EP2167053A2

EP2167053A2 - Nanocapsules with liquid lipidic core loaded with water-soluble or water-dispersible ingredient(s)

Info

Publication number: EP2167053A2
Application number: EP08805977A
Authority: EP
Inventors: Patrick Saulnier; Jean-Pierre Benoit; Nicolas Anton
Original assignee: Universite dAngers
Current assignee: Universite dAngers; Institut National de la Sante et de la Recherche Medicale INSERM
Priority date: 2007-06-11
Filing date: 2008-06-11
Publication date: 2010-03-31
Also published as: FR2916973B1; WO2009001019A2; CA2690471A1; FR2916973A1; WO2009001019A3; US9333180B2; US20100266676A1

Abstract

The invention relates to nanocapsules with a liquid lipidic core and a solid lipidic shell, the lipidic core being loaded with at least one water-soluble or water-dispersible ingredient, said ingredient being present in the form of a reverse micellar system.

Description

Water-soluble or water-dispersible liquid lipid core nanocapsules (actiffs)

The present invention aims at providing nanocapsules with a liquid lipid core loaded with active agents at this core into at least one water-soluble or water-dispersible active agent.

Nanovesicular systems, of nanocapsule or nanodroplet type whose size varies from 50 to 500 nanometers and formed of a liquid or solid core, surrounded by a hydrophobic outer membrane, are already known. The constituents of their membrane may be synthetic, for example of polymeric, protein or lipid nature like liposomes. For example, liposomes which have a lamellar structure formed of a stack of lipid layers separated from one another by aqueous compartments always have an aqueous core.

These nano-metric structures have also already been proposed for the purpose of encapsulating active agents either in their aqueous core when the active agent is water-soluble or water-dispersible, or in their lipid layer when the active ingredient is liposoluble or lipodispersible.

For example, US Pat. No. 5,961,970 proposes, as an active agent, submicron-scale oil-in-water emulsions, that is to say mini-emulsions whose droplets have a hydrophobic core of lipidic nature and are stabilized. at the surface by amphiphilic and / or nonionic surfactants, like phospho lipid-type surfactants. These droplets are thus kept in suspension in an aqueous phase. This type of submicron emulsion is obtained from a base emulsion by subjecting it to several successive cycles of homogenization under high shear.

US Patent 5,576,016 describes macroemulsions whose droplets are formed of a solid lipid core and which are stabilized by a phospholipid envelope. This phospholipid envelope has a lamellar structure formed of one or more layers of phospholipid molecules like liposomes. A highly hydrophobic active agent can be loaded at the core and a water-soluble active agent can be incorporated into the aqueous compartments present in the phospholipid envelope.

Furthermore, the inventors have also described in the patent EP 1 265 698 as a vehicle of liposoluble or lipodispersible active ingredients, nanocapsules with a liquid heart and solid bark of lipid nature and an original technology to access it. More precisely, these nanocapsules are obtained from a microemulsion, this microemulsion being prepared by the thermal phase inversion technique (PIT emulsion).

The principle of emulsification by phase inversion in temperature (English: Phase Inversion Temperature or PIT) is well known to those skilled in the art; it has been described in 1968 by K. Shinoda (J. Chem Soc Jpn., 1968, 89, 435). It has been shown that this emulsification technique makes it possible to obtain stable fine emulsions (K. Shinoda and H. Saito, J. Colloid Interface ScL, 1969, 30, 258).

The principle of this technique is as follows: an emulsion, for example W / O, is prepared at a temperature which must be greater than the phase inversion temperature of the system, ie the temperature at which the equilibrium between the hydrophilic and lipophilic properties of the surfactant system used is achieved. At high temperature, ie above the phase inversion temperature (> PIT), the emulsion is of the water-in-oil type, and during its cooling, this emulsion is reversed. at the phase inversion temperature, to become an oil-in-water type emulsion, and this having previously passed through a microemulsion state. This technique notably makes it possible to access an average size of the globules constituting the oily phase ranging from 0.1 to 4 μm (100 to 4000 nm).

However, the nanocapsules thus obtained are only proposed for the purpose of encapsulation, within their oily heart, of lipophilic or lipodispersible active agents. However, for obvious reasons, it would be advantageous to also take advantage of these nanocapsules for the encapsulation of water-soluble or water-dispersible actives.

For the purposes of the present invention, the water-dispersible active agent is advantageously a non-lipophilic active agent.

The present invention aims precisely to propose a solution for performing this type of encapsulation.

More precisely, the present invention aims, according to a first aspect, with nanocapsules having a liquid lipid core and solid lipid shell and loaded within their lipid core with at least one water-soluble or water-dispersible active agent, said active being incorporated therein in the form of of a reverse micellar system. According to another of its aspects, the present invention relates to a method useful for preparing nanocapsules with liquid lipid core and solid lipid shell and loaded at their lipid core into at least one water-soluble or water-dispersible active agent, said process comprising at least the steps comprising: disposing of an oil-in-water emulsion containing at least one water-soluble or water-dispersible active agent in the form of a reverse micellar system and at least one surfactant system containing at least one thermosensitive, nonionic and hydrophilic surfactant, and if necessary a lipophilic surfactant increase its temperature to a temperature T ₂ greater than its phase inversion temperature (TIP) to obtain a water-in-oil emulsion followed by a decrease in temperature to a temperature T ₁ , Ti <TIP <T ₂ to obtain an oil-in-water emulsion again, carry out one or more temperature cycles around the phase inversion zone between Ti and T ₂ , and stabilizing said system at a temperature in or near the phase inversion to form the expected microemulsion, and quenching said microemulsion to obtain nanocapsules formed of a lipid core liquid at room temperature coated with a lipidic bark solid at room temperature and comprising said active ingredient in the form of a reverse micellar system.

The present invention results more particularly from the observation by the inventors that, against all odds, an oil-in-water emulsion containing at least one water-soluble or water-dispersible active agent in the form of an inverse micellar system proves capable of forming, when it imposes at least a phase inversion operation temperature, a microemulsion whose quenching leads to the formation of nanocapsules containing within their lipid core micelles water soluble or hydrodispersible assets. Surprisingly, the progress of all the steps required to obtain the expected nanocapsules does not affect the stability of the reverse micellar system of the water-soluble or water-dispersible active. Active

For the purposes of the invention, the expression "reverse micellar system of water-soluble or water-dispersible active" designates an architecture in which the water-soluble or water-dispersible active agents are stabilized in an oily phase by means of the molecules of the surfactant or of the surfactant system forming the micellar system containing the active.

Reverse micelle systems are well known to those skilled in the art and in particular exploited to carry out selective extractions of proteins or enzymes of interest.

For obvious reasons, the choice of the surfactant system used to form the reverse micellar system must be carried out taking into account the solubility of the surfactant (s) forming it in the oily phase of the oil-in-water emulsion in which the asset is precisely intended to be formulated. This selection is clearly within the skill of those skilled in the art.

Advantageously, the surfactants used to develop these reverse micelles and suitable for the invention have an HLB value of less than 10, in particular less than or equal to 6. They may indifferently belong to the families of ionic, nonionic or amphoteric surfactants.

These surfactants may be used in an active (s) / surfactant (s) weight ratio ranging from 0.01 to 0.3 and in particular from 0.05 to 0.1.

Advantageously, these surfactants may be combined with co-surfactants such as, for example, phospholipids. As such, phosphatidylcholines (lecithin) are particularly interesting.

Other phospholipids suitable for the invention may be phosphatidylglycerol, phosphatidylinositol, phosphatidylserine, phosphatidic acid and phosphatidylethanolamine.

The reverse micellar system containing the water-soluble or water-dispersible active agent to be encapsulated is prepared before it is brought into contact with the emulsion so as to stabilize the inverse micelles in the oil. This oily micellar suspension is then either incorporated at the beginning of the formulation before the thermal cycling (s) or else, added once the system is in its microemulsion form, that is to say in the phase inversion zone. of the emulsified system.

For example, they can be prepared as follows:

A hydrophilic active agent, for example sodium fluororescein crystals, is incorporated under heating at 50 ^° C. and with stirring in an oily phase, for example Labrafac containing inverse micelles of a surfactant such as Span ^80® (10%). w / w).

By way of nonlimiting illustration, water-soluble or water-dispersible active agents that can be encapsulated according to the invention include 5-fluorouracil, gemcitabine, doxorubicin and low molecular weight heparins.

In addition to this water-soluble or water-dispersible active ingredient encapsulated in their lipid core, the nanocapsules can of course contain other water-soluble active agents adsorbed on their bark or other liposoluble active agents encapsulated in their lipid core.

For the purposes of the invention, the term "adsorbed" means that the active ingredient is incorporated within the bark. This adsorption phenomenon is to be distinguished from a simple covalent bond established between a function present on said active agent and a function present on the surface of the bark of the nanocapsules.

The active agent may especially be a pharmaceutically active compound, cosmetically active or still active in a phytosanitary or food field.

According to a preferred embodiment, this active ingredient is a pharmaceutically active ingredient.

In general, the nanocapsules of the invention are more particularly suitable for the administration of the following active principles: anti-infectives including antimycotics, antibiotics, anticancer drugs, immunosuppressants, active principles for the Central Nervous System who must pass the blood-brain barrier, such as anti-Parkinson's, analgesics and more generally the active ingredients for treating neurodegenerative diseases.

Such an active ingredient may also be of protein or peptide nature. It may also be nucleic acids such as a DNA plasmid or an interference RNA. The asset can also be a radiopharmaceutical. It can also be a gas or a fluid that can turn into gas.

Emulsion and Microemulsion

First of all, it is important to note that a microemulsion is different from a miniemulsion and a macroemulsion, such as illustrated in US Pat. Nos. 5,961,971 and 5,576,016. In fact, a microemulsion corresponds to a bicontinuous structuring of the material in the form of micellar structures swollen with oil or water. These micellar structures are strongly intertwined with each other and thus constitute a cohesive and stabilized homogeneous three-dimensional network. It is thus impossible to distinguish a dispersed phase from a continuous phase. This microemulsion is in thermodynamic equilibrium and therefore can only exist under very precise conditions of temperature, pressure and composition.

The starting emulsion intended to form the microemulsion may comprise at least one oily fatty phase, an aqueous phase and a surfactant system comprising at least one heat-sensitive, hydrophilic and nonionic surfactant and, where appropriate, according to a preferred embodiment, a lipophilic surfactant.

a-Oily fatty phase

The oily fatty phase is formed of at least one liquid or semi-liquid fatty substance at ambient temperature, and in particular at least one triglyceride, a fatty acid ester, or a mixture thereof.

The fatty acid ester may more particularly be chosen from C 8 to C ₁₈ fatty acid esters, in particular C ₈ to C ₁₂ fatty acid esters, and in particular ethyl palmitate, ethyl oleate or myristate. ethyl, isopropyl myristate, octydodecyl myristate and mixtures thereof.

The triglycerides used may be synthetic triglycerides or triglycerides of natural origin. Natural sources may include animal fats or vegetable oils eg soybean oils or sources of long chain triglycerides (LCTs).

Other triglycerides of interest are composed mainly of medium length fatty acids also called medium chain triglycerides (MCT). An oil to Medium chain triglycerides (MCT) is a triglyceride in which the carbohydrate chain has from 8 to 12 carbon atoms.

Such MCT oils are commercially available.

By way of example of these MCT oils, mention may be made of the TCRs (trade name of the industrial oilseeds company, France, for a mixture of triglycerides in which about 95% of the fatty acid chains have 8 or 10 carbon atoms. ) and Myglyol ^® 812 (triglyceride marketed by Dynamit Nobel, Sweden for a mixture of triesters of caprylic and capric acid glycerides).

The fatty acid units of these triglycerides may be unsaturated, monounsaturated or polyunsaturated. Mixtures of triglycerides with variable fatty acid units are also acceptable.

It should be noted that the higher the HLB index of the liquid or semi-liquid fatty substance, the higher the phase inversion temperature. On the other hand, the value of the HLB index of the fatty substance does not seem to have any influence on the size of the nanocapsules.

Thus, as the size of the end groups of the triglycerides increases, their HLB index decreases and the phase inversion temperature decreases.

The HLB index or hydrophilic-lipophilic balance is as defined by C. Larpent in the K.342 Treaty of TECHNIQUES DE L'INGENIEUR.

Particularly suitable for the invention, the triglyceride sold under the name Labrafac WL 1349 ^®.

b-Surfactant system

This surfactant system comprises at least one thermosensitive surfactant, hydrophilic and nonionic, which may be associated with a lipophilic surfactant.

According to a preferred embodiment, the surfactant system used in the claimed process is formed only of hydrophilic (s) and nonionic (s) heat-sensitive surfactant (s).

The hydrophilic surfactant is more particularly chosen from the usual oil-in-water emulsifying surfactants which have a HLB (HLB = Hydrophilic Lipophilic Balance) ranging from 8 to 18. These emulsifiers, thanks to their amphiphilic structure, are placed in the water. oily phase / aqueous phase interface, and thus stabilize the dispersed oil droplets. The surfactant system used in the microemulsion may comprise one or more surfactants whose solubility in the oil increases with increasing temperature. The HLB of these surfactants can vary from 8 to 18, and preferably from 10 to 16, and these surfactants can be chosen from ethoxylated fatty alcohols, ethoxylated fatty acids, partial glycerides of ethoxylated fatty acids, triglycerides of polyethoxylated fatty acids, and mixtures thereof.

As ethoxylated fatty alcohols, mention may be made, for example, of ethylene oxide adducts with lauryl alcohol, especially those containing from 9 to 50 oxyethylenated groups (Laureth-9 to Laureth-50 in CTFA names); adducts of ethylene oxide with behenyl alcohol, in particular those containing from 9 to 50 oxyethylenated groups (Beheneth-9 to Beheneth-50 in CTFA names); adducts of ethylene oxide with keto-stearyl alcohol (mixture of cetyl alcohol and stearyl alcohol), in particular those containing from 9 to 30 oxyethylenated groups (Ceteareth-9 to Ceteareth-30 in names) CTFA); adducts of ethylene oxide with cetyl alcohol, especially those containing from 9 to 30 oxyethylenated groups (Ceteth-9 to Ceteth- in CTFA names); adducts of ethylene oxide with stearyl alcohol, especially those containing from 9 to 30 oxyethylenated groups (Steareth-9 to Steareth-30 in CTFA names); adducts of ethylene oxide with isostearyl alcohol, especially those containing from 9 to 50 oxyethylenated groups (Isosteareth-9 to Isosteareth-50 in CTFA names); and their mixtures.

As ethoxylated fatty acids, mention may be made, for example, of ethylene oxide adducts with lauric, palmitic, stearic or behenic acids, and mixtures thereof, in particular those comprising from 9 to 50 oxyethylenated groups such as laurates of PEG-9 to PEG-50 (CTFA names: PEG-9 laurate to PEG-50 laurate); palmitates of PEG-9 to PEG-50 (in CTFA names: PEG-9 palmitate to PEG-50 palmitate); stearates from PEG-9 to PEG-50 (CTFA names: PEG-9 stearate PEG-50 stearate); palmitostearate from PEG-9 to PEG-50; behenates from PEG-9 to PEG-50 (in CTFA names: PEG-9 behenate to PEG-50 behenate); and their mixtures.

Mixtures of these oxyethylenated derivatives of fatty alcohols and fatty acids can also be used.

These surfactants can also be either natural compounds such as echolate phospholipids or synthetic compounds such as polysorbates which are fatty acid esters of polyethoxylated sorbitol (Tween ^®), polyethylene glycol fatty acid esters eg from castor oil (Cremophor ^®), polyethoxylated fatty acids, eg stearic acid (Simulsol M-53 ^®), fatty alcohol ethers polyoxyethylene (Brij ^®), polyoxyethylene nonphenyl ethers (Triton ^® N) of hydroxylphényle polyoxyethylene ethers (Triton ^® X).

It can especially be a 2-hydroxystearate polyethylene glycol and in particular that marketed under the name Solutol ^® HS 15 by BASF (Germany).

As specified above, the surfactant system selected according to the invention advantageously comprises, besides the heat-sensitive, hydrophilic and non-ionic surfactant, at least one lipophilic surfactant.

The lipophilic surfactant is more particularly based on phospholipids which are advantageous in view of their biocompatible nature.

Of the phospholipids, phosphatidylcholines (lecithin) are particularly interesting.

Other phospholipids may be phosphatidylglycerol, phosphatidylinositol, phosphatidylserine, phosphatidic acid and phosphatidylethanolamine.

Phospholipid derivatives can be isolated from natural sources or synthetically prepared.

As commercial products derived from phospholipids, mention may be made more particularly of:

- the EPICURON 120 ^® (Lukas Meyer, Germany) which is a mixture of about 70% phosphatidylcholine, 12% phosphatidylethanolamine and about 15% other phospholipids;

- VO VOTINE 160 ^® (Lukas Meyer, Germany) which is a mixture comprising about 60% phosphatidylcholine, 18% phosphatidylethanolamine and 12% other phospholipids,

- a mixture of purified phospholipids in the image of Lipoid E75 products or Lipoïds E-80 (Lipoid ^®, Germany) which is a phospholipid mixture comprising about 80% by weight phosphatidylcholine, 8% by weight of phosphatidylethanolamine, 3.6 % by weight of non-polar lipids and 2% of sphingomyelin. According to a preferred embodiment, the lipophilic surfactant is a lecithin whose proportion of phosphatidylcholine ranges from 40 to 80% by weight.

Particularly suitable as a source of phosphatidylcholine is Lipoid S75-3 (Lipoid ^® GmbH, Germany). This is soy lecithin. The latter contains about 69% phosphatidylcholine and 9% phosphatidylethanolamine. This component is the only solid component at 37 ° and at room temperature in the formulation.

One can also use polyglyceryl-6-dioleate (Plurol ^®).

The ratio of liquid fatty substance / lipid surfactant (s) may vary from 1 to 15, preferably from 1.5 to 13, more preferably from 3 to 8.

It should be noted that the particle size decreases when the proportion of hydrophilic surfactant increases and when the proportion of surfactants (hydrophilic and optionally lipophilic) increases. Indeed, the surfactant causes a decrease in the interfacial tension and thus a stabilization of the system which promotes the obtaining of small particles.

On the other hand, particle size increases as the proportion of oil increases.

For its part, the aqueous phase of the microemulsion may also advantageously contain 1 to 4% of a particularly inorganic salt, such as sodium chloride. Indeed, the modification of the salt concentration causes a displacement of the phase inversion zone. Thus, the higher the salt concentration, the lower the phase inversion temperature. This phenomenon is particularly interesting for the encapsulation of hydrophobic thermosensitive active ingredients.

According to a particular embodiment, the microemulsion advantageously contains from 1 to 3% of lipophilic surfactant (s), from 5 to 15% of hydrophilic surfactant (s), from 5 to 15% of an oily phase, from 64 to 89% of an aqueous phase (the percentages are expressed by weight relative to the total weight of the microemulsion).

According to one embodiment, a microemulsion of the invention may be formed of at least one fatty acid triglyceride and a 2-hydroxysterate derivative of polyethylene glycol, and optionally a lecithin. In a preferred embodiment, the fatty phase is a fatty acid triglyceride, the lipophilic surfactant is a lecithin and the hydrophilic surfactant is a derivative of 2-hydroxystearate polyethylene glycol and in particular Solutol ^® HS 15.

As specified above, the emulsion considered according to the invention is converted into a microemulsion according to the phase inversion technique, in particular by temperature change.

This phase inversion in temperature is advantageously caused by imposing at least one cycle of rise and fall in temperature to the emulsion.

The repetition of temperature cycles is advantageous for several reasons. Thus, it has been found that during the temperature cycles, the bark of the nanoparticles which form after dipping advantageously gains in thickness and therefore in stability.

In addition, it should be noted that the temperature of the phase inversion zone tends to decrease as and when the temperature cycles imposed. This phenomenon is precisely advantageous when the asset that it is desired to encapsulate or adsorb is a temperature-sensitive asset. Under such conditions, it is preferred to introduce the asset at the time of a temperature-compatible cycle.

More specifically, it is imposed on the emulsion considered according to the invention and before quenching to form the charged nanocapsules in at least one hydrophilic active agent, at least the steps of increasing its temperature to a temperature T ₂ greater than its phase inversion temperature (TIP) to obtain a water-in-oil emulsion followed by a decrease in temperature to a temperature T ₁ , Ti <TIP <T ₂ to obtain an oil-in-oil emulsion again water, if appropriate, perform one or more temperature cycles around the phase inversion zone between Ti and T ₂ and stabilize said system at a temperature located in or near the vicinity of the phase inversion to form the microemulsion expected.

Thus, it is advantageous to carry out one or more temperature cycles around the phase inversion zone between Ti and T ₂ , until a translucent suspension is observed, which corresponds to the formation of a microemulsion. The system is then stabilized at a temperature which corresponds to the structure of the system in the expected microemulsion. Specifically, the phase inversion between the oil / water emulsion and the water / oil emulsion results in a decrease in conductivity as the temperature increases until it vanishes.

Thus, Ti is a temperature at which the conductivity is at least 90 - 95% of the conductivity measured at 20 ⁰ C and T ₂ is the temperature at which the conductivity vanishes and the water-in-oil emulsion is formed. The average temperature of the phase inversion zone corresponds to the phase inversion temperature (TIP).

In the formation zone of a microemulsion (translucent mixture), the hydrophilic and hydrophobic interactions are balanced because the tendency of the surfactant system is to form both direct micelles and inverse micelles. By heating beyond this zone, an W / O emulsion (opaque white mixture) is formed, since the surfactant promotes the formation of a water-in-oil emulsion. Then during cooling below the phase inversion zone, the emulsion becomes an O / W emulsion.

The number of cycles applied to the microemulsion depends on the amount of energy required to form the nanocapsules.

This technology is more particularly described in patent EP 1 265 698, the content of which is incorporated in the present application.

Thus, all the constituents intended to form the microemulsion are weighed in a container. The mixture is homogenized, for example by means of a Rayneri 350 rpm, and heated by progressively increasing the temperature by means of a water bath to a temperature greater than or equal to the T2 phase inversion temperature, that is to say until a transparent or translucent phase is obtained (zone of microemulsion or lamellar phase) then of a more viscous white phase which indicates the obtaining of the inverse emulsion (E / H). The heating is then stopped and the stirring maintained until it returns to ambient temperature, via the phase inversion temperature T1, that is to say the temperature at which the expected microemulsion is formed. When the temperature has fallen below the zone of inversion of Phase in Temperature (Tl), one obtains this stable microemulsion.

The microemulsion having formed subsequently undergoes quenching according to the invention. This step intended to form the nanocapsules according to the invention consists in an abrupt cooling (or quenching) of the microemulsion at a temperature conducive to the solidification of the interfacial films comprising the microemulsion, advantageously at a temperature much lower than T1 under magnetic stirring.

For example, quenching said microemulsion loaded at least said active at a temperature at least 30 ⁰ C below the TIP at the time of soaking.

This quenching can be carried out by diluting the medium 3 to 10 times with deionized water at 20 ^° C +/- 1 ^° C., which is thrown into the fine microemulsion. The nanocapsules obtained are stirred for 5 minutes.

The organization of the system in the form of nanocapsules after soaking is reflected visually by a change of appearance of the initial system which changes from opaque white to translucent white with Tyndall effect (bluish tints). This change occurs at a temperature below the TIP. This temperature is generally between 6 to 15 ⁰ C below the TIP.

At the end of the process according to the invention, nanocapsules loaded at their lipid core into at least one water-soluble active agent are obtained.

For the purposes of the invention, the term nanocapsules is to be distinguished from nanospheres. Nanocapsules are understood to mean particles consisting of a liquid or semi-liquid core at ambient temperature, coated with a solid film at ambient temperature, as opposed to nanospheres which are matrix particles, ie whose whole mass is solid. . Thus, when the nanospheres contain a pharmaceutically active principle, it is finely dispersed in the solid matrix.

Advantageously, the nanocapsules obtained according to the invention have a mean size of less than 150 nm, preferably less than 100 nm, more preferably less than 50 nm. These sizes can be determined by photon correlation spectroscopy, scanning electron microscopy, transmission electron microscopy in cryoscopic mode.

The thickness of the solid film or bark is advantageously between 2 and 10 nm. It is equal to about one-tenth of the diameter of the particles. This thickness can be calculated by mass balance, or visualized by transmission electron microscopy. Negative shading or else by transmission electron microscopy in cryoscopic mode.

Given their size, the nanocapsules of the invention are colloidal lipid particles.

The polydispersity index of the nanocapsules of the invention is advantageously between 5 and 15%. This index is determined on the size histogram obtained by photon correlation spectroscopy method.

The nanocapsules are each composed of a substantially liquid or semi-liquid lipid core at room temperature, coated with a substantially lipidic bark solid at room temperature.

For the purposes of the invention, the expression "essentially lipidic" means that the core and the bark forming the nanocapsules according to the invention consist of more than 50% by weight, in particular more than 75% by weight, in particular more than 80% by weight, or even more than 90%, more particularly more than 95% of their respective weight, or even all of one or more lipid compounds (hydrophobic).

According to one embodiment, a nanocapsule according to the invention may comprise a bark formed of at least one solid lipophilic surfactant at room temperature.

The nanocapsules according to the invention are particularly advantageous as an asset formulation vehicle. For example, these nanocapsules may be useful for the manufacture of phytosanitary or pharmaceutical compositions.

The present invention also provides compositions containing nanocapsules according to the invention.

For the purposes of the invention, the expression "ambient temperature" designates a temperature ranging from 18 to 25 ^° C.

The present invention is illustrated by the following examples which are presented by way of nonlimiting illustration of the field of the invention. Example 1 Preparation of nanocapsules whose lipid core is loaded into a water-soluble active agent

Is carried out 5 g of an emulsion containing 75 mg of Lipoid ^® S75-3, 504 mg of Labrafac WL 1349 lipophilic ^®, 504 mg of Solutol ^® HS 15.383 g of water and 88 mg of sodium chloride.

At the same time, sodium fluorescein crystals (10 mg) are incorporated under heating at 50 ^° C. and with stirring in Labrafac (3 g) containing inverse micelles of Span 80 (0.6 g) (20% w / w). .

After homogenization of this micellar suspension, 0.25 ml are introduced into the preceding emulsion.

The whole is placed under magnetic stirring. Heating is applied until a temperature of 85 ^° C. is reached. With magnetic stirring, the system is allowed to cool down to a temperature of 60 ^° C. These thermal cycles (between 85 ^° C. and 60 ^° C.) are carried out. three times in order to obtain better and better structured microemulsions. The system is then maintained in its microemulsion form by stabilizing it at a temperature included in (or in the near vicinity) of the Phase Inversion Zone, in this case 65 ^° C.

The nanocapsules are finalized by dipping in cold water (5 ⁰ C). The nanocapsules are separated from the medium by centrifugation.

Claims

1. Nanocapsules with liquid lipid core and solid lipid bark and loaded within their lipid core in at least one water-soluble or water-dispersible active agent, said active being present in the form of a reverse micelle system.

2. Nanocapsules according to the preceding claim, wherein the reverse micellar system comprises a surfactant system formed of at least one surfactant having an HLB of less than 10.

3. Nanocapsules according to the preceding claim, wherein the surfactant system is implemented in an active (s) / surfactant (s) weight ratio ranging from 0.01 to 0.3 and in particular from 0.05 to 0.1. .

4. Nanocapsules according to any one of the preceding claims, the core of which is formed of at least one liquid or semi-liquid fatty substance.

5. Nanocapsules according to any preceding claim, wherein the core comprises at least one triglyceride, a fatty acid ester, or a mixture thereof.

6. Nanocapsules according to any preceding claim, wherein the bark is formed of at least one lipophilic surfactant solid at room temperature.

7. Nanocapsules according to the preceding claim, wherein the lipophilic surfactant is based on phospho lipid, and in particular is a lecithin whose proportion of phosphatidylcholine is between 40 and 80% by weight.

8. Nanocapsules according to claim 6 or 7, wherein the ratio of liquid fatty substance / lipophilic surfactant ranges from 1 to 15, in particular from 1.5 to 13 and more particularly from 3 to 8.

9. Nanocapsules according to any one of the preceding claims, having a mean size of less than 150 nm, especially less than 100 nm and more particularly less than 50 nm.

10. Nanocapsules according to any one of the preceding claims, having a solid bark thickness ranging from 2 to 10 nm.

11. Nanocapsules according to any one of the preceding claims, wherein the active ingredient is a pharmaceutically active compound, cosmetically active or active in a phytosanitary or food field.

12. Process useful for the preparation of nanocapsules with liquid lipid core and solid lipid bark and loaded at the level of their lipid core into at least one water-soluble or water-dispersible active agent, said process comprising at least the steps of: disposing of an oil emulsion in water, containing at least one water-soluble or water-dispersible active agent in the form of a reverse micellar system and at least one surfactant system containing at least one heat-sensitive, nonionic and hydrophilic surfactant, increasing its temperature to a temperature T ₂ greater than its phase inversion temperature (TIP) to obtain a water-in-oil emulsion followed by a decrease in temperature to a temperature T ₁ , Ti <TIP <T ₂ to obtain an oil emulsion again in water, if necessary, carry out one or more temperature cycles around the phase inversion zone between Ti and T ₂ , stabilize said system at a temperature of ature located in or near the vicinity of the phase inversion to form the expected microemulsion, and quenching said microemulsion, so as to obtain nanocapsules formed of a lipid core liquid at room temperature coated with a solid lipidic bark at room temperature, and containing said active in the form of a reverse micellar system.

13. Method according to the preceding claim, wherein the hydrophilic surfactant has an HLB ranging from 8 to 18, in particular from 10 to 16.

The method of claim 12 or 13, wherein the hydrophilic surfactant is selected from ethoxylated fatty alcohols, ethoxylated fatty acids, partial glycerides of ethoxylated fatty acids, polyethoxylated fatty acid triglycerides, and mixtures thereof.

15. Process according to any one of claims 12 to 14, wherein the oily fatty phase comprises at least one liquid fatty compound as defined in claim 5.

16. The method according to the preceding claim, wherein the surfactant system further comprises at least one lipophilic surfactant.

17. Method according to the preceding claim, wherein the lipophilic surfactant is as defined in claims 6 to 8.

The method of any of the preceding claims, wherein the reverse micellar system is as defined in claims 2 or 3.

19. A method according to any one of claims 12 to 18, wherein the microemulsion is formed of at least one fatty acid triglyceride and a 2-hydroxysterate derivative of polyethylene glycol, and optionally a lecithin .

20. Composition containing at least nanocapsules according to any one of claims 1 to 11.