CH664895A5 - STABLE ANTHRALIN COMPOSITION IN SATURATED FATTY ACID TRIGLYCERIDES OF PLANT ORIGIN HAVING 6 TO 12 CARBON ATOMS. - Google Patents

Description

DESCRIPTION

The present invention relates to an anhydrous anthralin composition, having good oxidation stability, for the treatment of skin diseases, in particular psoriasis, containing anthralin in a vehicle consisting of at least one triglyceride saturated fatty acids of vegetable origin having 6 to 12 carbon atoms.

The present invention further describes compositions according to the invention based on anthralin useful in the treatment of skin diseases, in particular the treatment of acne, warts, alopecia, eczema, and especially psoriasis.

Anthralin or dithranol (1,8,9-trihydroxy anthracene) is one of the few substances that has been shown to be particularly active in the topical treatment of psoriasis.

However, its use is not without presenting certain major drawbacks insofar as this substance is easily degraded by oxidation to quinones or to dark-colored polymer products, capable of staining not only the skin, but also clothing.

A great deal of research has been undertaken with a view to finding not only vehicles, but also certain agents which make it possible to avoid too brutal degradation of anthralin and, in this way, to keep it in its active form.

US Patent No. 4,287,214 suggests the use of α-hydroxy acids as stabilizing agents for anthralin-based compositions and, among these, glyceric acid, gluconic acid, galacturonic acid , malic acid, citric acid, tartaric acid or tartronic acid at a concentration of 0.01 to 1% by weight.

US Patent No. 4,367,224 also proposes, in order to obtain stable anthralin compositions, the use of oxalic acid at a concentration of 0.01 to 2% by weight.

In US Pat. No. 4,316,902, it is however proposed for anthralin-based compositions to use not only the stabilizing agents mentioned above, but also a vehicle consisting of myristate or isopropyl palmitate and of glyceryl monostea-io spleen.

More recently, it has been proposed in French patents No. 81.19952 and No. 82.01327 the use of fatty acid alkylesters as well as aromatic esters as the sole vehicles of anthralin, these esters, in the absence of any other stabilizing agent, having proven to constitute completely acceptable vehicles for the good conservation of anthralin.

Among these esters, isopropyl myristate has been found to be the most effective for the preservation of anthralin, the degradation rate, after two months, not exceeding about 15%.

It has however been possible to establish that the activity of the anthralin-based compositions is partly a function of its degree of solubilization in the vehicle or solvent used.

In other words, in order to obtain good action, a relatively large proportion of the anthralin should be soluble.

Most of the vehicles hitherto recommended and recalled above do not allow good solubilization of anthralin to be obtained in this regard, while keeping the degradation rate as low as possible.

As a result of new research, it has now been found that this solubility and stability problem of anthralin can be resolved by the use of triglycerides of saturated fatty acids of vegetable origin.

The use of these fatty acid triglycerides, while increasing the solubility and keeping the degradation rate at an acceptable percentage, has also made it possible to improve the properties of the compositions, the latter spreading more easily, being better tolerated and not leaving an unpleasant oily feel on the skin.

The subject of the present invention is, as a new industrial product, an anhydrous, oxidation-stable composition of anthralin, for the treatment of skin diseases, in particular psoriasis, the vehicle for said composition being consisting of at least one triglyceride of saturated fatty acids of vegetable origin having from 6 to 12 carbon atoms.

The distribution of fatty acids in the triglyceride is preferably as follows:

- caproic acid (C6): <3%

- caprylic acid C8): 50 to 80%

- capric acid (Cm): 15 to 45%

so— lauric acid (C12): <5%

The triglycerides of saturated fatty acids of vegetable origin as defined above preferably have a viscosity at 20 ° C of between 27 and 30 • 10-3 Pa • s.

Among the triglycerides of saturated fatty acids of vegetable origin 55 having from 6 to 12 carbon atoms, which can be used as a vehicle for anthralin, mention may be made of those sold by the company DYNAMIT NOBEL under the following names:

1. "MIGLYOL 810", the fatty acid distribution of which is as follows:

- caproic acid (C6): 3% max 60 - caprylic acid (C8): 65-80%

- capric acid (C10): 15 to 30%

- lauric acid (C12): 3% max and whose physicochemical characteristics are the following:

- acid number: 0.1 max

65 - saponification index: 340-360

- cloud point: 0 ° C max

- refractive index (20 ° C): 1.4490-1.4510

- viscosity at 20 ° C: 27-30 • 10 ~ 3 Pa • s

3

664,895

2. "MYGLYOL 812", the fatty acid distribution of which is as follows:

- caproic acid (C6): 3% max

- caprylic acid (C8): 50-65%

- capric acid (C10): 30-45%

- lauric acid (C12): 5% max and whose physicochemical characteristics are the following:

- acid number: 0.1 max

- saponification index: 325-345

- cloud point: 10 ° Cmax

- refractive index (20 ° C): 1.4480-1.4500

- viscosity at 20 ° C: 28-32 • 10-3 Pa • s.

According to the invention, the concentration of anthralin is generally between 0.05 and 3% by weight and preferably between 0.1 and 0.7%.

The compositions according to the invention can be in the form of lotions, gels or ointments.

These compositions can optionally be thickened using a thickening agent, which makes it possible to avoid any flow and thus prevent the phenomena of irritation on the healthy parts of the skin.

Among the thickening agents, it is preferred, according to the invention, to use silicas having an average particle diameter of less than 30 μm, and in particular the silicas sold under the names "AEROSIL 200" and "AEROSIL R 972" by the company DEGUSSA or under the names of "HDK", in particular silica "HDK N 20 E", by the company WACKER. The concentration of thickening agent is generally between 2 and 10% by weight.

Other ingredients can also be introduced into the compositions, for example oils, waxes and any other ingredient in the compositions for topical application insofar as these have no influence on the stability of the compositions.

When the compositions contain salicylic acid, this is generally present in a proportion of between 0.01 and 5% and preferably between 0.05 and 0.3%.

The following table (I) makes it possible to demonstrate, on the one hand, the good stability and, on the other hand, the low degradation rate of anthralin in “MIGLYOL 812” compared to other known vehicles anthralin.

Table I

Solubility

% Degradation

Products

at 20 ° C

after 2 months

(HPLC assay)

at 40 ° C

Miglyol 812

0.68% ± 0.04

3-5

Isopropyl myristate

0.36% ± 0.03

10-15

Benzyl salicylate

0.65% ± 0.05

> 40

Isopropyl palmitate

0.42% ± 0.03

15-20

Isopropyl stearate

0.51% ± 0.02

15-20

Butyl stearate

<0.5%

15-20

Ethyl myristate

<0.5%

20

Isocetyl stearate

<0.5%

10-15

Isodecyl neopentanoate

<0.5%

10-15

Vaseline oil

0.12% ± 0.03

4-10

Colza oil

0.42% ± 0.03

50-70

Peanut oil

<0.5%

> 10

Perhydrosqualene

0.12% ± 0.03

> 10

As can be seen, “MIGLYOL 812” combines both good solubility and a low degradation rate of anthralin, which is not the case for example with benzyl salicylate which, although having a power comparable solubilizer, however does not prevent the degradation of anthralin, since the rate observed is greater than 40%.

The analytical method for determining the degradation rate of anthralin is based on the determination of the active ingredient in the product after storage under defined conditions.

This dosage in the finished product is done by HPLC on a Lichrosorb RP 18 10 um column, internal diameter 4 mm, length 25 cm, in reverse phase, the mobile phase consisting of: methanol / water + 2% acetic acid in the proportions 85/15.

The detection is done at 250 nm in UV and the RT is 5.7 min.

The assay takes place in relation to a standard range for which the anthralin is dissolved extemporaneously in chloroform.

The finished product samples are treated by solubilization in chloroform.

The percentage of degradation is calculated relative to the content of active principle in the sample at zero time:

% degradation = rate at T.O - rate at T. 2 months at 40 ° C x m rate at T.O

The present invention also relates to a composition, in particular a shampoo, in the form of a packaging in two parts intended to be mixed at the time of use, the first part being constituted by the composition according to the invention and the second part being an aqueous solution containing an anionic or nonionic surfactant at a pH generally between 2 and 7, but preferably at an acidic pH between 3 and 5 by the addition, if necessary, of an acid such as citric acid, lactic acid or acetic acid.

In the aqueous phase, the concentration of the anionic or nonionic surfactant is preferably between 5 and 40%, preferably between 7 and 27%, and may also contain a thickening agent.

At the time of the first use, the two parts are mixed in variable proportions according to the desired efficiency, generally in a ratio of the anhydrous part to the aqueous part of between 10:90 and 50:50.

The mixture obtained is then applied to the scalp and the hair at a rate of approximately 20 to 40 g. It is then left to act for approximately 5 min to 1 h; then emulsified with water and rinsed thoroughly with water. The treatment is then continued every day or every two days using the same composition after having stored it at a temperature below about + 4 ° C.

The conditioning in two parts is carried out in such a way that it can allow, after mixing, to carry out a treatment of approximately one week at the rate of one or two shampoos every two days.

Good results in the treatment of psoriasis are usually achieved after 3 to 5 weeks.

Several examples of compositions according to the invention will now be given by way of illustration and without any limiting character.

Example 1:

A shampoo is packaged in the form of the following two parts:

1. Anhydrous part

- Anthralin 0.60 g

- MIGLYOL 812 q.s.p. 100g

2. Aqueous part

- Sodium laurylethersulfate oxyethylenated using

2.2 moles of ethylene oxide 12 g

- Lactic acid q.s.p. pH 4

- Water q.s.p. 100g

At the time of use, 25% of the anhydrous part (1) and 75% of the aqueous part (2) are mixed.

The resulting composition has a milky appearance and is applied to the scalp and hair about 30 g.

5

10

15

20

25

30

35

40

45

50

55

60

65

664,895

4

After an exposure time of the order of 20 min, it is emulsified at

i have skin and pon rmce.

After 2 weeks, there is a regression of psoriasis, and the treatment can be continued by spacing a day or two shampoos.

Example 2:

Composition in gel form for the treatment of psoriasis:

- Anthralin 0.6 g

- AEROSIL 200 8 g

- MIGLYOL 812 q.s.p. 100g

Example 3:

Ointment for the treatment of skin diseases and in particular psoriasis:

- Anthraline

- Salicylic acid

0.3 g 0.2 g

- Vaseline Codex

- MIGLYOL 812 q.s.p.

Example 4:

5 Ointment for the treatment of psoriasis:

- Anthraline

- Salicylic acid

- Vaseline Codex

- Codex io paraffin - MIGLYOL 812 q.s.p.

Example 5:

Lotion for the treatment of psoriasis. This lotion has the following composition: 15 - Anthraline

- Salicylic acid

- MIGLYOL 812 q.s.p.

40 d 100!

0.3 g 0.2 g 30 g 15 g 100 g

0.60 g 1 g 100 g

R

Claims (10)

664,895 1. Anhydrous anthralin composition, stable to oxidation, for the treatment of skin diseases, characterized in that it contains anthralin in a vehicle consisting of at least one triglyceride of saturated fatty acids d vegetable origin having from 6 to 12 carbon atoms. 2. Composition according to claim 1, characterized in that the triglyceride of saturated fatty acids of vegetable origin has a viscosity at 20 ° C between 27 and 30-10-3 Pa-s. 2 3. Composition according to one of claims 1 and 2, characterized in that the anthralin is present at a concentration of between 0.05 and 3% by weight and preferably between 0.1 and 0.7%. 4. Composition according to one of the preceding claims, characterized in that it contains a thickening agent. 5. Composition according to Claim 5, characterized in that the thickening agent is silica having an average particle diameter of less than 30 µm. 6. Composition according to one of claims 4 and 5, characterized in that the thickening agent is present at a concentration of between 2 and 10% by weight relative to the total weight of the composition. 7. Composition according to one of the preceding claims, characterized in that it contains salicylic acid at a concentration between 0.01 and 5% and preferably between 0.05 and 3%. 8. Packaging in two parts intended to be mixed at the time of use, characterized in that the first part consists of a composition according to one of claims 1 to 7 and that the second part is an aqueous solution containing a anionic or nonionic surfactant at a pH between 2 and 7. 9. Packaging according to claim 8, characterized in that the anhydrous part also contains a thickening agent. 10. Packaging according to claim 8, characterized in that the aqueous part contains an acid taken from the group consisting of citric acid, lactic acid and acetic acid, in order to maintain the pH between 2 and 7 and preferably between 3 and 5.