GB2165453A - Adhesive antipsoriasis skin patches - Google Patents

Abstract

Glucocorticoid-free pharmaceutical agents for local therapy of psoriasis, containing anti-psoriatic active substances known per se consist of a self-adhesive non-permeable film the adhesive layer of which contains the glucocorticoid-free anti-psoriatic active substance and preferably urea in a uniform fine distribution.

Description

SPECIFICATION Pharmaceutical Agent for the Local Treatment of Psoriasis The invention relates to a glucocorticoid-free pharmaceutical agent for the local treatment of psoriasis. More particularly it relates to an agent which contains an anti-psoriatic active substance known perse and optionally finely divided urea, salicyclic acid and/ortherapeutically permissible reducing agents and/or physiologically harmless complex-forming agents.

Psoriasis vulgaris, an erythematosq'uamous dermatitis, is thought to be a multi-factor inherited disease and is considerably affected by environmental factors. This dermatitis is found particularly frequently on the elbows, the backs of the knees, the scalp and the nails, i.e. all exposed parts of the body, and for this reason causes serious problems, not least of which are the associated psychological problems.

Conventional drugs for the local treatment of psoriasis include, for example, halogenated or nonhalogenated glucocorticoids applied topically. In view of the large number of possible indications for glucocorticoids, however, there are calls from some quarters for the use of this type of compound to be restricted to other types of disease. Other therapeutical substances applied in cases of psoriasis include, for example, allantoin, fumaric acid and the salts thereof, undecylenic acid, retinoic acid and ch rysarobene (1 ,8-dihydroxy-3- methylanth rone). Recently, the active substance dithranol (1,8,9-anthracentriol) has been used with some success in the treatment of psoriasis. The pharmaceutical forms used are restricted mainly to conventional preparations such as solutions, creams, ointments and the like.

The problems arising in therapy according to the prior art will now be explained more fully by taking the example of the application of dithranol as an active substance in the treatment of psoriasis.

Frequently, paste-like preparations of the active substance in Vaseline are used. These preparations generally take up a considerable amount of time for the patient and give rise to considerable inconvenience. The application of a Vaseline paste over large parts of the body cannot be carried out in the patient's home but only when staying in hospital. This also involves a considerable degree of soiling of clothes.

One attempt to shorten the therapy consisted in applying more highly concentrated dithranol creams, since it was found that the absorption of dithranol into deeper layers of the skin occurs extremely rapidly in psoriasis-damaged skin. One disadvantage of this is that healthy areas of the skin are greatly irritated with the result that the therapy is frequently discontinued. Recently, application in stick form has also been considered. (Cf. V. Watzig, Dermatol. Monatsschr. 169(8)533-34(1983).

Furthermore, attempts have already been made to improve the application of dithranol in psoriasis treatment by varying the vehicle base. Examples include preparations containing 0.1% dithranol in a 17% urea base. [("Psoradrates"). Cf. D. M.

Williamson in Clin. Exp. Dermatol. 8287-290 (1983)]. A combination with salicyciic acid as a keratolytic has also been used. Salicyclic acid certainly does not intensify the antipsoriatic efect For particularly resistant psoriasis sites which are only partly amenable to simple treatment, occlusive conditions are preferably used in dermatology, i.e. a diseased area of skin is coated with ointment and covered with a waterproof dressing. Below the dressing a sealed moist area is produced which allows the skin to swell up and promotes penetration into deeper layers.

Plasters containing drugs are known per se.

Usually, these are perforated to allow the skin to breathe and are applied to elastic material. (Cf.

Ullmanns Encyklopdie der technischen Chemie, 3rd Edition, 4th Volume, page 2426, Urban & BR< Schwarzenberg, 1953).

Thus in psoriasis sufferers, apart from the actual complaint, the circumstances accompanying the treatment are very distressing. It would therefore be desirable to improve the therapeutic conditions of psoriasis treatment and to make the therapy itself more effective and, if possible, more pleasant. It would also be desirable to provide a glucocorticoidfree localised treatment with as littie interference as possible with unaffected areas of the body. In the field of topical therapy using glucocorticoids, selfadhesive carrier films have been used containing the halogenated corticoid fluorandrenolone incorporated in the adhesive layer.

We have now found that glucocorticoid-free pharmaceutical agents comprising a self-adhesive non-permeable film, the adhesive layer of which contains a glucocorticoid-free antipsoriatic active substance in a uniformly fine distribution, are particularly suitable.

Thus according to one feature of the invention we provide a glucocorticoid-free pharmaceutical agent for local treatment of psoriasis, which comprises a self-adhesive non-permeable film the adhesive layer of which contains a glucocorticoid-free antipsoriatic active substance in a uniform fine distribution.

The agents according to the invention are particularly suitable for use with antipsoriatics selected from the group comprising the hydroxylated anthraquinones, the antipsoriatic carboxylic acids and allantoin and the group of tar products used as antipsoriatics. The latter include coal tar Pix lithranthracis), liquor carbon is detergens (20% coal tar in quillaja tincture), tars consisting of vegetable constituents such as charcoal tar, sulphonated shale oils such as, for example, ammonium bituminosulfuricum ("Ichtyol" and "Tumenol" ammonium). Particular mention should be made of dithranol, undecylenic acid (10 undecenoic acid), fumaric acid and the therapeutically useful salts thereof such as the disodium salt, retinoic acid and allantoin.The latter active substances are generally present in solid, usually crystalline form and can be brought to the desired degree of distribution in a manner known perse, e.g. by powdering (F. Gstirner, 'Einführung in die Verfah renstechnik der Arzneiforsch sung', 5th Edition, Wissenschaftliche Verlagsgesellschaft, Stuttgart, 1973). It is particularly advantageous if urea is simultaneously present in finely divided form in the adhesive layer of the film.It should be particularly emphasised that the combination of the glucocorticoid-free active substances (such as dithranol) with urea in a relatively high concentration, when adequately chemically stabilised, can be incorporated in the adhesive layer of a carrier film without undoing the adhesive effect of the coating and hence the occlusive conditions.

Generally, the content of the antipsoriatic active substance in the adhesive layer is 0.1 to 1000 pig per cm2 of area of coating, preferably from 1 to 250 pg, more particularlyfrom 2 to 150 per cm2 of area.

The urea content is preferably 100 to 300 times the content of the antipsoriatic active substance by weight. Preferably, urea (in the therapeutically permitted quality) is applied in micronised form, generally with a particle size in the range from 1-5 microns. The size of the particles of active substance is preferably of the same order of magnitude. The addition of salicylic acid in finely divided form in the adhesive layer is also envisaged within the scope of the invention. The content of salicylic acid should be 100 to 200 times the weight of the antipsoriatic active substance.

The carrier film material should preferably, as is usual for therapeutic purposes, be resistant to tearing, impervious to water (and steam) and air, i.e.

generally impermeable, smooth and flexible, well tolerated by the skin and resistant to external effects and must stay firmly and safely in place. (Cf.

Ullmanns Encyklopädie der Techn. Chemie, 4th Edition, Volume 18, pp. 164, 165,Verlag Chemie.

1979).

Physiologically inert films, preferably of polyethylene, polypropylene, polyurethane, polyvinyl chloride or mixtures thereof, are used, for example. Skin-coloured films are preferred for this particular therapy.

Preferably, conventional acrylate adhesives are used for the adhesive layer. In order to have the desired adhesive effect, the polymers generally have a dynamic freezing temperature T^maK (according to DIN 53 445 or 7724) of less than 20"C, preferably less than 10"C. It is also advisable to coverthe adhesive layers up to the moment of use with a removable paper which is pulled off just before use. Suitable acrylate adhesives are known, for example, from the manufacture of wound dressings.

These are preferably polymers based on alkylacrylates, particularly with up to 8 carbon atoms in the alcohol group, e.g. copolymers of several alkylacrylates and/or methacrylates with, for example, acrylic acid and/or other vinyl compounds such as vinyl acetate, whilst the content of acrylic ester is generally at least 25% by weight. Mention may be made, for example, of (co)polymers of the monomers butylacrylate, ethylacrylate, isooctylacrylate and optionally with hydroxy groupsubstituted esters of acrylic acid.

The active substance and any other adjuvants which are to be included are incorporated in the adhesive composition by dispersion or solution.

Advantageously, the active substance and any other additives such as urea, salicylic acid and optional stabilisers are added to the material intended for the adhesive layer beforethefilm is coated. It has proved particularly advisable to use aqueous plastics dispersions to produce the adhesive layer. Advantageously, the pH of these dispersions is within the acid range and may be up to, at most, the neutral range, for example below pH 7. The acid pH can be adjusted by buffering with suitable buffers.

Mention may be made, for example, of acrylic resin dispersions, preferably based on 2ethylhexylacrylate, ethylacrylate and 2hydroxypropylacrylate, for example in a weight ratio of 64:30:6.

It has proved particularly convenient to add certain stabilisers such as therapeutically permitted reducing agents to the adhesive layer in uniform distribution. Examples of such agents include ascorbic acid, sodium or potassium dithionite, cystein and the physiologically acceptable acid addition salts thereof such as the hydrochloride. The quantity added is generally of the order of 10 to 1000% by weight, preferably up to 200% by weight, based on the anti-psoriatic active substance.

Furthermore, the therapeutic agents according to the invention may conveniently also contain, in uniform distribution, physiologically harmless complex forming agents such as ethylenediamine tetraacetic acid, tartaric, lactic or citric acid or the physiologically acceptable salts thereof such as the alkaline or alkaline earth metal salts in amounts from 10 to 250 times the weight of the active substance.

The thickness of the foil coating is generally in the range from 20 to 400 pm,whilst the thickness of the adhesive layer is generally in the range from 1 to 100 pm. There are no direct limitations regarding the geometric shape of the films as pharmaceutical agents (apart from the limitations imposed by the use of machinery), but the coated films should be large enough to allow sections to be cut out which will completely cover the parts of the body affected by psoriasis.

By cutting out a suitable section of film it is possible to apply controlled treatment to affected parts of the skin whilst at the same time providing mechanical protection. The therapeutic agent according to the invention generally permits simple application of the active substances and, by providing optimum therapy conditions, results in a therapeutic effect which is increased by its deep action without any additional irritation of the skin.

Compared with conventional therapy the active substances are more uniformly metered and side effects are reduced whilst stability is improved. The sealing off of the active substances from the outside creates the occlusive conditions which are therapeutically favourable. Moreover, the discoloration of linen and clothing caused by dithranol is avoided. Psoriasis sites on exposed areas of skin are covered up by the skin-coloured film in a cosmetically attractive way and this improves the patient's acceptance of the often long-lasting therapy.

In practical use the procedure may be, for example, to dissolve the additives such as urea, salicylic acid and the reducing agent and so on in purified water and then finely disperse the active substance therein in a disperser (e.g. an "Ultra Turrax" apparatus made by Janke & Kunkel, Freiburg, West Germany). When dithranol is used, the quantities used are preferablyfrom 2.0 to 20 pg per cm2 of area of coating.If fumaric acid and the salts thereof are used the quantities are conveniently from 50--500 g/cm2 whilst for undecylenic acid the quantities are conveniently from 20--150 yg/cma, for retinoic acid the quantities are conveniently from 0.5 to 5,ug/cm2, when allantoin is used the quantities are conveniently from 20--200 yg/cm2 and tar preparations may be used in quantities of from 101001lg/cm2.

This mixture is added to the dispersion of the adhesive, they are mixed uniformly with a stirrer and the mixture is evenly applied to the plaster film with a doctor blade and then dried. The adhesive layer containing the active substance may be protected by covering with siliconised paper which is removed just before use.

The following non-limiting Examples serve to illustrate the invention.

Preparation of the Adhesive Dispersion 0.064 g of the sodium salt of a triisobutylphenol polyoxyethylenesulphate with 7 oxyethylene units and 0.60 g of ammonium per oxodisulphate dissolved in 865 g of totally salt-free water are placed at 85"C in a polymerisation vessel fitted with a stirrer, reflux condenser and thermometer. At 85"C an emulsion consisting of 12.8 g of the above emulsifier 10.2 g of ammonium peroxodisulphate 1.8 g of 2-ethyl hexylthiog lycolate 2458 g of 2-ethylhexylacrylate 1152 g of ethylacrylate 230 g of 2-hydroxypropylacrylate and 1620 g of water are added dropwise to this solution within the course of 5 hours.The dispersion is kept at 85"C for a further 2 hours, then cooled to ambient temperature and filtered through a fine-meshed wire screen made of stainless steel. A coagulate-free dispersion is obtained with a dry content of 60.3% and an average particle diameter, determined by photon correlation spectroscopy, of 580 nm. The pH was 2.0 and the actual viscosity 1450 mPa.s (Brookfield Viscosimeter, 1, 6).

EXAMPLE 1 210.6 mg of urea, 88.5 mg of ascorbic acid, 63.5 mg of sodium citrate, 10.5 mg of sodium dithionite are dissolved in 15g of purified water and 1.2 mg of dithranol are finely dispersed therein. This mixture is added to 15 g of adhesive dispersion (60% dry content), uniformly mixed and evenly applied with a doctor blade to a polyethylene film with a surface area of 250 cm2 (thickness 130pom) and then dried.

The adhesive layer containing the active substance is protected by covering with siliconised paper which is removed before use. The adhesive layer used is preferably one which is based on the copolymer of 2-ethylhexylacrylate, ethylacrylate and 2-hydroxypropylacrylate in a weight ratio of 64:30:6 described in the above Preparation.

EXAMPLE 2 180 mg of salicylic acid, 100.5 mg of ascorbic acid, 105 mg of sodium citrate, 60 g of tartaric acid and 13 mg of sodium dithionite are dissolved in a mixture of 5 g of purified water and 15 g of adhesive dispersion and 2.4 mg of dithranol are finely dispersed therein. The mixture is worked up as in Example 1.

EXAMPLE 3 (Use of tar products) 12.5 mg of Pix Juniperi, 62.5 mg of salicylic acid, 97.0 mg of tartaric acid, 25.0 mg of ethylenediamine tetraacetic acid, 1.0 g of Tween 801) and 250 mg of Span 802) are dissolved or finely dispersed in 15 g of purified water using a high speed stirrer. 25 g of adhesive dispersion are added to this mixture and uniformly mixed in. The mixture is worked up as in Example 1; drying is effected at 35"C with forced air circulation.

EXAMPLE4 (Use of fumaric acid and the salts thereof) 15.0 mg of fumaric acid, 50.0 mg of salicylic acid, 45.0 mg of tartaric acid, 22.5 mg of cystein and 300 mg of glycerol are dissolved in a mixture of 20.0 mg of water and 15.0 g of adhesive dispersion at ambient temperature with stirring and then worked up as in Example 1.

EXAMPLE 5 (Use of allantoin) 25.0 mg of allantoin, 25.0 mg of salicylic acid, 10.5 mg of sodium dithionite, 88.5 mg of ascorbic acid and 63.5 mg of sodium citrate are finely dispersed or dissolved in 10 g of purified waterwith intensive stirring. 15 g of adhesive dispersion and 300 mg of Tween 80 are added to this mixture, mixed thoroughly and worked up as in Example 1.

EXAMPLE 6 (Use of undecylenic acid) 6.3 mg of undecylenic acid, 105 mg of citric acid, 800 mg of Tween 80,20.0 mg of salicylic acid and 1.5 g of 70% sorbitol solution are dispersed or dissolved in 15 g of water at 30 C with intensive stirring, then mixed with 15 g of adhesive and worked up as in Example 1.

EXAMPLE 7 (Use of retinoic acid) 1.0 mg of retinoic acid, 50 mg of salicylic acid, 100.0 mg of Tween 80,7.5 mg of sodium dithionite, 75.0 mg of ascorbic acid and 58 mg of Na-citrate are Polyoxyethylene-(20)-sorbitan-monooleate; produced by Atlas 2)Sorbitan monooleate dispersed or dissolved in 10.0 g of purified water and then mixed with 15.0 g of adhesive dispersion.

The mixture is worked up as in Example 1.

Claims (20)

1. A glucocorticoid-free pharmaceutical agent for local treatment of psoriasis, which comprises a self-adhesive non-permeable film the adhesive layer of which contains a glucocorticoid-free antipsoriatic active substance in a uniform fine distribution.

2. A glucocorticoid-free pharmaceutical agent as claimed in claim 1, wherein the adhesive layer contains from 0.1 to 1000 pg ofanti,-psoriaticactive substance per cm2 of surface area of the layer.

3. A glucocorticoid-free pharmaceutical agent as claimed in claim 2, wherein the adhesive layer contains from 1 to 250 pg of anti-psoriatic active substance per cm2 of area of the layer.

4. A glucocorticoid-free pharmaceutical agent as claimed in claim 1, wherein the adhesive layer contains, in addition zo the anti-psoriatic active substance, urea in a uniformly fine distribution.

5. A glucocorticoid-free pharmaceutical agent as claimed in claim 4, wherein the urea content is from 100 to 300 times the content of the antipsoriatic active substance by weight.

6. A glucocorticoid-free pharmaceutical agent as claimed in claim 1, wherein the adhesive layer contains salicylic acid in addition to the antipsoriatic active substance.

7. A glucocorticoid-free pharmaceutical agent as claimed in claim 6, wherein the salicylic acid content is from 100 to 250 times the content of the antipsoriatic active substance by weight

8. A glucocorticoid-free pharmaceutical agent as claimed in any of claims 1 to 7, wherein the adhesive layer is produced by coating the film with a polymer in dispersion, the pH of the dispersion beina below 7.

9. A glucocorticoid-free pharmeutical agent as claimed in any of claims 1 to 8, wherein the adhesive layer additionally contains one or more therapeutically acceptable reducing agents.

10. A glucocorticoid-free pharmaceutical agent as claimed in claim 9, wherein the adhesive layer contains the therapeutically permitted reducing agents in quantities of form 10 to 1000% by weight, based on the anti-psoriatic active substance.

11. A glucocorticoid-free therapeutic agent as claimed in either of claims 9 and 10, wherein the therapeutically permitted reducing agent is ascorbic acid, sodium or potassium dithionite, cystein or a physiologically acceptable acid addition salt thereof.

12. A glucocorticoid-free therapeutic agent as claimed in any of claims 1 to 11,which additionally contains one or more physiologically harmless complex-forming agents.

13. A glucocorticoid-free therapeutic agent as claimed in claim 12, wherein the physiologically acceptable complex-forming agent is ethylenediamine tetraacetic acid, lactic acid, tartaric acid, citric acid or the physiologically acceptable salts of these acids.

14. A glucocorticoid-free therapeutic agent as claimed in any of claims 1 to 13, wherein the active substance is dithranol.

15. A glucocorticoid-free therapeutic agent as claimed in any of claims 1 to 13, wherein the active substance is allantoin.

16. A glucocorticoid-free therapeutic agent as claimed in any of claims 1 to 13, wherein the active substance is fumaric acid and/or a physiologically acceptable salt thereof.

17. A glucocorticoid-free therapeutic agent as claimed in any of claims 1 to 13, wherein the active substance is undecylenic acid.

18. A glucocorticoid-free therapeutic agent as claimed in any of claims 1 to 13, wherein the active substance is retinoic acid.

19. A glucocorticoid-free therapeutic agent as claimed in any of claims 1 to 13, wherein the active substance is an anti-psoriatic tar substance as herein defined.

20. A glucocorticoid-free therapeutic agent as claimed in claim 1 substantially as herein described and with reference to any of the Examples.