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    • 专利摘要:
    The invention relates to a microcapsule comprising a hydrophobic content surrounded by an envelope system which comprises a membrane comprising a combination of at least two complementary water-soluble polyelectrolytes chosen from water-soluble polyelectrolytes capable of generating microencapsulation by complex coacervation. According to the invention, said envelope system also comprises solid particles selected from solid particles capable of stabilizing a Pickering emulsion.
    公开号:FR3046088A1
    申请号:FR1563371
    申请日:2015-12-28
    公开日:2017-06-30
    发明作者:Gisele Ongmayeb；Magali Costard
    申请人:CAPSULAE；
    IPC主号:
    专利说明:

    Tableau 1 : Procédé d’obtention des microcapsules A
    Après refroidissement, NaOH est ajouté dans la solution de microcapsules afin d’obtenir un pH alcalin.
    La transglutaminase est ajoutée à une concentration comprise entre 5 et 20U/g de protéine, pour obtenir une réticulation de la membrane. La réaction se déroule toute la nuit à température ambiante (RT). 1.2. Propriétés des microcaosules 1.2.1. Stabilité des microcapsules et distribution en taille des microcapsules
    Afin de vérifier la stabilité des microcapsules formées, la distribution en taille des microcapsules a été réalisée avant et après centrifugation pendant 5 min, à 722 g.
    Comme on peut l’observer sur le tableau 2 ci-dessous, les microcapsules produites sont stables et leur taille varie entre 30 et 110 microns.
    Tableau 2 : Distribution en taille des microcapsu es A avant et après centrifugation.
    Dans ce tableau : - D (v; 0,1) = taille de particule pour laquelle 10% de l’échantillon se trouve en dessous de cette dimension ; - D (v; 0,5) = taille de particule à laquelle 50% de l’échantillon a une taille inférieure et 50% de l’échantillon a une taille supérieure ; - D (v; 0,9) = taille de particule pour laquelle 90% de l’échantillon se trouve en dessous de cette dimension ; - D (4; 3) = diamètre moyen (volume) ; - Span = mesure de la largeur de la distribution 1.2.2. Morphologie des microcapsules L’observation au microscope des microcapsules, lorsqu’elles sont conservées à température ambiante, montre la présence d’une membrane (coacervat) de polymères.
    En revanche, après un stockage à 105°C pendant 24H, la membrane est moins visible, voire inexistante.
    2. Exemple 2 - Produit B 2.1. Procédé d’obtention
    Tableau 3 : Procédé d’obtention des microcapsules B
    Après refroidissement, le NaOH est ajouté dans la solution des microcapsules afin d’obtenir un pH alcalin. La transglutaminase est ajouté à une concentration comprise entre 10 et 20 U/g de protéine. La réaction se déroule toute la nuit à RT. 2.2. Propriétés des microcaosules 2.2.1. Distribution de la taille des microcapsules
    Lorsque l’émulsion de Pickering est réalisée, la distribution en taille est déterminée (voir tableau 4).
    Une augmentation de la taille des microcapsules est observée par rapport à la taille de l’émulsion.
    Tout comme dans l’exemple 1, la taille des microcapsules avant et après centrifugation (5 min, à 722 g) a été mesurée. Là encore, une très bonne stabilité des microcapsules est observée au vu des résultats granulométriques. Les tailles des microcapsules sont comprises entre 15 et 85 microns.
    Tableau 4 : Distribution en taille de l’émulsion et des microcapsules « B >> avant et après centrifugation 2.2.2. Morphologie des microcapsules L’observation au microscope des microcapsules, lorsqu’elles sont conservées à température ambiante, montre la présence d’une membrane (coacervat) de polymères.
    En revanche, après un stockage à 105°C pendant 24H, la membrane est moins visible, voire inexistante. 2.2.3. Stabilité des microcapsules à la température L’incorporation des particules solides dans la formulation augmentent la stabilité des microcapsules à la température.
    Lorsque des microcapsules sont formées par coacervation complexe (par exemple gélatine, gomme arabique), les microcapsules sont détruites après un stockage à 50°C pendant une semaine. En revanche l’utilisation de particules solides, en combinaison avec les polymères utilisés en coacervation complexe, montre une meilleure stabilité à 50°C. En effet les microcapsules obtenues par ce procédé sont complètement stables pendant cette même période de temps.
    3. Relarqaqe du paprika microencapsulé pour le produit B
    Pour illustrer la libération du principe actif, du paprika (actif modèle) a été solubilisé dans le miglyol (utilisé comme solvant organique).
    Ce mélange constitue le cœur de deux types de microcapsules : - des microparticules témoins, formées par coacervation complexe entre la gélatine et la gomme arabique (sans particules solides), et - des microparticules B selon l’Exemple 2 ci-dessus, conforme à l’invention.
    Les figures 1 et 2 montrent le relargage du paprika (principe actif contenu dans la phase lipophile) dans des conditions particulières, à savoir dans un mélange d’éthanol et de miglyol (ratio éthanol / miglyol : 70/30).
    Les figures 1 et 2 montrent clairement que, lorsque les microcapsules contiennent des particules solides (produit B), elles sont moins perméables que les microcapsules sans particules solides (témoin). Même après un stockage à 50°C pendant une semaine (figure 2), la même tendance a été observée.
    Technical field to which the invention relates
    The present invention generally relates to the field of microencapsulation.
    It relates more particularly to microcapsules comprising an envelope system comprising a membrane obtained by complex coacervation.
    Technological background
    Microencapsulation is nowadays commonly used for the protection and for the control of the release of active principles.
    This technology consists of enclosing a solid substance, liquid or pasty, in a solid spherical envelope system (usually polymers). The size of the microparticles obtained generally varies from micrometer to millimeter.
    Microcapsules are particularly used in industrial sectors such as agriculture, sanitary products, health, cosmetics, detergent chemistry and textiles.
    In practice, the envelope system is generally formed by polymerization, interfacial crosslinking or complex coacervation.
    Because of its simplicity and low toxicity, microencapsulation called "complex coacervation" is often used to prepare microcapsules for human or animal nutrition, health or cosmetics.
    The complex coacervation is based on the phenomenon of desolvation of macromolecules (polymers) of opposite charges, resulting in the formation of two immiscible phases, starting from initially homogeneous aqueous colloidal solutions.
    The two phases obtained by complex coacervation are: - the coacervate, rich in macromolecules and depleted in water, which results from the formation of complexes between the positively charged and negatively charged macromolecules, and - the supernatant, which is poor in macromolecules and rich in water .
    For this, the encapsulation of an oil by complex coacervation consists of emulsifying the oil in an aqueous solution of two polymers.
    Coacervation is then usually induced by pH adjustment (usually acidification), so that both polymers have opposite charges to form polymer complexes. The polymer complexes formed adsorb on the oil droplets and thus isolate them from the external environment.
    The wall thus formed can then be cured by cooling the medium and crosslinked by the action of a crosslinking agent.
    In such a process of microencapsulation by complex coacervation, the prior formation of the emulsion is a crucial step.
    This step generally requires the use of specific chemical surfactants or polymers (gelatin, proteins, etc.) which adsorb at the interface of the droplets generated by a stirring system, and which make it possible to reduce and fix the size. droplets while stabilizing them.
    Most currently used surfactants are however of a chemical nature, which limits their use in the fields of cosmetics and food in particular.
    In addition, the surfactants do not improve the final stability of the microcapsules or their mechanical strength.
    It therefore remains necessary to develop new microcapsules, in particular meeting agri-food and / or cosmetic standards, which would also have optimal thermal stability and mechanical strength.
    Object of the invention
    In order to fulfill the aforementioned objective, the present invention provides microcapsules comprising a hydrophobic content surrounded by an envelope system which comprises a membrane comprising a combination of at least two complementary water-soluble polyelectrolytes chosen from water-soluble polyelectrolytes capable of generating a microencapsulation by complex coacervation.
    According to the invention, said envelope system also comprises solid particles chosen from solid particles able to stabilize (also called "to form" or "to obtain") a Pickering emulsion.
    Such microcapsules have the advantage of meeting agri-food and / or cosmetic criteria.
    They also have optimum thermal stability and mechanical strength.
    These microcapsules still allow: protection against oxidation phenomena, photostability, and protection against ultraviolet radiation, for the encapsulated product, and slowdown of the release of an active ingredient in a given environment. Other nonlimiting and advantageous features of the microcapsules according to the invention, taken individually or in any technically possible combination, are the following: the solid particles may be chosen from inorganic particles, for example clays, colloidal silicas latexes and / or organic particles, for example starches, chitosan, chitin, proteins; The water-soluble polyelectrolytes are preferably of natural origin; Said combination of at least two complementary water-soluble polyelectrolytes comprises at least two water-soluble polyelectrolytes having opposite charges, namely at least one water-soluble first polyelectrolyte having positive charges, preferably a protein, and at least one second water-soluble polyelectrolyte having charges negative, preferably a polysaccharide; Said at least one first water-soluble, positively charged polyelectrolyte may be chosen from gelatins, proteins (for example pea proteins, milk proteins), chitosan; Said at least one second water-soluble, water-soluble polyelectrolyte may be chosen from gums arabic, carboxymethylcelluloses, pectins and alginates; The water-soluble polyelectrolytes are preferably in a crosslinked state; The hydrophobic content of the microcapsule may be chosen from oils, especially vegetable oils, pharmaceutical oils (in particular miglyol-registered trademark), organic solvents or a phase-change material; The hydrophobic content advantageously contains at least one active principle; The envelope system of the microcapsule according to the invention is free of synthetic surfactants; The microcapsule according to the invention has a size less than 800 μm, preferably from 1 to 100 μm, more preferably from 1 to 50 μm. The invention also provides compositions containing microcapsules according to the invention. The invention also proposes a process for the manufacture of microcapsules, characterized in that it comprises: - obtaining droplets stabilized by solid particles chosen from solid particles capable of stabilizing a Pickering emulsion, and then - microencapsulation by coacervation complex of said first microcapsules by a combination of at least two complementary water-soluble polyelectrolytes selected from water-soluble polyelectrolytes capable of generating microencapsulation by complex coacervation.
    In a first variant, the method comprises the following steps: (a) mixing a lipid solution and an aqueous solution containing solid particles, on the one hand, capable of stabilizing a Pickering emulsion and, on the other hand, to form one of said two water-soluble polyelectrolytes to form a Pickering emulsion, (b) mixing said Pickering emulsion from step (a) with at least one second water-soluble complementary polyelectrolyte, said second water-soluble polyelectrolyte being advantageously in aqueous solution. (c) complex coacervation to obtain said microcapsules.
    In a second variant, the process is characterized in that it comprises the following steps: (a) mixing a lipid solution and an aqueous solution containing solid particles capable of forming a Pickering emulsion, for the formation a Pickering emulsion; (b) mixing said Pickering emulsion from step (a) and said combination of complementary water-soluble polyelectrolytes, the first and second water-soluble polyelectrolytes being added simultaneously or sequentially to said Pickering emulsion, and (c) complex coacervation to obtain said microcapsules. Other nonlimiting and advantageous features of the process according to the invention, taken individually or in any technically possible combination, are the following: step (b) of the process of the invention comprises: (b1) the mixture of said Pickering emulsion with a first aqueous solution comprising said first water-soluble polyelectrolyte, advantageously the cationic water-soluble polyelectrolyte, to obtain a first mixture, (b2) the mixture of said first mixture with a second aqueous solution containing said second water-soluble complementary polyelectrolyte, advantageously said anionic water-soluble polyelectrolyte, to obtain a second mixture; Step (c) of the process comprises: (c1) modifying the pH of the mixture, optionally acidification to a pH below the isoelectric point of a protein forming one of said water-soluble polyelectrolytes, and optionally (c2) cooling said mixture from step (c1); Step (c) is preferably followed by a step (d) of crosslinking said complementary water-soluble polyelectrolytes by means of at least one crosslinking agent; the crosslinking agent is advantageously chosen from natural crosslinking agents, in particular transglutaminase or genépine. The invention finally relates to the use of microcapsules according to the invention for the controlled and delayed release of an active ingredient under particular conditions of basic and / or enzymatic pH and / or temperature, for example under specific conditions of the invention. part of the digestive tract of a subject (particularly intestinal).
    Detailed description of the invention
    The description which follows, with regard to the experimental results given as non-limiting examples, will make it clear what the invention consists of and how it can be achieved.
    Unless otherwise specified, it is understood according to the present invention that the various embodiments described hereinafter can be combined with one another.
    In the appended figures: FIG. 1 illustrates the release, as a function of time, of paprika encapsulated in (1) microcapsules made of polymers only (without the presence of solid particles) and (2) microcapsules made with a combination of particles solids and polymers - Key: cumulative release (%) as a function of time in minutes; FIG. 2 illustrates the release, as a function of time and after storage at 50 ° C. for one week, of paprika encapsulated in (1) microcapsules made of polymers only (without presence of solid particles) and (2) microcapsules carried out. with a combination of solid particles and polymers - Key: cumulative release (%) as a function of time in minutes.
    Microcapsules according to the invention The invention relates to microcapsules comprising a hydrophobic content, surrounded by an envelope system which comprises: a membrane comprising a combination of at least two water-soluble polyelectrolytes chosen from water-soluble polyelectrolyte pairs capable of generating a microencapsulation by complex coacervation, and - solid particles selected from solid particles capable of stabilizing a Pickering emulsion.
    According to the invention, "microencapsulation" in particular means the process by which a product (solid, liquid or pasty) is enclosed in microcapsules.
    Still according to the invention, the term "microcapsule" in particular means an element of the "coacervate" type, that is to say a small spheroidal droplet of colloidal particles in suspension, whose coherence with respect to the surrounding liquid. is ensured by the hydrophobic forces of the contents. This microcapsule according to the invention is thus advantageously of the vesicular type.
    The microcapsule according to the invention thus constitutes a solid particle consisting of a solid envelope system surrounding a hydrophobic content (liquid, solid or pasty), said envelope system being obtained from a process comprising at least one technique complex coacervation.
    By "envelope system" is meant in particular a set of compounds surrounding the hydrophobic content, which isolates and protects this hydrophobic content with respect to the external environment, and / or which allows control of its release in an environment selected.
    In this case, the envelope system of the microcapsules according to the invention combines - a membrane resulting from a complex coacervation (also called "coacervate membrane") and - solid particles for Pickering emulsion.
    Membrane resulting from a complex coacervation
    The term "membrane" means, according to the invention, a substantially continuous wall of water-soluble polyelectrolyte materials, crosslinked or not, and formed around the hydrophobic content (solid or liquid) encapsulated.
    According to the invention, this membrane is derived from a complex coacervation technique, that is to say a simultaneous desolvation of two water-soluble polyelectrolytes carrying opposite charges, which is advantageously caused by a change in pH of the aqueous medium.
    The complex coacervation membrane thus comprises a combination of at least two complementary water-soluble polyelectrolytes chosen from couples of water-soluble polyelectrolytes capable of generating such microencapsulation by complex coacervation.
    By "complementary water-soluble polyelectrolytes" is thus meant at least first and second water-soluble polyelectrolytes which are capable of cooperating to generate a phenomenon of microencapsulation by complex coacervation.
    For this purpose, the combination of water-soluble polyelectrolytes according to the invention comprises at least two water-soluble polyelectrolytes having opposite charges, in particular for a determined pH value (hereinafter referred to as "coacervation pH" for the sake of simplification).
    The combination of water-soluble polyelectrolytes according to the invention thus comprises (where appropriate at the coacervation pH value): at least one positively charged cationic water-soluble polyelectrolyte, and at least one negatively charged, water-soluble anionic polyelectrolyte.
    By "water-soluble polyelectrolytes" is meant polymers whose repeated units carry an electrolyte group. These electrolytic groups are intended to dissociate in aqueous media, thus forming charged polymers either positively (cationic) or negatively (anionic).
    Water-soluble polyelectrolytes that are suitable for the invention may be chosen from proteins, polysaccharides, polyterpenes, polyphosphates, latices, thermoplastic polymers, such as polyhydroxyalkanoates, polymethacrylates, polymers of polyvinyl alcohols, or even styrenic polymers. .
    Preferably, the water-soluble polyelectrolytes are chosen from biopolymers.
    Biopolymers are polymers of natural origin, that is to say from biomass (produced by living plants, algae, animals, fungal, etc.).
    Such water-soluble polyelectrolytes can then be chosen from proteins and their derivatives (including polypeptides), polysaccharides, polyterpenes, polynucleotides or polyhydroxyalkanoates.
    These biopolymers can be natural or semi-natural (ie polymers of natural origin but having undergone chemical modifications after purification). Preferably, only natural biopolymers are used. The use of such biopolymers is particularly suitable in the fields of health, nutrition or cosmetics, for which the use of synthetic chemical components is restricted.
    Biopolymers particularly suitable for the invention are typically proteins and polysaccharides, as well as their derivatives.
    Among the proteins and their derivatives which can be used as polyelectrolytes according to the invention, mention may be made, in a nonlimiting manner, of milk proteins such as whey proteins (in particular beta lactoglobulin) and casein, albumin and gelatin. , plant proteins, collagen, and their derivatives.
    The plant proteins that can be used as polyelectrolytes according to the invention can be extracted from plants selected from the group comprising: lupine (genus Lupinus), soybean (genus Glycine), pea (genus Pisum), chickpea (Cicer) alfalfa (Medicago), faba beans (Vicia), lentils (Lens), beans (Phaseolus), rapeseed (Brassica), sunflower (Helianthus) and cereals such as wheat, maize, barley, malt and oats.
    Soy proteins (such as the protein marketed under the name SUPRO® 670), gliadin, wheat gluten and pea proteins (notably vicilin or the protein marketed under the name PISANE®) are vegetable proteins. particularly advantageous.
    Among the polysaccharides that may be used as polyelectrolytes according to the invention, mention may be made, in a nonlimiting manner, of glycosaminoglycans, such as hyaluronates, chondroitin sulfate or heparin; gum arabic (or acacia gum); Karaja gum; tragacanth gum; xanthan gum; agar agar; alginates; dextran; starch; cellulose; carrageenans; amylopectin; chitosan (or chitosan); pectin; and / or their respective derivatives.
    The cellulose derivatives include carboxymethylcelluloses (CMC), methylcelluloses, hydroxypropylcellulose (HPC), nitrocellulose and cellulose gum.
    In the present case, the anionic polyelectrolyte is advantageously chosen from those conventionally used by those skilled in the art: alginates (in particular sodium alginate), gum arabic (or acacia gum), polyphosphates, carboxymethylcelluloses sodium, carrageenans, xanthan gum, pectin, chondroitin sulfate, karaja gum, tragacanth gum, heparin or wheat gluten.
    For its part, the cationic polyelectrolyte is advantageously one of those conventionally used by those skilled in the art: latexes possessing a quaternary ammonium, chitosan, gelatin, albumin, collagen, casein, and pea proteins, soy protein or whey protein.
    By "gelatin", it includes in particular gelatines from pork, beef and fish.
    In particular, gelatin may be used: - type A, produced from pork bones and rinds, whose isoelectric point is greater than 6.5, or - type B, produced from the bones and skins of cattle whose isoelectric point is about 5.
    Preferably, type A gelatin will be used.
    The above examples of proteins and polysaccharides can be associated with each other to form the combination of the invention, insofar as they are of opposite charges.
    Thus, said combination is advantageously formed of at least one pair chosen from the following pairs: protein / protein, protein / polysaccharide or polysaccharide / polysaccharide.
    More preferably, the combination of polyelectrolytes according to the invention comprises at least one protein and at least one polysaccharide which respectively have charges opposite to a pH value of coacervation.
    In general, at least one of the water-soluble polyelectrolytes is advantageously chosen from compounds having an amphoteric character, in particular the proteins having the advantage of having an overall charge that can be reversed as a function of the pH value. In this respect, a protein has an isoelectric point (pHi or pl), that is to say a pH value for which the overall charge of this molecule is zero or, in other words, the pH for which the molecule is electrically neutral (zwitterionic form or mixed ion).
    If the pH is below pH, the overall protein load is positive; if the pH is greater than the pH, the overall charge of the molecule is negative.
    According to a preferred embodiment, the cationic water-soluble polyelectrolyte is chosen from proteins and the anionic water-soluble polyelectrolyte is chosen from polysaccharides.
    The protein is advantageously chosen with a pH greater than the pH of coacervation. For example, this protein is selected from proteins having a pl ranging from 4 to 8.
    In practice, this protein is intended to have a negative overall charge when it is mixed with the anionic water-soluble polyelectrolyte and a positive overall charge during the complex coacervation phenomenon. For the sake of simplification, the protein will then be referred to as "cationic water-soluble polyelectrolyte", complementary to the anionic water-soluble polyelectrolyte.
    For the sake of simplification, the protein is designated as a water-soluble cationic polyelectrolyte. For example, the combination of water-soluble polyelectrolytes can be chosen from the following combinations: acacia gum / gelatin, pectin / casein, pectin / gelatin, alginate / gelatin, alginate / chitosan, xanthan gum / chitosan, pectin / soy protein, gum acacia / soy protein, acacia gum / whey protein, pectin / whey protein, heparin / gelatin, hydroxypropyl methylcellulose (HPMC sodium dodecyl sulfate (SDS) / sodium carboxymethylcellulose (NaCMC), gelatin / SDS / NaCMC, collagen hydrolyzate / chitosan, pectin / beta-lactoglobulin, acacia gum / beta-lactoglobulin, gum acacia / pea protein , CMC / pea protein, alginate / pea protein, alginate / albumin, wheat gluten / casein. Those skilled in the art will still be able to refer to the teaching of the Kamdem documents Eugene Patrickab et al., "Microencapsulation by complex coacervation of fish oil using gelatin / SDS / NaCMC", P AK. J. FOOD SCI., 23 (1), 2013: 17-25; or Xiao Jun-xia et al, "Microencapsulation of Sweet Orange Oil by Complex Coacervation with Soybean Protein Isolate / Arab Gum", Food Chemistry 125 (2011) 1267-1272.
    The water-soluble polyelectrolytes forming the membrane of the microcapsule may be in a non-crosslinked state or in a crosslinked state.
    By "crosslinking" is meant the formation of a three-dimensional network, either chemically or physically, formed by bonds between the water-soluble polyelectrolytes.
    Indeed, because of the ionic nature of the interactions between the polyelectrolytes of the membrane, the microcapsules formed by complex coacervation are potentially fragile. Crosslinking therefore limits the risk of bursting microcapsules. In this regard, one skilled in the art can still refer to the document Izabela Dutra AL VIM et al, "Microparticles obtained by complex coacervation: influence of the type of crosslinking and the drying process on the release of the core material", Ciênc. Tecnol. Food., Campinas, 30 (4): 1069-1076, out.-dez. 2010.
    Solid particles capable of forming a Pickering emulsion
    The microcapsules of the invention are characterized in that the shell system also comprises solid particles selected from solid particles capable of stabilizing (or "forming" or "obtaining") an emulsion Pickering.
    By "Pickering emulsion" is meant in particular a dispersion of two immiscible liquids, stabilized by solid particles. Particle adsorption at the two-phase interface is responsible for the stabilization of this Pickering emulsion.
    In the present case, the applicant demonstrates that the formation of microcapsules, starting from a Pickering emulsion, makes it possible to obtain microcapsules whose stability and mechanical strength are improved.
    For the sake of simplicity, these solid particles are still referred to as "Pickering Solid Particles".
    Preferably, the Pickering solid particles are chosen from solid organic and / or inorganic particles.
    The organic particles that may be used according to the invention are, for example, solid particles derived from starch, chitosan, chitin or proteins.
    Such organic particles are advantageously chosen from soluble proteins (advantageously plant proteins, in particular pea proteins) which are capable of forming, on the one hand, Pickering solid particles and, on the other hand, one of the water-soluble polyelectrolytes.
    The inorganic particles that can be used according to the invention can be of natural origin or not.
    For example the inorganic particle can be selected from kaolin, colloidal clay (such as bentonite), colloidal silica, alumina, limestone, bauxite, gypsum, magnesium carbonate, calcium carbonate (soil and / or precipitate), perlite, dolomite, diatomite, huntite, magnesite, boehmite, palygorskite, mica, vermiculite, hydrotalcite, hectorite, hallyosite, gibbsite, kaolinite, montmorillonite, iNite, attapulgite, laponite, latex, and sepiolite, or their combination.
    The inorganic particles selected from colloidal clay, colloidal silica, and kaolin and mixtures thereof, are particularly advantageous.
    In general, the particles advantageously have a size of between 1 μm and 20 μm.
    These particles are advantageously used with a concentration of between 1% and 5% by weight relative to the weight of the microcapsules.
    In some embodiments, the solid particles are in the form of a mixture of different types of organic and / or inorganic particles.
    For example, it is possible to use mixtures of inorganic particles, such as colloidal silica or clay (colloidal or otherwise) with organic particles, in particular derived from chitosan, starch, xanthan gum, chitin or protein.
    Pickering solid particles, as well as the formation of such Pickering emulsions, are further detailed in the document Chevalier et al. <<Emulsions stabilized with solid nanoparticles: Emulsion Pickering, Colloids and Surfaces A: Physicochem. Eng. Aspects 439 (2013) 23-34.
    Surfactants The use of solid particles to stabilize the emulsion, prior to complex coacervation, makes it possible to dispense with the use of conventional surfactants.
    Thus, in certain embodiments, the microcapsules of the invention are devoid of surfactants, especially synthetic or chemical surfactants.
    Such an embodiment is particularly advantageous in the fields of health, nutrition or cosmetics.
    Hydrophobic content of microcapsules
    The hydrophobic content of the microcapsule (generally a hydrophobic liquid) may consist of a pure liquid, a mixture of miscible liquids, one or more solids dissolved in a liquid, an emulsion of a liquid hydrophilic or a solution in a hydrophobic liquid.
    Typically, the hydrophobic content of the microcapsule according to the invention is chosen from oils (in particular vegetable oils or pharmaceutical oils), organic solvents or - phase change materials.
    Any vegetable oil can be used according to the present invention. Those skilled in the art may however adapt the choice of vegetable oil depending on the field of use of the microcapsules and the product to be encapsulated. By way of example, the vegetable oil may be chosen from rapeseed, palm, olive, sunflower, coconut, coconut, walnut, flax, borage, sesame and argan oils. peanut, camelina, grape seed, pumpkin seed, etc., as well as mixtures of at least two of said vegetable oils.
    Pharmaceutical oils are suitable for pharmaceutical, cosmetic or agri-food use. These are generally - refined derivatives of vegetable oils (such as miglyol®, which is a derivative of coconut oil or coconut oil), - fish oils, or - mineral oils (such as paraffin and its derivatives or pharmaceutical white oils).
    The term "phase change material" means a material capable of changing its physical state within a restricted temperature range. This range is usually between 10 and 80 ° C.
    In this temperature range, the predominant phase change remains fusion / solidification. Such materials may be inorganic compounds, such as hydrated salts or organic compounds, such as phenol.
    The hydrophobic content may further consist of a hydrophobic powder or a wax having hydrophobic properties.
    Active principle Generally, the hydrophobic content also contains at least one active ingredient.
    This active ingredient may advantageously constitute from 1% to 100% of the aforementioned hydrophobic content.
    It may be an active ingredient pharmaceutical, cosmetic, food additives, pheromones, phytosanitary products, cells, microorganisms or catalysts for chemical reactions.
    In the food field in particular, an active ingredient may be chosen, for example, from flavors, minerals, probiotics, vitamins, fatty acids, antioxidants, etc.
    Physicochemical parameter of micro-cells
    A microcapsule according to the invention preferably has a size of less than 800 μm, in particular ranging from 1 to 100 μm.
    In a particularly preferred manner, a microcapsule of the invention has a size ranging from 1 to 50 μm.
    This size can be measured by laser granulometry (see, for example, Renliang Xu, "Light scattering: A review of particle characterization applications", Particuology 18 (2015) 11-21 or ISO 13320: 2009 and ISO 21501-2: 2007) .
    Without being limited by any theory, the size and stability of the microcapsules are influenced in particular by the concentration of water-soluble polyelectrolytes (ie membrane material) and the concentration of Pickering solid particles.
    Advantageously, a concentration of biopolymers ranging from 1% to 15% by weight relative to the total weight of the microcapsules is used.
    The ratio protein / polysaccharide in the envelope system varies from 1/1 to 3/1, and preferably of the order 1/1.
    The ratio between the hydrophobic content and the membrane (water-soluble polyelectrolytes, especially biopolymers) forming the envelope system varies from 1/2 to 1/6.
    Composition containing the microcapsules, and use
    The microcapsules according to the invention are able to be incorporated into a composition for use.
    The microcapsules according to the invention can then be mixed with any active ingredient or excipient well known to those skilled in the pharmaceutical, veterinary, cosmetic, food, agricultural, plant health, chemical and biomedical fields.
    The composition thus advantageously consists of a pharmaceutical, veterinary, cosmetic, agri-food, chemical and biomedical composition.
    Such a composition is advantageously a composition intended to be administered orally to a subject.
    In this case, the microcapsules according to the invention advantageously have the advantage of allowing controlled release of an active ingredient within the digestive tract of a subject.
    In such an application, water-soluble polyelectrolytes and Pickering particles are preferably nontoxic compounds. One of the water-soluble polyelectrolytes is preferably a protein, preferably selected from whey proteins or plant proteins such as soy protein or pea protein. The other of the water-soluble polyelectrolytes is advantageously a polysaccharide, preferably chosen from pectin, acacia gum, sodium alginate or carboxymethylcellulose.
    If surfactants are used in addition to Pickering solid particles to form the emulsion, they are surfactants recognized as non-toxic according to the standards in force in the pharmaceutical or food field.
    Without being limited by any theory, the microcapsules according to the invention then allow addressing of said at least one active principle within the digestive tract of a subject so as, on the one hand, to protect said at least one active principle with regard to conditions of the gastric medium (acid pH, enzymes) and, secondly, to release said at least one active principle into the intestinal medium (neutral to basic medium, for example intestinal medium containing in particular phosphate ions, hydrogencarbonate, carbonates).
    The microcapsules according to the invention also have the advantage of being particularly stable in time and at temperature (for example at 105 ° C. for 24 hours).
    Process for obtaining microcapsules
    The present invention also relates to the process for the manufacture of microcapsules according to the invention.
    In substance, this process according to the invention comprises two successive operations: - obtaining droplets stabilized by said solid particles chosen from solid particles capable of stabilizing a Pickering emulsion, and then - the complex coacervation of said droplets, by said at least two water-soluble polyelectrolytes chosen from water-soluble polyelectrolytes capable of generating microencapsulation by complex coacervation.
    Pickering Emulsion
    Prior to the complex coacervation operation, a Pickering emulsion is generated.
    This Pickering oil-in-water (O / W) emulsion is formed by emulsifying a lipid solution in an aqueous solution.
    The lipid solution constitutes the dispersed phase of the emulsion, and is intended to constitute the hydrophobic content of the microcapsules.
    The aqueous solution contains the above Pickering particles, and is intended to form the continuous phase of this emulsion.
    Preferably, in the Pickering emulsion, the size of the hydrophobic content droplets to be encapsulated is less than 300 μm, in particular less than 200 μm. Advantageously, the droplets have a size ranging from 5 to 200 μm.
    The size of the drops depends in particular on the agitation of the mixture during the emulsification step. Preferably, the emulsification is carried out in a device of the rotor / stator type.
    Also preferably, the oil / water ratio of the emulsion ranges from 20/80 to 45/55, especially from 25/75 to 50/50.
    In some embodiments, surfactants may be added to optimize the formation of the Pickering emulsion. These surfactants have been described above.
    Complex coacervation The complex coacervation operation may be carried out according to two variants, depending on whether one of the water-soluble polyelectrolytes is added either directly into the aqueous solution used to form the Pickering emulsion or after the formation of said Pickering emulsion. (The two water-soluble polyelectrolytes are advantageously added at the same time).
    Typically, and whatever the embodiment of the method, the microencapsulation phenomenon by complex coacervation is obtained because of the opposite charges between the reported water-soluble polyelectrolytes.
    These complementary water-soluble polyelectrolytes, as well as their combination in pairs of opposite charges, have been described previously.
    Advantageously, this combination of polyelectrolytes comprises at least one protein and one polysaccharide which have charges opposite to the pH of coacervation.
    In a first embodiment, the aqueous solution containing the Pickering particles also comprises at least one first water-soluble polyelectrolyte as defined above.
    Advantageously, according to this first embodiment, the process comprises the following steps: (a) the mixing between, on the one hand, a lipid solution and, on the other hand, an aqueous solution containing Pickering solid particles and at least one of the two water-soluble polyelectrolytes, to obtain a Pickering emulsion, (b) the mixture of said Pickering emulsion resulting from step (a) with at least one second water-soluble polyelectrolyte, said at least one second water-soluble polyelectrolyte being advantageously in solution (c) microencapsulation by complex coacervation of the mixture from step (b).
    In this first embodiment, in step (a), the Pickering solid particles and the first water-soluble polyelectrolyte are advantageously constituted by the same compound having the two desired properties.
    In a second embodiment, the water-soluble first and second polyelectrolytes are added to the Pickering emulsion after it has been formed.
    Preferably, in this second embodiment, the method comprises the following steps: (a) mixing a lipid solution and an aqueous solution containing the Pickering solid particles, for the formation of a Pickering emulsion, (b) mixing said Pickering emulsion from step (a) and said combination of water-soluble polyelectrolytes, and (c) complex coacervation microencapsulation of the mixture from step (b).
    During the mixing step (b), the water-soluble polyelectrolytes are added simultaneously or sequentially to said Pickering emulsion from step (a), preferably each in the form of an aqueous solution (e.g. dissolved or suspended in an aqueous solution).
    Advantageously, step b) of the "successive" type comprises: (b1) mixing said Pickering emulsion resulting from step (a) with a first aqueous solution comprising said first water-soluble polyelectrolyte, advantageously said first cationic polyelectrolyte to obtain a first mixture, (b2) the mixture of said first mixture resulting from step (b1) with a second aqueous solution containing said second water-soluble polyelectrolyte of opposite charge, advantageously said second anionic polyelectrolyte, to obtain a second mixture.
    In general, the water-soluble polyelectrolytes are incorporated with stirring, for example with magnetic stirring.
    In general, the water-soluble cationic polyelectrolyte is advantageously a protein.
    In this case, the complex coacervation step (c) advantageously comprises a modification of the pH of said mixture obtained after step b).
    If necessary, this change in pH consists of an acidification from a pH higher than the pH of the protein, the overall charge is then negative, until a pH of coacervation lower than the pH of said protein to obtain a positive overall charge.
    In general, several physico-chemical factors influence the formation of the complex coacervate, namely mainly the pH, the ionic strength, the ratio between the water-soluble polyelectrolytes of opposite charges (where appropriate, the protein / polysaccharide ratio) and the concentration of water-soluble polyelectrolytes. The skilled person can adjust these different parameters, taking into account in particular his general knowledge.
    The interactions between proteins and polysaccharides are observed when these two biopolymers are of opposite charges, or generally when the pH of the aqueous mixture obtained at the end of step (c) is less than the pH of the protein.
    Typically this pH is acidified, so that the protein forms a charge polycation opposite that of the polysaccharide. The combination of these biopolymers of opposite charge, mainly by electrostatic interactions, leads to the formation of insoluble complexes which then form droplets of liquids composed of polymers (polyelectrolytes) and solvent molecules, the coacervate.
    A phase separation is then observed if the pH is sufficiently lowered relative to the pH of the protein, while taking care to control this decrease to avoid neutralization of the polysaccharide. Those skilled in the art can then readily determine the pH range in which an optimal efficiency of complex coacervation is obtained by varying the pH during the complex coacervation step, as described in the study by Liu S., et al. (2010) "Effect of pH on the functional behavior of pea protein isolate-gum Arabia complexes", Food Research International, 43: 489-495. Acidification can be achieved by adding an acid solution to the mixture, for example acetic acid.
    Ionic strength plays an important role in coacervate formation because it also affects the charge of polyelectrolytes. Thus a very low or very high ionic strength causes a suppression of the electrostatic forces between proteins and polysaccharides.
    The ionic strength is influenced by the salt concentration of the mixture obtained at the end of step (c).
    The size and the stability of the microcapsules is again a function of various parameters such as the concentration of water-soluble polyelectrolytes, the protein / polysaccharide ratio in the envelope system or the ratio between the encapsulated material and the material forming the envelope system (the water-soluble polyelectrolytes, especially biopolymers). Advantageous values of these parameters have been described previously. At the end of these steps, microcapsules according to the invention are then obtained, the envelope system of which combines a complex coacervation membrane and solid Pickering particles.
    Cooling
    The complex coacervation is advantageously followed by a cooling step.
    This cooling step allows the solidification of the membrane of water-soluble polyelectrolytes.
    When one of the biopolymers used has gelling properties (such as gelatin), this step allows the rigidification / solidification of the envelope system.
    Alternatively, a gelling agent may be added to the mixture prior to step c) of complex coacervation.
    In general, the cooling step is carried out at a temperature below 15 ° C., in particular at a temperature of between -5 and + 10 ° C., preferably between -1 and + 5 ° C. The cooling step can optionally be carried out at an alkaline pH (greater than 7), preferably between 8 and 10 to participate in the stiffening. Generally, the alkalization of the microcapsule solution is obtained by adding an alkaline agent such as sodium hydroxide (NaOH). Crosslinking The complex coacervation step may also be followed by a step of crosslinking said water-soluble polyelectrolytes via at least one crosslinking agent.
    Effective polymerization can be achieved by treatment with a dialdehyde, such as glutaraldehyde. However, the toxicity of the latter limits their use.
    Preferably, the crosslinking is therefore carried out with non-toxic crosslinking agents, such as enzymes (transglutaminases or lactases), tannins (such as tannic acid), an iridoid compound (such as genipin) or else polyphenols, especially the compounds bioflavonoids (eg proanthocyanidin), grape seed extract, casein phosphopeptide amorphous calcium phosphate.
    Preferably, genipin, an enzymatic crosslinking agent such as transglutaminase, or even tannic acid is used.
    Enzymes, such as transglutaminase, are preferably used at a concentration of 10 to 25 U / g protein (used as the cationic polymer).
    EXPERIMENTAL RESULTS
    The examples below illustrate several embodiments of microcapsules according to the invention, without limiting the scope of the invention.
    1. Example 1 - Product A 1.1. Method of obtaining
    Table 1: Process for obtaining microcapsules A
    After cooling, NaOH is added to the microcapsule solution to obtain an alkaline pH.
    The transglutaminase is added at a concentration of between 5 and 20 U / g of protein, to obtain a crosslinking of the membrane. The reaction takes place overnight at room temperature (RT). 1.2. Properties of the microcapsules 1.2.1. Stability of microcapsules and size distribution of microcapsules
    In order to verify the stability of the microcapsules formed, the size distribution of the microcapsules was carried out before and after centrifugation for 5 min at 722 g.
    As can be seen in Table 2 below, the microcapsules produced are stable and their size varies between 30 and 110 microns.
    Table 2: Size distribution of microcapsules A before and after centrifugation.
    In this table: - D (v; 0,1) = particle size for which 10% of the sample is below this dimension; - D (v; 0.5) = particle size at which 50% of the sample is smaller and 50% of the sample is larger; - D (v; 0.9) = particle size for which 90% of the sample is below this dimension; - D (4; 3) = average diameter (volume); - Span = measure of the width of the distribution 1.2.2. Microcapsule morphology Microscopic observation of microcapsules, when stored at room temperature, shows the presence of a membrane (coacervate) of polymers.
    However, after storage at 105 ° C for 24H, the membrane is less visible or nonexistent.
    2. Example 2 - Product B 2.1. Method of obtaining
    Table 3: Process for obtaining microcapsules B
    After cooling, the NaOH is added to the solution of the microcapsules in order to obtain an alkaline pH. Transglutaminase is added at a concentration of between 10 and 20 U / g of protein. The reaction takes place all night at RT. 2.2. Properties of the microcapsules 2.2.1. Microcapsule size distribution
    When the Pickering emulsion is done, the size distribution is determined (see Table 4).
    An increase in the size of the microcapsules is observed with respect to the size of the emulsion.
    As in Example 1, the size of the microcapsules before and after centrifugation (5 min at 722 g) was measured. Here again, a very good stability of the microcapsules is observed in view of the particle size results. The sizes of the microcapsules are between 15 and 85 microns.
    Table 4: Size distribution of the emulsion and "B" microcapsules before and after centrifugation 2.2.2. Microcapsule morphology Microscopic observation of microcapsules, when stored at room temperature, shows the presence of a membrane (coacervate) of polymers.
    However, after storage at 105 ° C for 24H, the membrane is less visible or nonexistent. 2.2.3. Microcapsule Stability at Temperature Incorporating the solid particles into the formulation increases the stability of the microcapsules at temperature.
    When microcapsules are formed by complex coacervation (for example gelatin, gum arabic), the microcapsules are destroyed after storage at 50 ° C for one week. On the other hand, the use of solid particles, in combination with the polymers used in complex coacervation, shows a better stability at 50 ° C. In fact, the microcapsules obtained by this method are completely stable during this same period of time.
    3. Microencapsulated Paprika Relay for Product B
    To illustrate the release of the active ingredient, paprika (active model) was solubilized in miglyol (used as organic solvent).
    This mixture constitutes the core of two types of microcapsules: control microparticles, formed by complex coacervation between gelatin and gum arabic (without solid particles), and microparticles B according to Example 2 above, in accordance with FIG. 'invention.
    Figures 1 and 2 show the release of paprika (active principle contained in the lipophilic phase) under particular conditions, namely in a mixture of ethanol and miglyol (ratio ethanol / miglyol: 70/30).
    Figures 1 and 2 clearly show that when the microcapsules contain solid particles (product B), they are less permeable than the microcapsules without solid particles (control). Even after storage at 50 ° C for one week (Figure 2), the same trend was observed.
    权利要求:
    Claims (14)
    [1" id="c-fr-0001]
    Microcapsule comprising a hydrophobic content surrounded by an envelope system which comprises a membrane comprising a combination of at least two complementary water-soluble polyelectrolytes chosen from water-soluble polyelectrolytes capable of generating microencapsulation by complex coacervation, characterized in that said system The envelope also comprises solid particles selected from solid particles capable of stabilizing a Pickering emulsion.
    [2" id="c-fr-0002]
    2. Microcapsule according to claim 1, characterized in that the solid particles are chosen from inorganic particles and / or organic particles.
    [3" id="c-fr-0003]
    3. Microcapsule according to any one of claims 1 or 2, characterized in that the water-soluble polyelectrolytes are of natural origin.
    [4" id="c-fr-0004]
    4. Microcapsule according to any one of claims 1 to 3, characterized in that said combination of at least two complementary water-soluble polyelectrolytes comprises at least two water-soluble polyelectrolytes having opposite charges, namely: - at least one first water-soluble polyelectrolyte having positive charges, preferably a protein, and - at least one second water-soluble polyelectrolyte having negative charges, preferably a polysaccharide.
    [5" id="c-fr-0005]
    5. Microcapsule according to any one of claims 1 to 4, characterized in that the water-soluble polyelectrolytes are in a crosslinked state.
    [6" id="c-fr-0006]
    6. Microcapsule according to any one of claims 1 to 5, characterized in that the hydrophobic content is selected from oils, organic solvents or a phase change material.
    [7" id="c-fr-0007]
    7. Microcapsule according to any one of claims 1 to 6, characterized in that the casing system is free of synthetic surfactants.
    [8" id="c-fr-0008]
    8. Microcapsule according to any one of claims 1 to 7, characterized in that said microcapsule has a size less than 800 μm, preferably from 1 to 100 μm, more preferably from 1 to 50 μm.
    [9" id="c-fr-0009]
    9. Composition containing microcapsules according to any one of claims 1 to 8.
    [10" id="c-fr-0010]
    10. Process for the manufacture of microcapsules according to any one of claims 1 to 8, characterized in that it comprises: - obtaining droplets stabilized by solid particles selected from solid particles capable of stabilizing a Pickering emulsion then microencapsulation by complex coacervation of said first microcapsules by a combination of at least two complementary water-soluble polyelectrolytes selected from water-soluble polyelectrolytes capable of generating microencapsulation by complex coacervation.
    [11" id="c-fr-0011]
    11. Process for the production of microcapsules according to claim 10, characterized in that it comprises one of the following combinations of steps, namely: according to a first combination of steps: (a) the mixture, of on the one hand, of a lipid solution and, on the other hand, of an aqueous solution containing solid particles, on the one hand, capable of stabilizing a Pickering emulsion and, on the other hand, forming one of said two water-soluble polyelectrolytes, for the formation of a Pickering emulsion, (b) mixing said Pickering emulsion from step (a) with at least a second water-soluble complementary polyelectrolyte, (c) complex coacervation of the mixture from step (b), to obtain said microcapsules, or - according to a second combination of steps: (a) mixing a lipid solution and an aqueous solution containing solid particles capable of forming a Pickering emulsion, for formation of a Pickering emulsion, (b) mixing said Pickering emulsion from step (a) and said combination of complementary water-soluble polyelectrolytes, and (c) complex coacervation of mixture from step (b).
    [12" id="c-fr-0012]
    12. Process for the production of microcapsules according to claim 11, characterized in that said complex coacervation step (c) comprises: the modification of the pH of the mixture, where appropriate an acidification until a pH lower than the isoelectric point is reached; of a protein forming one of said water-soluble polyelectrolytes, and optionally - a cooling of said second mixture.
    [13" id="c-fr-0013]
    13. Process for the manufacture of microcapsules according to any one of claims 10 to 12, characterized in that said coacervation step (c) is followed by a step (d) of crosslinking said complementary water-soluble polyelectrolytes.
    [14" id="c-fr-0014]
    14. Use of microcapsules according to any one of claims 1 to 8 for the controlled release of an active ingredient in the digestive tract of a subject.
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    同族专利:
    公开号 | 公开日
    EP3397378A1|2018-11-07|
    WO2017115034A1|2017-07-06|
    FR3046088B1|2018-01-19|
    EP3397378B1|2021-12-15|
    引用文献:
    公开号 | 申请日 | 公开日 | 申请人 | 专利标题
    FR2340087A1|1976-02-04|1977-09-02|Medichemie Ag|Slow release oral medicament - for regulating blood circulation at night|
    WO2000069420A1|1999-05-14|2000-11-23|Coraltis Ltd.|Pulse-delivery oral compositions|
    CN102641703A|2011-05-27|2012-08-22|京东方科技集团股份有限公司|Electronic ink microcapsule and preparation method thereof|WO2021013710A1|2019-07-19|2021-01-28|Dsm Ip Assets B.V.|Encapsulation of lipophilic actives which are sensitive to acid degradation|
    CN107998907B|2017-12-18|2020-09-01|江南大学|Preparation method for preparing porous polylysine membrane from Graphene Oxidestable Pickering emulsion|
    CN109692634B|2019-01-31|2021-07-23|合肥工业大学|Micro-polymer particles based on eutectic solvent emulsion and preparation method thereof|
    法律状态:
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    2017-06-30| PLSC| Publication of the preliminary search report|Effective date: 20170630 |
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    2021-10-05| PLFP| Fee payment|Year of fee payment: 7 |
    优先权:
    申请号 | 申请日 | 专利标题
    FR1563371A|FR3046088B1|2015-12-28|2015-12-28|MICROCAPSULE COMPRISING A MEMBRANE FROM A COMPLEX COOPERATION MICROENCAPSULATION, AND PROCESS FOR OBTAINING THE SAME|FR1563371A| FR3046088B1|2015-12-28|2015-12-28|MICROCAPSULE COMPRISING A MEMBRANE FROM A COMPLEX COOPERATION MICROENCAPSULATION, AND PROCESS FOR OBTAINING THE SAME|
    EP16829272.0A| EP3397378B1|2015-12-28|2016-12-22|Microcapsule comprising a membrane obtained by microencapsulation using complex coacervation, and obtention method|
    PCT/FR2016/053628| WO2017115034A1|2015-12-28|2016-12-22|Microcapsule comprising a membrane obtained by microencapsulation using complex coacervation, and obtention method|
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