Gastroprotected, hydrophobic formulation of at least one active principle and method for obtaining same

Abstract

The invention relates to a gastroprotected, hydrophobic formulation of at least one active principle, characterised in that it is presented in the form of solid particles having a size of 5 μm to 3500 μm, the solid particles of the formulation comprising: - at least one waxy carrier forming a waxy matrix, and; - said at least one active principle chosen from the group made up of active principles for agri-food use, active principles for veterinary use, active principles for probiotic use, and active principles for pharmaceutical use; the solid particles being strictly hydrophobic, non-hygroscopic, non-injectable, free of water, free of surfactants, free of emulsifying agents, free of solvent, and free of shear-thinning polymer; the solid particles having a melting point of between 15°C and 60°C; said at least one active principle being uniformly distributed in the waxy matrix with a weight ratio of between 0.2% and 85%; said solid particles being suitable for protecting and stabilising said at least one active principle in the gastric medium and being dispersible in the intestinal medium.

Description

[0001] i

[0002] Gastro-protected and hydrophobic formulation of at least one

[0003] ACTIVE INGREDIENT AND PROCESS OF EXTRACTION

[0004] The invention relates to a novel formulation of compounds or active ingredients in a solid, divided, hydrophobic form, providing stabilization and gastroprotection while facilitating the administration of the formulated active ingredient. The invention also relates to a method for obtaining such a formulation. According to the invention, such a formulation is in the form of a solid in the divided state, i.e., a powder. Such a formulation is hydrophobic, stabilized, and gastroprotected, i.e., protected from the gastric environment. Such a formulation according to the invention can be used for the production of food, biotechnological, veterinary, technical, and pharmaceutical products.

[0005] Many compounds are used in powder form. We can distinguish between natural compounds obtained in their raw state and those transformed into powder by fragmentation and grinding according to the classical techniques described in the document "Randolph and Larson, Theory of Particulate Processes", 2nd Edition, Academy Press, NY, 1988" and in "JA Dodds, C. Frances, P. Guigon, A. Thomas "Methodologies for the Modeling of Fine Grinding, Colloquium on Powder Science and Technology, Lyon, France, November 1994".

[0006] Natural compounds obtained by solvent extraction, as well as synthetic and semi-synthetic compounds prepared by chemical synthesis, are recovered by the classical phase of solvent precipitation, as described in "Handbook of industrial Crystallization 2nd Edition, Allan S. Myerson, BH Editions, 2002".

[0007] For aqueous-phase products, other techniques based on solid / liquid separation allow for obtaining active compounds in powder form. This is the case with freeze-drying, well described in "SC Tsinontides, Freeze drying—principles and practice for successful scale-up to manufacturing, International Journal of Pharmaceutics vol 280, Issues 1-2, August 2004 pl-16". The atomization technique, also called spray-drying, is also used in solid / liquid separation, as described in "D. Kumar D. et al, Powder Preparation via Spray Dryer, Ceram. Forum Int., 5 (1988) 141-44".

[0008] Throughout the following, the term active, active compound or active principle means any compound that enables a physicochemical, technical, biological, pharmacological, physiological, pharmaceutical, cosmetic, agri-food, biotechnological effect to be obtained.

[0009] Many compounds or active ingredients in dry powder form produced by such processes present a number of drawbacks. Sensitive compounds or active ingredients can degrade under the influence of chemical, physical, and / or biological factors. Examples of degradation reactions include: hydrolysis upon contact with water, acid or alkali degradation, oxidation, photodegradation, enzymatic degradation, and instability of the crystalline form.

[0010] These phenomena can appear during manufacturing, storage, or subsequent use.

[0011] To address these difficulties, several solutions have been developed.

[0012] One solution involves modifying the preparation conditions. Degradation during preparation can be limited by changing the solvent, which provides a protective effect. For example, to protect ascorbic acid during grinding, EP1688130A1 suggests performing this step in an anhydrous oil phase. Other techniques aim to protect the active ingredient later during storage or use.

[0013] The most commonly used technical solution involves implementing a protection system by encapsulating the compound using polymers as described in US4434009.

[0014] These techniques are also applied to pharmaceutical active ingredients that are sensitive to hydrolysis or acid stress. These encapsulation or coating techniques are well known to those skilled in the art. A distinction can be made between physical coating processes, based on spraying the coating solution in a turbine or fluidized bed as described in WO00 / 30617 and W002 / 092106, and physicochemical coating based on coacervation or phase separation as described in US3341416. These coating techniques for pharmaceutical active ingredients make it possible to obtain stabilized and protected powders of active ingredients, possessing the sustained-release properties described in US6660382 and the stabilization and resistance to the highly acidic gastric environment described in EP1051174.

[0015] However, these techniques for preparing and / or processing powders have a number of drawbacks.

[0016] Thus, the technique of grinding in a protective oily or organic solvent requires obtaining a non-drying oily form. Removing the oily phase is difficult and involves the use of solvents or removal techniques such as drying or evaporation. All these techniques are expensive, time-consuming, and do not eliminate solvent residues. Finally, their effectiveness is too low to provide protection against long-term oxidation and acid degradation, for example, in a gastric environment.

[0017] The technique of modifying crystals and / or particles of active ingredients through surface treatment has the major drawback of inducing a chemical change in the active ingredient. For pharmaceutical, food, and biological applications, the treated active ingredient is no longer identical to the original active ingredient and therefore cannot be used.

[0018] Finally, coating or encapsulation technologies also present a number of drawbacks:

[0019] - The dissolution and dispersion kinetics of the active ingredient are significantly altered; - the coated particles range in size from a few hundred micrometers to a few millimeters and are perceptible upon absorption. In this case, their fragmentation can lead to an unpleasant taste upon administration.

[0020] - These technologies are difficult to reconcile with the preparation of stable liquid forms,

[0021] - these processes are complex, involve many steps, are costly and are incompatible with the preparation of freeze-dried forms or any process using an aqueous solvent.

[0022] These technologies for preparing and / or processing powders are therefore not entirely satisfactory.

[0023] The invention relates to a gastro-protected and hydrophobic formulation of at least one active ingredient, characterized in that it is in the form of solid particles with a size between 5 pm and 3500 pm, the solid particles of the formulation comprising:

[0024] - at least one waxy excipient forming a waxy matrix, and;

[0025] - said at least one active ingredient chosen from the group consisting of active ingredients for agri-food use, active ingredients for veterinary use, active ingredients for probiotic use, active ingredients for pharmaceutical use;

[0026] the solid particles being strictly hydrophobic, non-hygroscopic, non-injectable, free of water, surfactants, emulsifying agents, solvents, and shear-thinning polymers; the solid particles having a melting point between 15°C and 60°C;

[0027] said at least one active ingredient being uniformly distributed in the waxy matrix and in a mass proportion between 0.2% and 85%;

[0028] said solid particles being adapted to protect and stabilize said at least one active ingredient in the gastric environment and being dispersible in the intestinal environment.

[0029] Throughout the text, the terms "mixture", "mixture containing the active compound", "mixture containing the active ingredient", "matrix containing the active ingredient or active ingredient" or "product containing the active ingredient or active ingredient" refer to the liquid or solid result of mixing the waxy excipient(s) constituting the waxy matrix after melting in the reactor and at least one active ingredient.

[0030] In a completely unexpected turn of events, the inventors discovered that the formulation method according to the invention makes it possible to obtain a stable powder of particles in which the active ingredient(s) is / are protected against aqueous, acidic, basic, oxidative, and biological attack without encountering the aforementioned drawbacks. The active ingredient(s) thus formulated can / can be administered orally without gastric degradation. This formulation method allows, for example, the production of foods containing gastro-protected probiotic compounds, that is, compounds protected in a gastric environment, which are particularly beneficial for animal feed.

[0031] The formulation according to the invention, consisting of a waxy matrix powder containing at least one active ingredient, is thus characterized in that it is:

[0032] - composed of a waxy matrix protecting the active ingredient or mixture of active ingredients,

[0033] - strictly hydrophobic and gastro-protected,

[0034] - free from aqueous or organic solvents. A formulation according to the invention is free from any trace of aqueous or organic solvents. However, it is possible that a formulation according to the invention may contain a trace, i.e., a residual quantity at the limit of detection, of aqueous or organic solvents not resulting from a deliberate addition of aqueous or organic solvents to the formulation. These may be residues of aqueous or organic solvents contributed by the active ingredient(s).

[0035] - free from surfactants, amphiphilic compounds, or detergents,

[0036] - free of polymers and polymerizing agent residues,

[0037] - characterized by a homogeneous distribution of the active ingredient(s) within the waxy matrix of the solid particles, and without a radial gradient within the solid particles, - biocompatible and dispersible in the intestinal environment,

[0038] - the solid particles constituting the powder according to the invention are not administrable by parenteral route.

[0039] Advantageously, the solid particles of the formulation are formed exclusively of at least one waxy excipient forming the waxy matrix, and at least one active ingredient chosen from the group consisting of active ingredients for agri-food use, active ingredients for veterinary use, active ingredients for probiotic use, active ingredients for pharmaceutical use.

[0040] The formulation formed from a powder according to the invention exhibits increased stability under tropical storage conditions and / or in aqueous environments.

[0041] The formulation according to the invention is free of water and any aqueous polymeric gel. In particular, the solid particles of the formulation according to the invention are free of peripheral residual polymeric compound. They are free of any polymeric compound—in particular any aqueous polymeric compound—resulting from a lipid particle shaping process. The formulation according to the invention is a dry formulation.

[0042] The solid particles of the formulation according to the invention are of arbitrary shape. In particular, they do not exhibit a regular and spherical shape distribution. They have an irregular shape distribution and are not produced by a particle formation process within an aqueous polymer matrix.

[0043] The waxy matrix of the solid particles is hydrophobic and consists of a mixture of hydrophobic and water-insoluble compounds, solid at room temperature and completely free of surfactants, solvent residues, and water that could cause hydrolysis or oxidation reactions. An active ingredient (or ingredients) compatible with the waxy excipient(s) used, particularly of the lipid type, is added to this waxy matrix.

[0044] In some embodiments, the formulation according to the invention is in the form of hydrophobic solid particles having a size between 10 pm and 2500 pin (microns, micrometers), preferably between 150 pm and 800 pm.

[0045] For example, at least one—in particular each—waxy excipient may be selected from the group consisting of hydrophobic waxes or a mixture of hydrophobic waxes, whether vegetable, animal, synthetic, and / or mineral, as well as oils and hydrophobic compounds. At least one—in particular each—waxy excipient is selected to allow adjustment of the melting point, hardness, physicochemical properties, and biological properties of the formulation, including biodegradability. The waxy matrix may also contain additives, one or more soluble or insoluble active ingredient(s), such as mineral particles. According to the invention, mixtures of the waxy excipient(s) and the active ingredient(s) are used, with melting points between 15°C and 60°C, in particular between 25°C and 60°C, preferably between 32°C and 52°C.According to the invention, waxy excipient(s) are used having a melting point between 15°C and 60°C, in particular between 25°C and 60°C, preferably between 32°C and 52°C. Advantageously, the solid particles have a melting point between 25°C and 60°C, preferably between 32°C and 52°C.

[0046] As a waxy excipient, at least one triglyceride can be used, in particular at least one triglyceride whose fatty acids have 8 to 30 carbon atoms (C8 to C30). It is also possible to use other waxy excipients such as high molecular weight fatty alcohols, fatty acids (non-ionized and non-neutralized, in the carboxylic acid form -COOH) preferably linear and saturated even-numbered from C2 to C30, esters of fatty acids and high molecular weight alcohols, in particular esters of fatty acids from C8 to C30 and of alcohols from C2 to C32. In all cases, the waxy matrix and the mixture of the waxy matrix and the active ingredient(s) are in a solid state at room or physiological temperature and are characterized by the absence of water, the absence of surfactants, hydrophobic behavior, non-wetting by water and the absence of hygroscopicity.Throughout the text, the expression "fatty acid(s)" refers to one or more non-ionized and non-neutralized fatty acids, that is, in carboxylic acid form (-COOH).

[0047] In some embodiments, at least one waxy excipient of the wax matrix is ​​selected from the group consisting of palm oils, camauba waxes, candelilla waxes, alfa waxes, cocoa butters, vegetable waxes, beeswaxes, and modified beeswaxes. In some embodiments, the wax matrix comprises—in particular, is composed exclusively of—waxes of natural origin. The fatty acids used according to the invention are in a non-ionized and non-neutralized acidic (-COOH) form. Since the salts of these fatty acids form soaps, they cannot be used under any circumstances because they would promote the wettability of the matrix.

[0048] In some embodiments, at least one vegetable wax is chosen from the group consisting of olive wax, rice wax, hydrogenated jojoba wax, absolute flower waxes.

[0049] In some embodiments, at least one waxy excipient is selected from the group consisting of polyolefins, fatty acids (non-neutralized and non-ionized), esters of linear-chain fatty acids having a number of carbon atoms between 4 and 30, such as, for example, lauric acid, myristic acid, palmitic acid and stearic acid, esters of linear-chain fatty acids having a number of carbon atoms between 4 and 30 and hydrophobic lipids.

[0050] As a waxy excipient, at least one paraffin can be used.

[0051] To improve the solubility or dispersibility of the active ingredient(s) in the wax matrix, it is sometimes necessary to add an oil. This also allows for adjustment of the melting point.

[0052] In addition to the waxes mentioned above, the formulation according to the invention may contain a single oil or a mixture, selected from hydrophobic silicone oils, cyclomethicones, lipophilic organofluoride oils, squalene and its derivatives, short-chain triglycerides, and esters. Other oily compounds such as oleyl alcohol, sunflower oil, palm oil, olive oil, fatty acids, and fatty alcohols may be used, but the resulting mixture must be characterized by hydrophobic behavior and immiscibility with water. Those skilled in the art know that for this waxy matrix, the heating temperature must not exceed the degradation temperature of at least one component of the formulation.

[0053] Other compounds can be added to the wax matrix. These include fillers such as talc and kaolin, colorants, and agents that adjust the appearance, color, density, and hardness of the matrix. For biological and pharmaceutical applications, a suitable composition must be chosen, compatible in terms of toxicity, biocompatibility, non-immunogenicity, and biodegradability with oral or topical absorption. The wax matrix must be physiologically acceptable.

[0054] In certain embodiments of the invention, the waxy excipient(s) chosen from the group consisting of fatty acids and fatty acid esters are in mass proportions of between 0.5% and 85% by mass of the formulation, preferably between 25% and 75%.

[0055] According to the invention, the formulation, containing at least one active ingredient, possesses properties that protect the active ingredient(s). In certain embodiments, the formulation according to the invention masks the taste—in particular, the taste of the active ingredient(s). In certain embodiments, the formulation according to the invention modulates the release of the active ingredient(s).

[0056] In one embodiment, the mixture may contain components such as pigments, metal oxides, iron and copper salts, and aluminum and silver salts. It may also contain biologically active compounds, essential oils, flavorings, and other active substances. The loading capacity of the waxy matrix can range from 0.2% to 85% by weight. Those skilled in the art will know that when incorporating these components into a waxy matrix according to the invention, a suitable composition of hydrophobic waxy excipients should be chosen so that the formulation according to the invention can be implemented.

[0057] Among the components that can be incorporated into the waxy matrix are carotenoids, free radical scavengers, antiseptics, molecules acting on pigmentation, on inflammation, vitamins or pro-vitamins A, B, C, D, E, PP and their esters.

[0058] The matrix contains an active ingredient or a mixture of active ingredients, which may be in a dispersed or solubilized form, or both. Some active ingredients may be wholly or partly in amorphous form.

[0059] In some embodiments, at least one active ingredient is selected from among phosphate derivatives, potassium salts, nutrients for human or animal consumption, probiotic compounds, yeasts, compounds with biological activity, flavorings, compounds with pharmaceutical activity, anticancer compounds, anti-inflammatory compounds, immunomodulatory compounds, immunosuppressive compounds, antibiotic compounds, hypolipidemic compounds, antithrombotic compounds, proton pump inhibitor compounds, compounds for veterinary use, vaccines, alkaloids, oligonucleotides, carotenoids, free radical scavengers, hydroxy acids, pigmentation-enhancing molecules, vitamins and provitamins A, B, C, D, E, PP and their esters, pigments, carbon black, metal oxides, iron and copper salts, aluminum and silver salts.

[0060] In this description, the term active pharmaceutical ingredient is used to refer to any active therapeutic substance or mixture that can be advantageously administered to humans or animals for the diagnosis, treatment, reduction, management, or prevention of disease. Examples include anticancer and anti-inflammatory drugs, immunomodulators, immunosuppressants, antibiotics, lipid-lowering agents, antithrombotic agents, proton pump inhibitors, vasodilators, vasoconstrictors, antidiuretics and diuretics, antivirals and antiretrovirals, fibrates, antimalarials, veterinary compounds, vaccines, alkaloids, oligonucleotides, hormones, osteoporosis products, octreotide, somatostatin, and statins.In this description, the terms nutrient, probiotic, or dietary supplement are used to refer to any edible substance or mixture that can be advantageously administered to humans or animals for nutritional purposes. Examples include vitamins, minerals, proteins, amino acids, edible trace elements, and microorganisms such as Saccharomyces boulardii, used for their probiotic properties.

[0061] At least one active ingredient may be a biological catalyst. In this description, the term biological catalyst is used to refer to any molecule, microorganism, or mixture that can be advantageously used in a fermentation or biotransformation process. For example, Saccharomyces cerevisiae is used in breadmaking processes. Incorporating these yeasts into a hydrophobic waxy matrix according to the invention improves the quality of dry forms in regions subject to harsh climatic conditions in hot and humid countries. The invention provides better stability at room temperature and a longer shelf life characterized by improved fermentative power.

[0062] The powder formulation according to the invention can be packaged in single or multiple units. In some embodiments, the formulation according to the invention is ready-to-use. The formulation can be a conventional dosage form such as a capsule, tablet, softgel, orodispersible tablet, freeze-dried tablet, aqueous suspension, or powder in a sachet, particularly a dispersible powder in a sachet or bottle that allows for the preparation of a liquid form. Advantageously, a formulation according to the invention can be mixed with additives such as lubricating agents, for example, talc; homogeneity-improving agents such as silica; colorings; preservatives; sweeteners; and thickeners such as cellulose derivatives. The powder according to the invention can also be mixed with human or animal food preparations.

[0063] In some embodiments, the formulation according to the invention is contained in a unit or multiple container with a capacity between 0.1 gram and 1000 grams.

[0064] The invention also relates to a method for preparing a formulation according to the invention.

[0065] In a preferred embodiment of the invention, the powder is prepared according to a process comprising the following steps:

[0066] - a / preparation of the hydrophobic waxy matrix by melting said at least one waxy excipient under stirring at a temperature above the melting point of the mixture of said at least one waxy excipient. Advantageously, a / the waxy matrix is ​​prepared by melting said at least one waxy excipient under stirring, then by lowering the temperature to a temperature 3°C above the melting point of the waxy matrix,

[0067] - b / addition and mechanical dispersion of the active ingredient(s) in the molten wax matrix,

[0068] - c / recovery and solidification of the mixture of the wax matrix and said at least one active ingredient by cooling to at least 10°C below the melting point of the resulting mixture. Advantageously, the mixture of the wax matrix and said at least one active ingredient is cooled to a temperature at least 10°C below the melting point of said mixture, thereby solidifying the mixture.

[0069] - e / grinding at a temperature at least 20°C below the melting point of the matrix containing the active ingredient. Advantageously, the solidified mixture is mechanically ground at a temperature at least 20°C below the melting point of said mixture of the waxy matrix containing said at least one active ingredient, - f / recovery of the powder comprising the active ingredient. The formulation according to the invention is obtained, consisting of a powder of solid particles with a size ranging from 5 µm to 3500 µm.

[0070] In some embodiments the process includes a pre-grinding step of said solidified mixture prior to grinding.

[0071] In a first step of the invention, said at least one active ingredient is dispersed in a wax or a mixture of waxes and strictly hydrophobic excipients, referred to as a hydrophobic wax matrix, which has been previously melted. This at least one active ingredient is protected from any contact with oxygen and water, and more generally from any external chemical stress. The addition of said at least one active ingredient to the wax matrix is ​​carried out above the melting point of the wax matrix, at least 3°C ​​higher, preferably 5°C higher, than the melting temperature of the wax matrix, but always below the degradation or deactivation temperature of said at least one active ingredient. The resulting liquid wax matrix, containing said at least one active ingredient, is then solidified by cooling and optionally by a preliminary coarse grinding step (pre-grinding).

[0072] The matrix is ​​then ground to obtain a powder of solid particles with a controlled particle size, ready for use. This particulate matrix powder, containing at least one active ingredient, can be dispersed in water without risk to the active ingredient, due to its strictly hydrophobic nature.

[0073] This process is therefore quick to implement and requires no prior chemical modification of the active ingredient, nor any surface treatment of the particles and / or crystals of the active ingredient(s). It allows the active ingredient to be incorporated into the wax matrix during the first phase of mixing the wax matrix components. It is inexpensive and easy to implement.

[0074] The invention also relates to a formulation and a method for preparing such a formulation characterized, in combination or not, by all or part of the features mentioned above or below. Regardless of the formal presentation given, unless explicitly stated otherwise, the various features mentioned above or below should not be considered as closely or inextricably linked to each other; the invention may relate to only one of these structural or functional features, or only part of these structural or functional features, or only part of one of these structural or functional features, or any grouping, combination or juxtaposition of all or part of these structural or functional features.

[0075] Other objects, features and advantages of the invention will become apparent from the following description, given by way of non-limiting example, of some of its possible embodiments and which refers to the accompanying figures in which:

[0076] - Figure 1 is a schematic representation of a device for implementing a method according to the invention, and

[0077] - Figure 2 is a graphical representation of a result obtained by a formulation according to the invention.

[0078] Figure 2 is a graphical representation of the degradation in acidic medium (0.1N HCl) of 2-([4-(3-methoxypropoxy)-3-methylpyridin-2-yl]methylsulfinyl)-1H-benzo[d]imidazole (BZ). Figure 2 illustrates Example 1 and the improved stability of the active ingredient (O) formulated according to the invention compared to the unformulated active ingredient (Ψ).

[0079] The process does not involve surfactants, emulsifying agents, or amphiphilic products in the formulation, nor does it require organic solvents, the disposal of which remains difficult and whose use is increasingly restricted. It also does not involve shear-thinning agents. There is no contact between the formulation being prepared and any organic or aqueous solvent, or with water, during the process. This prevents the solubilization and extraction of water-soluble active ingredients that could interact with the other active ingredients and reduce physicochemical stability, shelf life, and loading rate. The active compound(s) or ingredient(s) is / are uniformly distributed throughout the divided wax matrix, unlike other techniques.

[0080] The mixing of the various components or waxy excipients of the wax matrix and the active ingredient(s), constituting the composition from which the final powder formulation will be obtained, is carried out in the first step of the process, in a thermostatically controlled reactor, a melter (1), or any other suitable system. The waxy excipient with the highest melting point is melted first, then the excipients are added successively in descending order of melting point. In a preferred embodiment, the temperature is reduced but always maintained at 3°C ​​above the melting point of the resulting mixture. The active ingredient is added last. It may be necessary to adjust the temperature according to the properties of the active ingredient, but always between 15°C and 105°C.

[0081] A suitable mechanical stirring method is applied to ensure the homogeneous dispersion of all components. According to a preferred embodiment of the invention, the stirring device is characterized by a blade equipped with a propeller (2), preferably a three-bladed, profiled Agimel TPE® type propeller, designed to disperse the molten mixture of waxy excipients. The active ingredient, alone or in a mixture, is then added to the molten mixture. In a particular embodiment of the invention, the use of a Turrax® T-series turbine or an Agimel TTC® turbine may be necessary to obtain a homogeneous dispersion of the active ingredient. The stirring time depends heavily on its nature. This mixing step is therefore rapid and does not require a long and delicate stirring step.

[0082] There is nothing to prevent the use of other suitable dispersion methods, for example sonication, extrusion, static mixers or linear mixers, recirculation pumps, but ensuring that the resulting mixture is homogeneous.

[0083] The resulting mixture is immediately cooled to protect the most sensitive active ingredient(s) and obtain a solid phase. According to a particular embodiment of the invention, for quantities less than 1 kg, the cooling of the molten matrix containing the active ingredient(s) dispersed within the molten matrix can be achieved by spreading it onto contact-cooling trays. Solidification is obtained in less than 120 seconds, and the trays are then placed in a cold room, allowing the steps to be separated if necessary.

[0084] For larger quantities, cooling can be achieved by passing the product through a continuous cooling system. The Sandvik model 321 continuous cooling system on a stainless steel belt is one example. According to a particular embodiment of the invention, the molten product is deposited in the form of droplets, filaments, or a film onto a stainless steel belt conveyor that passes through a cooling chamber and is collected in solid form at the outlet.

[0085] Cooling is achieved through heat exchange with a cold gas stream or by conduction with the cooled substrate. Depending on the quantity of product and the required solidification temperature, the technician will regulate the system parameters, particularly the material flow rate, the belt speed, the length, and the temperature of the cooling chamber. With some equipment, the belt is also cooled, for example, with liquid nitrogen.

[0086] In a particular embodiment, the reactor or melter containing the mixture of the molten waxy matrix and said at least one active ingredient is equipped with a pump allowing controlled flow transfer to the solidification system (3).

[0087] The cooling temperature of the mixture is controlled to be at least 10°C below its melting temperature, and preferably 15°C below this temperature, and in one particular embodiment, 45°C below the melting temperature. According to one embodiment of the invention, the cooling temperature is between -195°C and 45°C, and preferably from -10°C to 5°C. In one particular embodiment of the invention, the melter is equipped at the outlet with multiple dies (3) for producing filaments of molten matrix. These filaments are continuously solidified by contact on a refrigerated rotating drum system (4) made of stainless steel, as described in Figure 1. A scraper (5) in a tangential position detaches and fragments the solidified filaments.

[0088] The fragmented mixture is then cooled by contact or convection before being fed into the pre-grinding system. It is necessary to pre-grind the mixture, including the solidified matrix, to obtain fragments preferably smaller than 40 mm and, more specifically, smaller than 5 mm, to ensure proper feeding of the mill. For this purpose, rotor, hammer, or knife pre-mills such as the Retsch GM type, or jaw pre-mills such as the Jaw Crushers BB Series marketed by Retsch, or cryogenic screw conveyors such as the WAM CX type, cooled by the addition of liquid nitrogen, or any other suitable system, can be used. Some solidified mixtures are fragile and can be pre-grinded and ground in the same unit in a single step, but at different speeds.

[0089] In a final step, the pre-ground matrix, solidified by cooling, is reduced to powder by grinding (6). This final step yields a formulation according to the invention in the form of a hydrophobic powder as the final product. A wide variety of mills can be used, such as hammer mills, knife mills, rotor mills, ball mills, or jet mills. Examples include the APP® mill from Hosokawa Alpin AG, the FS®, L1A®, and M5A® type mills marketed by Fitzpatrick, and the SM, ZM, and GM series from Retsch. To facilitate the grinding of the waxy matrix, a preferred embodiment of the invention involves cooling the matrix to harden and embrittlead it. This operation takes place before or during the grinding step.

[0090] Cryogenic grinding is a well-known technique to those skilled in the art, as described in patent FR2550961. Many grinding systems can be equipped with specific liquid nitrogen or dry ice® cooling systems, such as the feed systems for mills offered by Fizpatrick Co. or Retsch. Some feed systems can also be used to cool the mixture. For example, WAM CX type conveyors cooled by the addition of liquid nitrogen can be cited. The resulting particulate matrix powder can be packaged directly. The powder according to the invention has a particle size between 5 µm and 3500 µm, and preferably between 10 µm and 2500 µm. In a preferred implementation, the powder has a particle size between 150 µm and 800 µm.

[0091] In a particular embodiment of the invention, the molten mixture containing the active ingredient can be solidified and fragmented before grinding using the cryopelletization technique described by Beteta and Ivanova in "Cool Down with Liquid Nitrogen CEP September 2015". As an example, the CRYOGENIC PELLETIZER from CES can be used. This technique yields pellets a few millimeters in size, solidified from the molten matrix. This step is followed by the grinding step.

[0092] The following examples are not limiting; they serve only to illustrate the invention. For some of the following examples, taste masking tests were conducted on a sample of 10 individuals. The tested products are never ingested.

[0093] The results are expressed according to the following scale:

[0094] - 1: the taste of the active ingredient is not detected,

[0095] - 2: the taste of the active ingredient is slightly perceived,

[0096] - 3: The taste of the active ingredient is detected.

[0097] - 4: the taste of the active ingredient is still acceptable,

[0098] - 5: the taste of the active ingredient is not acceptable.

[0099] The test value is calculated by averaging the scores obtained and dividing them by the maximum score out of 10. Example 1: Preparation of a gastro-resistant formulation (BZ-AT) containing a benzimidazole derivative unstable in acidic media. The derivative here referred to as (BZ) is 2-([4-(3-methoxypropoxy)-3-methylpyridin-2-yl]methylsulfinyl)-1H-benzo[d]imidazole.

[0100] Composition :

[0101] - Captex® Triglyceride Mixture (ABITEC company) 69.2 g

[0102] - DUB PP (Dubois Stearinerie) Triglycerides 10 g

[0103] - BZ (Sigma): 20 g

[0104] - Talc (Cooper) 0.5

[0105] - Sodium hydrogen carbonate (Cooper) 0.2g

[0106] - Silica (Aerosil) O.lg

[0107] In a 500 mL thermostatically controlled reactor, the compound with the highest melting point, DUB PP triglycerides, is heated to 55 °C. Then, the various compounds are added progressively, from highest to lowest melting point. The temperature of the mixture is gradually lowered to maintain it at 45 °C. During the addition of the composition, the three-bladed propeller is stirred at 100 rpm.

[0108] The BZ is added last. Dispersion of this active ingredient in the lipid phase is achieved using a Turrax T25 turbine-type stirring system at a speed of 6000 rpm. The matrix is ​​solidified by flow onto stainless steel trays heated to -10°C. The recovered fragments, with an average size of 35 millimeters, are then pre-ground and subsequently ground using a Retsch GM200 knife mill co-charged with dry ice under the following conditions:

[0109] - Pre-grinding: 20 seconds at 1500 rpm

[0110] - Grinding: 70 seconds at 3000 rpm

[0111] The particles thus obtained have an average size of 342 pm.

[0112] Measurement of particle stability in 0.1N hydrochloric acid solution by HPLC titration method:

[0113] - Column (ProntoSIL, Bischoff, Germany): 08.5pm, 120 Â, 4.6 x 150 mm,

[0114] - Mobile phase: methanol, 65% / Na2HPO4 10 mM, 35%, - Flow rate: 1.00 mL / min,

[0115] - Temperature: 20°C (thermostat),

[0116] - Detection: UV (λ = 310 nm)

[0117] - Injection volume: 20 pL.

[0118] Stability was measured in 0.1N HCl at 25°C, for a volume of 500 ml and 20 mg of BZ. The results shown in Figure 2 are expressed as a percentage of the initial dose.

[0119] The BZ prepared in Example 1 (BZ-T5, O) shows less than 8% degradation after 120 minutes of incubation. The degradation of the unformulated BZ (BZ, ¨) is 100%.

[0120] Preliminary gastroprotection and bioavailability test on animals. This test compares the protective capacity of the BZ-AT formulation according to the invention as described in this example and an unprotected form of BZ.

[0121] Each formulation is administered orally to male Sprague-Dawley rats weighing between 175 and 250 grams. Pure BZ and the BZ-AT formulation, rephrased at 10 mg / ml in the following aqueous solution, are tested:

[0122] - Sucrose 65 g

[0123] - Sodium methyl parahydroxybenzoate 0.015g

[0124] - Sodium propyl parahydroxybenzoate 0.03g

[0125] - Purified water qsp 100ml

[0126] The administrable volume is adjusted for each animal to achieve a dose of 4 mL / kg, equivalent to 40 mg / kg of benzodiazepine (BZ). Administration is performed orally on fasted animals. The results are summarized in Table 1 below.

[0127] Example 2: Preparation of a powder containing gastro-protected and stabilized fish oil with a masked taste, containing the polyunsaturated fatty acids EPA and DHA. Example given for the manufacture of 2.5 kg of particles containing high-dose Norwegian Cod Liver Oil.

[0128] Composition :

[0129] - Stearic acid 0.61 kg

[0130] - Triglycerides PPM 1 (Dubois Stearinerie) 1.24 kg

[0131] - Fish Oil (Solgar Norwegian Cod Liver Oil) 0.625 kg

[0132] - Talc 0.020 kg

[0133] - Silica 0.005 kg

[0134] In a 5-liter thermostatically controlled reactor, the compound with the highest melting point is heated 3°C above its melting point. Then, the various compounds, from highest to lowest melting point, are added progressively. The temperature of the mixture is gradually lowered to maintain it at 3°C ​​above the melting point of the new mixture, in this case 48°C. Fish oil is added last. Dispersion of these components in the molten wax phase is achieved using a stirring system equipped with an anchor-shaped impeller at a speed of 200 rpm. Finally, agitation is applied using a Turrax T25 turbine at 4500 rpm for 6 minutes to obtain complete dispersion.

[0135] The matrix is ​​solidified by flow through a rotating cylinder heated to 4°C. The recovered fragments, with an average size of 4 millimeters, are then cooled with dry ice. The mixture is pre-ground and then ground using a Retsch GM Inox knife mill.

[0136] - Speed: 3000 (rpm),

[0137] - Duration: 90 seconds,

[0138] - Granulometry: average diameter of 445 µm.

[0139] This fish oil powder is then evaluated by taste test. The result of the taste test gives an average value of 1.20. The average value is less than 2; the flavor of the oil is not detectable.

[0140] Example 3: Preparation of powder containing stabilized and gastro-protected fish oil with a masked taste, containing EPA and DHA polyunsaturated fatty acids, and flavored. This product is intended for the preparation of food supplements: Example given for the manufacture of 2.5 kg of particles containing high-dose Norwegian Cod Liver Oil flavored with mint.

[0141] Composition :

[0142] - Triglycerides PPM1 (Dubois Stearinerie) 1.24 kg

[0143] - Stearic acid 0.608 kg

[0144] - Fish Oil (Solgar Norwegian Cod Liver Oil) 0.625 kg

[0145] - Talc 0.020 kg

[0146] - Silica 0.005 kg

[0147] - Mint flavoring 0.002 kg

[0148] The powder is prepared according to the protocol described in Example 2. The resulting powder is characterized by the absence of detection of the fish oil flavor, with a score of 1.2

[0149] The resulting powder is characterized by a marked mint flavor with a score of 5 in the taste test.

[0150] Example 4: Preparation of a water-dispersible powder containing BZ-charged particles according to Example 1 for oral administration. Composition:

[0151] - BZ-AT particles according to example 1 100 g

[0152] - Mannitol 80 g

[0153] - Flavoring 10 g

[0154] - Aspartame 8 g

[0155] - Xanthan gum (Xanthural 180) 2 g

[0156] The composition is placed in a Turbula-type powder mixer (WAB France). After mixing, the powder is dispensed into individual 400 mg sachets.

[0157] Example 5: Preparation of particles containing stabilized ascorbic acid.

[0158] Composition :

[0159] - Triglycerides Suppositories DM (Dubois Stearinerie) 65 g

[0160] - Palmitic acid (Sigma) 4g

[0161] - solid paraffin (Sigma) 1 g

[0162] - Ascorbic acid (Sigma) 30 g

[0163] In a temperature-controlled container, the compound with the highest melting point is heated 3°C above its melting point. Then, the various compounds are added progressively, from highest to lowest melting point. During the addition of the compounds, the three-bladed propeller is stirred at 180 rpm ± 20. Stirring is maintained for 60 seconds after the addition is complete. The temperature of the mixture is then gradually lowered to maintain it at 5°C above the melting point of the new mixture. Ascorbic acid is added last. Dispersion of this component is achieved using a Turrax T25 turbine-type stirring system at a speed of 3000 rpm for 3 minutes.

[0164] The matrix is ​​solidified by flow onto stainless steel trays heated to -4°C. The recovered fragments, with an average size of less than 15 millimeters, are then pre-ground and ground using a thermostatically controlled -10°C IKA M20 type mill, according to the following conditions:

[0165] - Pre-grinding: 30 seconds at 1500 rpm,

[0166] - grinding: 90 seconds at 6000 rpm.

[0167] The final measured particle size distribution is characterized by an average particle diameter of 345 pm.

[0168] Example 6: Preparation of stabilized, gastro-protected live yeast powder according to the procedure of example 2:

[0169] - DUB Triglycerides (Dubois Stearine Factory) 650 g

[0170] - Triglycerides Suppository CM 100 g

[0171] - Stearic acid 50 g

[0172] - Saccharomyces Cerevisiae desiccated 720 g

[0173] - Hydrophobic silica 5 g

[0174] The resulting powder has the following characteristics:

[0175] - particle size = 910 pm,

[0176] - concentration of viable cells:

[0177] - initial powder: 2.8 x 10 10 UFC / g,

[0178] - matrix powder containing yeasts: 1.72 x 10 10 UFC / g.

[0179] The invention is capable of numerous variations and applications other than those described above. In particular, it is understood that, unless otherwise indicated, the various structural and functional features of each of the embodiments described above should not be considered as combined and / or closely and / or inextricably linked to one another, but rather as mere juxtapositions. Furthermore, the structural and / or functional features of the various embodiments described above may be juxtaposed or combined, in whole or in part, in any different manner.

Claims

DEMANDS 1 / - Gastro-protected and hydrophobic formulation of at least one active ingredient, characterized in that it is in the form of solid particles with a size between 5 pm and 3500 pm, the solid particles of the formulation comprising: - at least one waxy excipient forming a waxy matrix, and; - said at least one active ingredient chosen from the group consisting of active ingredients for agri-food use, active ingredients for veterinary use, active ingredients for probiotic use, active ingredients for pharmaceutical use; the solid particles being strictly hydrophobic, non-hygroscopic, non-injectable, free of water, surfactants, emulsifying agents, solvents, and shear-thinning polymers; the solid particles having a melting point between 15°C and 60°C; said at least one active ingredient being uniformly distributed in the waxy matrix and in a mass proportion between 0.2% and 85%; said solid particles being adapted to protect and stabilize said at least one active ingredient in the gastric environment and being dispersible in the intestinal environment. 2 / - Formulation according to claim 1, characterized in that at least one waxy excipient of the waxy matrix is ​​selected from the group consisting of triglycerides and their derivatives, palm oil, camauba wax, candelilla wax, esparto grass wax, cocoa butter, vegetable waxes, olive wax, rice wax, hydrogenated jojoba wax, absolute flower waxes, beeswax, modified beeswax, polyolefins, non-neutralized and non-ionized fatty acids, linear-chain fatty acid esters having a number of carbon atoms between 4 and 30, such as, for example, lauric acid, myristic acid, palmitic acid and stearic acid, linear-chain fatty acid esters having a number of carbon atoms between 4 and 30 and hydrophobic lipids. 3 / - Formulation according to any one of claims 1 to 2, characterized in that the waxy excipients selected from the group consisting of fatty acids and acid esters fats are in mass proportion between 0.5% and 85% of the mass of the formulation, preferably between 25% and 75%. 4 / - Formulation according to any one of claims 1 to 3, characterized in that it is in the form of hydrophobic solid particles having a size between 10 pm and 2500 pm and preferably between 150 pm and 800 pm. 5 / - Formulation according to any one of claims 1 to 4, characterized in that the melting point is between 25°C and 60°C, preferably between 32°C and 52°C. 6 / - Formulation according to any one of claims 1 to 5, characterized in that at least one active ingredient is selected from among phosphate derivatives, potassium salts, nutrients intended for human or animal consumption, probiotic compounds, yeasts, compounds with biological activity, flavorings, compounds with pharmaceutical activity, anticancer compounds, anti-inflammatory compounds, immunomodulatory compounds, immunosuppressive compounds, antibiotic compounds, hypolipidemic compounds, antithrombotic compounds, proton pump inhibitor compounds, compounds for veterinary use, vaccines, alkaloids, oligonucleotides, carotenoids, free radical scavengers, hydroxy acids, pigmentation-affecting molecules, vitamins and provitamins A, B, C, D, E, PP and their esters, pigments, carbon black, metal oxides, iron and copper salts,aluminum and silver salts. 7 / - Formulation according to any one of claims 1 to 6 characterized in that it is ready to use in the form of powder in sachet, tablet, lyophilized tablet, capsule, caplet, powder allowing reconstitution of a liquid composition in bottle by addition of water. 8 / - A method for preparing a formulation according to any one of claims 1 to 7, characterized in that it comprises the following steps: - a / preparation of the waxy matrix by melting said at least one waxy excipient under agitation, then reducing the temperature to a temperature 3°C higher than the melting temperature of the waxy matrix, - b / addition and dispersion of said at least one active ingredient in the molten waxy matrix, - c / cooling the mixture of the waxy matrix and said at least one active ingredient to a temperature at least 10°C lower than the melting temperature of said mixture, thereby causing the mixture to solidify, - e / mechanical grinding of the solidified mixture at a temperature at least 20°C lower than the melting temperature of the waxy matrix containing said at least one active ingredient, - f / that by which a powder of solid particles of size between 5 pm and 3500 pm is formed. 9 / - Method according to claim 8, characterized in that step e / of grinding the waxy matrix containing said at least one active principle is carried out by means of a hammer mill or a knife mill or a disc mill or a jaw mill or a ball mill or a jet mill. 10 / - Process according to one of claims 8 or 9, characterized in that the solidification, pre-grinding and / or grinding steps are carried out by cooling with dry ice® or with liquid nitrogen. 11 / - Method according to any one of claims 8 to 10, characterized in that step c / of cooling the waxy matrix is ​​carried out by flowing the waxy matrix onto a refrigerated rotating drum comprising a tangential knife ensuring the detachment of the solidified waxy matrix and its concomitant pre-grinding. 12 / - Method according to any one of claims 8 to 11, characterized in that step e / is carried out by means of a crusher fed by a screw conveyor cooled by the addition of liquid nitrogen or dry ice®, allowing pre-crushing and feeding of the crusher in a single step.

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