FR2964332A1 - Nanodispersion, useful for preparing e.g. pharmaceutical-, dermatological-, and parapharmaceutical- formulation, comprises a continuous oil phase having oil and stabilizing agent and a dispersed aqueous phase comprising water - Google Patents

Abstract

Nanodispersion comprises a continuous oil phase and a dispersed aqueous phase, where the aqueous phase comprises water and the oil phase comprises at least one oil and at least one stabilizing agent comprising non ionic or zwitterionic surfactants. An independent claim is included for a preparation of the nanodispersion comprising preparation of the oil phase containing oil and at least one stabilizing agent, preparation of the dispersed aqueous phase comprising water, adding the dispersed aqueous phase to the oil phase and mixing the aqueous phase and oil phase to obtain the nanodispersion and recovering the formed nanodispersion.

Description

Stable inverse nanodispersions

The present invention relates to stable reverse nanodispersions comprising a continuous oily phase and a dispersed aqueous phase, their preparation processes, as well as their uses in the cosmetic and pharmaceutical fields. Emulsions, that is to say the dispersion of a liquid in another in the form of droplets, are materials commonly used in a very large number of fields (food, cosmetics, pharmaceuticals, phytosanitary, glue and paint, ink, bitumen ...). The nature of the dispersed phase (also called discontinuous or internal) and that of the continuous phase (also known as external or dispersing) make it possible to define two types of emulsion: oil-in-water emulsions (O / W or O / W). for 'oil in water' in English) where the dispersed phase is lipophilic and the continuous phase hydrophilic; and the water-in-oil type emulsions (W / O or W / O for "water in oil" in English) where this time the dispersed phase is hydrophilic and the continuous phase is lipophilic. Recently the development of nano-sized emulsion (Mason TG, Wilking JN, Meleson K, et al., Nanoemulsions: formation, structure, and physical properties (vol 19, pg 079001, 2007) Journal of Physics-Condensed Matter) ( diameter less than 200 nm) has given these materials new properties: greater stability, optical transparency and better bioavailability. However, the majority of this work relates to oil-in-water emulsions. However, it is possible to describe the case of the inverse nanoemulsions used for the formation of polymer nanoparticles (Katharina Landfester, Mirjam Willert and Markus Antonietti, Macromolecules, 2000, 33 (7)). 2370-2376). In these systems, the hydrophilic monomers in aqueous solution are dispersed as droplets in a continuous lipophilic medium. The polymerization is then carried out within the reservoirs formed by the droplets. However, if the stability of these droplets is sufficient for the polymerization process, where the reverse nanoemulsion is finally only a time-limited step in the manufacturing process, it is different for products in which the inverse nanoemulsion constitutes part or all of the finished product.

Thus, it has been shown that reverse nanoemulsions are destabilized by Ostwald coalescence or ripening processes (Colloids and Surfaces A: Physicochemical and Engineering Aspects, Volume 249, Issues 1-3, 30 November 2004, Pages 115 -118, M. Porras, C. Solans, C. Gonzalez, A. Martinez, A. Guinart, JM Gutiérrez). In this work, the inverse nanoemulsions composed of water droplets in decane, stabilized with mixtures of Tween® and Span®, are rapidly destabilized. Thus, even the most advantageous formulations described in this document show an increase in the size of the drops over time from the first days after manufacture. In conclusion, despite significant potential, inverse nanoemulsions are not stable enough to be used as an ingredient or cosmetic product. So far there is a need for the preparation of stable and translucent reverse nanoemulsions. The present invention aims to provide stable and translucent reverse nanoemulsions. The present invention also aims to provide reverse nanoemulsions for incorporating hydrophilic active stably while increasing the viscosity and maintaining translucency. The present invention relates to a nanodispersion comprising a continuous oily phase and a dispersed aqueous phase, wherein said aqueous phase comprises water and said oily phase comprises at least one oil and at least one stabilizing agent selected from nonionic surfactants or zwitterionic. The term "nanodispersion" refers herein to a preparation wherein the aqueous phase is dispersed as nanoscale droplets in an oily continuous medium. The droplets can be solid or liquid at room temperature. The term "nanoemulsion" is also used. These nanodispersions (or nanoemulsions) are of water-in-oil type and thus comprise an aqueous phase (or dispersed phase) and an oily phase (or continuous phase). The nanodispersions according to the invention are in the form of a liquid that can be translucent, low viscosity and non-sticky. These dispersions are stable for several months and are not sensitive to the phenomenon of creaming and sedimentation.

The term "stabilizing agent" refers to a compound capable of stabilizing the interface between the dispersed phase and the continuous phase. The oily phase may also comprise a mixture of stabilizing agents. The term "surfactant" is understood to mean compounds with an amphiphilic structure which gives them a particular affinity for the oil / water and water / oil type interfaces, which gives them the capacity to lower the surface energy between the two non-aqueous phases. miscible and thus increases the kinetic stability of the dispersed systems. According to a preferred embodiment, the oily phase comprises a mixture of oils. Preferably, the oil or oils of the oily phase of the nanodispersions of the invention are chosen from oils having a surface tension greater than 19 mN / m, preferably greater than 25 mN / m. Preferred oils are selected from the group consisting of paraffin oil, petroleum jelly oil, hydrogenated polyisobutene (eg Parleam® or Luvitol® Lite), dodecane, decane, isododecane squalene, squalane, jojoba oil, fatty acid esters and silicone oils. Preferably, the nanodispersions according to the present invention comprise, in their oily phase, polyisobutene or liquid paraffin as an oil. According to a particular embodiment, the oily phase of the nanodispersions of the invention comprises from 0.01% to 50% by weight of stabilizing agent. The nanodispersions of the invention are characterized in that they preferably comprise from 1% to 50% by weight of aqueous phase and from 50% to 99% by weight of oily phase. According to a preferred embodiment, the nonionic or zwitterionic surfactants of the nanodispersions according to the invention are chosen from the group consisting of polyhydroxystearate esters, block copolymers of ethylene oxide and propylene oxide, esters or polyglycerol ethers and fatty acid ethers, polyoxyethylene and fatty acid esters or ethers, sucrose esters or ethers (sucroester), fatty acids, fatty alcohols, ceramides, esters or acid ethers and sorbitan, cholesterol and its derivatives, phospholipids, proteins and silicones modified with hydrophobic and hydrophilic groups.

More particularly, among the surfactants, there may be mentioned PEG-30 dipolyhydroxystearate (Arlacel® P135) and polyglyceryl diisostearate (Plurol® diisostearic). The nanodispersions according to the present invention may comprise several stabilizing agents in their oily phase. In this case, the oily phase comprises a stabilizing agent and a co-stabilizing agent. Preferably, in the nanodispersions according to the present invention, the oily phase comprises at least one co-stabilizing agent chosen from nonionic surfactants. The aqueous phase is composed of water to which can be added various additives such as dyes, stabilizers and preservatives, and / or modifying agents chosen from the agents of texture, viscosity, pH, osmotic force or refractive index modifiers. Thus, the aqueous phase preferably comprises by weight from 20% to 99.90% water (based on the total weight of the aqueous phase). According to a particular embodiment, in the nanodispersions according to the invention, the aqueous phase further comprises a thickening agent (or a mixture of thickeners) preferably chosen from the group consisting of glycerol, polymers, saccharides such as oligosaccharides and polysaccharides, gums and proteins. The preferred thickening agent according to the invention is glycerol. The aqueous phase of the nanodispersions according to the present invention advantageously comprises from 0 to 50% by weight, preferably from 0.1% to 30% by weight, and preferably from 1% to 20% by weight of thickening agent. Of course, the aqueous phase may further contain other additives such as colorants, stabilizers and preservatives in an appropriate amount. The aqueous phase for the dispersed phase of the emulsion can be prepared by simply mixing the various constituents with the chosen aqueous medium. According to another embodiment, the nanodispersions according to the present invention comprise an osmotic agent (or a mixture of osmotic agents) in their aqueous phase. Preferably, the osmotic agent is selected from the group consisting of inorganic and organic salts, polyelectrolytes, glycerol, glycerides and water-soluble polymers. As osmotic agent, there may be mentioned in particular sodium chloride and glycerol.

The aqueous phases of the nanodispersions according to the invention can also comprise a pH-controlling agent (or a mixture of agents controlling the pH). As a pH-controlling agent, mention may in particular be made of all the weak acids and bases for the manufacture of buffer solutions (citrate, phosphate, benzoate, trizma, acetate, carbonate, etc.), and more particularly the hydroxide of sodium and hydrochloric acid. According to a particular embodiment, the aqueous phase of the nanodispersions according to the invention further comprises a nonionic surfactant. Preferably, the nanodispersions of the invention comprise particles Io of aqueous phase having a particle size of less than 200 nm, and more particularly less than 50 nm. The nanodispersions according to the invention are homogeneous and characterized in that the mean particle diameter is from 1 nm to 200 nm, preferably from 10 nm to 100 nm, and preferably from 10 nm to 50 nm. The nanodispersions according to the invention are characterized in that they are translucent or transparent. The nanodispersions according to the invention may also comprise a compound that is active in the aqueous phase and / or in the oily phase, said active compound being chosen from therapeutic, cosmetic and perfume agents. Therapeutic, cosmetic and perfuming agents are selected from active agents well known to those skilled in the art. The nanodispersions according to the invention can therefore be used to prepare pharmaceutical, parapharmaceutical, dermatological, cosmetic and perfume compositions. The present invention also relates to the use of the aforementioned nanodispersions for the preparation of a pharmaceutical, parapharmaceutical, dermatological, cosmetic or perfume formulation. The present invention relates to a process for the preparation of the reverse nanoemulsions as defined above, comprising the following steps: a) preparation of the continuous oil phase comprising at least one oil and at least one stabilizing agent; b) preparing the dispersed aqueous phase comprising water; c) adding the dispersed aqueous phase to the continuous oily phase and mixing the aqueous and oily phases under the action of sufficient shear to obtain a nanodispersion; and d) recovering the nanodispersion thus formed. The oily phase is prepared from the stabilizing agent and the oil. This step is in particular carried out by mixing the various components. The aqueous phase is prepared from water and optional agents by mixing these different components. These two phases are mixed and homogenized and then harvested to obtain a nanodispersion. Advantageously, if one of the phases solidifies at room temperature, it is preferable to carry out the mixing with one or preferably the two phases Io heated to a temperature greater than or equal to the melting temperature. The nanodispersion as described can be readily prepared by dispersing appropriate amounts of oil phase and aqueous phase by shearing. The dispersion under the shearing effect is preferably carried out using a sonifier or a microfluidizer. According to a first embodiment, the oily phase and then the aqueous phase are introduced in the desired proportions into a suitable cylindrical container and the sonifier is then immersed in the medium and started for a sufficient time to obtain a nanodispersion, most often a few minutes. According to another method of preparation, the two phases are roughly premixed (mechanical stirring) before being injected into a high-pressure sonication or homogenization chamber. The dispersion can pass several times in these chambers in order to obtain the desired particle size.

EXAMPLES The procedure used is as follows: In a suitable container, the oily phase (continuous phase) was prepared by homogenization at 50 ° C. of the oil and of the stabilizing agent. In a second suitable container, the aqueous phase (dispersed phase) was prepared by homogenization at room temperature of any additives in the water as well as the various optional hydrophilic adjuvants (osmotic agent, thickener, preservative, etc.). The dispersed phase is added to the continuous phase either manually or by magnetic or turbine stirring. The two phases are roughly mixed and then the mixture is ultrasonically homogenized using devices such as the AV505® sonifier (Sonics, Newtown) for volumes below 200 g or IUP 1000hd (Hielsher, Germany) for volumes. more important. During sonication, the container containing the dispersion is thermostated. The mean diameter of the dispersed phase is determined by quasi-elastic light scattering (Zetasizer nano ZS, Malvern Instrument).

EXAMPLE 1 Compounds Mass% (mg) by weight Demineralized water (disperse phase) 0.139 6.95 Glycerol (osmotic agent) phase 0.050 2.50 dispersed Tris (buffering agent) 0.010 0.50 Sodium chloride (osmotic agent) 0.001 0, 05 Parleam® (oil - continuous phase) 1.550 77.50 Phase Arlacel® P135 (surfactant) 0.200 10.00 continuous Plurol® diisostearic (surfactant) 0.050 2.50 A stable stable nanodispersion is obtained with a droplet size of less than 50 nm. EXAMPLE 2 Compounds Mass% (mg) by mass Demineralized water (disperse phase) 0.119 5.95 Glycerol (osmotic agent) 0.050 2.50 Dispersed phase Tris (buffering agent) 0.010 0.50 Sodium chloride (osmotic agent) 0.001 0 , 05 Peptide (active) 0.020 1.00 Parleam® (oil - continuous phase) 1.550 77.50 Phase Arlacel® P135 (surfactant) 0.200 10.00 continuous Plurol® diisostearic (surfactant) 0.050 2.50 A stable stable nanodispersion is obtained whose drop size is less than 50 nm.

EXAMPLE 3 Compounds Mass% (mg) mass Demineralized water (dispersed phase) 0.161 8.05 Phase PEG 35000 (thickening agent) 0.018 0.89 dispersed Sodium hydroxide (pH control) 0.002 0.08 PreventhaliaTM (peptide) (active) 0.020 0.98 Parleam® (oil - continuous phase) 1.550 77.50 Phase Arlacel® P135 (surfactant) 0.200 10.00 continuous Plurol® diisostearic (surfactant) 0.050 2.50 A stable, transparent nanodispersion is obtained whose drop size is less than 50 nm.

EXAMPLE 4 Compounds Mass% (mg) mass Phase Demineralized water (dispersed phase) 9,000 9.00 dispersed Sodium ascorbyl phosphate (active) 1,000 1.00 Luvitol® Lite (oil - continuous phase) 77.50 77.50 Phase Arlacel® P135 (surfactant) 10.00 10.00 continuous Plurol® diisostearic (surfactant) 2.500 2.50 85 A stable stable nanodispersion is obtained with a droplet size of less than 50 nm.

EXAMPLE 5 Compounds Mass% (mg) mass Phase Demineralized water (dispersed phase) 9.890 9.89 dispersed Peptide (active) 0.100 0.10 Parleam® (oil - continuous phase) 75.010 75.01 Phase Arlacel® P135 (surfactant) 10, 00 12.50 continues Phospholipon® 75 (surfactant) 2.500 2.50 A stable stable nanodispersion is obtained with a droplet size of less than 50 nm.

EXAMPLE 6 Compounds Mass% (mg) by mass Demineralized water (dispersed phase) 1,730 8.65 Dispersed phase Sodium chloride (osmotic agent) 0.070 0.35 Hyaluronic acid (active) 0.200 1.00 Codex oil AAB2 (continuous phase) 14.100 70.50 Phase Parleam®V (oil - continuous phase) 1,400 7,00 continuous Arlacel® P135 (surfactant) 2,000 10.00 Plurol® diisostearic (surfactant) 0,500 2,50 A transparent stable nanodispersion is obtained whose drop size is less than 50 nm. 15

Claims (14)

REVENDICATIONS1. A nanodispersion comprising a continuous oily phase and a dispersed aqueous phase, wherein said aqueous phase comprises water and said oily phase comprises at least one oil and at least one stabilizing agent selected from nonionic or zwitterionic surfactants. 2. Nanodispersion according to claim 1, characterized in that it comprises particles of aqueous phase having a particle size of less than 200 nm. The nanodispersion according to claim 1 or 2, wherein the oil is selected from oils having a surface tension greater than 19 mN / m, preferably greater than 25 mN / m. The nanodispersion according to any one of claims 1 to 3, wherein the oil is selected from the group consisting of paraffin oil, petroleum jelly, hydrogenated polyisobutene, dodecane, decane, Isododecane, squalene, squalane, jojoba oil, fatty acid esters and silicones. The nanodispersion according to any of claims 1 to 4, wherein the nonionic or zwitterionic surfactants are selected from the group consisting of polyhydroxystearate esters, ethylene oxide and propylene oxide block copolymers. polyglycerol and fatty acid esters or ethers, polyoxyethylene and fatty acid esters or ethers, sucrose esters or ethers (sucroester), fatty acids, fatty alcohols, ceramides, esters or ethers fatty acid and sorbitan, cholesterol and its derivatives, phospholipids, proteins and silicones modified with hydrophobic and hydrophilic groups. The nanodispersion according to any one of claims 1 to 5, wherein the oily phase comprises at least one co-stabilizing agent selected from nonionic surfactants. Io 30 35 The nanodispersion of any one of claims 1 to 6, wherein the aqueous phase comprises an osmotic agent. The nanodispersion of claim 7, wherein the osmotic agent is selected from the group consisting of inorganic and organic salts, polyelectrolytes, glycerol, glycerides, and water-soluble polymers. The nanodispersion according to any of claims 1 to 8, wherein the aqueous phase comprises a pH controlling agent. The nanodispersion according to any of claims 1 to 9, wherein the aqueous phase comprises a nonionic surfactant. The nanodispersion according to any one of claims 1 to 10, wherein the aqueous phase further comprises a thickening agent preferably selected from the group consisting of glycerol, polymers, saccharides, gums and proteins. 12. Nanodispersion according to any one of claims 1 to 11, further comprising a compound active in the aqueous phase and / or in the oily phase, said active compound being selected from therapeutic agents, cosmetics and perfumes. 13. Use of a nanodispersion according to claim 12 for the preparation of a pharmaceutical, dermatological, parapharmaceutical, cosmetic or perfume formulation. 14. Process for the preparation of a nanodispersion according to any one of claims 1 to 12, comprising the following steps: e) preparation of the continuous oily phase comprising at least one oil and at least one stabilizing agent; f) preparing the dispersed aqueous phase comprising water; g) adding the dispersed aqueous phase to the continuous oily phase and mixing the aqueous and oily phases under the action of shear sufficient to obtain a nanodispersion; and h) recovering the nanodispersion thus formed.