Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
  • A61Q19/00—Preparations for care of the skin
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
  • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
  • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
  • A61K47/56—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule
  • A61K47/61—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule the organic macromolecular compound being a polysaccharide or a derivative thereof
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
  • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
  • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
  • A61K47/62—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being a protein, peptide or polyamino acid
  • A61K47/66—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being a protein, peptide or polyamino acid the modifying agent being a pre-targeting system involving a peptide or protein for targeting specific cells
  • A61K47/665—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being a protein, peptide or polyamino acid the modifying agent being a pre-targeting system involving a peptide or protein for targeting specific cells the pre-targeting system, clearing therapy or rescue therapy involving biotin-(strept) avidin systems
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K8/00—Cosmetics or similar toiletry preparations
  • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
  • A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
  • A61K8/60—Sugars; Derivatives thereof
  • A61K8/606—Nucleosides; Nucleotides; Nucleic acids
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K8/00—Cosmetics or similar toiletry preparations
  • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
  • A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
  • A61K8/64—Proteins; Peptides; Derivatives or degradation products thereof
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K8/00—Cosmetics or similar toiletry preparations
  • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
  • A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
  • A61K8/64—Proteins; Peptides; Derivatives or degradation products thereof
  • A61K8/645—Proteins of vegetable origin; Derivatives or degradation products thereof
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K8/00—Cosmetics or similar toiletry preparations
  • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
  • A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
  • A61K8/64—Proteins; Peptides; Derivatives or degradation products thereof
  • A61K8/65—Collagen; Gelatin; Keratin; Derivatives or degradation products thereof
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K8/00—Cosmetics or similar toiletry preparations
  • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
  • A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
  • A61K8/68—Sphingolipids, e.g. ceramides, cerebrosides, gangliosides
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K8/00—Cosmetics or similar toiletry preparations
  • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
  • A61K8/72—Cosmetics or similar toiletry preparations characterised by the composition containing organic macromolecular compounds
  • A61K8/73—Polysaccharides
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K8/00—Cosmetics or similar toiletry preparations
  • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
  • A61K8/72—Cosmetics or similar toiletry preparations characterised by the composition containing organic macromolecular compounds
  • A61K8/73—Polysaccharides
  • A61K8/735—Mucopolysaccharides, e.g. hyaluronic acid; Derivatives thereof
• • B—PERFORMING OPERATIONS; TRANSPORTING
  • B82—NANOTECHNOLOGY
  • B82Y—SPECIFIC USES OR APPLICATIONS OF NANOSTRUCTURES; MEASUREMENT OR ANALYSIS OF NANOSTRUCTURES; MANUFACTURE OR TREATMENT OF NANOSTRUCTURES
  • B82Y5/00—Nanobiotechnology or nanomedicine, e.g. protein engineering or drug delivery
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K2800/00—Properties of cosmetic compositions or active ingredients thereof or formulation aids used therein and process related aspects
  • A61K2800/40—Chemical, physico-chemical or functional or structural properties of particular ingredients
  • A61K2800/57—Compounds covalently linked to a(n inert) carrier molecule, e.g. conjugates, pro-fragrances
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
  • A61Q17/00—Barrier preparations; Preparations brought into direct contact with the skin for affording protection against external influences, e.g. sunlight, X-rays or other harmful rays, corrosive materials, bacteria or insect stings
  • A61Q17/04—Topical preparations for affording protection against sunlight or other radiation; Topical sun tanning preparations

Definitions

• Bifunctional cosmetic and / or dermatological ingredients their uses and method of preparation, the compositions containing them.
• the main subject of the present invention is new cosmetic and / or dermatological ingredients which are bifunctional or even trifunctional. It also relates to the uses of said ingredients, their preparation process and the compositions containing, in particular cosmetic and / or dermatological compositions and emulsifying compositions.
• Said new ingredients are complexes produced from two cosmetic and / or dermatological ingredients of the prior art (ingredients of different type).
• cosmetic ingredient is a term well known to those skilled in the art. It includes active substances in cosmetics as well as other substances capable of being used in cosmetic compositions, other substances (additives) such as emulsifying agents, viscosity regulating agents, etc. Found in the "International Cosmetic Ingredient Dictionary, 6 tn Edition, 1993 (edited by The Cosmetic, Toiletry and Fragrance Association, Inc; N * ISBN 1-882621 - 06 - 9) "a list of said cosmetic ingredients, known in 1993. The ingredients in this list can be used in the preparation complexes of the invention.
• cosmetic and / or dermatological ingredient any substance capable of entering into the composition of cosmetic and / or dermatological compositions, as active ingredient and / or as an additive.
• the context of the present invention is therefore that of cosmetics and dermatology.
• Cosmetics at first, only allowed to cover the skin and make up; then, gradually, it extended its field of application. It is moving more and more towards cosmetology which favors hygiene and care. Cosmetic products, in particular dermo-cosmetics applied topically, have thus become extrinsic factors, capable of playing, in certain cases, a major role in the processes of protection against physical, chemical and biological external aggressions, in hydration processes, in processes of stimulation of extracellular matrix synthesis, in processes for controlling cellular and enzymatic activities, in the processes of pigmenta ⁇ tion and depigmentation, in the processes of keratinization ...
• the complexes of the invention capable of expressing a double or even a triple activity, are also easily formulated.
• Said ingredients consist of the products of the coupling reaction between a first cosmetic and / or dermatological ingredient comprising at least one reactive hydroxyl and / or inactive chemical function and a second cosmetic and / or dermatological ingredient comprising at least one chosen reactive chemical function among the hydroxyl, thiol, carboxylic acid and amino functions; said coupling between said first and second ingredients being carried out with a suitable coupling agent (having at least two reactive chemical functions, capable of reacting for at least one of them with at least one reactive chemical function (of the NH2 and or OH type) of said first ingredient and for at least the other with at least a reactive chemical function (of the NH 2 and or OH and / or SH and or COOH type) of said second ingredient); said first and second cosmetic and / or dermatological ingredients belonging to different families; at least one of said first and / or second cosmetic and / or dermatological ingredients belonging to one of the following four families:
• the first object of the present invention consists of bifunctional cosmetic and / or dermatological ingredients which correspond to the formula below:
• Ri is a hydrocarbon radical corresponding to a first cosmetic and or dermatological ingredient of formula Ri (NH2) ⁇ (OH) z , in which x and z, whole numbers, are such that x + z ⁇ 1;
• R2 is a hydrocarbon radical corresponding to a second cosmetic and / or dermatological ingredient of formula R2 (NH2) (OH) s (SH) t (COOH) u , in which r, s, t, u, whole numbers, are such that r + s + t + u; tl; .
• S is a radical corresponding to a bridging agent having at least two reactive chemical functions, capable of reacting for at least one of them with at least one reactive chemical function (of the NH2 ct / ° u OH type) of the first cosmetic and / or dermatological ingredient and for at least the other with at least one reactive chemical function (of the NH 2 and / or OH and / or SH and / or COOH type) of the second cosmetic and / or dermatological ingredient; .
• T represents at least one bond of the type -NHCO- or -OCO-;
• V represents at least one bond of the type -CONH-, -COO-, -COS-, -OOC- or -COOCO-.
• the new ingredients of the invention contain in their structure two cosmetic and / or dermatological ingredients of the prior art, of a different nature, indirectly linked via a polyfunctional coupling agent, at least bifunctional. It will be noted here that, in addition to the covalent bonds between each of said ingredients (constituting the complexes of the invention) and the coupling agent, it can develop, within the complexes (cosmetic and / or dermatological ingredients) of the invention, Van der Waals type bonds, Ionic type ...
• ingredients of the complexes of the invention therefore correspond, for one to the formula (OH) z , for the other with the formula R2 (NH2) r (OH) s - (SH) (COOH) u . They are different in nature.
• the complexes of the invention are asymmetrical (binary, bifunctional complexes) and insofar as one of their constituent ingredients is chosen from one of the four families listed (that of proteins or that of carbohydrates or that of lipids or that nucleic acids), the other is chosen from another of said four families or from outside of said four families. In any event, it presents one or the other of the formulas indicated. If we stick to said four families, the new cosmetic and / or dermatological ingredients of the invention can therefore be bifunctional binary complexes of 6 types: protein / carbohydrate - lipid protein - protein / nucleic acid complexes; carbohydrate lipid - carbohydrate / nucleic acid complexes; lipid - nucleic acid complexes.
• At least one of the constituent ingredients of the complexes of the invention is a macromolecule chosen from: - proteins, peptides (proteins);
• polynucleosides polynucleosides, polynucleotides (nucleic acids).
• At least one of said constituent ingredients of the complexes of the invention may however consist of a low molecular weight molecule and for example an amino acid, one of its salts or derivatives (protide ) or as a dare, one of the salts or derivatives (carbohydrate).
• at least one of said constituent ingredients of the complexes of the invention consists of a protein, a polysaccharide or a phospholipid.
• polysaccharides it is possible to use, for example, a dextran, a galactomananne, a glucomananne, fructosan, a glycosaminoglycan, a carrageenan, an alginate, a pectin, amylose, amylopectin, a linear or cyclized dextrin, glycogen, xanthan.
• proteins which are particularly advantageous, mention may be made of proteins extracted from plants, in particular extracted from plant seeds such as a protein extract from peas, lupine, faba beans, wheat, oats, corn. or soy. Mention may also be made of a collagen or elastin solution.
• the two constituent ingredients of the complexes of the invention are chosen from the said four families specified above and advantageously from the macromolecules, expressly mentioned above.
• one of said constituent ingredients belongs to one of said four families (consists of a protein, a carbohydrate, a lipid or a nucleic acid) and the other consists of a molecule of low molecular weight, preferably having up to 20 carbon atoms, and advantageously chosen from: - kojic acid or one of its salts;
• sunscreens such as benzophenone-4, benzophenone-3, salicylic acid and its derivatives, para-aminobenzoic acid and its derivatives; - carotenoids;
• the cosmetic and / or dermatological bifunctional ingredients of the invention exist according to very numerous variants and are therefore capable of developing numerous activities.
• the polyfunctional bridging agent which binds the two ingredients of the new ingredients of the invention it can also exist according to many variants.
• it is chosen from: - polyaldehydes, in particular dialdehydes such as glutaraldehyde, formaldehyde;
• acid polyhalides in particular acid di- or tri-chlorides, such as oxalic acid dichloride, terephthalic acid dichloride, sebacic acid dichloride, benzoic acid trichloride;
• diisocyanates such as hexane diisocyanate.
• the bridging generally involves reactive chemical functions of said bridging agent of the COC1, CHO or CO-O-CO type.
• the new ingredients of the invention constitute the main object of the present invention.
• These new products are per se interesting. They are obtained by indirect coupling (by means of a coupling agent) of two ingredients, of a different nature, from the prior art.
• aqueous phase After this coupling, generally carried out in the aqueous phase (see below), they can be isolated (more or less purified) or used as such; that is to say in a composition - generally an aqueous suspension - containing said new ingredients (binary complexes) and at least one of said ingredients used for their preparation (at least one of the reagents of formula R ⁇ (NH2) x (OH) z or of formula R2 (NH2) ⁇ (OH) s (SH) t - (COOH) u ).
• composition in addition to the binary complex, mainly one of said ingredients (in the free state) when the coupling has been implemented in the presence of a strong excess thereof. There is generally found in said composition a certain amount of the two ingredients, in the free state (unreacted). One of said ingredients (or both) may (may) be present) in said composition in the form of a salt insofar as it (s) may (may) be subsequently salified.
• the cosmetic and / or dermatological ingredients of the invention - bifunctional ingredients - are generally used in the form of such compositions (that is to say unpurified).
• the invention relates to the process for preparing new cosmetic and / or dermatological ingredients described above.
• Said method consists, as already indicated, of an indirect coupling. It consists more precisely in coupling, via a bridging agent corresponding to the radical S (see above the definition of said radical S), the first ingredient of formula R ⁇ (NH2) ⁇ (OH) z with the second ingredient of formula R2 (NH2) ⁇ (OH) s (SH) t - (COOH) u ; at least one of said first and second ingredient being chosen from one of the four families mentioned above.
• the coupling is carried out in an aqueous medium, generally at room temperature; in any event, at a mild temperature (not degrading either the first or the second ingredient) preferably less than 85 ° C.
• Said coupling involves the reactive chemical functions NH2, OH, SH, COOH, COC1, COOH, CHO ... of each of the reactants and of the bridging agent.
• Said polyfunctional, at least bifunctional bridging agent is advantageously chosen, as specified above, from polyaldehydes, polyanhydrides, polyhalide acids and polyisocyanates.
• the complex formed is isolated, in a more or less pure form. It is possible, according to another advantageous variant, to subject the crude reaction product comprising the reaction aqueous medium to a drying step. Said drying advantageously comprises a lyophilization step. After this drying, the complex formed is recovered as a mixture with the reactant (s) (first and / or second ingredients) which have not reacted.
• the initial pH of the reaction medium is basic and is kept basic throughout the reaction.
• Said pH may be only very slightly basic (pH> 7, of the order of 7.2 - 7.5 ). However, better yields are observed when the coupling is carried out at pH values greater than 8.
• the initial pH of the reaction medium is basic and is advantageously adjusted to at least 9, even better to at least 10 throughout the reaction.
• the initial pH of the reaction medium is basic and is not adjusted during the reaction.
• the present invention also has as its object - fourth object - the use of the new entities designed within its framework; new entities which consist either of cosmetic and / or dermatological bifunctional ingredients per se, or of compositions containing them, compositions which advantageously consist of the medium in which the coupling reaction has been carried out for the preparation of said bifunctional ingredients.
• the present invention more particularly has as a fourth object the use of said new entities as active ingredient and / or emulsifying agent.
• the complexes of the invention can therefore intervene in the dry state, after drying and more particularly after lyophilization or in suspension, generally aqueous, in compositions which also contain at least one of the reagents used. for their preparation.
• Said compositions advantageously consist of the reaction medium in which the coupling of the reagents has been implemented (for the synthesis of said complexes).
• the bifunctional cosmetic and / or dermatological ingredients of the invention are generally used at concentrations of between 0.01 and 20% by weight; advantageously between 0.1 and 5% by weight.
• the invention relates respectively to emulsifying compositions and cosmetic and / or dermatological compositions which contain an effective amount of at least one of said new entities identified above (new cosmetic and / or dermatological ingredients dry or in aqueous suspension).
• Said compositions can therefore also consist of compositions containing the coupling product and one and / or the other of the unreacted reagents and advantageously in the reaction medium in which the coupling of the reagents has been carried out.
• the bifunctional cosmetic and / or dermatological ingredients of the invention generally occur at concentrations of between 0.01 and 20% by weight, advantageously between 0.1 and 5% by weight.
• compositions express the properties of the bifunctional ingredients which they contain; namely the properties of each of the constituent ingredients of said bifunctional ingredients and optionally in addition, the properties inherent in said bifunctional ingredients.
• sphingolipids (approximately 1 mole) are placed in 250 g of sebacic acid dichloride (approximately 1 mole). The whole is kneaded for a few minutes at room temperature, then brought to 80 ° C. with stirring for 10 min in a hood.
• phase A is poured very slowly, with very vigorous stirring - of the ultraturrax type, 20,000 rpm - into phase B at room temperature.
• the pH is adjusted between 8 and 10 by adding 6N sodium hydroxide.
• the reaction mixture is kept for 2 h with moderate stirring, then neutralized to the desired pH (for example at pH 6.5) with HCl, 6N.
• the complex thus formed has many cosmetic properties.
• it has, or even strengthens, the properties of each of the two constituents: in fact the soy proteins provide hydration, flexibility, comfort, softness, and gelling power; sphingolipid molecules provide restructuring and allow the repair of damaged or damaged skin.
• this complex also has new cosmetic properties: in fact, soy proteins are made amphiphilic by grafting lipophilic molecules, which allows the complex to have strong emulsifying properties, and can also be used at the same time. in the aqueous or oily phases of cosmetic formulations.
• Example 1a The procedure is as described in Example 1, except that an excess of sebacic acid dichloride is used, so:
• Example lb 100 g of sphingolipids, 300 g of sebacic acid dichloride, 100 g of soy protein in 3 l of water.
• Example lb 100 g of sphingolipids, 300 g of sebacic acid dichloride, 100 g of soy protein in 3 l of water.
• Example la The procedure is as in Example la, except that 100 g of sphingolipids, 700 g of sebacic acid dichloride, 100 g of soy protein in 5 l of water are used.
• the procedure is as described in Examples 1a and 1b but the reaction is carried out at a temperature of approximately 60 ° C.
• the grafting yields are improved.
• the product produced is in the form of a homogeneous powder, easy to handle in cosmetic formulations.
• reaction mixture is ultrafiltered through mineral or organic membranes with very low cut-off threshold - 1000 to 5000 D.
• the mineral reaction salts such as sodium chloride, which may be desirable to remove from the product, are removed.
• Example 1? The procedure is as described in any of the examples 1a to 1d above, but in this case, the reaction mixture is lyophilized without having been dialyzed or ultrafiltered beforehand.
• Example 1f The procedure is as described in any one of Examples 1a to the above, but in this case, the pH is not adjusted during the reaction.
• the reaction medium therefore changes from an initial pH adjusted to 10, to a final pH close to 1.
• the pH is then brought to the desired pH, close to 6.5, by addition of 30% sodium hydroxide in water, for cosmetic, pharmaceutical or food applications.
• pH corrections are carried out by a strong base (KOH, etc.), by a weak base (TEA, etc.). ) or with a buffer (borate, etc.).
• a lupine protein isolate A lupine protein isolate.
• a faba bean protein isolate A faba bean protein isolate.
• Example 2d A protein extract of wheat.
• a protein extract of oats A protein extract of oats.
• a protein extract of corn is A protein extract of corn.
• a glycosaminoglycan A glycosaminoglycan.
• a carrageenan A carrageenan.
• Example 3i Amylose.
• a linear or cyclized dextrin A linear or cyclized dextrin.
• the assembly is then heated to 80 ° C and then 200 g of terephthalic acid dichloride (approximately 1 mole) are added under strong agitation - of the type Ultraturrax 20000 rpm. Throughout the reaction, the pH is adjusted between 8 and 10 by adding 6N sodium hydroxide.
• reaction mixture After stirring of this type for 30 min, the reaction mixture is kept for 2 h with moderate stirring, then neutralized to the desired pH (for example at pH 6.5) with HCl, 6N.
• the product is then preferably lyophilized, then sterilized by gamma radiation.
• sphingolipids or approximately 1 mole
• the assembly is then heated to 80 ° C and then 130 g of oxalic acid dichloride (approximately 1 mole) are added under strong agitation - of the type Ultraturrax 20000 rpm.
• the pH is adjusted between 8 and 10 by adding 6N sodium hydroxide. After stirring of this type for 30 min, the reaction mixture is kept for 2 h with moderate stirring, then neutralized to the desired pH (for example at pH 6.5) with HCl, 6N. The product is then preferably lyophilized, then sterilized by gamma radiation.
• Example fi Manufacture of a bifunctional active principle: sphingolipid grafted on soy proteins by means of hexane diisocvanate
• reaction mixture After stirring of this type for 30 min, the reaction mixture is kept for 2 h with moderate stirring, then neutralized to the desired pH (for example at pH 6.5) with HCl, 6N.
• the product is then preferably lyophilized, then sterilized by gamma radiation.
• EXAMPLE 7 Manufacture of a bifunctional active principle: alpha hvdroxvlé acid grafted on kojic acid by means of terephthalic acid dichloride
• 1 mole of glycolic acid is dissolved in 2000 ml of demineralized water at room temperature, then 1 mole of kojic acid is added to this mixture.
• the pH is adjusted to 10 using calcium hydroxide (milk of lime).
• the temperature of the reaction mixture is then rapidly brought to 80 ° C.
• 1 mole of terephthalic acid dichloride was dispersed in 1000 ml of deionized water with stirring strong of the type of that obtained using a Silverson or Ultraturrax stirrer (10,000 to 20,000 rpm), then the whole is quickly poured into the reaction mixture. Under strong continuous stirring (ultraturrax), the pH of the reaction medium is adjusted between 8 and 10 throughout the reaction using calcium hydroxide. After 30 min, the reaction medium is stirred more slowly for 1 h 30 during which the temperature is lowered to 25 ° C.
• the pH is then adjusted between 3 and 7 by the addition of 6N hydrochloric acid.
• the reaction mixture is then lyophilized and then sterilized. It is in the form of a cream-colored powder, with a characteristic odor, capable of being dissolved hot in the aqueous phase of an emulsion.
• the characteristic bonds which, in this complex, connect glycolic acid to kojic acid are on the one hand covalent bonds of the ester type (for example, between the alcohol function of glycolic acid and the acid function of l bridging agent) or anhydride (for example between the acid function of kojic acid and the acid function of the bridging agent), on the other hand ionic bonds which bind the carboxylic functions to each other via calcium cations , finally by weak Van der Waals type bonds which the particular drying method used for the production of the products of the invention makes it possible to promote.
• ester type for example, between the alcohol function of glycolic acid and the acid function of l bridging agent
• anhydride for example between the acid function of kojic acid and the acid function of the bridging agent
• the cosmetic properties of the complex described in this example are multiple since they combine both the properties of each of the two constituents, which will be released under the enzymatic action on the surface of the skin, as well as the properties which are specific to the complex. (synergy of the active ingredients in the bleaching properties of the skin, great stability with respect to oxidation, absence of irritation phenomena with such a complex because the penetration of the active agents into the skin is limited thanks to the increase of their apparent molecular mass ).
• Example 7b Same protocol as that described in Example 7 but in this case, the pH is adjusted by a strong base (KOH, NaOH ...) a weak base (borate, ...); similarly during the reaction, the pH can be continuously adjusted between 8 and 10 or else, it may not be adjusted and in this case, it will decrease to a value close to 1. In all cases, the pH of the reaction mixture must be adjusted to a pH value compatible with cosmetic use (between 3 and 7).
• Example 7 Same protocol as that described in Example 7 but in this case, the temperature is kept close to room temperature.
• the grafting yields are lower in this case, but gentle operating conditions make it possible to limit the degradation of the active ingredients which are sometimes sensitive to temperature.
• the product obtained after lyophilization and sterilization is less colored than the product obtained in the process described in Example 1.
• Example 7c Same protocol as that described in Example 7 but in this case, the product is not lyophilized; it is used as it is in the aqueous phase of a cosmetic emulsion.
• Example 7d Same protocol as that described in Examples 7, 7a to 7c but in this case, the alpha hydroxylated acid used is not glycolic acid but lactic acid, malic acid, tartaric acid , citric acid, salicylic acid, a mixture of these acids or a polymer of these acids.
• the bridging agent used is sebacic acid dichloride, benzene triacid trichloride, oxalic acid dichloride, a diisocyanate, or any other bridging agent used in the gentle synthesis of organic esters or amides.
• Example 8 Manufacture of a bifunctional active principle: alpha hvdroxvlé acid grafted on ceramides via sebacic acid dichloride
• the reaction mixture is then lyophilized and then sterilized. It is in the form of a creamy, slightly oily powder, with a characteristic odor, capable of being dissolved hot in the aqueous phase or in the oily phase of an emulsion.
• the characteristic bonds which, in this complex, connect the malic acid to the ceramic are on the one hand covalent bonds of the ester type (for example, between the alcohol function of the ceramic and the acid function of the bridging agent) or anhydride (for example between the acid function of malic acid and the acid function of the bridging agent), on the other hand weak Van der Waals type bonds than the particular drying mode used for the production of the products of the invention lets promote.
• the cosmetic properties of the complex described in this example are multiple since they combine both the properties of each of the two constituents, which will be released under the enzymatic action on the surface of the skin, as well as the properties which are specific to the complex. (absence of irritation phenomena and absence of symptoms of dry skin with such a complex because ceramides make it possible to plasticize the epidermis and limit the loss of transepidermal water which is usually caused by a keratolytic treatment with alpha hydroxyl acids ... ). In addition, with such a complex, emulsifying properties are highlighted, which makes it possible to limit the contents of chemical emulsifiers usually used in cosmetic formulations.
• Example 9 Manufacture of a bifunctional active principle: biotin grafted onto a phospholipid via sebacic acid dichloride 0.1 mole of biotin is dissolved in 4000 ml of water buffered to pH 7.5 with 0.5 M phosphate buffer. An amount of 0.1 mole of sebacic acid dichloride is then placed to react with the reaction mixture containing biotin, at room temperature, for 10 minutes. An amino function carried by an organic molecule is then placed to react with the reaction mixture described above. Thus, 0.1 mole of phosphatidylethanolamine are added to the reaction medium. The reaction is carried out at pH adjusted to 7.5 with 6N NaOH. After complete dissolution of the phospholipids, the reaction medium is kept under moderate mechanical stirring at room temperature for 4 h.
• the pH of the whole is then adjusted to a value compatible with the pHs used in cosmetics, that is to say between 3.5 and 8, with strong or weak acids, in particular with 6N HCl.
• the product resulting from this grafting is in the form of a very homogeneous solution, of characteristic pale yellow color.
• This product is then used as a preliposomal phase, with which it is possible to spontaneously form liposomes, using agitation of the ultraturrax type or a continuous homogenizer.
• an active ingredient is amphiphilic and emulsifying.
• Biotin carried deep into the skin structures by phospholipids, is integrated into the bilayers of the cell membranes of active epidemic cells, then is directly used by cell metabolism as a vitamin.
• the pH can be adjusted using a strong base (KOH, NaOH ...), a weak base (borate %) or a buffer other than phosphate (TRIS, .. .).
• the phospholipid used can be phosphatidylserine, phosphatidyl-ethanolamine, or a mixture of phospholipids in which one or the other of these two phospholipids are present.
• example 9 Identical to example 9 and its variants.
• 200 g of a soy protein isolate is placed to react with 0.1 mole of the biotin solution and 0.1 mole of oxalic acid dichloride.
• the product is then lyophilized and is in the form of a pale beige powder, odorless.
• the pH is then adjusted between 3 and 7 by the addition of 6N hydrochloric acid.
• the reaction mixture is then lyophilized and then sterilized. It is in the form of an off-white to pale yellow powder, with a characteristic odor, capable of being dissolved hot in the aqueous phase of an emulsion.
• the characteristic bonds which, in this complex, connect the sunscreen (benzophenone-4) to the wheat peptide are on the one hand covalent bonds of the amide type (for example, between the amino functions of the wheat peptide and the acid function of the bridging agent) or ester (for example between the alcohol function of the sunscreen and the acid function of the bridging agent), on the other hand ionic bonds which link the carboxylic functions to the amino functions, finally by weak bonds of Van der Waals type that the particular drying method used for the production of the products of the invention makes it possible to promote.
• the cosmetic properties of the complex described in this example are multiple since they combine both the properties of each of the two constituents which will be released under the enzymatic action on the surface of the skin, as well as the properties which are specific to the complex. So, for example, sun filters which tend to be easily absorbed by the skin or to be easily eliminated by washing with water, will, thanks to the grafting on the peptide, stabilize in a much more intense and lasting way in the cutaneous structure, which goes from a on the one hand to increase the persistence and the persistence of the sun filters, and on the other hand, to limit their penetration and consequently, to limit the risks of irritations and sensitization that their intensive use can cause.
• the complex manufactured in this example has been tested for its safety; it does not cause skin or eye irritation when tested at 10% in demineralized water, and it is not toxic when used at a concentration of 5 g kg of body weight.
• Example 11 The procedure is as described in Example 11 above, but in this case, the pH is not adjusted during the reaction.
• the reaction medium therefore changes from an initial pH adjusted to 10, to a final pH close to 1.
• the pH is then brought to the desired pH, close to 6.5 for the most conventional cosmetic applications.
• Example 11b The procedure is as described in Example 11 above, but in this case, the pH corrections are made by a strong base (KOH, etc.), by a weak base (TEA, etc.) or by a buffer (borate, etc.).
• Example 1c The procedure is as described in Example 11 above, but in this case, another acid dichloride or trichloride is used (sebacic acid dichloride, oxalic acid dichloride, benzoic triacid trichloride). ..).
• another acid dichloride or trichloride is used (sebacic acid dichloride, oxalic acid dichloride, benzoic triacid trichloride). ..).
• Example 11d The procedure is as described in Example 11 above, but in this case, another peptide or even another protein, totally or partially soluble in water, is used (soy polypeptides, cotton isolate, isolate peas, collagen peptides, etc.).
• Example lie

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