MXPA97006435A - Stabilization of a non-stable retinoid in emulsions of oil in water for compositions for the care of the p - Google Patents

Abstract

The present invention relates to oil-in-water emulsions containing an unstable retinoid (retinol or C2 to C3 ester) in an oil phase. Retinol is stabilized in the emulsions of the invention, despite the presence of 50% to 98% of an aqueous phase. The emulsions also preferably include a hydroxy

Description

STABILIZATION OF A NON-STABLE RETINOID IN EMULSIONS OF OIL IN WATER FOR COMPOSITIONS FOR CARE OF THE SKIN FIELD OF THE INVENTION Skin care compositions containing retinol or short chain esters thereof in an oil-in-water emulsion.

BACKGROUND OF THE INVENTION Vitamin A, natural and synthetic derivatives have been used extensively in the treatment of a variety of skin disorders and have been used as skin repair or renewal agents. Retinoic acid has been used to treat a variety of conditions on the skin, for example, acne, wrinkles, psoriasis, age spots and discoloration. See, for example, Vahlquist, A. et al., J. Invest. Derma tol. , Vol. 94, holland D.b. and Cunliffe, W.J. (1990), pp. 496-498; Ellis, C.N. et al., "Pharmacology of Retinols in Skin", Vasel, Karger, Vol. 3, (1989), pp. 249-252; Lowe, N.J. et al., "Pharmacology of Retinols in Skin", Vol. 3 (1989), pp. 240-248; PCT Patent Application No. WO 93/19743.

It is believed that the use of a retinol or retinol short chain esters could be preferred over retinoic acid. Retinol is an endogenous compound, which occurs naturally in the human body and is essential for normal epithelial cell differentiation. The short chain esters of retinol are hydrolyzed in vivo to produce retinol. Retinol and retinyl esters are considered safer than retinoic acid. Long chain retinyl esters, especially retinyl palmitate, have been used extensively in cosmetic compositions for the skin. Such compositions may be oil-in-water emulsions, such as, for example, Age Defying Complex ™, produced by Chesebrough-Pond's. However, it has been found as part of the present invention that retinol or short chain esters of retinol are more effective than long chain retinol esters, such as retinyl palmitate (see Example 7). It is believed that retinyl palmitate is not hydrolyzed in vivo to produce retinol and / or does not penetrate the skin. Unfortunately, retinol and short chain retinyl esters are more unstable than retinoic acid or long chain retinyl esters. See Idson, "Vitamins and the Skin", Cosmetics & Toiletries, Vol. 108, December 1993, pp. 79-94, Allured Publishing Corp. (1993); Hoff an-La Roche Inc., Data Sheet "Vitamin A - The 'Nor alizer'", Roche Vita ins & Fine Chemicals; Hoffman-La Roche Inc.,. Product Data "Vitamin A Alcohol Blend". Specifically, they degrade rapidly in the presence of water. Compositions containing anhydrous retinol are known in the art. See, for example, Dulak et al., U.S. Patent 4,888,363, and Wilmott et al., U.S. Patent 4,826,828. But such compositions generally do not include water-soluble skin beneficial ingredients, especially if such ingredients are to be included in high amounts. Water-in-oil emulsions containing retinol in an oil phase are also known. See, for example, European Patent 440,398 (Johnson and Johnson), International Patent Application WO 93/00085 (Johnson &Johnson), and European Patent Application 631,772 (Johnson &Johnson). A serious disadvantage of anhydrous compositions and water-in-oil emulsions is that they are more greasy and cosmetically less pleasant than oil-in-water emulsions, because the continuous phase is an oil phase. Thus, it is desirable to formulate a retinol or short chain esters of retinol in oil-in-water emulsions. However, due to the high exposure of a retinol to an aqueous phase in such systems (compared to anhydrous systems or water-in-oil emulsions), it has not been possible to stabilize an unstable retinol in such systems. See for example the aforementioned European Patent 440, 398, which teaches on page 1, lines 34-37, that retinoids in oil-in-water emulsions "are unstable ... and chemically degrade and are, therefore, unavailable over time for their alleged utility. " The aforementioned international application WO 930085 teaches on page 8, lines 2-7: "For reasons which are not clearly understood satisfactory stability for a commercial product has been achieved for certain specific retinoids, only by using a specific form of emulsion, that is, water in oil, and then, only employing a specific stabilization system The present invention is based, in part, on the discovery that a non-stable retinoid, i.e. retinol or its short chain esters, can be stabilized in oil-in-water emulsions by virtue of the combination of several critical parameters, such as: employing a specific oil phase to form oil droplets containing the solubilized, non-stable retinoid and using selected combinations of solid compounds to form a barrier layer of crystals specifically sized for oil drops.

The solid compounds and / or oils used in the present invention to form oil droplets surrounded by a crystalline barrier layer have been used in skin care compositions, for example, as emollients. Some of these compositions also include retinoids, most retinoic acid or retinyl palmitate. See, for example, the summary of the Roman patents RO 92,576, RO 93,807, RO 84,823; U.S. Patent 3,906,108 (Felty et al.); U.S. Patent 5,380,764 (Herzog); U.S. Patent 4,981,845 (Pereira); U.S. Patent 5,037,850 (Elliott et al.); U.S. Patent 4,333,924 (Bo ley et al.); U.S. Patent 5,492,894 (Basco et al.). However, such compositions differ from the present invention at least in that they do not contain an unstable retinol (retinol or its short chain esters) within the oil droplets surrounded by a crystal barrier of defined size. The prior art does not provide a stable oil-in-water emulsion containing retinol or its short chain esters.

BRIEF DESCRIPTION OF THE INVENTION The present invention includes, in part, an oil-in-water emulsion for conditioning the skin, the emulsion comprising: (a) an oil phase comprising 0.1% to 50% by weight of the emulsion, of a few drops of oil comprising a fluid oil and from 0.001 to 10% by weight of the emulsion, of a retinoid selected from the group consisting of retinol and C2-C3 esters of retinol, wherein the retinoid is solubilized in the oil; (b) from 50% to 98% by weight of the emulsion, of an aqueous phase; and (c) from 1% to 20% by weight of the emulsion of a barrier ingredient, wherein the barrier ingredient provides a crystalline barrier layer between the oil droplets and the aqueous phase, wherein the size of the crystals of the barrier layer is determined by a Microscopic Crystal Dimension Test (described below), is in the range of lμm to 50 μm; and wherein the size ratio of an individual oil drop to an individual crystal in the barrier layer is in the range of 5: 1 to 100: 1; and wherein the melting point of a mixture of the fluid oil and the barrier ingredient is in the range of 40 ° C to 100 ° C. The term "conditioning" as used herein, means the prevention and treatment of dry skin, photodamaged skin, appearance of arriigas, age spots, aged skin, increased flexibility of the stratum corneum, and generally increased brightness, radiation and skin quality. The composition can be used to improve skin desquamation and epidermal differentiation. In accordance with the present invention, by virtue of creating drops of oil containing an unstable retinoid solubilized and surrounded by a crystal barrier of a scale of defined size, the stability of the retinoid in an oil-in-water emulsion is substantially improved. The presence of oil droplets containing the retinoid and surrounded by the crystalline barrier is ensured in accordance with the present invention by selecting fluid oils and barrier ingredients, which satisfy the melting point, the crystal size and the solubility requirements. described in more detail later.

DETAILED DESCRIPTION OF THE INVENTION All amounts are by weight of an oil in water emulsion unless otherwise indicated. The oil-in-water emulsion included in the compositions of the invention contains drops of oil in a continuous aqueous phase. The drops of oil contain, as the first essential ingredient, a retinoid from the group consisting of retinol and C2-C3 retinol esters. As illustrated in Example 7, they are more effective than retinyl palmitate. The term "retinol" as used herein includes the following retinol isomers: trans-retinol, 13-cis-retinol, 11-cis-retinol, 9-cis-retinol, 3,4-didehydro-retinol. The preferred isomers are trans-retinol, 13-cis-retinol, 3,4-didehydro-retinol, 9-cis-retinol. The most preferred is trans-retinol, due to its wide commercial availability. The retinyl ester is an ester of retinol. The term "retinol" has been defined above. Retinyl esters suitable for use in the present invention are retinyl C2-C3 esters also known as retinyl acetate and retinyl propionate. Retinyl acetate is an especially preferred ester, since it is very effective, is more commercially available and is less expensive. For the same reasons, the most preferred retinoid for use in the present invention is retinol. The retinol or a retinyl ester is employed in the composition of the invention in an amount of 0.001% to 10% by weight of the emulsion, preferably in an amount of 0. 01% to 0.5% of greatest preference in an amount of 0.05% a 0. 2%. The second essential ingredient of the emulsion oil phase of the invention is a fluid oil. The oil phase in the emulsions of the invention can be formed of an individual compound or a mixture of compounds. The oil phase according to the present invention must be fluid and must be capable of solubilizing, at a storage temperature (typically 25 ° C), the required amount of retinol or its esters of 2_3- In addition, a mixture of the phase of oil and the barrier ingredient should satisfy the melting point test discussed in more detail below. The term "fluid" as used herein means that at least 50% of an oil is liquid at 25 ° C. Suitable compounds for forming the oil phase include, but are not limited to, esters of fatty acids or alcohols and hydrocarbons, preferably monoesters of fatty acids or alcohols, provided they meet the melting point and solubility requirements described herein. . More preferably, the fluid oil is selected from the group consisting of isostearyl palmitate, tridecyl salicylate, C12_15 octanoate, isopropyl etherate, isopropyl myristate, and isopropyl palmitate. Drops of oil containing the retinoid may be included in the emulsions herein in an amount of 0.1% to 50% by weight of the emulsion, preferably from 1% to 30%, most preferably from 5% to 15% . The third essential component of the emulsions of the invention is a barrier ingredient. The term "barrier ingredient" as used herein means a mixture of at least two classes of compounds: the first compound is a compound used for the formation of crystals ("crystal-forming compound"); the second is the compound required to control the size of the crystals ("glass sizing compound"). It has been found that, as part of the present invention, if only one crystal-forming compound is used, the crystals formed are too large (see Example 4) and the retinoid is unstable in such compositions. It has also been found that the second crystal sizing compound, although incapable of forming crystals of sufficient size by itself, controls the size of the crystals (see Example 5). The co-presence of crystal-forming compounds and crystal sizers is necessary to stabilize the retinoid. The size of the crystals is critical to ensure the stability of the emulsions of the invention. If the crystals surrounding the oil drop are too large, the crystals will migrate from the surrounding oil / water surface and remain as separate entities in emulsion. If the crystals are too small, the exposure of the oil phase to the water increases. In both cases, the stability of a retinoid in an oil phase is impaired. The average size of an individual crystal in the emulsions of the invention, as determined by the Microscopic Crystal Dimension Test, is in the range of lμm to 50μm, preferably in the range of lμm to 20μm and most preferably in the range from 5μm to 10μm. The identity and the amounts of the ingredients that will form the fluid phase and the crystalline barrier determine the size of the crystals.

Microscopic Glass Dimension Test The fluid oil and the intended barrier-forming compounds are co-melted in the same proportions as those intended by the final emulsion. A drop of the fusion mixture is placed on a microscope slide with a coverslip. Observe the size and shape of the crystals under the microscope. The crystals should be small and relatively smooth (not like pointed needles). The determined size taking a -micrography and measuring the crystals with a ruler, taking into account amplification. Several crystals (ie, at least 5 crystals, and preferably at least 10 crystals) must be sized and averaged to avoid the risk of measuring an atypical crystal or a group of crystals. Initially, the crystallization pattern can be qualitatively observed using a light microscope under polar crossing conditions. If the initial observation is that the crystals may be of an adequate size, the Microscopic Crystal Dimension Test, as described above, is conducted.

Melting point In addition, the barrier ingredient and the fluid oil must thus be selected, and in such quantities, that the melting point of the mixture is in the range of 40 ° C to 100 ° C. The melting point should be in this range in order to ensure that the crystalline barrier is present during storage. Although the oil phase is released during topical application. Preferably, the melting point of the mixture is in the xango from 40 ° C to 75 ° C, more preferably in the range of 45 ° C to 55 ° C. In addition, the melting point and the mixture of the fluid oil and the components of the barrier ingredient must be absolutely sharp, that is, the components in the barrier ingredient and the fluid oil must all be very compatible with each other. The extension at the melting point should not be greater than 25 ° C, preferably not greater than 10 ° C, more preferably the melting point is an individual acute peak as determined by Differential Scanning Calorimetry (DSC). The barrier ingredient (ie, the mixture of at least two kinds of compounds that form the barrier layer) is employed in the inventive compositions in an amount of 1% to 20% by weight of the emulsion, preferably in a amount from about 5% to about 15%, most preferably in an amount from about 8% to about 12%. As explained above, the barrier layer according to the present invention is formed through the interaction of at least two kinds of compounds: the crystal-forming compound and the crystal-sizing compound. The glass sizing compound is added at levels of 1% to 75% by weight of the glass-forming compound, preferably from 5% to 40%, more preferably from 10% to 20%. The glass-forming compounds suitable for use in the emulsions of the invention include, but are not limited to, fatty acids, mixtures of fatty acids with their soaps, fatty alcohols, and their ethoxylated derivatives of fatty acids or fatty alcohols, sterols ( for example, lanolin or cholesterol) and their mixtures. Preferably, the crystal-forming compounds are selected from the group consisting of fatty acids or alcohols of C22 and preferably their ethoxylated derivatives, and mixtures thereof .. More preferably, the crystal-forming compounds are selected from the group consisting of consists of palmitic acid, stearic acid, stearyl alcohol, cetyl alcohol, behenic acid, behenyl alcohol, cholesterol and sorbitan stearate and their mixtures.The crystal sizing compound is selected from the group consisting of hydroxylated fatty acids or alcohols ^ c'i2_C22 And their ethoxylated derivatives Preferably, the hydroxylated fatty acids or mixtures thereof are used The preferred chain length is from the group of preference, the crystal sizing compound is selected from the group which consists of glyceryl monohydroxystearate, hydroxystearic acid, isostearyl alcohol, isostearic acid, and mixtures thereof.

The crystal sizing compound may or may not be contained in the actual crystals forming a crystalline barrier layer. The glass sizing compound regulates the size of the glass and thus is essential to form a suitable glass barrier, but its location can be in the glass or it can be in the drop of oil or in a combination of the two locations. The relative size of the individual oil drop to the individual crystal in the emulsions of the invention is in the range of 5: 1 to 100: 1, preferably in the range of 5: 1 to 50: 1, most preferably in the range from 5: 1 to 20: 1. The crystal size is measured through a Microscopic Crystal Dimension Test as described above. The oil drop size can also be measured through the Microscopic Crystal Dimension Test or using a particle size analyzer (for example, MastersizerR). The total size of a particle formed from a drop of oil and crystals surrounding the drop is also important according to the present invention. The half-life of the retinoid in the particle is inversely related cor. the size of the particle. The larger the particle, the slower the diffusion of the retinoid. Even the physical stability of the emulsion is affected if the particle size is too large. In this way, the particle size must be such in order to obtain the chemical stability of the retinoid, even to preserve the physical stability of the emulsion. It has been found as part of the present invention that the average particle size of heavy volume should be in the range of 5 μm to 500 μm preferably in the range of 10 μm to 50 μm. The particle size can be measured using a particle size analyzer (eg, MastersizerR) and measuring d (5.3), or d (4.3) an average particle diameter, as described in the Mastersizer manual. Another essential ingredient of the emulsions of the invention is the aqueous phase. The aqueous phase of the emulsions of the invention comprises at least 20% water. However, a particular advantage of the emulsions of the invention is that it can incorporate a large amount of water. Preferred emulsions contain at least 40% water, preferably 40% to 95% water, more preferably 60% to 70% water. An aqueous phase may optionally contain other ingredients or water soluble solvents. The particularly preferred water soluble ingredient incorporated in an aqueous phase is a hydroxy acid as described in greater detail below. The total aqueous phase is preferably at least 65%, more preferably at least 70% by weight of the emulsion.

The compositions of the invention have a life of at least 15 days at 50 ° C, preferably from 20 days to 45 days and more preferably from 35 to 45 days. "Half-life time" is defined as the time it takes for retinol or its short-chain ester to degrade to half its final concentration at a given temperature. Preferred compositions according to the present invention are essentially free of simple lower chain alcohol, such as methanol, ethanol or propanol, to avoid drying or the irritating effect of such alcohols on the skin. The pH is in the compositions in the range of 2.5 to 10. Preferred compositions of the invention have a pH of from about 6 to about 9, more preferably from about 6.5 to about 7.5. It should be understood that the emulsions of the invention can be co-blended with other emulsions, including multiple emulsions. In addition, the emulsions of the invention may contain other oil droplets, which may not contain a fluid oil or the retinoid of the invention. A composition is within the scope of the invention as long as it contains an oil-in-water emulsion, the oil phase of which contains from about 0.1% to about 50% oil droplets described herein.

Materials and Auxiliary Skin Benefit Cosmetics, Optional Various types of skin beneficial ingredients may be present in the cosmetic emulsions of the present invention. Although not limited to this category, general examples include anti-wrinkle and sunscreen compounds and tanning agents. An optional ingredient, particularly preferred is a hydroxy acid. One of the advantages of the emulsions of the invention is that they can incorporate a high amount of the aqueous phase. Consequently, a high amount of the water soluble active, in general, and hydroxy acids in particular may be co-present with a retinoid active. The hydroxy acid may be chosen from -hydroxy acids, β-hydroxy acids, or other hydroxycarboxylic acids (eg, dihydroxycarboxylic, hydroxydicarboxylic, hydroxytricarboxylic acid). and mixtures thereof or a combination of their stereoisomers (DI, D or L). The hydroxy acid can be chosen from < -hydroxy acids, β-hydroxy acids (eg, salicylic acid), other hydroxycarboxylic acids (eg, dihydroxycarboxylic acid, hydroxy-dicarboxylic acid, hydroxytricarboxylic acid) and mixtures thereof and a combination of their stereoisomers (DL, D or L). Preferably, the hydroxy acid (ii) is chosen from α-hydroxy acids having the general structure (1) OH I (i) MCHCOOH where M is H or a straight or branched saturated or unsaturated hydrocarbon chain containing from 1 to 27 carbon atoms. Even more preferred, the hydroxy acid is selected from glycolic acid, lactic acid, 2-hydroxyoctanoic acid, hydroxylauric acid, and mixtures thereof. When stereoisomers are present, it is more preferred to be L-isomer. Preferably, the amount of the hydroxy acid component present in the emulsion according to the present invention is from 0.01 to 20%, more preferably from 0.05 to 12% and more preferably from 0.5 to 8% by weight of the emulsion. Sunscreens include those materials commonly used to block ultraviolet light. Illustrative compounds are the derivatives of PABA, cinnamate and salicylate. For example, octyl methoxycinnamate and 2-hydroxy-4-methoxybenzophenone (also known as oxybenzone) may be used. Octyl methoxycinnamate and 2-hydroxy-4-methoxybenzophenone are commercially available under the tradenames, Parsol MCX and Benzophenone-3, respectively. The exact amount of sunscreen employed in the emulsions may vary depending on the degree of protection desired from the sun's UV radiation.The optional auxiliary ingredients in the cosmetic compositions of the present invention are the thickeners.A thickener will usually be present in amounts of 0.1 to 20% by weight, preferably from 0.5% to 10% by weight of the emulsion. Illustrative thickeners are entangled polyacrylate materials available under the trade name Carbopol from B.F. Goodrich Company. Gums such as xanthan, carrageenan, gelatin, karaya, pectin and locust bean gum can be used. Under certain circumstances, the thickening function can be achieved by a material that also serves as a silicone or emollient. For example, silicone gums in an excess of 10 centistokee and esters such as glycerol stearate having dual functionality. Powders can be incorporated in the cosmetic composition of the invention. These powders include chalk, talc, Fullers earth, kaolin, starch, smectite clays, chemically modified manganese-aluminum silicate, organically modified montmorillonite clay, hydrous aluminum silicate, fuming silica, octenyl succinate, aluminum starch and mixtures thereof. Other minor auxiliary components can also • be incorporated into cosmetic compositions. These ingredients may also include coloring agents, opacifiers and perfumes. The amounts of these minor auxiliary materials may vary from 0.001% to 20% by weight of the emulsion. In addition, it is important to ensure that other ingredients do not interfere with the location of the crystals, for example, if an emulsifier with a high HLB is used, it can destroy the crystals.

Formation of Composition The preferred method for preparing the compositions of the present invention include the following steps: (1) preparing an aqueous phase and heating to 75-80 ° C, while mixing; (2) prepare an oil phase, containing a fluid oil and barrier ingredient, but not a retinoid, and heat at 75-80 ° C while mixing; (3) slowly add the oil phase to the aqueous phase with both phases at 75-80 ° C; (4) mixing the mixture obtained in step (3) for at least 15 minutes at 75-80 ° C; (5) add a retinoid after cooling the mixture to 50-55 ° C, while mixing; (6) fill storage containers. If the final composition contains a hydroxy acid, it is preferably added separately, after step (4) at 50-60 ° C.

Use of Composition The composition according to the present invention is intended to be used primarily as a product for topical application to human skin, especially as an agent for conditioning and softening the skin, and to avoid or reduce the appearance of dryness, wrinkles or aging skin. . During use, a small amount of the composition, for example from 1 to 100 ml, is applied to the exposed areas of the skin, from a suitable container or applicator and, if necessary, then sprayed on and / or spread on the skin using your hand or fingers or an appropriate device.

Form v Product Packaging The emulsions of the invention can be formulated as a lotion, a liquid cream, a cream or a gel. The composition can be packaged in a suitable container to improve its viscosity and its intended use by the consumer. For example, a liquid lotion or cream can be packaged in a bottle or in a ball applicator, or a capsule, or an aerosol device driven by a propellant or a container equipped with a pump suitable for operation with the fingers. When the composition is a cream, it can simply be stored in a non-deformable bottle or compressible container, such as a tube or a bottle with a lid. The invention therefore also provides a closed container containing a cosmetically acceptable composition as defined above. The following specific examples further illustrate the invention.

Stability Assessment A composition that is to be tested is prepared and packed in a high density polyethylene (HDPE) bottle or tube. The bottle or tube is sealed and placed for storage in an oven at 30 ° C to 41 ° C or 50 ° C. The stability study was conducted at 50 ° C, it is an accelerated stability study. The average times depend on the temperature in the ratio 1: 6: 9: 18 by 50 ° C: 30 ° C: 25 ° C: 20 ° C. For example, an average life time of 40 days at 50 ° C corresponds to 8 months at 30 ° C. 1 year at 25 ° C (normal room temperature) and 2 years at 20 ° C. In addition, the stability study was accelerated by storing samples under unfavorable conditions in the presence of an excess of oxygen as described below. For optimum stability in commercial samples it is recommended to use the system in an inert atmosphere of argon (preferred) or nitrogen. The absence of excess air will increase the stability of retinol by at least a factor of two. For studies stabilized under aerated conditions, the tube or container was filled to 1/3 with one composition and 2/3 of the upper space and air was applied at each point. The composition was analyzed at regular intervals until less than 10% of the initial retinol remained un oxidized. All stability studies in the following Examples were performed under aerated conditions. Studies have shown that the oxidation of retinol in the compositions evaluated for this invention follow a first-order kinetics with respect to the concentration of retinol. Thus, to determine the reaction half-life, the natural logarithm of the retinol concentration (InC) must be plotted against the storage time (t) and a straight line with an inclination -k, where k is the velocity of oxidation of retinol in the reciprocal unit of time. The half-life of retinol (t-l / 2) in the system under study is then determined by the ratio of InC2 / k.

Analysis of Retinol through CLAP All samples were analyzed for retinol content using high pressure liquid chromatography (hardware: Waters 600-MS system controller, Waters 717 autosampler, Waters 996 photodiode array detector, software: Millenium 2010). The column parameters used for the retinol analysis were as follows: Column: Nucleosil C 185μm (Sigma-Aldrich) 250mm x 4.6mm Catalog: Z226181 Mobile Phase: 47% (v / v) acetonitrile 45% (v / v) ) methanol 8% (v / v) methylene chloride All CLAP grade solvents injection volume: 10 μl Flow rate: 1 ml / minute Operating time: 10 minutes Detector: UV / VISIBLE at 325 nm with arrangement of photodiode Retention time: approximately 5 minutes for retinol.

Preparation of Normal Solutions A normal curve was generated where the samples were analyzed for the retinol content. Normal solutions of retinol were prepared by serially diluting the mixture of retinol in isopropanol to produce normal solutions with final concentrations of 0, 10, 20, 30, 40 and 50 ppm (w / w). Normal solutions were prepared on a weekly basis and stored at -21 ° C.

Preparation of the Sample Many samples were prepared by simply diluting in isopropanol so that the final concentrations of retinol were within the normal curve range, preferably around 30 ppm. Emulsion samples such as thickening creams containing gums, were more difficult to prepare. In order to ensure the complete removal of retinol from the emulsion, the sample was treated as follows: Approximately 0.5 g of the sample, measured accurately, was initially mixed with 6 to 7 grams of water and swirled . to form a suspension. Approximately 10 grams of isopropanol were then added to the suspension followed by a second vortex period. The sample was then brought to the final weight with isopropanol. The sample was subsequently filtered using a disposable syringe equipped with a disposable 0.2 μm filter. All samples were prepared in triplicate or in quintuplicate on a w / w basis using an analytical equilibrium.

Analysis of Retinyl Acetate through CLAP Using the same method and the same mobile phase as cor. ei re.ir.ol. Retinyl acetate was eluted approximately 30 seconds after retinol.

EXAMPLE 1 The compositions 1, 2 and 3 (all within the scope of the invention were prepared).

^ -Barrier ingredients: glyceryl hydroxystearate is a glass sizing compound, the rest are crystal-shaped. 2 Fluid oil 3A mixture containing: retinol -51.3%, BHA -0.6%, BHT 3.1% and Tween 20 -45%. (This mixture was used in all the examples herein). The following procedure was used to make the compositions: 1. Heat the water phase (A) to 75-80 ° C, while mixing in a top mixer. 2. Heat the oil phase (B) to 75-80 ° C while mixing. 3. Slowly add the oil phase (B) to the water phase (A) with both phases at 75-80 ° C. 4. Use water from. { Or heated to 75-80 ° C to flood the rest of the oil phase. 5. Mix for at least 15 minutes at 75-80 ° C. 6. Start cooling 7. Prepare phase (D) at room temperature and add to (ABC) at 50-60 ° C 8. Add the retinol mixture (E) to the batch at 50 ° C-55 ° C while mixture. 9. Mix while cooling to 40 ° C. 10. Add (F) at 40 ° C while mixing. • 11. Stop mixing and fill in storage containers.

OBSERVATIONS: Compositions 1, 2 and 3 essentially had similar characteristics when observed under a light microscope: spherical oil droplets approximately 50 microns in diameter, surrounded by a glass barrier layer as determined by the presence of a bright birefringent circle in the perimeter of each drop when observed under polar crossing. This was confirmed by the fact that the bulky aqueous phase was essentially free of individual crystals. Using the Microscopic Crystal Dimension Test, crystals were found regularly and approximately 8 microns in diameter.

COMPARATIVE EXAMPLE 2 Comparative compositions A, B, C, TABLE 1 STABILITY IN STORAGE were prepared TABLE 1A STABILITY IN STORAGE TABLE 1B STABILITY IN STORAGE Observations : The storage stability measurements of compositions A and B (Table 1A) show that retinol is much more stable in an oil environment (Composition A) than in a water environment (Composition B): tl / 2 for A is of 34 days at 50 ° C (297 days at 30CC) against 2 days at 50 ° C (24 days at 30 ° C) for B. Unexpectedly, compositions 1 to 3 exhibited an amount of retinol similar to that of retinol in oil mineral (Composition A): tl / 2 for 1, 2 and 3 are 20, 39 and 20 days at 50 ° C, respectively, and 120, 260 and 149 days at 30 ° C, respectively. The stability of the retinol of the compositions 1 to 3 is remarkable considering the fact that these systems contain 80% w / w of the continuous aqueous phase. The retinol is stabilized since it is maintained in a microenvironment of dietary oil within the emuleion by the preemption of the crystalline barrier of the adjacent surface of the invention. Compositions C to G show that retinol is more unstable in a polar environment such as' Tween 20, butylene glycol, glycerin, or decyl alcohol (tl / 2 is 36 hours, 14 hours, 19 hours and 25 hours at 90 ° C, respectively) in a non-polar environment such as mineral oil (tl / 2 is 77 hours at 90 ° C). Since the more polar environment is less stable are the retinoids, we can understand why retinol or short chain esters are less stable than long chain esters such as retinyl palmitate in aqueous emulsion systems. Retinol or certa chain esters are more polar than long chain esters such as CC. Or retinyl palmitate being more polar, they will tend to divide more favorably in a polar solvent, such as water than long chain esters. The more they are separated from the oil and the more unstable unpleasant oil, explaining why retinyl palmitate is generally more stable than retinyl or retinyl acetate in emulsion systems (see, B. Idson, C & T, Vol. 108, p 86: "vitamin A palmitate is the most stab of available vitamin A esters", Roche: "retinol is more sensitive than fatty acid esters of vitamin A").

COMPARATIVE EXAMPLE 3 Compositions Gl and H (both outside the scope of the invention) were prepared. Both compositions contained rel'inol capsules, i.e., retinol in petroleum jelly dispersed in a hardened polyacrylic / carrageenan gel, forming a capsule which was then further dispersed (cold) in a final composition (Gl or H). The resulting compositions were beyond the scope of the invention.

Composition of LetinoJ capsules: A petrolat? d ni'-ve 17.1% A retinol mixture 3.1% B Aculyn 33 solution (4% neutralized 45.3% at pH 7) B Gelcarin 6P-911 (kappa carrageenan) 34.5% Capsule preparation: I clarify the retinol and petrolatum of snow at 40-45 ° C to form phase A. Heat at 60-70 ° C a solution of Aculyn 33 (polyacrylic acid) previously neutralized to pH 7 and add carrageenan. Add B to A and emulsify for 4 minutes at 650 rpm, using low shear time (eg, Denver flotation instrument). The capsules were made by pouring the emulsion dropwise into a hardening bath made of 10% KCL and 0.5% triton X-100. The desiccated capsules were dried on a filter paper, weighed and cold added through moderate manual agitation to a concentrated emulsion of the invention. The other components listed in Table 2 were cold aggregated through moderate agitation. The content of retinol in both compositions Gl and H was measured to be 0.1% at the beginning of the period dr > storage.

* The same composition as composition 1 in Example 1, except that phases Y) and fi were not included. Although the compositions (Jl and H) contained the bath ingredients as composition L in Example 1, these ingredients did not serve as a barrier layer around the retinol, since the retinol capsules were post-added to composition 1, to produce compositions Gl and H. Both compositions Gl and H contained retinol solubilized in a fluid oil phase, but 3J ' this oil phase was not surrounded by a combination of barrier ingredients, forming a crystalline barrier layer according to the invention. Fluorescence micrographs showed that retinol was located within the petrolatum phase of the capsule. The light microscope did not show the presence of a uniform abutting surface barrier, but showed the presence of crystals randomly dispersed within the petrolatum. The storage stability of the Gl and III compositions was measured according to the procedure described above (the aeration test was used). The results that were obtained are summarized in Table 3 The storage values of Table 3 were compared with the storage stability of compositions 1 and 2 in Table 1. In contrast to compositions Gl and H, compositions 1 and 2 contained Barrier compositions around the retinol drops. In the absence of the barrier ingredients of the invention around the retinol drops, the half-life was reduced from 20 days for the composition 1 to 6 days for the composition G 1 at 50 ° C; and 39 days for the composition 2 to 12 days for the composition H. This presents the evidence of a crucial role in the presence of barrier ingredients, around the retinol drops to stabilize retinoids in the compositions of the invention. This example also demonstrates the critical ability to employ the process of the invention for the manufacture of the compositions of the invention.

COMPARATIVE EXAMPLE 4 Composition K was prepared (outside the scope of the invention). The composition contained a crystal sizing compound in the barrier ingredient, but not a glass forming compound. Composition K was identical to composition 1 (pIJ-3.6) except that crystal-forming compounds, ie, stearic acid and stearyl alcohol were absent from composition K. Storage stability of composition K was measured according to procedure described in the above (the aeration test was used). The results that were obtained are summarized in Table 4.

The storage stability results in Table 4 were compared with the storage stability of compositions 1 and 2 (Table 1). In the absence of the glass-forming compound of the invention, the half-life was reduced from 20 days (composition 1) to 4 days (composition K) at 50 ° C. This gave evidence of a crucial role of the crystal-forming compound for stabilizing retinoids in the compositions of the invention. Microscopic observation of composition K revealed the presence of very small crystals with less than 1 miera in diameter (outside the range presented in the present claims).

COMPARATIVE EXAMPLE 5 Composition L (outside the scope of the invention) was prepared. The composition contained a compound formed of crystal in the barrier ingredient, but no crystal sizing compound. First, the retinol concentrate was prepared by adding R a A at 73 ° C, while mixing at 500 rpm for 15 minutes at 45-55 ° C. Then, the concentrate was added at 35-40 ° C to composition 1, except that phases D and E were absent to produce a retinol concentration of approximately 0.1%. Alphahydroxy acids straw were added producing a pH-3.6.

Jetinol concentrate: A Denionized water 59.25% A Keltrol 1000 0.5% A TEA (99%) 0.25% B Benzoic acid 12% B ISP 20% B Retinol mixture 8% Composition L: modified composition 1 74. .96% Deionized Water? Glycolic acid (70%) 11..4% Ammonium hydroxide (29%) 2. .5% Hydroxycapric acid 0. 1% Retinol concentrate 3.. U Deionized Water 2. 51% Bisabolol 0. 2% Fragrance 0. 03% The storage stability of composition L was measured. The results that were obtained are summarized in Table 5.

In the absence of the crystal sizing compound, the half-life was reduced from 20 days (composition 1) to 8 days (composition L) at 50 ° C, respectively. This was evidence of a crucial role of the crystal sizing component for stabilizing retinols in the compound of the invention. The lack of the crystal sizing compound manifested itself by the presence of irregularly large sized crystals (diameter of about 60 microns) when observed under the microscope.

COMPARATIVE EXAMPLE 6 Compositions M and N (outside the scope of the invention) were prepared. The compositions contained a fluid oil incompatible with retinol (a high molecular weight silicone oil). First, a retinol dispersion in the concentrate was prepared in the compatible oil (Dow high molecular weight silicone oil). Then, the concentrate was added at 50-55 ° C to composition 1, except that phases D and E were absent to produce a retinol concentration of about 0.05%.

Dispersion of Retinol Concentrate: fluid Dow 200 10,000 cst 79.4% cab-o-sil TS 720 (silica) 9% Retinol mixture (Roche) 11.6% Composition M Modified composition 1 74.96% Deionized water 16.8% Concentrated dispersion of retinol 8% Bisabolol 0.2% Fragrance 0.03% pH 7.4 Composition N Modified composition 1 74.96% Deionized water 2.81% glycolic acid (70%) 11.4% Ammonium hydroxide (29%) 2.5% Hydroxycaprilic acid 0.1% Retinol concentrate dispersion 8% Bisabolol 0.2% Fragrance 0.03% pH .7 The storage stability of the compositions M and was measured. The results that were obtained are summarized in Table 6.

TABLE 6 STABILITY IN STORAGE In the absence of a compatible retinoid oil of the invention, the half-life is decreased by 20 days (composition 1) at 4 days (composition N) at 50 ° C and 39 days (composition 2) at 13 days (composition M). The retinoids were removed from the diffusion to the oil phase to the modified composition 1, using silica to trap the retinoids in the silicone droplets where they were insoluble as evidenced by observation under a light microscope (retinol dispersed as droplets different in the high molecular weight silicone but it was not solubilized).

This gave evidence of a crucial role of the fluid oil for stabilizing retinoids in the compositions of the invention.

EXAMPLE 7 OBJECTIVE The objective of this study was to evaluate the efficacy of the following formulations: 1. 8% of L-Lactic against 8% of L-Lactic / 0.174% of Retinyl Acetate (both in an emulsion base) 2. 8% of -Lactical against 8% of L-Lactic / 0.25% of Palmitoate of Itininii? (both in an emulsion base) 3. 8% L-Lactic / 0.075% Retinol vs. 8% L-Lactic / 0.09% Retinol Acetate (both in an emulsion base). Treatment group 1 contained 16 women subjects (with an age of 45 years or older), while groups 2 and 3 contained 17 subjects each. The formulations are not within the scope of the invention: the study was conducted merely to establish a relative efficacy of retinol against retinyl acetate against retinyl acetate, not to assess stability.

Within each treatment group, the test products were randomized left / right. The subjects self-administered the test products at home, twice a day (morning and evening) twice a week. The test was conducted with double blindness. Fifty women with moderate roughness (appearance of wrinkles) on the forearm participated. The subjects continued their normal cleaning routine, but were instructed not to apply any moisturizing product to their forearms and hands for a week before the baseline visit (week 0). At the baseline, weeks 2, 4, 8 and 12, a visual evaluation was conducted (the evaluation included the analysis of the roughness type condition and the total appearance). Wherever possible, the evaluations were conducted in the same location under > consistent light. All products were weighed at each visit to determine their usage activity.

Analysis: Clinical Evaluation The following parameters were evaluated through a trained analysis.

External Forearm: Skin of rough / wavy type - surface skin lost, sunken / foamed / arched (an improvement indicates more firmness, less wrinkles) total appearance (photodamage) - a global analysis of the condition of the area with respect to the texture and full surface aspects (an improvement indicates better overall condition of the skin) Was used in the evaluation range of 0 to 9 points of curly / wavy type skin: SOFT 1 - 3 Small, thin circular lines It can not be obviously real at first glance; see more with skin twisting Less than 25% of the forearm / palm of the lower external hand MODERATE 4-6 Obvious lined pattern, circular lines with "bulky" appearance More than 25% cover, but not the entire forearm / palm of the hand SEVERE 7-9 Up to 100% coverage of the lower external forearm / palm of the hand Very obvious, very haggard Long "cushioned" long lines (depth) The middle category grades were assigned for answers that do not guarantee a total category increase .

Neither the analyzer nor the study were aware of the identity of the formulations tested.

STATISTICAL ANALYSIS The data were analyzed using a macrocomputer program based on SAS% SIGNRNK, which performs the Wilcoxon Signed-Rank, Pratt version. Statistical analyzes were performed separately for each product comparison in matching pairs, the test site (external forearm, palm of the hand), the time point of the evaluation and the attribute measurement were measured. Statistical comparison analyzes were performed for each treatment group. The differences were judged to be statistically significant at p > 95% The clinical analysis of the differences between treatment comparisons are summarized in Tables 7A-7C below.

TABLE 7A 8% L-lactic acid (8LL) vs. 0.174% Retinyl Acetate (RA) Positive ripple scale differences in favor of RA 9-week ripple scale 8LL RA Difference 0 4.28 4.28 0 2 4.27 4.23 0.04 4 4.43 4.40 0.03 8 4.17 3.93 0.24 * 12 3.90 3.77 0.13 * statistically significant TABLE 7B 8% L-lactic acid (8LL) against 8% L-lactic acid + 0. 25% Retinyl Palmitate (8LLRP) Positive ripple scale differences in favor of 8LLRP 9-week ripple scale 8LL 8LLRP Difference 0 4.41 4.41 0 2 4.32 4.35 -0.03 4 4.50 4.41 0.09 8 4.26 4.23 0.03 12 4.03 4.06 - 0.03 TABLE 7C 8% L-lactic acid + 0.075% Retinol (8LLR) against 8% L-lactide acid + 0.09% Retinol Acetate (8LLRA) Positive curl scale differences in favor of 8LLRA Curl scale 9 points week 8LLR 8LLRA Difference 0 4.74 4.74 0 2 4.69 4.72 -0.03 4 4.56 4.68 -0.12 8 4.29 4.24 0.05 12 3.87 4.23 -0.36 * * statistically significant Results: A composition containing 8% L-lactic acid and 0.25% retinyl palmitate, did not produce significantly more improvement to the skin of the ripple-type arm than 8% L-lactic acid in the same basic formulation. . In contrast, the same base formulation containing 8% L-lactic acid and 0.17% retinyl acetate produced a more clinically significant, significant improvement to curly-type skin, both by a physician's evaluation and forced choice ( the last results not shown here) with respect to 8% L-lactic acid in the same formulation base (p> 95% at week 8). In addition, the same base formulation contained 8% L-lactic acid and 0.075% retiiiol produced significantly more clinically determined improvement to curly-type skin by both clinical evaluation and forced choice on 8% L-lactic acid and 0.09% retinyl acetate in the same base formulation (p> 95% at week 12). In conclusion, retinyl palmitate did not increase the anti-wrinkle efficacy of a hydroxy acid formulation, whereas retinyl acetate did. Efficacy was further improved when retinol was used in place of reticulillo acetate, making retinol the most preferred retinol to be used in the present invention.

EXAMPLE 8 The following additional compositions were prepared within the scope of the invention. They were prepared by the method of the invention. They are suitable for cosmetic use. In particular, the compositions are suitable to be applied to wrinkled, lined, rough, dry, scaly, aged and / or UV-damaged skin, to improve the appearance and feel thereof, as well as the application to healthy skin to avoid or retard its deterioration.

COMPOSITION Ingredient Chemical Name / CTFA 8A 8B 8C% w / w% w / w% w / w Water DI Same 47.10 47.28 51.41 Disodium EDTA Equal 0.05 0.05 0.05 Veegum Ultra Silicate Aluminum-Magnesium 0.60 .0.60 0.60 Methylparaben Equal 0.15 0.15 0.15 Aloe Vera Powder Aloe Vera Gel 0.10 0.10 0.10 Triethanolamine (99%) Equal 1. .20 1. .20 1 .20 Antifoam Simethicone 0. .01 0, .01 0. .01 Glycerin Equal 2. .00 2. .00 2 .00 Butylene glycol Equal 3. .00 3, .00 3, .00 Keltrol CG1000 Xanthan gum 0, .20 0. .20 0, .20 Natrosol 250HHR Hydroxie i 1 cellulose 0, .30 0, .30 0. .50 Cleaning with water DI Same 1.00 1.00 1.00 SSL Pationic Sodium Stearyl Lactylate 0.50 Naturchem GMHS Hydroxystearate from gU Cerilo 1.50 1.50 1.50 Lanette 18 DEO Stearyl alcohol 1.50 1.50 1.50 Parsol MCX Octyl methoxycinnamate P-methoxycinnamate ethylhexyl 7.50 7.50 Univol M-40 Bt nzophenone-3-oxy-benzone 2.50 2.50 Finsolv TN • Cl2-15 alkyl benzoate 3.00 3.00 Protac em ISO-6,00 stearyl stearate Hetester FAO / Fine C12-L5 alkyl octonate 3.00 Silico-Dimethicone fluid 1.00 na 50 Cholesterol Equal 0.50 0.50 0.50 Arlacel 60 Sorbitan stearate 1.00 1.00 1.00 BHT Butylated hydroxytoluene 0.05 0.05 0.05 Acetate of Vitamin E Tocopheryl Acetate 0.10 0.10 0.10 Myrj 59 PEG-100 Stearate 2. 00 2. 00 2. 00 Pristerene 4911 Stearic Acid 3. . 00 3. 00 3. 00 Propylparaben Equal 0. . 10 0. 10 0. 10 Silicone fluid 10 Dimethicone 2.00 2.00 MEA of linoleamide Equal 1.00 1.00 Cleaning with water DI Equal 1.50 1.50 1.47 Water DI Same 8.00 8.00 8.29 Hydroxy caprylic acid Same 0.10 Glycolic acid 70% Equal 5.70 5.70 5.70 Ammonia, Aqua 28% Ammonium hydroxide 1.30 1.30 1.20 Cleaning with water DI Equal 1 .50 1 .50 2. .23 Palmitateate Palmitate of Vitamin A Retinyl 0. .10 0, .10 0, .10 Bisabolol Equal 0, .20 0, .20 0. .20 Fragrance Equal 0, .03 0. .03 0. .03 Retinol 50% Vitamin A alcohol 0. .20 0. .02 0. .20 Acetate of Vita¬ Acetate Retinyl mine A 0, .01 0. .01 Total 100.00 100.00 100.00

Claims (10)

1. A stable oil-in-water emulsion for a skin conditioning composition, the emulsion is characterized in that it comprises: (a) an oil phase comprising from 0.1% to 50% by weight of the emulsion, of oil droplets comprising a fluid oil and from 0.01% to 10% by weight of a retinoid emulsion selected from the group consisting of retinol, retinyl acetate, and retinyl propionate, wherein the retinoid is solubilized in the oil; (b) from 50% to 98% of an aqueous phase; and (c) from 1% to 20% by weight of an emulsion of the barrier ingredient, which comprises a crystal-forming compound and a glass sizing compound, wherein the barrier ingredient provides a crystalline barrier layer between the drops of oil and the aqueous phase. wherein the average size of an individual crystal in the barrier layer, as determined by the Microscopic Crystal Dimension Test, is in the range of lμm to 50μm; and wherein the size ratio of an individual oil drop to an individual crystal in the barrier layer is in the range of 5: 1 to 100: 1; and wherein the melting point of a mixture of the fluid oil and the barrier ingredient is in the range of 40 ° C to 100 ° C.

2. The emulsion in accordance with the claim 1, characterized in that the crystal-forming compound is selected from the group consisting of fatty acids of C-, 2"C 'mixtures of C12 ~ 22 fatty acids with their soaps, C12 fatty alcohols" c22"fatty acid ethoxylated derivatives of ^ i2_ < -22 fatty alcohols of ^ i2 ~ ^ 22 And their mixtures.

3. The emulsion according to claim 1 or 2, characterized in that the crystal sizing compound is selected from the group consisting of hydroxylated fatty acids, hydroxylated fatty alcohols, and ethoxylates and their derivatives, and mixtures thereof.

4. The emulsion according to any of claims 1-3, characterized in that the fluid oil is selected from the group consisting of isostearyl palmitate, tridecyl salicylate, C-1 octanoate, --S, -, I, - > , 'isopropyl stearate, isopropyl isomer and isopropyl palmitate.

5. The emulsion according to any of claims 1-4, characterized in that the retinoid is selected from the group consisting of retinol and retinyl acetate.

6. The emulsion according to any of claims 1-5, characterized in that the emulsion contains at least 40% water.

7. The emulsion according to any of claims 1-6, characterized in that the aqueous phase of the composition comprises an alpha hydroxy acid.

8. The emulsion according to any of claims 1-7, characterized in that the half-life of the composition at 50 ° C is at least 15 days.

9. The method for making a stable oil-in-water emulsion according to any of claims 1-8, the method is characterized in that it comprises: (i) preparing an aqueous phase and heating at the temperature in the range of 75 ° C to 80 ° C. ° C, while mixing; (ii) preparing a mixture containing fluid oil and barrier ingredient compounds, and heating the mixture to a temperature in the range of 75 ° C to 80 ° C, while mixing; (iii) slowly adding the mixture from step (ii) to the aqueous phase; (iv) mixing the mixture obtained in step (iii) for at least 15 minutes at a temperature in the range of 75 ° C to 80 ° C; (v) adding a retinoid after cooling the mixture obtained in step (iv) to a temperature in the range of 50 ° C to 55 ° C, while mixing; (vi) fill the storage container.

10. The method according to claim 9, characterized in that it comprises adding a hydroxy acid, after step iv, at a temperature in the range of 50 ° C