DE3438005A1 - PHARMACEUTICAL AGENT FOR LOCAL THERAPY OF PSORIASIS - Google Patents

Description

Pharmaceutical agent for the local therapy of psoriasis

Field of invention

The invention relates to a glucocorticoid-free pharmaceutical agent for the local therapy of psoriasis, the one in itself known antipsoriatic active ingredient and optionally fine distributed urea, salicylic acid and / or therapeutically permissible reducing agents and / or physiologically harmless Contains complexing agents.

State of the art

Psoriasis vulgaris (psoriasis) is an erythematosquamous one Dermatosis ,. Probably represents a multifactorial hereditary condition, but it is significantly influenced by environmental factors will. This dermatosis is particularly common on the elbows, the extensor sides of the knees, the hairy head and the nails, So quite exposed parts of the body manifest and are serious for this reason - not least mental - problems.

Common drugs for the local therapy of psoriasis are e.g. halogenated or non-halogenated glucocorticoids in topical application. Given the multitude of possible However, there are also indications for glucocorticoids who would like to see the use of this class of compounds restricted to other disease fields. Others used against psoriasis therapeutic principles include, for example, allantoin, funaric acid and its salts, undecylenic acid, vitamin

Α-acid and chrysarobe (1st S-dihydroxy-S-methylanthrone). Lately the active ingredient dithranol (1.8.9-anthracentriol) tjei the treatment of psoriasis with relative success applied. The dosage forms used were mainly limited to conventional preparations such as solutions. Creams. Ointments o.a.

Those occurring in the therapy according to the state of the art Problems are explained in more detail based on the use of the active ingredient dithranol in psoriasis therapy.

Often paste-like preparations of the active ingredient in petrolatum are used. These mentioned applications brought usually a considerable expenditure of time and considerable inconvenience for the patient. The large ones Applications of a vaseline paste on large parts of the body could not be used in the patient's home, only be carried out in a stationary manner. This was also associated with a high degree of soiling of the clothing. One attempt to shorten the therapy was, for example, to apply more concentrated dithranol creams, as it has been shown Has. that the absorption of the dithranol in the deeper layers of the skin in psoriasis-damaged skin takes place very quickly. The disadvantage here is that healthy skin areas are particularly strongly irritated, so that the therapy is frequently discontinued.

More recently, pen administration has also been considered. (Cf. V. Watzig. Dermatol. Monatsschr. 169 - (8). 533-34 (1983).

Attempts have also been made to use of dithranol in psoriasis therapy by varying the carrier base. These include e.g.

- z-

Preparations with 0.1% dithranol in a 17% urea base. [("Psoradrate"). See D.M. Williamson in Clin. Exp. Deraatol. _8th, 287-290 (1983)]. The combination with salicylic acid as a keratolytic is also used. Salicylic acid increases, however the anti-psoriatic effect does not.

For particularly resistant psoriasis foci, that of a simple one Treatment only partially accessible is in dermatology Preferably occlusive conditions are used, i.e. a diseased skin area is smeared with ointment and with a covered moisture-proof bandage. Underneath, a dense, moist space is created, which makes the skin swell and the Promotes penetration into deeper layers.

Medication-containing plasters are known per se. Most of these are perforated and elastic for better skin breathing Painted fabric. (See Ulimann's Ehcyklopadie der technischen Chemie, 3rd edition, 4th volume, pp. 24-26, Urban & Schwarzenberg, 1953).

Task and solution
20th

In psoriasis sufferers, in addition to the actual ailment, the accompanying circumstances of the treatment are very stressful. The task was therefore to improve the therapeutic conditions of psoriasis treatment and the therapy itself more effective and, if possible, more pleasant. A glucocorticoid-free localized therapy was among the best possible aim for less stress on unaffected areas of the body. In the field of topical therapy with glucocorticoids self-adhesive backing films were used, in the adhesive layer of which the halogenated corticoid fluorandrenolone is incorporated.

It has now been found that glucocorticoid-free pharmaceutical Means consisting of a self-adhesive, non-permeable Foil, the adhesive layer of which is a glucocorticoid-free, Contains antipsoriatic active ingredient in a uniformly fine distribution, are particularly suitable for solving the problem. the Agents according to the invention are particularly suitable for use on antipsoriatic agents from the group of hydroxylated anthraquinones, the anti-psoriatic carboxylic acids and allantoin as well as the group of anti-psoriatic tar products.

The latter include coal tar (Pix lithanthracis). Liquor carbonis detergens (20% coal tar in Quillaja tincture), tars made from vegetable components such as charcoal tar, sulfonated shale oils such as Ammonium bitumino-sulfuricum (ICHTYOI @ and TUMENOL®Ammonium).

Particular mention should be made of dithranol, undecylenic acid [ündecen- (10) acid- (1) I and fumaric acid and their therapeutically applicable salts such as the disodium salt. the

the last named vitamin A acid and the named allantoin. The "!" Active ingredients are generally in solid, generally crystalline form and can be brought to the desired degree of distribution in a manner known per se, for example by means of powders (F..Gstirner. "Introduction to the process engineering of drug research" ₇ 5 - Edition, Wissenschaftliche Verlagsgesellschaft. Stuttgart. 1973) · The simultaneous presence of urea in finely divided form in the adhesive layer of the film is particularly beneficial.

The finding that the combination of the glucocorticoidf pure active ingredients (such as dithranol) with urea in a relatively high concentration with sufficient chemical Stabilization can be incorporated into the adhesive layer of a carrier film without the adhesive effect of the Coating and thus canceling the occlusive conditions.

In general, the content of the antipsoriatic active ingredient in the adhesive ^{layer is from 1 to 1000 μg per cm 2 of} layer area, preferably from 1 to 250 μg, particularly preferably from 2 to 150 % per cm ^{2 of} area.
^ The content of urea is preferably 100 to 300 times the weight of the antipsoriatic active ingredient. Urea (in the therapeutically permissible quality) is expediently used in micronized form, usually with a particle size of the urea particles in the range 1- $ μ. The size of the active ingredient particles is expediently of the same order of magnitude. Also the addition of salicylic acid in finely divided form to the adhesive layer. is contemplated within the scope of the present invention. The salicylic acid content should be 100 to 200 times the weight of the antipsoriatic active ingredient.

As is customary for therapeutic purposes, the carrier film material should expediently be tear-resistant, water (vapor) and air-impermeable, ie generally impermeable, pliable, well tolerated by the skin and insensitive to external influences and keep 2-® firm and secure. (See Ulimann's Encyklopadie der Techn. Chemie, 4th edition, Volume 18, pp. 164, 165, Verlag Chemie. 1979).

For example, physiologically indifferent foils, preferably made of polyethylene, polypropylene, polyurethane, are used.

Polyvinyl chloride or mixtures thereof. In terms of the intended therapy, the foils are skin-colored preferred.

The acrylate adhesives which are customary per se are preferably used. In order to have the desired adhesive effect, wise the polymers usually have a dynamic glass transition temperature (according to DIN 53 445 or 7724) of <20 ° C, preferably <10 ° C,

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on. It is also best to keep the adhesive layer up to To cover the application with a release paper, which is only peeled off before use.

Suitable acrylate adhesives are known, for example, from the production of wound dressings.

These are preferably polymers based on ethyl acrylates, in particular with up to 8 carbon atoms Alcohol residue, e.g. from copolymers of several alkyl acrylates, for example with acrylic acid and / or other vinyl compounds such as vinyl acetate, the acrylic ester content generally being at least 25% by weight. Examples include (Co) polymers from the monomers butyl acrylate. Ethyl acrylate. Isooctyl acrylate and optionally with hydroxyl group-5 performed esters of acrylic acid.

The active ingredient and any other adjuvants that may be added are incorporated into the adhesive mass Dispersion or solution).

Advantageously, the active ingredient and, if necessary, further additives such as urea. Salicylic acid and optionally stabilizers are added to the material provided for the adhesive layer before the film is coated. The use of aqueous plastic dispersions for producing the adhesive layer has proven particularly useful. The pH of these dispersions is advantageously in the acidic to at most neutral range, for example see below. below -pH - 7. The acidic pH can be adjusted by buffering with suitable buffers.

Acrylic resin dispersions, preferably on, may be mentioned, for example

* and / or methacrylates

Based on 2-ethylhexyl acrylate, ethyl acrylate and 2-hydroxypropyl acrylate for example in a weight ratio of 64: 30: 6.

The addition of certain stabilizers such as therapeutically acceptable reducing agents to the adhesive layer has proven to be very useful proven to be evenly distributed. An example of such an agent is ascorbic acid. Sodium or potassium dithionite, Cysteine and its physiologically acceptable acid addition salts such as the hydrochloride. Of the Addition is generally in the order of 10 to 1000 times the weight of the active ingredient, preferably up to 200 times.

Furthermore, the therapeutic agents according to the invention can expediently be physiologically distributed evenly harmless complexing agents such as ethylenediaminetetraacetic acid, tartaric acid, lactic acid, citric acid or their Physiologically acceptable: Salts such as the alkali or alkaline earth salts in amounts from 10 to 250 times, based on weight

of the active ingredient.
20th

The thickness of the film layer is generally in the range from 20 to 400 µm, and the thickness of the adhesive layer is generally in the range Range 1 to 100 µm. There are no immediate limits to the geometric shape of the foils as a pharmaceutical agent (except for those caused by the use of the machine), however, the coated foils should be large enough to remove them To be able to cut out parts that are able to fully cover the psoriatic diseased body parts.

Beneficial effects

By cutting out an adapted piece of film, the targeted treatment of diseased skin areas is possible, whereby mechanical protection is achieved at the same time. The therapeutic agent according to the invention generally enables one simple application of the active ingredients and, thanks to optimal therapy conditions, achieves a deep effect therapeutic effect without additional skin irritation. Compared to conventional therapy, the active ingredients are more even dosed and side effects reduced with improved stability. The tight seal of the active ingredients to the outside creates the therapeutically favorable occlusive conditions. In addition, e.g. the discoloration of the laundry caused by dithranol 5 can be avoided. Psoriasis foci on exposed areas of the skin covered by the skin-colored film and in a cosmetically appealing way thus increasing patient acceptance of the often long-lasting therapy.

Practical implementation

In the practical implementation, for example, the procedure can be that the additives such as urea, salicylic acid, dissolves the reducing agent in purified water, among other things, and finely disperses the active ingredient in it with the help of a dispersant

(For example with an ULTRA-TURRAX ^ device. (Janke & Kunkel, Freiburg, Federal Republic). When using dithranol, the amounts used are preferably 2.0 to 20 ug per cm ^{2 of} layer area when using fumaric acid and its salts 50-500 µg / cm ² when using undecylenic acid

20-150 µg / cm ² for vitamin A acid at 0.5 to 5 µg / cm ² , when using allantoin at 20-200 µg / cm ² , when using tar preparations at 10-100 µg / cm ² .

This mixture is added to the dispersion of the adhesive, mixed uniformly with a stirrer and this mixture is applied evenly to the plaster film with a doctor blade and dried. The active ingredient-containing adhesive layer is protected, for example, by covering it with siliconized paper, which is removed before application.
10

The following examples serve to illustrate the invention.

Preparation of the adhesive dispersion

In a polymerization vessel. equipped with a stirrer, reflux condenser and thermometer, 0.064 g of the Na salt of a Triisobutylphenolpolyoxyethylensulfats 7 oxyethylene units and 0.60 g iknmoniumperoxodisulfat dissolved in 865 g deionized water at 85 ⁰ C vorgelegt- To this solution was added at 85 ⁰ C, an emulsion of

12.8 g of the above emulsifier 10.2 g of ammonium peroxodisulphate

1.8 g 2-ethylhexyl thioglycolate 2458 g 2-ethylhexyl acrylate 1152 g ethyl acrylate
230 g of 2-hydroxypropyl acrylate and 1620 g of water

added dropwise over the course of 5 hours. ^{The dispersion was then kept at 85 °} C. for a further 2 hours, then cooled to room temperature and filtered through a fine-mesh screen made of stainless steel.

A coagulate-free dispersion with a dry content of 60.3% and an average particle diameter determined by photon correlation spectroscopy, obtained from 580 nm. The pH was 2.0, the current one Viscosity 1450 mPa-s (Brookfield viscometer, I, 6), 25th

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example 1

"'210.6 mg urea, 88.5 mg ascorbic acid. 63.5 mg sodium citrate.

10.5 mg of sodium dithionite are dissolved in 15 g of purified water and 1.2 mg of dithranol are finely dispersed therein. This batch is added to 15 g of adhesive dispersion (60% dry content), mixed uniformly and ^{evenly applied by means of a doctor blade to an area of 250 cm 2 of} a polyethylene film (130 μm thick) and dried. The active ingredient-containing adhesive layer is protected by covering it with siliconized paper, which is removed before application. The adhesive layer used is preferably one based on the copolymer of 2-ethylhexyl acrylate, ethyl acrylate and 2-hydroxypropyl acrylate in a weight ratio of 64: 30: 6.

Example 2

18O mg salicylic acid, 100.5 mg ascorbic acid, 105 mg sodium citrate, 60 g of tartaric acid and 13 mg of sodium dithionite are added to a mixture of 5 g of purified water and 15 g of adhesive dispersion dissolved and finely dispersed therein 2.4 mg of dithranol. The batch is worked up as in Example 1.

Example 3 (use of tar products)

12.5 mg Pix Juniperi, 62.5 mg salicylic acid, 97.0 mg tartaric acid,

® 1) 25.0 mg of ethylenediaminetetraacetic acid, 1.0 g of Tween 80, 250 mg

® _n 2)
Span 80 are dissolved or finely dispersed in 15 g of purified water using a fast stirrer. 25 g of adhesive dispersion are added to this batch and mixed evenly. The work-up corresponds to Example 1; Drying is performed at 35 ⁰ C under forced air.

Polyoxyethylene (20) sorbitan monooleate; Product of the atlas

2)

Sorbitan monooleate - "-

Example 4 (use of fumaric acid and its salts)

15.0 mg of fumaric acid, 50.0 mg of salicylic acid, 45.0 mg of tartaric acid, 22.5 mg of cysteine, 300 mg of glycerol are added with stirring Room temperature dissolved in a mixture of 20.0 mg water and 15.0 g adhesive dispersion and worked up according to Example 1.

Example 5 (use of allantoin)

25.0 mg allantoin, 25.0 mg salicylic acid, 10.5 mg sodium dithionite, 88.5 mg ascorbic acid, 63.5 mg sodium citrate are mixed in 10 g with vigorous stirring. Purified water finely dispersed or solved. 15 g of adhesive dispersion and 300 mg of Tween 80 are added to this batch, mix well and work according to Example 1 on.

Example 6 (Use of undecylenic acid [undecenoic (10) acid (1)

6.3 mg of undecylenic acid, 105 mg citric acid, 800 mg Tween 20.0 mg of salicylic acid and 1.5 g of sorbitol solution, 70% strength be at 3O ⁰ C dispersed with vigorous stirring in 15 g of water and dissolved, mixed with 15 g gluten and worked up according to Example 1.

Example 7 (use of vitamin A acid)

1.0 mg tretinoin, 50 mg salicylic acid, 100.0 mg Tween 80® 7.5 mg Sodium dithionite, 75.0 mg of ascorbic acid and 58 mg of sodium citrate are dispersed or dissolved in 10.0 g of purified water and then mixed with 15.0 g adhesive dispersion. Work-up takes place as in Example 1.

Claims (18)

34380G5 Pharmaceutical agent for the local therapy of psoriasis Patent claims 1. Glucocorticoid-free pharmaceutical agent for local use Therapy of psoriasis containing known antipsoriatic agents, characterized, that the pharmaceutical agent consists of a self-adhesive non-permeable film, the adhesive layer of which the Contains glucocorticoid-free antipsoriatic active ingredient in an evenly fine distribution. 2. Glucocorticoid-free pharmaceutical agent according to claim 1, characterized in that the adhesive ^{layer has a content of the antipsoriatic active ingredient of 0.1 to 1000 µg per cm 2 of} layer area. 3. Glucocorticoid-free pharmaceutical agent according to claim 2, characterized in that the adhesive ^{layer has a content of the antipsoriatic active ingredient of 1 to 250 µg per cm 2 of} layer area. U. Glucocorticoid-free pharmaceutical agent according to claim 1, characterized in that the adhesive layer in addition to the antipsoriatic active ingredient, it also contains urea in an evenly fine distribution. 5. Glucocorticoid-free pharmaceutical agent according to claim 4, characterized in that the content of Urea 100 to 300 times the weight of the antipsoriatic Active ingredient. 6. Glucocorticoid-free pharmaceutical agent according to claim 1, characterized in that the adhesive layer In addition to the antipsoriatic active ingredient, it also contains salicylic acid. 7. Glucocorticoid-free pharmaceutical agent according to claim 6, characterized in that the content of Salicylic acid is 100 to 250 times the weight of the antipsoriatic agent. 8. Glucocorticoid-free pharmaceutical agent according to claims 1 to 7, characterized in that the Adhesive layer by coating the film with an in Dispersion located polymer is produced, wherein was below the pH of the dispersion ■ 7. 9. Glucocorticoid-free pharmaceutical agent according to claims 1 to 8, characterized. that it still additionally contains therapeutically acceptable reducing agents. 10. Glucocorticoid-free pharmaceutical agent according to claim 9, characterized in that it is therapeutic permissible reducing agents in amounts of 10 to 1000% by weight, based on the antipsoriatic active ingredient, contains. ιi 59Q7E 11. Glucocorticoid-free therapeutic agent according to Claims 9 and 10, characterized in that the therapeutically permissible reducing agent is selected from the group consisting of ascorbic acid, sodium or potassium dithionite, cysteine and its physiologically acceptable Acid addition salts. .12. Glucocorticoid-free therapeutic agent according to Claims 1 to 11, characterized in that they also contain physiologically harmless complexing agents. 13. Glucocorticoid-free therapeutic agent according to claim characterized in that the physiologically harmless complexing agents are selected from the group consisting of from ethylenediaminetetraacetic acid, lactic acid., tartaric acid. 14. Glucocorticoid-free therapeutic agent according to FIGS Claims 1 to 13, characterized in that it contains dithranol as an active ingredient. 15. Glucocorticoid-free therapeutic agent according to Claims 1 to 13, characterized in that it contains allantoin as an active ingredient. 16. Glucocorticoid-free therapeutic agent according to FIGS Claims 1 to 13, characterized in that it contains fumaric acid and / or physiologically harmless salts contains the same as an active ingredient. 17. Glucocorticoid-free therapeutic agent according to claims 1 to 13, characterized in that it Contains uhdecylenic acid as an active ingredient. 18. Glucocorticoid-free therapeutic agent according to claims 1 to 13, characterized in that it Contains vitamin A acid as an active ingredient. 19- Glucocorticoid-free therapeutic agent according to the Claims 1 to 13, characterized in that there are antipsoriatic tar products as active ingredients contains.