FR2848879A1 - Nanocapsules useful in cosmetic or pharmaceutical compositions comprise a water-insoluble polysilsesquioxane shell and a lipid core comprising a lipophilic active ingredient - Google Patents

Abstract

Nanocapsules comprise water-insoluble polymeric envelope comprising polysilsesquioxane (I) shell and a lipid core comprising a lipophilic active ingredient. Nanocapsules comprise a water-insoluble polymeric envelope comprising polysilsesquioxane shell, preferably of formula (RSiO3/2)x (I) and a lipid core comprising a lipophilic active ingredient. R = optionally halogenated linear, branched, cyclic and optionally saturated hydrocarbyl, e.g. CnH2n+1 (methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, dodecyl, tridecyl, tetradecyl, hexadecyl, octadecyl, eicosyl, phenyl, tolyl, cyclobutyl, cyclopentyl, cyclohexyl, vinyl, allyl, 2-phenylethyl or benzyl (optionally substituted with one or more F or Cl); n = 1-20; and x = 1-10. Independent claims are also included for: (1) aqueous suspension (C1) containing the nanocapsules; (2) cosmetic or pharmaceutical composition (C2) containing the nanocapsules or suspension; (3) production of the nanocapsules by dissolving the polysilsesquioxane, a lipid phase comprising the active ingredient and optionally a coating agent in a water-miscible organic solvent, adding the solution to an aqueous surfactant solution while stirring, and evaporating off the solvent and optionally part of the aqueous phase.

Description

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The present invention relates to nanocapsules based on silicone polymers, their method of preparation as well as cosmetic or pharmaceutical compositions, especially dermatological compositions, comprising them.

The encapsulation or absorption of lipophilic active principles in submicron-sized particles has been known for several years and is widely used in particular in the cosmetic and dermatological fields. Indeed, these particles called nanoparticles are able to cross the superficial layers of the stratum corneum and penetrate into the upper layers of the living epidermis to release the active ingredient. This penetration into deeper layers widens the action space of active ingredients and protects them from rapid elimination by simple friction.

The term "nanoparticles" mainly encompasses two different systems: "nanospheres" consisting of a porous polymeric matrix in which the active ingredient is absorbed and / or adsorbed, as well as "nanocapsules" having a core-envelope structure, that is to say a structure consisting of a lipid core forming or containing the active ingredient, which heart is encapsulated in a continuous protective envelope insoluble in water.

The present invention relates only to this second vesicular type of nanoparticles, that is to say nanocapsules with lipid core surrounded by a polymeric membrane.

The encapsulation of active principles in submicron-sized capsules makes it possible, indeed, to transport the active molecules deeper into the skin, but it does not always ensure, contrary to what this "protective" structure might suggest, sufficient stability of the active ingredient with respect to surrounding physicochemical conditions. Indeed, the problem of the instability of the active ingredient arises particularly for substances sensitive to oxidation, light, high temperatures and / or acidic or basic pH. Such a substance that is widely used in cosmetics is, for example, retinol (vitamin A), as well as its derivatives, which are sensitive to oxidation, in particular at acidic pH.

It has been proposed, in particular by WO96 / 31194, to stabilize retinol by adding to the compositions containing lipophilic antioxidants and chelants, and by adjusting the pH of these compositions to a value between 5 and 10.

It has also been proposed, for example by EP1029587, to encapsulate the active ingredients in nanocapsules based on polyesters of poly (alkylene adipate) type, which makes it possible to improve the stability of retinol, especially in the absence of antioxidants.

However, these methods employing polymers such as polycaprolactone or polyethylene adipate to form the vesicles, do not allow for

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 stable nanocapsules whose heart includes certain active ingredients derived from vitamin A, such as in particular vitamin A propionate or C8-C10 esters of vitamin A, more particularly if the quantity of these active ingredients is important, for example greater than 2.5% by weight.

The object of the present invention is to propose new stable nanocapsules capable of stabilizing active substances such as vitamin A or any derivatives thereof in a significant amount, for example of the order of 15-20% by weight. compared to the nanocapsule, while having a small particle size and a good rate of encapsulation.

Surprisingly and unexpectedly, the applicant has demonstrated that the use of very particular silicone polymers made it possible to produce nanocapsules capable of stabilizing in a long-lasting manner such active ingredients as retinol derivatives, and this even in the absence of antioxidants.

The present invention therefore relates to nanocapsules consisting of: - a lipid core forming or comprising a lipophilic active principle and - a continuous polymeric shell insoluble in water comprising at least one polysilsesquioxane silicone polymer, especially a polyalkylsilsesquioxane of formula: (R-SiO3 / 2) x as defined below.

The invention also relates to a cosmetic or pharmaceutical composition comprising, in a physiologically acceptable medium, said nanocapsules or an aqueous suspension comprising them.

The inventino also relates to a process for preparing these nanocapsules, as defined below.

In addition, the Applicant has also demonstrated that it was possible to prepare the nanocapsules according to the invention through a particular manufacturing process, requiring amounts of water and solvent much lower than in the prior art. However, this is not feasible in the prior art, for example when the polymers employed are polyesters such as polycaprolactone. Another object of the invention is therefore such a preparation process.

It has been found that the encapsulation of retinol in nanocapsules having an envelope formed by silicone polymers of the type described below confers on this active molecule a satisfactory stability, namely a loss of activity of less than 35% after 2 months of preservation at 45 C, whereas, under equivalent conditions, this same molecule encapsulated in other polymers commonly used for nanoencapsulation (for example polycaprolactone, polyethylene adipate or cellulose derivatives) has a significant loss of activity, up to 100%.

In addition, the initial encapsulation rate (at To) is of the order of 100%.

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Moreover, after two months of storage, at room temperature (20 ° C.), it has been found that the nanocapsules are still stable, and there is no yellowing of the nanocapsules, no significant loss of active ingredient, no increase in the granulometry.

It has been found that the invention makes it possible to stabilize the sensitive lipophilic active agents, and in particular makes it possible to protect them against oxidation and hydrolysis, while preserving at the polymeric wall its watertightness with respect to the continuous aqueous phase. . By sensitive lipophilic active is meant in particular any compound which will degrade by at least 1% by weight after exposure to ambient air, for 24 hours at 20 C.

The silicone polymers described below are therefore used to prepare nanocapsules consisting of a lipid core forming or comprising at least one lipophilic active principle, and surrounded by a shell formed by these polymers.

These polymers are not soluble in water but are soluble in solvents usually used in cosmetics such as acetone.

The polymers making it possible to obtain such a favorable effect are silicone polymers known under the name polysilsesquioxane, which are silicone resins comprising 1.5 oxygen atoms for 1 silicon atom, such as, for example, polyalkylsilsesquioxanes which can be represented by the following formula: (R-SiO3 / 2) x wherein R represents a hydrocarbon radical, saturated or unsaturated, linear, branched or cyclic; for example of the type -C n H 2 n + 1, with n being an integer ranging from 1 to 20, especially a methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, dodecyl, tridecyl, tetradecyl or hexadecyl radical; octadecyl and eicosyl; or an aryl group, especially phenyl or tolyl; a cycloalkyl group, especially cyclobutyl, cyclopentyl or cyclohexyl; an alkenyl group, especially vinyl or allyl; an aralkyl group, especially 2-phenylethyl or benzyl; R may also include one or more halogen atoms, especially fluorine or chlorine; preferably R is a methyl, ethyl, propyl or phenyl radical; and x is the number of units, and may be between 1 and 10, especially 1 to 4.

These polymers of the polymethylsilsesquioxane type may in particular be prepared according to US Pat. No. 4,528,390, for example by hydrolysis then polycondensation of methyltrialkoxysilanes; or according to US5936031 which describes the preparation of polyalkylsilsesquioxane particles by dissolving a surfactant in an alkyltrialkoxysilane and then adding water and a base.

JP2000186148, which describes a process for the preparation of spherical particles of polymethylsilsesquioxane for controlling their diameter, and US Pat. No. 6,376,078, which relates to the manufacture of spherical particles, can also be cited.

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 silicone resin.

The polymethylsilsesquioxanes according to the invention may also have undergone a complementary treatment, such as that described in US4871616, and which makes it possible to obtain perfectly spherical particles whose particle size is controlled.

Particularly preferred polymers that may be mentioned include polymethylsilsesquioxane, and especially the commercial products sold under the name Wacker-Belsil PMS MK by the company Wacker Chemie or under the name KR-220L by the company Shin Etsu.

The silicone polymers may be present in an amount of 0.1 to 5% by weight, especially 0.5 to 3% by weight, relative to the total weight of the aqueous suspension of nanocapsules.

The nanocapsules according to the invention may be more particularly prepared according to the preparation method described in EP-A-0274961 and comprises the following steps: dissolving the polymer, the lipid phase forming or comprising the active ingredient and optionally a surfactant playing the role of coating agent in a suitable organic solvent, i.e., miscible with water, non-toxic and more volatile than water (usually acetone and / or a C 1 -C 6 alcohol) ), in order to obtain an organic phase, - preparing a solution of a second suitable surfactant in water (nonsolvent of the polymer and of the lipid phase), in order to obtain an aqueous phase, - pouring said organic phase into said aqueous phase while moderately stirring it, which results in the spontaneous formation of a nanocapsule emulsion, and then evaporating the organic phase and, optionally, a part of the aqueous phase, to obtain a suspension with centered nanocapsules in an aqueous phase, or aqueous suspension of nanocapsules.

This preparation process generally involves heating the organic phase and / or the aqueous phase at temperatures between 35 and 70 ° C., depending on the nature of the organic solvent, the temperature preferably being lower than the boiling point of said organic solvent. phase.

However, it has been found that with the silicone polymers used in the present invention, it was possible to carry out this process at ambient temperature (20-25 ° C.), which constitutes an important advantage, in particular for limiting the decomposition, in the course of encapsulation, active ingredients sensitive to oxidation and / or heat such as retinol or its derivatives.

The surfactant dissolved in the aqueous phase (or second surfactant) is mainly used to make the emulsion. It ensures the stability of nano-

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 capsules in the emulsion resulting from the pouring of the organic phase, especially acetone, in the aqueous phase and prevents their coalescence.

Any surfactant of hydrophilic, preferably nonionic, character can be used. By way of example, mention may be made of polyoxyethylenated or non-polyoxyethylenated monoesters of polyoxyethylene glycol fatty alcohol ethers, condensates of ethylene oxide and of propylene oxide, such as the product PLURONIC F-68 sold by the company. BASF or Synperonic PE / F108 from Uniqema, or phospholipids such as lecithin.

Said second surfactant is advantageously present in an amount of between 0.01 and 1% by weight, preferably 0.1 and 0.8% by weight, more particularly 0.3 to 0.5% by weight, relative to total weight of the aqueous suspension of nanocapsules.

The nanocapsules according to the invention generally have an excellent seal with respect to the active principle. They therefore do not require the presence of a lamellar coating which is often essential to prevent migration of the lipophilic active principle contained in the nanocapsules of the prior art to another lipid phase of the composition in which they are incorporated.

In some cases, however, it may be desirable to provide the nanocapsules of the invention with such a lamellar coating. It is a structure organized into one or more lipid sheet (s) each consisting of a bilayer of amphiphilic molecules similar to that of biological membranes. This coating, in addition to its function of adjusting the size of the nanocapsules, further improves the sealing of the nanocapsules vis-à-vis a leakage of the active ingredient to another lipid phase of the composition.

The surfactants acting as coating agents, which can be used to form the lamellar coating, are preferably surfactants of a hydrophobic nature, soluble in the organic phase mentioned above, and which are capable of in the presence of water, to form the lipid double layers described above. In a preferred embodiment of the method of encapsulation of active ingredients, this coating agent is dissolved in the organic phase (for example acetone / alcoholic) containing the polymer and the lipid phase.

Examples of such coating agents include phospholipids such as lecithin according to the application EP-A-447318, certain polycondensates of ethylene oxide and propylene oxide, such as the products sold under the name PLURONIC by BASF such as PLURONIC L121 or under the name SYNPERONIC by ICI, or certain silicone surfactants, such as those described in US-A-5,364,633 and US-A-5,411,744 and used in US Pat. FR-A-2,742,677, for example the dimethicone copolyols sold by the company Dow Corning under

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 the names DC 5329, DC 7439-146, DC 2-5695 and Q4-3667.

According to a particular embodiment of the invention, the nanocapsules are free of such a lamellar coating.

dans laquelle : Ri, R2, R3, indépendamment les uns des autres, représentent un radical alkyle en Ci-Ce ou un radical -(CH2)x - (OCH2CH2) y - (OCH2CH2CH2)z - OR4, au moins un radical Ri, R2 ou R3 n'étant pas un radical alkyle ; R4 étant un hydrogène, un radical alkyle ou un radical acyle ; A est un nombre entier allant de 0 à 200 ; B est un nombre entier allant de 0 à 50 ; à la condition que A et B ne soient pas égaux à zéro en même temps ; x est un nombre entier allant de 1 à 6 ; y est un nombre entier allant de 1 à 30 ; z est un nombre entier allant de 0 à 5. According to another particular embodiment of the invention, the nanocapsules are provided with a lamellar coating obtained from a silicone surfactant such as those of formula (I) below, as described in EP780115.

in which: R 1, R 2, R 3, independently of each other, represent a C 1 -C 6 alkyl radical or a radical - (CH 2) x - (OCH 2 CH 2) y - (OCH 2 CH 2 CH 2) z - OR 4, at least one radical R 1, R2 or R3 not being an alkyl radical; R4 being a hydrogen, an alkyl radical or an acyl radical; A is an integer from 0 to 200; B is an integer from 0 to 50; provided that A and B are not equal to zero at the same time; x is an integer from 1 to 6; y is an integer from 1 to 30; z is an integer from 0 to 5.

The average size of the nanocapsules according to the invention is advantageously less than 1 micron, especially between 100 and 800 nm, preferably between 200 and 500 nm. The determination of this size is carried out for example using a laser granulometer (model Amtech Bl 90 from Broohaven Instrument).

The active ingredients that may be encapsulated in the nanocapsules of the present invention may be chosen from any known lipophilic cosmetic or pharmaceutical active ingredient.

By way of example, emollients, anti-inflammatories, anti-bacterials, anti-fungals, anti-virals, anti-seborrhoeics, anti-acneics, keratolytics may be mentioned by way of example, alone or as a mixture. , antihistamines, anesthetics, healing agents, pigmentation modifiers, sunscreens, free radical scavengers, moisturizers, vitamins and other similar lipophilic compounds.

According to the present invention, the encapsulated lipophilic active principle is preferably

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 A lipophilic active principle is sensitive to surrounding physicochemical conditions such as temperature, pH, light or the presence of oxidizing agents.

Examples of preferred lipophilic active principles that may be mentioned include vitamins such as vitamin A (retinol) or esters thereof, such as saturated or unsaturated C 1 -C 30 esters, more particularly C 2 -C 18 esters. , and especially retinol acetate and retinol propionate; vitamin E or esters thereof such as tocopherol acetate; vitamin D or derivatives thereof such as 7-dehydrocholesterol; vitamin F or derivatives thereof such as linoleic or linolenic acids; carotenes such as p-carotene and derivatives thereof such as lycopene; salicylic acid or its derivatives, in particular those described in documents FR-A-2,581,542, EP-A-378,936 and EP-A-570230, in particular n-octanoyl-5-salicylic, n-decanoyl acids; 5-salicylic, n-dodecanoyl-5-salicylic, n-octyl-5-salicylic, n-5-heptyloxy salicylic and n-heptyloxy-4-salicylic acid; vitamin K; unsaturated oils such as borage oil and fish oils, as well as derivatives thereof.

Excellent results have been obtained notably for the encapsulation of retinol (vitamin A), a molecule very sensitive to oxidation at acidic pH, as well as for the esters of C 1 -C 30, more particularly of C 3 -C 6, of this compound. ci, such as retinol acetate and retinol propionate.

Among the active agents, there may also be mentioned sunscreens, especially photoinstable or photosensitive, such as derivatives of dibenzoylmethane and cinnamic acid derivatives.

Among the derivatives of dibenzoylmethane, mention may be made of: 2-methyldibenzoylmethane, 4-methyldibenzoylmethane, 4-isopropyldibenzoylmethane, 4-tert-butyldibenzoylmethane, 2,4-dimethyldibenzoylmethane, 2,5-dimethylbenzoylmethane. dimethyldibenzoylmethane, 4,4'-diisopropyldibenzoylmethane, 4,4'-dimethoxydibenzoylmethane, 4-tert-butyl-4'-methoxydibenzoylmethane, 2-methyl-5-isopropyl-4'-methoxydibenzoylmethane, 2-methyl-5-tert-butyl-4'-methoxydibenzoylmethane, 2,4-dimethyl-4'-methoxydibenzoylmethane, 2,6-dimethyl-4-tert-butyl-4'-methoxydibenzoylmethane.

Among the dibenzoylmethane derivatives mentioned above, all

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 particularly according to the present invention, 4-tert-butyl-4'-methoxydibenzoylmethane available commercially under the name PARSOL 1789 from the company HOFFMANN-LAROCHE.

Le principe actif peut être présent dans la suspension aqueuse de nanocapsules à raison de 1 à 30% en poids, notamment 5 à 15% en poids par rapport au poids total de ladite suspension. Among the derivatives of cinnamic acid, mention may be made of isopentyl 4-methoxy cinnamate, 2-ethylhexyl 4-methoxy cinnamate, methyl diisopropyl cinnamate, isoamyte 4-methoxy cinnamate and 4-methoxy cinnamate of diethanolamine, and especially 2-ethylhexyl p-methoxycinnamate, sold in particular under the trade name PARSOL MCX by GIVAUDAN Company and having the following structural formula:

The active principle may be present in the aqueous suspension of nanocapsules in a proportion of 1 to 30% by weight, especially 5 to 15% by weight relative to the total weight of said suspension.

The organic solvent used to dissolve the polymer and the lipid phase forming or comprising the active ingredient, may be any non-toxic organic solvent, more volatile than water currently used in the cosmetic field. C2-C3 ketones, in particular acetone, are preferably used; C1-C6 alcohols, for example ethanol, n-propanol or isopropanol, or methylal, ethyl acetate, or mixtures of these solvents.

Said organic solvent may be used at a proportion of 1 part of solvent to 1 to 3 parts of water, during the preparation of the aqueous suspension of nanocapsules.

The silicone polymer is preferably present in the organic phase at a concentration of between 0.01 and 20% by weight, in particular 0.5 to 5% by weight, more preferably 0.1 to 2% by weight, relative to the weight total of the aqueous suspension of nanocapsules.

Moreover, it has been found that it is possible to prepare the nanocapsules according to the invention by means of a particular manufacturing process, requiring amounts of water and solvent that are half as small as in the prior art.

The nanocapsules according to the invention can thus be prepared according to a process comprising the following steps: the polymer is dissolved, the lipid phase forming or comprising the active principle and optionally a surfactant acting as a coating agent in a solvent organic, that is to say, miscible with water, non-toxic

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 that and more volatile than water (usually acetone and / or a C1-6 alcohol), in order to obtain an organic phase, the mixture 'polymer + lipid phase + active ingredient + surfactant' may be present in a ratio (weight / volume) of 3.5 g for 40 to 75 ml of organic solvent, especially 3.5 g for 45-55 ml of organic solvent; a solution of a second suitable surfactant in water (non-solvent of the polymer and of the lipid phase) is prepared in order to obtain an aqueous phase, said second surfactant being able to be present in the solution in a ratio (weight / volume) 0.25 g for 80 to 150 ml of water, especially 0.25 g for 90-110 ml of water; said organic phase is poured into said aqueous phase, while moderately agitating it, which results in the spontaneous formation of a nanocapsule emulsion, and then the organic phase is evaporated and, if appropriate, part of the aqueous phase; to obtain a concentrated suspension of nanocapsules in an aqueous phase.

The aqueous suspension of nanocapsules according to the invention, or the fraction of the nanocapsules, can be present in cosmetic or pharmaceutical compositions, especially dermatological compositions, furthermore comprising in a physiologically acceptable support, in a quantity generally of between 0.1 and 30%. by weight, preferably between 0.5 and 15% by weight, more particularly 1 to 10% by weight, relative to the total weight of the composition.

The physiologically acceptable medium may be a cosmetically or pharmaceutically acceptable medium which may comprise, in addition to the nanocapsules and the aqueous phase, conventional cosmetic and / or pharmaceutical adjuvants, such as fatty substances, petroleum jelly, pH-regulating agents. preservatives, thickeners, dyes or perfumes.

Of course, those skilled in the art will take care to choose this or these optional additional compounds and their amount so that the advantageous properties intrinsically attached to the cosmetic or dermatological composition according to the invention are not, or not substantially impaired by the addition or additions envisaged.

The compositions according to the invention may for example be in the form of a serum, a lotion, an aqueous, aqueous-alcoholic or oily gel, an emulsion of water-in-oil or oil-in-water or even of aqueous dispersions of lipid vesicles consisting of ionic or non-ionic lipids or a mixture thereof, which vesicles contain or not an oily phase.

The compositions according to the invention find a particular application

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 in the field of skincare or makeup compositions for the skin of the body or face.

The invention is illustrated in more detail in the following examples.

EXAMPLE 1 Manufacture of Vitamin A Propionate Nanocapsules with a Diluted Process In a 250 ml amber glass flask, under an inert atmosphere, at room temperature (20 ° C.), and with stirring are dissolved: 0.5 g of dimethicone copolyol (DC2-5695 from Dow Corning), 0.5 g of polymethylsilsesquioxane (Belsil PMS MK resin from Wacker) in 100 ml of acetone.

In another 250 ml amber glass flask, 2.5 g of vitamin A propionate is weighed, then the above acetone phase is added and the mixture is stirred at ambient temperature until the active ingredient is completely dissolved.

In another 0.5 liter amber glass flask, 0.25 g of poloxamer 338 (triblock polycondensate of ethylene oxide and propylene oxide sold under the name Synperonic PE / F108 by Uniqema is dissolved under an inert atmosphere. ) in 200 g of water at room temperature with stirring.

The acetone phase is poured into the aqueous phase while maintaining stirring.

Then the acetone and a portion of the water are evaporated using a rotary evaporator until a final volume of 50 ml is obtained.

An aqueous suspension of nanocapsules having an average diameter of 259 nm is obtained.

EXAMPLE 2 Manufacture of Vitamin A Propionate Nanocapsules with a Diluted Process In a 250 ml amber glass flask, under an inert atmosphere, at room temperature (20 ° C.), and with stirring are dissolved: 0.5 g of dimethicone copolyol (DC2-5695 from Dow Corning), 0.5 g of polymethylsilsesquioxane (KR-220L resin from Shin Etsu) in 100 ml of acetone.

In another 250 ml amber glass flask, 2.5 g of vitamin A propionate is weighed, then the above acetone phase is added and the mixture is stirred at ambient temperature until the active ingredient is completely dissolved.

In another 0.5 liter amber glass flask, 0.25 g of poloxamer 338 (triblock polycondensate of ethylene oxide and propylene oxide sold under the name Synperonic PE / F108 by Uniqema is dissolved under an inert atmosphere. ) in 200 g of water at room temperature with stirring.

The acetone phase is poured into the aqueous phase while maintaining stirring,

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 then the acetone and a part of the water are evaporated using a rotary evaporator until a final volume of 50 ml is obtained.

An aqueous suspension of nanocapsules having an average diameter of 261 nm is obtained.

Example 3: Stability Tests of Vitamin A Encapsulated in Different Polymers The stability of vitamin A enclosed in the nanocapsules according to the invention is compared with the stability of this active ingredient in nanocapsules based on known polymers: polycaprolactone and polyethylene adipate, coated with a nonionic surfactant (DC2-5695).

The nanocapsules containing vitamin A are kept in closed containers and sealed to light and gases, in the form of aqueous suspension for two months at 45 C. After this period of conservation, the loss of active ingredient by HPLC assay is evaluated. . with detection at 325 nm.

The results obtained are collated in the following table.

<Tb>
<Tb>

Polymer <SEP> Belsil <SEP> PMS <SEP> MK <SEP> KR-220 <SEP> L <SEP> Polyethylene <SEP> Poly <SEP>#<SEP> Caproadipate <SEP> Lactone
<tb> (EP1029587)
<tb> Mass <SEP> molar <SEP> - <SEP> 10000 <SEP> 80000
<tb> Agent <SEP> of enro- <SEP> Silicone <SEP> Silicone <SEP> Silicone <SEP> Silicone
<tb> bage <SEP> DC2-5695 <SEP> DC2-5695 <SEP> DC2-5695 <SEP> DC2-5695
<tb> Diameter
<tb> average <SEP> of <SEP> 259 <SEP> nm <SEP> 261 <SEP> nm <SEP> 296 <SEP> nm <SEP> 290 <SEP> nm
<tb> nanocapsules
<tb> pH <SEP> of <SEP><SEP> com <SEP> 8.0 <SEP> 8.3 <SEP> 6.7 <SEP> 7.2
<tb> position
<tb>% <SEP> of <SEP> loss <SEP> 26% <SEP> 32% <SEP> 37% <SEP> 50%
<tb> after <SEP> 2 <SEP> months <SEP> to
<tb> 45 C
<Tb>
These results show that the use of the silicone polymers according to the invention for the preparation of nanocapsules significantly improves the oxidation stability of the encapsulated vitamin A.

EXAMPLE 4 Manufacture of Nanocapsules of Vitamin A Esters with a Concentrated Process

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 In an amber glass flask of 250 ml, under an inert atmosphere, at room temperature (20 ° C.), and with stirring are dissolved: 0.5 g of dimethicone copolyol (DC2-5695 from Dow Corning), 0.5 g of polymethylsilsesquioxane (Belsil PMS MK) in 50 ml of acetone.

In another 250 ml amber glass flask was weighed 2.5 grams of C8C10 esters of vitamin A and the above acetone phase was added and stirred at room temperature until complete dissolution of the active.

In another 0.5 liter amber glass flask, 0.25 g of poloxamer 338 (ethylene oxide / propylene oxide triblock polycondensate sold under the name Synperonic PE / F108 was dissolved under an inert atmosphere by Uniqema) in 100 g of water at room temperature with stirring.

The acetone phase is poured into the aqueous phase while stirring is maintained, then the acetone and a part of the water are evaporated using a rotary evaporator until a final volume of 50 is obtained. ml.

An aqueous suspension of nanocapsules having an average diameter of 267 nm is obtained without loss of active ingredient.

For comparison, the nanocapsules made under the same conditions with a poly # caprolactone polymer have a size greater than 300 nm and the loss in active is very important, as is shown in the following table:

<Tb>
<tb> Polymer <SEP> poly <SEP>#<SEP> caprolac- <SEP> poly <SEP>#<SEP> caprolac- <SEP> Belsil <SEP> PMS <SEP> MK
<tb> tone <SEP> tone
<tb> Mass <SEP> molar <SEP> 50000 <SEP> 80000
<tb> Coating Agent <SEP><SEP> Silicone <SEP> Silicone <SEP> Silicone
<tb> DC2-5695 <SEP> DC2-5695 <SEP> DC2-5695
<tb> Diameter <SEP> average <SEP> of <SEP> 359 <SEP> nm <SEP> 307 <SEP> nm <SEP> 267 <SEP> nm
<tb> nanocapsules
<tb> SEP Encapsulation Rate <SEP> 1.49 <SEP>% <SEP> 1.51 <SEP>% <SEP> 2.3%
<tb><SEP> caprylate <SEP> of <SEP> retinyl
<tb> (tx <SEP> theoretical: <SEP> 2.23%)
<tb>% <SEP> of <SEP> loss <SEP> to <SEP> TO <SEP> 33% <SEP> 32% <SEP> 0%
<tb> SEP Encapsulation Rate <SEP> 1.08% <SEP> 1.18% <SEP> 1.68%
<tb> of <SEP> caprate <SEP> of <SEP> Retinyl
<tb> (tx <SEP> theoretical: <SEP> 1.64%)
<tb>% <SEP> of <SEP> loss <SEP> to <SEP> TO <SEP> 34% <SEP> 32% <SEP> 0%
<Tb>

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 Example 5 A day cream for skin care, of the oil-water emulsion type, comprising: Oily phase: Diglycerol monostearate 2.0% Stearate POE (200E) 1.5% N Stearoyl L Glutamic acid disodium 0 , 5% (Acylglutamate HS 21) Vaseline oil 3.0% Vaseline 1.0% Stearyl Heptanoate 3.0% Apricot almond oil 5.0% Hydrogenated polyisobutene 5.0% Isoketyl palmitate 2.0% Silicone volatile 5.0% Preservative qs Aqueous phase 1: Glycerol 5.0% Preservatives qs Distilled water qs 100% Aqueous phase 2: Carbomer 0.4% Triethanolamine 0.4% Preservatives qs Distilled water 15.0% Aqueous phase 3: Nanocapsules according to Example 1 10% The aqueous phase 1 is introduced at 60 C in the oily phase itself at this temperature, with very vigorous stirring. The temperature and stirring are maintained for 30 minutes. The suspension is then brought to room temperature. The aqueous phase 2 is then dispersed in the suspension, using a non-shearing disperser. Then the aqueous phase 3 is then introduced with gentle stirring.

Claims (18)

 1. Nanocapsules consisting of: - a lipid core forming or comprising a lipophilic active ingredient and - a continuous polymeric shell insoluble in water comprising at least one polysilsesquioxane silicone polymer, especially a polyalkylsilsesquioxane of formula: (R) -SiO3 / 2) x, wherein R represents a hydrocarbon radical, saturated or unsaturated, linear, branched or cyclic; for example of the type -C n H 2 n + 1, with n being an integer ranging from 1 to 20, especially a methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, dodecyl, tridecyl, tetradecyl or hexadecyl radical; octadecyl and eicosyl; or an aryl group, especially phenyl or tolyl; a cycloalkyl group, especially cyclobutyl, cyclopentyl or cyclohexyl; an alkenyl group, especially vinyl or allyl; an aralkyl group, especially 2-phenylethyl or benzyl; R may also include one or more halogen atoms, especially fluorine or chlorine; and x is the number of units, and may be between 1 and 10, especially 1 to 4. 2. Nanocapsules according to claim 1, wherein R represents a methyl, ethyl, propyl or phenyl radical. 3. Nanocapsules according to one of the preceding claims, wherein the encapsulated lipophilic active ingredient is a lipophilic active principle sensitive to surrounding physicochemical conditions such as temperature, pH, light or the presence of oxidizing agents. 4. Nanocapsules according to one of the preceding claims, wherein the active ingredient is selected from, alone or in combination, emollients, anti-inflammatories, anti-bacterials, anti-fungals, anti-virals, anti-seborrheic drugs, anti-acne drugs, keratolytics, antihistamines, anesthetics, healing agents, pigmentation modifiers, sunscreens, free radical scavengers, moisturizers, vitamins and others similar lipophilic compounds. 5. Nanocapsules according to one of the preceding claims, wherein the active ingredient is selected from, alone or in combination, vitamins such as vitamin A (retinol) or esters thereof such as esters C1-30 saturated or unsaturated, more particularly C 2 -C 18, or even C 3-6, and especially retinol acetate and retinol propionate; vitamin E or esters thereof such as tocopherol acetate; vitamin D or derivatives thereof such as 7-dehydrocholesterol; vitamin F or derivatives thereof such as <Desc / Clms Page number 15>  linoleic or linolenic; carotenes such as p-carotene and derivatives thereof such as lycopene; salicylic acid or its derivatives, in particular n-octanoyl-5-salicylic acid, n-decanoyl-5-salicylic acid, n-dodecanoyl-5 salicylic acid, n-octyl-5-salicylic acid, n-heptyloxy-5-salicylic acid and n-heptyloxy-4salicylique; vitamin K; unsaturated oils such as borage oil and fish oils, as well as derivatives thereof. 6. Nanocapsules according to one of the preceding claims, wherein the active ingredient is selected from, alone or in mixture, sunscreens, including photoinstable or photosensitive, such as dibenzoylmethane derivatives and cinnamic acid derivatives. 7. Nanocapsules according to one of the preceding claims, wherein the active ingredient is selected from, alone or in mixture, 2-methyldibenzoylmethane, 4-methyldibenzoylmethane, 4isopropyldibenzoylmethane, 4-tert-butyldibenzoylmethane, 2,4-dimethyldibenzoylmethane, 2 , 5-dimethyldibenzoylmethane, 4,4'diisopropyldibenzoylmethane, 4,4'-dimethoxydibenzoylmethane, 4-tert-butyl-4'-methoxydibenzoylmethane, 2-methyl-5-isopropyl-4'-methoxydibenzoylmethane, 2-methyl -5-tert-butyl-4'-methoxydibenzoylmethane, 2,4-dimethyl-4'-methoxydibenzoylmethane, 2,6-dimethyl-4-tert-butyl-4'-methoxydibenzoylmethane; isopentyl 4-methoxy cinnamate, 2-ethylhexyl 4-methoxy cinnamate, methyl diisopropyl cinnamate, isoamyl 4-methoxy cinnamate, diethanolamine 4-methoxy cinnamate, and 2-ethylhexyl pmethoxycinnamate. 8. Nanocapsules according to one of the preceding claims, having an average size of less than 1 micron, especially between 100 and 800 nm, preferably between 200 and 500 nm. 9. Nanocapsules according to one of the preceding claims, wherein the polymeric envelope is further surrounded by a lamellar coating having an organized structure in one or more sheet (s) each consisting of a double layer of amphiphilic molecules. called embedding agent. 10. Nanocapsules according to claim 9, characterized in that said coating agent is chosen from phospholipids, in particular lecithin, polycondensates of propylene oxide and ethylene oxide and silicone surfactants, capable of to form lamellar structures. <Desc / Clms Page number 16> 11. An aqueous suspension comprising the nanocapsules according to one of the preceding claims. 12. Cosmetic or pharmaceutical composition comprising, in a physiologically acceptable medium, the nanocapsules according to one of claims 1 to 10 or the aqueous suspension according to claim 11. 13. Composition according to claim 12, in which the fraction of the nanocapsules or the aqueous suspension is present in an amount of between 0.1 and 30% by weight, preferably between 0.5 and 15% by weight, more particularly 1 to 10% by weight, relative to the total weight of the composition. 14. Composition according to one of claims 12 to 13, wherein further comprising conventional cosmetic and / or pharmaceutical adjuvants, such as fatty substances, petroleum jelly, pH-regulating agents, preservatives, thickening agents, dyes or perfumes. 15. Composition according to one of claims 12 to 14, in the form of serum, lotion, aqueous gel, hydroalcoholic or oily, water-in-oil or oil-in-water emulsion or in the form of aqueous dispersions of lipid vesicles consisting of ionic or nonionic lipids or a mixture thereof, which vesicles contain or not an oily phase. 16. Composition according to one of claims 12 to 15, in the form of a composition for care or makeup of the skin of the body or face. 17. Process for preparing nanocapsules according to one of claims 1 to 10, comprising the following steps: dissolving a polymer, a lipid phase forming or comprising an active ingredient and optionally a coating agent in an organic solvent miscible with water, non-toxic and more volatile than water, in order to obtain an organic phase, - preparing an aqueous solution of a second surfactant, in order to obtain an aqueous phase, - pouring said organic phase into said aqueous phase while moderately agitating it, evaporating the organic phase and, optionally, part of the aqueous phase, in which the polymer is a polysilsesquioxane silicone polymer, in particular a polyalkylsilsesquioxane of formula: (R-SiO 3/2) x, <Desc / Clms Page number 17>  in which R represents a hydrocarbon radical, saturated or unsaturated, linear, branched or cyclic; for example of the type -C n H 2 n + 1, with n being an integer ranging from 1 to 20, especially a methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, dodecyl, tridecyl, tetradecyl or hexadecyl radical; octadecyl and eicosyl; or an aryl group, especially phenyl or tolyl; a cycloalkyl group, especially cyclobutyl, cyclopentyl or cyclohexyl; an alkenyl group, especially vinyl or allyl; an aralkyl group, especially 2-phenylethyl or benzyl; R may also include one or more halogen atoms, especially fluorine or chlorine; and x is the number of units, and may be between 1 and 10, especially 1 to 4. 18. The method of claim 17 wherein: the mixture 'polymer + lipid phase + active ingredient + surfactant' is present relative to the organic solvent in a ratio (weight / volume) of 3.5 g for 40 to 75 ml of organic solvent, especially 3.5 g for 45-55 ml of organic solvent; and / or the second surfactant is present in the aqueous solution in a ratio (weight / volume) of 0.25 g for 80 to 150 ml of water, in particular of 0.25 g for 90-110 ml of water. .