Microemulsion for cosmetic or pharmaceutical use

The invention relates to a new microemulsion designed in particular for use in the pharmaceutical industry or in cosmetology.

In the following description and in the claims, by "microemulsion" denotes a homogeneous transparent micellar solution, formed of several components, generally comprising two immiscible phases, namely a water-soluble phase and a lipidic phase. In practice, these emulsions which comprise particles whose dimensions are between one hundred and five hundred angstroms, are always made of four components, namely respectively:<ul><li>. a water-soluble phase, such as water, alcohol, polyol, glycerol or mixtures of these compounds;</li><li>. an oil phase, also called lipid, such as mineral, vegetable, animal or synthetic;</li><li>. at least one surfactant;</li><li>. at least one cosurfactant.</li></ul>

As is known, the "surfactants" are chemical compounds pronounced hydrophilic character, intended to cause the formation of micelles. A surfactant used alone only can form a micelle solution.

In contrast, "cosurfactants", also sometimes referred to as cosurfactants agents are chemical compounds, but more hydrophobic character as to cause the mutual solubilization of the aqueous and oily phases in a microemulsion.

As is known, microemulsions require the combined use of surfactants and cosurfactants.

Microemulsions have been widely studied for the recovery of oil. For this purpose, they contain high proportions of aggressive surfactants, usable in pharmaceutical or cosmetic applications. In the pharmaceutical and cosmetic industries, widely used emulsions. However, they are composed of particles greater than or equal to one micrometer dimensions. The difficulty lies in training and especially their thermal and mechanical stability.

The invention overcomes these drawbacks. It is a microemulsion particularly suitable for the pharmaceutical industry or in cosmetology, which is compatible with such applications, has good safety both by topical, oral, rectal or transdermal, and thermodynamic stability, no comparison with that of traditional emulsions.

This microemulsion for pharmaceutical or cosmetic use, of the type comprising a water-soluble phase and a lipidic phase, essentially comprising in admixture:<ul><li>at least one water-soluble phase</li><li>at least one lipidic phase,</li><li>at least one surfactant based on polyethylene glycol,</li><li>at least one cosurfactant based on polyglycerol,</li></ul><b><u>characterized</u></b><b>:</b><ul><li>in that the surfactant is a mixture of glycerol ester and said polyethylene glycol, and is at least ten percent (10%) by weight of the mixture;</li><li>in that the cosurfactant is an ester of said polyglycerol and liquid fatty acids, which is in the mixture in proportion lower than that of the surface active agent represents at least five per cent (5%) by weight the mixture;</li><li>and finally, in that the lipid compound has a hydrophilic / lipophilic balance of three.</li></ul>

In other words, the invention consists in having selected of surfactants and cosurfactants individuals, that when combined with a water-soluble phase and a lipidic phase form a stable microemulsion having excellent safety, good skin tolerance a virtual absence of toxicity and no detergent action. In this way, can be used successfully and safely as in the pharmaceutical industry and in cosmetology. Thus, the invention lies in having selected specific microemulsions for the industry of cosmetology and / or pharmaceutical, and specifically having selected surfactants and specific cosurfactants which, combined, will achieve microemulsions having excellent inoccuité.

In the description and claims:<ul><li>"compound with detergent action" is meant chemical compounds to clean by wetting, solubilization or moving dirt or filth and with a high power emulsifier; </li><li>by "good skin tolerance" means an absence or low irritation by applying to the skin or mucous membranes;</li><li>we say "a compound has virtually no toxicity" when its lethal dose (LD50) is very high.</li><li>Finally, by "mixed glycerol and polyethylene glycol ester" means compounds having only ester bonds, to the exclusion of all other active connections, such as in particular ethers.</li></ul>

Most generally, the surfactant is at least fifteen percent (15%) by weight of the mixture and cosurfactant and proportion of cosurfactant is close to half that of the surfactant.

Advantageously, in practice:<ul><li>for the surfactants and / or co-surfactants show good safety, that is to say, excellent skin tolerance, and a virtual absence of toxicity, they should also be prepared with pure raw materials as possible and in using non-toxic catalysts and non-aggressive, and they should be purified;</li><li>in the surfactant, the polyethylene glycol has an average molecular weight between 100 and 1000 and preferably is close to 400, which gives it a non-detergent character; as already stated, this surfactant must represent weight at least ten percent (10%) of the weight of the microemulsion; indeed, it was found that if this weight is less than ten percent (10%) was not obtained a microemulsion but simply a traditional emulsion, ie opaque, whereas if the proportion is high, the dispersion will be so much easier, but the cost will be even higher without proportional improvement; we obtain good results with a proportion of neighbor surfactant twenty (20%);</li><li>in the cosurfactant, the polyglycerol having a molecular weight of between 100 and 1000 and the fatty acid is preferably a liquid fatty acid, such as for example oleic acid or isostearic acid, alone or in admixture; as already said, the proportion of the cosurfactant is generally less than that of the surfactant, but this excess of five (5%), preferably ten percent (10%);</li><li>as lipid phase is used any liquid oily compound commonly used for pharmaceutical applications and / or cosmetic having a hydrophilic / lipophilic balance (HLB) of at most three, preferably about two;</li><li>the water soluble phase may be water or any other compound to water-soluble character, such as alcohols, polyols, glycerol .., alone or in admixture;</li><li>Finally, the microemulsion may also include:<ul><li>. active pharmaceutical ingredients that later is desired to introduce in the state or in solution in a suitable solvent;</li><li>. preservatives, such as including antiseptics,</li><li>. perfumes, in particular for application in cosmetics,</li><li>. biological or plant derivatives,</li><li>. other cosmetic additives.</li></ul></li></ul>

To prepare emulsions, it has been proposed to use surfactants based on polyethylene glycol or ester based polyglycerol fatty acid (eg EPA-0216557 and US Patent 4,555,524 and 4,690,774). The invention is not intended these compounds in their use as surfactants, but is to be determined that by mixing some of these specific compounds in suitable proportions, ie majority surfactants but at least equal to 10% one could prepare stable micro-emulsions with excellent inoccuité, what we do not know until then, provided also that the hydrophilic / lipophilic balance (HLB) of the lipid phase is at most equal to 3 and preferably close to 2.

The mixture of these compounds is carried out in proportions previously determined by experience, no special precautions or specific, especially at room temperature, stirring gently.

How the invention can be implemented and the advantages thereof will appear better from the exemplary embodiments that follow, indicative and not limiting.

<u>example 1</u>

:

In a beaker were mixed at room temperature:<ul><li>32.9 grams of a surfactant consisting of a coester C8 / C10 glycerol and polyethylene glycol of average molecular weight 400, marketed by the Applicant under the name "Labrasol";</li><li>13.2 grams of a cosurfactant consisting of a methyl-2 heptadecanoate polyglycerol marketed by the Applicant under the name <b>"PLUROL Isostearique"</b> ;</li><li>41.8 grams of deionized water;</li><li>12.0 grams of methyl 2-methyl-2 heptadecanoate heptadecanoyl (compound lipid) of neighbor HLB of 2, marketed by the Applicant under the name <b>"Isostearyl isostearate"</b> ;</li><li>0.1 grams of an antiseptic preservative sold by Rohm and Haas under the name "Kathon-CG", and consisting of an aqueous solution of:<ul><li>. 5-chloro-2-methyl-4-isothiazolin-3-one</li><li>. and 2-methyl-4-isothiazolin 3-one complexed by magnesium chloride and stabilized by magnesium nitrate.</li></ul></li></ul>

At room temperature, this mixture was stirred by hand for about five minutes.

One then obtains a clear microemulsion, fluid and clear, slightly yellow, stable in a temperature range between -20 ° C and + 50 ° C.

This microemulsion suitable as excipient for the pharmaceutical industry or as a base for cosmetics because of its stability and its excellent skin safety.

<u>example 2</u>

:

In a beaker were mixed at room temperature:<ul><li>32.1 grams of surfactant <b>LABRASOL</b> Applicant described in Example 1;</li><li>16.1 grams of the same cosurfactant <b>"PLUROL Isostearique"</b> as in Example 1;</li><li>10.7 grams of the lipid compound described in Example 1, sold by the Applicant under the name <b>"Isostearyl isostearate"</b> ;</li><li>2.2 grams of sweet almond oil;</li><li>1.1 grams of cereal germ oil;</li><li>and finally 0.5 gram of ointment marketed by the Applicant under the name <b>"ROSALEVRE - MA 1445"</b>.</li></ul>

then added to this mixture:<ul><li>26.8 grams of deionized water;</li><li>8.0 grams of an aqueous placental extract sold by the Applicant under the name <b>"PHYLDERM FILATOV"</b> ;</li><li>2.4 grams of extract hydroglycolic <b>Calendula</b>Marketed the Applicant under the name <b>"VEGETOL MCF 774</b>";</li><li>Finally, 0.1 grams of antiseptic preservative of Example 1.</li></ul>

After stirring by hand for five minutes at room temperature, we obtain a clear microemulsion orange-yellow color, particularly suitable as skin preparation of personal hygiene.

<u>Example 3:</u>

In 22.5 grams of deionized water was dispersed 5.6 grams of a compound sold by the Applicant under the name <b>"ATELOGLYCANE"</b>And 0.1 grams of the same antiseptic preservative as in Example 1.

always added at room temperature in this release:<ul><li>53.1 grams of the surfactant of Example 1;</li><li>9.7 grams of the cosurfactant of Example 1;</li><li>9.0 grams of the lipid compound isostearyl isostearate of Example 1.</li></ul>

gently mixed at room temperature for five minutes.

a stable microemulsion is obtained, clear, yellow, usable for hair applications.

<u>Example 4:</u>

In 15.5 grams of propylene glycol, mixed:<ul><li>29.9 grams of the surfactant referred <b>LABRASOL</b> described in Example 1,</li><li>42.5 grams of the cosurfactant referred <b>"PLUROL Isostearique"</b>, Also described in Example 1,</li><li>12.1 grams of the lipid phase <b>"Isostearyl isostearate"</b>, As described in Example 1.</li></ul>

at room temperature mixing for five minutes, stirring gently.

Is obtained an anhydrous microemulsion, stable, clear, yellow, successfully usable as cosmetological excipient, in particular for skin care.

The microemulsions prepared according to the invention have many advantages. We can cite :<ul><li>high safety, including subcutaneous, transdermal, rectal or oral;</li><li>excellent stability at normal working temperatures, that is to say in a range from -30 ° C to + 80 ° C;</li><li>lack of separation in case of freezing, which facilitates preservation;</li><li>improving the bioavailability of pharmaceutical active ingredients;</li><li>possibility to heat sterilization and sterile filtration.</li></ul>

These microemulsions can have varied presentations, such as traditional microemulsions, foams, pressurized forms, aerosols, capsules, ampoules etc. .

In this way, they can be successfully used in all cosmetic applications or pharmaceutical skin external (topical), internal (oral, rectal, injection), or as carriers, vectors, strong physiological compatibility excipients.