WO2004073707A1

WO2004073707A1 - Topical composition containing alkyl gallate or alkyl hydroxybenzoate or phenol alkyloxy as agent against acne

Info

Publication number: WO2004073707A1
Application number: PCT/EP2003/014868
Authority: WO
Inventors: Alexander Gordon James
Original assignee: Unilever N.V.; Unilever Plc; Hindustan Lever Limited
Priority date: 2003-02-19
Filing date: 2003-12-19
Publication date: 2004-09-02
Also published as: AU2003298241A1

Abstract

Compounds of formula (I) wherein: R1, R2, R3 and R4 are the same or different and are selected from H, OH, and OCH3; R is alkyl containing from 5 to 20 carbon atoms; and X is -C(O)- or is absent; are useful in the treatment of acne and may be used in topical anti-acne compositions together with, optionally, a further anti-acne agent which is not a compound of formula (I) and a topically acceptable diluent or carrier.

Description

TOPICAL COMPOSITION CONTAINING ALKYL GALLATE OR ALKYL HYDROXYBENZOATE OR PHENOL ALKYLOXY AS AGENT AGAINST

ACNE

This invention relates to compositions for the treatment of acne, to methods of treating acne using the compositions and to the use of certain compounds in the treatment of acne .

Acne is a common inflammatory pilosebaceous disease characterized by comedones, papules, pustules, inflamed nodules, superficial pus-filled cysts, and in extreme cases, sinus formation and deep inflammation, sometimes associated with purulent sacs. For example, acne vulgaris is a polymorphic skin eruption characterised clinically by blackheads, white heads, papules, nodules, cysts and scars occurring particularly on areas of the skin rich in sebaceous glands, such as the face, forehead and back.

The pathogenesis of acne is complex. An interaction between hormones, keratinization, sebum, and bacteria somehow determines the course and severity of the disease. Acne begins at puberty when the increase of androgens causes an increase in the size and activity of the sebaceous glands. The earliest microscopic change is intrafollicular hyperkeratosis, which leads to restriction of the pilosebaceous follicle with consequent formation of the co edone composed of sebum, keratin, and microorganisms, particularly Propionibacteriu acnes . Lipases from P. acnes break down triglycerides in the sebum to form free fatty acids (FFA) , which may irritate the follicular wall. Retention of sebaceous secretions and dilation of the follicle may lead to cyst formation. Rupture of the follicle with release of the contents into the tissues induces an inflammatory reaction which heals with scarring in severe cases .

Acne tends to appear during puberty and to fade away again, usually spontaneously when growth has stopped. Only rarely does it recede before the age of 20 and occasionally it is still to be found at the age of 30 and beyond. The face, back, and shoulders are the predominant areas affected.

Acne can be treated by topical application of various lotions, salves, and the like or by, for example, localized treatment with sulphur, resorcinol, salicylic acid, benzoyl peroxide, vitamin A acids, antibiotics such as erythromycin, and the like.

DE-A-3805685 discloses the use of n-octyl gallate for the treatment of psoriasis.

US 3,833,732 describes the use of propyl gallate for the treatment of inflammation or edema.

WO 01/93825 teaches that n-octyl gallate and n-dodecyl gallate can be used in certain cosmetic compositions as antioxidants .

WO 99/22728 discloses that compounds that inhibit 5-alpha- reductase can be used to treat prostate cancer, breast cancer, obesity, skin disorders and baldness. n-Octyl gallate and n-dodecyl gallate were among the many compounds tested. There is no disclosure in the document that these specific compounds could be used in topical compositions for the treatment of acne.

There remains a need for compounds and compositions that are effective in the treatment of acne. Compounds that are capable of being delivered effectively to the target site and that have beneficial secondary effects are particularly- desirable.

According to the present invention, there is provided an anti-acne composition for topical application comprising:

from 0.01 % to 20 % by weight of a compound of formula (I)

(I)

wherein:

Rl, R2, R3 and R4 are the same or different and are selected from H, OH, and OCH₃;

R is alkyl containing from 5 to 20 carbon atoms; and

X is -C (O) - or is absent; optionally, a further anti-acne agent which is not a compound of formula (I)

and a topically acceptable diluent or carrier,

provided that when Rl and R2 are both OH and R3 and R4 are both H, the composition further comprises from 0.1 % to 20 % by weight of the further anti-acne agent.

In another aspect, the invention provides the use of a compound of formula (I)

(i)

wherein:

R is alkyl containing from 5 to 20 carbon atoms; and

X is -C(O)- or is absent;

in the manufacture of a composition for the treatment of acne, provided that when Rl and R2 are both OH and R3 and R4 are both H, R is not n-octyl or n-dodecyl.

Also provided by the invention in another aspect is a method of treating acne in humans which comprises topically applying to the skin of a human suffering from acne a composition of the invention.

Compound of Formula (I)

The present invention is based on the surprising finding that compounds of formula (I) can have activity as anti-acne agents .

The compounds of formula (I) can be used in the present invention either singly or as mixtures of different compounds of formula (I) .

The compositions of the invention comprise the one or more compounds of formula (I) in an amount of from 0.01 % to 20 % by weight, such as from 0.1 % to 10 % by weight, preferably from 0.6 % to 5 % by weight, more preferably from 0.8 % to 3 % by weight, e.g., from 1.5 % to 2.5 % by weight.

Preferably, in the compounds of formula (I) , R is alkyl containing 5 to 12 carbon atoms, more preferably 5 to 8 carbon atoms . Examples of alkyl groups containing 5 to 8 carbon atoms are n-pentyl, n-hexyl, n-heptyl, n-octyl and 2- ethylhexyl . The term alkyl, as used herein, refers to straight chain and branched aliphatic and alicyclic saturated hydrocarbon groups (preferably the alkyl groups are aliphatic) . Alkyl groups may contain one or more carbon-carbon double bonds, but are preferably saturated.

In certain compounds of the invention, Rl, R2, R3 and R4 are all H. Thus, one group of compounds that are preferred for use in the invention are the compounds in which Rl, R2, R3 and R4 are all H, X is -C(O)- and R is alkyl containing from 5 to 20 carbon atoms, more preferably 5 to 8 carbon atoms.

Another preferred group of compounds of formula (I) for use in the invention comprise compounds wherein Rl and R2 are both OH and R3 and R4 are both H. In this preferred group of compounds, X is -C(O)- and R is alkyl containing from 5 to 20 carbon atoms, more preferably 5 to 8 carbon atoms.

Yet another group of compounds of formula. (I) comprise the compounds in which X is absent i.e., the compounds containing a phenoxy ether linkage in which the group RO in the compounds of formula (I) is bonded directly to the aromatic ring. However, it is preferred that X is present and is -C(O) - .

Examples of compounds that may be used in the invention are n-octyl gallate, n-hexyl gallate, n-heptyl gallate, n-pentyl gallate, 2-ethylhexyl gallate, n-pentyl p-hydroxybenzoate, n-hexyl p-hydroxybenzoate, n-heptyl p-hydroxybenzoate, n- octyl p-hydroxybenzoate and 2-ethylhexyl p-hydroxybenzoate. The p-hydroxybenzoates are also known in the art as parabens .

Topically-Acceptable Diluents and Carriers

The compositions of the invention comprise a topically acceptable diluent or carrier (i.e., a dermatologically/cosmetically acceptable vehicle) to act as a diluent, dispersant or carrier for the active. The carrier may comprise materials commonly employed in skin care products such as water, liquid or solid emollients, silicone oils, emulsifiers, solvents, humectants, thickeners, powders, propellants and the like, some of which are also described separately herein under specific headings.

The compositions that are useful in the present invention comprise a safe and effective amount of the topically- acceptable carrier or diluent which can have a variety of different forms. By "safe and effective" is meant an amount sufficient to act as a suitable vehicle for the required components and any other optional components, but not so much as to cause any side effects or skin reactions. The topically-acceptable carrier should be non-irritant. "Topically-acceptable" therefore means that the carrier is suitable for topical application to the skin without causing any untoward safety or toxicity concerns. In other words, these carriers are suitable for use on mammalian skin. The typical carrier can be in the form of a hydroalcoholic system (e.g. liquids and gels), an anhydrous oil or silicone based system, or an emulsion system, including, but not limited to, oil-in-water, water-in-oil, water-in-oil-in- water, and oil-in-water-in-silicone emulsions. The emulsions can cover a broad range of consistencies including thin lotions (which can also be suitable for spray or aerosol delivery) , creamy lotions, light creams, heavy creams, and the like. The emulsions can also include microemulsion systems . Other suitable topical carriers include anhydrous solids and semisolids (such as gels and sticks) ; and aqueous based mousse systems. Nonlimiting examples of the topical carrier systems useful in the present invention are described in the following four references, all of which are incorporated herein by reference in their entirety: "Sun Products Formulary", Cosmetics & Toiletries, vol. 105, pp. 122-139 (December 1990); "Sun Products Formulary", Cosmetics & Toiletries, vol. 102, pp. 117-136 (March 1987); U.S. Pat. No. 4,960,764 to Figueroa et al . , issued Oct. 2, 1990; and U.S. Pat. No. 4,254,105 to Fukuda et al . , issued Mar. 3, 1981.

The topically-acceptable diluents or carriers, in total, typically constitute from about 0.1% to about 99.8% by weight of the compositions of the present invention, preferably from about 80% to about 99%, and most preferably from about 85% to about 95% by weight.

One suitable diluent or carrier for use in the compositions of the invention comprises water together with one or more components selected from aliphatic alcohols containing two to four, more preferably two or three, carbon atoms. An example of topically-acceptable diluent or carrier useful in the present invention is therefore a hydroalcoholic system comprising, by weight of the total composition, from about 1% to about 99% of ethanol, isopropanol, t-butanol or mixtures thereof, and from about 1% to about 99% of water. Preferred is a carrier comprising from about 5% to about 60% by weight of ethanol, isopropanol, or mixtures thereof, and from about 40% to about 95% by weight of water. More preferred is a carrier comprising from about 20% to about 50% by weight of ethanol, isopropanol, or mixtures thereof, and from about 50% to about 80% by weight of water.

Optional Components

In addition to the required components of the compositions useful in the present invention, a variety of optional components can also be incorporated. Preferred optional components include preservatives, antioxidants (e.g., BHT) , fragrances, clays (e.g., bentonite) , surfactants, gel- forming materials, silicones, emollients, humectants and pigments. These optional materials may be used singly or two or more of each type of materials may be used (for example, a composition may include two or more different clays) . These optional components may be used in admixture e.g., a composition may contain a preservative, a fragrance and a clay.

Specific examples of optional components, some of which are also mentioned hereinafter, are alkyl alcohols containing from 12 to 24 carbon atoms, alkyl carboxylic acids containing from 12 to 24 carbon atoms, polyvinyl pyrrolidone, polyethylene glycol, mineral oil, polysorbates, nonionic surfactants, sorbitol, methyl cellulose, propylene glycol esters, zinc salts, titanium dioxide and mixtures thereof .

Preservatives

The compositions of the invention may optionally comprise one or more preservatives for maintaining the antimicrobial integrity of the compositions. Although the compounds of formula (I) may act to some extent as antimicrobial preservatives, the compositions of the invention preferably comprise one or more preservative compounds which are not compounds of formula (I) . Preferably, the composition comprises from 0.001 % to 5 % by weight of the composition of the one or more preservative compound which is not a compound of formula (I) . Examples of such compounds are triclosan, benzoic acid, benzoic acid salts (e.g., sodium benzoate) , benzyl alcohol, hexamidine, o-phenyl phenol, phenoxyethanol , dichlorobenzyl alcohol, iodopropynyl butylcarbamate and preferably Cl to C4 alkyl 4- hydroxybenzoates (parabens) , such as methyl paraben and propyl paraben.

Further Anti-Acne Agents

The compositions useful in the present invention can also contain further anti-acne agents in addition to the one or more compounds of formula (I) . It is believed that the compounds of formula (I) have particularly advantageous properties in terms of their anti-acne properties when used in combination with further anti-acne agents.

Preferably, the further anti-acne agent is selected from antibacterials, desquamators , keratolytics and retinoid boosters.

These other anti-acne agents are preferably present in the compositions in an amount of from about 0.1% to about 20% by weight, more preferably from about 0.1% to about 10%, and most preferably from about 0.1% to about 5%. Mixtures of these additional anti-acne actives may also be used.

Examples of these other anti-acne agents include salicylic acid, keratolytics such as sulfur, lactic acid, glycolic acid, pyruvic acid, urea, resorcinol, and N-acetylcysteine; retinoids such as retinoic acid and its derivatives (e.g., cis and trans) ; antibacterials (including antibiotics and antimicrobials) , antif ngals, antiprotozoals, and antivirals (e.g., benzoyl peroxide, octopirox, erythromycin, tetracyclin, triclosan, azelaic acid and its derivatives, phenoxy ethanol and phenoxy propanol, ethyl acetate, clindamycin and meclocycline, chlorhexidine, tetracycline, neo ycin, miconazole hydrochloride, octopirox, parachlorometaxylenol, nystatin, tolnaftate, clotrimazole, cetylpyridinium chloride and the like) ; sebostats such as flavonoids; hydroxy acids (e.g., malic acid); antipruritic drugs including, for example, topically-acceptable salts of methdilizine and trimeprazine; and bile salts such as scymnol sulfate and its derivatives, deoxycholate, and cholate. The compositions may also comprise pantothenic acid or a pantothenic acid derivative, as described in US 5,612,324, the contents of which are incorporated herein by reference .

Also useful are non-steroidal anti-inflammatory drugs (NSAIDS) . The NSAIDS can be selected from the following categories: propionic acid derivatives; acetic acid derivatives; fenamic acid derivatives; biphenylcarboxylic acid derivatives; and oxicams . All of these NSAIDS are fully described in the U.S. Pat. No. 4,985,459 to Sunshine et al . , issued Jan. 15, 1991, incorporated by reference herein. Most preferred are the propionic NSAIDS including but not limited to aspirin, acetaminophen, ibuprofen, naproxen, benoxaprofen, flurbiprofen, fenoprofen, fenbufen, ketoprofen, indoprofen, pirprofen, carprofen, oxaprozin, pranoprofen, miroprofen, tioxaprofen, suprofen, alminoprofen, tiaprofenic acid, fluprofen and bucloxic acid. Also useful are the steroidal anti-inflammatory drugs including hydrocortisone and the like.

Other examples of compounds that are useful as the further anti-acne agents, either alone or in combination with the further anti-acne agents mentioned above are retinoid boosters. Retinoid boosters are compounds that mimic the effect of retinoic acid on skin by enhancing the conversion of retinol or retinyl esters to retinoic acid. Retinoid boosters may be used singly or as combinations of two or more compounds. Retinoid boosters are described in WO 02/02074, the contents of which are incorporated herein by reference. Specific retinoid boosters include, for example, ceramides, phosphatidyl choline, linoleic acid, 12- hydroxystearic acid and climbazole. Humectants

Another optional component of the compositions useful in the instant invention is at least one humectant (which term includes moisturizers and skin conditioners) . A variety of these materials can be employed and each can be present at a level of from about 0.1% to about 20%, more preferably from about 1% to about 10% and most preferably from about 2% to about 5% by weight of the composition. These materials include urea; guanidine; glycolic acid and glycolate salts (e.g. ammonium and quaternary alkyl ammonium) ; lactic acid and lactate salts (e.g. ammonium and quaternary alkyl ammonium) ; extracts of natural products, such as extracts of Pyrus malus and aloe vera in any of its variety of forms (e.g., aloe vera gel); polyhydroxy alcohols such as sorbitol, glycerol, hexanetriol, propylene glycol, hexylene glycol and the like; polyethylene glycol; sugars and starches; sugar and starch derivatives (e.g., alkoxylated glucose) ; hyaluronic acid; lactamide monoethanolamine; acetamide monoethanolamine; and mixtures thereof.

Surfactants

The compositions useful in the methods of the present invention can optionally comprise one or more surfactants. The surfactants can be present at a level from about 0.1% to about 10%, more preferably from about 0.2% to about 5%, and most preferably from about 0.2% to about 2.5% by weight of the composition. Suitable surfactants include, but are not limited to, nonionic surfactants such as glyceryl carboxylates (e.g., glyceryl stearate) , polyalkylene glycol ethers of fatty alcohols (e.g., PPG-15 stearyl ether), anionic surfactants such as taurates and alkyl sulfates and. amphoteric surfactants such as cetyl betaine. Nonlimiting examples of these surfactants include isoceteth-20, steareth-21, sodium methyl cocoyl taurate, sodium methyl oleoyl taurate, and sodium lauryl sulfate. See U.S. Pat. No. 4,800,197, to Kowcz et al . , issued Jan. 24, 1989, which is incorporated herein by reference in its entirety. Examples of a broad variety of additional surfactants useful herein are described in McCutcheon' s, Detergents and Emulsifiers, North American Edition (1986) , published by Allured Publishing Corporation, which is incorporated herein by reference in its entirety.

Gel-Forming Materials

Another optional component of the compositions useful in the methods of the instant invention is a gel-forming material. Examples of such a material are carboxylic copolymers

(acrylic acid copolymers) . Most preferred is Carbomer 1342 (available as Carbopol 1342 from B. F. Goodrich) . These polymers are more fully described in U.S. Pat. No. 4,509,949, to Huang et al . , issued Apr. 5, 1985, and U.S. Pat. No. 2,798,053, to Brown, issued Jul . 2, 1957, these patents both of which are incorporated herein by reference in their entirety. Also useful are the acrylate/alkyl acrylate crosspolymers such as Acrylates/C10-C30 Alkyl Acrylate Crosspolymer (available as Pemulen TR-1 and Pemulen TR-2 from Goodrich) . These polymers may be present in the compositions in an amount of from about 0.025% to about 0.75%, preferably from about 0.05% to about 0.25% and most preferably from about 0.075% to about 0.175% by weight of the composition.

Emollients

The compositions useful in the methods of the present invention can also optionally comprise at least one emollient. Examples of suitable emollients include, but are not limited to, volatile and non-volatile silicone oils, highly branched hydrocarbons, hydrogenated castor oil and non-polar carboxylic acid and alcohol esters (e.g., dibutyl adipate) , and mixtures thereof. Emollients useful in the instant invention are further described in U.S. Pat. No.

4,919,934, to Deckner et al . , issued Apr. 24 1990, which is incorporated herein by reference in its entirety.

The emollients are typically present in the compositions in an amount of from about 1% to about 50%, preferably from about 1% to about 25%, and more preferably from about 1% to about 10% by weight of the compositions.

pH

A wide variety of acids, bases, and buffers can be utilized to adjust and/or maintain the pH of the compositions useful in the instant invention. Although triethanolamine is preferred, other nonlimiting examples of materials useful for adjusting and/or maintaining the pH include sodium carbonate, sodium hydroxide, hydrochloric acid, phosphoric acid, sodium hydrogen phosphate, sodium dihydrogen phosphate, citric acid, and the like.

Other Optional Components

A variety of additional ingredients can be incorporated into the compositions useful in the present invention. Non- limiting examples of these additional ingredients include other vitamins and derivatives thereof (e.g., ascorbic acid, vitamin E, tocopheryl acetate, and the like) ; thickening agents (e.g. polyacrylamide and C13-14 isoparaffin and laureth-7, available as Sepigel from Seppic Corporation) ; resins; gums; cationic polymers and thickeners (e.g., cationic guar gum derivatives such as guar hydroxypropyltrimoniu chloride and hydroxypropyl guar hydroxypropyltrimonium chloride, available as the Jaguar C series from Rhone-Poulenc; copolymers of acrylamide and a cationic acrylate (available as Salcare SC92 from Allied Colloid) ; emulsifiers; polymers for aiding the film-forming properties and substantivity of the composition (such as a copolymer of eicosene and vinyl pyrrolidone, an example of which is available from GAF Chemical Corporation as Ganex V- 220@R) ; skin penetration aids such as DMSO, 1-dodecyl- azacycloheptan-2-one (available as Azone from the Upjohn Co.) and the like; artificial tanning agents such as dihydroxyacetone and the like; skin bleaching (or lightening) agents including but not limited to hydroquinone, ascorbic acid, kojic acid and sodium metabisulfite; chelators and sequestrants; and aesthetic components such as colorings, essential oils, skin sensates, astringents, skin soothing agents, skin healing agents and the like, nonlimiting examples of these aesthetic components include clove oil, menthol, camphor, eucalyptus oil, eugenol, menthyl lactate, witch hazel distillate, allantoin, bisabalol, dipotassium glycyrrhizinate and the like. Further optional components include antistatic agents (e.g., distearyldimonium chloride and oxidised polyethylene) , viscosity controlling agents (e.g., sodium chloride), bittering agents to inhibit against ingestion (e.g., denatonium benzoate) and components to protect against degradation by light (e.g., benzophenone-2) .

Product Forms

Product types suitable for the compositions of the invention include: skin products such as creams, lotions, ointments, sunscreens, anti-aging formulations, sunless tanners; colour cosmetics, including foundations and moisturisers; perfumes; hair treatments including shampoos, conditioners, mousses and gels; personal wash products including soap bars and shower gels; and shaving preparations. The products may take any shape or form. They may be liquids (preferably emulsions) , gels, sticks, aerosols, mousses, skin patches, wiping articles, pads, pastes or powders.

Delivery Methods for the Compositions

The compositions useful in the invention can be delivered directly from the package or container for use by the user of the product (e.g., by application via the user's hand or fingers) or from a a variety of delivery devices. The following are two nonlimiting examples. Medicated Cleansing Pads

The compositions useful herein can be incorporated into a medicated cleansing pad. Preferably these pads comprise from about 50% to about 75% by weight of one or more layers of nonwoven fabric material and from about 20% to about 75% by weight (on dry solids basis) of a water soluble polymeric resin. These pads are described in detail in U.S. Pat. No. 4,891,228, to Thaman et al . , issued Jan. 2, 1990 and U.S. Pat. No. 4,891,227, to Thaman et al . issued Jan. 2, 1990; both of which are incorporated by reference herein in their entirety.

Dispensing Devices

The compositions useful herein can also be incorporated into and delivered from a soft-tipped or flexible dispensing device. These devices are useful for the controlled delivery of the compositions to the skin surface and have the advantage that the treatment composition itself never need be directly handled by the user. Nonlimiting examples of these devices comprise a fluid container including a mouth, an applicator, means for holding the applicator in the mouth of the container, and a normally closed pressure-responsive valve for permitting the flow of fluid from the container to the applicator upon the application of pressure to the valve. The valve can include a diaphragm formed from an elastically fluid impermeable material with a plurality of non-intersecting arcuate slits therein, where each slit has a base which is intersected by at least one other slit, and where each slit is out of intersecting relation with its own base, and wherein there is a means for disposing the valve in the container inside of the applicator. Examples of these applicator devices are described in U.S. Pat. No. 4,693,623, to Schwartzman, issued Sep. 15, 1987; U.S. Pat. No.

4,620,648, to Schwartzman, issued Sep. 15, 1987; U.S. Pat. No. 3,669,323, to Harker et al . , issued Jun. 13, 1972; U.S. Pat. No. 3,418,055, to Schwartzman, issued Dec. 24, 1968; and U.S. Pat. No. 3,410,645, to Schwartzman, issued Nov. 12, 1968; all of which are incorporated herein by reference in their entirety. Examples of applicators useful herein are commercially available from Dab-O-Matic, Mount Vernon, N.Y.

Methods for Treating Acne

The present invention relates to a method for treating acne in humans. Such a method comprises topically applying to the skin an effective amount of a composition of the invention. The term "effective amount", as used herein, means an amount sufficient to provide an anti-acne benefit. The composition can be continually applied at appropriate intervals, preferably about once or twice a day until the acne subsides .

The method preferably involves topical, local application to the area of the skin affected by acne or susceptible to acne, for example the face, forehead, neck and back. Therefore, compositions of the invention are preferably suitable for topical application to the face and/or forehead and/or neck and/or back. The invention is particularly useful for treating acne vulgaris. The organism implicated in acne vulgaris is typically Propionibacterium acnes .

The following non-limiting examples illustrate the invention. In the examples and throughout the specification, all percentages are percentages by weight based on the total weight of the composition unless otherwise indicated.

EXAMPLES

Example 1

An in vi tro model system, reproducing the biotransformation of glucose to propionic acid by Propionibacterium spp., was used to demonstrate the antibacterial properties of several active ingredients according to the invention. To each of several 7 ml glass vials was added 6.0 ml synthetic medium (see below), supplemented with glucose substrate (2.0 mg/ml). To each vial (other than controls) was also added one of the indicated test materials, from a 1.0-10.0% (w/v) stock solution in 50% (v/v) ethanol. Each of the vials was inoculated with fresh bacterial biomass (Propionibacterium acnes G63 [skin isolate] or P. avidum NCTC 11864) , pre-grown for 48 h, under anaerobic conditions, in TSBT (see below) , to give starting optical densities (A ₅₉₀) of -1.0. Following inoculation, the flasks were incubated anaerobically at 35°C, with agitation (120 rpm) , for 24 h. After this time, culture viability was determined by total viable count (TVC) analysis on ACX plates (see below) , following serial dilution in quarter-strength Ringers solution. Also, at the end of each experiment, the extent of glucose biotransformation to propionic acid was measured by capillary gas chromatography (GC) (see below) , and the dose response data used to calculate, for each active ingredient, a BIC_S0 value (50% biotransformation inhibition concentration) . The mode of action (bacteriostatic or bactericidal) at this level was elucidated by reference to culture viability data, which was also used to determine the MBC (minimum bactericidal concentration) , defined as the minimum level of each active effecting a >3 log₁₀ ml^"1 reduction in viability. Finally, the data for P. acnes G63 and P. avidum NCTC 11864 were combined to generate mean and range values (Table 1) .

Composition of synthetic medium (g/1): KH₂P0 (1.6); (NH)2HP0 (5.0); Na₂S0₄ (0.38); KN0₃ (0.1); NaHC0₃ (1.0); sodium thioglycolate (1.0); sodium pyruvate (1.0); yeast nitrogen base (Difco) (3.35); MgCl₂.6H₂0 (0.5).

Composition of TSBT (g/1) : Tryptone soya broth (Merck)

(30.0); yeast extract (Beta Lab) (10.0); Tween 80™ (5.0).

Composition of ACX (g/1) : blood agar base no. 2 (Oxoid) (39.5); yeast extract (Beta Lab) (3.0); glucose (2.0); Tween 80™ (5.0); defibrinated horse blood (50 ml/1).

Methodology for GC determination of propionic acid: 1.0 ml aliquots from each assay vial were transferred into sampling tubes, an internal standard (1.0 mg/ml caproic acid) added to each tube, and the culture medium acidified (pH ~2) by the addition of HC1. Liquid-liquid extraction was then carried out using 2 vol (2 ml) ethyl acetate, with organic and aqueous phases being resolved by centrifugation (2000 rpm, 2 min) . -0.75 ml of each organic (upper) phase was then transferred to a fresh sampling tube prior to analysis on a Perkin Elmer 8000 (Series 2) GC fitted with a 15 m x 0.32 mm (internal diameter) FFAP fused silica capillary column (film thickness 0.25 μm) (Quadrex) . Metabolite levels were quantified by comparison of peak areas with known amounts of both internal (caproic acid) and externally-run (propionic acid) standards. GC running conditions as indicated: injector (split/splitless) , 300°C; detector (flame ionisation) , 300°C; oven, 80°C (2 min), 80-155°C (7.5°C/min), 155°C (1 min); injection volume, 1.0 μl .

Table 1. .Siti-propionifoacterial properties of actives according to the invention

^ICso, mean concentration at 50% inhibition of glucose biotransformation to propionic acid, by P. acnes G63 and P. avidum NCTC 11864;

²Mode(s) of action at BIC₅₀ levels for P. acnes G63 and P. avidum NCTC 11864;

³Range of minimum bactericidal levels for P. acnes G63 and P. avidum NCTC 11864;

⁴>5-fold superior efficacy against P. acnes G63 than P. avidum NCTC 11864.

Example 2

The following is an example of a topical composition which is prepared by combining the following components utilizing conventional mixing techniques .

This composition is useful for topical application for the treatment of acne.

Examples 3 to 6 The following are examples of topical compositions which are prepared by combining the following components utilizing conventional mixing techniques.

Example 7

A gel composition is prepared by combining the following components utilizing conventional mixing techniques.

Example 8

^Available as Salcare SC92 from Allied Colloids.

Claims

1. An anti-acne composition for topical application comprising:

from 0.01 % to 20 % by weight of a compound of formula (I)

(I)

wherein:

R is alkyl containing from 5 to 20 carbon atoms; and

X is -C(0)- or is absent;

optionally, a further anti-acne agent which is not a compound of formula (I)

and a topically acceptable diluent or carrier,

provided that when Rl and R2 are both OH, and R3 and R4 are both H, the composition further comprises from 0.1 % to 20 % by weight of the further anti-acne agent.

2. Composition as claimed in Claim 1 further comprising from 0.001 % to 5 % by weight of a preservative compound which is not a compound of formula (I) .

3. Composition as claimed in Claim 1 or Claim 2, wherein the cosmetically acceptable diluent or carrier comprises water together with one or more components selected from aliphatic alcohols containing two or three carbon atoms.

4. Composition as claimed in any one of the preceding claims, which comprises one or more of a fragrance, a clay, a surfactant, a gel-forming material, a silicone, an emollient, an antioxidant, a humectant and a pigment.

5. Composition as claimed in any one of the preceding claims further comprising one or more components selected from alkyl alcohols containing from 12 to 24 carbon atoms, alkyl carboxylic acids containing from 12 to 24 carbon atoms, polyvinyl pyrrolidone, polyethylene glycol, mineral oil, polysorbates, nonionic surfactants, sorbitol, methyl cellulose, propylene glycol esters, zinc salts, titanium dioxide and mixtures thereof .

6. Composition as claimed in any one of the preceding claims, wherein the further anti-acne agent is selected from antibacterials, desquamators, keratolytics and retinoid boosters .

7. Composition as claimed in any one of the preceding claims, wherein the further anti-acne agent is selected from one or more of benzoyl peroxide, resorcinol, resorcinol monoacetate, sulfur, povidone-iodine, salicylic acid, phenol, fluocinolone acetonide, para-aminobenzoic acid, sodium thiosulfate, meclocyline sulfosalicylate, tetracycline hydrochloride, sodium sulfacetamide, aliphatic dicarboxylic acids, sulfurated lime and retinoid boosters.

8. Composition as claimed in any one of the preceding claims, wherein R is alkyl containing 5 to 8 carbon atoms.

9. Composition as claimed in any one of the preceding claims, wherein X is -C(0)- and Rl, R2 , R3 and R4 are all H.

10. Composition as claimed in any one of the preceding claims, wherein X is -C(0)- Rl and R2 are both OH and R3 and R4 are both H.

11. Use of a compound of formula (I)

(I)

wherein:

Rl, R2, R3 and R4 are the same or different and are selected from H, OH, and OCH₃; R is alkyl containing from 5 to 20 carbon atoms; and

X is -C(O)- or is absent;

in the manufacture of a composition for the treatment of acne,

provided that when Rl and R2 are both OH and R3 and R4 are both H, R is not n-octyl or n-dodecyl .

12. Method of treating acne in humans which comprises topically applying to the skin of a human suffering from acne a composition of any one of Claims 1 to 10.