Microcapsules incorporating a UV filter

Abstract

The present invention relates to microcapsules having a core surrounded by a gelled shell, wherein the core further contains at least one active agent and the shell contains dispersed colloidal UV filter particles, to a method for producing such microcapsules, and to their use in various fields of application.

Description

Technical Field

[0001] The present invention relates to microcapsules in the form of O / W and W / O emulsions having an aqueous or oily liquid core or surrounded by a gelled shell, the core further containing at least one active agent, and the shell containing dispersed colloidal UV filter particles, a method for producing said microcapsules, their use in various application fields such as the treatment of crops and / or seeds, human and / or animal nutrition, pharmaceuticals, cosmetics, and the purification of soil and wastewater.

Background Art

[0002] When active compounds, especially organic compounds, are exposed to ultraviolet (UV) light, free radicals are formed through oxidation reactions. Among organic molecules, the DNA bases that make up the genome can mutate and may become harmful to microorganisms.

[0003] The energy radiated from the sun and reaching the earth's surface can be classified as follows: ultraviolet 5%, visible light 45%, and infrared 50%. Ultraviolet light is the most harmful because it has high energy.

Summary of the Invention

[0004] The present invention relates to introducing a concentrated suspension of colloidal UV filter particles into the shell of the capsule in order to assist in protecting the active agent at the center of the capsule. In the case of microorganisms, the inventors have found that this incorporation improves the viability of the microorganisms after exposure to ultraviolet light.

[0005] An anti-UV filter is a molecule or particle that absorbs, reflects, and / or diffuses ultraviolet light from radiation. It has been covered that this is used in cosmetics in the form of nanoparticles to protect the skin from the harmful effects of ultraviolet light.

[0006] The effectiveness of a UV filter is determined by its ability to absorb, reflect, and / or scatter light. Multiple physicochemical parameters, such as particle size, refractive index, concentration, etc., affect these physical phenomena.

[0007] Accordingly, the present invention relates to microcapsules having a liquid core surrounded by a gelled shell, wherein the microcapsules, when in the hydrated form, have an average diameter of 50 to 4000 μm and are as follows. a. The core further contains at least one active agent. b. The shell contains dispersed colloidal UV filter particles, and the UV filter is not a soluble antioxidant compound.

[0008] The present invention also relates to a method for producing microcapsules, which includes the following steps. a. Separately conveying in a double envelope a first solution containing at least one active agent and a second liquid solution containing a biopolymer having gelling properties and dispersed colloidal UV filter particles. b. At the outlet of the double envelope, forming a series of droplets, each droplet including a central core formed of the first solution and a surrounding film formed of the second solution that completely covers the central core. c. Reacting with the biopolymer having gelling properties to transition the biopolymer from a liquid state to a gelled state, forming a gelled envelope, and immersing each droplet in a gelling solution in which the central core can form a liquid core. d. Recovering the formed capsules.

[0009] The present invention also relates to the microcapsules obtained by this method.

[0010] The object of the present invention is the use of microcapsules for any purpose aimed at protecting an active agent from the harmful effects of ultraviolet rays. For example, during storage of the capsules under extreme sunlight conditions, during a process involving the step of using UV exposure, and further during the use / application of the capsules in various fields such as agriculture, agro-food products, cosmetics, pharmaceuticals, etc.

[0011] The object of the present invention relates to the use of microcapsules for the treatment of plant crops and / or their seeds, for nutrition and / or animal feed, for human nutrition and / or food, for the formulation of cosmetic and / or pharmaceutical compositions, and for the removal of soil and wastewater contamination.

[0012] The present invention also relates to a pharmaceutical composition comprising microcapsules according to the present invention.

[0013] The present invention also relates to a method for treating crops and / or their seeds, comprising spraying, foliar spraying or coating the seeds with a suspension of microcapsules according to the present invention.

[0014] Detailed description of the invention Microcapsules As used herein, "microcapsules" means capsules having an average diameter of less than 10 mm and comprising at least a core and a shell. Such capsules preferably comprise a liquid core encapsulated by a substantially solid gelled envelope. This type of capsule is applied in many technical fields. The shell comprises one or more concentric or non-concentric compartments. Preferably, the microcapsules according to the present invention comprise only a single core covered by a shell.

[0015] Therefore, these microcapsules are very different from microbeads, since microbeads are mainly composed of a solid or gelled matrix containing a plurality of small inclusions.

[0016] By using microcapsules instead of microbeads, it is also possible to confine without immobilizing microorganisms.

[0017] According to a preferred embodiment of the present invention, the ratio of the volume of the core to the total volume of the microcapsule exceeds 20%. Thus, these microcapsules make it possible to protect a large amount of core, and thus the active agent, with respect to a given volume of shell.

[0018] Microcapsules are known to those skilled in the art and can be formed by different techniques and may have different shell compositions.

[0019] Typically, the microcapsules used in connection with the present invention are manufactured according to the manufacturing process described in French Patent Invention No. 2939012.

[0020] As will be explained below, the microcapsules of the present invention can be dehydrated. However, when in a hydrated form, such as suspended in an aqueous solution for example, the microcapsules according to the present invention have an average diameter of 50 to 4000 μm, preferably 100 to 2000 μm, more specifically 200 to 1000 μm, and advantageously 200 to 600 μm. This average diameter can be measured by various techniques well known to those skilled in the art, such as particle size distribution based on laser light diffraction, fractionation by sieving, or imaging by optical microscopy.

[0021] In one embodiment, the microcapsules according to the present invention further comprise an intermediate layer between the core and the shell. Preferably, this layer is composed of at least one biopolymer in the form of a solution or a hydrogel. This limits, inter alia, the possible interaction between the UV filter and the active agent.

[0022] Preferably, the microcapsules according to the present invention are free, that is, not included in another structure such as a film, beads, gel, etc., or not double-encapsulated, but are in direct contact with the environment surrounding the microcapsules. These are usually a liquid (for example in the case of a suspension) or a gas.

[0023] Core The core of the microcapsules according to the present invention is a liquid core containing at least one active agent. Preferably, the viscosity of the core is less than 2000 mPa·s.

[0024] The core of the microcapsules according to the present invention may be in the form of an aqueous, oily, or water-in-oil (O / W) or oil-in-water (W / O) emulsion.

[0025] “Aqueous core” means a core based mainly on an aqueous phase in which the active agent is dispersed or solubilized.

[0026] “Oily core” means a core based mainly on an oily phase in which the active agent is dispersed or solubilized.

[0027] When the core is an O / W emulsion, the hydrophobic active agent is dispersed in the oil droplets. This type of emulsion also makes it possible to encapsulate both hydrophobic and hydrophilic active agents.

[0028] “Active agent” means an active substance, active ingredient, or active component that is known and / or used for a specific purpose. Preferably, the active agent is sensitive to UV. That is, exposure to UV can cause irreversible changes in the active agent and potentially reduce its activity.

[0029] Advantageously, the active agent is selected from microorganisms, natural extracts, infochemical compounds, and mixtures thereof.

[0030] “Microorganism” means an organism that is not visible to the naked eye and cannot be observed without using a microscope, particularly bacteria, fungi, microalgae, viruses, etc.

[0031] “Natural extract” means an extract derived from animals, plants, or minerals, for example, extracts of plants, algae, minerals, microorganisms, essential oils, etc.

[0032] For example, in one embodiment, the active agent is a biocontrol agent, a biofertilizer, and / or a biostimulant.

[0033] The term "biocontrol agent" means an agent aimed at protecting crops and / or their seeds from diseases and pests based on the utilization of natural mechanisms. These agents include plant protection products composed of natural substances of macroorganisms (insects and nematodes), microorganisms (viruses, bacteria, fungi), chemical mediators (pheromones and kairomones), plants, animals, or minerals.

[0034] The term "biofertilizer" means a non-pathogenic biological substance or microorganism that can enhance its availability to plants.

[0035] The term "biostimulant" means a substance or non-pathogenic living microorganism that has the ability to stimulate natural processes to improve / improve the nutrient uptake, nutrient efficiency, tolerance to abiotic stress, and / or food quality of crops, regardless of the nutrient content of the biostimulant.

[0036] In another embodiment, the active agent may be macronutrients (carbohydrates, lipids, and proteins) or micronutrients (vitamins, minerals, trace elements, or amino acids) preferably aimed at providing sensory stimulation characteristics or nutritional characteristics. Thus, the active agent can be a food supplement or an agent that promotes the digestion and / or absorption of specific compounds. For example, the active agent in the microcapsules according to the present invention can be vitamins, amino acids, and fatty acids.

[0037] In another embodiment, the active agent may be a cosmetic. The term "cosmetic" means any substance or mixture intended to come into contact with the surface parts of the human body (epidermis, hair and capillary system, nails, lips, and external genitalia), or the visible teeth and oral mucosa. They are used exclusively or mainly for cleaning, perfuming, modifying appearance, protecting, maintaining in good condition, or correcting body odor.

[0038] In another embodiment, the agent may be an active ingredient contained in the composition of the agent and having a therapeutic or prophylactic effect.

[0039] In another embodiment, the agent can be an active ingredient used for removing contamination of water or soil, for example, in a water treatment plant.

[0040] Preferably, the core of the capsule according to the present invention does not contain UV filter particles.

[0041] Shell The microcapsule according to the present invention preferably contains at least one liquid core encapsulated by a substantially solid gelled envelope called a shell.

[0042] Preferably, the shell of the microcapsule according to the present invention is mainly composed of a biopolymer having gelling properties. This biopolymer, which occupies most of the shell, will hereinafter be referred to as the main biopolymer. Such biopolymers having gelling properties are, for example, alginates, gellan gum, xanthan gum, pectin, chitosan, agar or carrageenan.

[0043] The material constituting the shell is preferably biodegradable and of biological origin. The shell is preferably semi-permeable to gases and low molecular weight molecules.

[0044] The gel forming the shell can be physical or chemical, i.e., formed by coacervation or polymerization

[0045] The gelation of these biopolymers can be carried out by a change in temperature (gellan gum), a change in pH (chitosan, pectin), or a change in ions (alginate, carrageenan).

[0046] Preferably, the shell of the microcapsule according to the present invention is mainly composed of a biopolymer having gelling properties by an ion change or a temperature change.

[0047] Preferably, the shell of the microcapsules according to the present invention is mainly composed of alginate.

[0048] The shell may further contain one or more biopolymers other than the main biopolymer, such as starch (in various forms, such as amylose, pregelatinized starch), potato protein, or a biopolymer other than the main biopolymer having gelling properties such as alginic acid, gellan gum, xanthan gum, pectin, chitosan, agar or carrageenan.

[0049] Preferably, the shell of the microcapsules according to the present invention contains a gel comprising water, one or more biopolymers having gelling properties, and optionally a surfactant resulting from its manufacturing process.

[0050] Preferably, the shell of the microcapsules according to the present invention contains a gel comprising water, alkaline alginate, and optionally a surfactant resulting from its manufacturing process.

[0051] Preferably, the alkali alginate is sodium alginate or potassium alginate. Alginate is produced from brown algae called kelp and is called "seaweed" in English. Such alginate preferably has an α-L-guluronic acid content of more than about 50%, preferably more than 55%, and even more preferably more than 60%.

[0052] The surfactant is preferably an anionic surfactant, a nonionic surfactant, a cationic surfactant or a mixture thereof. The molecular weight of the surfactant is from 150 g / mol to 10,000 g / mol, preferably from 250 g / mol to 1500 g / mol.

[0053] When the surfactant is an anionic surfactant, it is selected from, for example, alkyl sulfates, alkyl sulfonates, alkyl aryl sulfonates, alkaline alkyl phosphates, dialkyl sulfosuccinates, and alkaline earth salts of saturated or unsaturated fatty acids. These surfactants preferably have at least one hydrophobic hydrocarbon chain having 5 or more, and more preferably more than 10 carbon atoms, and at least one hydrophilic anionic group such as a sulfate, sulfonate or carboxylate bonded to one end of the hydrophobic chain. When the surfactant is a cationic surfactant, it is selected from, for example, alkyl pyridinium or alkyl ammonium halide salts such as n-ethyldodecylammonium chloride or n-ethyldodecylammonium bromide, cetylammonium chloride or bromide (CTAB). These surfactants preferably have at least one hydrophobic hydrocarbon chain having 5 or more, and more preferably more than 10 carbon atoms, and at least one hydrophilic cationic group such as a quaternary ammonium cation. When the surfactant is a nonionic surfactant, it is selected from, for example, aliphatic alcohols, fatty acids, or polyoxyethylenated and / or polyoxypropylenated derivatives of alkylphenols and arylphenols, or alkyl glucosides, polysorbates, and cocamides.

[0054] In one embodiment, the surfactant is sodium lauryl sulfate (LSS), also known as sodium dodecyl sulfate, and / or polyoxyethylene sorbitan monoleate (polysorbate 80).

[0055] Preferably, the surfactant is polyoxyethylene sorbitan monooleate (polysorbate 80).

[0056] In one embodiment, the mass content of the surfactant in the shell is greater than 0.001%, preferably greater than 0.1%. Advantageously, the mass concentration of the surfactant is about 0.03%.

[0057] The thickness of the shell of the microcapsules is preferably 0.1% to 30% of the diameter of the capsules, advantageously 1% to 20%, and preferably 10% to 20%.

[0058] The microcapsule shell further contains dispersed colloidal UV filter particles. In fact, the UV filter particles are preferably present within the shell of the microcapsules and advantageously not present within their core. This can reduce the amount of filter used to obtain equivalent anti-UV activity, but can also limit the interaction between the anti-UV filter and the active agent.

[0059] "Colloidal particles of UV filter" means particles with an average size of 10 nm to 10 μm, more preferably 100 nm to 5 μm. Generally, the smaller the particles, the higher the effect against ultraviolet rays. Using these filters can also make the microcapsules opaque.

[0060] Preferably, the UV filter is not a soluble antioxidant compound. In fact, these compounds tend to decompose faster when exposed to ultraviolet rays.

[0061] The UV filter according to the present invention may be an organic filter, an inorganic filter, or a mixture of an organic filter and an inorganic filter.

[0062] Preferably, the UV filter is selected from titanium oxide, carbon black, biochar, charcoal, latex, silica, clay, and mixtures thereof.

[0063] Biochar is a pyrolysis product of biomass and is used as an agricultural soil improver.

[0064] The clay used as a UV filter is, for example, talc or kaolin, and mixtures thereof.

[0065] Kaolin is a type of clay and is used to cut ultraviolet rays. It is also used to protect specific crops from pests in agriculture.

[0066] Preferably, the UV filter according to the present invention is biodegradable and / or edible and / or acceptable as a cosmetic and / or pharmaceutically acceptable.

[0067] Here, "acceptable as a cosmetic" means a composition and molecular entity that do not cause side reactions, allergic reactions, or other undesirable reactions when administered to a subject. Thus, a UV filter acceptable as a cosmetic is compatible with the skin, epidermis, and / or mucous membranes and does not induce discomfort or, more generally, a disease that may cause the user to interrupt or discontinue the administration of the cosmetic composition containing it.

[0068] Here, "pharmaceutically acceptable" means a composition and molecular entity that cause few or no side reactions, allergic reactions, or other undesirable reactions when administered to a subject. Thus, a pharmaceutically acceptable UV filter does not induce a disorder that may cause the user to interrupt or discontinue the administration of the pharmaceutical composition containing it.

[0069] "Dispersed UV filter particles" means particles dispersed within the shell of the microcapsule to enable a uniform anti-UV effect on the surface of the microcapsule.

[0070] The microcapsules according to the present invention can exist in a dehydrated form. Preferably, the dehydration is partial, and the microcapsules according to the present invention have a humidity level of less than 10% as measured by a humidity analyzer after dehydration.

[0071] In the dehydrated state, the average diameter of the microcapsules tends to decrease. Preferably, the microcapsules according to the present invention have an average diameter of 10 μm to 4 mm in the dehydrated form.

[0072] Manufacturing process The present invention also relates to a method for manufacturing microcapsules, comprising the following steps. a. Separately transporting, within a double envelope, a first solution containing at least one active agent and a second liquid solution containing a biopolymer having gelling properties and dispersed colloidal UV filter particles; b. At the outlet of the double envelope, forming a series of droplets, each droplet comprising a central core formed of the first solution and a surrounding film formed of the second solution that completely covers the central core; c. Immersing each droplet in a gelling solution that can react with the biopolymer having gelling properties to transition the biopolymer from a liquid state to a gelled state, forming a gelled envelope, and allowing the central core to form a liquid core; d. Recovering the formed capsules.

[0073] Preferably, the present invention relates to a method for manufacturing microcapsules, comprising the following steps. a. Separately transporting, within a double envelope, a first liquid solution containing at least one active agent and a second liquid solution containing alkali alginate and dispersed UV filter particles; b. At the outlet of the double envelope, forming a series of droplets, each droplet comprising a central core formed of the first solution and a surrounding film formed of the second solution that completely covers the central core; c. Immersing each droplet in a gelling solution containing a reagent that reacts with the alkali alginate to transition from a liquid state to a gelled state, forming a gelled outer skin, and allowing the central core to form a liquid center; d. Recovering the formed capsules.

[0074] The definitions defined in the section on microcapsules apply equally here.

[0075] In one embodiment of the method according to the present invention, the second solution contains at least one surfactant before contacting the first solution.

[0076] The surfactant is preferably selected from anionic surfactants, cationic surfactants, nonionic surfactants, or mixtures thereof.

[0077] For example, the surfactant is an alkyl sulfate, alkyl sulfonate, alkyl aryl sulfonate, alkaline alkyl phosphate, dialkyl sulfosuccinate, alkaline earth metal salt of saturated or unsaturated fatty acid, alkyl ammonium halide salt such as methyl dodecyl ammonium chloride or methyl dodecyl ammonium bromide. Or cetyl ammonium bromide, aliphatic alcohol, fatty acid or alkylphenol, or arylphenol, alkyl glucoside, polysorbate, cocamide or polyoxyethylenated and / or polyoxypropylenated derivatives of mixtures thereof.

[0078] In one embodiment, the surfactant is sodium lauryl sulfate (LSS), also known as sodium dodecyl sulfate, and / or polyoxyethylene sorbitan monoleate (polysorbate 80).

[0079] Preferably, the surfactant is polyoxyethylene sorbitan monooleate (polysorbate 80).

[0080] The total mass percentage of the surfactant in the second solution is preferably greater than 0.01% by mass, and advantageously between 0.01% and 0.5% by mass.

[0081] The mass content of the biopolymer having gelling properties in the second solution is advantageously less than 5% by mass, and preferably 0.5 - 3% by mass.

[0082] Preferably, in the case of producing microcapsules having a shell mainly containing alginate, the mass content of the alkaline alginate in the second solution is advantageously less than 5% by mass, and preferably 0.5 - 3% by mass.

[0083] Preferably, the alkaline alginate of the second solution has an α-L-guluronic acid block content of more than 50%, especially more than 55%.

[0084] Preferably, the second solution contains 0.1 to 20% v / v of a UV filter.

[0085] The ratio of the flow rate of the first solution to the flow rate of the second solution at the outlet of the double envelope is between 0.01 and 100, preferably between 0.05 and 50, more specifically between 0.1 and 10. For the gelled envelope, the thickness after recovering the formed capsules is between 0.1% and 30% of the diameter of the capsules, preferably between 1% and 20%, more specifically between 10% and 20%.

[0086] The "gelling solution capable of reacting with the biopolymer" means a solution at a specific temperature, or a specific pH, or a solution containing a specific reagent that enables the biopolymer of the second solution to transition from a liquid state to a gelled state.

[0087] When producing microcapsules having a shell mainly composed of alginate, the gelling solution is, for example, an aqueous solution of a reagent of the X n l m type, where X is a chloride ion, a bromide ion, an iodide ion or a fluoride ion, and it is advantageous that I is a polyvalent cation of an alkaline earth metal such as calcium, magnesium, barium, etc., and n and m are 1 or more. Preferably, the gelling solution is polysorbate 20 or polysorbate 80.

[0088] The polyvalent ions present in the gelling solution thus formed can react with the alginate when the second solution comes into contact with the gelling solution to form bonds between different alginate chains present in the second solution. When the alginate is sodium alginate (NaAlg) and the reagent is calcium chloride, the reaction that occurs is as follows. 2NaAlg + CaCl2 → Ca(Alg)2 + 2NaCl

[0089] In the method according to the invention, the concentration of the reagent in the gelling solution is advantageously between 5% and 20% by weight.

[0090] Preferably, the gelling solution is arranged below and away from the outlet of the double envelope, and the droplets formed by coextrusion within the double envelope naturally fall through the air volume by gravity into the gelling solution and are immersed therein.

[0091] In one embodiment, the microcapsules formed can follow an additional rinsing step by passing through a rinsing and storage solution consisting essentially of water.

[0092] The method according to the invention may further comprise a step (step e) of dehydrating the microcapsules. This step can be carried out by techniques well known to those skilled in the art, such as thermal drying techniques or lyophilization techniques. Preferably, this step is carried out by steaming, freeze-drying, or osmotic dehydration. In certain embodiments, the dehydration is carried out by drying on a fluidized air bed and / or by freeze-drying. Preferably, the dehydration step makes it possible to remove at least 90% of the water (by weight) from the microcapsules.

[0093] The invention also relates to microcapsules obtainable by the method according to the invention.

[0094] Uses and methods The definitions defined in the section on microcapsules apply here as well.

[0095] Preferably, in the method and use according to the invention, the microcapsules are used as such, i.e., the microcapsules are not included in another structure (such as a film, beads, gel, or second encapsulation), but are used directly, although in some cases they may be used suspended in a liquid.

[0096] The present invention relates to the use of microcapsules according to the invention for treating plant crops and / or their seeds.

[0097] "Treatment of plant crops and / or their seeds" means biocontrol, biofertilizer, and / or biostimulation treatments that can be carried out before, during, or after cultivation.

[0098] In fact, the active agent of the microcapsules according to the present invention can be an agent that affects plant cultivation and / or their seeds. In particular, the active agent can protect the crops and / or their seeds from diseases or pests, but can also function as a fertilizer and / or promote the growth of plant crops and / or their seeds.

[0099] Therefore, the present invention particularly relates to the use of microcapsules for treating plant crops and / or their seeds, wherein the active agent is a biocontrol agent, biofertilizer, and / or biostimulant. The microcapsules can be used suspended in a liquid or dehydrated and used in a solid state.

[0100] The present invention includes a method for treating crops and / or seeds, including the application of microcapsules according to the present invention. Therefore, the present invention also relates to a method for treating crops and / or seeds, which comprises spraying, foliar spraying, or coating the seeds with microcapsules according to the present invention, preferably microcapsules in which the active agent is a biocontrol agent, biofertilizer, and / or biostimulant. In this method, the microcapsules can be used in a state suspended in a liquid or dehydrated and in a solid state.

[0101] In another embodiment, the present invention relates to the use, preferably non-therapeutic, of the microcapsules according to the invention for the nutrition and / or food of animals and / or humans. In this embodiment, the active agents used are preferably not therapeutic agents. That is, they are interesting from a nutritional or dietary point of view, but they are not such that they can prevent or treat the diseases of the subjects who ingest them. Preferably, the active agents used are edible agents, preferably having sensory or nutritional properties. Thus, in this application, the active agents are preferably interesting from a nutritional or dietary point of view, but they cannot prevent or treat the diseases of the subjects who ingest them.

[0102] "Diet" means the habitual or frequent intake of food. In fact, the microcapsules can contain various active agents that make it possible to improve the properties of food, such as the sensory properties, shelf life, and even the bioavailability of the food.

[0103] "Nutrition" usually means taking nutritional supplements more frequently or during treatment in order to avoid or compensate for deficiencies. In fact, the microcapsules according to the present invention can contain various active agents that even make it possible to improve the intake of nutrients by improving bioavailability or to modify the intestinal microbiota.

[0104] "Animal" means wild animals or livestock. Preferably, the animal is a domestic animal, a breeding animal, or a pet. In particular, the animals according to the present invention are selected from pets such as dogs, cats, fish, rabbits, horses, turtles, etc., farmed species such as cows (cattle, cows), sheep, goats, rabbits, pigs (pigs), camels, etc., and birds (chickens, quails, etc.) raised for poultry farming.

[0105] The present invention also relates to the use of the microcapsules according to the invention for the formulation of cosmetics. In this embodiment, the active agents used are preferably not therapeutic agents. That is, the active agents are interesting from a cosmetic point of view, but they cannot be used to prevent or treat the diseases of the subjects.

[0106] The present invention also relates to the use of the microcapsules according to the invention for the formulation of pharmaceutical compositions. In this embodiment, the active agents used are preferably therapeutic active agents, i.e., they enable the prevention or treatment of the diseases of the subject who ingests them.

[0107] In fact, the use of the microcapsules according to the invention makes it possible to facilitate the storage, packaging, or preparation of cosmetic or pharmaceutical formulations while maintaining the good quality of the active agent.

[0108] Pharmaceutical compositions and therapeutic applications The present invention also relates to pharmaceutical compositions comprising the microcapsules according to the invention. This application also relates to the microcapsules according to the invention for use as a medicament.

[0109] The present invention also relates to a method of treating a subject comprising administering to the subject in need of treatment a therapeutically effective amount of the microcapsules according to the invention.

[0110] In this embodiment, the microcapsules according to the invention advantageously contain a therapeutic active agent.

[0111] "Therapeutic active agent" means an active agent as defined in the section on the microcapsules above and is further known to be used for a specific therapeutic purpose, i.e., it is known to be used for the treatment or prevention of diseases or the active agent used.

[0112] The term "pharmaceutical composition" as defined herein means a mixture or solution containing at least one therapeutic agent administered to a subject for the prevention or treatment of a specific disease affecting the subject.

[0113] Thus, the pharmaceutical compositions as defined herein preferably also contain pharmaceutically acceptable excipients.

[0114] As used herein, "pharmaceutically acceptable" means a composition and molecular entity that does not produce side reactions, allergic reactions, or other undesirable reactions when administered to a subject.

[0115] As used herein, "subject" means an organism, preferably a mammal, more specifically a human.

[0116] As used herein, "therapeutically effective amount" means an effective amount for a dose and period required to obtain a desired therapeutic result. This amount can vary depending on factors such as the disease, the degree of the disease, the age, sex and weight of the subject, and the ability of the microcapsules to produce the desired therapeutic result. A therapeutically effective amount includes any amount where the toxic or harmful effects are less important than the therapeutically beneficial effects. A therapeutically effective amount also includes an amount sufficient to provide a benefit, such as a clinical benefit.

[0117] Such pharmaceutical compositions are preferably adapted to the route of administration.

[0118] In certain embodiments, the pharmaceutical composition is suitable for oral, sublingual, buccal, intranasal or topical administration.

[0119] The present invention also relates to the use of the microcapsules according to the present invention for the manufacture of pharmaceuticals. The present invention also relates to the use of the microcapsules according to the present invention for the formulation of pharmaceutical compositions.

[0120] For these uses, the microcapsules according to the present invention advantageously contain a therapeutic active agent.

[0121] In fact, the use of the microcapsules according to the present invention makes it possible to facilitate the storage, packaging, or preparation of pharmaceutical compositions while retaining the active agent.

[0122] As used herein, "treatment" or "treating" means partially or substantially achieving one or more of the following results: partially or completely reducing the degree of a disease, improving clinical symptoms or indicators associated with the disease, delaying the disease, suppressing or preventing the progression of the disease.

[0123] "Prevention" or "preventing" as used herein means, for the purposes hereof, partially or substantially achieving one or more of the following results: preventing or delaying the onset of at least one of a disease or its symptoms, preventing or delaying the worsening of an "indicator" associated with the onset of the disease.

[0124] The present invention also relates to the use of the microcapsules according to the invention for the removal of soil or wastewater contamination. Indeed, such compositions make it possible to protect the active agent and remove the contamination from ultraviolet light, for example during use in a sewage treatment plant or on the ground surface.

[0125] In this specification and the following examples, unless otherwise specified, % is by weight, and the ranges of values expressed as "between... and...", "between... and...", or "greater than..." include the specified limits.

[0126] Throughout this application, the expression "comprising" or "comprises" means, unless otherwise specified, "comprising at least one" or "comprises at least one".

[0127] The following examples are presented for illustrative purposes and are not intended to limit the field of the present invention.

Brief Description of the Drawings

[0128]

Figure 1

Figure 2

Figure 3

Mode for Carrying Out the Invention

[0129] Example: Example 1 In the clinical examination of bacterial samples, an accelerated aging test was conducted. Comparison of the survival rate of the genus Bacillus bacteria. Suspension (non-encapsulated) and encapsulation have been established when exposed to artificial ultraviolet light. The encapsulation of these bacteria was carried out in a shell formed of alginate and carbon black known as a UV filter. The ultraviolet light source used is an oven equipped with a mercury vapor lamp having an output about 18 times that of solar radiation (noon on a summer day in the United States). This means that about 1 minute in the oven is equivalent to 18 minutes in the wild. Two exposure times were tested. 3 minutes and 5 minutes.

[0130] The results are shown in Figure 1. The inventors observed that the survival rate of encapsulated bacteria is higher compared to bacteria in suspension. After 5 minutes of exposure (equivalent to one and a half hours in the wild), the survival rate of bacteria in suspension is 1%, while the survival rate of encapsulated bacteria is 57%.

[0131] Example 2 Encapsulation operating conditions: Core solution (or core liquid): Dilute the bacterial suspension in TSB medium (tryptone soy broth) to 1 / 10 to limit the growth of bacteria during UV exposure.

[0132] Shell solution (or shell liquid): 1.8 wt% alginate solution, 0.5 mM SDS surfactant, 1.5% v / v biochar.

[0133] The flow rate ratio of the core suspension to the shell suspension is set to 0.5. Therefore, the inventors want to maximize the thickness of the shell.

[0134] The total fluid flow rate is 340 mL / h.

[0135] Under these conditions, the average diameter of the formed capsules was 516 μm, and the coefficient of variation (CV) was 17%.

[0136] For the test, two UV filters, biochar and kaolin, were selected.

[0137] The characterization of these two candidates was carried out to verify their compatibility with the microencapsulation process. Therefore, the particle size distribution of those constituting them was examined. Furthermore, the UV absorbance of these compounds was studied spectrophotometrically. The inventors observed that at the same volume fraction (0.01%), the UV absorbance by kaolin was slightly higher than that of biochar.

[0138] The effectiveness of UV protection by biochar was evaluated by measuring the survival rate of bacteria in the suspension exposed to artificial UV and the survival rate of bacteria encapsulated without biochar compared to the survival rate of bacteria encapsulated with biochar in the shell. The bacteria used in these tests belong to the species Paraburkholderia phytofirmans of the PsJN strain. These are bacteria that stimulate plant growth and help protect plants from specific biotic and abiotic stresses.

[0139] The results obtained from these tests are shown in Figure 2. The survival rate of bacteria encapsulated with 1.5% v / v biochar is higher than that of free-floating bacteria or bacteria encapsulated without biochar. In fact, the survival rate of bacteria in the suspension after 10 minutes of exposure is 8%, while the survival rate of bacteria encapsulated with biochar is 46%.

[0140] Therefore, encapsulating biochar within the shell represents a very interesting solution for protecting microorganisms from ultraviolet light.

[0141] The performance of biochar with respect to protection against ultraviolet light was also evaluated using the bacteriophage of the M13K07 strain. Two capsule prototypes were fabricated and their performance was evaluated. Prototypes 1 and 2 correspond to wet alginate capsules without biochar and wet alginate capsules containing biochar, respectively.

[0142] The operating conditions for encapsulation are as follows. The diameter of the injector nozzle is 200 μm. The total flow rate of the core fluid and the shell fluid, called Qtot, is 500 mL / h, the flow rate ratio of the core fluid to the shell fluid, called Rq, is 0.8, and the membrane thickness is at least 30 μm.

[0143] Heart solution (or heart fluid): Bacteriophage suspension in physiological medium diluted 1 / 200 e (To limit the growth of bacteria during ultraviolet exposure).

[0144] Shell solution (or shell fluid): 1.8 mass% alginate solution, 0.5 mM SDS surfactant, 2.9% v / v biochar.

[0145] Under these conditions, the average diameter of the capsules of Prototype 1 is 462 μm and the coefficient of variation (CV) is 17%.

[0146] The average diameter of the capsules of Prototype 2 is 542 μm and the coefficient of variation (CV) is 18%.

[0147] The survival rate of bacteriophage encapsulated with biochar in the shell was estimated by comparing it with the survival rate of bacteriophage encapsulated without biochar and the survival rate of bacteriophage in the suspension exposed to artificial ultraviolet light. The results obtained from these tests are shown in Figure 3 and Table 1 below.

[0148]

Table 1

[0149] The survival rate of bacteriophage in the suspension after 30 minutes was 0.00005% (i.e., a loss of about 6 logs), while the survival rate of the capsule-shaped bacteriophage in the presence of biochar on the hull was 30% (i.e., a loss of about 6 logs), and the survival rate was 0.002% (a loss of approximately 4 logs).

[0150] These results confirm that microorganisms, in this case bacteriophage, are effectively protected from ultraviolet light when in capsule form in the presence of biochar inside the shell. Furthermore, it is observed that the survival rate is slightly higher when the bacteriophage is encapsulated than when it is in suspension.

[0151] Example 3: Encapsulation operating conditions: Core solution (or core fluid): An inverse emulsion (W / O - water-in-oil) containing phenylalanine solubilized in the aqueous phase. This emulsion is prepared as follows.

[0152] Preparation of the aqueous phase by solubilizing phenylalanine (960 mg) in 120 mL of ultrapure water while stirring with a magnetic bar for 30 minutes. 1.37 g of polyglycerol polyricinoleate (PGPR 90) surfactant is introduced into MCT oil. PGPR 90 is dispersed in the oil phase using a rotor-stator at 12,000 rpm for 2 minutes. Then, an emulsion is formed by introducing the aqueous phase into the oil phase while stirring with a rotor-stator. While introducing the aqueous phase into the oil phase, the rotor-stator is used at 18,000 rpm.

[0153] Shell solution (or shell fluid): 1.8 mass% alginate solution, 0.5 mM SDS surfactant, 4 mass% E-153 edible charcoal.

[0154] The flow rate ratio of the core emulsion to the shell solution was set to 0.5.

[0155] The total fluid flow rate is 350 mL / h.

[0156] The diameter of the injector nozzle is 145 μm.

[0157] UV exposure is performed using a lamp with an irradiance of 0.76 mW / cm at 254 nm. The sample is placed 10 cm away from the light source. The UV protection effect by activated carbon is evaluated by spectrophotometry by measuring the absorbance at 280 nm of the aqueous phase of the emulsion at exposure times t0, t20 minutes, and t1 hour for the emulsion alone, the encapsulated emulsion without edible carbon, and the encapsulated emulsion with edible carbon. 2 The aqueous phase of the emulsion is extracted by introducing 500 mg to 1 g of the sample into 8 mL of PBS containing 25 mM EDTA in a 15 mL tube placed on a shaker for 20 minutes. Next, the tube is placed in an ultrasonic bath for 8 minutes. Finally, the tube is placed in a centrifuge at 4700 rpm for 15 minutes. Then, the aqueous phase is collected in each tube below the oil phase and filtered using a filter with a porosity of 0.2 μm.

[0158] The aqueous phase of the emulsion is extracted by introducing 500 mg to 1 g of the sample into 8 mL of PBS containing 25 mM EDTA in a 15 mL tube placed on a shaker for 20 minutes. Next, the tube is placed in an ultrasonic bath for 8 minutes. Finally, the tube is placed in a centrifuge at 4700 rpm for 15 minutes. Then, the aqueous phase is collected in each tube below the oil phase and filtered using a filter with a porosity of 0.2 μm.

[0159] Result: Phenylalanine exposed to this UV source is modified, and the absorbance measured at 280 nm increases as the exposure progresses. The lower the increase in this absorbance, the more effective the UV protection is.

[0160] For the absorbance at 280 nm of the emulsion sample alone, the absorbance increased by more than 300 after 1 hour. In the case of the encapsulated emulsion without edible charcoal, this absorbance became 13 times, while in the case of the capsule containing edible charcoal, this absorbance was limited to less than 2 times.

[0161] [Table 2]

[0162] [Table 3]

Claims

1. A microcapsule comprising a liquid core surrounded by a gelled shell, wherein the average diameter of the microcapsules in the hydrated state is 50 to 4000 μm, a. the core further contains at least one active agent, b. the shell contains dispersed colloidal UV filter particles, and the UV filter is not a soluble antioxidant compound, The microcapsule.

2. The microcapsule according to claim 1, wherein the core does not contain UV filter particles.

3. The microcapsule according to claim 1 or 2, comprising an intermediate layer between the core and the shell.

4. The microcapsule according to any one of claims 1 to 3, wherein the UV filter is organic or inorganic.

5. The microcapsule according to any one of claims 1 to 4, wherein the UV filter is selected from titanium oxide, carbon black, biochar, charcoal, latex, silica, clay, and mixtures thereof.

6. The microcapsule according to any one of claims 1 to 5, wherein at least one active agent is selected from microorganisms, natural extracts, infochemicals, and mixtures thereof.

7. The microcapsule according to any one of claims 1 to 6, which is in a dehydrated form.

8. A method for producing microcapsules comprising the following steps: a. Separately transporting in a double envelope a first solution containing at least one active agent and a second liquid solution containing a biopolymer having gelling properties and dispersed colloidal UV filter particles, b. At the outlet of the double envelope, forming a series of droplets, each droplet comprising a central core formed of the first solution and a surrounding film formed of the second solution that completely covers the central core, c. Reacting with a biopolymer having gelling properties to transition the biopolymer from a liquid state to a gelled state, forming a gelled envelope, and immersing each droplet in a gelling solution in which the central core can form a liquid core, d. Recovering the formed capsules.

9. The method for producing microcapsules according to claim 8, wherein the second solution contains 0.1 to 20% v / v of the UV filter.

10. e. The method for producing microcapsules according to claim 8 or 9, comprising dehydrating the microcapsules.

11. Microcapsules obtained by the production method according to any one of claims 8 to 10.

12. Use of the microcapsules according to any one of claims 1 to 7 and 11 for treating plant crops and / or their seeds.

13. A method for treating crops and / or seeds, comprising spraying, foliar spraying, or coating the seeds with a suspension of the microcapsules according to any one of claims 1 to 7 and 11.

14. Use of the microcapsules according to any one of claims 1 to 7 and 11 for nutrition and / or animal feed.

15. Use of the microcapsules according to any one of claims 1 to 7 and 11 for nutrition and / or human food.

16. Use of the microcapsules according to any one of claims 1 to 7 and 11 for the formulation of cosmetics.

17. Use of the microcapsules according to any one of claims 1 to 7 and 11 for the formulation of pharmaceutical compositions.

18. A pharmaceutical composition comprising the microcapsules according to any one of claims 1 to 7 and 11.

19. Use of the microcapsules according to any one of claims 1 to 7 and 11 for the removal of soil or wastewater pollution.

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