LU86393A1 - STABLE ANTI-ACNE COMPOSITION BASED ON ERYTHROMYCIN - Google Patents

Description

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The present invention relates to a stable composition, based on erythromycin, for the treatment of acne by the topical route.

More particularly, the composition is intended for the treatment of predominantly papulopustular acne and component polymorphic acne. 5 inflammatory.

Acne, which particularly affects young people aged between 14 and 30 years, is manifested by the appearance on the face, neck and possibly the back and chest of pimples, blackheads or pustules.

This manifestation of acne results from the hyperkeratinieation of the Iq conduit of the sebaceous glands causing a narrowing of the passage so that the sebum cannot flow freely and thus forms an environment conducive to bacterial proliferation.

Bacteria are generally not considered to play a primary role in the origin of acne, but their importance is essential due to the fact that they are capable of disrupting the behavior of the sebaceous glands and thus releasing irritating fatty acids. causing local inflammation phenomena.

Due to this action of the bacteria present in the sebum, various antibiotics have been proposed in topical preparations, in particular erythromycin.

The topical application of erythromycin makes it possible to act very effectively against acne, because this antibiotic inhibits the lypolitic enzymes produced by the main germs responsible for the manifestations of acne, namely more particularly Corynebacterium acnes and 25 Propionibacterium granulosum present on the surface of the skin and considered to be the main agents responsible for the manifestations of acne.

By acting by inhibition of the lipolytic enzymes, the hydrolytic cleavage of normal triglycerides of the sebum is thus avoided, which makes it possible to prevent the formation of long chain fatty acids which are at the origin of the phenomena of inflammation typical of lesions of the skin. 'acne.

The use of erythromycin compared to other antibiotics has the particular advantage of not giving rise to allergic phenomena when applied topically.

However, the use of erythromycin topically raises two difficulties, namely, on the one hand, its low penetration through the skin and, on the other hand, its lack of stability in solution.

Indeed erythromycin in solution degrades quickly at room temperature giving birth to erythromycin A-enol-ether and / or anhydro-erythromycin, these degradation products favoring the birth of 40 strains resistant to erythromycin .

: ', -2- Improving the stability and penetration of erythromycin has been the subject in recent years, many studies and different "solutions have been proposed on this subject.

Thus, British Patent No. 1,152,644 describes stable compositions of erythromycin in an oil having from 8 to 18 carbon atoms and an iodine index less than 42.

If such compositions in a lipophilic base exhibit better stability, these are not entirely satisfactory since they do not allow adequate release of the antibiotic. Far elsewhere, the use of fatty substances is not particularly sought after in the therapeutic treatment of acne.

US Pat. No. 4,000,263 describes a solution based on erythromycin having good storage stability, the erythromycin being in solution in a vehicle consisting of propylene glycol, ethyl alcohol and polyoxyethylenated lauric alcohol.

French patent n ° 77.07785 describes compositions for the local treatment of acne containing erythromycin as well as an excipient promoting penetration, the latter being dimethylsulfoxide, chloroform or an alkyl ester added with a compound moisturizer such as glycerin, glycol or other polyalcohol.

French patent n ° 77.32761 as well as European patent application n ° 80.20929 (0027286) describe antimicrobial compositions in the treatment of acne, erythromycin being associated with a penetrating agent, the latter being a fatty alcohol or an ester fatty acid, the composition further containing an alcohol preferably ethanol and optionally glycerol mono-oleate.

Finally, mention may also be made of US Pat. No. 4,469,684, which describes a pharmaceutical composition topically stable on storage containing erythromycin in the form of its zinc salt in t-butanol.

As the analysis of the prior art shows, the solutions which have been proposed tend either to improve the stability or to promote penetration, but to date a composition has not been proposed topically. having both good stability over time and good penetration.

35 After a systematic study of many compounds, it has now been found quite surprisingly that this double objective could be achieved by using at least one monoalkyl (C ^ -C ^) ether of propylene glycol or dipropylene glycol.

The present invention relates to a stable anti-acne composition 40, based on erythromycin, for topical application, this composition containing a therapeutically active amount of erythromycin base in a pharmaceutically acceptable vehicle comprising from 20 to 99.5% of at least one monoalkyl (Cj-C ^) ether of propylene glycol or dipropylene glycol.

Among the monoalkyl (C ^ -C ^) ethers of propylene glycol and of dipro-5 pylene glycol which can be used in the compositions according to the invention, mention may in particular be made of propylene glycol monomethyl ether (methoxypropanol), propylene glycol monoethyl ether, monomethyl ether of dipropylene glycol and the monoisobutyl ether of propylene glycol ·

The monomethyl ether of propylene glycol or methoxypropanol can be in two isomeric forms, namely on the one hand the form a or methoxy-1 propanol-2 and on the other hand the form $ or methoxy-2 propanol-1.

The industrial preparation methods generally lead to a mixture of these isomers, the a isomer of which is largely preponderant generally greater than 90%, the remainder being constituted by the 3 isomer.

As a methoxypropanol which is particularly suitable for constituting the vehicle for the compositions according to the invention, use may be made of the commercial product sold by the company DOW Chemical under the name of "DOWANOL PM" which is a mixture of at least 95% by weight of l isomer a.

The physical characteristics of DOWANOL PM are as follows:

20 Boiling point: 120eC

Density at 25 ° C: 0.919 Viscosity: 1.86 (centistokes) at 25 ° C

The stabilizing effect of monoalkyl (C ^ -C ^) ethers of propylene glycol and dipropylene glycol has been demonstrated following numerous stability tests carried out on various solvents by thin layer chromatography, high performance (HPCCM) on silica plate.

These stability studies made it possible to show that, unlike the ethers of ethylene and of diethylene glycol and unlike propylene glycol itself, the monoalkyl (Cj-C ^) ethers of propylene glycol and of dipropylene-glycol allowed to lead to solutions. stable erythromycin endowed with excellent skin tolerance.

The concentration of erythromycin base in the compositions according to the invention can be variable according to the nature of the acne lesions to be treated but is generally of the order of 0.5 to 6% and preferably of 1.5 to 5% per 35 relative to the total weight of the composition.

Although the propylene or dipropylene glycol monoalkyl (C ^ -C ^) ether (s) can be used as vehicle carrier, it is preferred according to a first embodiment of the invention to use them in admixture with at least a lower aliphatic alcohol such as ethanol or isopropanol.

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According to this embodiment, the compositions consist of: - Erythromycin base: 0.5 to 6% - Alcohol: 15 to 79.5%, 5 - Monoalkyl (C ^ -C ^) ether of propylene glycol or dipropylene glycol: 20 at 80%.

According to another preferred embodiment of the invention, the vehicle additionally contains at least one fatty acid triglyceride or a polyoxyethylenated fatty acid glyceride. According to this other embodiment, the compositions consist of: - Erythromycin base: 0.5 to 6% - Alcohol: 15 to 69.5% - Triglyceride of fatty acids or glyceride of polyoxyethylenated fatty acids: 10 to 40 % 15 - Monoalkyl (C ^ -C ^) ether of propylene glycol or dipropylene glycol: 20 to 74.5%.

The fatty acid triglycerides are preferably triglycerides 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 (Cg): ^ 3% - Caprylic acid (Cg): 50 to 80% - Capric acid (C ^ q): 15 to 45% - Lauric acid (C ^): K ^ 25 Among the fatty acid triglycerides which can be used in the compositions, mention may be made of those sold by the company DYNAMIT NOBEL under the names "MIGLYOL 810" and "MIGLYOL 812".

Among the polyoxyethylenated fatty acid glycerides which can be used as a replacement for the fatty acid triglycerides or as a mixture with these, mention may be made of those sold by the company GATTEFOSSE under the following names: "LABSAFIL WL 1318 CS (isostearic glycerides polyoxyethylenated) - "LABRAFIL M 1944 CS" (polyoxyethylene oleic glycerides) - "LABRAFIL M 1980 CS" or "LABRAFIL M 2700 CS" (polyoxyethylene oleic glycerides) - "LABRAFIL 35 M 2125 CS" (polyoxyethylene oleic and linoleic glycerides) - " LABRAFIL WL 2609 BS "(polyoxyethylenated oleolinoleic glycerides) -" LABRAFIL M 2130 CS "(polyoxyethylenated lauropalmitostearic glycerides) and" LABRASOL "(polyoxyethylenated Cq-C ^ q acid glycerides).

The compositions according to the invention as described above are anhydrous and are in the form of more or less fluid lotions which are easy to apply to acne lesions.

". If it is desired to obtain gels, 0.1 to 5% by weight of a thickening agent such as, for example, cellulose derivatives such as methylcellulose, hydroxymethylcellulose, hydroxyethylcellulose or hy is added. - droxypropylcellulose.

Various ingredients can also be introduced into the compositions, for example oils, waxes as well as any other ingredient of the compositions for topical application insofar as these do not influence the stability or the penetration of erythromycin. .

We will now give by way of illustration and without any limiting character, several examples of compositions according to the invention in the form of lotions and gels.

15 EXAMPLES

1. LOTIONS

A) - Erythromycin base .............. 2% - Isopropanol ..................... 49% - Methoxypropanol .. ............... 49% 20 B) - Erythromycin base .............. 2% - Triglycerides of caprylic and capric acids "MIGLYOL 812" .................. 20% 25 - Isopropanol .................... 58% - Methoxypropanol ... ............. 20% C) - Erythromycin base ............. 2% - Glycerides lauropalmito 30 polyoxyethylene stearic "LABRAFIL M 2130 CS" ... ........ 20% - Ethanol ........................ 58% - Methoxypropanol .......... ...... 20%

The above lotions obtained are fluid and result from the mechanical mixing of the various ingredients.

By application to acne lesions, at a rate of about 2 to 5 mg / cm 2 two to three times a day for 5 to 10 weeks, there is a marked reduction in the number of acne lesions and inflammation phenomena.

Lotions are particularly stable over time and do not require any special storage conditions.

* *. -6-2. GELS

D) - Erythromycin base ................. 2% - Hydroxypropylcellulose ............. 1.5¾ m - Absolute ethanol .... ................. 60% 5 - Methoxypropanol .................... 36.5% E) - Erythromycin base ................. 2% - Triglycerides of caprylic and capric acids 10 "MIGLYOL 812" .................. .... 23% - Hydroxypropylcellulose ............. 1.5% - Absolute ethanol ..................... 48 % -Methoxypropanol .................... 25.5%

The above gels are obtained by mixing, with stirring, the various ingredients. These gels, because of their consistency, are perfectly suitable for application limited to the only areas of acne lesions to be treated.

These gels are very stable, no significant decrease in activity having been observed after more than six months of storage at room temperature (20-25 ° C).

We observe after treatment of about three months, at the rate of two applications per day, the almost total disappearance of acne lesions.

Prior to the application of the lotions and gels according to the invention it is desirable to carry out a light washing of the skin with a non-alkaline soap and little detergent.

Claims (8)

1. Stable anti-acne composition, based on erythromycin, for topical application, characterized in that it contains a therapeutically active amount of erythromycin base in a pharmaceutically acceptable vehicle comprising from 20 to 99.5% by weight of at least one mono-alkyl (C ^ -C ^) ether of propylene glycol or dipropylene glycol. 2. Composition according to Claim 1, characterized in that it contains from 0.5 to 6% and preferably from 1.5 to 5% by weight of erythromycin. Iq 3. Composition according to any one of the preceding claims, characterized in that the monoalkyl (C ^ -C ^) ether of propylene glycol is methoxypropanol. 4. Composition according to any one of claims 1 to 3, characterized in that it contains: 15 0.5 to 6% of erythromycin, 15 to 79.5% of a lower aliphatic alcohol, 20 to 80% monoalkyl (Cj-C ^) ether of propylene glycol or dipropylene glycol. 5. Composition according to any one of claims 1 to 3, characterized in that it contains: 0.5 to 6% of erythromycin, 15 to 69.5% of a lower aliphatic alcohol, 10 to 40% of a fatty acid triglyceride and / or a polyoxyethylenated fatty acid glyceride, 25 to 74.5% of propylene glycol or dipropylene glycol monoalkyl (Cj-C ^) ether. 6. Composition according to any one of claims 4 and 5, characterized in that the lower aliphatic alcohol is ethanol or isopropanol. 7. Composition according to any one of the preceding claims, characterized in that it also contains a thickening agent in a proportion of 0.1 to 5% by weight. 8. Composition according to claim 7, characterized in that the thickening agent is hydroxypropylcellulose. 35