Inclusion complexes of organic peroxides and cyclodextrins, process for their preparation and uses.

0001The present invention relates to inclusion compounds of cyclodextrins enclosing organic peroxides, methods of preparing said inclusion compounds and their uses in the pharmaceutical, cosmetic or food industry, and as a polymerization or copolymerization initiator. .

0002Cyclodextrins are cyclic oligosaccharides composed of glucose residues linked by α → 1,4 bonds and comprising a cavity. There are generally three types of cyclodextrins: α cyclodextrins, consisting of six glucose residues, β cyclodextrins, consisting of seven glucose residues, and γ cyclodextrins consisting of eight glucose residues. Cyclodextrins δ, comprising 9 glucose residues have also been described. Cyclodextrins can be prepared from starches of various origins, modified or unmodified, glycogen, or fractions of starches such as maltodextrins, amyloses or amylopectins. These starting materials are liquified for example by gelatinization or by treatment using a liquefaction enzyme such as an α-amylase, then are subjected to the action of a cyclodextrin-glucosyl-transferase (CGTase). Mention may more particularly be made of the process for the preparation of cyclodextrins described in US 3,923,598 according to which the CGTase used is produced by Bacillus sp. specific. These methods generally make it possible to obtain a mixture of α, β and γ cyclodextrins in variable proportions. It is however possible to isolate each type of cyclodextrin according to conventional methods or for example according to the methods described in US Patents 4,418,144 and US 4,384,898.

0003Other cyclodextrins are known, which are modified cyclodextrins, generally obtained from said cyclodextrins α, β and γ. Among these cyclodextrins, mention may be made of those modified with acyl, alkyl, hydroxyalkyl, glucosyl or maltosyl groups. These modified cyclodextrins can be obtained by the methods described in particular in French patent application No. 2,597,785, in "cyclodextrins and their industrial uses" Dominique Duchêne, ed. de Santé, 1987, pages 366-388 or in "Cyclodextrin Technology", Jozsef Szejtli, ed. Kluwer Academic Publishers, page 2.

0004Cyclodextrins are generally used either to form powders of perfumes, tea, spices, insecticides, fungicides, flavors or fat-soluble vitamins, and thus preserve the properties of these products, or to remove bitter components present for example in citrus fruits.

0005Organic peroxides are compounds of the general formula <maths id="math0001" num=""><math display="block"><mrow><mtext>R₁-OO-R₂</mtext></mrow></math><img file="EP0441690A2_D0001.tif" /></maths>in which R₁ and R₂ are identical or different and represent a residue R₃ or a residue<chemistry id="chem0001" num="0001"><img file="EP0441690A2_D0002.tif" /></chemistry> being a hydrocarbon residue.

0006Organic peroxides can decompose easily by supplying energy in the form of a heat, light or mechanical shock such as impact or friction. It is therefore recommended to store and handle said peroxides taking great care. In addition, most organic peroxides are toxic and irritating to the skin and eyes, making their use delicate. Finally, organic peroxides are not very soluble in water. Improved solubility of said organic peroxides can modify their use in certain applications, in particular in their use as a polymerization or copolymerization initiator.

0007A first object of the present invention consists of compounds comprising such organic peroxides so as to make them less sensitive to decomposition, which make it possible to reduce their toxicity and their irritant effect and which make them more soluble in an aqueous medium.

0008A second subject of the invention consists of processes for the preparation of such compounds.

0009A final object of the invention relates to the use of said compounds in the pharmaceutical, cosmetic and food industry and as a polymerization or copolymerization initiator.

0010The present invention therefore relates to inclusion compounds of cyclodextrins characterized in that they consist of cyclodextrin molecules enclosing organic peroxides of formulas R₁-OO-R₂ in which R₁ and R₂ are identical or different and represent a residue R₃ or<chemistry id="chem0002" num="0002"><img file="EP0441690A2_D0003.tif" /></chemistry> R₃ being a hydrocarbon residue.

0011By the term "enclosing" is meant in the context of the present invention, that at least a part of the molecule of said organic peroxide is included in the cavity of the cyclodextrin molecule.

0012Said cyclodextrin inclusion compounds can be formed from α, β, γ or δ cyclodextrins or α, β, γ or δ cyclodextrins modified by acyl, alkyl, hydroxyalkyl, glucosyl or maltosyl groups. It is also possible to use mixtures of such cyclodextrins or mixtures of cyclodextrins and dextrins or linear oligosaccharides. However, β cyclodextrins are preferred.

0013Said organic peroxides are preferably molecules in which R₃ is a linear or branched, saturated or unsaturated aliphatic radical or an aryl radical.

0014Advantageously R₃ can be a C₁-C₁₀ alkyl radical or a phenyl radical. The inclusion compounds according to the present invention are more particularly suitable for organic peroxides in which R₁ and R₂ represent a residue<chemistry id="chem0003" num="0003"><img file="EP0441690A2_D0004.tif" /></chemistry> Such organic peroxides can in particular be dibenzoyl peroxide or dioctanoyl peroxide.

0015Said cyclodextrin inclusion compounds may contain more than 5%, generally from 10 to 30% by weight of organic peroxides relative to the total weight of the inclusion compound.

0016The inclusion compounds according to the invention are generally present in solid and pulverulent form.

0017The invention also relates to methods for preparing said inclusion compounds. According to a first preparation process, the following steps are carried out:<ul id="ul0001" list-style="none"><li>a) The cyclodextrins are solubilized in a solvent in which the organic peroxide is added before, simultaneously or after the said cyclodextrins,</li><li>b) The mixture thus obtained is brought to a temperature between 25 and 70 ° C, preferably between 40 and 65 ° C,</li><li>c) recovering the inclusion compound thus formed,</li></ul>

0018The solvent used to dissolve the cyclodextrins can be water or a mixture of water and at least one organic solvent miscible in water. Such organic solvents can be alcohols such as methanol, ethanol, n-propanol or isopropanol, ketones such as acetone or ethers such as dioxane. Said alcohols are however preferred. When using such a mixture, the weight ratio of water / organic solvent is generally between 2/1 and 20/1, preferably between 2/1 and 5/1. The mixture obtained at the end of step a) may contain from 70 to 95%, preferably from 80 to 90% by weight of solvent, from 4 to 20%, preferably from 8 to 15% by weight of cyclodextrins and from 0.5 to 10%, preferably from 0.5 to 5% by weight of organic peroxide.

0019Cyclodextrins and organic peroxide are generally introduced into the solvent with stirring. Said organic peroxide can then be in the form of a powder or in solution in one of the solvents mentioned above.

0020Stage b) of heating the mixture generally lasts from one to ten hours, preferably from one to four hours.

0021The inclusion compound can be recovered either by lyophilization of the mixture, or by decreasing the temperature of the mixture so as to obtain a precipitate consisting of said inclusion compounds.

0022In the latter case, the temperature is generally lowered at most to 0 ° C, preferably between 5 and 10 ° C. The time for lowering the temperature is not critical but is generally greater than one hour, from preferably between three and eight hours. Then said precipitate is separated from the mixture, by conventional methods, for example by filtration.

0023The separated precipitate can then be dried to obtain a powder.

0024A second process for preparing the inclusion compounds according to the invention consists of the following steps:<ul id="ul0002" list-style="none"><li>a) Cyclodextrins and an organic peroxide are mixed in a solvent so as to obtain a paste,</li><li>b) the dough is dried until a solid product is obtained,</li><li>c) Said solid product is ground until a powder is obtained.</li></ul>

0025The paste obtained in step a) comprises from 20 to 60%, preferably from 40 to 50% by weight of solvent, from 30 to 70%, preferably from 40 to 55% by weight of cyclodextrins and from 1 to 15 %, preferably from 4 to 10% by weight of organic peroxide.

0026As the solvent, those mentioned in the context of the first process described above can be used. Water is however a preferred solvent.

0027The organic peroxide can be either in the form of a powder, or be mixed with at least part of said solvent.

0028The solvent, the cyclodextrins and the organic peroxide are generally mixed for at least thirty minutes, preferably for three to ten hours and more preferably for five to eight hours. Mixing can be done at room temperature.

0029The inclusion compounds according to the present invention can be used as a medicament and in particular for the preparation of a medicament intended to treat acne.

0030They can also be used in the food industry, in particular as a bleaching agent, in particular flours, oils, waxes or milk intended for the preparation of certain cheeses. The inclusion compounds according to the invention can also be used in cosmetic compositions, in particular cosmetic compositions intended for cleaning the skin.

0031For the uses and applications mentioned above, preference is given to using inclusion compounds comprising dibenzoyl peroxide.

0032The inclusion compounds according to the invention, in particular those containing benzoyl peroxide and dioctanoyl peroxide can also be used as initiator for polymerization or copolymerization of vinyl monomers or dienes, such as ethylene, vinyl chloride, styrene, acrylic acid and its esters, methacrylic acid and its esters, vinyl acetate, acrylonitrile and butadiene. Said inclusion compounds are more particularly advantageous when they are used for the polymerization and copolymerization in aqueous phase of water-soluble vinyl monomers.

0033The following examples are intended to illustrate the present invention:

EXAMPLE 1

0034120 g of water are introduced into a Guittard® mixer of the ML2 type, then 100 g of β cyclodextrins sold by the company Rhône-Poulenc under the brand Rhodocap-N®. Then added to the solution 10 g of dibenzoyl peroxide. It is mixed for seven hours, then the paste obtained is dried, leaving it at room temperature until a solid product is obtained.

0035The latter is ground to give a powder consisting of the inclusion compounds of β cyclodextrins enclosing dibenzoyl peroxide.

EXAMPLES 2 TO 8

0036Is introduced into a solvent which can be a water / ethanol mixture or a water / acetone mixture, β cyclodextrins (βCD) of the same nature as those of Example 1. To this solution is then added either dibenzoyl peroxide (PDB ), or dioctanoyl peroxide (PDO), powder. The mixture thus obtained is stirred for two hours at variable temperatures. At the end of the stirring period, the temperature is lowered steadily to 5 ° C for five hours. A precipitate of the inclusion compounds is then obtained which is isolated from the mixture by filtration. The recovered precipitate is dried in an oven at 40 ° C for two hours.

0037The level of peroxide enclosed in the inclusion compound of cyclodextrin β is then assayed according to the method described below.

0038The reaction parameters as well as the level of peroxide enclosed in the inclusion compound expressed in% by weight relative to the total weight of said dried precipitate (title) are shown in Table I below.<tables id="tabl0001" num="0001"><img file="EP0441690A2_D0005.tif" /></tables>

Method for assaying the peroxide titer enclosed in the inclusion compounds:

003990 mg of the inclusion compound enclosing the peroxide to be assayed are introduced into a 200 ml conical flask containing 20 ml of acetone. 3 ml of a 50% aqueous solution of potassium iodide are added. A pink color develops. The released iodine is titrated using a 0.1 N sodium thiosulfate solution until the pink color disappears.

0040The peroxide titer is then determined by the following formula:

0041title = anM0.555, in which:<ul id="ul0003" list-style="dash"><li>a is the volume of the sodium thiosulfate solution used</li><li>n is the normality of the sodium thiosulfate solution</li><li>M is the molecular weight of the metered peroxide</li></ul>

EXAMPLE 9

0042The inclusion compound of β cyclodextrin enclosing dibenzoyl peroxide as obtained in Example 7 is dissolved in water. It is determined by UV absorption that the solubility threshold in water of said inclusion compound is 44 mg / l which corresponds to a 6 mg peroxide content. By way of comparison, it has been found that the solubility threshold in water of a powder of the same peroxide is less than 3 mg / l. The inclusion compounds according to the invention therefore make it possible to significantly increase the solubility of peroxides in water.