JPH0343247B2 - - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention provides an anhydrous topical anthralin composition for treating skin diseases, which is based on anthralin or one of its derivatives having an acid substituent at the 10-position and is stable against oxidation. Especially acne, warts,
Concerning its application in the treatment of alopecia, especially psoriasis.

Psoriasis is a particularly frequent skin disease that occurs simultaneously on the elbows, the back of the forearms, the knees, the lower legs, the sacrum-lumbar region, and the scalp.

Among the various substances already recommended for the treatment of psoriasis, special mention must be made of anthralin or dithranol (1,8,9-trihydroxyanthracene). Although this has proven to be particularly effective in treating psoriasis, some disadvantages arise as the compound is very easily degraded by oxidation to form dark polymeric products that can stain skin and clothing. .

In order to avoid its deterioration, the liquid composition can be applied to the skin to be treated in a concentrated carrier, especially in petrolatum, not only to improve its stability, but also to avoid dispersion to healthy areas of the skin. It has been proposed to combine some stabilizers or antioxidants in order to obtain compositions that are able to avoid the irritating phenomena observed in .

Obtaining compositions that are highly stable over long periods of time despite the presence of stabilizers or antioxidants such as butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA) or even some alpha-hydroxy acids is particularly important when concentrated. This was impossible due to the fact that the drug was used.

This time, by blending anthralin or one of its derivatives into a carrier consisting of some higher fatty acid ester mixed with some silica particles or polyethylene powder, it is stable at room temperature for a long time without relying on stabilizers or antioxidants. It was confirmed that a composition with extremely good properties and little variation in quality could be produced.

The invention is therefore based not only on the selection of specific fatty acid alkyl esters, but also on the selection of certain thickening agents.

We have been able to demonstrate that in fact only silica particles and polyethylene powders yield stable compositions in long-term storage tests, and the color of the compositions remains unchanged or nearly unchanged, indicating that the color of the compositions remains unchanged or almost unchanged, and that the color of the compositions remains unchanged or almost unchanged by physicochemical means. Measurements have confirmed this good stability, which effect was absent in the case of other thickening agents, such as some modified clays such as Bentone, or some aluminosilicates such as zeolites.

The present invention is a novel industrial product which is an oxidatively stable anhydrous composition effective in the treatment of skin diseases, particularly psoriasis, based on anthralin or one of its derivatives having an acid substituent at the 10-position, Anthralin or one of its derivatives having an acid substituent at position 10 (i) fatty acid alkyl ester in which the fatty acid moiety consists of 12 to 18 carbon atoms and the alkyl ester residue moiety consists of 2 or 3 carbon atoms; and (ii) at least one thickening agent consisting of silica with a particle size of less than 30 mμ or polyethylene powder with a volumetric weight of 0.9 to 0.96 g/cm ³ . With the goal.

Among the fatty acid alkyl esters meeting the above definition, mention may be made of isopropyl laurate, isopropyl myristate, isopropyl palmitate, ethyl myristate or mixtures thereof.

Among usable anthralin derivatives having an acid substituent at position 10, French Patent Application No. 8022454 and No.
Examples include the compounds described in 8022455.

That is, the anthralin derivative having an acid substituent at the 10th position as defined in this specification is specified in French Patent Application No. 8022454 corresponding to JP-A-57-140740 (1,8-dihydroxy -9-anthrone)-10-yl succinamic acid (compound No. 19 of Example 8 of French Patent Application No. 8022454) or (1,8-dihydroxy-9-anthrone)-
10-yl propanoic acid (French patent application no. 8022454)
Compound No. 11) of Example 7 of No.

According to the invention, the proportion of anthralin or one of its derivatives having an acid substituent at position 10 in the composition is preferably 0.01 to 5% by weight based on the total weight of the composition.
The proportion of fatty acid alkyl ester is 66 to 99% by weight, the proportion of silica particles and/or polyethylene powder is 0.1 to 20% by weight, preferably 2 to 15% by weight.

Among silica particles with an average particle size of less than 30 mμ
AEROSIL 200 from DEGUSSA
and WACKER under the name AEROSIL R 972
One may mention the silica commercially available under the name HDK, especially HDK N 20E, from the company. These silicas may be used alone or in combination.

Among the polyethylene powders defined above that can be used according to the invention, mention may be made of the following:

(i) Melt temperature 104-113°C measured according to the method of ASTM-D2117-64 or ASTM-D2839.
Volumetric weight measured according to the method of 0.914 to
Low density polyethylene powder of 0.923g/cm ³ (23℃). An example of a polyethylene powder that exhibits these properties is LOTRENE from CDF Chimie.
Mention may be made of polyethylene powders commercially available under the names UA7000S and LOTRENE UA4000S.

(ii) High-density polyethylene powder with a softening temperature of 128-129°C measured according to the method of ASTM-E28 and a volumetric weight of 0.96 g/cm ³ measured according to the method of ASTM-D1505. ALLIED is an example of a polyethylene powder that exhibits these properties.
Polymist B6 and Polymist from CHEMICAL
Mention may be made of the polyethylene powder commercially available under the name B12.

(iii) Polyethylene powder having a softening temperature of 102 DEG -117 DEG C., measured according to the method of ASTM-E28, and a volumetric weight of 0.90 to 0.94 g/ ^cm.sup.3 , determined according to the method of ASTM-D1505. An example of a polyethylene powder exhibiting these properties is the polyethylene powder commercially available from ALLIED CHEMICAL under the name Polyethylene AC 6A.

(iv) Ethylene with a softening temperature of 92-108°C determined according to the method of ASTA-E28 and a volumetric weight of 0.93 g/cm ³ determined according to the method of ASTM-D1505.
Acrylic acid copolymer. An example of a powder that exhibits these properties is from ALLIED CHEMICAL.
Mention may be made of the ethylene-acrylic acid copolymer commercially available under the name Polyethylene AC540.

The composition according to the invention can also additionally contain salicylic acid as a component of the dermatological agent.

The anthralin of the present invention or
The invention is not limited thereto, although some examples of compositions based on one of its derivatives having an acid substituent in position 10 are given.

Example 1 A skin gel is prepared according to the invention by mixing the following ingredients: Anthralin 0.4 g Silica HDK N20E (commercially available fumed silica from WACKER) 7.0 g Isopropyl myristate is added to give a total volume of 100 g
Make it g.

Example 2 A skin gel is prepared according to the invention by mixing the following ingredients: Anthralin 3 g Silica (Aerosil R972) 8 g Salicylic acid 0.2 g Isopropyl myristate is added to make the whole 100 g
Make it g.

Example 3 A skin gel is prepared according to the invention by mixing the following ingredients: Anthralin 5 g Silica (Aerosil 200) 8 g Isopropyl myristate is added to make the whole 100 g
Make it g.

In this example, the same amount of silica HDK N20E can be used in place of the silica Aerosil 200.

Example 4 A skin gel for the treatment of psoriasis is prepared according to the invention by mixing the following ingredients: Anthralin 1g Polyethylene powder (Polyethylene AC 6A)
Add 7.5g isopropyl myristate to 100%
Make it g.

In Examples 1 to 4 above, isopropyl myristate can be replaced with an equivalent amount of isopropyl palmitate, isopropyl laurate, or ethyl myristate.

Example 5 A skin gel for the treatment of psoriasis is prepared according to the invention by mixing the following ingredients: Anthralin 1g Polyethylene powder (Polyethylene AC 540)
Add 7.5g ethyl myristate to bring the total to 100g.

In this example, ethyl myristate can be replaced with an equal amount of isopropyl myristate.

When the above compositions 1 to 5 are applied to the skin or scalp to be treated in an amount sufficient to cure the disease, it can lead to regression and treatment of skin diseases, particularly psoriasis, after a treatment period of about 3 to 5 weeks.

As mentioned above, the topical composition for treating skin diseases of the present invention, which contains anthralin and a specific carrier consisting of a fatty acid alkyl ester mixed with silica particles or a polyethylene powder thickener, is effective in treating psoriasis. However, it is clear that anthralin itself is effective in the treatment of psoriasis according to the literature “Hand book of Experimental Pharmacology”.
Experimental Pharmacology) Skin Pharmacology () Ed. Greases and Shuster Springer (1989)
Excerpted from “Anthralin Chapter 34 B. Shroot et al. 459
``Anthralin has occupied a crucial role in the clinical treatment of psoriasis since the pioneering work of Unna (1961)'' (p. 459) and ``Short-contact treatment with anthralin Schaefer et al. (1980) discloses that 1% anthralin in petrolatum is effective in treating psoriasis with drug-skin contact times of up to 1 hour.'' (p. 468);
"Anthralin" excerpted from "Maidach (1985)"
Chapter 27, B. Shroot et al., pp. 327-334, states that ``Hydroxyanthracene derivatives have played an important role in the treatment of psoriasis since 1868, and are known as anthralin or dithranol (1,8-dihydroxy-anthra-9-
(on) is a widely used and highly effective drug of this type. ” (p. 327) and “Anti-psoriasis efficacy could be established using 1% anthralin in petrolatum for 1 hour per day” (p. 332).

Oxidative Stability Test The external composition for treating skin diseases of the present invention can be prepared by using a thickening agent consisting of silica or polyethylene powder in combination with a fatty acid alkyl ester.
Thus, in order to demonstrate that the use of a particular carrier provides superior results regarding the oxidative stability of anthralin to those obtained using other thickening agents, a comparative study was carried out as follows. .

First, the following composition was prepared; Comparative composition 1 Anthralin 0.1g Bentone gel CAO (modified Montmorillon clay)
10g isopropyl myristate
Required amount to make the total 100g Comparison composition 2 Anthralin 0.1g Theolite "Molecular Sieve A40" (sodium aminosilicate) 10g Isopropyl myristate
Required amount to make the total 100g Composition of the present invention 3 Anthralin 0.1g Silica "HDK N20E" 10g Isopropyl myristate
Required amount to make the total 100g Composition of the present invention 4 Anthralin 0.1g Silica (Aerosil 200) 10g Isopropyl myristate
Required amount to make the total 100g Composition of the present invention 5 Anthralin 0.1g Polyethylene AC6A 10g Isopropyl myristate
Required amount to make the total 100g Composition of the present invention 6 Anthralin 0.1g Polyethylene AC540 10g Isopropyl myristate
Required amount to make the total 100 g Compositions 1 to 6, which were entirely white to pale yellow, were poured into bottles with screw caps, and the six bottles were observed (time 0). The bottles were then left at room temperature for 8 days. This period (time + 8 days)
These bottles were later observed again.

Comparative compositions 1 and 2 using thickening agents outside the scope of the present invention are clearly unstable because they clearly separate into two layers and the lower layer turns brown after 8 days at room temperature. It is. However, compositions 3 to 6 of the present invention
It is clear that even after this period (hours + 8 days) not only the composition itself but also the color remains unchanged and is therefore stable.

The following composition was then prepared: Composition of the invention 1 Anthralin 0.1 g Silica (Aerosil 200) 2 g Isopropyl myristate
Required amount to make the total 100g Comparative composition 2 Anthralin 0.1g Zeolite (Molecular Sieve A40) 2g Isopropyl myristate
Required amount to give a total of 100 g The pale yellow compositions 1 and 2 thus obtained were poured into a bottle with a screw cap. Two bottles were observed (time 0) and then the bottles were left at room temperature for 8 days.
Two bottles were observed again after this period (hours + 8 days).

The concentration of thickener was 2% instead of 10% in the above test example.
Composition 1 of the invention remains unchanged and stable after storage for 8 days even when reduced to It is clear that it is unstable because it separates into two layers and produces a brown lower layer.

The following two anthralin derivatives: 1 (1,8-dihydroxy-9-anthrone)
-10-yl succinamic acid (Compound No. 19 of Example 8 of French Patent Application No. 8022454) 2 (1,8-dihydroxy-9-anthrone)
-10-yl propanoic acid (French patent application no.
8022454, Example 7 Compound No. 11) in the following carrier: Carrier A: Bentone Gel IPM Carrier B: Aerosil 200 10 g Isopropyl myristate
It was produced in the required amount to make the whole 100g.

Bentone Gel IPM is commercially available from NL.Chemicals and contains 10% in isopropyl myristate.
% of modified Montmorillon clay, this thickening agent is the same as the thickening agent contained in the bentone gel CAO used in the previous test and is outside the scope of the present invention.

Comparative composition 1A (1,8-dihydroxy-9-anthrone)-
10-yl succinamic acid 0.10g Bentone gel IPM commercially available from NL.Chemical
Comparative composition 3A (1,8-dihydroxy-9-anthrone)-
10-yl propanoic acid 0.10g Bentone gel IPM commercially available from NL.Chemical
Amount required to make the total 100.00 g Composition of the present invention 1B (1,8-dihydroxy-9-anthrone)-
10-yl succinamic acid 0.10g Aerosil 200 commercially available from Degussa 10.00g Isopropyl myristate
Composition of the present invention 3B (1,8-dihydroxy-9-anthrone)-
10-yl propanoic acid 0.10g Aerosil 200 commercially available from Degussa 10.00g Isopropyl myristate
Required amount to make the total 100.00g Divide each composition into two flasks,
This was closed with a screw cap.

One flask of each composition was observed (time 0) and then stored at room temperature (RT) for 1 hour.

The remaining flask was placed in a drying oven at a constant temperature of 45°C for a period of one week. The flasks were observed after this period (1 week).

Comparative compositions using thickening agents outside the scope of the invention
1A and 3A darkened considerably in color during storage, whereas compositions 1B and 3B of the present invention remained substantially unchanged in color over the same period of time. It was therefore confirmed that anthralin derivatives also exhibit the same behavior as demonstrated for anthralin itself.

Claims (1)

[Scope of Claims] 1. An anhydrous composition containing anthralin or one of its derivatives having an acid substituent at the 10-position, which is effective for the treatment of skin, particularly psoriasis, and which comprises (1) a fatty acid moiety of 12 to 18 fatty acids; At least one fatty acid alkyl ester consisting of carbon atoms, the alkyl ester residue portion consisting of 2 or 3 carbon atoms, and (ii) particle size of 30 m
Silica less than μ or volumetric weight 0.9 to 0.96 g/cm ²
An external composition for treating skin diseases, characterized in that it contains anthralin or one of its derivatives in a carrier comprising at least one thickening agent made of polyethylene powder. 2. The composition according to claim 1, wherein the fatty acid alkyl ester is isopropyl laurate, isopropyl myristate, isopropyl palmitate, ethyl myristate, or a mixture thereof. 3. A composition according to claim 1 or 2, wherein anthralin or one of its derivatives is present in a concentration of 0.01 to 5% by weight relative to the total weight of the composition. 4. The composition according to any one of claims 1 to 3, wherein the proportion of the fatty acid alkyl ester is 60 to 99% by weight based on the total weight of the composition. 5. The composition according to any one of claims 1 to 4, wherein the proportion of silica particles and/or polyethylene powder is 0.1 to 20% by weight based on the total weight of the composition. 6. Claims 1 to 5 additionally contain salicylic acid as a commonly used ingredient for preparations for skin diseases.
The composition according to any of paragraphs.