GB2157173A - Topical dithranol containing compositions - Google Patents

Abstract

A pharmaceutical agent in stick form for the treatment of psoriasis, contains as active substance 1,8,9-anthracentriol (dithranol) in amounts of from 0.01 to 0.2% by weight and urea in micronised form in amounts of from 10 - 20%, based on the stick composition.

Description

SPECIFICATION Pharmaceutical agent for the treatment of psoriasis This invention relates to a pharmaceutical agent in stick form for the treatment of psoriasis.

For decades the active substance dithranol (1,8,9-anthracentriol) has been used for the treatment of psoriasis. Generally paste-type preparations in Vaseline have been used. As a rule these preparations have taken considerable time to apply and involved substantial inconvenience. The application of this Vaseiine pasteto extensive parts of the body cannot be done in the patient's home and furthermorethe patient must be kept motionless. Use of the paste also involves considerable soiling of clothes. One attempt to make the treatment shorter consisted of applying more highly concentrated dithranol creams, since it has been found that the absorption of dithranol into lower layers of skin occurs very rapidly in psoriasis-damages skin.A disadvantage ofthis is that healthy areas of skin are particularly badly irritated sothatfrequenctly treatment is discontinued. More recently, administration in stick form has been considered. (Cf. V. Watzig, Dermatol, Monatsschr. 169, (8) 533-34 (1983).

Attempts have also been made to improve the use of dithranol in the treatment of psoriasis by varying the vehicle base used. These include, for example, preparations containing 0.1% dithranol in a 17% urea base [("Psoradrates"). Cf. D.M. Williamson in Clin. Exp. Dermatol. 8, 287-290 (1983)1.

Dithranol is used, for example, in preparations together with salicylic acid. Certainly salicylic acid does not itself intensify the antipsoriatic effect and occasionally it even provokes local and systemic toxic effects. There istherefore still a need to improvethetherapeutic possibilities of the treatment of psoriasis with dithranol and to make the therapy itself more effective and pleasant. In particular, it should be possible and would be desirable to treat the condition by topical application with the least possible side-effects on unaffected areas of the body.

We have now found that pharmaceutical compositions in stick form which contain 1,8,9-anthracentriol (dithranol) as active substance, generally in addition to other constituents which are knownperse, satisfy the requirements for a modern, rational application of the active substance particularly well if they also contain finely divided micronised urea.

According to the invention, therefore, we provide a pharmaceutical agent in stick form for the treatment of psoriasis which comprises 1,8,9-anthracentriol (dithranol) as active substance in a quantity of from 0.01 to 0.2% by weight and urea in micronised form in an amount of from 10 to 20% by weight, based on the stick composition. The particle size of the urea is appropriately in the range of from 1 to 10 tjm.

The stick may be produced similarly to sticks for the treatment of acne or cosmetic sticks such as lipsticks, deodorant sticks and the like. Generally, the sticks according to the invention should be prepared without any added emulsifier. The stick composition should form a lipid film after topical application, i.e. the substance should rub off like a wax. Advantageously, the stick composition is substantially an hydrous and redox-stable.

Preferably, the drop point of the materials used should be, after formulation, about 60 t 7"C (according to Deutsches Arzneibuch, 8th edition, page 11) or the melting point, using the open capillary method (according to Europ. Arzneibuch, Volume Ill, page 29) should be about 55"C.

Thus, for example, saturated organic compounds of wax nature which melt at between 60 and 80"C and liquid constituents which, when mixed with the solid constituents, produce the desired consistency, e.g. oils such as castor oil or isopropylmyristate, are suitable. The stick compositions may therefore advantageously be made up of triglycerides and other esters of long-chained saturated fatty acids and/or from paraffinic hydrocarbons which satisfy the above criteria. Examples of suitable materials include candelilla wax, beeswax, carnauba wax and ozocerite.

The dithranol content of the sticks is in the range from 0.01 to 0.2% by weight, preferably 0.05 to 0.1% by weight, based on the stick composition suitable for therapeutic use.

To produce the sticks, the solid constituents of the stick are melted, optionally in the presence of any liquid constituents, and converted into a melt in the range from 60 to 80 in order to obtain suitable pouring conditions. Then the active substances and any excipients desired are added and dispersed or dissolved therein, preferably by continuous stirring, in this temperature range, conveniently with the aid of an intensive stirrer or a dissolver disc.

The combination of the active substance dithranol with urea in micronised form according to the invention surprisingly has a synergistic effect in terms of its antipsoriatic effect. Consequently, it is possible to reduce the quantities of dithranol required fortherapy. The known combination of dithranol and salicylic acid does not, for example, have this effect. The disadvantageous or even toxic side-effects of this combination previously described can be avoided. The waxy composition of the sticks according to the invention gives an effect of occlusion which ensures optimum penetration of the active substance. At the same time the occluding film prevents transdermal water loss sathat the skin remains soft and smooth.

Using the stick described it is now readily possible to treat precisely circumscribed areas of the body several times a day. Application, comparable with that of an acne stick or lipstick, is greatly simplified compared with the application of a cream since the skin is not solid. The substance rubs offlike a wax and produces only afilm which is resistant to abrasion. This has the added advantage of avoiding discoloration of clothing. As a result of the precisely circumscribed site of application, irritation of healthy skin by dithranol is avoided.

Dithranol therapy, which is not always tolerated in the same way by the patient, can now be actively controlled by the patient and the concentration of active substance can be increased to the limit of tolerance without irritation, so that high concentrations of active substance can be applied to the seat of the psoriasis.

The interaction ofthe dithranolwiththe urea is largely responsibleforthe optimum availability ofthe active substance.

Comparative studies with different dermatological bases have shown the following: the use of hydrophilic vehicle systems does admittedly lead to higher concentrations of urea in the upper layers of skin in the short term but the concentration in the deeper layers of skin (Stratum basale) is so small that no adequate antipsoriatic effect is obtained. Owing to the absence of an occluding film, moreover, there is a high rate of transportation ofwaterfrom the inside of the body through the skin to the surface of the skin, resulting in high losses of moisture caused by epidermal evaporation.

By contrast, lipophilic systems have the following advantage: due to the film of lipid on the skin they bring about lower hydration ofthe upper layers of skin, shortly after application, with slower penetration ofthe urea, however high urea concentrations can be detected even in the deeper layers of skin after a fairly lengthy period ( > 1.5 hours). The lipophilic base is found to be advantageous if hydration periods of more than 5 hours are considered. The particular advantage of the lipophilic base is that the urea from lipid preparations penetrates into the deeper layers of skin, preparing the way for the action of the pharmaceutical composition.

By contrast with the hydrophilic base, the transepidermal water loss is eliminated by the use of a lipophilic base, so that better hydration of the dry psoriatic skin is ensured and the skin is quickly healed, while the availability of the active substance is improved in deeper layers of skin by the aid to penetration.

Frequently, after a course of treatment of psoriasis, the situation arises that the degree of cure is reduced by a few areas which are resistant to the treatment. In the view of both the patient and the doctor, these do not require any major treatment over a large area, either by ultraviolet light or by application of dithranol cream to a large area. in these instances the possibiiity of treatment with a dithranol stick which can be applied to the few psoriasis sores without causing irritation is particularly advantageous and again enables the patient to apply his own treatment whilst moving around freely.

The following non-limiting Examples serveto illustratethe production ofthe pharmaceutical agents in stick form according to the invention.

The percentages given relate to percent by weight Examples of compositions 1st Example Paraffin subliquidum Hard paraffin (mp 42 - 46"C) - 77.35% Hard paraffin (mp 68 - 72"C) Palmitic acid 5.5 % Urea 17.0 % Dithranol 0.05% Perfume 0.1 % The stick components are liquefied in melt containers at 75"C, the solids are dispersed therein and the finished composition is poured into stick cases.

2nd Example Paraffin subliquidum Hard paraffin (mp 42 - 46"C) - 73.3% Hard paraffin (mp 68 - 72%C) - Palmitic acid 5.5% Candelilla wax 4.0% Dithranol 0.1% Urea 17.0% Perfume 0.1% The composition is processed to form sticks as described above.

Claims (11)

1. A pharmaceutical agent in stick form forthe treatment of psoriasis which comprises 1,8,9-anthracentriol (dithranol) as active substance in a quantity of from 0.01 to 0.2% by weight and urea in micronised form in an amount of from 10 to 20% by weight, based on the stick composition.

2. A pharmaceutical agent in stick form as claimed in claim 1 which contains from 0.05 to 0.1% by weight of dithranol.

3. A pharmaceutical agent in stick form as claimed in either of claims 1 or 2 wherein the agent contains urea having a particle size in the range from 1 to 10 ,a.

4. A pharmaceutical agent in stick form as claimed in any of claims 1 to 3 wherein the agent is prepared without the addition of emuisifier.

5. A pharmaceutical agent in stick form as claimed in any of claims 1 to 4 wherein the agent acts to form a film of lipid after topical application.

6. A pharmaceutical agent in stick form as claimed in any of claims 1 to 5 wherein the stick composition is anhydrous and redox-stable.

7. A pharmaceutical agent in stick form as claimed in any of claims 1 to 6 wherein the stick composition is based upon saturated compounds of a waxy nature which melt at between 60 and 80"C.

8. A pharmaceutical agent in stick form as claimed in claim 7 wherein the stick composition contains triglycerides or esters of saturated fatty acids.

9. A pharmaceutical agent in stick form as claimed in claim 7 wherein the stick composition contains paraffinic hydrocarbons.

10. A pharmaceutical agent as claimed in claim 1 substantially as hereinbefore described.

11. A pharmaceutical agent in stick form for the treatment of psoriasis substantially as hereinbefore described with reference to the Examples.