Cosmetic or pharmaceutical composition containing chitosan derivatives

<u>Technical area</u>

0001The invention relates to a new type of cosmetic or pharmaceutical composition containing derivatives of chitosan, that is to say deacetylated chitin soluble in acid medium, having a degree of acethylation (DA) at most equal to 40%.

<u>Previous techniques</u>

0002As we know, chitin or poly- (N-acetyl-D-glucosamine) is the most abundant polysaccharide on earth with cellulose. This polymer, although widely used, has the drawback of being insoluble in water.

0003Chitosan is the product of the deacetylation of chitin whose N-acetyl groups in Cyl are deacetylated by alkaline reagents. Due to the presence of free amine groups, chitosan, a cationic polymer (in an acid medium), is soluble in water at an acid pH. In order to improve the solubility of chitosan in an alkaline medium, it has been proposed to modify its molecule (see for example document FR-A-2 137 684).

0004In document EP-A-0 371 878, organosoluble O-carboxylated chitosan derivatives have been described which consist of a statistical chain of two specific units. These derivatives, useful as sequestering agents, for the preparation of films or for the coating of food additives for ruminants, are soluble in the usual organic solvents. In addition, these polymers derived from chitosan have a low molecular weight (less than 80,000, in practice between 10 and 20,000), which affects the stability of the emulsions produced from these polymers, stability required in the field of cosmetics.

0005In document US-A-4,027,068, it has been proposed to use O-carboxyalkylated or N-carboxylated chitosan derivatives as anti-fogging agents for automobile windshields. These derivatives are obtained by O-carboxylation, then N-alkoxylation by means of halogenated alkyl compounds. This type of reaction does not make it possible to effectively replace long-chain alkyl radicals (in C₁₂ and above), necessary for obtaining a hydrophilic-hydrophobic balance suitable for cosmetic applications. The polymers obtained are detergent, transparent, soluble in water, but hygroscopic, which does not allow them to be used effectively in cosmetic applications. In addition, cosmetic products and anti-fog agents for windshields belong to different and very distant technical fields.

0006The invention aims to obtain polymers derived from chitosan, consisting of several different monomer units, randomly distributed in the molecule of the polymer of chitosan, which have an emulsifying power, improved gelling properties and a very high smoothness, property increasingly most sought after in the field of cosmetology.

<u>Brief description of the invention</u>

0007The invention relates to a cosmetic or pharmaceutical composition containing from 0.1 to 5% by weight of a polymer derived from chitosan consisting of several monomer units distributed randomly in the polymer molecule, respectively:<ul id="ul0001" list-style="none"><li>A - an N-acetylated or N-alkylated glucosamine unit<chemistry id="chem0001" num="0001"><img file="EP0699433A2_D0001.tif" /></chemistry> with R equal to -COCH₃ or (CH₂) n - CH₃</li><li>B - a glucosamine motif<chemistry id="chem0002" num="0002"><img file="EP0699433A2_D0002.tif" /></chemistry>    <u>characterized</u> in that said polymer contains at least two other monomer units, respectively:</li><li>C - in majority quantity, a glucosamine-O-carboxymethylated or N-acetylated O-carboxymethylated glucosamine unit of general formula:<chemistry id="chem0003" num="0003"><img file="EP0699433A2_D0003.tif" /></chemistry></li><li>and D - an N-alkylated glucosamine-O-carboxymethyl unit of general formula:<chemistry id="chem0004" num="0004"><img file="EP0699433A2_D0004.tif" /></chemistry> wherein :<ul id="ul0002" list-style="none"><li>. R₁ and R₂ denote the hydrogen atom or the radical -CH₂COOX, in which X denotes H or a monovalent cation;</li><li>. and R₃ denotes H, a radical -COCH₃ or the radical -CH₂COOX in which X denotes H or a monovalent cation;</li><li>. and R₄ denotes a C radical to C₁₈ alkyl radical, linear or branched, saturated or not.</li></ul></li></ul>

0008In other words, the invention relates to a polymer derived from chitosan consisting of at least four monomer units randomly distributed in the molecule of the polymer, namely two units A and B glucosamine, already known for this application, combined with two other motifs C, majority, and D glucosamine-O-carboxymethylated N-alkylated.

0009In other words, the invention relates to compositions containing polymers derived from chitosan, in which the primary or secondary alcohol functions associated with carbon atoms no. 6 or no. 3 of the repeating unit of chitosan undergo, mainly, an O-carboxymethylation reaction, and in which the compound thus obtained is grafted by an alkyl radical on the nitrogen of the primary amine function of the glucosamine unit, carboxymethylated or not.

0010As is known, the O-carboxymethylation of chitosan is a known operation which consists in fixing a carboxymethyl radical (-CH₂COOX) on the oxygen of the alcohol function associated with the carbon atom 6 and / or 3 of the monomer of chitosan. This operation is described in "Advances in chitin and chitosan, Ed Brine, Sanford and Zitakis, Elsevier (1992), 516-525". This O-carboxymetylation operation brings hydrophilicity to the molecule, therefore promotes solubilization in an alkaline medium in the form of sodium salt for example.

0011N-alkylation is, as we know, an operation which consists in grafting an alkyl chain on the nitrogen of the amine function of the repeating unit of chitosan. Such compounds and the manufacturing process are described for example in documents US-A-4,424,346 and US-A-4,027,068 cited in the preamble.

0012We know that O-carboxymethylated chitosan is soluble in water at neutral or alkaline pH (pH> <i>7</i>) or at very acidic pH (pH <2.5). It is also known (see US-A-4,424,346) that the partially alkylated chitosan gives gelled solutions in dilute acetic acid.

0013It has been found that, if the operations of O-carboxymethylation and of partial N-alkylation of chitosan are combined, the derivative obtained has unexpected properties, such as in particular:<ul id="ul0003" list-style="dash"><li>auto-associativity: the hydrophobic chains grafted onto the macromolecular chain can associate during dissolution (in water for example) by bringing into play a thermodynamic phenomenon called "hydrophobic interaction"; this phenomenon is demonstrated by a notable increase in the viscosity of the solution in water, when the polymer concentration becomes greater than 0.3 to 0.4% by weight; for these concentrations, the viscosity increases with temperature;</li><li>self-associativity with surfactants: the hydrophobic chains of polymers associate with the hydrophobic part of the surfactant molecules and when the concentration of these is sufficient, this generates an increase in viscosity, even the freezing of the solution;</li><li>better solubility, since the compound obtained is soluble in pure water, dilute acid solutions and in water / organic solvent mixtures such as water / DMSO, water / dioxane, etc .;</li><li>emulsifying properties; in fact, when a solution of these polymers is added with vigorous stirring to petroleum jelly oil or isostearyl isostearate for example, an emulsion is formed and remains stable for at least two months at room temperature; the polymer concentration used for this application can be as low as 0.5% by weight relative to the final emulsion; this stability is not affected by an increase in temperature to at least 50 ° C.</li></ul>

0014These properties depend on the degree of O-carboxymethylation (DS), that is to say on the average number of -CH₂COOX units per medium unit statistically C and D. This degree can vary from 0.1 to 2, the length of the carbon chain of the alkyl group which can be chosen between C₂ and C₁₈ and of the number of these chains distributed along the macromolecule; the quality of chitosan which is defined by its degree of residual acetylation DA and the viscosity of its 1% solutions in 1% acetic acid; DA is less than 20% and the viscosity is between 5 and 1500 m.Pa.s.

0015The linear alkyl radical R₄ at C₂ to C₁₈, is preferably C₆ to C1₂. Indeed, it has been found that with alkyl radicals having less than six carbon atoms, the properties of chitosan were little improved. Low molecular weight aldehydes (up to C₁₀) are strongly odorous.

0016This is why, in practice, it is advantageous to use lauric aldehyde (lauraldehyde).

0017In an advantageous embodiment:<ul id="ul0004" list-style="dash"><li>R₁ and R₂ is -CH₂COOX at a percentage varying from 10 to 100% (DS between 0.2 and 2), and preferably between 25 and 65% (DS between 0.5 and 1.3);</li><li>R₃ is the acetyl radical with a percentage between 0 and 20, preferably 5 and 10%;</li><li>R₃ is H at least 50%;</li><li>R₄ is an alkyl radical in a percentage less than 50%, and preferably between 6 and 8% when this radical is in C₁₂.</li></ul>

0018Advantageously:<ul id="ul0005" list-style="dash"><li>R₁ and R₂ are -CH₂COONa at a rate of 25 to 65%;</li><li>R₃ is an acetyl radical for a maximum of 10%;</li><li>R₄ is the lauryl radical for a percentage between 6 and 8%.</li></ul>

0019In another advantageous embodiment, R₁ and / or R₂ and / or R₃ is -CH₂COOX for 50% of the monomers of the polymer obtained.

0020The amount of minority monomers A, B and D varies according to the desired properties, in particular the degrees of substitution, therefore of solubilization in water.

0021A process for the preparation of these compounds consists of:<ul id="ul0006" list-style="dash"><li>first, to O-carboxymethylate the chitosan;</li><li>then, to N-alkylate the compound obtained.</li></ul>

0022Alternatively, one can first N-alkylate the chitosan, then O-carboxymethylate the compound obtained.

0023The polymers obtained in this way in accordance with the invention are advantageous. They are in the form of a powder, generally cream in color, of molecular weight between 20 and 800,000, preferably close to 200,000, soluble in water at room temperature at a pH below 6 or above 8.5 , especially with stirring. These pH values ​​depend on the percentage of alkylation and the degree of substitution (DS) of the carboxymethylation reaction.

0024These polymers dissolve in water at a concentration of 0.5 to two percent (0.5 to 2%) by weight to lead to compositions having the consistency of honey.

0025These polymers have many advantages over those known to date. We can cite :<ul id="ul0007" list-style="dash"><li>the possibility, after incorporation in a base of cosmetic products or in an emulsion, to confer on the latter a desired stability, even at high temperature;</li><li>the formation of gels and emulsions.</li></ul>

0026In this way, these compounds can be successfully used in the manufacture of cosmetic or even pharmaceutical products.

0027The manner in which the invention can be implemented and the advantages which ensue therefrom will emerge more clearly from the embodiments which follow.

<u>Way of carrying out the Invention</u>

<u>General procedure</u>

0028The chitosan is purified beforehand by dissolution in dilute acetic acid, filtration, precipitation at pH8 by neutralization using dilute sodium hydroxide and washing of the precipitate with alcoholic solutions of increasing concentrations 70-80-95% by volume.

O-carboxymethylation reaction

0029This method is described in the reference M Rinaudo, P Le Dung, M. Milas "A new and simple method of synthesis of carboxymethylchitosan", 5th conference on Chitin and Chitosan, Ed-Brine, Sandford and Zitakir, Elsevier (1992) 516- 525.

0030One gram (1 g) of chitosan is dissolved in 40 ml of an aqueous 1% acetic acid solution.

003140.3 g of 50% by weight aqueous NaOH solution are added with vigorous stirring and one hour after 9 g of Na monochloroacetate.

0032The reaction lasts two to four hours (2 to 4 h) at a temperature between 20 and 50 ° C with stirring.

0033The dissolved carboxymethylchitosan is precipitated with ethanol (300 ml), centrifuged and washed with alcohol 70-80-95% by volume, then dried at room temperature. Too much drying harms the subsequent solubility of the compound obtained.

0034The degree of substitution (DS) obtained by potentiometric determination and NMR is measured. 0.1 to 1.30 is obtained depending on the conditions used.

N-alkylation reaction

0035The O-carboxymethylchitosan in the form of the Na⁺ salt (0.5 g, 2.10⁻³ monomole) is dissolved in a mixture of distilled water (40 ml) and ethanol (15 ml). The aldehyde in the desired amount (x mole% per mole of chitosan) is added. The reaction takes place (20h, 25 ° C) in the presence of sodium cyanoborohydride (0.4 g, 6.10⁻³ monomole).

0036The desired compound is precipitated with ethanol (300 ml) purified by two precipitation stages, successive washings, then dried at room temperature.

0037Too much drying harms the subsequent solubility of the compound obtained.

<u>Example 1</u>

:

0038Chitosan is used with a residual acetylation degree equal to 10%.

0039Its viscosity at 1% by weight in a solution of acetic acid at 1% by weight, is 500 mPa.s.

0040The reaction takes place at room temperature between 20 and 25 ° C for four hours.

0041An O-carboxymethylated chitosan with DS = 0.5 soluble in distilled water is obtained. This means that on average R₁ and / or R₂ and / or R₃ is -CH₂COOX for 50% of the monomers of the polymer obtained.

0042The alkylation reaction is carried out with a C₁₂ aldehyde in molar proportion relative to the O-carboxymethylchitosan of 0.08 or 8%

0043A compound is obtained in the form of a beige powder soluble in water at pH 8.5 with vigorous stirring, to give an aqueous solution which gels at 2%.

0044This compound responds statistically to the general formula:<chemistry id="chem0005" num="0005"><img file="EP0699433A2_D0005.tif" /></chemistry>    in which :<ul id="ul0008" list-style="none"><li>. R₁ and R₂ = H or -CH₂COOX</li><li>. X = H or Na depending on pH<5.5 or> 8.5</li><li>. R₁ + R₂ = 25% of the OH units</li><li>. R₃ = H or -COCH₃</li><li>. R₄ = C₁₂ in 8% of the repeating patterns.</li></ul>

Properties

0045Acidified to pH 5.5 with lactic acid, a 2% solution turns into a translucent gel whose viscosity measured with Rhéomat 115 is three times higher at 44 ° C than at 4 ° C, and has a hysteresis , when one measures the stress according to the gradient of shear in rise then in descent, symbol of an associated structure.

0046A 1% solution adjusted to pH 5.5 with lactic acid is used to make 5% and 20% emulsions of petrolatum oil or glycerol trioctanoate by vigorous stirring. These white emulsions have the appearance of a gel on which no coalescence is observed after two weeks at room temperature or at 50 ° C. They have a particularly pleasant touch suitable for improving cosmetic emulsions (creams or milk) with the formulations below:<tables id="tabl0001" num="0001"><table frame="all"><tgroup cols="2" colsep="1" rowsep="0"><colspec colnum="1" colname="col1" colwidth="78.75mm" /><colspec colnum="2" colname="col2" colwidth="78.75mm" /><thead valign="top"><row><entry namest="col1" nameend="col2" align="left"><u>Thick milk</u></entry></row></thead><tbody valign="top"><row><entry namest="col1" nameend="col1" align="left">emulsifier based on ethoxylated fatty alcohols, marketed by the Applicant under the name "Tefose 2000"</entry><entry namest="col2" nameend="col2" align="right">7 %</entry></row><row><entry namest="col1" nameend="col1" align="left">Cetyl alcohol</entry><entry namest="col2" nameend="col2" align="right">1 %</entry></row><row><entry namest="col1" nameend="col1" align="left">petrolatum oil</entry><entry namest="col2" nameend="col2" align="right">5 %</entry></row><row><entry namest="col1" nameend="col1" align="left">polymer derived from Example 1</entry><entry namest="col2" nameend="col2" align="right">0,8 %</entry></row><row><entry namest="col1" nameend="col1" align="left">Lactic acid</entry><entry namest="col2" nameend="col2" align="right">sufficient quantity to obtain a pH of 5.5</entry></row><row rowsep="1"><entry namest="col1" nameend="col1" align="left">Distilled water</entry><entry namest="col2" nameend="col2" align="right">sufficient quantity to adjust to 100% (QSP)</entry></row></tbody></tgroup></table></tables>

0047The polymer of Example 1 is dissolved in distilled water acidified to pH 5.5 with lactic acid (for example), then warmed to 70 ° C. All of the oily compounds heated to 70 ° C. are added to the aqueous phase with stirring. The emulsion is kept under stirring during cooling.

0048We obtain a thick, shiny white milk, smooth to the touch, stable at 50 ° C for at least five days.

0049In the absence of compound no. 1, the touch is less pleasant on the one hand, and this formula is unstable after twenty-four hours at room temperature on the other hand, which clearly demonstrates the effects of compound no. 1.<tables id="tabl0002" num="0002"><table frame="all"><tgroup cols="2" colsep="1" rowsep="0"><colspec colnum="1" colname="col1" colwidth="78.75mm" /><colspec colnum="2" colname="col2" colwidth="78.75mm" /><thead valign="top"><row><entry namest="col1" nameend="col2" align="left"><u>Fluid milk</u></entry></row></thead><tbody valign="top"><row><entry namest="col1" nameend="col1" align="left">Polyethylene glycol isostearate with molecular weight 300</entry><entry namest="col2" nameend="col2" align="left">5 %</entry></row><row><entry namest="col1" nameend="col1" align="left">sweet almond oil</entry><entry namest="col2" nameend="col2" align="left">15 %</entry></row><row><entry namest="col1" nameend="col1" align="left">polymer derived from Example 1</entry><entry namest="col2" nameend="col2" align="left">0,4 %</entry></row><row><entry namest="col1" nameend="col1" align="left">Lactic acid</entry><entry namest="col2" nameend="col2" align="left">QSP pH 5.5</entry></row><row rowsep="1"><entry namest="col1" nameend="col1" align="left">distilled water</entry><entry namest="col2" nameend="col2" align="left">QSP 100</entry></row></tbody></tgroup></table></tables>

0050The polymer of Example 1 is dissolved in distilled water, acidified to pH 5.5. The oily phase is incorporated into the aqueous phase with stirring at room temperature. A fluid, shiny, stable milk is obtained at 50 ° C. for at least five days.

0051In the absence of compound no. 1, this formula is unstable at room temperature and hot after twenty-four hours, which clearly shows the effect of the polymer derived from Example 1 according to the invention.<tables id="tabl0003" num="0003"><table frame="all"><tgroup cols="2" colsep="1" rowsep="0"><colspec colnum="1" colname="col1" colwidth="78.75mm" /><colspec colnum="2" colname="col2" colwidth="78.75mm" /><thead valign="top"><row><entry namest="col1" nameend="col2" align="left"><u>Microemulsion</u> (according to the method described in the document of the Applicant EP-B-0334 777)</entry></row></thead><tbody valign="top"><row><entry namest="col1" nameend="col1" align="left">polyglycerol isostearate</entry><entry namest="col2" nameend="col2" align="char" char=",">13,2 %</entry></row><row><entry namest="col1" nameend="col1" align="left">emulsifier based on polyethylene glycol ester</entry><entry namest="col2" nameend="col2" align="char" char=",">32,9</entry></row><row><entry namest="col1" nameend="col1" align="left">isostearyl isostearate</entry><entry namest="col2" nameend="col2" align="char" char=",">12,0</entry></row><row><entry namest="col1" nameend="col1" align="left">water</entry><entry namest="col2" nameend="col2" align="char" char=",">21,8</entry></row><row><entry namest="col1" nameend="col1" align="left">polymer derived from Example 1</entry><entry namest="col2" nameend="col2" align="char" char=",">0,1</entry></row><row rowsep="1"><entry namest="col1" nameend="col1" align="left">water</entry><entry namest="col2" nameend="col2" align="char" char=",">20,0</entry></row></tbody></tgroup></table></tables>

0052The polymer derived from Example 1 is dissolved in the second fraction of distilled water to make a 0.5% solution. This solution is incorporated into the mixture of the preceding constituents with stirring, to form a translucent microemulsion.

0053A second microemulsion is made with the same constituents without however containing the derivative polymer characteristic of the invention.

0054The comparison of the microemulsions obtained in skin application brings out an improved sliding sensation in the presence of the polymer derived from Example 1.

<u>Example 2</u>

:

0055The same raw materials and the same conditions are used as in Example 1, except the proportion of aldehyde C₁₂ which becomes 0.06 molar.

0056Compound no. 2 obtained is a beige powder soluble in water at pH 8.5, with vigorous stirring, which gels at 2%. Acidified to pH 5.5 with lactic acid, a 2% solution becomes a translucent gel.

0057A 1% solution at pH 5.5 makes it possible to produce gelled emulsions with 5 and 20% vaseline oil or glycerol trioctanoate. After one week at room temperature or at 50 ° C., no coalescence is observed.

<u>Examples 3 to 8</u>

:

0058The results of all tests 1 to 8 are collated in the appended table.<tables id="tabl0004" num="0004"><img file="EP0699433A2_D0006.tif" /></tables>

0059From these examples, it can be deduced that the combination of O-carboxymethylation and N-alkylation reactions applied to chitosan with an acetylation degree of less than 20% and a viscosity greater than or equal to 50 mPa.s (in 1% solution ), gives this polymer particularly advantageous properties.

0060The compounds according to the invention are soluble in alkaline medium (pH> 8.5) or acidic medium (pH ≦ 5.5), even in dilute solution (0.5%).

0061The more concentrated solutions gel the better the higher the temperature, in particular at pH 5.5 or lower.

0062Stable emulsions can be obtained for several days, simply by emulsifying an oil in a solution containing 0.5% or more of the compound according to the invention, in order to obtain a gelled emulsion which is pleasant to spread on the skin.

0063It is also possible to incorporate the compound according to the invention in emulsions for cosmetic or pharmaceutical use. At concentrations of 0.5% and 1%, a considerable improvement in feel and consistency at high temperature (50 ° C) is obtained.

0064It is also possible to incorporate the compound according to the invention in microemulsions for cosmetic or pharmaceutical use.

0065At the concentration of 0.5%, an improvement in the feeling of sliding on application is obtained.