in a formulation according to the invention may for example be substituted with one or more chloro groups, for example two or more chloro groups (in other words, it may be a chlorinated salicylanilide). It may instead or in addition be substituted with one or more, for example two or more, iodine atoms. It may instead or in addition be substituted with one or more, for example two or more, in particular three, fluorine atoms.

In an embodiment, the salicylanilide is not dibromsalan, metabromsalan or tribromsalan.

In an embodiment, the salicylanilide is selected from ClosantelTM, niclosamide, rafoxanide, oxyclozanide and mixtures thereof.

In an embodiment, the salicylanilide is selected from ClosantelTM, niclosamide and mixtures thereof In another embodiment, the salicylanilide is niclosamide. In a further embodiment, the salicylanilide is ClosantelTM.

A formulation according to the invention may contain more than one halogenated salicylanilide.

For use in the present invention, a halogenated salicylanilide may be in the form of a derivative, in particular a pharmaceutically acceptable derivative. It may be for example a salt, ester, complex or solvate or a so-called "prodrug" form or protected form which reverts to an active form of the relevant compound at an appropriate time on or after administration.

In particular, the salicylanilide may be used in the form of a pharmaceutically acceptable salt, for example a metal salt or an ammonium salt (in particular the NH4 salt). Suitable metal salts include the alkali metal salts (for example the sodium or potassium salts, in particular the former) and the alkaline earth metal salts (for example the calcium salt). Other potential salts include substituted ammonium (for example alkanolammonium, in particular ethanolammonium) salts, and piperazine salts.

In particular where the salicylanilide is closantel, it may be used in the form of its sodium salt.

In particular where the salicylanilide is niclosamide, it may be used in the form of the free base, or of a salt such as the ethanolammonium or piperazine salt, and/or in the form of a hydrate such as a monohydrate.

The concentration of the salicylanilide (d) in a formulation according to the invention, in particular a formulation for topical delivery, might suitably be 0.05 or 0.1 % w/v or greater, preferably 0.3 or 0.5 % w/v or greater. Its concentration might be up to 5 % w/v, for example up to 3 or 2 or 1.5 or 1 % w/v. Its concentration may for instance be from 0.05 to 2 % w/v or from 0.1 to 1.5 % w/v, for example about 1 % w/v.

As used herein, the term "dialkyl sulphosuccinate" or "DAS" means a dialkyl ester of sulphosuccinic acid, in which the sulphonic acid group is present as -S(O)2-OH.

Derivatives of dialkyl sulphosuccinates can include salts such as metal salts, ammonium salts (in particular the NH4 salt) and any form of the compound in which the sulphonic acid group is present as the sulphonate -S(O)2-0, as well as solvates and so-called "prodrug" forms or protected forms which revert to an active form of the compound at an appropriate time on or after administration.

The two alkyl groups of the DAS may be for example C1 to C18 alkyl groups, in particular C2 to C12 or C2 to C10 alkyl groups, such as C6 to Cio and in particular C8.

Thus the DAS is suitably a dioctyl sulphosuccinate. The alkyl groups may be substituted or unsubstituted, preferably the latter. If substituted, they may for example be mono-, di-or tn-substituted, and may suitably include one or more substituents selected from amido groups and ethers. They may be either straight chain or branched.

They may include one or more unsaturated carbon-carbon bonds. In an embodiment of the invention, the alkyl groups of the DAS are not substituted with ether groups. In an embodiment, the alkyl groups do not include unsaturated carbon-carbon bonds.

The DAS or derivative is conveniently used in the form of a salt in which the sulphonic acid group is present as the sulphonate -S(O)2-0, such as in particular a metal salt or ammonium salt. Suitable metal salts include the alkali metal salts (for example the sodium or potassium salts, in particular the former) and the alkaline earth metal salts (for example the calcium salt).

The DAS or derivative is suitably pharmaceutically acceptable.

In an embodiment of the invention, the DAS is used in the form of its sodium salt, for example dioctyl sodium sulphosuccinate (also known as dioctyl sulphosuccinate sodium or docusate sodium).

In general a "derivative" of a DAS may be a pharmaceutically acceptable derivative. It may be for example a salt, complex or solvate or a so-called "prodrug" form or protected form as described above. Such a derivative may be a free acid -ie, an alkyl sulphosuccinnic acid -from which the sulphosuccinate can be derived. In an embodiment, however, the DAS is present in the form of the sulphosuccinate.

A formulation according to the invention may contain a mixture of two or more DASs or derivatives thereof.

The concentration of the DAS or derivative in the formulation might suitably be 0.1 or 0.2 or 0.5 % w/v or greater, preferably 1 or 1.5 % w/v or greater, more preferably 2 or 3 or 3.5 or 4 % w/v or greater. Its concentration might be up to 15 % w/v, preferably up to 10 or 9 or 8 or 7 or 6 or 5 % w/v. For example, its concentration might be in the range from 0.1 to 10% w/v, or from 1 or 2 or 3 or 3.5 to 10% w/vor from2 or 3 or 3.5 to 8 % w/v, more preferably from 3 or 3.5 to 7 % w/v or from 4 to 6 % w/v, such as about 5 % w/v. In an embodiment of the invention, the DAS or derivative is present in the formulation at a concentration of 3.5 % w/w or greater.

A formulation according to the invention is preferably suitable for topical application to, and/or contact with, the skin, in particular human skin. A formulation which is "suitable for" topical application may also be adapted for topical application.

The formulation may take any suitable physical form, example of which are well known to those skilled in the art of preparing topical skin care or pharmaceutical preparations. It will typically be a fluid, which term includes a cream, paste, gel, lotion, foam, ointment, varnish or other viscous or semi-viscous fluid, as well as less viscous fluids such as might be used in sprays. The anti-acne active(s) and if applicable the DAS or derivative may each independently be present in the form of a solution or suspension, the term "suspension" including emulsions, micellar systems and other multi-phase dispersions.

Any or all of the anti-acne active(s) and if applicable the DAS or derivative may, whether separately or together, be carried in or on a delivery vehicle which is suitable for targeting or controlling its release at the intended site of administration. Such vehicles include liposomes and other encapsulating entities, for example niosomes, aspasomes, microsponges, microemulsions, hydrogels and solid lipid nanoparticles.

In a formulation according to the invention, the combination of components (i) to (iii) is suitably present as an anti-acne agent (ie, as an agent which is active against acne (which includes against a symptom and/or a cause of acne), although it may also be used as an excipient for the other active(s) present. The anti-acne active(s) (a) to (d) are suitably present as anti-acne agents, and/or as antibacterial agents (in particular against one or more micro-organisms associated with acne). The DAS or derivative, if applicable, is suitably present as an anti-acne and/or antibacterial agent.

Suitably, the DAS or derivative (if present) is not used purely or even primarily as a stabiliser for another substance such as an active ingredient, or as a surface active agent (surfactant), or as a wetting or solubilising or dispersing or emulsifying agent, or as a processing aid.

Antibacterial activity encompasses activity against both Gram-positive and Gram-negative bacteria. It may be growth inhibitory activity or more preferably bactericidal (ie, lethal to the relevant organism). It may comprise activity against sessile and/or planktonic bacteria.

In the context of this invention, activity against a particular species of bacterium may be taken to mean activity against at least one, preferably two or more, strains of that species.

Antibacterial activity may be or include the ability to disrupt and/or suppress bio film formation by the relevant organism. The bio film may in particular be formed by Propionibacterium acnes.

In the present context, the disruption of bioflim formation embraces any negative effect on the ability of an organsim to form, maintain or exist in a bio film, and/or on a bio film already formed by the organism. Thus, it may involve reducing the amount of a previously formed bio film, and/or impairing such a bio film. It may involve killing or inhibiting sessile bacteria within a bio film.

Suppression ofbiofilm formation embraces any degree of impairment (including complete prevention) of the ability of an organism to form, or more typically to co-aggregate with, a bio film. It thus embraces total or partial impairment, including reducing the amount andlor strength of biofilm which the organism is able to form and/or the speed with which it is able to do so. It may involve preventing or reducing the growth or the rate of growth of an existing bio film formed by the organism.

An anti-acne active (a) to (d), used in a formulation according to the present invention, may be active against Gram-positive and/or Gram-negative bacteria, in particular Gram-positive bacteria. More particularly, it may be active against one or more bacteria associated with acne, in particular propionibacteria such as P. acnes and in some instances P. granulosum. The overall formulation is also suitably active against one or more such bacteria.

The anti-acne active, and/or the overall formulation, is preferably active against bacteria, in particular propionibacteria, which are wholly or partially resistant to one or more antibiotics, for instance those which are in common clinical use. For example it is ideally active against one or more macrolide-lincosamide-streptogramin (MLS) resistant and/or macrolide-lincosamide-streptogramin-ketolide (MLSK) resistant strains of bacteria. In particular it may be active against one or more erythromycin-resistant, clindamycin-resistant and/or tetracycline-resistant strains of bacteria, for example P. acnes strains, the term tetracycline here referring to the class of antibiotics including for example minocycline and doxycycline as well as the specific antibiotic known as tetracycline.

Antibacterial activity may be measured in conventional manner, for instance using the tests described in the examples below. Generally tests for activity involve treating a culture of the relevant micro-organism with the candidate antibacterial compound, incubating the treated culture under conditions which would ordinarily support growth of the organism, and assessing the level of growth, if any, which can occur in the presence of the candidate compound.

Preferably a bismuth salt (a) used in the formulation of the invention has a minimum inhibitory concentration (MIC), against propionibacteria, of 200.ig/ml or less, preferably 100 or 50 or 40.ig/ml or less or in cases 20 or 10 or even 5 or 2.ig/ml or less, such as from 0.5 to 50 pg/ml. Its corresponding minimum bactericidal concentration (MBC) is preferably 200 g/ml or less, more preferably 100 or 70 pg/m1 or less, in cases 50 or 20 or 10.ig/ml or less, such as from 0.5 to 70 or 0.5 to 50.ig/ml.

Suitably the ratio of its MIC to its MBC is from 0.125 to 1, ideally from 0.5 to 1.

Preferably a copper salt (b) used in a formulation according to the invention has an MIC against propionibacteria of 200 pg!ml or less, more preferably 100 or 50 or 20 .ig/ml or less, such as from 0.2 to 20 pg'ml. Its corresponding MBC is preferably 200 .ig/ml or less, more preferably 50.ig/ml or less, in cases 20.ig/ml or less, such as from 0.25 to 50 pg/ml. Suitably the ratio of its MIC to its MBC is from 0.125 to 1, ideally from 0.5 to 1.

Preferably an antibiotic (c) used in the invented formulation has a MIC against propionibacteria of 200 ig/ml or less, more preferably 100 or 50 or 20 or 10.ig/ml or less.

Preferably a halogenated salicylanilide (d) used in the invented formulation has a MIC against propionibacteria, of 250.ig/ml or less, more preferably 200 or 100 or 50 pg/ml or less, most preferably 25 or 20 or 15 or 10 or 5 or in cases 2 or even 1 or 0.5.ig/ml or less. Its corresponding MBC is preferably 250.ig/ml or less, more preferably 100 or 50.ig/ml or less, most preferably 25 or 15 or 10 or 5 or in cases 2 or even 1 or 0.5 25.ig/ml or less. Suitably the ratio of its MIC to its MBC is from 0.01 to 1 or from 0.125 to 1, ideally from 0.5 to 1. More preferably the salicylanilide also exhibits such characteristics in the presence of at least one of, preferably both of, lipid and sodium chloride.

Preferably the DAS or derivative, if used in the invented formulation, has a MIC against propionibacteria of 200.ig/ml or less, more preferably 125 or 100 or 50 or in cases 20 ig/ml or less, such as from 31.25 to 3.9.ig/ml. Its corresponding MBC is preferably 125.ig/ml or less, preferably 70.ig/ml or less. More preferably the DAS or derivative also exhibits such characteristics in the presence of at least one of, preferably both of, lipid and sodium chloride.

In general an anti-acne active included in a formulation according to the invention will preferably have an MBC which is no higher than 10, preferably no higher than 8, times its MIC.

MIC and MBC values may be measured using conventional assay techniques, for instance as described in the examples below.

As described above, a formulation according to the invention may take the form of a lotion, cream, ointment, varnish, foam, paste, gel or any other physical form known for topical administration. It may take the form of a solution or suspension, for instance for use as a skin cleanser. It may comprise a formulation which is, or may be, applied to a carrier such as a sponge, swab, brush, tissue, cloth, wipe, pad, skin patch, skin adhesive or other material designed for application to a tissue surface, to facilitate its topical administration. It may be intended for pharmaceutical use.

As described above, the formulation may contain one or more agents suitable for targeting a desired site and/or time of delivery. Such agents may for instance target the formulation to the skin or hair follicles. They may delay or otherwise control release of the formulation over a particular time period. Any or all of the components of the formulation, in particular the anti-acne active(s) and if applicable the DAS or derivative, may be microencapsulated, for instance in liposomes -particularly suitable liposomes, for topical application to the skin, are those made from stratum corneum lipids, eg, ceramides, fatty acids or cholesterol.

Generally speaking a formulation according to the invention may contain standard excipients and other additives known for use in pharmaceutical formulations. It may for example contain one or more solvents, solubilising agents and/or thickeners in addition to the components (i) to (iii). In an embodiment of the invention, however, the formulation does not contain a solubilising agent other than the polyoxyalkylene-based solubilising agent (i). In an embodiment, the formulation does not contain an organic solvent other than component (ii). In an embodiment, it does not contain a thickening agent other than component (iii).

Examples of suitable excipients and additives include perfumes, antioxidants, preservatives, stabilisers, gelling agents and surfactants; others may be found in Williams' "Transdermal and Topical Drug Delivery", Pharmaceutical Press, 2003, and other similar reference books. See also Date, A. A. et al, Skin Pharinacol. Physiot, 2006, 19(1): 2-16 for a review of topical drug delivery strategies.

A formulation according to the invention may further contain additional active agents such as antimicrobial (in particular antibacterial) agents. For example, it may contain one or more agents selected from anti-acne agents, keratolytics, comedolytics, agents capable of normalising keratinocyte and/or sebocyte ftrnction, anti-inflammatories, anti-proliferatives, antibiotics, anti-androgens, sebum controlling agents, anti-pruritics, immunomodulators, agents which promote wound healing, additional antimicrobial agents and mixtures thereof; it may instead or in addition contain one or more agents selected from sunscreens, moisturisers, emollients and mixtures thereof An additional antimicrobial agent may for example be selected from the group consisting of biocides, disinfectants, antiseptics, antibiotics, bacteriophages, enzymes, anti-adhesins, immunoglobulins and mixtures thereof; it is preferably active as a bactericide, in particular against propionibacteria.

It may however be preferred for the components (i) to (iii), the anti-acne active(s) (a) to (d) and if applicable the DAS or derivative to be the only active agents in the formulation, or at least to be the only anti-acne active agents.

In the case where the formulation is intended for application to the skin as an antiseptic, it may take the form of a solution or suspension of the components (i) to (iii) and the anti-acne active(s) in an appropriate fluid vehicle. Again conventional excipients and other additives may be included, as may one or more additional antimicrobial (in particular antibacterial) agents.

In particular when the formulation is for use in controlling the transmission of a bacterial infection, it may be in the form of a skin wash (for example a hand wash).

Generally speaking a formulation according to the invention may contain one or more agents which enhance the activity of another active agent present in the formulation, or reduce a side effect of such an active, or improve patient compliance on administration of the formulation. It may contain one or more agents which facilitate penetration of an active agent into microbial biofilms. It may contain one or more agents which control the site and/or rate of release of an active agent following administration.

A formulation according to the invention may be incorporated into, and hence applied in the form of, another product such as a cosmetic, a skin care preparation (for example a skin cleanser, toner, astringent, scrub or moisturiser, a cleansing preparation (for example a hand wash or facial wash), a pharmaceutical preparation, a cosmeceutical preparation or a toiletry product (for instance a bath or shower additive, a body spray or a soap). The formulation may be, or be incorporated into, a leave-on or a wash-off skin treatment product.

In particular where the formulation contains an antibiotic (c) and/or a halogenated salicylanilide (d), it may be preferred for the formulation to be incorporated into, or applied in the form of, a pharmaceutical preparation.

The invention thus provides, according to a second aspect, a product which incorporates an anti-acne formulation according to the first aspect.

A formulation according to the invention may be marketed with an indication that it has anti-acne activity or enhanced anti-acne activity. The marketing of such a formulation may for example include an activity selected from (a) enclosing the formulation in a container or package that comprises the relevant indication; (b) packaging the formulation with a package insert that comprises the indication; (c) providing the indication in a publication that describes the formulation; and (d) providing the indication in a commercial which is aired for instance on the radio, television or internet. The anti-acne activity of the formulation may be attributed, in such an indication, at least partly to the presence of either or both of the combination of components (i) to (iii) and the anti-acne active(s) (a) to (d), in particular to the presence of the combination (i) to (iii). It may be attributed at least partly to the DAS or derivative, if present.

The anti-acne activity of the formulation may be assessed during or after its preparation. The activity may be assessed both before and after incorporation of the combination (i) to (iii) and/or the anti-acne active(s), for example so as to confirm that either or both contribute to the anti-acne activity of the formulation.

The formulation of the invention may be prepared in situ, at or immediately before its point of use, for instance its application to the skin or another surface. Thus according to a third aspect, the present invention provides a kit for preparing an anti-acne formulation, such as a formulation according to the first aspect, the kit comprising sources of the components (i) to (iii), or more conveniently a source of a combination of components (i) to (iii), and source(s) of the relevant anti-acne active(s) (a) to (d) which again may be pre-combined in one or more single sources. Such a kit also comprises instructions for combining the components so as to make the formulation at or before the point of intended use, and/or for the co-administration of the components to a surface such as the skin. Any or all of the components may be present in suitable respective vehicles. Water may be included as a separate component of the kit, or pre-mixed with one or more of the other components, or the kit may include instructions for mixing one or more of the other components with water.

A fourth aspect of the invention provides a method for preparing an anti-acne formulation, which method involves mixing together the components (i) to (iii) and the relevant anti-acne active(s) (a) to (d), preferably with water and optionally with a DAS or derivative thereof.

According to a fifth aspect of the invention there is provided a formulation (preferably a formulation according to the first aspect of the invention) containing the components (i) to (iii) as defined above, together with one or more anti-acne actives selected from (a) to (d) above, for use in the treatment of acne.

Again the formulation suitably also contains water. It may contain a DAS or derivative thereof.

In the context of the present invention, treatment of a condition encompasses both therapeutic and prophylactic treatment, of either an infectious or a non-infectious condition, in particular in a human. It may involve complete or partial eradication of the condition, removal or amelioration of associated symptoms, arresting subsequent development of the condition, and/or prevention of, or reduction of risk of, subsequent occurrence of the condition. It will typically involve use of the invented formulation as an anti-acne combination. It will typically involve use of the components (i) to (iii) as a combination active against non-inflamed acne lesions.

Treatment may involve use of the formulation against one or more propionibacteria, including against propionibacterial bio film formation. It may involve use against P. acnes and/or in some instances against P. granulosum.

The treatment is preferably administered topically.

Acne is a multifactorial disease of the pilosebaceous follicles of the face and upper trunk, characterised by a variety of inflamed and non-inflamed lesions such as papules, pustules, nodules and open and closed comedones. Its treatment can therefore encompass the treatment (which embraces prevention or reduction) of any of these symptoms, and references to use as an anti-acne agent may be construed accordingly.

In particular, the treatment of acne encompasses the treatment (including prevention, or reduction of risk of) of lesions and/or scarring associated with acne. It also encompasses the treatment of a propionibacterial infection and/or the inhibition of propionibacterial activity which could cause or be otherwise associated with acne or its symptoms.

In general, the present invention will be used for the treatment of symptoms which are directly due to acne rather than for instance infections which may arise as a consequence of treating acne with other actives such as antibiotics, and/or secondary infections caused by opportunistic pathogens, which can arise in skin already affected by acne.

According to the fifth aspect of the invention, the formulation combining the components (i) to (iii) and the anti-acne active(s) may be prepared in situ, at or immediately before the point of administration. This aspect of the invention thus pertains to any use of the components (i) to (iii) with one or more anti-acne actives selected from (a) to (d), in the treatment of acne, the components being administered either simultaneously or sequentially.

According to a sixth aspect, the invention provides the use of the components (i) to (iii) as defined above, together with one or more anti-acne actives selected from (a) to (d) as defined above, in the manufacture of a medicament (typically a formulation) for the treatment of acne.

The components (i) to (iii) and the anti-acne active(s) will typically be used as an anti-acne combination in the manufacture of the medicament. The components (i) to (iii) will typically be used, in the medicament, as a combination active against non-inflamed acne lesions.

The invention further provides, according to a seventh aspect, the use together of the components (i) to (iii) and one or more anti-acne actives selected from (a) to (d), as a combined anti-acne agent, in the manufacture of an anti-acne formulation.

An eighth aspect provides a method for controlling the growth of a propionibacterium, the method comprising applying, to an area or surface which is infected or suspected to be infected or capable of becoming infected with the bacterium, a combination of the components (i) to (iii) as defined above with one or more anti-acne actives selected from (a) to (d) as defined above. Again the components of the combination may be applied simultaneously or sequentially. They are suitably applied in a formulation of the type described above. They may in particular be applied to an area or surface which is infected with the relevant bacterium.

In this context, "controlling the growth" of a bacterium embraces inhibiting or preventing its growth, whether completely or partially, as well as killing either completely or partially a culture of the organism. It also embraces reducing the risk of subsequent growth of the bacterium in or on the area or surface being treated. It may embrace reducing the risk of transmission of the bacterium from the area or surface being treated to another area or surface and/or living body. The method of the invention may thus be used to treat an existing occurrence of the bacterium or to prevent, or reduce the risk of, a potential subsequent occurrence. Controlling the growth of a bacterium may also embrace the disruption and/or suppression of biofilm formation by the bacterium, as described above.

The area or surface to which the components (i) to (iii) and the anti-acne active(s) are applied will typically be a surface such as human tissue, in particular the skin, typically of a living human. Thus the method of the eighth aspect of the invention encompasses a method of treatment of a patient who is suffering from or at risk of suffering from acne, the method involving administering to the patient a therapeutically (which term includes prophylactically) effective amount of a formulation containing the components (i) to (iii) as defined above together with one or more anti-acne actives selected from (a) to (d) as defined above. The formulation is preferably administered topically.

In accordance with the eighth aspect of the invention, the formulation is suitably administered to a human patient. The patient is suitably suffering from acne. The method of the eighth aspect of the invention preferably involves applying a formulation according to the first aspect.

A ninth aspect of the invention provides the use of the components (i) to (iii) as defined above in an anti-acne formulation, in combination with one or more anti-acne actives selected from (a) to (d) as defined above, for the purpose of increasing the anti-acne activity of the formulation and/or of reducing the amount of the anti-acne active(s) (a) to (d) in the formulation without or without undue loss of anti-acne activity.

An increase in anti-acne activity may be as compared to that of the relevant anti-acne active(s) alone, at the same concentration as used when combined with the components (i) to (iii). Ideally the increase is as compared to the sum of the activities of the anti-acne active(s) and the components (i) to (iii) individually, again at the same respective concentrations as used when all are combined.

A reduction in the amount of the anti-acne active(s) (a) to (d) in the formulation may be as compared to the amount which would otherwise have been used in the formulation in order to achieve a desired level of activity, in particular in order to have acceptable efficacy in the context of its intended use. The reduction may be manifested by reduced side effects which would otherwise have been observed during use of the formulation, for example local irritation and/or undesirable systemic absorption of the anti-acne active(s). According to the invention, the components (i) to (iii) may therefore be used for the dual purposes of reducing an undesired property of a formulation containing one or more anti-acne actives selected from (a) to (d), without or without undue loss of anti-acne activity.

Preferably the components (i) to (iii) are used without any reduction in anti-acne activity compared to the level exhibited by the formulation prior to addition of the components (i) to (iii). More preferably they are used to give an increase in anti-acne activity, in particular in vivo. They may however be used to reduce the amount of the anti-acne active(s) present, and/or their associated side effects, whilst maintaining the anti-acne activity of the resultant formulation at a level, albeit lower than that which it would otherwise have exhibited, which is still acceptable in the context of its intended use.

According to a tenth aspect, the present invention provides an antibacterial or anti-acne formulation containing one or more anti-acne actives selected from (a) to (d) as defined above, together with a DAS or derivative thereof.

An eleventh aspect provides a formulation according to the tenth aspect, for use in the treatment of a condition affecting the human or animal body, which condition is caused by, transmitted by and/or exacerbated by (in particular either caused or transmitted by) bacterial activity. The activity may in particular be propionibacterial activity. The condition may be a skin or skin structure condition, in particular acne.

A twelfth aspect provides the use of a formulation according to the tenth aspect, in the manufacture of a medicament (typically a formulation) for the treatment of a condition which is caused by, transmitted by and/or exacerbated by (in particular either caused or transmitted by) bacterial activity. The condition may in particular be acne. The anti-acne active(s) and the DAS or derivative will typically be used as an antibacterial and/or anti-acne combination in the manufacture of the medicament.

A thirteenth aspect provides a method for controlling the growth of a bacterium (in particular a propionibacterium), the method comprising applying, to an area or surface which is infected or suspected to be infected or capable of becoming infected with the bacterium, a combination of one or more anti-acne actives selected from (a) to (d) as defined above with a DAS or derivative thereof A fourteenth aspect provides a method of treatment of a human or animal patient suffering from or at risk of suffering from a condition which is caused by, transmitted by and/or exacerbated by (in particular either caused or transmitted by) bacterial activity, the method involving administering to the patient a therapeutically (which term includes prophylactically) effective amount of a formulation containing one or more anti-acne actives selected from (a) to (d) as defined above and a DAS or derivative thereof Again the bacterial condition may be caused, transmitted and/or exacerbated by propionibacteria, and may in particular be acne. The formulation may be administered in an antibacterially effective amount. It is suitably administered topically.

A fifteenth aspect of the invention provides an anti-acne formulation containing: (i) a polyoxyalkylene-based solubilising agent; (ii) an organic solvent, in particular an alcohol; and (iii) a thickening agent; together with one or more additional anti-acne actives selected from the group consisting of bismuth salts, for example those listed above as potential anti-acne actives (a); copper salts, for example those listed above as potential anti-acne actives (b); antibiotics, such as those listed above as potential anti-acne actives (c); halogenated salicylanilides (in particular those listed above as potential anti-acne actives (d)); benzoquinones and hydroquinones of the type referred to in WO- 2006/100495, in particular alkyl-substituted benzo/hydroquinones such as t-butyl-p-hydroquinone or t-butyl-p-benzoquinone, or resorcinol, or alkyl-substituted resorcinols; Antioxidant 2246; Antioxidant 425; bis-quinolinium salts, in particular dequalinium salts such as dequalinium chloride or dequalinium acetate; pyridine thiols, in particular pyrithiones such as zinc pyrithione; retinoids and retinoid-like compounds such as adapalene, isotretinoin, tretinoin and tazarotene; salicylic acid and derivatives (in particular salts) thereof; peroxides, such as hydrogen peroxide or metal peroxides or diacyl peroxides, in particular diacyl peroxides such as benzoyl peroxide; compounds, for example urea peroxide (carbamide peroxide), which are capable of generating hydrogen peroxide in situ; nicotinamide; cyproterone acetate; spironolactone; metformin; alpha-hydroxy acids such as glycolic acid and mandelic acid; polyhydroxy acids such as gluconolactone; essential oils such as tea tree oil, bergamot oil, rosewood oil and lavender oil; fatty acids (including omega-3 -6 and -9 polyunsaturated fatty acids) and their salts, for example linoleic acid or linolenic acid or salts thereof; plant extracts such as of Hamamelis virginiana (witch hazel), Brassica, Pinus, Quercus, Nasturtium or Salvia; di-carboxylic acids such as azelaic acid; salicylamides; thiosalicylic acid; urea; allantoin; biotin; carbocysteine; propolis; thiazolidinediones and other PPAR gamma antagonists; and mixtures thereof.

Such combinations are also expected to exhibit anti-acne activity, due to the presence of the components (i) to (iii) (which are together active against non-inflamed acne lesions) and the additional anti-acne active.

A formulation according to the fifteenth aspect of the invention suitably also includes water. It may also include a DAS or derivative thereof.

A sixteenth aspect of the invention provides a formulation according to the fifteenth aspect, for use in the treatment of acne.

A seventeenth aspect provides the use of a formulation according to the fifteenth aspect, in the manufacture of a medicament (typically a formulation) for the treatment of acne. The components (i) to (iii) and the anti-acne active(s) will typically be used as an anti-acne combination in the manufacture of the medicament.

An eighteenth aspect provides a method for controlling the growth of a propionibacterium, the method comprising applying, to an area or surface which is infected or suspected to be infected or capable of becoming infected with the bacterium, a formulation according to the fifteenth aspect of the invention.

A nineteenth aspect provides a method of treatment of a patient suffering from or at risk of suffering from acne, the method involving administering to the patient a therapeutically (which term includes prophylactically) effective amount of a formulation according to the fifteenth aspect. Again the formulation is suitably administered topically.

Throughout the description and claims of this specification, the words "comprise" and "contain" and variations of the words, for example "comprising" and "comprises", mean "including but not limited to", and do not exclude other moieties, additives, components, integers or steps.

Throughout the description and claims of this specification, the singular encompasses the plural unless the context otherwise requires. In particular, where the indefinite article is used, the specification is to be understood as contemplating plurality as well as singularity, unless the context requires otherwise.

Preferred features of each aspect of the invention may be as described in connection with any of the other aspects.

Other features of the present invention will become apparent from the following examples. Generally speaking the invention extends to any novel one, or any novel combination, of the features disclosed in this specification (including any accompanying claims and drawings). Thus features, integers, characteristics, compounds, chemical moieties or groups described in conjunction with a particular aspect, embodiment or example of the invention are to be understood to be applicable to any other aspect, embodiment or example described herein unless incompatible therewith.

Moreover unless stated otherwise, any feature disclosed herein may be replaced by an alternative feature serving the same or a similar purpose.

The present invention will now be further described with reference to the following non-limiting examples.

Detailed description

Experimental tests were conducted to determine the anti-acne activity of formulations according to the invention. Example 1 demonstrates the activity of the combination of components (i) to (iii), in an aqueous gel formulation, against non-inflamed acne lesions. Example 2 demonstrates the anti-acne activity of formulations according to the invention, which contain the combination (i) to (iii) together with an additional anti-acne active.

Exam le 1 -activity against non-inflamed acne lesions A trial was carried out on human patients to assess the anti-acne activity of a formulation containing components (i) to (iii) according to the invention. The test formulations were: A a formulation containing 20 % w/w SolutolTM HS 15 (solubilising agent), 20 % w/w ethanol, 1 % w/w hydroxyethyl cellulose (thickening agent) and the balance water.

B the same as formulation A, but additionally containing 5 % w/w of dioctyl sodium sulphosuccinate, 20 % w/w SolutolTM HS 15, 20 % w/w ethanol, 1 % w/w hydroxyethyl cellulose and the balance water.

C as a positive control, a commercially available anti-acne product (L'OrealTM Pure Zone Deep Control Moisturiser, purchased in the EU).

This contained salicylic acid, which is a keratolytic agent known to be effective against non-inflamed acne lesions.

One further test formulation, not within the scope of the present invention, was also investigated in the trial.

Formulations A and B were prepared using the following method. Firstly, the hydroxyethyl cellulose was added to the water with continuous stirring. In a separate vessel, dehydrated ethanol (or in the case of formulation B a pre-prepared mixture of dehydrated ethanol and the dioctyl sodium sulphosuccinate) was mixed with the SolutolTM, using a magnetic stirrer. This mixture was then added to the water/thickening agent combination, and mixed well using a propellor.

The trial was a randomised, controlled trial with four arms, and was performed double-blind for the test treatments and single-blind for the positive control. Its primary aim was to compare the efficacy of the test formulations in subjects with acneic skin.

The trial was carried out in six centres throughout Germany; people of either sex with acne of at least grade 3 on the eight point scale of Allen & Smith [Allen BS, Smith JG, "Various parameters for grading acne vulgaris", Arch Dermatol. 1982, 118: 23-25] were eligible to participate. Treatment (approximately 0.5 g) was applied by the participants once a day for eight weeks, to the entire face. No concomitant anti-acne medications were permitted and previous treatment was stopped at least four weeks before the baseline visit. There were between 27 and 31 patients in each of the four test groups, and each group was assigned one of the four test formulations.

Inflamed and non-inflamed lesions were counted at 8, 15, 29 and 57 days after treatment began. Formulation success rates were also assessed on each of these occasions using (a) a "physician's global assessment" and (b) a "global satisfaction score" allocated by the participants themselves. (a) was carried out by medical practitioners using the Allen & Smith scale referred to above, and took account of initial acne severity. (b) was assessed using a 6-point Likert-like scale where 1 = extremely dissatisfied and 6 = extremely satisfied. The reference for this scale is Rapp DA et al, "Anger and Acne: Implication for Quality of Life, Patient Satisfaction and Clinical Care", BrJDermatol 2004, 151: 183-89. Participants rated how well the relevant product worked, its ease of use and the time spent using it.

The results are shown in Table 1 below, for mean inflamed lesion counts (INFL), mean non-inflamed lesion counts (NNFL), mean total lesion counts (LES), mean physician's global assessment scores (PGA) and mean subjects' global satisfaction scores (SGSS). The figures quoted are percentage changes from the baseline (ie, the mean counts or scores at the baseline visit prior to starting treatment), apart from the SGSS values which represent the mean scores at each assessment visit.

Table 1

Measured Day Formulation Formulation Formulation property A B C (control) 1NFL 8 -14.45 -4.72 -16.08 -13.17 -1.09 -18.02 29 -10.26 -8.38 -24.55 57 -1364 f 234 f 1554 N1NFL 8 -4.63 -2.71 -9.72 -13.74 -14.10 -5.15 29 -17.62 -16.17 +2.19 57 -25 2 f -22 86 f 86 LES 8 -8.51 -3.40 -12.53 -13.52 -9.91 -10.80 29 -14.71 -13.48 -9.59 57 -21 01 f 04 f ii 67 1 PGA 8 -9.56 -2.56 -14.05 -12.18 -12.07 -13.22 29 -17.39 -19.83 -18.18 Measured Day Formulation Formulation Formulation property A B C (control) 57 2522.344 297 SGSS 8 37.9 63.0 70.0 55.2 66.7 76.7 29 62.1 77.8 63.3 57 9O 77 7Q0 Table 1 shows the following: * that the test formulation A had achieved a markedly greater reduction in non-inflamed lesion counts, by the end of the trial, than the positive control.

* that in terms of total lesion counts (the mean change in numbers of all lesions, whether inflamed or not, from the baseline), the test formulations A and B had both performed as well as the positive control by the end of the eight week trial period.

* that the physician's global assessment scores indicate a performance for each of the test formulations A and B which is at least comparable with that of the control.

* that the inclusion of the DAS in formulation B boosts activity against inflammatory lesions specifically and also overall anti-acne activity.

* that the combination of components (i) to (iii) with a DAS can provide an improved anti-acne product compared to existing marketed formulations.

* that by the end of the trial, subject satisfaction scores were high for the test formulations A and B, and compared favourably with those for the positive control.

The end-of-trial changes versus the baseline were statistically significant for the test formulation A, across all outcomes except the inflamed lesion count. Those for formulation B were statistically significant across all outcomes.

These data demonstrate the utility of formulations according to the invention in the topical treatment of acne. In particular they show that the combination of components (i) to (iii), as in a formulation according to the invention, can be surprisingly effective in the treatment of non-inflamed acne lesions, despite the absence of any conventional anti-acne agents and despite its apparently low antibacterial activity (propionibacteria being associated with inflamed but not with non-inflamed acne lesions). In this respect the combination (i) to (iii) appears to perform better than the commercially available salicylic acid-containing product.

It is of note that the trial participants reported no treatment-related local side effects for either of the treatments A or B. This indicates that formulations according to the invention are likely to be well tolerated in use on human skin.

Exami'les 2 & 3 -activity against P. acnes The following examples tested the activity of formulations according to the invention, and of halogenated salicylanilides alone, against propionibacteria. These are the main pathogens implicated in inflammatory acne.

Test micro-organism The test micro-organism used was Propionibacterium acnes NCTC 737. This is a propionibacterial strain and is the type strain of the genus; it is fully susceptible to antibiotics.

The propionibacteria are clinically significant due to their involvement in acne. This is a very common, complex and multi-factorial skin disease in which P. acnes and other Propionibacterium spp. (for example P. granulosum) play key roles. They are also opportunistic pathogens in compromised hosts. Thus, activity observed against these micro-organisms is expected to be a good predictor of activity against acne.

The propionibacteria were cultured and maintained on Wilkins-Chalgren Anaerobe Medium (agar and broth) at pH 6.0; all cultures were incubated anaerobically at 37 °C for 72 hours.

The following tests were carried out to assess antibacterial activity against the test organism.

(a) Minimum inhibitory concentration (MIC) assay This is a standard international method for quantitatively assessing the antimicrobial activity of a compound in a liquid medium. The method used a sterile 96-well microtitre plate, capable of holding about 200 tl of liquid per well. The wells contained liquid culture medium and ranges of decreasing concentrations of the relevant test compound in doubling dilutions (eg, 1000, 500, 250, 125.. .tg/ml, etc..

down to 0.49 tg/ml). The culture media were as described above.

The wells were inoculated with a liquid suspension of freshly grown micro-organism and incubated under the conditions described above. After incubation, the microtitre plate was examined visually (with the aid of a light box) for cloudiness in each well, which would indicate microbial growth. The MIC value was recorded as the lowest concentration of test compound required to inhibit microbial growth, ie, the lowest concentration for which the liquid in the well remained clear.

The assays included both negative (culture medium with no micro-organisms) and positive (culture medium plus diluting solvent plus micro-organism) controls.

Since inhibition does not necessarily indicate killing of microbial cells, merely that growth as visible to the naked eye has been inhibited, it is desirable to conduct a further test (the MBC assay described below) to establish the concentration of the test compound needed to kill the test organism.

(b) Minimum biocidal (bactericidal) concentration (MBC) assay This assay, normally carried out after an MIC assay, determines the minimum concentration of a compound that is lethal to the micro-organism being tested.

Following an MIC assay, a 5 tl sample was withdrawn from the first microtitre well that showed positive growth and from all the subsequent wells that showed no growth.

These samples were then individually sub-cultured on antibiotic-free agar medium, under the incubation conditions described above. Following incubation they were examined visually for microbial growth. The MBC was taken to be the lowest test compound concentration for which the incubated sample showed no growth.

(c) Well diffusion assay (WDA) This test is based on the agar diffusion principle and is designed to assess the relative activity of a test compound(s) in any given formulation.

Holes were cut using a sterilized stainless steel cork borer (number 4) with a diameter of 8 mm and the plugs' removed from agar plates onto which the test micro-organism had been inoculated by surface swabbing. The prepared formulations were then added, in triplicate, to the wells in 100 tl volumes. The plates were then incubated as described above, following which they were examined visually for signs of microbial growth. If a test formulation demonstrated antimicrobial activity, a circular zone of no growth was obtained around the bored hole. The diameter of this zone of "inhibition" was measured using a Pr0t0COLTM automated zone sizer (Synbiosis, Cambridge, UK).

(d) Disc diffusion assay (DDA) This is an internationally recognised standard method for qualitatively assessing the antimicrobial activity of a compound.

A sterile paper disc was impregnated with a sample of the test compound in a suitable solvent and 30 minutes allowed for the solvents to evaporate (where possible). The disc was then placed on an agar plate onto which the test micro-organism had been inoculated. The plate was then incubated under the conditions described above, following which it was examined visually for signs of microbial growth. If the test compound had antimicrobial activity, a circular zone of no growth would be obtained around the disc. The diameter of this zone of "inhibition" was measured using a Pr0t0COLTM automated zone sizer (Synbiosis, Cambridge, UK). In general, a greater diameter and/or area of the zone of inhibition indicates a greater antimicrobial activity in the relevant test compound, although other factors such as test compound mobility through the agar gel may also influence the result.

(e) Supplemented disc diffusion assays The DDA test may be carried out using an agar gel supplemented with salt to simulate one of the major components present in human skin and to assess whether this substance might affect the antimicrobial activity observed for the test compound.

Performance under these conditions can provide a more reliable indication of activity on topical application. The supplement used in Example 3 below was sodium chloride (100 mlvi).

Test formulations The test formulations, according to the present invention, were prepared using the following ingredients: GlyceroxTM 767 (Croda Chemicals, UK) (GX) Ethanol (96 %; Sigma Aldrich, UK) Purified water (Sigma Aldrich, UK) KlucelTM HF (Hercules, USA) (1(L) Propylene glycol (Sigma Aldrich, UK) (PG) TranscutolTM P (Gattefosse, France) (TR) LauroglycolTM 90 (Gattefosse, France) LabrasolTM (Gattefosse, France) (LS) Docusate sodium (Sigma Aldrich, UK) (DOS) Bismuth subsalicylate (Sigma Aldrich, UK) [CAS -14882-18-9] Copper usnate (Variati, distributed by Just for Today Ltd, Nottingham) [CAS - 94246-73-8] Chloramphenicol (Sigma Aldrich, UK) [CAS -56-75-7] Trimethoprim free base (Sigma Aldrich, UK) [CAS -73 8-70-5] Trimethoprim lactate salt (Sigma Aldrich, UK) [CAS -23256-42-0] Niclosamide (Sigma Aldrich, UK) [CAS -50-65-7].

GlyceroxTM 767 is a mixture of PEG-6 caprylic/capric glycerides. LabrasolTM is a mixture of PEG-8 caprylic/capric glycerides. Both can be used as polyoxyalkylene-based solubilisers (i) in the formulations of the invention.

Lauroglyco 1TM 90 is propylene glycol mono laurate, and TranscutolTM P is diethylene glycol monoethyl ether; both these components were used as cosolvents and penetration enhancers.

A first set of test formulations (I) was prepared using GlyceroxTM 767 HC (GX) as the solubilising agent. These gel formulations contained either bismuth subsalicylate, chloramphenicol, trimethoprim free base, trimethoprim lactate or niclosamide as the anti-acne active. Their compositions are shown in Table 2 below; all figures are percentages by weight.

Table 2

Formulation Active compound Active OX EtOH Purified KL PG TR __________________ ______ _______ water __________ Ii Placebo 0 20 20 58.5 1.5 0 0 aBismuth 1 20 20 57.7 1.3 0 0 Iii ______________ subsalicylate _______ _______ ________ __________ _______ ____________ _______ liii aChloramphenil 1 20 20 57.7 1.3 0 0 aTnmethoprim 1 30 30 17.7 1.3 10 10 lv free base aTnmethoprim 1 20 20 57.7 1.3 0 0 Iv free base aTnmethoprim 1 20 20 57.7 1.3 0 0 vi ______________ lactate _______ _______ ________ __________ _______ ____________ _______ lvii aNiclosamide 1 20 20 57.7 1.3 0 0 1% w/w solution The test formulations (I) were prepared as follows: 1. GlyceroxTM, ethanol and if required propylene glycol and TranscutolTM P were mixed to form a clear solution.

2. The desired anti-acne active was then added to the solution and stirred with heating until all of the active had frilly dissolved, or in the case of bismuth subsalicylate until the active had formed an even dispersion of suspended particles.

3. The KlucelTM thickening agent was added with stirring until fully dispersed.

4. Finally the water was slowly added, with gentle stirring, until a gel was formed.

A second set of test formulations (II) was prepared, also using GlyceroxTM 767 HC as the solubilising agent but including in addition 5 % w/w of docusate sodium (dioctyl sodium sulphosuccinate, DOS). Again these gel formulations contained either bismuth subsalicylate, chloramphenicol, trimethoprim free base, trimethoprim lactate or niclosamide as an anti-acne active. Their compositions are shown in Table 3 below; all figures are percentages by weight.

Table 3

Formulation Active compound Active DOS GX EtOH Purified KL PG TR _________________ _______ water __________ Iii Placebo 0 43.85 0.95 nla 53.5 1.5 0 0 aBismuth 1 52.5 1.5 0 0 liii ____________ subsalicylate ______ 44.27 1.00 0.42 ________ __________ if" aChloramphenil 1 74.17 2.30 30.32 52.5 1.5 0 0 aTñmethoprim 1 52.5 1.5 0 0 ___________ freebase ______ 53.23 1.41 9.38 _______ _________ aTñmethoprim 1 52.5 1.5 0 0 ____________ lactate ______ 51.56 1.62 7.71 ________ __________ JJ aNiclosamide 1 45.63 0.54 1.78 52.5 1.5 0 0 1% w/w solution The formulations (II) were prepared in the same way as formulations (I), except that the docusate sodium was added to the solution formed in step (1) (and stirred with gentle heating until fully dissolved) prior to addition of the other anti-acne active.

Two further sets of test formulations (III) and (IV) were prepared, using LabrasolTM (LS) as the solubilising agent. The formulations (IV) included 5 % w/w of docusate sodium (dioctyl sodium sulphosuccinate) in addition to an anti-acne active selected from bismuth subsalicylate, copper usnate, chloramphenicol, trimethoprim free base, trimethoprim lactate and niclosamide, whilst the formulations (III) did not contain docusate sodium. The compositions of the formulations (III) and (IV) are shown in Tables 4 and 5 respectively; again all figures are percentages by weight.

Table 4

________________ _____________________ ________ ________ ___________ _______________ _______

Formulation Active compound Active LS EtOH Purified KL Lauroglycol PG TR ___________ _______________ ______ ______ water 90 _____ liii Placebo 0 10 30 40 1.5 3.5 15 0 aBismuth 1 10 30 39 1.5 3.5 15 0 Thu ______________ subsalicylate _______ _______ _________ _____________ ______ JJJffl aChloramphenil 1 10 30 39 1.5 3.5 15 0 aTñmethoprim 1 10 30 39 1.5 3.5 15 0 "lv free base aTñmethoprim 1 10 30 39 1.5 3.5 15 0 Thy ______________ lactate _______ _______ _________ _____________ ______ III. aNiclosamide 1 10 30 29 1.5 3.5 15 10 JJJ usnate 1 10 30 19 1.5 3.5 15 20 1% w/w solution

Table 5

Formulation Active compound Active DOS LS EtOH Purified KL Lauroglycol PG TR ___________ _______________ ______ ______ water 90 IVi Placebo 0 5 10 30 35 1.5 3.5 15 0 aBismuth 1 5 10 30 34 1.5 3.5 15 0 IVii ______________ subsalicylate _______ _______ _________ ______________ IViii aChloramphenicol 1 5 10 30 34 1.5 3.5 15 0 aTñmethoprim 1 5 10 30 34 1.5 3.5 15 0 IViv free base aTñmethoprim 1 5 10 30 34 1.5 3.5 15 0 IVy ______________ lactate _______ _______ _________ ______________ IVvi aNiclosamide 1 5 10 30 25 1.5 3.5 15 10 IVvii aCopper usnate 1 5 10 30 14 1.5 3.5 15 20 1% w/w solution The test formulations (III) and (IV) were prepared as follows: 1. Labraso 1TM, ethanol, Lauroglyco ITM 90, propylene glyco 1 and if required TranscutolTM P were mixed to form a clear solution.

2. In the case of the formulations (IV), docusate sodium was then added to this mixture and stirred with gentle heating until frilly dissolved.

3. The desired anti-acne active was then added to the solution and stirred with heating until all of the active had frilly dissolved, or in the case of bismuth subsalicylate and copper usnate until the active had formed an even dispersion of dissolved and/or suspended particles.

4. The KlucelTM thickening agent was added with stirring until fully dispersed.

5. Finally the water was slowly added, with gentle stirring, until a gel was formed.

Example 2 -activity against P. acnes -formulations (I)-(IV) The formulations (I) were tested for activity against P. acnes NCTC 737 using the well difftision assay described above. The results are shown in Table 6 below; all are collated from a number of experiments.

Table 6

Zol increase Active Mean Zol (compared to Formulation Active compound ZoISD (mm) % w/w (mm) formulation ___________ _______________ ______ _________ _____________ placebo) (mm) Ii Placebo 0 21.04 0.48 n/a aBismuth 1 11 subsalicylate ______ 35.52 1.41 14.48 ___________ aChloramh.l 1 >90 n/a >68.96 aTnmeth 1 _________ free base _____ 56.25 1.43 35.21 aTnmeth 1 _________ freebase _____ 61.67 1.60 40.63 aTnmeth 1 __________ lactate ______ 58.13 1.08 37.09 ___________ aNiclosaid 1 41.88 1.65 20.84 Iii Placebo 0 43.85 0.95 n/a aBismuth 1 11 subsalicylate ______ 44.27 1.00 0.42 ___________ aChloramh.l 1 74.17 2.30 30.32 aTnmethi 1 __________ free base ______ 53.23 1.41 9.38 aTnmethi 1 __________ lactate ______ 51.56 1.62 7.71 JJ aNiclosaid 1 45.63 0.54 1.78 Zol increase Active Mean Zol (compared to Formulation Active compound ZoISD (mm) %w/w (mm) formulation ___________ _______________ ______ _________ _____________ placebo) (mm) liii Placebo 0 20.73 4.15 n/a aimfl 1 11 subsalicylate ______ 37.50 0.83 16.77 JJJffl aChloramh.l 1 72.60 1.91 51.87 aTñmeth* 1 _________ freebase _____ 57.08 1.60 36.35 aTñmeth* 1 "Iv __________ lactate ______ 56.88 1.90 36.15 JJJ aNiclosaid 1 32.08 2.84 11.35 JJJ usnate 1 54.27 1.30 33.54 IVi Placebo 0 35.83 1.48 n/a aBismuth 1 IVii ___________ subsalicylate ______ 35.63 0.31 -0.20 IViii aChloramphenicol 1 70.73 1.83 34.90 aTñmeth* 1 IViv _________ freebase _____ 52.81 2.05 16.98 aTñmeth* 1 IVy __________ lactate ______ 51.15 0.36 15.32 jy aNiclosamide 1 40.52 1.26 4.69 IVvii aCopper usnate 1 56.98 1.10 21.15 a 1% w/w solution It can be seen from Table 6 that all of the invented formulations are more active against P. acnes NCTC 737 than the relevant placebo. The formulations containing chloramphenicol proved to be the most active and gave the largest zones of inhibition in all the formulation groups. Bismuth subsalicylate and niclosamide were active in vehicles that did not contain DOS. One or both may have been active in formulations with DOS but the activity of each combination was not greater than that of DOS alone.

The antibiotic trimethoprim was active in formulations both with and without DOS, whether used as the free base or the lactate salt. Copper usnate was also active in formulations with and without DOS.

These results indicate the likely activity of the invented combinations as anti-acne agents, the propionibacteria being implicated in acne.

Exam le 3 -salicylanilide activity against Propionibacterium sjj This example demonstrates the activity of halogenated salicylanilides against P. acnes NCTC 737, and hence their utility as anti-acne agents.

MIC, MBC and DDA assays, as described above, were carried out using as the test compounds ClosantelTM, niclosamide, rafoxanide and oxyclozanide (all ex Sigma Aldrich, UK). The solvents used were DMSO for the ClosantelTM and niclosamide, and ethanol for the rafoxanide and oxyclozanide. All four actives were used in the form of their free bases rather than as salts.

Supplemented DDA assays were also carried out in the presence of sodium chloride, again as described above.

The results are shown in Table 7 below. All tests were conducted in triplicate.

Table 7

____________________________ _________ ___________ ___________ ___________

Test compound MIC MBC DDA DDA + ______________________ (ig/ml) (ig/ml) (mm) salt (mm) 29.79 27.92 ClosantelTM 0.12 0.49 (�0.18) (�1.1) 43.44 41.98 Niclosamide 0.03 0.98 (�1.36) (�0.98) 21.46 22.92 Rafoxanide 0.12 0.98 (�0.95) (�3.34) 52.6 50.73 Oxyclozanide 0.49 1.95 (�1.78) (�1.41) It can be seen from Table 7 that all four compounds are highly active as antibacterial agents against P. acnes NCTC 737. Thus, formulations according to the invention which contain a halo genated salicylanilide in addition to the components (i) to (iii) can be expected to possess activity against propionibacteria and thus against acne.

The high level of anti-propionibacterial activity appears to be maintained in the presence of salt.

Exam i'le 4 -to,ical anti-acne formulations The results from Examples 1 to 3 show that a formulation according to the invention can be effective not only against non-inflamed acne lesions (due to the presence of components (i) to (iii), as tested in Example 1) but also as an antibacterial agent against the bacteria associated with acne. This can be of use in preparing anti-acne formulations, in particular for topical application to the skin, either to treat or to reduce the risk of acne.

A topical formulation for use against acne may for example be prepared by combining an active selected from (a) to (d) with the combination of components (i) to (iii), suitably in the presence of water and optionally together with conventional additives.

A DAS or derivative thereof may also be included in the formulation. Suitable additives and excipients may be for instance as found in Williams' "Transdermal and Topical Drug Delivery", Pharmaceutical Press, 2003 and other similar reference books, and/or in Rolland A et al, "Site-specific drug delivery to pilosebaceous structures using polymeric microspheres", Pharm. Res. 1993; 10: 1738-44; Mordon S et at, "Site-specific methylene blue delivery to pilosebaceous structures using highly porous nylon microspheres: an experimental evaluation", Lasers Surg. Med. 2003; 33: 119-25; and Alvarez-Roman R et at, "Skin penetration and distribution of polymeric nanoparticles", J. Controlled Release 2004; 99: 53-62.

The formulation may be prepared and administered using known techniques. It may in particular be in the form of a gel.

The concentrations of the anti-acne active(s), and of the components (i) to (iii), may be in the ranges described above, and will be determined based on the intended use of the formulation, its intended mode of administration and the activities of the particular chosen active agent(s). Suitably, the formulation is administered topically to acne-affected skin.

By way of example, gel formulations for use in the topical treatment of acne may be prepared in the same way as the test formulations (I) to (IV) in the examples above.

Claims (73)

1. Claims 1. An anti-acne formulation containing: (i) a polyoxyalkylene-based solubilising agent; (ii) an organic solvent; and (iii) a thickening agent; together with one or more anti-acne actives selected from the following: (a) bismuth salts; (b) copper salts; (c) antibiotics; (d) halogenated salicylanilides; and mixtures thereof.
2. 2. A formulation according to claim 1, which additionally includes water.
3. 3. A formulation according to claim 1 or claim 2, which additionally includes a dialkyl sulphosuccinate (DAS) or derivative thereof.
4. 4. A formulation according to any one of the preceding claims, which is suitable for topical application to human skin.
5. 5. A formulation according to any one of the preceding claims, wherein the solubilising agent is polyoxyethylene (polyethylene glyco 1, PEG)-based.
6. 6. A formulation according to any one of the preceding claims, wherein the solubilising agent comprises a polyoxyalkylene ether or ester.
7. 7. A formulation according to any one of the preceding claims, wherein the solubilising agent is selected from (a) polyethoxylated esters, other than polyethoxylated sorbitan esters, and (b) polyethoxylated alkyl ethers.
8. 8. A formulation according to claim 7, wherein the polyethoxylated ester is a polyethoxylated fatty acid ester.
9. 9. A formulation according to claim 8, wherein the fatty acid component of the ester is a C12 to C18 group.
10. 10. A formulation according to claim 8 or claim 9, wherein the fatty acid component of the ester is a hydroxyl-substituted fatty acid group.
11. 11. A formulation according to claim 10, wherein the solubilising agent is Solutol� HS 15.
12. 12. A formulation according to claim 7, wherein the polyethoxylated ester is a polyethoxylated glyceryl ester.
13. 13. A formulation according to claim 12, wherein the glyceride components of the ester contain from 8 to 18 carbon atoms.
14. 14. A formulation according to claim 13, wherein the solubilising agent is a GlyceroxTM ester or LabrasolTM.
15. 15. A formulation according to claim 7, wherein the polyethoxylated alkyl ether is an ether of a C14 to C20 fatty alcohol.
16. 16. A formulation according to any one of the preceding claims, wherein the organic solvent is an alcohol.
17. 17. A formulation according to claim 16, wherein the alcohol is selected from methanol, ethanol, isopropanol, phenoxyethanol and mixtures thereof.
18. 18. A formulation according to claim 17, wherein the alcohol is ethanol.
19. 19. A formulation according to any one of the preceding claims, wherein the thickening agent is a gelling agent.
20. 20. A formulation according to any one of the preceding claims, wherein the thickening agent is a cellulose-based gelling agent.
21. 21. A formulation according to claim 20, wherein the gelling agent is hydroxyethyl cellulose or hydroxypropyl cellulose.
22. 22. A formulation according to any one of the preceding claims, wherein the solubilising agent is present at a concentration of 2 % w/w or greater.
23. 23. A formulation according to any one of the preceding claims, wherein the solubilising agent is present at a concentration of up to 50 % w/w.
24. 24. A formulation according to any one of the preceding claims, wherein the organic solvent is present at a concentration of 10 % w/w or greater.
25. 25. A formulation according to any one of the preceding claims, wherein the organic solvent is present at a concentration of up to 30 % w/w.
26. 26. A formulation according to any one of the preceding claims, wherein the thickening agent is present at a concentration of 0.2 % w/w or greater.
27. 27. A formulation according to any one of the preceding claims, wherein the thickening agent is present at a concentration of up to 5 % w/w.
28. 28. A formulation according to any one of the preceding claims, which contains a bismuth salt selected from bismuth halides, bismuth nitrates and bismuth carboxylates.
29. 29. A formulation according to claim 28, wherein the bismuth salt is bismuth subsalicylate.
30. 30. A formulation according to any one of the preceding claims, which contains a bismuth salt at a concentration of 0.05 % w/v or greater.
31. 31. A formulation according to any one of the preceding claims, which contains a bismuth salt at a concentration of up to 5 % w/v.
32. 32. A formulation according to any one of the preceding claims, which contains a copper salt selected from copper halides, copper sulphate and copper usnate.
33. 33. A formulation according to claim 32, wherein the copper salt is copper (II) usnate.
34. 34. A formulation according to any one of the preceding claims, which contains a copper salt at a concentration of 0.01 % w/v or greater.
35. 35. A formulation according to any one of the preceding claims, which contains a copper salt at a concentration of up to 10 % w/v.
36. 36. A formulation according to any one of the preceding claims, which contains an antibiotic selected from phenicols, folate pathway inhibitors, lincosamides, macro lides, and mixtures thereof.
37. 37. A formulation according to claim 36, wherein the antibiotic is a phenicol.
38. 38. A formulation according to claim 37, wherein the antibiotic is chloramphenico 1.
39. 39. A formulation according to claim 36, wherein the antibiotic is a folate pathway inhibitor.
40. 40. A formulation according to claim 39, wherein the antibiotic is trimethoprim.
41. 41. A formulation according to any one of the preceding claims, which contains an antibiotic at a concentration of 0.01 % w/v or greater.
42. 42. A formulation according to any one of the preceding claims, which contains an antibiotic at a concentration of up to 5 % w/v.
43. 43. A formulation according to any one of the preceding claims, which contains a halogenated salicylanilide selected from ClosantelTM, niclosamide, rafoxanide, oxyclozanide and mixtures thereof.
44. 44. A formulation according to claim 43, wherein the salicylanilide is either ClosantelTM or niclosamide.
45. 45. A formulation according to any one of the preceding claims, which contains a halogenated salicylanilide at a concentration of 0.05 % w/v or greater.
46. 46. A formulation according to any one of the preceding claims, which contains a halogenated salicylanilide at a concentration of up to 5 % w/v.
47. 47. A formulation according to claim 3 or any claim dependent thereon, wherein the DAS or derivative is in the form of a salt in which the sulphonic acid group is present as the sulphonate -S(O)2-0.
48. 48. A formulation according to claim 3 or any claim dependent thereon, wherein the DAS or derivative is in the form of a metal salt.
49. 49. A formulation according to claim 48, wherein the metal salt is a sodium, potassium or calcium salt.
50. 50. A formulation according to claim 49, wherein the metal salt is a sodium salt.
51. 51. A formulation according to claim 3 or any claim dependent thereon, wherein the DAS is a C2 to Cio dialkyl sulphosuccinate.
52. 52. A formulation according to claim 51, wherein the DAS is a dioctyl sulphosuccinate.
53. 53. A formulation according to claim 3 or any claim dependent thereon, wherein the concentration of the DAS or derivative is 1.5 % w/v or greater.
54. 54. A formulation according to claim 3 or any claim dependent thereon, wherein the concentration of the DAS or derivative is up to 10 % w/v.
55. 55. A formulation according to claim 3 or any claim dependent thereon, wherein the concentration of the DAS or derivative is from 2 to 8 % w/v.
56. 56. A formulation according to any one of the preceding claims, which additionally contains one or more agents selected from anti-acne agents, keratolytics, comedolytics, agents capable of normalising keratinocyte and/or sebocyte function, anti-inflammatories, anti-proliferatives, antibiotics, anti-androgens, sebum controlling agents, anti-pruritics, immunomodulators, agents which promote wound healing, additional antimicrobial agents, and mixtures thereof.
57. 57. A formulation according to any one of the preceding claims, which is in the form of a cream, paste, gel, lotion, foam, ointment, varnish or other viscous or semi-viscous fluid.
58. 58. A formulation according to any one of the preceding claims, which is, or may be, applied to a carrier selected from a sponge, swab, brush, tissue, cloth, wipe, pad, skin patch, skin adhesive or other material designed for application to a tissue surface.
59. 59. An anti-acne formulation which is substantially as herein described.
60. 60. A product containing an anti-acne formulation according to any one of the preceding claims.
61. 61. A kit for preparing an anti-acne formulation, the kit comprising sources of components (i) to (iii) as defined in claim 1, and source(s) of one or more anti-acne actives selected from (a) to (d) as defined in claim 1, together with instructions for combining the components so as to make the formulation at or before the point of intended use, and/or for the co-administration of the components to a surface.
62. 62. A method for preparing an anti-acne formulation, which method involves mixing together components (i) to (iii) as defined in claim 1, and one or more anti-acne actives selected from (a) to (d) as defined in claim 1.
63. 63. A formulation containing components (i) to (iii) as defined in claim 1 and one or more anti-acne actives selected from (a) to (d) as defined in claim 1, for use in the treatment of acne.
64. 64. Use of components (i) to (iii) as defined in claim 1, together with one or more anti-acne actives selected from (a) to (d) as defined in claim 1, in the manufacture of a medicament for the treatment of acne.
65. 65. A method for controlling the growth of a propionibacterium, the method comprising applying, to an area or surface which is infected or suspected to be infected or capable of becoming infected with the bacterium, components (i) to (iii) as defined in claim 1 and one or more anti-acne actives selected from (a) to (d) as defined in claim 1.
66. 66. A method of treatment of a patient suffering from or at risk of suffering from acne, the method involving administering to the patient a therapeutically (which term includes prophylactically) effective amount of a formulation containing components (i) to (iii) as defined in claim 1 and one or more anti-acne actives selected from (a) to (d) as defined in claim 1.
67. 67. Use of the components (i) to (iii) as defined in claim 1 in an anti-acne formulation, in combination with one or more anti-acne actives selected from (a) to (d) as defined in claim 1, for the purpose of increasing the anti-acne activity of the formulation and/or of reducing the amount of the anti-acne active(s) (a) to (d) in the formulation without or without undue loss of anti-acne activity.
68. 68. An antibacterial or anti-acne formulation containing one or more anti-acne actives selected from (a) to (d) as defined in claim 1, together with a dialkyl sulphosuccinate (DAS) or derivative thereof.
69. 69. A formulation according to claim 68, for use in the treatment of a condition affecting the human or animal body, which condition is caused by, transmitted by and/or exacerbated by bacterial activity.
70. 70. A method of treatment of a human or animal patient suffering from or at risk of suffering from a condition which is caused by, transmitted by and/or exacerbated by bacterial activity, the method involving administering to the patient a therapeutically (which term includes prophylactically) effective amount of a formulation according to claim 68.
71. 71. An anti-acne formulation containing (i) a polyoxyalkylene-based solubilising agent; (ii) an organic solvent; and (iii) a thickening agent; together with one or more additional anti-acne actives selected from the group consisting of bismuth salts; copper salts; antibiotics; halogenated salicylanilides; benzoquinones and hydroquinones of the type referred to in WO-2006/ 100495; Antioxidant 2246; Antioxidant 425; bis-quino linium salts; pyridine thiols; retinoids and retinoid-like compounds; salicylic acid and its salts; peroxides; compounds which are capable of generating hydrogen peroxide in situ; nicotinamide; cyproterone acetate; spironolactone; metformin; aipha-hydroxy acids such as glycolic acid and mandelic acid; polyhydroxy acids such as gluconolactone; essential oils such as tea tree oil, bergamot oil, rosewood oil and lavender oil; fatty acids (including omega-3 -6 and -9 polyunsaturated fatty acids) and their salts, for example linoleic acid or linolenic acid or salts thereof plant extracts such as of Hamamelis virginiana (witch hazel), Brassica, Pinus, Quercus, Nasturtium or Salvia; di-carboxylic acids such as azelaic acid; salicylamides; thiosalicylic acid; urea; allantoin; biotin; carbocysteine; propolis; thiazolidinediones and other PPAR gamma antagonists; and mixtures thereof
72. 72. A formulation according to claim 71, for use in the treatment of acne.
73. 73. A method of treatment of a patient suffering from or at risk of suffering from acne, the method involving administering to the patient a therapeutically (which term includes prophylactically) effective amount of a formulation according to claim 71.