The present invention relates to a medicament composition, notably one containing methotrexate and its analogues, and to a method for administering the medicament topically, notably in the treatment of proliferative skin disorders e.g. psoriasis and some cutaneous malignant neoplasms.

BACKGROUND TO THE INVENTION:

Some diseases of the dermis and epidermis are characterised by cellular hyper proliferation (increased cell turnover rates), for example psoriasis. Current treatment regimes range from topical corticosteroid therapy to active chemotherapy with tar and dithranol paints and baths and phototherapy involving PϋVA. The risks attached to the steroid regimes are those associated with the long term use of potent steroids (viz. adrenocortical suppression); whilst the latter regimes suffer from the unpleasantness attached to the treatment schedule and, with PUVA, to questions concerning long term safety and carcinogenicity.

Methotrexate has been used for the treatment of active psoriasis since at least 1958 (Edmundson & Guy). It is effective in controlling moderate to severe psoriasis using divided doses generally not exceeding 25mg/week, the doses being administered either orally or parenterally. However, the use of methotrexate as currently practised is invariably associated with long term changes in liver function and possible damage to other dividing cells, e.g. in the bone marrow and gut.

In order to reduce these undesirable side effects of methotrexate, it has been proposed that it should be applied topically. However, no successful topical preparation or

method of application has yet been achieved. Thus, a number of workers have reported on failures to control psoriasis with topical applications of methotrexate in a variety of formulations [see for instance Weinstein (1969), Van Scott (1959), Nurse (1963) and Cor aish (1969)]. In British Application No 2143433A it has been proposed to use the methotrexate entrapped in a liposomal formulation. However, the preparation of such an entrapped form of the medicament is complex and expensive, the composition is not effective to transfer the medicament across the skin and problems with long term stability and shelf life exist.

European Patent Application No 0247900A reviews much of the earlier work on the topical application of methotrexate and confirms that the earlier work had failed to find a satisfactory method for applying the medicament topically. In that application it was proposed to use a skin penetration agent, such as a l-substituted-azacycloheptan-2- one (Azone), to assist transport of the medicament across the skin. Whilst the penetration agent did aid transport of the methotrexate across the skin, the levels achieved were still comparatively low.

We have now devised a carrier composition containing a synergistic mixture of ingredients for methotrexate and its analogues which enables a surprisingly high rate of transdermal transport of the medicament to be achieved, thus enabling a satisfactory method for treating psoriasis and other proliferative skin disorders to be achieved.

It has been proposed in US Patent No 4560553 to use eucalyptol as a means for enhancing the skin penetration of biologically active materials, including methotrexate. Eucalyptol is an essential oil within the meaning of the term as used herein. However, in that proposal, the

eucalyptol was stated to. be the ingredient responsible for the transdermal properties of the compositions described therein and therefore must be present in such compositions. We have found that the synergistic properties of the mixture of the ingredients of our compositions enables the essential oil to be omitted and this is contrary to the requirements of the US proposal.

SUMMARY OF THE INVENTION:

Accordingly, the present invention provides a composition suitable for the topical application of methotrexate and its analogues, notably in the topical treatment of proliferative skin disorders, which composition comprises a therapeutic- ally effective amount of the medicament in a dermatologic¬ ally acceptable carrier medium, characterised in that the carrier medium comprises as essential components at least three ingredients selected from the group consisting of: a. aphysiologicallyacceptablepolyalkylene-ether-glycol, notably one of the empirical formula HO-(C _n H _2n O) _m -OH, where n has an average value of from 2 to 6 and m has an average value of from 2 to 30 or more, in which the alkylene groups can be straight or branched chain, saturated or unsaturated, and in which the hydroxyl groups can be primary, secondary and/or tertiary, and/or a physiologically acceptable polyalkylene-glycol, notably one of the empirical formula HO-(C _p H _2p ) _q -OH, where p_ has a value of from 2 to 6 and g has an average value of from 1 to 30, in which the alkylene groups can be straight or branched, saturated or unsaturated, and the hydroxyl groups can be primary, secondary and/or tertiary; or mixtures of such ether glycols and/or glycols; b. a physiologically acceptable C ₈ -C _u aliphatic monohydric alcohol, notably a C ₉ . ₁₂ alcohol, for example lauryl or dodecyl alcohol, which latter may be derived from propylene

tetramer; c. a physiologically acceptable plant extract having anti- fungal and/or anti-bacterial properties at physiologically acceptable dosage levels, for example an essential oil, notably one containing a terpenoid compound, preferably an oxygen-containing terpene or mixture of such terpenes, for example as is present in tea tree oil and other essential oils derived from vegetable matter; and d. a physiologically acceptable material having skin moisturising properties.

We have found that the ingredients of the composition of the invention interact synergistically to achieve a greater than expected transdermal effect and this effect is achieved when three of the specified ingredients are present in the composition. However, it is preferred that the composition contains all four of the essential ingredients, optionally in admixture with other ingredients typically present in topical preparations. Typically, the medicament is present in from 0.1 to 10%, the ether glycol and/or glycol ingredient a is present in a total amount of from 0.25 to 30%, the essential oil ingredient c_ is present in from 0.1 to 10%, the alcohol ingredient b is present in from 0.5 to 10%, and the skin moisturiser ingredient d is present in from 0.1 to 5%, all percentages being by weight of the active ingredient based on the total composition. The remainder of the composition is typically water or a water based gel or matrix having the medicament and essential ingredients uniformly distributed throughout.

The invention also provides a method for treating a proliferative skin disorder in a mammal, which method comprises administering a medicament transdermally by applying a biologically effective amount of a composition of the invention to the skin of the mammal, notably to or

adjacent to the locus or. expected locus of the disorder.

The invention is applicable to methotrexate and its analogues which are effective against proliferative skin disorders. The analogues of methotrexate suitable for present use include 3' ,5'-dichloromethotrexate-, and mono- and/or dialkyl esters of methotrexate or 3 ' ,5'—dichloro¬ methotrexate, notably those where the alkyl groups contain from 1 to 5 carbon atoms, for example the mono- or di-methyl or mono- or di-ethyl esters. The invention may also be applied to precursors of the active medicaments, for example an acetate or acyl derivative, an alkali metal salt or an amine salt or complex thereof.

For convenience, the term medicament will be used herein to denote in general terms methotrexate itself, its analogues and precursors thereof, whether alone or in admixture with one another.

The composition of the invention finds widespread use in the treatment of a wide range of conditions for which the medicaments have been indicated, notably in the treatment of proliferative skin disorders for example: psoriasis; primary malignant disease, for example squamous cell carcinoma, basal cell carcinoma, malignant melanoma, Kaposis sarcoma, etc;; and secondary deposits in the skin and neoplasms due to or associated with warts, herpes simplex, human papilloma virus etc.. For convenience, the invention will be described hereinafter in terms of the topical treatment of psoriasis.

We have surprisingly found that, in laboratory in vitro transdermal experiments using isolated human stratum corneum preparations, the skin penetration properties of formulations containing at- least three, and preferably all

four, of the specified ingredients in the carrier composition are generally superior to the rates obtained with formulations which contain other ingredients, for example Azone as a penetration assistant, or formulations which do not contain at least three of the specified ingredients. The invention thus offers the ability to apply methotrexate and its analogues transdermally in effective amounts and also to use lower concentrations of the medicament. For example, the compositions of the invention preferably contain from 0.01 to 2% by weight of methotrexate, which is of advantage where large areas of the skin are to be treated. However, where localised application of the medicament is required, for example in the treatment of a small skin cancer, higher proportions, for example from 5 to 10% by weight, may be used if desired and acceptable.

The medicament is put up in a carrier composition for application to the skin. The carrier composition may contain customary ingredients used in such compositions. However, we have found that the carrier composition must contain at least three of the specified ingredients in order to obtain the enhanced penetration of the medicament through the skin. The order of preference for the specified ingredients to be present is:

- 1. the plant extract ingredient c_;

2. the skin moisturising material ingredient d;

3. the long chain alcohol ingredient b; and

4. the alkylene glycol or polyalkylene ether glycol ingredient a.

The polyalkylene ether glycols or alkylene glycols for present use as ingredient a typically have a molecular weight in the range 100 to 600,000, but are preferably those having a molecular weight in the range 200 to 6000. We have

found that such ether ,glycols and glycols provide the carrier with occlusive properties as well as providing solvent and transdermal properties. Their inclusion in the carrier composition is especially preferred when the medicament is to be applied over a prolonged period where drying out of the skin could occur. The ehter glycols and glycols also assist formation of a matrix within which the other components of the composition are dispersed to provide a stable viscous gel consistency to the composition. Where the ehter glycol or glycol has a short chain, for example 2 to 5 carbon atoms, the ether glycol or glycol may also serve as a solvent or co-solvent for other components of the composition.

The polyalkylene ether glycols and/or alkylene glycols are typically present in a total amount up to about 30% by weight of the total composition, preferably 1 to 25%, and mixtures of glycols and ether glycols may be used.

The long chain alcohol ingredient b is preferably a straight chain aliphatic alcohol containing from 9 to 12 carbon atoms, or the analogous branched chain alcohols obtained by condensation of propylene. The alcohol serves as a lubrifacient to aid direct application of the composition to the skin and also assists transdermal penetration of the medicament. The presence of the long chain alcohol is therefore preferred when the composition would otherwise be excessively viscous and is particularly desirable when the polyalkylene ether glycol or alkylene glycol is also present.

The long chain alcohol ingredient b is present in an amount of up to about 30%, for example from 1 to 25%, preferably 1 to 10%, of the total composition.

The plant extract ingredient c. can be selected from a wide range of such material which exhibit anti-fungal and/or anti-bacterial properties. Preferably, the plant extract also exhibits preservative properties at dosage rates of the ingredient which are physiologically acceptable. That is, the plant extract exhibits physiologically useful effects at a dosage rate similar to the rate at which the other ingredients are applied to the skin in the composition. Thus, the amount of the plant extract required to achieve useful effects does not imbalance the overall composition.

Preferably, the plant extract is an essential oil as defined at page 670 of Martindale, The Extra Pharmacopoeia, 28th edition. Such essential oils include those derived from the foliage of plants and trees and are typified as containing terpenoid compounds. These may be hydrocarbon terpenes or oxygen containing compounds, for example terpene alcohols, ketones or oxides. Specific preferred terpene compounds include a-pinene, a-terpinene, limonene, 1,8-cineol, gamma- terpinene, p-cymene, l-terpinen-4-ol, aromadendrene, a- terpineol, and mixtures thereof. The terpene compounds for present use may be synthetic or naturally occurring, as when a eucalyptus type tree oil is used, notably the oil from Melaleuca alternifolia tree, known as Tea Tree Oil.

The plant extract ingredient c. may thus be used as the naturally occurring mixture of materials containing the active ingredient, or may be used in the form of an isolated and refined extract containing a raised proportion of the active ingredient or as an individual synthetically prepared single compound or mixture of isomers.

The plant extract ingredient c is typically present in up to

15%, for example from 0.1 to 10%, preferably 0.5 to 5%, notably from 0.5 to 2.5%,- by weight of active ingredient

based on the total composition and serves primarily as a penetration assistant in the composition. It is therefore preferred that such a plant extract or essential oil be present as one of the specified ingredients in any composition according to the invention.

The skin moisturising agent for use as ingredient d is a compound or mixture of compounds which maintains or increases the hydration of the stratum corneum of the skin. A number of materials are known to possess this property and specific examples include: urea; lactic, ascorbic or glycollic acids and salts thereof; cholesterol; liposomes and niosomes; pyrrolidone carboxylic acid and salts thereof; gamma-linoleic acid and its salts; mono- and poly- aminosaccharides; chitins and chemically modified chitins which contain ether and extra alkyl groups; and hyaluronic acid. Mixtures of such skin moisturising agents may be used if desired.

The skin moisturising agent ingredient d is present in an amount of up to about 10%, for example from 0.1 to 5%, preferably from 0.1 to 2% by weight of the total composition.

As stated above, the composition may contain other ingredients normally present in topically applied compositions. Typically these will provide up to 50%, for example from 0.1 to 35% by weight of the total composition. Such other ingredients include for example solvents or co- solvents, such as water, low molecular weight alcohols, eg. ethyl or propyl alcohols or glycols; and penetration enhancers, such as long chain acids, esters, glycols or saccharide derivatives. The presence of long chain fatty acids and derivatives, notably esters, thereof is especially preferred since they aid formation of stable gels when all

four of the specified ingredients are present. Particularly preferred fatty acids and esters thereof for present use are those of the empirical formula Alk-OOCAcid where Alk denotes a straight or branched alkyl group containing from 2 to 18 carbon atoms and Acid denotes a saturated or unsaturated straight or branched chain alkyl group which may carry one or more Alk-OOC- substituents. Typical of such fatty acid esters are C ₁ to C ₁₈ alkyl esters of octanoic acid or octanoic acid itself.

Other ingredients which may also be present include, for example, a pH controlling agent such as sodium, potassium, ammonium or an alkaline-earth metal hydroxide, or an organic base of the primary, secondary or tertiary amine type, to give a final pH in the range 4.5 - 9.0 and more preferably 7.0 - 8.5.

The ingredients c are often obtained from natural materials and will therefore differ in composition and be a mixture of the desired ingredient with other materials. Such mixtures may be used without the need to isolate the specified essential ingredient and the percentages given above are in terms of the desired component of such mixtures. Where the mixture contains large amounts of physiologically acceptable other components, these may themselves provide beneficial other properties, for example fragrance to the composition, and it may be necessary to use larger amounts of the mixture to achieve the desired proportion of the desired essential oil than the percentages given above. The percentages should therefore be treated as guides to the desired amounts and the optimal amounts can be readily determined by simple tests.

The compositions of the invention can be prepared using a wide range of techniques., for example by admixing and

stirring together the . desired amounts of the various ingredients to form a cream, paste or gel. If desired, the ingredients can be pre-dissolved or suspended in one or more of the other ingredients, for example in a propylene glycol solvent, to aid formation of a stable gel or emulsion. In some cases it may be desirable to subject the composition at some stage during its preparation to high speed shear working taking care to avoid entraiment of air, notably where a resin thickener or cellulose derivative is used as a gelling agent. Where necessary, the pH of the composition can be adjusted by the addition of a suitable pH regulator after the other ingredients have been incorporated.

The compositions of the invention are applied to the affected areas of the skin of a mammal, notably a human being, to treat the psoriasis or other skin disorder by applying the composition as a coating over the affected area or can be applied to any other desired area where the medicament is to be absorbed into the body for a systemic effect elsewhere in the body. This can be achieved by applying the composition directly in the required amount as a cream, paste or gel to the skin, for example by wiping a gel stick presentation of the composition which exposes the desired length of the gel stick across the desired area pf the skin until the exposed portion of the stick has been applied to the skin. Alternatively, the composition can be put up in a pressurised dispenser formulation and applied as a spray, foam, mousse or gel via a metered dose valve, which dose can thenn be spread over and/or massaged into the skin. Alternatively, the composition can be applied to an adhesive plaster, pad, gauze or other backing support member or carrier which is then applied over the affected area. The coating of the composition on the skin or the backing support can have applied thereto a vapour barrier film, for example a plastic film or a spray on film-forming resin, for

example a synthetic skin. _, type composition, which serves to retain water and other fluids in the composition and the skin. However, where the polyalkylene ether glycol or alkylene glycol ingredient a is present in sufficient amounts, this may provide a gel matrix for the other components and also impart sufficient occlusive properties for the use of a vapour barrier membrane not to be necessary.

The amount of the composition of the invention applied to the skin will be sufficient to apply the biologically effective amount of the medicament. This amount will vary according to the treatment required and the content of active ingredient in the composition. The optimal amount of the composition to be applied can be readily established as is known from a knowledge of these.

DESCRIPTION OF THE PREFERRED EMBODIMENTS OF THE INVENTION:

The following examples are provided for illustration only and are not intended or designed to limit the scope of the invention. All parts and proportions are given by metric weight and volume units unless stated otherwise.

Example 1

A co-solution of stearic acid (8 parts by weight) and propylene glycol (8 parts by weight) was prepared at 70°C with, mechanical stirring. A separate solution of a mixture of polyethylene glycol (ingredient a, average molecular weight 400, 6 parts by weight) in polyethyene glycol (ingredient a, average molecular weight 4000, 20 parts by weight) was prepared similarly. The two solutions were mixed together at 60-65°C using a mixer without entrainment of air. A solution of sodium hydroxide (1.12 parts), a polyaminosaccharide condensate skin moisturising agent

(ingredient d, 1.1 parts., by weight) in deionised water (25 parts by volume) was slowly added with stirring. The mixture was slowly cooled to 30°C with high shear mixing without entrainment of air to give a visous white pastey mass. The mass was mixed with a solution of Tea Tree oil (ingredient c, l part by volume), dodecanol (ingredient b, 2 parts by weight) and, as a lubrifacient to aid preparaton of the mixture and application of the composition to the skin, an emollient ester of polypropylene glycol and myristic acid (0.2 parts by weight) in ethanol (24 parts by volume) . The mixture was stirred continuously for one hour to give a creamy hydrogel base and packed into a sealed container until used (Formulation II, FII). Similar hydrogel base compositions were made but with varying ingredients as set out below:

Formulation I: FII, dodecanol ingredient b omitted Formulation III: FII, cetyl alcohol replaces dodecanol Formulation IV: FII, moisturising agent ingredient d omitted

Formulation V: FII, methyl cellulose (5 parts) in place of polyethylene glycol ingredient a Formulation VI: FII, emollient and moisturising agent ingredients . d replaced with a saccharide ester emollient

Formulation VII: FII, omitting the essential oil ingredient c _.

Methotrexate of BP grade was mechanically admixed in varying amounts (1% w/w, 0.5% w/w, 0.25% w/w, 0.2% w/w and 0.1% w/w) with the hydrogel bases and the resultant compositions stored in sealed, light-tight containers until used.

The compositions were applied as a coating of 0.05 to 0.1 grams per square cm to samples of isolated human stratum

corneum (obtained from mammary reduction or abdomenoplasty for several different donors) prepared as described by Skerrow & Skerrow (1985) or Kligman & Christophers (Arch.Der atol. 88.702 (1974).

Transdermal delivery was measured in micrograms per square centimetre per hour using a stability indicating hplc assay method, sampling the stirred receptor layer over periods up to 96 hours. The cells (made of glass) were similar to those described by Franz (Curr. Probl. Dermatol.7-58 (1978). The compositions ^' were applied to the epidermal surface of the stratum corneum and the dermal side was bathed by a stirred phosphate buffered saline solution containing 10% ethanol. The system was maintained at 32 degrees, light was excluded and the exposed surface of the applied composition was occluded to prevent alcohol and water loss. Two or more cells were run for each formulation and the skin integrity was assessed visually both before and after the experiment using a hand lens.

The results for these tests are set out in Tables 1, 2 and 3 below.

Table 1 - donor 2

1% w/w MTX 72 hr release rate of MTX in microgram/cm ² /hour

Formulation I 1.0

II 5.5 III 1.0

IV 0.1

V None detected

VI 0.6

VII 0.7

Table 2 - donor 2

0.25 and 0.5% MTX 72 hour release rate Formulation II 0.25% 5.0 II 0.5% 4.5

Ha 0.5% 5.8

Formulation Ila = formulation II with addition of 1 part of a silicone wetting agent - dimethicone CS20.

Table 3 - using Formulation II, varying amounts of MTX:

Cumulative amount of MTX released in mcg/cm ²

0.2% MTX Donor 1 Donor 2 Donor 3 Donor 4

0.1% MTX Donor 4

0.5% MTX Donor 4

1.0% MTX Donor 4

For Formulation II containing all four specified ingredients, significant penetration of methotrexate (MTX) occurred at 24, 48 and 72 hours when compared to results obtained by previous workers (see for example K R Brain et al, Int. J. Pharm. vol 71 R9, 1991 where only 200 nanograms per square centimetre per 24 hours, and approximately 600 nanograms at 48 hours, were achieved). When formulations in

which one of the specified ingredients had been omitted were used, the above results show that lower but still useful penetration of the MTX was achieved.

Example 2:

Attempts were made to prepare a composition containing only two of the four specified ingredients required for the formulations of the invention. In all cases the products were unacceptable as being unstable or as being too thick and could not easily be incorporated into formulations for application .to the skin. No useful results could be obtained from such compositions due to the impossibility of applying them effectively to the skin.