US3450820A - Pharmaceutical composition containing triacetate of anthralin - Google Patents

Description

US. Cl. 424-311 7 Claims ABSTRACT OF THE DISCLOSURE Tri-esters of dithranol (1,8,9-trihydroxyanthracene), especially 1,8,9-triacetoxyanthracene, are useful in the treatment of psoriasis.

This invention relates to preparations for topical application in the treatment of psoriasis.

Psoriasis is. an intractable condition in which the skin becomes covered in areas of greater or lesser extent with white scales, the removal of which reveals reddened skin beneath. While it is not a disabling condition, it is disfiguring, and very difficult to treat satisfactorily. One known procedure consists in applying to the areas affected by psoriasis, compositions containing dithranol, i.e. 1,8,9- trihydroxy-anthracene, known in the United States also as anthralin. (The related compound, 1,9-dihydroxy-anthracene, has also been used.) While this treatment is quite effective, dithranol has a very marked effect on normal skin and compositions containing it must therefore be applied by skilled personnel under hospital conditions.

Moreover, even if this is done, the use of dithranol occasionally leads to unacceptable side effects.

It has now been found that certain esters of dithranol, 3-methyl-dithranol (also known as chrysarobin), and 1,9- dihydroxy-anthracene show similar activity to dithranol itself on areas of skin affected by psoriasis, but have little or no deleterious effect on normal skin.

The invention accordingly provides pharmaceutical compositions suitable for application to skin affected by psoriasis or a like proliferative condition comprising a triester of dithranol, a trior di-ester of chrysarobin, or a diester of 1,9-dihydroxy-anthracene dispersed in a suitable vehicle. The ester is preferably derived from a lower alkanoic acid containing, e.g., up to 4 carbon atoms. Dithranol triacetate is effective, readily prepared and preferred.

While the invention does not depend on any theoretical explanation, it is suggested that the psoriatic plaques contain esterases which cause hydrolysis of the ester, while normal skin contains fewer such esterases, with the result that the di or triester is substantially only activated by hydrolysis in those areas where it is required. Whether or not this explanation is a correct one, it has been found that the aforesaid esters may be applied in unskilled mannerto psoriatic areas without any risk that contact with the surrounding normal skin will lead to any undesirable side effects. In fact, it appears that the esters are ordinarily Without effect on normal skin.

The new compositions ordinarily contain from 0.1 to 2.0% by weight of the dior triester (calculated as unesterified hydroxy compound corresponding to about 0.15 to 3.0% of the preferred dithranol triacetate), but smaller proportions can be used, though this will not ordinarily be preferred because of the comparative lack of effect which the compositions will then show. In addition, amounts greater than 2.0 up to say 10% (calculated as free hydoxy compound) can be used, though in this case nited- States Patent "ice the use of such large amounts is liable to be wasteful because the ester may be removed, e.g. by contact with clothes before it has had any effect on the psoriasis.

The new compositions may be in any of the forms customarily used for application to the skin, e.g. ointments, creams, pastes, and lotions, but it is preferred that the compositions for which a long shelf life is required contain only a small proportion of water, e.g. less than 1%, or no water at all, because of the danger that water in an aqueous composition may cause hydrolysis of the ester groups. Such substantially anyhdrous compositions may contain a small proportion, usually 0.1 to 2% by weight, of an alkali such as sodium carbonate to promote hydrolysis of the ester after the composition has been applied to a psoriatic area.

Preferred compositions in accordance with the invention comprise a vehicle based on a greasy material, e.g. white soft parafiin, or stearyl alcohol, in which may be dispersed a wetting agent so as to give a product which spontaneously emulsifies on contact with water.

The compositions may also comprise adjuvant substances useful to promote removal of the psoriatic plaques, e.g. keratolytic agents such as salicylic acid or proteolytic enzymes such as pancreatin. Such substances, when used, will ordinarily be present in amount from 0.1 to 5% by weight, preferably 1 to 3% by weight, of the composition.

The following are three examples of vehicles for use in the compositions of the invention.

This is the composition known as Lassars Paste, which is conventionally used when dithranol itself is applied to the skin in the treatment of psoriasis.

Example 3 G. Cetyl stearyl alcohol 27 Sodium lauryl sulphate 3 White soft paraffin 50 Liquid parafiin 20 These ingredients are mixed together to form a homogeneous self-emulsifying ointment. Owing to the presence of Water in the starting materials, the ointment ordinarily contains about 0.4% by weight of water.

These three vehicles may be made up into compositions in accordance with the invention as follows:

Example 4 G. Dithranol triacetate 3 Vehicle of Example 2, ad

Example 5 Dithranol triacetate 10 Sodium carbonate, anhydrous 1 Vehicle of Example 3 5 Distilled water 10 Vehicle of Example 2, ad 100 The distilled water is preferably omitted if the composition is likely to be stored for any length of time.

3 Example 6 G. Dithanrol triacetate 3 Sodium carbonate, anhydrous 1 Trition X45 (registered trade mark) which is isooctyl phenyl polyethoxy ethanol OPE-3 Vehicle of Example 2, ad 100 Example 7 Dithranol triacetate Sodium carbonate, anhydrous 1 Distilled water 2 Pancreatin 1 Vehicle of Example 3, ad 100 Example 8 Dithranol triacetate 2 Sodium carbonate, anhydrous 1 Vehicle of Example 3 35 Distilled water, ad 100 Example 9 Dithranol triacetate 3 Sodium carbonate, anhydrous 1 Vehicle of Example 3, ad 100 Example 10 Dithranol triacetate 3 Sodium carbonate, anhydrous 1 Zinc oxide 0.8 Salicylic acid 2.8 Vehicle of Example 3, ad 100 In these examples, the vehicle of Example 2 may be replaced, if desired, by the vehicle of Example 1 and a very similar composition is obtained. Similarly the dithranol triacetate may be replaced by, for example, 1,9-diacetoxyanthracene, 1,8,9-triacetoxy-3-methylanthracene, or 1,9- diacetoxy-8-hydroxy-3-methylanthracene.

While dithranol triacetate is not a new compound, the following method for its preparation, which has been found to be useful, differs from that previously described in the literature.

Dithranol (150 g.) was ground with anhydrous sodium acetate (70 g.) and acetic anhydride (1000 g.) was added. The mixture was then refluxed for 30 minutes, and the tri acetyl derivative precipitated by pouring the product into 8 litres of iced water, and separated by filtration. It was recrystallized from benzene, and then formed pale yellow odourless needles melting at 208 C. The yield is 195 g. or 84% of theory.

The new compositions are used in the treatment of psoriasis in similar manner to the known compositions containing dithranol but with the conspicuous and important advantages that, unlike the said known compositions, the new compositions neither burn nor stain normal skin while having an action on psoriatic plaques which is just as elfective as dithranol but without the side effects of burning and staining ordinarily encountered with that compound. This has the valuable result that application of the new compositions can be carried out by unskilled personnel. The composition, e.g. that described in any one of Examples 4 to 10, is generally rubbed into the psoriatic areas once or twice daily, and the treated areas are left uncovered unless covering is necessary to prevent the compositions being rubbed off or soiling the clothes. Where the composition contains substantially no water, it is generally advisable to wet the psoriatic area before the composition is rubbed in. Improvement is generally observed within a few days, and in most cases a complete regression is obtained in two to five weeks. Thus the manner of use of the new composition is very simple and improvement or complete regression of the psoriaris is very rapidly obtained.

We claim:

1. A pharmaceutical composition comprising 0.1 to 10% by weight of the triacetate of anthralin, calculated as anthralin, dispersed in an inert vehicle selected from the group consisting of ointments, creams, pastes and lotions.

2. A pharmaceutical composition according to claim 1 in which the ointment base is white soft paraffin.

3. A pharmaceutical composition according to claim 1 in which the said triester is dispersed in a cream base consisting of self-emulsifying ointment base in water.

4. A pharmaceutical composition according to claim 1 containing 0.1 to 2% by weight of said triacetate, calculated as anthralin.

5. A pharmaceutical composition according to claim 2 which also contains zinc oxide and starch.

6. A method of treating psoriasis which comprises applying to a psoriatic area an elfective amount of the triacetate of anthralin.

7. A method according to claim 6 in which the triacetate is dispersed in an inert vehicle selected from the group consisting of ointments, creams, pastes and lotions, in an amount of 0.1 to 10% by weight calculated as anthralin.

References Cited Maclennan et 211., British Journal of Dermatology, 1961, vol. 73, pp. 439-444.

ALBERT T. MEYERS, Primary Examiner.

D. R. MAHANAND, Assistant Examiner.

US. Cl. X.R. 424-168, 343 I z