GB2456376A - Antibacterial/anti-acne formulations comprising a halogenated salicylanilide in combination with one or more anti-acne agents - Google Patents

Abstract

Antibacterial/anti-acne formulations comprising a halogenated salicylanilide, in combination with one or more anti-acne actives selected from (a) diacyl peroxides and hydrogen peroxide; (b) alkyl-substituted benzo- and hydroquinones; (c) antibiotics; (d) dialkyl sulphosuccinates; (e) pyridine thiols; (f) bismuth salts; (g) bisphenols; (h) copper salts; (i) alkyl sulphates and sulphonates; (j) diterpenes; and (k) nicotinic acid, alkyl nicotinates and nicotinamides. Further agents which may be used include bis-quinolinium salts; retinoids, salicylic acid and derivatives; cyproterone acetate; spirolactone; metformin; alpha-hydroxy acids, polyhydroxy acids; essential oils; plant extracts; di-carboxylic acids; thiosalicylic acid; urea; allantonin; biotin; carbocysteine; thiazolidinediones and other PPAR (peroxisome proliferator-activated receptor) gamma antagonists and mixtures thereof. The formulation is suitable for topical application in the treatment of acne or conditions caused by, transmitted by and/or exacerbated by propionibacterial activity. A kit comprising a source of a halogenated salicylanilide and source(s) of one or more anti-acne agents is also outlined.

Description

Formulations

Field of the invention

This invention relates to antibacterial and anti-acne formulations, and to the use of certain combinations of compounds as antibacterial and 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 also a cause of significant distress to those suffering from it, there is always a need to find new and preferably 0 more effective anti-acne treatments.

Certain types of salicylanilide, including halogenated salicylanilides, are known for use as anthelmintics and anti-parasitic agents and are used in particular to destroy or expel tapeworms in domestic animals. They are also known (see WO-2004/006906) to act as antiproliferative agents.

Certain brominated salicylanilides are also known to have antibacterial and antifungal activities, and are used for example as disinfectants in medicated soaps: these include 4',5- dibromosalicylanilide (also known as dibromsalan, CAS #: 87-12-7); 3,5- dibromosalicylanilide (also known as metabromsalan, CAS #: 2577-72-2); and 3,4',5-tribromosalicylanilide (also known as tribromsalan, CAS #: 87-10-5) which is used as a bacteriostat in detergents.

FR-I.568.910 for example describes the use of halogcnated (in particular brominated) salicylanilides as topical disinfectants. EP-l 362 581 mentions the use of tribromsalan as an antimicrobial agent, in combination with an anti-perspirant, in a pharmaceutical or cosmetic composition for topical application to the skin. EP-0 934 742 also refers to tribromsalan as an antimicrobial agent, for use in topical antimicrobial cleansers.

US-4,205,061 discloses an oral antimicrobial composition containing a synergistic combination of 3,5-dibromo-3'-trifluoromethyl salicylanilide and cetyl pyridinium chloride; the composition is intended to help prevent plaque and gingival diseases, without tooth staining.

Other halogenatcd salicylanilides arc known for use as antimicrobial agents in certain contexts. For example, CU-506 292 discloses an oral health care composition, particularly for use against dental caries, which contains a halogenated trifluoromethyl salicylanilide and an alkali metal trimetaphosphate. GB-2 403 905 mentions the use of salicylanilides against fungi. WO-02/28819, meanwhile, describes the use of naphthyl-substituted salicylanilides as topical antibacterial and anti-inflammatory agents; the inclusion of the naphthyl group is said to confer activity against a range of bacteria.

Macielag et al (.1 Med Chem 1998, 41: 2939-2945 and Ciiemtracts -Organic chemist;y, 12: 656-661 (1999)) describe the activity of closantel, tetrachlorosalicylanilide and other related salicylanilides in inhibiting bacterial regulatory systems. Hamada et al Journal of the Pharmaceutical Society qf Japan, 101 (7): 633-641) describe the antibacterial activity of a number of substituted (including halogenated) salicylanilides, demonstrating activity against several Gram-positive bacteria including S. aureus. Taborsky et al (Journal qf the American Pharmaceutical Association, vol. XLV1II, no. 9: 503-507) describe the antibacterial activity of various nitro-and halo-substituted salicylanilides, including against S. aureus, but the authors report wide variations in activity between differently Rotmistrov et al (Mikrobiolohichny Zhurnal, vol. 27, no. 2, 1965: 52-56 and Mikrobiolohichny Zhurnal, vol. 34, no. 1, 1972: 8-9) describe antimicrobial activity for certain salicylanilides, including some halogenated compounds. US-4,3 10,682 discloses antifungal and bactericidal activity for halogenated (primarily brominated) salicylanilides of a specific formula, in which an alkyl group at the 2'-position appears to be critical for the activity.

Salicylanilides are also known as 2-hydroxy-N-phcnylbenzamides or 2-hydroxybcnzanilides. They have the following basic structure: ()5OH 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-methylphcnyl] -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 ClosanteltM 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. ClosantelTM 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 -chloro-N-(2-chloro-4-nitrophcnyl)-2-hydroxybenzami de. It is used as a veterinary anthelmintic against cestodes, and its ethanolaminc salt is also known for use as a molluscicide.

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

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

II has now surprisingly been found that certain types of salicylanilide can be active against propionibacteria, the bacteria implicated in acne. It has further been found that combinations of such salicylanilides with certain types of known anti-acne agent can be effective as anti-acne agents.

Statements of the invention

According to a first aspect of the present invention there is provided an antibacterial or anti-acne formulation containing a halogenated salicylanilide, together with one or more anti-acne actives selected from the following: (a) diacyl peroxides and hydrogen peroxide; (b) alkyl-substituted benzo-and hydroquinones, and resorcinol; (c) antibiotics; (d) dialkyl suiphosuccinates; (e) pyridine thiols; (f) bismuth salts; (g) bisphenols; (h) copper salts; (i) alkyl sulphates and sulphonates; (j) diterpenes; (k) nicotinic acid, alkyl nicotinates and nicotinamide; and mixtures thereof.

it has surprisingly been found, as demonstrated in the examples below, that halogenated sali cyl an i Ii des can be antibacterially active against propionibacteria, which are the key pathogens implicated in acne. They can therefore be effective as anti-acne agents.

The presence of the additional anti-acne active selected from (a) to (k) can serve to improve the overall efficacy of the formulation, in many cases by increasing its activity against propionibacteria.

At the same time, the activity contributed by the salicylanilide can make it possible to reduce the concentration of the additional anti-acne active needed in the formulation whilst still retaining acceptable efficacy overall. This can be of particular value where the additional anti-acne active is 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 andlor allergic reactions which can accompany the administration of certain types of antibiotic.

A halogenated salicylanilide is substituted at either or both of its phenyl rings with one or more halo groups. A halo substituent may be selected from fluoro, chloro, bromo and iodo, in particular fluoro, chloro and iodo, more particularly chloro and iodo. In cases it may be preferred for the salicylanilide not to be substituted with any bromo groups.

In an embodiment, 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 C1-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 pheny! 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.

The salicylanilide may for example be substituted with one or more chioro 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, iodo groups.

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

In an embodiment of the invention, 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 Closantel't'M.

A halogenated salicylanilide may be used in the form of a derivative. A "derivative" of a halogenated salicylanilide may in particular be a pharmaceutically acceptable derivative, which includes a derivative which is acceptable for veterinary use. A "derivative" may for example be selected from salts, esters, solvates and also so-called "prodrug" forms or protected forms which revert to an active form of the relevant compound at an appropriate time on or after administration.

The salicylanilide may be used in the form of 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 ClosantelTM or niclosamidc, 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, andlor in the form of a hydrate such as a monohydrate.

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

The concentration of the salicylanilide 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 I % w/v. Its concentration may for instance be from 0.05 to 2% wlv or from 0.1 to 1.5 % w/v, for example about I % w/v.

For oral delivery, from about 50 mg to 2 g of the salicylanilide may be administered daily, whether as a single dose or as two or more divided doses. Thus the salicylanilide may be formulated in dosage forms -for example tablets or capsules -containing up to about 2 g, for instance from about 50 mg to 2g, of the active substance.

The anti-acne active (a) The anti-acne active (a) is either a diacyl peroxide or hydrogen peroxide. Such materials -in particular benzoyl peroxide -are known to be active as anti-acne agents (see for example WO-20061l00495).

A diacyl peroxide is a compound having the formula R'-C(O)-OO-C(O)-R2, where R' and R2 are each independently selected from alkyl, cycloalkyl and aryl groups, preferably aryl. Suitable alkyl groups may be selected from C1 to C20 groups, preferably from C1 to C16 groups, more preferably from Ci to C12 groups, most preferably from C1 to C8 or C1 to C6 or C1 to C4 (for example methyl, ethyl, propyl (preferably iso-propyl) or butyl (preferably t-butyl)) groups. A suitable aryl group is phenyl.

A diacyl peroxide may in particular be derived from a fatty acid source: for example it may be a dilauryl, diamyl or dicumyl peroxide. An alkyl, cycloalkyl or aryl group may be substituted with one or more other groups, but is preferably unsubstituted.

Suitably R1 and R2 arc each independently selected from C1 to C12 alkyl and C1 to C8 aryl, in particular phenyl. R' and R2 are preferably the same.

Some suitable diacyl peroxides, of medium chain (C6 to C12) fatty acids, are disclosed for instance in US-4,479,939. More preferably at least one of R' and R2 (preferably both) is phenyl.

A particularly preferred peroxide for use in the present invention is therefore benzoyl peroxide (also known as dibcnzoyl peroxide or benzoyl superoxide), which has the formula Ph-C(O)-O-O-C(O)-Ph. Benzoyl peroxide is already widely lown for use as a topical anti-acne agent.

The diacyl peroxide (a) is suitably pharmaceutically acceptable.

The anti-acne active (a) may be present as a derivative, in particular a stabilised form which is capable of generating the relevant peroxide in situ. For example a formulation according to the invention may contain, as the anti-acne active (a), a compound such as urea peroxide (carbamide peroxide) which is a stabilised form of hydrogen peroxide and capable of generating hydrogen peroxide in situ.

A formulation according to the invention may contain more than one diacyl peroxide, or a mixture of hydrogen peroxide with one or more diacyl peroxides.

The concentration of a peroxide (a) in the formulation might suitably be 0.05 % w/v or greater, preferably 0.1 % w/v or greater. Its concentration might be up to 10 % w/v, preferably below or equal to 5 or 2.5 % w/v. For example it might be present in the formulation at from 0.5 to 2.5 % w/v or from 0.5 to 2 % w/v, such as about I % w/v.

The anti-acne active b) The anti-acne active (b) is an alkyl-substitutcd benzoquinone or hydroquinone, or resorcinol. It is preferably an alkyl-substituted benzo-or hydroquinonc of the type referred to in WO-2006/100496, in which such quinones are disclosed for use as antibacterial and anti-acne agents.

In the context of the present invention, the term "bcnzoquinonc" means a cyclohexadiene dione (typically a cyclohexadicne-l,4-dione or cyclohexadicne-1,2-dione). The term "hydroquinone" (sometimes known as a "hydroxyquinonc") means a bcnzoquinone in which one or more (preferably both) of the C=O groups is instead present as a C-OH group, or as a radical group C-0. A hydroquinone may therefore be a compound having an unsaturated 6-membered hydrocarbon ring, typically a phenyl ring, which carries two or more -OH or Os groups.

A benzo/hydroquinone may be present as a mixture of two or more of these forms, for instance as an equilibrium mixture of a benzoquinone and its corresponding hydroquinone.

The two C=O groups or C-OH groups of a benzo-or hydroquinone may be positioned ortho, mcta or para to one another. When positioned ortho to one another, this is known as a cyclohexadiene-I,2-dione or o- bcnzoquinone or, in the case of the corresponding hydroquinonc, a catechol. When positioned meta to one another, this is known as a cyclohexadiene-1,3-dione or an in-benzoquinone or, in the case of the corresponding hydroquinone, a resorcinol. When positioned para to one another, this is known as a cyclohcxadiene-1,4-dione or ap-benzoquinone or, in the case of the para-substituted HO-Ph-OH, simply as "hydroquinone".

Preferably the two C=O groups or C-OH groups are positioned ortho or para to one another, most preferably para as in p-benzoquinone (cyclohexadiene-I,4-dione) or the corresponding para-substituted hydroquinone HO-Ph-OH.

The term "hydroquinone" is not intended to embrace phenols, which have only one -OH group attached to a six-membered hydrocarbon ring.

Such compounds arc substituted with one or more alkyl groups. They are not generally substituted with other, non-alkyl substituents. An alkyl group may be either a straight or a branched chain alkyl group, of which the latter may be preferred, especially where the number of carbon atoms is 3 or greater. It may be or contain cycloalkyl moieties. It may contain for instance from 1 to 12 carbon atoms, preferably from 1 to 10, more preferably from I to 8. Particularly preferred alkyl groups are those selected from C1 to C6 alkyl groups, more preferably C1 to C5 alkyl groups, yet more preferably C1 to C4 alkyl groups, for instance methyl, ethyl, iso-propyl or t-butyl groups.

The quinone may include up to six or more suitably four alkyl groups, but in particular may be mono-or di-substituted with such groups, more preferably mono-substituted.

The quinone may be a mixture of an alkyl-substituted benzoquinone and an alkyl-substituted hydroquinonc, in particular a mixture of an alkyl-substituted benzoquinone and its corresponding hydroquinone. More preferably it is an alkyl-substitutcd hydroquinone.

In an alkyl-substituted hydroquinone, an alkyl substituent may be attached to a carbon atom of the cyclohexyl ring or to an oxygen atom (thus replacing the hydrogen atom of a hydroxyl group on the cyclohexyl ring). Preferably it is attached to a carbon atom.

The hydroquinone may be substituted with one or two or more butyl groups. A butyl group is preferably a t-butyl group. Instead or in addition, the hydroquinone may be substituted with one or two or more methyl groups. Instead or in addition, the hydroquinone may be substituted with one or two or more propyl groups. A propyl group is suitably an iso-propyl group. Instead or in addition, the hydroquinone may be substituted with one or two or more ethyl groups.

Instead or in addition, the hydroquinone may be substituted with one or two or more pentyl (preferably t-amyl) groups.

In particular the hydroquinone may be substituted with just one t-butyl group.

Alternatively the hydroquinone may be substituted with two butyl groups, which prcfcrably occupy the 2 and 5 positions. In both cases the butyl groups are preferably t-butyl groups.

An alkyl-substituted hydroquinone may be selected from the group consisting of 2-t- butyl-p-hydroquinone (TBHQ), 2,5 -di-t-butyl-p-hydroq uinone, 2-propyl-p- hydroquinone, 2-isopropyl-p-hydroquinone, 2-ethyl-p-hydroquinonc, 2-mcthyl-p-hydroquinone and mixtures thereof. In cases it may be thymohydroquinone, which is a para-hydroquinonc substituted at the 2-position with an isopropyl group and at the 5-position with a methyl group. In cases it may be an alkyl-substituted resorcinol. It may in particular be TBHQ, ic, a para-hydroquinone substituted at the 2 position with a t-butyl group.

An alkyl-substituted benzoquinone may be substituted with one or more alkyl groups, an alkyl group being as defined above. Substituents on a benzoquinone will be is attached to carbon atoms of the cyclohexyl ring.

A benzoquinone may be substituted with up to four alkyl groups, but in particular may be a mono-or di-alkyl bcnzoquinone, preferably the former.

Such a benzoquinone may be substituted with one or two or more methyl groups.

Instead or in addition, it may be substituted with one or two or more propyl groups. A propyl group is preferably an iso-propyl group. It may be substituted with one or two or more butyl groups. A butyl group is preferably a t-butyl group. It may be substituted with one or two or more ethyl groups. It may be substituted with one or two or more pentyl (preferably t-amyl) groups.

A substituted benzoquinone may be selected from the group consisting of 2-t-butyl-p- benzoquinonc (also known simply as t-butyl benzoquinone, or TBBQ), 2,5-di-t-butyl-p-benzoquinone, 2-ethyl-p-benzoquinone, 2-methyl-p-benzoquinone and mixtures thereof. In cases it may be thymoquinone, which is a para-benzoquinone substituted at the 2-position with an iso-propyl group and at the 5-position with a methyl group. It may in particular be TBBQ.

in the present context an alkyl-substituted benzo/hydroquinone may be present in the form of a dimer, oligomer or polymer, the monomer unit of which is an alkyl-substituted bcnzo/hydroquinone as defined above. Preferably, however, the benzo/hydroquinone is present in the form of a single, underivatised benzo/hydroquinone molecule.

Most preferred alkyl-substituted quinones for use according to the invention arc those selected from TBHQ, TBBQ and mixtures thereof. In particular the quinone may be TBE-IQ.

The bcnzo/hydroquinone (b) is suitably pharmaceutically acceptable.

A formulation according to the invention may contain more than one alkyl-substituted benzo-or hydroquinone, or a mixture of resorcinol with one or more alkyl-substituted benzo/hydroquinones..

The concentration of an atkyl-substituted benzo/hydroquinonc, or ofresorcinol, in the formulation might suitably be 0.05 % w/v or greater, preferably 0.1 % w/v or greater.

is Its concentration might be up to 5 % w/v, preferably up to 2.5 % w/v.

The anti-acne active (c) The anti-acne active (c) is an antibiotic, which in the context of the present invention 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, Ic, 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 dapsonc or trirncthoprim; tetracyclines (eg oxytetracycline, minocyci me, doxycyc line, lymecycl me, tetracycline or chiortetracycline); azalides (eg azithromycin); phenicols such as chioramphenicol; fusidanes such as fusidic acid; and mixtures thereof.

An antibiotic (c) used in a formulation according to the present invention may in particular be selected from phenicols such as chioramphenicol; folate pathway inhibitors such as trimethoprim; lincosamides such as clindamycin; macrolides such as erythromycin; tetracyclines such as tetracycline; fusidanes such as fusidic acid; and mixtures thereof.

In an embodiment of the invention, the antibiotic (c) is clindamycin, which is already known for use in the topical treatment of acne (Guay DR. "Topical clindamycin in the management of acne vulgaris", Expert Opin Pharniacother, 2007, 8: 2625-64). In an embodiment, the antibiotic is erythromycin, which is also known for use in topical anti-acne formulations (Dréno B, "Topical antibacterial therapy for acne vulgaris", is Drugs 2004, 64: 2387-97). In another embodiment, the antibiotic 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.! Derinatol, 1999, 141: 757-8) and topical delivery (see CN-1483408).

In an embodiment, the antibiotic (c) is tetracycline, another known anti-acne agent (see Del Rosso JQ, Kim G, "Optimizing use of oral antibiotics in acne vulgaris", Dermatol C/in, 2009, 27: 33-42). In another embodiment, it is chloramphenicol, a compound which is also 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 chloramphenicol", Curr Med Res Opin 1980; 6: 46 1-5; also Fluhr JW, Gloor M, Tvlerkel W et al, Arznein,nitte!/brschung 1998; 48: 188-96).

In an embodiment, the antibiotic (c) is fusidic acid. This is also a known anti-acne agent (see Sommer 5, Bojar R, Cunliffe Wi, Holland D, Holland KT, Knaggs H, "investigation of the mechanism of action of 2% fusidic acid lotion in the treatment of acne vulgaris", Clin Exp Dermatol 1997; 22: 211-5).

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 "prodrug" 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 or of a hydrohalide such as the hydrochloric acid salt. A tetracycline antibiotic may similarly be used in the form of a hydrohalide salt.

Fusidic acid may be used in the form of the free acid or of a salt such as the sodium 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 as from 0.25 to 2 % w/v.

The anti-acne active (d) The anti-acne active (d) is a dialkyl sulphosuccinate. As used herein, the term "dialkyl suiphosuccinate" or "DAS" means a dialkyl ester of suiphosuccinic acid, in which the sulphonic acid group is present as -S(O)2-OH. Such a compound may be used in the form of a derivative; suitable DAS derivatives 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.

DASs have been disclosed for use as topical anti-acne agents in GB-2 449 973.

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 arc not substituted with ether groups. In an embodiment, the alkyl groups do not include unsaturated carbon-carbon bonds.

The DAS is conveniently used in the form of a salt in which the suiphonic acid group is present as the sulphonate -S(O)2-O, 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).

IS The DAS 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 suiphosuccinate sodium or docusate sodium).

A DAS may be used in the form of a derivative, which may be a pharmaceutically acceptable derivative. 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.

The concentration of a DAS (d) in a formulation according to the invention might suitably be 0.1 or 0.2 or 0.5 % w/v or greater, in cases I or 1.5 or 2 or 3 or 4 % w/v or greater. Its concentration might be up to 15 % w/v, preferably up to 10 or in cases 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, orfromO.5 or ito 10% w/vorfrom 0.1 orO.5 or ito 8 %w/v.

The anti-acne active (e) The anti-acne active (e) is a pyridine thiol.

Pyrithione, also known as 1-hydroxy-2(IH)-pyridinethione, 2-pyridinethiol-1-oxide or 2-mercaptopyridine N-oxide, is a type of pyridine thiol and is known for use as a bactericide and fungicide. It is typically used in the form of a metal salt (sfrictly, a chelated complex) such as zinc pyrithione. In particular the zinc salt is known as an antiseborrheic, an antifungal and an antibacterial agent, as well as for the treatment of scalp conditions such as dandruff and as an anti-acne agent (see for example WO- 2008/035078). It has also been used as a cosmetic preservative, for inhibiting mould growth on fabrics in commercial laundries and as a preservative (persistence agent) for topical antiseptic formulations. (See Guthery, E. et al, Am. .1. Infect. Control (l), 2005: 15-22.) In the context of the present invention, a pyndine thiol may for example be a 2-pyridine thiol, 3-pyridine thiol or 4-pyridine thiol, in particular a 2-or 4-pyridine thiol.

It may be present in the form of a salt or other derivative, for instance a pyridine thiol oxide or hydroxide. It is preferably a pyrithione (ie, an N-oxide pyridine thiol) or tautomer or derivative thereof.

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-I, I -dioxide).

Suitable salts of pyridine thiols, in particular pyrithiones, include metal salts such as zinc, selenium, silver, copper and sodium salts, preferably zinc or copper, most preferably zinc (eg zinc-2-pyridinethiol-I-oxide).

Thus most preferably the pyridine thiol is present as a pyrithione salt, in particular a metal salt/complex such as are mentioned above. Most preferably it is zinc pyrithione.

The pyridine thiol is preferably pharmaceutically acceptable.

A formulation according to the invention may contain a mixture of two or more differcnt pyridine thiols.

The concentration of a pyridine thiol (e) in the formulation of the invention might suitably be 0.01 % w/v or greater, preferably 0.05 % wlv or 0.1 % w/v or greater. its concentration might be up to 3 % w/v, in cases up to 2 or I or 0.5 or 0.25 % w/v.

The anti-acne active (f The anti-acne active (0 is a bismuth salt. 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-l 702 621 discloses antimicrobial combinatiofts 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-0l/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 antifungal 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 a halogenated salicylanilide 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 suiphadiazine, bismuth sulphate, bismuth nitrate, bismuth subnitrate, bismuth carbonate, bismuth subcarbonate, bismuth oxide, bismuth oxychioride, bismuth hydroxide, bismuth phosphate, bismuth aluminate, bismuth tribromophenate, bismuth thiol, bismuth peptides, bismuth salts of quinolines and their derivatives (eg bismuth hydroxyquinolines), bismuth pyrithione and other bismuth salts of pyridine thiols, 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, propionatc, stearatc, 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 a bismuth salt (f') in a formulation according to the invention 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 fromlto2%w/v.

The anti-acne active The anti-acne active (g) is a bisphenol. in particular it may be a bisphenol antioxidant such as in particular Antioxidant 2246 or Antioxidant 425. Examples of such compounds are disclosed in WO-2008/l 13981 as anti-acne agents.

In an embodiment of the invention, the bisphenol (g) has the formula (I) below: Formula (I) wherein each of R' and R2 is independently selected from methyl and ethyl and R3 is hydrogen. R' and R2 are suitably the same; they may for example both be methyl.

In an embodiment, the compound of formula (I) is selected from Antioxidant 2246 (AO 2246, also known as 2,2'-mcthylene-bis(4-methyl-6-tert-butylphenol), in which R' and R2 arc both methyl); Antioxidant 425 (AO 425, or 2,2'-methylene-bis(4-ethyl-6-tert-butyiphenol), in which R' and R2 arc both ethyl); and mixtures thereof.

In another embodiment, the compound of formula (I) is AO 2246.

A compound (I), in particular AO 2246, is ideally used in the form of the isolated compound (whether naturally or synthetically derived, preferably the latter) rather than as part of a plant extract containing a number of different materials. It is thus suitably used in a substantially pure form, for instance containing I % w/w or less, preferably 0.5 or 0.2 or 0.1 % w/w or lcss, in cases 0.05 % w/w or less, of impurities.

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

The concentration of a bisphenol (g) in a formulation according to the invention might suitably be 0. 1 or 0.2 % wlv or greater, preferably 0.5 % w/v or greater. Its concentration might be up to 5 % w/v, preferably up to 2 % w/v, such as from 0.5 to 2 % w/v or from 1 to 2 % w/v. In cases, the concentration of an active (g) in the formulation may be from 1 to 5 % w/v or from 2 to 5 % w/v.

The anti-acne active (h) The anti-acne active (h) is a copper salt. In the context of the present invention, the term "copper salt" includes copper (1), (11) and (Ill) salts. Preferably the copper salt in a formulation according to the invention is a copper (I) (cuprous) or copper (11) (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 I, 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 a halogenated salicylanilide 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 pentahydratc), copper nitrate, copper carbonate, copper oxide, copper oxychloridc, copper hydroxide, copper peptides, copper amino acid salts (eg copper glutamate, copper aspartate and copper glycinatc), copper silicates, copper salts of quino lines -especially hydroxyquinolines -and their derivatives (eg the copper salt of 8-hydroxyquino line), 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-pyridinc 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 (h) 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, copper salicylatc and copper usnate; or 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 prescncc of an organic solvent.

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

The concentration of a copper salt (h) in a formulation according to the invention 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 I %w/v.

The anti-acne active ü) The anti-acne active (i) is an alkyl sulphate or suiphon ate.

Alkyl suiphates, in particular longer chain alkyl sulphates such as those derived from fatty acid sources, are known for use as anionic surfactants.

Sodium tetradecyl sulphate (STS), for example, is used as a wefting agent in various industrial applications. In a pharmaceutical context, it is also known for use as an irritant and scierosing agent for haemorrhoids and varicose veins, a sclerosing agent being used to improve the cosmetic appearance of varicose veins and similar conditions without surgery. Common synonyms for STS include sodium myristyl sulphate and 1-tetradccanol hydrogen sulphate sodium salt.

The alkyl chain of STS can be cither linear, as in formula (Ii) below (CAS registration no. 1191-50-0): H3CO--O Na + Formula (II) or branched, as in the compound of formula (Ill) below: CH2CH(CH3)2 CH3(CH2)3CH(CH)2CHOSONa C2H5 0 Formula (111).

The chemical name for the compound of formula (Ill) is 7-ethyl-2-methyl-4-hendecanol sulphate sodium salt. It is commercially known as Sotradecol� (Cumberland Pharmaceuticals mc, USA), which is a FDA-approved sterile non-pyrogenic scierosing agent, and as FibroVeinTM (STD Pharmaceutical Products Ltd) which is a mixture of four stereoisomers. It is also sometimes used to help bleeding varices in the oesophagus during endoscopy. It is approved for intravenous use at concentrations of 1 and 3 % w/v.

Sadick et al in Dermatol Surg, 22: 369-71 describe the use of detergent sclerosing agents, including Sotradecol� and also polidocanol, in combination with the antibiotic penicillin, to suppress penicillin (and hence also methicillin and oxacillin) resistance in S. aureus. The Sotradecol� was used in the form of a 1 % solution and the Polidocanol at 0.5 %; in cases both appeared to augment the antibacterial activity of the antibiotic.

In addition to the tetradecyl (myristyl) sulphates, other known and widely available alkyl sulphate surfactants include the decyl sulphates, the lauryl sulphates and the cetyl sulphates. These are often used in the form of their sodium salts.

Alkyl suiphonates, like the alkyl suiphates, are also commonly used anionic surfactants and wetting agents, and in addition have the potential to be used as alkylating agents in cancer therapy. They have not however, to our knowledge, been proposed for use as anti-acne agents in combination with a halogenatcd salicylanilide.

An alkyl sulphate or suiphonate used in a formulation according to the invention is suitably a C8 to C20 alkyl sulph(on)ate, or a C8 to Cl 8 alkyl sulph(on)ate, or a Cl 0 to C20 alkyl sulph(on)atc, or a ClO to C18 alkyl sulph(on)atc, in particular a ClO to C16 alkyl sulph(on)atc. It may for example be a ClO to C14 alkyl sulph(on)ate such as a decyl, lauryl (dodecyl) or myristyl (tetradecyl) sulph(on)ate, in particular a C12 or Cl4 alkyl sulph(on)atc and more particularly a C14 alkyl sulph(on)ate.

Other suitable alkyl sulph(on)ates include the C16 alkyl sulph(on)ates such as cetyl sulph(on)ates, and the C 18 alkyl sulph(on)atcs such as stearyl sulph(on)ates.

The alkyl chain may be either straight chain or branched.

In cases the alkyl chain may include one or more unsaturated carbon-carbon bonds, for example as in palmitoleyl, elaidyl, oleyl and linoleyl groups.

The alkyl chain may include one or more alkoxy, in particular ethoxy (-OCH2CH3), or alkoxyl, in particular ethoxyl (-OCH2CH2), groups, for example as in the laureth suiphates. In other words, the alkyl sulph(on)ate may be an alkyl ether sulph(on)ate.

In cases however it may be preferred for the alkyl chain not to include any unsaturated carbon-carbon bonds. In cases it may be preferred for the alkyl chain not to include any alkoxy or alkoxyl groups. In cases it may be preferred for the alkyl chain not to be branched.

A particularly preferred alkyl sulph(on)ate for use in the present invention is a C14 alkyl sulph(on)ate such as a linear n-tetradecyl sulph(on)ate or a branched chain isomer thereof. In an embodiment, the alkyl sulph(on)ate is an n-tetradecyl sulph(on)ate, in particular sodium n-tetradecyl sulph(on)ate. In another embodiment, the alkyl sulph(on)ate is a 7-cthyl-2-methyl-4-hendecanol sulph(on)ate, again in particular the sodium salt.

In cases it is preferred for the alky! sulph(on)atc to be an alkyl sulphate rather than an alkyl suiphonate.

An alkyl sulphate or suiphonate may be used in the form of a salt with any suitable, preferably pharmaceutically acceptable, cation. Examples include metal cations (in particular alkali metals such as lithium, sodium or potassium and alkaline earth metals such as calcium and magnesium); and ammonium ions. Particularly preferred metal cations are sodium, potassium and magnesium, in particular sodium. Ammonium ions may be substituted ammonium ions, for example alkyl-or alkanolyl-substituted ammonium ions such as methyl-, dimethyl-, trimethyl-, tetramethyl-, ethyl-, diethyl or triethylanimonium ions or other substituted (typically quaternary) ammonium ions such as dimethyl piperidinium cations, or simply NH4, of which the latter may be preferred. A mixture of two or more different cations may be present.

An alkyl sulphate or sulphonate may be used in the form of a derivative. Such a derivative -which is suitably pharmaceutically acceptable may be a free acid (for example an alkyl sulphonic acid) from which the sulphate or sulphonate can be derived. Preferably, however, the alkyl sulph(on)ate is present in the form of the sulph(on)ate alone.

A formulation according to the invention may contain a mixture of two or more different alkyl sulphates or sulphonates. It may contain a mixture of two or more stereoisomers of an alkyl sulph(on)ate having a certain number of carbon atoms in its alkyl chain.

The concentration of an alkyl sulph(on)ate (i) in a formulation according to the invention might suitably be 0.05 % w/v or greater, for example 0.1 or 0.5 or I or 2 % w/v or greater. Its concentration might be up to 20 % w/v, preferably up to 15 or 10 % w/v, more preferably up to 5 % w/v, such as from 0.05 to 10 % w/v or from 0.05 to 5 (0 w/v or from 0.1 or 0.5 or I to 5 (0 w/v. In cases, for instance when the alkyl sulphate or sulphonate is for use in the disinfection of a tissue surface such as the skin, its concentration in the formulation may be for example from 1 to 20 % w/v. in cases, for instance when the alkyl sulphate or suiphonate is for use in the treatment of a skin or skin structure condition such as acne, its concentration in the formulation may be for example 1.2 or 1.5 or 2 or 2.5 or 3 % w/v or greater.

The anti-acne active (1) The anti-acne active U) is a diterpene. It may for example be a diterpene antioxidant.

II may be a tricyclic diterpene. It may for example be selected from carnosic acid, totarol, carnosol, 12-0-methyl carnosic acid, and mixtures thereof. In particular it may be either carnosic acid or totarol, more particularly carnosic acid.

Carnosic acid ((4aR, I OaS)-5,6-dihydroxy-7-isopropyl-1,1 -dimethyl-2,3,4,9, 10,1 Oa-hexahydrophenanthrene-4a-carboxylic acid; CAS #: 3650-09-7) is known for use as an anti-acne agent (see Weckesser 5, Engel K, Simon-Haarhaus B, Wittmer A, Pelz K, Schempp CM, "Screening of plant extracts for antimicrobial activity against bacteria and yeasts with dermatological relevance", Phytornedicine 2007; 14: 508-16).

Totarol (I 4-isopropylpodocarpa-8, 11,1 3-trien-I 3-ol; 4b,5,6,7,8,8a,9, 1 0-octahydro- 4b,8,8-trimethyl-1 -(1 -methylethyl)-2-phenanthrcnol) is a related compound (CAS #: 511-15-9) which is also used as an anti-acne active. Totarol is known to be an antibacterial agent with potent effects on Gram-positive organisms, including Streptococcus inutans, Bacillus subtilis, S. aureus and Propionibacteriuin acnes (see Kubo I, Muroi H, Himejima M,JNat Prod 1992; 55: 1436-1440). The topical use of totarol as an antibacterial agent is described in JP-2700071-B2. JP-131 1019 also describes its use as an antibacterial agent against acne and periodontal conditions. See also Nixon D, "The use of totarol to treat acne in an adolescent: A case study", New Zealand Family Physician 2006; 33: 253-255.

The structural formulae for carnosic acid and totarol are shown below.

)X..ir (arnosic acid Jj [ i:r.' /\ Iotar& Carnosic acid 12-methyl ether is also known as an anti-acne agent and as an anti-inflammatory agent (see WO-2008/06 1724). Carnosol, which is the naturally occurring oxidative by-product of carnosic acid, is also mentioned as an anti-acne agent by Weckesser et al (supra).

In a formulation according to the invention, carnosic acid may be used in the form of a derivative such as in particular a salt. A camosate salt may be for example a metal salt or ammonium salt. Suitable metal salts include the alkali metal salts (for example the sodium and potassium salts, in particular the former). Other carnosic acid derivatives include carnosic acid esters, in particular alkyl esters, more particularly C1-C20 or C1-Cio or C1-C6 alkyl esters and yet more particularly methyl esters such as 12-0-methyl carnosic acid.

Camosic acid may be used in the form of its racemate, or of pure (4aR,lOaS)-camosic acid or pure (4 S, 10 R)-camosic acid or any mixture thereof. It may be used in the form of any of its diastercoisomers or any mixture of such isomers.

Similarly, the 12-0-methyl ether of carnosic acid may be used in the form of its racemate, or of pure (4aR,lOaS)-carnosic acid 12-methyl ether or pure (4aS, I OaR)-carnosic acid 12-methyl ether or any mixture thereof. It may be used in the form of any of its diastereoisomers or any mixture of such isomers.

In an embodiment of the invention, carnosic acid is present in the form of the free acid, although dependent on the pH of the formulation the acid may be present in dissociated form, typically as camosate anions and protons.

Carnosic acid (or any derivative thereof used in a formulation according to the invention) may be either naturally or synthetically derived. It may for example be obtained from a natural source such as rosemary (Rosnzarinus officinalis); it may be used in the form of a rosemary extract. A suitable rosemary extract for use in the present invention can be obtained by grinding the dried leaves of Rosmarinus qi/Icinalis. The thus manufactured rosemary extract preferably contains> 35 % w!w of carnosic acid, preferably > 40 % w/w of camosic acid, preferably> 50 % w/w of carnosic acid, based on the total weight of the rosemary extract.

In a formulation according to the invention, camosol may be used in the form of its racemate, or of pure (4 R,9S,10 5)-carnosol or pure (4 S,9R,l0 R)-camosol or any mixture thereof. lt may be used in the form of any of its diastereoisomers or any mixture of such isomers.

Totarol may also be used in the form of its racemate, or of pure (4bS,8a5)-totarol ((+)-totarol, trans-totarol) or pure (4bR,8aR)-totarol or any mixture thereof. It may be used in the form of any of its diastereoisomers or any mixture of such isomers.

Totarol may be used in the form of a derivative. Suitable pharmaceutically acceptable derivatives of totarol include salts and esters. Salts of totarol include for example those formed with pharmaceutically acceptable organic acids such as acetic, lactic, maleic, citric, malic, ascorbic, succinic, benzoic, methenesulphonic, toluenesulphonic or pamoic acids, as well as polymeric acids such as tannic acid or carboxymethyl cellulose. Derivatives of totarol also include salts with inorganic acids such as hydrohalic acids (eg hydrochloric acid), sulphuric acid and phosphoric acid. Examples of pharmaceutically acceptable totarol esters include C2-C6 alkyl esters such as methyl esters and ethyl esters.

Totarol (or any derivative thereof used in a formulation according to the invention) may be either naturally or synthetically derived. It may for example be obtained from a natural source such as the bark of Podocarpus nagi and related trees.

A formulation according to the invention may contain a mixture of two or more diterpenes, for example of the type described above.

The concentration of a diterpene (j) in a formulation according to the invention might suitably be 0.01 % w/v or greater, preferably 0.05 or 0.1 or 0.5 % w/v or greater. Its concentration might be up to 20 % w/v, preferably up to 15 or 10 or 5 % wlv, such as fromO.1 to5%w/v.

The concentration of carnosic acid in a formulation according to the invention might suitably be 0.01 % w/v or greater, preferably 0.05 or 0.1 or 0.5 % w/v or greater. Its concentration might be up to 10 % w/v, preferably up to 5 % w/v, such as from 0.1 to 5 IS %w/v.

The concentration of totarol in a formulation according to the invention might suitably be 0.01 % w/v or greater, preferably 0.05 or 0.1 or 0.5 % w/v or greater. Its concentration might be up to 20 % w/v, preferably up to 15 or 10 or 5 % w/v, such as fromO.1 to5%w/v.

The anti-acne active k) The anti-acne active (k) is selected from nicotinic acid, alkyl nicotinates and nicotinamide. It may in particular be nicotinamide.

Nicotinamide (CAS #: 98-92-0), also known as niacinamide, nicotinic acid amide or pyridine-3-carboxamide, is the water soluble amide of vitamin B3 (niacin). Its anti-inflammatory properties in skin diseases are well recognised and it is known for use as an anti-acne agent (see Shalita AR, Smith JG, Parish LC, Sofman MS, Chalker DK, "Topical nicotinamide compared with clindamycin gel in the treatment of inflammatory acne vulgaris", Int.J Dermatol 1995; 34: 434-7). It exhibits multiple modes of action including but not limited to antioxidant effects and stabilisation of epidermal barrier function (Otte N, Borelli C, Korting HC, "Nicotinamide -biologic actions of an emerging cosmetic ingredient", IntfGosnzetSci 2005; 27: 255-61 and Gehring W, "Nicotinic acid/niacinamide and the skin", I Cosmet Dermatol 2004; 3: 88-93).

US-4,505,896 discloses the use of nicotinic acid and nicotinamide to treat acne, whilst US-2005/0 169948 discloses the use of a combination of nicotinic acid and JO nicotinamide to treat acne either orally or topically. US-5,240,945 discloses the use of lower alkyl nicotinates against acne, and WO-1998/052927 describes the use of methyl nicotinate to treat acne.

In an alkyl nicotinate for use in the present invention, the alkyl group may be either straight chain or branched. It may be a lower alkyl group, for example a C1 to C6 alkyl group or a C1 to C5 or C1 to C4 or C1 to C3 alkyl group. It may in particular be a methyl group.

In a formulation according to the invention, nicotinamide may be used in the form of an isomer such as isonicotinamide (CAS #: 1453-82-3).

Nicotinamide, nicotinic acid or an alkyl nicotinate may be either naturally or synthetically derived. Nicotinamide may for example be obtained from a natural source such as a foodstuff.

A formulation according to the invention may contain a mixture of two or more compounds selected from nicotinic acid, alkyl nicotinates and nicotinamide.

The concentration of an anti-acne active (k) in a formulation according to the invention might suitably be suitably be 0.05 % w/v or greater, preferably 0.5 % w/v or greater.

Its concentration might be up to 10 % w/v, preferably up to 5 % w/v, such as from 1 to % w/v or from 2 to 4 % w/v.

In general an anti-acne active used in a formulation according to the invention may be present 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.

A formulation according to the present invention is preferably suitable for topical application to, and/or contact with, the skin, in particular human skin. The salicylanilide and the anti-acne active(s) are therefore preferably contained in a pharmaceutically acceptable vehicle which can safely be applied to, and/or contacted with, the skin. The formulation is ideally suitable for topical application to human skin.

A formulation which is "suitable for" topical application may also be adapted for topical application.

Suitable vehicles for topical formulations will be well known to those skilled in the art of preparing topical skin care or pharmaceutical preparations. The vehicle 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 or drops. The salicylanilide and the anti-acne active(s) may each independently be present in the form of a solution or suspension, the term 2() "suspension" including emulsions, micellar systems and other multi-phase dispersions.

The formulation may in general, however, be delivered by any appropriate route, whether local or systemic. it may for example be delivered orally, for instance in the form of a tablet, capsule, powder, granules, solution or suspension. in this case the formulation should be suitable andlor adapted for oral ingestion. Again suitable vehicles for use in such formulations will be well lmown to those skilled in the art of preparing pharmaceutical preparations for oral delivery.

Alternatively the formulation may be delivered transdermally, for instance via a skin patch.

Where the formulation contains an antibiotic selected from macrolides (especially erythromycin), folate pathway inhibitors (especially trimethoprim) and tetracyclines (especially tetracycline itself), it may be better delivered topically.

Any or all of the salicylanilide and the anti-acne active(s) may, whether separately or together, be carried in or on a delivery vehicle which is suitable for targeting or controlling their 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 salicylanilide is suitably present as an active (ie, antibacterially active) agent. It 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 and/or against one or more micro-organisms associated with acne)). The anti-acne actives (a) to (k) are suitably present as anti-acne agents, and/or as antibacterial agents (in particular against one or more micro-organisms associated with acne).

In an embodiment of the invention, it may be preferred for the salicylanilide not to be for use as a general skin disinfectant, such as in a hand or face wash or other general cleansing preparation. It may be preferred for the salicylanilide not to be for use as an anti- inflammatory agent.

Antibacterial activity encompasses activity against both Gram-positive and Gram-negative bacteria, in particular propionibacteria. 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 andlor suppress bioflim formation by the relevant organism. The biofilm may in particular be formed by P. acnes.

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

Suppression of biofilm 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 bioflim. It thus embraces total or partial impairment, including reducing the amount and/or strength of biofllm 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 biofllm formed by the organism.

A formulation according to the invention is suitably active against one or more bacteria associated with acne, in particular propionibacteria such as P. acnes and in some instances P. granulosurn.

The formulation is preferably active against bacteria, in particular propionibacteria, which are wholly or partially resistant to one or more antibiotics, for instance those which arc in common clinical use. For example it is ideally active against one or more macro lide-l incosamide-streptogramin (M LS) 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(s), incubating thc 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 the halogenated salicylanilide has a minimum inhibitory concentration (M1C), at least against propionibacteria, of 250.tg/ml or less, more preferably 100 or j.g/ml or less, most preferably 25 or 1 5 or 10 or 5 or in cases 2 or even I or 0.5 pg!ml or less. Its corresponding minimum biocidal concentration (MBC) is preferably 250 1g/ml or less, more preferably 100 or 50 ig/ml or less, most preferably 25 or 15 or or 5 or in cases 2 or even I or 0.5 ig/ml or less. Suitably the ratio of its MIC to its MBCisfrom 0.01 to I orfrom 0.125 to l,ideally from 0.5 to I. Morepreferablythe salicylanilide also exhibits such characteristics in the presence of at least one of, preferably both of, lipid and salt (sodium chloride) -these are species which can be present at the surface of the skin and hence performance in this context can be indicative of suitability for use in topical skin treatment formulations.

is 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 (which includes veterinary but is preferably human) use, andlor for cosmetic or other non-medical care purposes (for example, for general hygiene or skin cleansing or for improving the appearance of the skin).

The vehicle in which the salicylanilide and the anti-acne active(s) are contained may be any vehicle or mixture of vehicles which is suitable for topical application; the type chosen will depend on the intended mode and site of application. Many such vehicles are known to those skilled in the art and are readily available commercially. In the context of formulations for topical application to the skin, examples may for instance be found in Williams' "Transdermal and Topical Drug Delivery", Pharmaceutical Press, 2003, and other similar reference books. Sec also Date, A. A. et al, Skin Pharinacol. Phvsiol., 2006, 19(1): 2-16 for a review of topical drug delivery strategies.

As described above, the vehicle may be such as to target a desired site and/or time of delivery of the formulation. It may for instance target the formulation to the skin or hair follicles. It may delay or otherwise control release of the formulation over a particular time period. Either or both of the salicylanilide and the anti-acne active(s) may be microencapsulated, for instance in liposomes -particularly suitable liposomes, for topical application to the skin, arc those made from stratum corneum lipids, eg ceramides, fatty acids or cholesterol.

In some cases a polar vehicle may be preferred. Where the formulation is intended for use on the skin, the vehicle may be primarily non-aqueous, although in the case of an anti-acne treatment an aqueous vehicle may be used. The vehicle is suitably volatile.

In cases it may be alcohol-based or silicon-based.

By way of example, a lotion or gel formulation according to the invention, in particular one intended for application to the skin, may contain a mixture of water, an alcohol such as ethanol or phenoxyethanol and a glycol such as propylene glycol.

Generally speaking a formulation according to the invention may contain standard excipients and other additives known for use in pharmaceutical formulations. For example, where the formulation is intended for topical application to the skin, examples of suitable excipients and additives include emollients, perfumes, antioxidants, preservatives, stabilisers, gelling agents and surfactants; others may be found in Williams' "Transdermal and Topical Drug Delivery", supra. For the treatment of acne, however, it may be preferred for the formulation not to contain an emollient.

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 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; 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 salicylanilide and the anti-acne active(s) (a) to (k) to be the only active agents in the formulation, or at least to be the only antibacterially active agents and/or the only anti-acne active agents.

The formulation may be in the form of a skin wash (for example a hand wash). It may be carried in or on a cloth, wipe or brush; in such cases an item may be impregnated with, or coated with, the formulation.

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 or hair care preparation (for example a skin cleanser, toner, astringent, scrub or moisturiser, or a shampoo or conditioner), a cleansing preparation (for example a facial wash), a pharmaceutical (which includes veterinary) preparation, a cosmeceutical preparation, a toiletry product (for instance a bath or shower additive, a body spray or a soap), or a laundry or other fabric treatment product. The formulation may be, or be incorporated into, a leave-on or a wash-off skin treatment product.

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

A formulation according to the invention may be marketed with an indication that it has antibacterial (such as anti-propionibacterial) or anti-acne activity, or enhanced antibacterial or anti-acne activity, in particular 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 antibacterial or 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 halogenated salicylanilide and the anti-acne active(s) (a) to (k), in particular to the presence of the salicylanilide.

The antibacterial or 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 salicylanilide andlor the anti-acne active(s), for example so as to confirm that either or both contribute to the antibacterial or 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. Thus according to a third aspect, the present invention provides a kit for preparing an antibacterial or anti-acne formulation, such as a formulation according to the first aspect, the kit comprising a source of a halogenated salicylanilide, and source(s) of the relevant anti-acne active(s) (a) to (k) as defined above. The anti-acne act ives, if there arc two or more, 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.

A fourth aspect of the invention provides a method for preparing an antibacterial or anti-acne formulation, which method involves mixing together a halogenated salicylanilide and one or more anti-acne actives selected from (a) to (k) above.

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 a halogenated salicylanilide together with one or more anti-acne actives selected from (a) to (k) above, 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) propionibacterial activity. The condition may be a skin or skin structure condition, in particular acne.

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 either a human or animal but in particular a human. it may involve complete or partial eradication of the condition, removal or amelioration of associated symptoms, arresting subsequent development of the condition, andlor prevention of, or reduction of risk of, subsequent occurrence of the condition. It will typically involve use of the invented formulation as a bactericidal or anti-acne combination.

Treatment may involve use of the formulation to treat a condition which is caused, transmitted and/or exacerbated by (in particular caused or transmitted by) propionibacterial biofilm formation.

In general the treatment may be administered orally, transdermally or topically. It is preferably administered topically.

in an embodiment of the fifth aspect of the invention, the formulation is for use against one or more bacteria selected from P. acnes and P. granulosum.

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 3g 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 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.

Instead or in addition, the invented formulation may be for use against an opportunistic infection which is caused, transmitted and/or exacerbated by (in particular caused by) propionibacteria, for instance an infection associated with an indwelling surgical device (a prosthetic joint, for example). It may be for use in treating an infected wound, burn or ulcer. It may be for use against any other infection or condition which involves or can involve propionibacteria, for example an eye infection such as endophthalmitis. In cases it may be used in the treatment of body odour, in particular in the axilla and/or feet, since this is a condition in which propionibacteria can sometimes be implicated.

According to the fifth aspect of the invention, the formulation of salicylanilide and 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 a halogenated salicylanilide, with one or more anti-acne actives selected from (a) to (k) as defined above, in the treatment of a propionibacterial condition or more particularly acne, the components being administered either simultaneously or sequentially.

According to a sixth aspect, the invention provides the use of a halogenated salicylanilide, together with one or more anti-acne actives selected from (a) to (k) as defined above, in the manufacture of a medicament (typically a formulation) for 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) propionibacterial activity. Again the condition may be a skin or skin structure condition, in particular acne. The salicylanilide and the anti-acne active(s) will typically be used as an antibacterial and/or anti-acne combination in the manufacture of the medicament.

The invention further provides, according to a seventh aspect, the usc together of a halogenated salicylanilide and one or more anti- acne actives selected from (a) to (k) as defined above, as a combined antibacterial or anti-acne agent, in the manufacture of an ant i-propionibacterial or 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 formulation containing a halogenated salicylanilide and one or more anti-acne actives selected from (a) to (k) 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 biofllm formation by the bacterium, as described above.

The area or surface to which the salicylanilide and the anti-acne active(s) are applied will typically be a surface such as human or animal tissue, in particular the skin, typically of a living human or animal. In this case the invented combination may be applied for therapeutic purposes or for non-therapeutic (eg purely cosmetic) purposes.

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 a condition which is caused by, transmitted by and/or exacerbated by (in particular either caused or transmitted by) propionibacterial activity, the method involving administering to the patient a therapeutically (which term includes prophylactically) effective amount of an antibacterial or anti-acne formulation containing a halogenated salicylanilide together with one or more anti-acne actives selected from (a) to (k) as defined above. The formulation is suitably administered in an antibacterially effective amount. it may be administered by any appropriate route, preferably topically.

Again the condition may be a skin or skin structure condition, in particular acne.

In accordance with the eighth aspect of the invention, the formulation is suitably administered to a human patient. The patient is suitably suffering from the relevant condition. 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 a halogenated salicylanilide in an antibacterial or anti-acne formulation, in combination with one or more anti-acne actives selected from (a) to (k) as defined above, for the purpose of increasing the antibacterial and/or anti-acne activity of the formulation and/or of reducing the amount of the anti-acne active(s) (a) to (k) in the formulation without or without undue loss of antibacterial and/or anti-acne activity.

An increase in antibacterial or 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 salicylanilide. Ideally the increase is as compared to the sum of the activities of the anti-acne active(s) and the salicylanilide 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 (k) 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 salicylanilide 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 (k), without or without undue loss of antibacterial or anti-acne activity.

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

A tenth aspect of the invention provides the use of one or more anti-acne actives selected from (a) to (k) as defined above, in an antibacterial or anti-acne formulation, in combination with a halogenated salicylanilide, for the purpose of increasing the antibacterial and/or anti-acne activity of the formulation and/or of reducing the amount of the salicylanilide in the formulation without or without undue loss of antibacterial and/or anti-acne activity. The above comments regarding the ninth aspect of the invention apply mutatis inutandis to the tenth aspect.

An eleventh aspect of the invention provides an antibacterial or anti-acne formulation containing a halogenated salicylanilide, together with one or more additional anti-acne actives selected from the group consisting of the actives (a) to (k) identified above; bis-quinolinium salts, in particular dequalinium salts such as dequalinium chloride or dequalinium acetate; retinoids and retinoid-like compounds such as adapalene, isotretinoin, tretinoin and tazarotene; salicylic acid and derivatives (in particular salts) thereof; 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; plant extracts such as of Hamamelis virgin iana (witch hazel); di-carboxylic acids such as azelaic acid; thiosalicylic acid; urea; allantoin; biotin; carbocysteine; th iazo lidinedio nes and other PPAR (peroxiso mc proliferator-activated receptor) gamma antagonists; and mixtures thereof.

Such combinations are also expected to exhibit anti-propionibacterial and anti-acne activity, due to the presence of the salicylanilide (which the present inventors have shown to be active against propionibacteria) and the additional anti-acne active.

A twelfth aspect of the invention provides a formulation according to the eleventh 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) propionibacterial activity. The condition may be a skin or skin structure condition, in particular acne.

A thirteenth aspect provides the use of a formulation according to the eleventh 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) propionibacterial activity. The condition may in particular be acne. The halogenated salicylanilide and the additional anti-acne active(s) will typically be used as an antibacterial and/or anti-acne combination in the manufacture of the mcdi cament.

A fourteenth 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 eleventh aspect of the invention.

A fifteenth 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) propionibacterial activity, the method involving administering to the patient a therapeutically (which term includes prophylactically) effective amount of a formulation according to the eleventh aspect. Again the propionibacterial condition may in particular be acne. The formulation is suitably administered in an antibacterially effective amount. It 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-propionibacterial and anti-acne activity of formulations according to the invention.

Test micro-organisms The principal test micro-organism used was P. 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 arc also opportunistic pathogens in compromised hosts. Thus, activity observed against these micro-organisms is expected to be a good predictor of activity against acne.

Other propionibacterial strains were also tested, as described in Example 3 below.

These included certain antibiotic-resistant propionibacteria, such as the two P. acnes strains designated PRP-002 and PRP-O1O which are resistant respectively to macrolides-lincosamides-streptogramins (MLS) and tetracycline and to macrolides-lincosamides-streptogramins-ketolides (MLSK) -in other words, PRP-002 is resistant to erythromycin, clindamycin and tetracycline and PRP-010 to crythromycin, clindamycin and tetracycline.

In addition, a number of strains of P. granulosum, another bacterium involved in acne, were also tested in Example 3.

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 organisms.

(a,) Minimu,n 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 i1 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 p1 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.

The ratio of MIC to MBC should ideally be as close to I as possible. This facilitates selection of the lowest possible effective concentration of a test compound with a reduced risk of selecting a sub-lethal concentration which could promote resistance or allow the target microbial population to recover.

(c) Agar dilution MIC assay This is a standard international method for quantitatively assessing the antimicrobial activity of a compound in a solid medium. The test compound was prepared to 4�x the highest concentration required (eg 10 mg/mi for a final concentration of 250 g'mI) and a series of doubling dilutions were performed in a suitable solvent. A set amount of these antimicrobial stock solutions was then added to molten agar medium (ca 55°C), mixed thoroughly, poured into sterile Petri dishes and allowed to cool/set.

The culture medium was as described above.

A Multipoint"TM Inoculator (AQS Manufacturing Ltd, UK) was used to inoculate the plates by spotting the inocula onto the surface of the agar, delivering approximately 1 to 2 pi per spot (yielding I 0 CFU (colony forming units) per spot).

The plate(s) were then incubated under the conditions described above, following which they were examined visually for signs of bacterial growth. The MIC value was ascertained when there was a marked reduction in, or total loss of, growth on the test plate at the lowest concentration as compared to that of the growth on the control plate.

The assays were conducted in triplicate and included a positive control (culture medium, diluting solvent and inoculum).

(d) Disc d?jfusion 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 ProtoCOL'I'M 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) Svner' disc djfth,sion assay (SDDA) This is a variation on the DDA method, in which two compounds are tested together for their combined antimicrobial activity.

Two test compounds A and B were placed on a single paper disc and the above described DDA procedure repeated. The diameter of the zone of inhibition was taken as an indication of the antimicrobial activity of the A+B combination.

An increase in diameter of the zone of inhibition, compared to the greater of the zone diameters for the two compounds individually, was taken to indicate potential antimicrobial synergy. In practical terms, an increase of greater than 5 mm could be treated as significant, while zone diameter changes of �4.99 mm were not treated as significant.

(/) Supplemented disc diffusion assays An (S)DDA test may be carried out using an agar gel supplemented with salt andlor lipid to simulate two of the major components present in human skin and to assess whether these substances 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 2 below was sodium chloride (100 mM). Those used in Examples 4 and 5 were lipid (triolein at 1% v/v) and sodium chloride (100 mM).

Example 1 -activity against P. acnes The following experiments all used P. acnes NCTC 737 as the test organism.

(S)DDA assays, as described above, were carried out using combinations of test compounds according to the present invention. Each disc was loaded with the halogenated salicylanilide niclosamide, dissolved in DMSO, and also with an anti-acne active selected from those shown in Table I below. The table also shows the solvents in which the actives were dissolved, and the quantities in which they were loaded onto the discs.

Table 1

Active compound Source Solvent Quantity loaded q'pg) Benzoyl peroxide Sigma-Aldrich EtOH 200 t-butyl-p-hydroquinonc EtOH 200 (TBHQ) Sigma-Aldrich Clindamycin HC1 Sigma-Aldrich 20 1 Erythromycin Sigma-Aldrich EtOH 1 Trimethoprim Sigma-Aldrich DMSO 50 Tetracycline HCI Sigma-Aldrich 20 Chioramphenicol Sigma-Aldrich EtOH 10 Dioctyl sulphosuccinate EtOH 200 sodium salt (DOSS) Sigma-Aldrich Zinc pyrithionc Sigma-Aldrich DMSO 200 Bismuth subsalicylate Sigma-Aldrich DMSO 200 AO 2246 Sigma-Aldrich DMSO 200 Copper usnate Just For Today Ltd DMSO 200 Sodium n-tctradecyl sulphate Sigma-Aldrich dH2O 200 Carnosic acid Sigma-Aldrich EtOH 200 Nicotinarnide Sigma-Aldrich dH20 200 Fusidic acid Oxoid DMSO 100 For all experiments, 100 ig of the niclosamide was loaded onto each disc. The experiments were conducted in triplicate.

The results are shown in Table 2 below; all are collated from a number of experiments.

Table 2

Test compound SDJ)A with SDDA DDA SDDA area niclosamide change change (%) (mm) (mm) (mm)

_____________________ I I I

Niclosamide 49.73 (�2.07) 48.29(� I ____________________________ 0.99)' ___________ ________ ___________ AO 2246 10.49 49.22 -0.52 -2.08 _____________________________ (�0.18) (�0.54) ________ ____________ Benzoyl peroxide 21.49 50.57 0.83 3.37 _____________________________ (�0.62) (� 1.00) ________ ____________ Bismuth subsalicylate 28.14 50.15 0.42 1.68 ___________________________ (�2.42) (�1.43) _______ ___________ Carnosic acid 41.22 46.72 -3.01 -11.74 _____________________________ (�0.78) (�0.93) ________ ____________ Chloramphenicol 53.58 56.79 3.22 12.38 _____________________________ (�1.65) (�0.48) ________ ____________ Clindamycin HCI 34.26 49.22 -0.52 -2.08 _____________________________ (�0.31) (�0.82) ________ ____________ Copper usnate 64.58 60.95 -3.63 -10.94 ___________________________ (�1.26) (�1.77) _______ ___________ DOSS 51.08 60.12 9.03 38.49 _____________________________ (�0.31) (�0.31) ________ ____________ Erythromycin 22.22 49.22 -0.52 -2.08 _______________________________ (�0.72) (�0.82) _________ ____________ Nicotinamide 0.00 47.14 -2.60 -10.17 ________________________________ (�0.00) (�0.36) _________ _____________ Sodium n-tetradccyl sulphate 37. 07 58.35 8.62 37.66 ____________________________ (�1.65) (�1.09) ________ ___________ TBHQ 13.81 52.64 2.91 12.03 _____________________________ (�0.48) (�1.12) ________ ____________ Tetracycline HCI 29.38 49.01 -0.73 -2.90 _____________________________ (�1.18) (�0.90) ________ ____________ Trimethoprim 44.85 49.32 -0.42 -1.66 _____________________________ (�0.82) (�1.18) ________ ____________ Zinc pyrithione 61.36 82.75 21.39 81.86 ____________________________ (�1.12) (�2.50) ________ ___________ Fusidic acid 40.57 52.51 4.22 18.24 ____________________________ (�1.17) (�0.31) ________ ___________ For the fusidic acid experiments It can be seen from Table 2 that the invented combination of a halogenatcd salicylanilide and an anti-acne active selected from the list (a) to (k) above is highly active as an antibacterial agent against P. acnes NCTC 737. This indicates the likely activity of such combinations as anti-acne agents, the propionibacteria being implicated in acne.

For certain of the pairs tested, including those containing DOSS, zinc pyrithionc and sodium n-tetradccyl sulphate, the DDA zone diameter was greater than that for either of the individual actives alone. This indicates a potentially synergistic antibacterial interaction between the relevant actives, which again could be of value in preparing anti- acne formulations.

Example 2 -activity against P. acncs -salicvianilide alone This example illustrates the anti-propionibacterial activity (and hence the anti-acne activity) of halogenated salicylanilides. Again P. acnes NCTC 737 was used as the test organism.

MIC, MBC and DDA assays, as described above, were carried out using as the test compounds the halogenated salicylanilides closantel, niclosamide, rafoxanide and oxyclozanide (all cx Sigma Aldrich, UK). The solvents used were DMSO for the ClosanteP'M 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 3 below. All tests were conducted in triplicate.

Table 3

Test compound MIC MBC DDA DDA + _____________________ 41g/ml) 4ig/ml) (mm) salt (mm) 29.79 27.92 ClosanteP'M 0.12 0.49 (�0.18) (� 1. 1) 43.44 41.98 Niclosamide 0.03 0.98 (� 1.36) (�0.98) Test compound MIC MBC DDA DDA + ______________________ fig/mi) flig/m (mm) salt (mm) 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 3 that all four compounds are highly active as antibacterial agents against P. acnes NCTC 737. This indicates their likely utility as anti-acne agents. Their high level of activity appears to be maintained in the presence of salt.

Example 3 -activity against other ProDionibacterium spy -salicvlanilide alone The activities (MIC by agar dilution) of ClosantelTM and niclosamide were determined against a panel of different propionibacterium strains. DMSO was used as the solvent.

All tests were performed in triplicate.

The results are shown in Table 4 (ClosantelTM MICs) and Table 5 (niclosamide MlCs) below; the resistance phenotype for each of the test species/strains is also indicated.

Table 4

Test organism Resistance MIC fig/mi,) ______________________________________ phenotype _____________ Propionthacierium acnes NCTC 737 None 0.12 P. granulosum NCTC 11865 None 0.49 P. acnes PRPOO2 Tet/MLS 0.12 P. acnes PRPOO3 Tet 0.12 P. acnes PRPOO4 Tet 0.12 P. granulosum PRP-005 MLSK 0.25 P. granulosum PPR-006 MLS 0.49 P. acnes PPR-007 Clin 0.12 P. acnes PRP-008 Cliii 0.12 Test organism Resistance MIC (.Lg/mI) _______________________________________ phenotype _____________ P. acnes PRP-010 MLSK 0.12 P. acnes PRP-017 MLS 0.12 P. granulasum PRP-019 MLSK 0.25 P. granulosurn PRP-021 MLS 0.49 P. acnes PRP-023 MLSK 0.12 P. acnes PRP-026 MLS 0.12 P. acnes PRP039 Tet/MLS 0.12 P. granulosum PRP-043 MLS 0.25 P. granulosurn PRP-044 MLS 0.49 P. acnes PRP046 None 0.12 P. acnes PRP-053 Tct/MLS 0.12 P. granulosum PRP055 None 0.12 P. acne. PRP-059 MLS 0.12 P. acnes PRP-068 Ery 0.12 P. acnes PRP-101 Tct/MLS 0.12 P. acnes PRP-102 TetJMLS 0.12 [Abbreviations: National Collection of Type Cultures (NCTC), Propionibacterium Panel Number (PRP), Tetracycline (Tet), Erythromycin (Ery), Clindamycin (Clin), Macrolide-Lincosarnide-Streptogramin (MLS), M acrolide-Lincosamide-Streptogramin-Ketolide (MLSK).]

Table 5

Test organism Resistance MIC (j1g/m ______________________________________ phenotype _____________ Propionthacterium acnes NCTC 737 None 0.03 P. granulosum NCTC 11865 None 0.06 P. acnes PRP-002 Tet/MLS 0.03 Test organism Resistance MIC 4tg/m _____________________________________ phenotype _____________ P. acnes PRPOO3 Tet 0.03 P. aenes PRPOO4 Tet 0.03 P. granulosum PRP-005 MLSK 0.06 P. granulosum PPR-006 MLS 0.06 P. acnes PPROO7 Clin 0.03 P. acnes PRPOO8 Clin 0.03 P. acnes PRP-010 MLSK 0.03 P. acnes PRP-017 MLS 0.03 P. granulosum PRP-0 19 MLSK 0.06 P. granulosum PRP-02 I MLS 0.06 P. acnes PRP-023 MLSK 0.03 P. acnes PRP-026 MLS 0.03 P. acnes PRP039 Tet/MLS 0.03 P. granulosum PRP-043 MLS 0.06 P. granulosuni PRP-044 MLS 0.06 P. acnes PRP046 None 0.03 P. acnes PRP-053 Tet/MLS 0.03 P. granulosuni PRP055 None 0.03 P. acnes PRP-059 MLS 0.03 P. acnes PRP068 Ery 0.03 P. acnes PRP-101 Tct/MLS 0.03 P. aenes PRP-102 Tet/MLS 0.03 [Abbreviations: National Collection of Type Cultures (NCTC), Propionibacterium Panel Number (PRP), Tetracycline (Tet), Erythromycin (Ery), Clindamycin (Clin), Macrolide-Lincosamide-Strcptogramin (MLS), Macrolide-Lincosamide-Streptogramin-Ketolide (M LSK).] Both ClosantelTM and niclosamide can be seen to possess an excellent level of activity against the wide range of propionibacterial strains tested. This further indicates the utility of such halogenated salicylanilides either to treat or to prevent infections associated with such bacteria, in particular acne. The results are likely to be of particular clinical value for the antibiotic resistant test strains.

Example 4 -activity against P. acnes -aiki'l sulphate alone This example illustrates the anti-propionibacterial activity (and hence the anti-acne activity) of alkyl sulphates. Again P. acnes NCTC 737 was used as the test organism.

MIC, MBC and DDA assays, as described above, were carried out using as the test compound sodium n-tctradecyl sulphate (STS, ex Sigma Aldrich, UK), dissolved in distilled water. All the experiments were conducted in triplicate.

For the DDA experiments, 200 pg of the test compound was loaded onto each disc.

The results are shown in Table 6 below; all are collated from a number of experiments.

Table 6

MIC (1g/ml) 3.9 MBC (ig/rnl) 3.9 MIC/MBC ratio I DDA (mm) 29.87 (� 1.42) DDA + salt (mm) 31.62 (�0.47) DDA + lipid (mm) 33.67 (�0.99) it can be seen from Table 6 that the STS is highly active as an antibacterial agent against P. acnes NCTC 737. Furthermore, this activity is increased to some extent in the presence of salt and lipid, which are important constituents of the human skin environment. This indicates the likely activity of the compound as an anti-acne agent, the propionibacteria being implicated in acne.

Example 5 -activity against P. acncs -other alkvl suiphates Example 4 was repeated, using two other alkyl suiphates as the test compounds. The first was sodium lauryl sulphate (SLS, cx Sigma Aldrich, UK), dissolved in distilled water. The second was ammonium lauryl sulphate (ALS, cx Sigma Aldrich, UK), also dissolved in distilled water.

The MIC/MBC experiments were conducted in duplicate and the DDAs as single replicates.

For the DDA experiments, 200 tg of the test compound was loaded onto each disc.

The results are shown in Table 7 below; all are collated from a number of experiments.

Table 7

Test MIC MBC MI/MBC DDA JJDA + DDA + compound (pg/ml,) (pg/m ratio (mm) salt lipid ________ _____ _____ ______ _____ (mm) (mm) SLS 31.25 62.5 0.5 30.70 28.22 28.22 ALS 31.25 125 0.25 22.19 24.06 20.31 The Table 7 data show that other alkyl suiphates are also active against P. acnes NCTC 737, and are also therefore suitable candidates for use as anti-acne agents and for use against other conditions in which propionibacteria are implicated. The salt and lipid supplements do not appear to unduly reduce antibacterial activity in these tests.

Example 6 -topical anti-acne fhrmulations The results from Examples 1 to 5 show that a formulation according to the invention can be effective 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 a halogenated salicylanilide such as niclosamide with one or more additional anti-acne actives such as those tested in Example 1, in a suitable fluid vehicle and optionally together with conventional additives. Such vehicles and additives 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 eta!, "Site-specific drug delivery to pilosebaceous structures using polymeric mierospheres", Pharm Res 1993; 10: 1738-44; Mordon S eta!, "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 eta!, "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 for example take the form of a cream, lotion or in particular a gel.

The concentrations of the anti-acne active(s), and of the salicylanilide, 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 agents. Suitably, the formulation is administered topically to acne-affected skin.

Claims (40)

1. Claims I. An antibacterial or anti-acne formulation containing a halogenated salicylanilide, together with one or more anti-acne actives selected from the following: (a) diacyl peroxides and hydrogen peroxide; (b) alkyl-substituted benzo-and hydroquinones; (c) antibiotics; (d) dialkyl sulphosuccinates; (e) pyridine thiols; (0 bismuth salts; (g) bisphenols; (h) copper salts; (i) alkyl sulphates and suiphonates; (j) diterpenes; (k) nicotinic acid, alkyl nicotinates and nicotinamide; and mixtures thereof.
2. 2. A formulation according to claim I, which is suitable for topical application to human skin.
3. 3. A formulation according to claim I or claim 2, wherein the salicylanilide is substituted with one or more halogen atoms selected from chlorine and iodine atoms.
4. 4. A formulation according to claim 3, wherein the salicylanilide is a chlorinated salicylanilide.
5. 5. A formulation according to claim 4, wherein the salicylanilide is substituted
6. 6. A formulation according to any one of the preceding claims, wherein the salicylanilide is substituted with two or more iodine atoms.
7. 7. A formulation according to any one of the preceding claims, wherein the salicylanilide is selected from ClosantelTM, niclosamide, rafoxanide, oxyclozanide and mixtures thereof.
8. 8. A formulation according to claim 7, wherein the salicylanilide is selected from Closantel'I'M, niclosamide and mixtures thereof.
9. 9. A formulation according to any one of the preceding claims, wherein the salicylanilide is present at a concentration of 0.05 % w/v or greater.
10. 10. A formulation according to any one of the preceding claims, wherein the salicylanilide is present at a concentration of up to 5 % w/v.
11. I I. A formulation according to any one of the preceding claims, which contains a diacyl peroxide (a) which is benzoyl peroxide.
12. 12. A formulation according to any one of the preceding claims, which contains an alkyl-substituted benzo-or hydroquinone (b) which is TBHQ.
13. 13. A formulation according to any one of the preceding claims, which contains an antibiotic (c) which is selected from phenicols; folate pathway inhibitors; lincosamides; macrolides; tetracyclines; and mixtures thereof.
14. 14. A formulation according to claim 13, wherein the antibiotic (c) is selected from chloramphenico 1, tn methoprim, clindamycin, erythromycin, tetracycline, and mixtures thereof.
15. 15. A formulation according to any one of the preceding claims, which contains a dialkyl suiphosuccinate (d) which is a dioctyl suiphosuccinate.
16. 16. A formulation according to any one of the preceding claims, which contains a pyridinc thiol (e) which is a metal pyrithione.
17. 17. A formulation according to any one of the preceding claims, which contains a bismuth salt (f) which is selected from bismuth subsalicylate, bismuth 0 salicylate, bismuth subgallate, bismuth subcitrate, bismuth citrate, bismuth acetate, bismuth nitrate, bismuth subnitratc, and mixtures thereof.
18. 18. A formulation according to any one of the preceding claims, which contains a bisphenol (g) which is either Antioxidant 2246 or Antioxidant 425.
19. 19. A formulation according to any one of the preceding claims, which contains a copper salt (h) which is selected from copper sulphate, copper gluconate, copper salicylate, copper usnate, and mixtures thereof.
20. 20. A formulation according to any one of the preceding claims, which contains an alkyl sulphate (i) which is a tetradecyl sulphate.
21. 21. A formulation according to any one of the preceding claims, which contains a diterpene U) which is either camosic acid or totarol.
22. 22. A formulation according to any one of the preceding claims, which contains an anti-acne active (k) which is nicotinamide.
23. 23. 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 andlor 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.
24. 24. 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.
25. 25. 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.
26. 26. An antibacterial or anti-acne formulation which is substantially as herein described.
27. 27. A product containing an antibacterial or anti-acne formulation according to any one of the preceding claims.
28. 28. A kit for preparing an antibacterial or anti-acne formulation, the kit comprising a source of a halogenated salicylanilide, and source(s) of one or more anti-acne actives selected from (a) to (k) as defined in claim I, 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.
29. 29. A method for preparing an antibacterial or anti-acne formulation, which method involves mixing together a halogenated salicylanilide and one or more anti-acne actives selected from (a) to (k) as defined in claim 1.
30. 30. A formulation containing a halogenated salicylanilide and one or more anti-acne actives selected from (a) to (k) as defined in claim I, 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 propionibacterial activity.
31. 31. A formulation containing a halogenated salicylanilide and one or more anti-acne actives selected from (a) to (k) as defined in claim 1, for use according to claim 30, wherein the condition is acne.
32. 32. Use of a halogenated salicylanilide, together with one or more anti-acne actives selected from (a) to (k) as defined in claim 1, in the manufacture of a medicament for the treatment of a condition which is caused by, transmitted by and/or exacerbated by propionibacterial activity.
33. 33. Use according to claim 32, wherein the condition is acne.
34. 34. 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 halogenated salicylanilide and one or more anti-acne actives selected from (a) to (k) as defined in claim I.
35. 35. 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 andlor exacerbated by propionibacterial activity, the method involving administering to the patient a therapeutically (which term includes prophylactically) effective amount of a formulation containing a halogenated salicylanilide and one or more anti-acne actives selected from (a) to (k) as defined in claim 1.
36. 36. A method according to claim 35, wherein the condition is acne.
37. 37. Use of a halogenated salicylanilide in an antibacterial or anti-acne formulation, in combination with one or more anti-acne actives selected from (a) to (k) as defined in claim I, for the purpose of increasing the antibacterial or anti-acne activity of the formulation andlor of reducing the amount of the anti-acne active(s) (a) to (k) in the formulation without or without undue loss of antibacterial andlor anti-acne activity.
38. 38. An antibacterial or anti-acne formulation containing a halogenated salicylanilide, together with one or more additional anti- acne actives selected from the group consisting of the actives (a) to (k) as defined in claim 1; bis-quinolinium salts; retinoids and retinoid-like compounds; salicylic acid and derivatives (in particular salts) thereof cyproterone acetate; spironolactone; metformin; alpha-hydroxy acids; polyhydroxy acids; essential oils; plant extracts; di-carboxylic acids; thiosalicylic acid; urea; allantoin; biotin; carbocysteine; thiazolidinediones and other PPAR (peroxisome proliferator-activated receptor) gamma antagonists; and mixtures thereof.
39. 39. A formulation according to claim 38, 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 propionibacterial activity.
40. 40. 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 propionibacterial activity, the method involving administering to the patient a therapeutically (which term includes prophylactically) effective amount of a formulation according to claim 38.