GB2216793A - Treatment or prophylaxis of acne, dandruff or related conditions - Google Patents

Abstract

A preparation for the topical treatment or prophylaxis of acne, dandruff or related conditions of the human skin or scalp or for related veterinary use, comprises two components. The first component is selected from chlorphenesin, chlorphenesin derivatives, and pharmaceutically acceptabie salts thereof. The second component comprises a pharmaceutically acceptable salt of an aromatic diamidine. The two components are present in the preparation in effective amounts as active substances in a pharmaceutically acceptable carrier. The applicant also describes gel formulations for pharmaceutical preparations for the topical treatment of prophylaxis of the skin, scalp or mucous membranes of humans or animals, in which one or more pharmaceutical substances are provided in pharmaceutically effective amounts in the gel formulation which is based upon one or more cationic guar gums or their derivatives as the or the principal gelling agent.

Description

TREATMENT OR PROPHYLAXIS OF ACNE, DANDRUFF OR RELATED CONDITIONS pescription This invention relates to the treatment or prophylaxis of acne, dandruff or related conditions of the human skin or scalp. As will become clear from the description below, the invention provides novel preparation for the topical treatment or prophylaxis of these conditions, and also to novel pharmaceutical bases particularly useful in the production of practical such preparations.

Acne vulgaris, the most common form of acne, is generally regarded as no more than a minor medical problem although it affects most adolescents to some extent and may persist in some individuals to the age of 30 and beyond. The onset of acne is closely correlated to puberty and to the increase in size and activity of the pilosebaceous glands, particularly in the production of sebum, as a direct result of the increase of androgens at puberty. The sebaceous glands are enlarged and restricted by intrafollicular hyperkeratosis leading to the characteristic formation of comedones composed of sebum, keratin and micro-organisms. The principal organisms most often linked with acne are Prooionibacterium acnes, StaphYlococcus epidermidis and Pitvrosorum ovale.It is believed that exoenzymes of these micro-organisms have a significant effect on the pathogenesis of acne, breaking down triglycerides in the sebum to form free fatty acids which irritate the follicular wall causing hyperkeratinisation and inflammation as a result of which the initial comedones may progress to papules, pustules and cysts.

Although acne is commonly regarded as no more than a minor medical problem, particularly because it primarily affects the face, those suffering from it regard it as a serious personal and social embarrassment. Severe cases may lead to considerable surface disfigurement which can be distressing for the person affected.

A fuller account of the causes of acne and of the methods of treatment currently available can be found in the literature, see for example "Spotlight on Acne", B. Cunliffe, Pharmacy Update, July 1985 at page 150 to 153 and "OTC Products for Acne", N. Harris, Pharmacy Update, July 1985 at pages 154 to 156. A number of topical preparations in cream, gel, lotion or solution form and in a soap bar are available but all these known preparations suffer from a lack of effectiveness and/or side effects. In addition to the above cited Cunliffe and Harris articles, reference may be made to Chemist and Druggist, 10th August 1985 at page 229-230 and Chemist and Druggist, 24th August 1985 at page 324.

Preparations containing anti-microbial agents such as chlorhexidine, triclosan, resorcinol, salicylic acid and sulphur have been reported by some workers to be without significant activity.

Preparations containing benzoyl peroxide are currently the most widely used of the available treatments, but the preparations suffer from several side effects. Benzoyl peroxide which is both anti-microbial and keratolytic has been reported to elicit redness and burning of the skin and is a weak sensitizer. It can also stain or bleach hair and clothing. More recently, however its continued use has been questioned because of reports that it may act as a tumour promoter. Combination products of benzoyl peroxide with hydroxyquinoline or miconazole are available on the market, the combination with miconazole being sold under the Trade Mark Acnidazil, clinical trials having shown this combination to perform better than benzoyl peroxide alone. The side effects, however, remain unchanged.

Topical preparations containing vitamin A acid are also available but have been found to be not well tolerated because of erythema and scaling. There is again a suspicion of tumour-promoting activity with such preparations.

The current position in the treatment and prophylaxis of acne, dandruff and related conditions of the human skin or scalp as seen from the pharmacist's point of view is well summed up in the "Conclusion" in the article in Chemist and Druggist, 10th August 1985 at pages 229-230 where the writer concludes: "Progress is being made in the management of acne.

However, all of the effective treatments available are far from being ideal. New experimental findings have cast doubt on the long-term safety of some well-established remedies, and the pharmacist will need to keep up with the literature to ensure that patients receive the most objective and well informed advice available".

There is clearly a need for more effective and better tolerated preparations for the topical treatment or prophylaxis of acne, dandruff and related conditions.

A non-ionic emulsion cream formulation containing Imazalil and hexamidine isethionate has been proposed in European Patent Specification 0093186 for the topical treatment of acne. It is claimed that the activity of the combined formulation is higher than that of the individual substances, it being suggested that there is synergism between the two active components of the formulation. So far as the applicant is aware, no commercial formulation based on the disclosure of the said European Patent Specification has yet reached the market place, and the efficacy of treatments based on the disclosure of the said European Patent Specification must therefore at present remain in doubt.

In accordance with a principal aspect of the present invention there is provided a preparation for the topical treatment or prophylaxis of acne, dandruff or related conditions of the human skin or scalp, comprising: a first component comprising chlorphenesin, a chlorphenesin derivative, or pharmaceutically acceptable salts thereof; and a second component comprising a pharmaceutically acceptable salt of an aromatic diamidine; the first and second components being present in effective amounts as active substances in a pharmaceutically acceptable carrier.

The preferred first component is chlorphenesin itself.

Chlorphenesin or 3-(4-chlorophenoxy) propane 1, 2 diol is known to be an effective anti-fungal agent and has been used extensively as a foot powder or cream for its anti-fungal properties. Commercially available antifungal preparations containing chlorphenesin are sold under the Trade Marks Mycil, Kolpicortin and Soorphenesin.

The present applicant is not aware of any prior proposals to incorporate chlorphenesin, its derivatives or its salts as active constituent of an anti-acne preparation.

Derivatives of chlorphenesin and their salts are disclosed in the patent literature (for example British Patent Specifications 1394397 and 1401817 of Eisai Co.

Ltd) and are reported as having improved anti-allergic activity as compared with chlorphenesin. These compounds are not readily available commercially so that, as yet, the present applicant has not been able to test their efficacy in preparations according to the present invention, but it is to be expected that all such pharmaceutically acceptable derivatives and their pharmaceutically acceptable salts would be useful in the practice of the present invention. The reported enhanced anti-allergic activity of the Eisai compounds may make them preferable to chlorphenesin itself in acne patients such as those suffering from acne excoriée who tend to show less tolerance to topical preparations generally.

Numerous aromatic diamidines have been synthesized and studied (see Journal of Molecular Medicine, 2, 1977, 124) and would be useful in the practice of the present invention. The preferred such compounds are those with two rings and the amidino groups in the para position, for example stilbamidine and its derivatives such as 2hydroxystilbamidine and diphenyldiamidines with the

where R1 and R2 each separately comprise phenyl optionally halogenated and n > 3. Preferred such compounds of the formula I include propamidine, 2,2dibromopropamidine, 2, 2-dichloropropamidine, pentamidine and hexamidine.

In each case the second component is present as a pharmaceutically acceptable salt of the aromatic diamidine. The preferred such salt in each case is its isethionate salt (in the case of the diphenyl diamidines, the diisethionates).

Hexamidine isethionate, or 4, 4'- (hexamethylenedioxy) dibenzamidine bis (2-hydroxyethanesulphonate), is known to have bactericidal properties and has been used as a 0.1% solution for infections of the ears and eyes and as a mouthwash and for wounds and infections of the skin.

Preparations containing hexamidine isethionate are available under the Trade Marks Desomedine, Hexomedine and Ophtamedine.

Propamidine isethionate, or 4, 4'trimethylenedioxydibenzamidine bis (2hydroxyethanesulphonate), has been shown to have antibacterial properties which are not reduced by tissue fluids, serum, or pus. Propamidine isethionate has been used as a 0.15% cream and as an ophthalmic solution (0.1%), in each case for the treatment of conjunctivitis.

Commercial preparations include Brolene eye drops and M & BR< B antiseptic cream.

Dibromopropamidine isethionate, or 4,4' - trimethylenedioxy bis (3-bromobenzamidine) bis (2hydroxyethanesulphonate) has properties similar to those of propamidine isethionate, commercial preparations including Brolene eye ointment and Brulidane cream.

So far as the applicant is aware, neither propamidine isethionate nor the dibromo substituted compound have previously been proposed for inclusion in an anti-acne preparation as an active ingredient.

The other preferred aromatic diamidines with amidino groups in the para position, namely dichloropropamidine isethionate, pentamidine and stilbamidine and its derivatives, and in particular the 2-hydroxy substituted derivative, are also known to have anti-bacterial properties, though so far as the applicant is aware none has previously been proposed for incorporation as an active ingredient in an anti-acne preparation.

The ratio of the first component to the second component in practical preparations in accordance with the present invention may vary widely in the range of 1,000:1 to 1:1 weight for weight. A more preferred range is from 10:1 to 2:1. The most preferred ratio is 5:1.

In vitro studies described in more detail below with practical formulations of preparations in accordance with the present invention with the preferred ratio of 5:1 of the first component to the second component have shown a minimum inhibitory concentration for the first component against all three of the micro organisms P. acnes, S. epidermidis and P. ovale as low as 32 pg/ml with a consequent minimum inhibitory concentration of 6.4 pg/ml for the second component. The first component is accordingly preferably present in practical preparations in accordance with the present invention in an amount of at least 0.0032% and the second component is preferably present in an amount of at least 0.00064%. A more preferred range is at least 0.02% of the first component and at least 0.004% of the second component.

The preferred concentration for the first component is from 0.5 to 4% for the second component from 0.1 to 2%.

The combination of 1% of the first component and 0.2% of the second component is specially preferred.

Preparations in accordance with the present invention can be formulated in any of the conventional formulations for topical application, including gel formulations, emulsions such as lotions or creams, cleansers such as aqueous alcoholic solutions, shampoos, surfactant detergents and soaps such as soap bars.

Practical examples of various such formulations are described in detail below in a number of non-limiting examples.

A particularly preferred formulation which is believed novel Der se is a cosmetically elegant translucent to clear gel preparation.

Conventional gelling agents used in pharmaceutical preparations include Carbopol, polyvinyl copolymers, cellulose polymers such as carboxymethyl cellulose and natural polymers such as alginates. Many of these gelling agents are not pleasant to the feel, interact with other ingredients of pharmaceutical preparations and result in a product which is cloudy and/or of reduced viscosity. Certain polymers may also inhibit the activity of anti-microbial agents incorporated in the preparations. In particular, we have found that Carbopol which is a particularly common gelling agent for use in topical anti-acne preparations has the effect of reducing activity of our aromatic diamidines because of its cationic character.

As a secondary and to some extent independent aspect of the applicant's research for improved preparations for the topical treatment or prophylaxis of acne, dandruff and related conditions of the human skin or scalp, research has also been directed to the development of improved gel formulations which overcome or at least mitigate the problems with such gel formulations heretofore.

I have found that the use of one or more cationic guar gums as the gelling agent avoids or at least substantially mitigates the problems encountered heretofore with anti-acne gels.

Guar gum is a natural water soluble polymer derived from the endosperm of the guar plant. It is a galactomannan (polysaccharide) which when dissolved in water forms a stable gel with a high viscosity and compatible with electrolytes. The preferred guar derivatives for use in topical gel preparations in accordance with this second aspect of the present invention are cationic and preferably hydroxypropylated, phosphated or carboxymethylated. The most preferred cationic guar gum derivatives for use in the second aspect of the present invention are guar hydroxypropyl trimonium chloride. Such derivatives are available under the trade designations Jaguar C13 SD, Jaguar C15, Jaguar C17 and Jaguar I.D.261 from Chesham Chemicals. These Jaguar gums differ in the degree of substitution.

The present invention in its second and alternative aspect accordingly provides a pharmaceutical preparation for the topical treatment or prophylaxis of the skin, scalp or mucous membranes of humans or animals, the preparation comprising one or more pharmaceutical active substances provided in pharmaceutically effective amounts in a gel formulation based upon one or more cationic guar gum derivatives as the or a principal gelling agent.

It has also been found that cationic guar gum derivatives can with advantage be incorporated into alternative presentations including facial washes, cream emulsions and anti-dandruff shampoos. The incorporation of cationic guar gum derivatives into such formulations appears to have the effect of enhancing the activity of the active ingredients of our chlorphenesin/diamidine preparations for the treatment or prophylaxis of acne, dandruff and related conditions of the human skin and scalp in that the guar gum derivative appears to enhance the activity of both the first and second components.

The gel preparations preferably additionally incorporate an anti-inflammatory agent such as vitamin E, ascorbyl palmitate, panthenol and a - bisabolol. The preferred anti-inflammatory agent is panthenol which is both water soluble and had been found to enhance the activity of our formulations particularly against P.

ovale. Panthenol is preferably present in the range of 1-10% of the preparation.

The addition of a lower aliphatic alcohol, preferably methanol, ethanol or propanol and/or glycol, preferably glycerol, propylene glycol or polythene glycol, is advantageous in enhancing diffusion of the first and second components into the pilosebaceous duct. The aliphatic alcohols serve as solvents both for the first component and also for sebum. The glycols serve both as solvents and also as emollients.

Preparations in accordance with the present invention formulated as alcoholic skin cleansing lotions may have one or more alcohols, preferably ethanol, in any percentage conventional for such cleansing lotions (typically of the order of 30%). In addition, the formulations may advantageously include one or more surfactants such as amphoteric surfactants and/or anionic surfactants. Typical amphoteric surfactants are the carboxylated imidazoline derivatives, for example cocoamphodiacetate which is available under the trade name Miranol C2M Conc. Typical anionic surfactants include sodium lauryl ether sulphate and disodium lauryl sulphosuccinate.

A typical anti-dandruff shampoo in accordance with the present invention will include the first and second components, for example in their preferred percentages of 1% and 0.2% respectively, together with any of the surfactants commonly incorporated in shampoos and present in any of the conventional percentage ratios. A typical such shampoo formulation may for example include of the order of 35% sodium lauryl ether sulphate together with of the order of 10% of disodium lauryl sulphosuccinate.

The shampoo formulation may also include amphoteric surfactants for such as cocoamphodiacetate, typically present in the order of 5%, and non-ionic surfactants such as coconut diethanolamide, which may be present, for example, in the order of 2%. Other typical constituents of shampoos such as vegetable protein in the case of a protein shampoo may also be added.

Preparations in accordance with the present invention formulated as an emulsion cream base will include the first and second components, again, for example, present in their preferred percentages of 1% and 0.2 respectively, in any conventional emulsion cream base formulation. Preferably, however, the formulation again includes additionally an amount of cat ionic guar gum derivative, typically present in an amount of the order of 2%. The cream formulation may suitably include nonionic emulsifiers conventionally used in such formulations, such polyoxyethylene aliphatic acid esters, for example partial esters of a polyhydric alcohol containing 2-6 carbon atoms (for example glycerol monostearate), typically present in an amount of the order of 5%.

Typical conventional emollients included in such creams formulations include aliphatic alcohols containing 4-20 carbon atoms, such as cetyl alcohol and glycols and their polymers, for example propylene glycol, which may be included in any of the percentage ratios common in emulsion cream bases (for example propylene glycol of the order of 5% and cetyl alcohol of the order of 2%). A suitable thickener may be added, for example micro-crystalline cellulose, which, again, may be present in any of the percentage ratios conventional, a typical such percentage ratio being 10%.

Preparations in accordance with the present invention provided in the form of facial washes will again include the aforesaid first and second components, for example in their most preferred percentages of 1% and 0.2% respectively. Advantageously the facial wash also includes a cationic guar gum derivative, suitably present in an amount of the order of 1%.

When formulated as a soap bar, the active ingredients of the first and second components may again be present in their preferred percentage ratios, namely 1% and 0.2% respectively.

The soap bar also usefully includes a proportion of cationic guar gum derivative, typically of the order of 1 or 2%.

As appropriate in the various presentations and formulations, additional convention carriers and auxiliary agents such as emulsifiers, emollients, thickening agents, solvents colouring agents, perfume and anti-foaming agents may be incorporated.

The invention is hereinafter more particularly described by way of example only with reference to the following examples: EXAMPLE 1 Four gel formulations as set out in Table I were prepared according to the method described hereinbelow and tested for their activities as described in more detail below: TABLE I Formulation 1 2 3 4 Hexamidine isethionate 0.2 0.2 0.2 0.2 Chlorphenesin 1.0 1.0 1.0 1.0 Ethanol 40.0 30.0 30.0 30.0 Propylene glycol 30.0 5.0 5.0 5.0 Carbopol 940 1.0 - - Jaguar C13SD - 2.0 2.0 Jaguar ID.261 - - - 4.0 Panthenol - - 3.0 3.0 Triethanolamine 0.35 Citric acid - 0.3 0.3 0.3 Perfume and colour q.s. q.s. q.s. q.s.

Water to 100.0 100.0 100.0 100.0 Formulation 1 includes Carbopol and triethanolamine as the gelling agents. Formulations 2, 3 and 4 differ from formulation 1 in firstly having a smaller proportion of ethanol and particularly of propylene glycol and in substituting Jaguar gums as the gelling agent.

Formulations 3 and 4 differ from Formulation 2 by the addition of panthenol as an anti-inflammatory agent. As is further explained below, the addition of panthenol also enhances activity against P. ovale in particular.

Formulation 4 differs from Formulations 2 and 3 in the particular Jaguar gum. A small proportion of citric acid is present in Formulations 2, 3 and 4 to regulate acidity.

Formulation 1 of Table I may be manufactured by dissolving chlorphenesin in the alcohol and propylene glycol. Perfume and colour if present may be added to the alcoholic solution. Carbopol is dispersed in a major portion of the water (suitably about 60% of the water) and the alcoholic solution is added to the Carbopol dispersion and mixed until the whole is homogeneous, suitably for half an hour or more.

Separately the hexamidine isethionate is dissolved in the minor portion (about 40%) of the water by warming to 50"C. this solution is added to the alcoholic dispersion. The mixture is neutralised by the addition of triethanolamine and stirred for about 15 minutes to produce the resultant gel.

In the case of Formulations 2, 3 and 4, the chlorphenesin is again first dissolved in the alcohol and propylene glycol and the Jaguar gum is then added to this alcoholic solution and fully dispersed with mild stirring. To this dispersion is added the main proportion of water (suitably 60%) and the whole is stirred for half an hour. Hexamidine isethionate, citric acid and panthenol if present are dissolved in the remaining water by warming to 50 C. The alcoholic dispersion is added to the acid solution and stirred for 15 minutes until a uniform translucent gel is formed.

EXAMPLE 2 An alcoholic skin cleansing lotion is produced with a formulation as set out in Table II: TABLE II Stilbamidine isethionate 0.2 Chlorphenesin 1.0 Ethanol 30.0 Miranol C2M conc (cocoamphodiacetate) 2.0 Glycerol 5.0 Panthenol 3.0 Perfume q.s.

Colour q.s.

Water to 100.0 A cleansing lotion with formulation as shown in Table II may be produced by first dissolving chlorphenesin in the alcohol and glycerol, the perfume and colour suitably being added to the alcoholic solution. About half the water is added to this solution. The stilbamidine isethionate and panthenol are dissolved in the remainder of the water by warming to 50"C and the Miranol surfactant is added to the cooled aqueous solution. The alcoholic solution is then added to the aqueous solution and stirred.

EXAMPLE 3 A facial wash is produced with formulation as set out in Table III: TABLE III Pentamidine isethionate 0.2 Chlorphenesin 1.0 Empicol (sodium lauryl ether sulphate) 10.0 Miranol C2M conc 3.0 Empilan CDE (coconut diethanolamide) 2.0 Jaguar ID 261 1.0 Glycerol 3.0 Citric acid 0.1 Perfume q.s.

Colour q.s.

Water to 100.0 Chlorphensin is first dissolved in a mixture of glycerol and the Miranol and Empicol surfactants by warming to about 60"C with stirring. The Jaguar gum is added, and stirring continued for half an hour. A separate solution of pentamidine isethionate and citric acid is prepared using a minor portion of the water by warming to 60"C with stirring. The remainder of the water together with perfume and colour, if present, is added to the clorphenesin phase and well stirred. The pentamidine solution is added with further stirring and then the Empilan surfactant. The dispersion is cooled to 35"C.

EXAMPLE 4 A shampoo suitable for the treatment or prophylaxis of dandruff is prepared according to the formulation set out in Table IV: TABLE IV Propamidine isethionate 0.2 Chlorphenes in 1.0 Sodium lauryl ether sulphate 35.0 Cocoamphodiacetate 5.0 Disodium lauryl sulphosuccinate 10.0 Coconut diethanolamide 2.0 Jaguar C13SD 0.5 Vegetable protein 1.0 Citric acid 0.1 Colour q.s.

Perfume q.s.

Water to 100.0 Chlorphenesin is first dissolved in a mixture of the sodium lauryl ether sulphate, cocoamphodiacetate and disodium lauryl sulphosuccinate by warming to about 60"C with stirring. The vegetable protein and Jaguar gum are added, and the whole stirred for half an hour. A separate aqueous solution, using a minor portion of the water, of the propamidine isetionate and the citric acid is prepared also by warming to about 600C with stirring.

The remainder of the water together with the perfume and colour if present are added to the chlorphenesin phase, which is stirred well before the further addition of the propamidine solution with continued stirring and addition of coconut diethanolamide. The dispersion is cooled to 35"C.

EXAMPLE 5 A cream is manufactured according to the formulation shown in Table V below: TABLE V 2,2-dibromopropamidine isethionate 0.2 Chlorphenesin 1.0 Ethanol 15.0 Propylene glycol 5.0 Glycerol monostearate S.E. 5.0 Cetyl alcohol 2.0 Microcrystalline cellulose 10.0 Jaguar ID 261 2.0 Citric acid 0.2 Perfume q.s.

Colour q.s.

Water to 100.0 The chlorphenesin is dissolved in the ethanol and propylene glycol and the perfume and colour are added to the alcoholic solution. The Jaguar gum is then added with mild stirring to fully disperse the gum in the alcoholic phase. The 2,2-dibromopropamidine isethionate is dissolved by heating to 50"C in the water. An oil phase is prepared from the glycerol monostearate and cetyl alcohol and microcrystalline cellulose is added to the oil phase. An emulsion is then prepared by hot addition of the oil phase to the diamidine solution. The alcoholic chlorphenesin and gum dispersion is then added to the bulk which is mixed until homogeneous.

Selected examples of preparations in accordance with this invention have been tested for their activity against the principal organisms linked with acne, namely P. acnes, S. epidermidis and P. ovale to obtain the results which are set out below.

Formulations 1 to 4 of example 1 were tested for growth of P. ovale only in the case of Formulation 1, S.

epidermidis, P. acnes and P. ovale in the case of Formulations 2 and 3 and P. acnes only in the case of Formulation 4. The Formulations were tested at serial doubling dilutions in appropriate media for P. acnes, S.

epidermidis and P. ovale respectively dispensed in Petri dishes and using controls without test material. For activity against P. ovale, a Pityrosporum medium was prepared in the form of a molten agar medium consisting of 10 gm/l bacteriological peptone, five gm/l glucose, 0.1 gm/l glycerol monostearate, 12 gm/l agar and 0.5 ml/l Tween 60 at pH 6.2. For S. epidermidis there was used an Oxoid CM3 nutrient agar and for P. acnes there was used an Oxoid CM151 reinforced clostridial agar.

In each case 20 ?tl of culture with a nephelometer reading of 20 was inoculated on to the surface of the test and control media. P. ovale was incubated at 37 C for seven days, S. eDidermidis at 37"C for two days and P. acnes at 37"C for seven days in an anaerobic cabinet.

All tests and controls were tested in triplicate.

TABLE VI Minimum inhibitory Concentration ugm/ml Formulation S. epidermidis P. acnes P. ovale 1 - - 200 40 2 16.0 62.5 125 3.2 12.5 25 3 16.0 62.5 31.25 3.2 12.5 6.25 4 ~ 32.00 6.40 It will be seen that, while Formulation 1 is quite active, it is not so active as Formulations 2, 3 or 4.

We attribute this to the fact that Formulation 1 employs Carbopol rather than the Jaguar gums as gelling agent.

The diamidines are cationic, and it is thought that Carbopol interferes with the activity of the diamidine.

For an otherwise identical Formulation (Formulation 3 as compared with Formulation 2) the addition of panthenol significantly enhances activity against P. ovale.

Formulation 4 was compared with a leading product presently available on the market for the treatment or prophylaxis of acne, namely Acnidazil, supplied by Jannsen Pharmaceuticals and which contains 5% of Benzoyl peroxide and 2% miconazole nitrate, in a zone diffusion test using P. acnes as the indicator organism.

A fresh isolate of P. acnes was grown in Brain Heart Infusion broth supplied by Difco at 37"C for three days in an anaerobic cabinet. This culture was used evenly to inoculate three Brain Heart Infusion (BHI) plates and three Reinforced Clostridial Agar (RCA) plates. Two 4 mm diameter wells were cut from each plate and used to hold either 50 p1 of Acnidazil or of Formulation 4. After incubation at 37"C in an anaerobic cabinet for three days the diameters of the resultant zones of inhibition were measured. The average results are set out in Table VII below: TABLE VII DIAMETER OF ZONES (cm) Product BHI RCA Formulation 4 6.13 3.4 Acnidazil 1.3 1.1 This simple in vitro test suggests that Formulation 4 of Example 1 is substantially more effective than Acnizadil, a typical product presently available on the market, in inhibiting the growth of P. acnes.

Application of the various formulations of Examples 1 to 4 to the human skin shows that each of these formulations is well tolerated.

Claims (32)

CLAIMS:

1. A preparation for the topical treatment or prophylaxis of acne, dandruff or related conditions of the human skin or scalp or for related veterinary use, comprising: a first component selected from chlorphenesin, chlorphenesin derivatives, and pharmaceutically acceptable salts thereof; and a second component comprising a pharmaceutically acceptable salt of an aromatic diamidine; the first and second components being present in effective amounts as active substances in a pharmaceutically acceptable carrier.

2. A preparation according to Claim 1, wherein said first compound comprises Chlorphencsin succinate having t:hc formula

or an alkali metal salt thereof.

3. A preparation according to Claim 1, wherein the first component comprises a chorphenesin derivative having the general formula

wherein R is a hydrogen atone or a mcthyl group; or an inorganic acid addition salt tnereof.

4. A preparation according to any preceding claim, wherein the said aromatic diamidine comprises two aromatic rings with amidino groups in the para position.

5. A preparation according to Claim 4, wherein the aromatic diamidine comprises stilbamidine or a derivative thereof.

6. A preparation according to Claim 5 wherein said aromatic diamidine comprises 2-hydroxystilbamidine.

7. A preparation according to Claim 4, wherein said aromatic diamidine comprises a diphenyldiamidine

where R1 and R2 eacn separately comprise phenvl optionally halogenated and n > 3.

8. A preparation according to Claim 7, wherein said aromatic diamidine comprises: propamidine, 2,2dibromopropamidine, 2, 2-dichloropropamidine, pentamidine or hexamidine.

9. A preparation according to any preceding claim wherein said second component comprises the isethionate salt of the said aromatic diamidine.

10. A preparation according to any preceding claim wherein the weight ratio of the first component to the second component lies in the range from 10:1 to 2:1.

11. A preparation according to Claim 10, wherein the said ratio of the first component to the second component is 5:1.

12. A preparation according to any preceding claim, wherein the said preparation comprises at least 0.0032% of said first component and at least 0.00064% of said second component by weight.

13. A preparation according to Claim 12, wherein said preparation comprises at least 0.02% of said first component and at least 0.004% of said second component by weight.

14. A preparation according to Claim 13, wherein said preparation comprises from 0.5 to 4% of said first component and from 0.1 to 2% of said second component by weight.

15. A preparation according to Claim 14 wherein said preparation comprises 1% of said first component and 0.2% of said second component by weight.

16. A preparation according to any preceding claim formulated for topical application in a gel formulation, in an emulsion formulation for use as a lotion or as a cream, in an aqueous alcoholic solution for use as a cleanser, in a shampoo formulation, in a surfactant detergent formulation, or in a soap bar formulation.

17. A preparation according to Claim 16 provided in a gel formulation, wherein the gelling agent comprises one or more cationic guar gums or their derivatives.

18. A preparation according to Claim 16 otherwise than in a gel formulation, wherein the formulation includes one or more cat ionic guar gums or their derivatives.

19. A preparation according to Claims 17 or 18, wherein said guar gum is hydroxypropylated, phosphated or carboxymethylated.

20. A preparation according to Claim 19, wherein said guar gum derivative comprises guar hydroxypropyl trimonium chloride.

21. A preparation according to any preceding claim other than Claim 17 in a gel formulation, additionally incorporating one or more anti-inflammatory agents.

22. A preparation according to Claim 21, wherein said one or more anti-inflammatory agents are selected from vitamin E, ascorbyl palmitate, panthenol and abisabolol.

23. A preparation according to Claim 21 or Claim 22, wherein said preparation includes panthenol in a proportion of 1 to 10% by weight of the preparation.

24. A preparation according to any preceding claim additionally incorporating a lower aliphatic alcohol and/or a glycol to enhance diffusion of said first and second components into the pilosebaceous ducts of a patient in use.

25. A first component selected from chlorphenesin, chlorphenesin derivatives, and pharmaceutically acceptable salts thereof; and a second component comprising a pharmaceutically acceptable salt of an aromatic diamidine; for use concomitantly for the topical treatment or prophylaxis of acne, dandruff or related conditions of the human skin or scalp or for related veterinary use.

26. Use of chlorphenesin, a chlorphenesin derivative, or of pharmaceutically acceptable salts thereof for the manufacture of a preparation for the topical treatment or prophylaxis of acne, dandruff or related conditions of the human skin or scalp or for related veterinary use.

27. Use of the isethionate salts of propamidine, dibromopropamidine, dichloropropamidine, pentamidine, or of stilbamidine and its derivatives, for the manufacture of a preparation for the topical treatment or prophylaxis of acne, dandruff or related conditions of the human skin or scalp or for related veterinary use.

28. A pharmaceutical preparation for the topical treatment or prophylaxis of the skin, scalp or mucous membranes of humans or animals, the preparation comprising one or more pharmaceutical active substances provided in pharmaceutically effective amounts in a gel formulation based upon one or more cationic guar gums or their derivatives as the or the principal gelling agent.

29. A preparation according to Claim 28, wherein said guar gum is hydroxypropylated, phosphated or carboxymethylated.

30. A preparation according to Claim 29, wherein said guar gum derivative comprises guar hydroxypropyl trimonium chloride.

31. A pharmaceutical preparation for the topical treatment or prophylaxis of the skin, scalp or mucous membranes of humans or animals according to Claim 29 and substantially as hereinbefore described.

32. A preparation according to Claim 1 and substantially as hereinbefore described, for the topical treatment or prophylaxis of acne, dandruff or related conditions of the human skin or scalp or for related veterinary use.