Lipid composition for encapsulating an active substance, allowing the release rate of said active substance to be controlled

Abstract

A lipid composition is disclosed, comprising, per 100% by weight: - from 40% to 99.9% by weight of the following complex, which, per 100% by weight, comprises from 90% to 0% by weight of beeswax and up to 10% by weight of at least one other lipid excipient, - from 0.1% to 60% by weight of at least one lipophilic surfactant.

Description

[0001] The present invention relates to a lipid composition, a controlled-release composition comprising the lipid composition and capable of controlling the release rate of an active substance contained therein, and a method for manufacturing a galenical formulation comprising the controlled-release composition.

[0002] Active ingredients developed and used in human and veterinary pharmaceutical preparations, as well as in preparations from the food supplement industry, are sensitive to environmental factors, both during the manufacture of the relevant galenical form (in particular to the high temperatures used in certain processes, oxidative phenomena, etc.) and / or during the life of said galenical form, and / or during consumption in the human or animal body (when said galenical form comes into contact with degradation and / or digestion molecules present in the body of the user).

[0003] Furthermore, the molecules that make up all or some of the active ingredients present in these galenical forms may have organoleptic properties that are inconsistent with those when consumed directly: poor taste, inappropriate odor, etc.

[0004] Molecules introduced into capsules, hard gels, tablets or even foods with the goal of providing nutritional or therapeutic benefits should not dissolve at the same rate and in the same environment.

[0005] Especially for these different reasons, many active molecules are involved in a process known as encapsulation, the purpose of which is to prepare a composition (C A ). This encapsulation method has the function of protecting the at least one active ingredient from undesired interactions with a particular external environment, and has the function of transporting the one or more active ingredients to another environment, where the conditions allow the release of the active agent so as to achieve its intended therapeutic or nutritional function. This method is a specific example of a method known to those skilled in the art as "direct functionalization".

[0006] The term "direct functionalization" is understood to mean the modification of at least one physicochemical property of the active pharmaceutical ingredient by carrying out a specific formulation and with the aid of a specific method.

[0007] Among the best known encapsulation techniques, mention may be made of techniques using mainly hydrophilic compounds, but also of techniques using mainly hydrophobic compounds, such as the "prilling" technique, i.e. a technique comprising the steps of atomizing a lipid form containing at least one active agent so as to obtain a solid spherical form (also called "spray freezing" or "spray cooling"), congealing, hot-melt coating, hot-melt extrusion, melt granulation, pelletization, spheronization, thermogranulation, etc.

[0008] This “direct functionalization”, especially by means of encapsulation techniques, can therefore present the advantages of stabilizing certain compounds that are inherently unstable, such as, for example, volatile compounds, preventing oxidation phenomena and generally preserving the pharmaceutical or nutritional activity.

[0009] This initial "direct functionalization" step (especially by means of encapsulation technology) can also have an effect on the release kinetics of the active agent in the host organism. Such an effect is usually sought, especially with the aim of masking taste, odor or in order to obtain a delayed, controlled release of the active agent in a target biological area in the human or animal body.

[0010] During the phase of development of a therapeutic or prophylactic or nutritional composition, the impact of this "direct functionalization" step on the release profile of the active agent is taken into account.

[0011] However, during the scale-up phase of the process using industrial shaping tools which involve mechanical stress on the galenic form, those skilled in the art find themselves faced with the recurring problem of undesired variations in the controlled release profile compared to the formulations initially tested on a scale not requiring the use of such tools.

[0012] As an example, the release profile of the active agent after "direct functionalization" can be greatly modified, accelerated or slowed down after using a method for inducing significant mechanical stress (such as a compression method). Therefore, it is possible that the lipid protection induced by the initial "functionalization" is compromised by weakening the "protective shell" during compression, which can induce an accelerated release profile of the active agent.

[0013] During the downstream steps of galenic molding of these extended release formulations, it was observed that the release profile of the active agent obtained and demonstrated after functionalization can be significantly affected and can show significant differences relative to the release profile of the active agent before galenic molding. Therefore, after implementing a step (such as a compression step) involving significant mechanical stress in the method for preparing the functionalized active agent, the release profile of the active agent after functionalization can be greatly modified, accelerated or slowed down. More particularly as an example, the lipid protection induced by the initial functionalization can be compromised by weakening the "protective shell" during compression, which can lead to an accelerated and undesirable release profile of the active agent.

[0014] To date and according to the Applicant's knowledge, the person skilled in the art has no solution making it possible to develop and manufacture a formulation comprising an active ingredient that is released in a delayed or prolonged manner and whose release profile is not altered by a manufacturing process comprising at least one step subjecting the formulation and / or galenic form to significant mechanical stress, wherein the galenic form is manufactured by a process comprising at least one step applying significant mechanical stress.

[0015] The solution of the present invention is a lipid composition comprising, per 100% by weight:

[0016] - from 40% to 99.9%, more particularly from 40% to 98% and still more particularly from 40% to 95% by weight of a component comprising, per 100% of its weight, from 90% to 100% by weight of beeswax and at most 10% by weight of at least one other lipid excipient,

[0017] - from 0.1% to 60% by weight, more particularly from 2% to 60% by weight and still more particularly from 5% to 60% by weight of at least one lipophilic surfactant chosen from polyethoxylated fatty acids, esters of fatty diacids and polyethylene glycol, esters of polyglycerol and fatty acids, esters of propylene glycol and fatty acids, mixtures of esters of propylene glycol and glycerol, fatty acid diglycerides, sterols and sterol derivatives, esters of fatty acids and sorbitan, esters of sorbitan with polyethylene glycol and fatty acids, ethers of polyethylene glycol and alkyl groups, sucrose esters, and polyoxyethylene-polyoxypropylene block copolymers.

[0018] The composition according to the invention can take various forms that are solid at ambient temperature (beads, spheres, scales, flakes, beads, etc.). It is primarily intended for use in the formation of active agents in animal or human medicine, in the therapeutic and / or preventive industrial sectors, in food supplements and / or in the human and animal food industry.

[0019] For the purposes of the present invention, the term "lipid excipient" is understood to mean an excipient having a melting point less than or equal to 120°C, preferably less than or equal to 100°C, which is solid at ambient temperature (greater than or equal to 15°C and less than or equal to 30°C) and which is insoluble or sparingly soluble in water.

[0020] The beeswax used in the composition according to the invention is yellow or white, also denoted by reference E901 and has a melting point between 60 and 67°C.

[0021] With respect to lipophilic surfactants, it is specified herein that the terms "lipophilic" and "hydrophilic" are relative terms. An empirical parameter commonly used to characterize the relative lipophilicity and hydrophilicity of nonionic amphiphilic compounds is the hydrophilicity-lipophilicity balance, a value known as "HLB".

[0022] Thus, surfactants with lower HLB values ​​are more lipophilic and have greater solubility in oils, whereas surfactants with higher HLB values ​​are more hydrophilic and have greater solubility in aqueous solutions.

[0023] Using the HLB value as a guide, hydrophilic surfactants are generally considered to be compounds having an HLB value greater than or equal to 10, and are also anionic, cationic, or zwitterionic compounds for which the HLB scale is generally not applicable. Likewise, lipophilic surfactants are compounds having an HLB value less than about 10. In both cases, the term "about" is mentioned due to the variability caused.

[0024] As appropriate, the lipid composition according to the invention may have one or more of the following characteristics:

[0025] - lipid excipients are chosen from animal waxes, vegetable waxes, mineral waxes, synthetic waxes or hydrogenated vegetable oils;

[0026] - lipophilic surfactants are selected from esters of fatty acids and sugars;

[0027] - the lipophilic surfactant is a lipophilic surfactant from the family of sorbitan esters, more particularly an element from the group consisting of sorbitan monolaurate, sorbitan monopalmitate, sorbitan monostearate and sorbitan monooleate, and even more particularly sorbitan monopalmitate or sorbitan monostearate, and even more particularly sorbitan monostearate;

[0028] - the composition comprises from 0% to 20% by weight, more particularly from 0% to 10% by weight, of one or more hydrophilic surfactants;

[0029] - one or more hydrophilic surfactants selected from soya lecithin, polyethoxylated sorbitan esters, polyethoxylated alcohols, polyethoxylated acids, polyglycerol esters, glucose ethers and block copolymers of ethylene oxide and propylene oxide;

[0030] - the lipophilic surfactant is a sorbitan ester and the hydrophilic surfactant is selected from polyethoxylated sorbitan esters;

[0031] - The composition comprises: 80% beeswax, 20% sorbitan stearate;

[0032] - the composition comprises: 94% beeswax, 1% sorbitan stearate, and 5% sorbitan oleate polyethoxylated with 20 moles of ethylene oxide (also known as polysorbate 80);

[0033] - the composition comprises: 75% beeswax, 20% sorbitan stearate, and 5% sorbitan oleate polyethoxylated with 20 moles of ethylene oxide (also known as polysorbate 80);

[0034] - The composition comprises: 50% beeswax, 45% sorbitan stearate, and 5% sorbitan oleate polyethoxylated with 20 moles of ethylene oxide (or polysorbate 80);

[0035] - the composition comprises from 0 to 20% by weight and more particularly from 0 to 10% by weight of at least one coating auxiliary;

[0036] - One or more coating aids are selected from diluents, flavoring agents, appetizers, colorants, antioxidants, plasticizers, defoamers and disintegrants.

[0037] About lipid excipients:

[0038] - As animal waxes, mention may be made of: spermaceti, having a melting point between 52° C. and 55° C., lanolin, having a melting point between 37° C. and 44° C., and shellac, having a melting point between 77° C. and 90° C.;

[0039] - As vegetable waxes, mention may be made of: carnauba wax having a melting point between 78° C. and 88° C., candelilla wax having a melting point between 67° C. and 79° C., and rice wax having a melting point close to 78° C.;

[0040] - As mineral waxes, mention may be made of paraffin waxes having a melting point between 50° C. and 71° C., and microcrystalline waxes having a melting point between 54° C. and 102° C.;

[0041] - As synthetic waxes, there may be mentioned: Fischer-Tropsch wax, polyethylene (or polypropylene) wax, poly(ethylene oxide) or poly(propylene oxide) wax, etc.;

[0042] - As hydrogenated vegetable oils, mention may be made of: palm oil, having a melting point between 58 and 62°C, and stearin, having a melting point between 61 and 65°C.

[0043] Among the lipophilic surfactants, mention may be made of:

[0044] - esters of fatty acids and glycerol, the fatty acids being chosen from stearic acid, palmitic acid, ketostearic acid, arachidic acid and behenic acid;

[0045] - ethers of fatty alcohols and sugars, the fatty alcohols being stearyl alcohol, palmityl alcohol, ketostearyl alcohol, arachidyl alcohol and behenyl alcohol; the sugars being, for example, reducing sugars and more particularly glucose, xylose, arabinose, mannose or sucrose;

[0046] - divalent salts of fatty acids, such as magnesium, zinc or calcium salts of stearic acid, palmitic acid, ketostearic acid, arachidic acid and behenic acid;

[0047] - fatty alcohols condensed with propylene oxide and / or butylene oxide;

[0048] - block copolymers of alcoholates (ethylene, propylene, butylene, etc.), rich in propylene oxide or butylene oxide;

[0049] - esters of fatty acids and sugars; the fatty acids are selected from stearic acid, palmitic acid, ketostearic acid, arachidic acid and behenic acid; the sugars are, for example, glucose, sorbitol, mannose, mannitol, sucrose, mannose, xylitol or xylose;

[0050] - Among the esters of fatty acids and sugars, mention may in particular be made of the esters of fatty acids and sorbitol, and the esters of fatty acids and sorbitan.

[0051] Among the sorbitan esters that can be combined with the composition that is the subject of the invention, mention may be made of:

[0052] - Sorbitan monolaurate, marketed by SEPPIC under the trade name Montane TM 20 sold by Croda under the trade name Span TM 20 sold by, and by,

[0053] - Sorbitan monopalmitate, marketed by SEPPIC under the trade name Montane TM 40 and sold by Croda under the trade name Span TM40 for sale,

[0054] - Sorbitan monostearate, marketed by SEPPIC under the trade name Montane TM 60 and sold by Croda under the trade name Span TM 60 for sale,

[0055] - Sorbitan monooleate, marketed by SEPPIC under the trade name Montane TM 80 and sold by Croda under the trade name Span TM 80 for sale,

[0056] - Sorbitan trioleate, marketed by SEPPIC under the trade name Montane TM 85 and sold by Croda under the trade name Span TM 85 for sale,

[0057] - Sorbitan sesquioleate, marketed by SEPPIC under the trade name Montane TM 83 sold by Croda under the trade name CrillT M 43 sold by, and by,

[0058] - Sorbitan tristearate, marketed by SEPPIC under the trade name Montane TM 65 and sold by Croda under the trade name Span TM 65 for sale,

[0059] - Sorbitan monoisostearate, marketed by SEPPIC under the trade name Montane TM 70 and sold by Croda under the trade name CrillT M 6 for sale.

[0060] The composition according to the invention optionally comprises from 0 to 20% of one or more hydrophilic surfactants chosen from soya lecithin, ethoxylated sorbitan esters, polyethoxylated alcohols, polyethoxylated acids, polyglycerol esters, glucose ethers and block copolymers of ethylene oxide and propylene oxide.

[0061] Among the ethoxylated sorbitan esters that may be combined with the composition that is the subject of the invention, mention may be made of:

[0062] - Sorbitan monolaurate ethoxylated with 20 mol of ethylene oxide, marketed by SEPPIC under the trade name Montanox TM 20 and sold by Croda under the trade name Tween TM 20 for sale,

[0063] - Sorbitan monolaurate ethoxylated with 4 moles of ethylene oxide, sold under the trade name Tween TM 21 for sale,

[0064] - Sorbitan monolaurate ethoxylated with 6 mol of ethylene oxide, commercially available from Nikko under the trade name Nikkol T M Sold by GL-I,

[0065] - Sorbitan monopalmitate ethoxylated with 20 moles of ethylene oxide, marketed by SEPPIC under the trade name Montanox TM 40 and sold by Croda under the trade name Tween TM 40 for sale,

[0066] - Sorbitan monostearate ethoxylated with 20 mol of ethylene oxide, marketed by SEPPIC under the trade name Montanox TM 60 and sold by Croda under the trade name Tween TM 60 for sale,

[0067] - Sorbitan tristearate ethoxylated with 20 moles of ethylene oxide, marketed by SEPPIC under the trade name Montanox TM 65 and sold by Croda under the trade name Tween TM 65 for sale,

[0068] - Sorbitan monooleate ethoxylated with 20 moles of ethylene oxide, marketed by SEPPIC under the trade name Montanox TM 80 and sold by Croda under the trade name Tween TM 80 for sale,

[0069] - Sorbitan trioleate ethoxylated with 20 moles of ethylene oxide, marketed by SEPPIC under the trade name Montanox TM 85 and sold by Croda under the trade name Tween TM85 for sale,

[0070] - Sorbitan monoisostearate ethoxylated with 20 mol of ethylene oxide, marketed by SEPPIC under the trade name Montanox TM 70 and sold by Croda under the trade name Tween TM 120 for sale,

[0071] - Sorbitan monostearate ethoxylated with 4 mol of ethylene oxide, marketed by Croda under the trade name Tween TM 61 for sale,

[0072] - Sorbitan monooleate ethoxylated with 5 mol of ethylene oxide, marketed by SEPPIC under the trade name Montanox TM 81 and sold by Croda under the trade name Tween TM 81 for sale.

[0073] As hydrophilic surfactant, among the ethoxylated fatty alcohols that can be combined with the composition that is the subject of the invention, mention may be made of oleyl alcohol ethoxylated with 2 mol of ethylene oxide, oleyl alcohol ethoxylated with 3 mol of ethylene oxide, oleyl alcohol ethoxylated with 5 mol of ethylene oxide, oleyl alcohol ethoxylated with 10 mol of ethylene oxide, oleyl alcohol ethoxylated with 20 mol of ethylene oxide, lauryl alcohol ethoxylated with 4 mol of ethylene oxide, lauryl alcohol ethoxylated with 7 mol of ethylene oxide, lauryl alcohol ethoxylated with 9 mol of ethylene oxide. ethoxylated with 10 mol of ethylene oxide, lauryl alcohol ethoxylated with 23 mol of ethylene oxide, cetyl alcohol ethoxylated with 2 mol of ethylene oxide, cetyl alcohol ethoxylated with 10 mol of ethylene oxide, cetyl alcohol ethoxylated with 20 mol of ethylene oxide, stearyl alcohol ethoxylated with 2 mol of ethylene oxide, stearyl alcohol ethoxylated with 10 mol of ethylene oxide, stearyl alcohol ethoxylated with 20 mol of ethylene oxide, or stearyl alcohol ethoxylated with 100 mol of ethylene oxide.

[0074] As hydrophilic surfactant, among the ethoxylated fatty acids that may be combined with the composition that is the subject of the invention, mention may be made of monolauric acid ethoxylated with between 4 and 200 mol of ethylene oxide, and more particularly monolauric acid ethoxylated with 4 mol of ethylene oxide, monolauric acid ethoxylated with 6 mol of ethylene oxide, monolauric acid ethoxylated with 7 mol of ethylene oxide, monolauric acid ethoxylated with 8 mol of ethylene oxide, monolauric acid ethoxylated with 10 mol of ethylene oxide, monolauric acid ethoxylated with 50 mol of ethylene oxide. The present invention relates to monooleic acid, monolauric acid ethoxylated with 100 mol of ethylene oxide or monolauric acid ethoxylated with 200 mol of ethylene oxide, monooleic acid ethoxylated with between 4 mol and 200 mol of ethylene oxide, and more particularly monooleic acid ethoxylated with 1 mol of ethylene oxide, monooleic acid ethoxylated with 2 mol of ethylene oxide, monooleic acid ethoxylated with 4 mol of ethylene oxide, monooleic acid ethoxylated with 5 mol of ethylene oxide, monooleic acid ethoxylated with 6 mol of ethylene oxide, monooleic acid ethoxylated with 8 mol of ethylene oxide, monooleic acid ethoxylated with 9 mol of ethylene oxide. ethylene oxide, monooleic acid ethoxylated with 10 mol of ethylene oxide, monooleic acid ethoxylated with 50 mol of ethylene oxide, monooleic acid ethoxylated with 100 mol of ethylene oxide or monooleic acid ethoxylated with 200 mol of ethylene oxide, monostearic acid ethoxylated with between 4 mol and 200 mol of ethylene oxide, and more particularly monostearic acid ethoxylated with 1 mol of ethylene oxide, monostearic acid ethoxylated with 2 mol of ethylene oxide, monostearic acid ethoxylated with 4 mol of ethylene oxide, monostearic acid ethoxylated with 5 mol of ethylene oxide, and monostearic acid ethoxylated with 10 mol of ethylene oxide. ethylene oxide, monostearic acid ethoxylated with 6 moles of ethylene oxide, monostearic acid ethoxylated with 8 moles of ethylene oxide, monostearic acid ethoxylated with 9 moles of ethylene oxide, monostearic acid ethoxylated with 10 moles of ethylene oxide, monostearic acid ethoxylated with 50 moles of ethylene oxide, monostearic acid ethoxylated with 100 moles of ethylene oxide, monostearic acid ethoxylated with 200 moles of ethylene oxide, monostearic acid ethoxylated with 300 moles of ethylene oxide, or monostearic acid ethoxylated with 1000 moles of ethylene oxide.

[0075] As hydrophilic surfactant, among the hydrogenated and ethoxylated castor oils that can be combined with the composition that is the subject of the invention, mention may be made of hydrogenated castor oil ethoxylated with 5 mol of ethylene oxide, hydrogenated castor oil ethoxylated with 7 mol of ethylene oxide, hydrogenated castor oil ethoxylated with 10 mol of ethylene oxide, hydrogenated castor oil ethoxylated with 20 mol of ethylene oxide, hydrogenated castor oil ethoxylated with 25 mol of ethylene oxide, hydrogenated castor oil ethoxylated with 30 mol of ethylene oxide, hydrogenated castor oil ethoxylated with 40 mol of ethylene oxide, hydrogenated castor oil ethoxylated with 45 mol of ethylene oxide, hydrogenated castor oil ethoxylated with 50 mol of ethylene oxide, hydrogenated castor oil ethoxylated with 60 mol of ethylene oxide, hydrogenated castor oil ethoxylated with 80 mol of ethylene oxide or hydrogenated castor oil ethoxylated with 100 mol of ethylene oxide.

[0076] The composition according to the invention optionally comprises from 0 to 20% of at least one coating aid selected from diluents, plasticizers, defoamers and disintegrants.

[0077] Among the diluents that can be combined with the composition that is the subject of the invention, mention may be made of: lactose, sucrose, mannitol, sorbitol, xylose, xylitol, isomalt, talc, natural starch, silica, silicadioxide and magnesium stearate.

[0078] Among the plasticizers that can be combined with the composition that is the subject of the invention, mention may be made of: glycerol, polypropylene glycol, polyethylene glycol or their derivatives condensed with fatty acids or fatty alcohols, stearic acid and its derivatives, acetylated monoglycerides, esters of citric acid (such as, for example, triethyl citrate, acetyl triethyl citrate or acetyl tributyl citrate), triacetin, sorbitol or dibutyl sebacate.

[0079] Among the antifoaming agents that can be combined with the composition that is the subject of the present invention, mention may be made of silicone derivatives.

[0080] Among the disintegrants that may be combined with the composition that is the subject of the present invention, mention may be made of: cellulose derivatives, crospovidone, croscarmellose sodium and sodium starch glycolate.

[0081] It should be noted that other adjuvants, such as aromas, flavorings, appetizers, colorants, pigments and antioxidants, may be combined with the composition that is the subject of the present invention.

[0082] The subject of the present invention is also a controlled release composition (C A ), which contains:

[0083] - at least one lipid composition according to the invention, and

[0084] - At least one active pharmaceutical, prophylactic or food substance.

[0085] The composition according to the present invention (C A ) will preferably be intended for oral administration to humans or animals.

[0086] According to another preferred embodiment, the composition (C A ) will be in solid form.

[0087] Among the active pharmaceutical ingredients, there can be mentioned nonsteroidal anti-inflammatory and antirheumatic drugs (ketoprofen, ibuprofen, flurbiprofen, indomethacin, phenylbutazone, allopurinol, etc.), analgesics (acetaminophen, phenacetin, aspirin, etc.), antitussives (codeine, codeine, alimamazine, etc.), sterols (hydrocortisone, cortisone, progesterone, testosterone, triamcinolone, dexamethasone, betamethasone, paramethasone, fluocinolone, beclomethasone, etc.), barbiturates (barbital, allobarbital, phenobarbital, pentobarbital, amobarbital, etc.), antimicrobial agents (penicillin, phenobarbital, pentobarbital, etc.), Derivatives of fluoroquinolones, sparfloxacin and quinolone, tetracycline, synergistins, metronidazole, etc.), medicines intended for the treatment of allergies, antiasthmatics, vitamins (vitamin A, vitamin B, vitamin C, vitamin E, vitamin D, vitamin K), antispasmodics and antisecretory agents (omeprazole), cardiovascular agents and cerebral vasodilators (quinacranolol, oxathioprenolol, propranolol, nicergoline, etc.), brain protectants, liver protectants, gastrointestinal therapeutic agents, vaccines, antihypertensive drugs and cardioprotective agents (such as beta-blockers and nitro derivatives).

[0088] Among the nutritional agents, mention may be made of active ingredients commonly used in the field of nutrition, such as bioactive lipids, water-soluble or water-dispersible trace element salts, water-soluble or fat-soluble vitamins, prebiotics, probiotics, milk proteins and / or milk protein concentrates, plant or animal enzymes, amino acids, peptides, sugars, flavor enhancers, flavorings, vegetable ingredients (ginger, curcumin, St. John's wort, valerian vegetable extracts, blueberry extract, pomegranate extract, Chlorella vulgaris extract, artichoke extract, hibiscus extract).

[0089] Among the biologically active lipids, mention may be made of phytosterols, such as those extracted from vegetable oils, and more particularly extracts of sea buckthorn oil, corn oil or soybean oil; phytosterol complexes isolated from vegetable oils, such as, for example, phytosterols (cholestatin) (composed of campesterol, stigmasterol and brassicasterol); phytostanols; carotenoids, which belong to the terpenoid family and are extracted from algae, green plants, fungi or bacteria; polyunsaturated fatty acids of the ω-3 group, such as, for example, α-linolenic acid, eicosapentaenoic acid or docosahexanoic acid; polyunsaturated fatty acids of the ω-6 group, such as, for example, linoleic acid, γ-linolenic acid, acid,

[0090] Among the water-soluble or water-dispersible trace element salts used in the ingestible solid form coated with the coating composition that is the subject of the invention, mention may be made of ferrous carbonate, ferrous chloride tetrahydrate, ferrous chloride hexahydrate, ferrous citrate hexahydrate, ferrous fumarate, ferrous lactate tetrahydrate, ferrous sulfate monohydrate, ferrous sulfate heptahydrate, ferrous chelates of amino acid hydrates, ferrous glycinate chelates; calcium iodate hexahydrate, calcium iodate anhydrous; sodium iodide, potassium iodide; cobalt acetate tetrahydrate, basic cobalt carbonate monohydrate, cobalt carbonate hexahydrate, cobalt sulfate heptahydrate, cobalt sulfate monohydrate, cobalt nitrate hexahydrate; copper acetate monohydrate, copper monohydrate Basic copper carbonate, copper chloride dihydrate, copper methionine, copper sulfate pentahydrate, cuprous chelate of amino acid hydrate, cuprous chelate of glycine hydrate, copper chelate of methionine hydroxy analog; manganese carbonate, manganese chloride tetrahydrate, manganese hydrogen phosphate trihydrate, manganese sulfate tetrahydrate, manganese sulfate monohydrate, manganese chelate of amino acid hydrate, manganese chelate of glycine hydrate, manganese chelate of methionine hydroxy analog; ammonium molybdate, sodium molybdate, sodium selenite, sodium selenate; selenium produced by Saccharomyces cerevisiae, selenomethionine (inactivated selenium yeast), and organic forms of selenomethionine produced by Saccharomyces cerevisiae (inactivated selenium yeast).

[0091] Among the inorganic salts, mention may be made of salts of metal cations such as, for example, sodium, potassium, calcium, magnesium, zinc, manganese, iron, copper, cobalt, silver, barium, zirconium and strontium cations, and of salts of organic anions such as, for example, edible organic anions having at least one carboxylic acid function in the form of a carboxylate, chosen from elements in the group consisting of glycolic acid, citric acid, tartaric acid, salicylic acid, lactic acid, mandelic acid, ascorbic acid, pyruvic acid, fumaric acid, glycerophosphoric acid, retinoic acid, benzoic acid, kojic acid, malic acid, gluconic acid, galacturonic acid, propionic acid, heptanoic acid, 4-aminobenzoic acid, cinnamic acid, benzalmalonic acid, aspartic acid and glutamic acid.

[0092] Among the inorganic salts, mention may more particularly be made of zinc gluconate, calcium gluconate, manganese gluconate, copper gluconate, magnesium aspartate, calcium aspartate, calcium glycerophosphate, calcium, magnesium glycerophosphate.

[0093] Among the water-soluble or fat-soluble vitamins, mention may be made of vitamin A, more particularly in the form of retinol, retinyl acetate, retinyl palmitate or beta-carotene, vitamin D2, more particularly in the form of ergocalciferol or -hydroxycalciferol; vitamin D3, more particularly in the form of cholecalciferol; vitamin K, more particularly in the form of phylloquinone (phytomenadione hydrochloride) or menaquinone; vitamin B1, more particularly in the form of thiamine hydrochloride, thiamine mononitrate, thiamine chloride monophosphate or thiamine chloride pyrophosphate; vitamin B2, more particularly in the form of riboflavin or riboflavin 5′-sodium phosphate; vitamin B6, more particularly in the form of pyridoxine hydrochloride, pyridoxine 5′-phosphate or pyridoxal 5′-phosphate; vitamin B12, more particularly in the form of cyanocobalamin, hydroxocobalamin, 5′-deoxyadenosylcobalamin or methylcobalamin. ; vitamin C, more particularly in the form of L-ascorbic acid, sodium L-ascorbate, calcium L-ascorbate, potassium L-ascorbate, the calcium salt of 6-palmitoyl-L-ascorbic acid or sodium ascorbyl monophosphate; pantothenic acid, more particularly in the form of calcium D-pantothenate, sodium D-pantothenate, dexpanthenol or pantethine; vitamin PP, more particularly in the form of niacin, nicotinic acid, niacinamide or inositol hexanicotinate (inositol hexanicotinate); vitamin B9, more particularly in the form of folic acid or a folate, more particularly in the form of pteroylmonoglutamate, calcium L-methylfolate or (6S)-5-methyltetrahydrofolate in the form of a glucosamine salt; vitamin H2, B7 or BW, more particularly in the form of biotin, choline, more particularly in the form of choline chloride, choline dihydrogen citrate or choline bitartrate, inositol, carnitine, more particularly in the form of L-carnitine or L-carnitine L-tartrate or taurine.

[0094] Among the prebiotics, mention may be made of inulin, transgalacto-oligosaccharides, fructans and manno-oligosaccharides.

[0095] Among the probiotics, various strains of Saccharomyces cerevisiae, Bacillus cereus var. toyoi, Bacillus subtilis alone or in combination with Bacillus licheniformis, or other strains of Enterococcus faecium, lactic acid bacteria and more particularly lactobacilli, bifidobacteria and streptococci may be mentioned. These microbial strains are usually combined with a solid carrier such as calcium carbonate, dextrose or sorbitol.

[0096] Among the proteins and / or protein concentrates, mention may be made of milk proteins resulting from milk lysis, such as: colostrum in the form of a freeze-dried or atomized powder; whey in the form of a powder, a purified fraction or a fraction enriched in IgG, lactoferrin or lactoperoxidase. Among the plant or animal enzymes, mention may be made of promutase, superoxide dismutase (SOD), 3-phytase, 6-phytase, endo-1,4-β-glucanase, endo-1,4-β-xylanase or other enzymes that improve or promote digestion.

[0097] Among the peptides, mention may be made of avocado peptides, lupin peptides, quinoa peptides, maca peptides, fermented or non-fermented soy peptides, rice peptides, peptides present in an Acacia macrostachya seed extract or peptides present in a Passionflower seed extract.

[0098] Among the amino acids, mention may be made of alanine, arginine, asparagine, aspartic acid, cysteine, glutamic acid, glutamine, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, hydroxyproline, pyrrolysine, selenocysteine, serine, threonine, tryptophan, tyrosine, valine, sarcosine or ornithine.

[0099] Among the sugars, mention may be made of water-soluble polysaccharides, or low molecular weight sugars such as oligosaccharides or mono- or disaccharides such as, for example, glucose, lactose or dextrose.

[0100] Among the flavor enhancers, mention may be made of: glutamates, such as, for example, glutamic acid, monosodium glutamate, monopotassium glutamate, calcium diglutamate, ammonium glutamate or magnesium diglutamate; guanylate salts, such as, for example, guanylic acid (guanylic acid monophosphate), disodium guanylate, dipotassium guanylate or calcium guanylate; inosinate salts, such as, for example, inosinic acid, disodium inosinate, dipotassium inosinate or calcium inosinate; or also strong sweeteners, such as Stevia extract or rebaudiosides.

[0101] A subject of the present invention is also the use of a lipid composition according to the invention for encapsulating active pharmaceutical, therapeutic, prophylactic or food substances for humans or animals in galenical formulations.

[0102] For the purposes of the present invention, the term "encapsulation" is understood to mean an operation that allows the lipid composition and one or more active ingredients to be brought together. One or more active agents can be located inside the shell formed by the "cooled" lipid composition or dispersed within the shell.

[0103] Finally, a final subject of the invention is a process for preparing a galenical form comprising a composition (CA) according to the invention, comprising at least:

[0104] a) a step of preparing a lipid composition according to the present invention,

[0105] b) mixing and encapsulating an active pharmaceutical, prophylactic or food substance with the lipid composition prepared in step a) in order to obtain a composition according to the invention (C) A ), and

[0106] c) the composition (C) prepared in step b) A ) Galenic forming step, which involves mechanical stress.

[0107] The term "mechanical stress" is understood to mean a tension or pressure acting on a material and which can modify the shape or properties of said material. In the context of the present invention, this is the stress exerted on the composition CA during its use in the preparation of the final galenical form (step c).

[0108] Still in the context of the present invention, it is noteworthy that the release profile of the active substance in the final galenical form is similar to or does not differ greatly from that of the active substance in composition CA. In particular, this is due to the resistance of the lipid composition according to the invention to mechanical stress, and therefore little or no change in the release profile is observed.

[0109] Among the encapsulation methods used in step b), mention may be made of prilling, spray freezing or spray cooling, spray congealing, hot melt coating, hot melt extrusion, melt granulation, pelletization, spheronization, or thermogranulation, etc. (insert French translation whenever possible).

[0110] The term "prilling" refers to a method of coating by dissolving or dispersing one or more active ingredients in a molten lipid composition and then spraying it into ambient or cooled air, or into a cooled liquid.

[0111] The processes of "spray freezing", "spray cooling" and "spray congealing" are special cases of the prilling process.

[0112] The term "hot melt coating" refers to a coating process by spraying a molten lipid composition onto solid particles consisting of an active agent or a mixture of active agents.

[0113] Depending on the circumstances, the manufacturing method according to the invention may have one or more of the following features:

[0114] - The mixing and encapsulation step b) comprises: a first sub-step of heating the lipid composition prepared in step a) to a temperature 10°C to 15°C higher than the highest melting point of the various components of the lipid composition, so as to melt the lipid composition; a second sub-step of mixing the molten lipid composition with the active substance in dispersed or molten form; and a third sub-step of spraying the composition obtained in the second sub-step into ambient air or cooled air or into a cooled liquid, so as to obtain a composition (C A ) solidified particles; the term "ambient air" is understood to mean air at an ambient temperature, usually around 25°C; the term "cooled air" or "cooled liquid" is understood to mean air or liquid at a temperature less than the ambient temperature, in other words less than 25°C;

[0115] - The galenic forming step involving mechanical stress is selected from the process of conversion into a solid oral dosage form and for example compression, forming into hard capsules (capsule filling / forming), compacting (compacting, rolling), packaging, placing into sachets, forming into bars (bar and sachet filling), extrusion, granulation, and pelletization; these techniques can lead to the manufacture of the following forms (non-exhaustive): oral powders, beads, hard capsules (capsules), granules, sugar-coated granules, beads, pellets, spheres (pellets), tablets, sachets, bars, chewables, gums, chewable tablets, chewable gums.

[0116] The lipid composition according to the invention makes it possible to shape the active substance by various coating techniques, unexpectedly inducing a stability in the release profile of the active substance thus coated compared to the release profile of the active substance in galenical form that has not been obtained by a process involving a mechanical stressing step.

[0117] In other words, the subject matter of the present invention makes it possible to maintain the release profile of the active substance initially sought, regardless of the downstream galenic forming processes carried out and regardless of the mechanical stresses applied to transform the active agent into the final product form (mixing, compacting, forming into hard capsules, forming into strips, tableting, etc.).

[0118] For the purposes of the present invention, the term "shaped according to a technique for coating an active agent" is understood to mean any essential technique or any method which makes it possible to give to the composition comprising said active agent a physical form, preferably a form that is solid at ambient temperature.

[0119] The following examples illustrate the invention without however limiting it.

[0120] Examples

[0121] The qualification of the encapsulation composition as described above to induce resistance to the mechanical stress of downstream galenic steps was established by setting up the analysis described below.

[0122] An active agent was selected as the master model active agent. Note that the term "active agent" is understood to mean an active substance. The active substance is caffeine, which has an average solubility of 20-25 g / l in water at ambient temperature (25°C).

[0123] Molecular formula: C8H10N4I2; molecular weight: 194.194 g / mol.

[0124] The active agent is encapsulated with the composition that is the subject of the present invention at a rate of 20% to 30% by means of the rotating disk granulation technique.

[0125] Rotating disk granulation technique: method for preparing composition M1

[0126] For each test, a waxy liquid dispersion was prepared. The waxy liquid dispersion consisted of:

[0127] the composition which is the subject of the invention in molten form;

[0128] • Model active agent in dispersed solid form. In general, it should be remembered that an active agent can be present in dispersed or liquid form, depending on the value of its melting point.

[0129] For this purpose, a "predispersion" - the result of melting and / or mixing in the liquid state the various elements of the composition subject of the invention - is prepared beforehand: mixture preparation M0.

[0130] The temperature at which this predispersion and then the reconstituted dispersion are maintained should be adjusted so as to be 10-15° C. above the highest melting point of the various ingredients of the composition. Before starting the manufacturing process, the active agent is added (in this case dispersed) under mechanical stirring while maintaining the previously established temperature.

[0131] The rotating disk granulation process is then carried out. The dispersion is conveyed by means of an insulated pipe to a spray nozzle located in a space / tower, which after spraying results in the production of fine droplets. These fine droplets are then solidified in a stream of cold ambient air, resulting in the formation of small spherical beads, characterized in that 50% by volume of these beads have a diameter between 300 μm and 500 μm. It will be noted that the particle size distribution of the beads is measured by means of a Mastersizer 3000 laser particle size analyzer from Malvern used in a dry path at a pressure of 1 bar.

[0132] Silica or another flow / anti-sticking agent may optionally be pre-added to the microbeads thus produced in order to facilitate their subsequent handling.

[0133] Likewise, sieving may be performed on a 500 μm sieve in order to remove any undesirable aggregates / residues having a particle size greater than or equal to 500 μm.

[0134] The microbeads thus obtained are then incorporated into a mixture of excipients of a grade compatible with the tablet-type galenic forming process.The tablet form was chosen as a model final galenic forming process because it represents one of the most extreme cases of induced mechanical stresses.

[0135] Tabletting was performed on an instrumented Dott Bonapace reciprocating single punch press or an instrumented Riva Piccola rotary 8-punch press, applying a compression force between 5 kN and 20 kN; 500 mg tablets with a breaking strength between 80 N and 120 N were thus produced.

[0136] Proof of technical effectiveness:

[0137] The release profile of the active agent coated in the composition that is the subject of the present invention and then incorporated in a tablet form was established with the aid of an Erweka dissolution tester, in accordance with the recommendations of the European Pharmacopoeia, version 7.3, paragraph 2.9.3.

[0138] The primary dissolution medium of choice was phosphate buffer at pH 7.2 maintained at a temperature of 37° C. Samples were taken periodically for up to 6 hours. The samples were then analyzed by reverse phase HPLC with UV detection in order to determine the amount of active agent present in each sample and thereby establish a dissolution profile for each sample to be evaluated.

[0139] Dissolution profiles are compared from composition to composition or before / after application of a mechanical stress to determine if two profiles differ from each other or if one profile differs from a control profile.

[0140] In the following cases, it is judged that the two curves are similar or not very different, and it is therefore judged that the composition has improved resistance to mechanical stress:

[0141] Time-time difference, which is calculated as follows:

[0142] abs[% release (Txi) tablet -% release (Txi) μ beads] ≤ y%

[0143] in:

[0144] % Release (Txi) Tablet = % of active agent released at sampling point Txi when the formulation has been subjected to the tableting process.

[0145] % Release (Txi) μbeads = % of active agent released at sampling point Txi when the formulation has not been subjected to mechanical stress

[0146] and which is represented by a y value of less than or equal to 30 + / - 2% over a dissolution time of up to 2 hours, and Less than or equal to 20 + / - 2% during the remaining evaluation time.

[0147] The profiles were judged to be similar when the difference across the dissolution tests was less than or equal to 15%.

[0148] Starting from the 3-hour dissolution time, the change between the values ​​before and after the application of mechanical stress is less than or equal to 30%. Calculated as follows:

[0149]

[0150] in:

[0151] Txi>=180min

[0152] % Release (Txi) Tablet = % of active agent released at sampling point Txi when the formulation has been subjected to a tableting process (involving a compression step).

[0153] % Release (Txi) μbeads = % of active agent released at sampling point Txi when the formulation has not been subjected to mechanical stress

[0154] Example 1:

[0155] In this example, lipid compositions, which contain the same beeswax as component A, the same amount of polysorbate 80, and the same proportions of various lipophilic surfactants as component B. The composition of the prepared lipid compositions is recorded in Table 1 below. With caffeine as the active ingredient, these lipid compositions are used for coating according to the granulation method as described above. The purpose of this example is to show the effectiveness of the combination of beeswax and certain lipophilic surfactants for coating by the granulation method of active agent caffeine by observing the maintenance or non-maintenance of the release curve over time, so that certain combinations of beeswax and lipophilic surfactants may not be considered appropriate before they are subjected to the compression step.

[0156]

[0157] Table 1

[0158] The active agent was dispersed in the composition at 20%. The granulation process was carried out.

[0159] Microbeads with a median diameter between 350 and 400 μm were obtained.

[0160] These microbeads are stable for a minimum duration of 28 months at ambient temperature protected from light.

[0161] The dissolution profiles of the microbeads were studied either after the manufacturing process or after a minimum shelf life of 28 months. Various sampling times were implemented; a comparison of the profiles was performed at the 120 minute point.

[0162] Table 2 below gives the percentage values ​​of caffeine released at the 120 minute sampling point:

[0163]

[0164] Table 2

[0165] Table 3 below gives the values ​​of the time-time difference* at the 120 minute sampling point:

[0166]

[0167] Table 3

[0168] (*): When comparing the release curves at T0 and after a period of stabilization, the specific definition of the time-time difference should be noted. Therefore, the time-time difference is redefined here as calculated by:

[0169] abs[% released (120x′i) μ beads - % released (120xi) μ beads] y%

[0170] in:

[0171] % Release (120x'i)μ Beads = % of active agent released at the 120 minute sampling point when the formulation has been stored at ambient temperature for a defined duration.

[0172] % Release (120xi)μbeads = % of active agent released at the 120 minute sampling point, ie the value at T0 generated from the microbeads, when the formulation has not been stored.

[0173] Two curves are judged to be of the same magnitude when the time-to-time difference, represented by the y-value, at the sampling point in question is less than or equal to 20 + / - 2%.

[0174] When the time-to-time difference is less than or equal to 15%, the curves can be judged to be similar.

[0175] For this example, it can be observed that compositions CL1' and CL2' make it possible to maintain over time the release profile of the active agent caffeine contained in the microbeads resulting from the granulation process. Composition CL3' containing glyceryl monostearate as component B has been deductible.

[0176] Example 2:

[0177] In this example, a lipid composition containing wax as component A and oils from various sources is used for coating by the pelletization process of the active agent caffeine as described above. The purpose of this example is to demonstrate the specificity of beeswax in combination with other components for making it possible to maintain a similar / not significantly different, or otherwise, release profile of the coated active agent after the galenic forming process / after mechanical stress.

[0178] The following compositions were therefore used in parallel (Table 4):

[0179]

[0180] Table 4

[0181] The active agent was dispersed in the composition at 20%. The granulation process was carried out.

[0182] Microbeads with a median diameter between 350 and 400 μm were obtained.

[0183] These microbeads are then introduced into the mixture for tablets. Thus, 500 mg tablets with a diameter of 11 mm are prepared according to the following composition: for 40% by weight of microbeads, 27% by weight of microcrystalline cellulose, 29% by weight of dibasic calcium phosphate dihydrate, 3% by weight of crospovidone and 1% by weight of magnesium stearate are added.

[0184] The dissolution profiles of the microbeads were studied before and after the compression method. The sampling times were as follows: 60 minutes, 120 minutes, 180 minutes, 240 minutes, 300 minutes and 360 minutes.

[0185] Table 5 below gives the percentage values ​​of caffeine released over time:

[0186]

[0187] Table 5

[0188] Table 6 below gives the values ​​and rates of change of the time-time differences at 180 minutes and above:

[0189]

[0190] Table 6

[0191] For this example, it can be seen that only composition CL1 allows to improve the resistance to mechanical stress, which is here illustrated by a tablet-shaped galenic forming method.

[0192] Example 3:

[0193] In this example, a lipid composition containing a ratio of beeswax and candelilla wax as component A is used for coating by a granulation process of the active agent caffeine. The purpose of this example is to demonstrate the possibility of mixing beeswax with another lipid compound to a certain ratio, combined with other components, while still making it possible to maintain a similar / not significantly different, or otherwise release profile of the coated active agent after the galenic forming process / after mechanical stress.

[0194] Therefore the following compositions are used in parallel:

[0195]

[0196] Table 7

[0197] The active agent was dispersed in the composition at 20%. The granulation process was carried out.

[0198] Microbeads with a median diameter between 350 and 400 μm were obtained.

[0199] These microbeads were then introduced into the mixture for the preparation of tablets according to the procedure described in Example 2. Thus, 500 mg tablets having a diameter of 11 mm were prepared.

[0200] The dissolution profiles of the microbeads were studied before and after the compression method. The sampling times were as follows: 60 minutes, 120 minutes, 180 minutes, 240 minutes, 300 minutes and 360 minutes.

[0201] The following table gives the percentage of caffeine released according to time:

[0202]

[0203] Table 8

[0204] The following table gives the values ​​and rates of change of the time-time differences at and above 180 minutes:

[0205]

[0206] Table 9

[0207] In this example, compositions CL1 and CL5 allow an improvement in the resistance to mechanical stress, with a similar curve for composition CL1 and a not significantly different curve for composition CL5.

[0208] Example 4:

[0209] In this example, a lipid composition having component A (beeswax) and component B (a hydrophobic surfactant of the sorbitan ester type) is used for coating by a granulation process of the active agent caffeine.

[0210] The purpose of this example is to demonstrate the possibility of mixing component A and component B in certain ratios to maintain a similar / not significantly different, or otherwise, release profile of the coated active agent after the galenic forming process / after mechanical stress.

[0211] Therefore the following compositions are used in parallel:

[0212]

[0213] Table 10

[0214] The active agent was dispersed in the composition at 20%. The granulation process was carried out.

[0215] Microbeads with a median diameter between 350 and 400 μm were obtained.

[0216] These microbeads were then introduced into the mixture for the preparation of tablets according to the procedure described in Example 2. Thus, 500 mg tablets having a diameter of 11 mm were prepared.

[0217] The dissolution profiles of the microbeads were studied before and after the compression method. The sampling times were as follows: 30 minutes, 60 minutes, 120 minutes, 180 minutes, 240 minutes, 300 minutes and 360 minutes.

[0218] Table 11 below gives the percentage values ​​of caffeine released over time:

[0219]

[0220] Table 11

[0221] The following table gives the values ​​and rates of change of the time-time differences at and above 180 minutes:

[0222]

[0223] Table 12

[0224] In this example, compositions CL8 and CL9 allow to improve the resistance to mechanical stress. Via composition CL7, it is observed that the least amount of component B is required.

Claims

1. A galenical formulation comprising a controlled release composition (CA), Wherein the controlled release composition comprises: - at least one lipid composition, and - at least one active pharmaceutical or food substance, Wherein the lipid composition comprises per 100% by weight: - from 40% to 99.9% by weight of a component comprising, per 100% of its weight, from 90% to 100% by weight of beeswax and up to 10% by weight of at least one other lipid excipient, - from 0.1% to 60% by weight of at least one lipophilic surfactant selected from sorbitan monolaurate, sorbitan monopalmitate, sorbitan monostearate, sorbitan monooleate and glyceryl distearate, and The galenical form is manufactured by a process comprising at least the following steps: a) a step of preparing the lipid composition; b) a step of mixing and encapsulating at least one active drug or food substance with the lipid composition prepared in step a) to obtain the controlled release composition, and c) a step of galenically shaping the controlled release composition prepared in step b), which involves mechanical stress, wherein the galenically shaping step is selected from compression, extrusion, and pelletization.

2. The galenical form according to claim 1, characterized in that The lipid excipient is selected from animal wax, vegetable wax, mineral wax, synthetic wax or hydrogenated vegetable oil.

3. The galenical form according to claim 1, characterized in that The lipid composition comprises per 100% by weight: - from 40% to 98% by weight of a component comprising, per 100% of its weight, from 90% to 100% by weight of beeswax and up to 10% by weight of at least one other lipid excipient, - from 2 to 60% by weight of said at least one lipophilic surfactant.

4. The galenical form according to claim 3, characterized in that The lipid composition comprises per 100% by weight: - from 40% to 95% by weight of a component comprising, per 100% of its weight, from 90% to 100% by weight of beeswax and at most 10% by weight of at least one other lipid excipient.

5. The galenical form according to claim 3, characterized in that The lipid composition comprises per 100% by weight: - from 5 to 60% by weight of said at least one lipophilic surfactant.

6. The galenical form according to claim 1, characterized in that The lipid composition comprises per 100% by weight: - 80% to 98% by weight of a component which, per 100% of its weight, comprises from 90% to 100% by weight of beeswax and up to 10% by weight of at least one other lipid excipient, - 2 to 20% by weight of said at least one lipophilic surfactant.

7. The galenical form according to claim 6, characterized in that The lipid composition comprises per 100% by weight: - 80% to 95% by weight of a component which, per 100% of its weight, comprises from 90% to 100% by weight of beeswax and up to 10% by weight of at least one other lipid excipient.

8. The galenical form according to claim 6, characterized in that The lipid composition comprises per 100% by weight: - 5 to 20% by weight of said at least one lipophilic surfactant.

9. The galenical form according to claim 1, characterized in that The lipid composition comprises per 100% by weight: - 80% by weight of a component which, per 100% of its weight, comprises from 90 to 100% by weight of beeswax and up to 10% by weight of at least one other lipid excipient, - 20% by weight of said at least one lipophilic surfactant.

10. The galenical form according to any one of claims 1 and 9, characterized in that The lipophilic surfactant is selected from sorbitan monostearate and glyceryl distearate.

11. The galenical form according to any one of claims 1 to 9, characterized in that The lipid composition comprises from 0 to 20% of one or more hydrophilic surfactants.

12. The galenical form according to claim 10, characterized in that The lipid composition comprises from 0 to 20% of one or more hydrophilic surfactants.

13. The galenical form according to claim 11, characterized in that The one or more hydrophilic surfactants are selected from soybean lecithin, ethoxylated sorbitan esters, polyethoxylated alcohols, polyethoxylated acids, polyglycerol esters, glucose ethers, and block copolymers of ethylene oxide and propylene oxide.

14. The galenical form according to claim 11, characterized in that The lipophilic surfactant is a sorbitan ester, and the hydrophilic surfactant is selected from polyethoxylated sorbitan esters.

15. Galenical form according to claim 14, characterized in that The lipid composition comprises: -75% beeswax, -20% Sorbitan Stearate, and - 5% sorbitan oleate polyethoxylated with 20 moles of ethylene oxide.

16. The galenical form according to claim 14, characterized in that The lipid composition comprises: -50% beeswax, -45% Sorbitan Stearate, and - 5% sorbitan oleate polyethoxylated with 20 moles of ethylene oxide.

17. The galenical form according to any one of claims 1 to 9, characterized in that The lipid composition comprises from 0 to 20% of at least one coating aid.

18. Galenical form according to claim 17, characterized in that One or more of the coating aids are selected from diluents, flavoring agents, appetizers, colorants, antioxidants, plasticizers, defoamers and disintegrants.

19. The galenical form according to any one of claims 1 to 9, characterized in that The galenical form is intended for oral administration to humans or animals.

20. The galenical form according to any one of claims 1 to 9, characterized in that The galenical form is in solid form.

21. The galenical form according to any one of claims 1 to 9, characterized in that The mixing and encapsulation step b) comprises: - a first sub-step: heating the lipid composition prepared in step a) to a temperature 10°C to 15°C higher than the highest melting point of the various components of the lipid composition, so as to melt the lipid composition, - a second sub-step of mixing the molten lipid composition with said at least one active drug or food substance in dispersed or molten form, and - Third sub-step: spraying the composition obtained in the second sub-step into ambient air or cooled air or into a cooled liquid in order to obtain solidified particles of the controlled release composition.

22. The galenical form according to any one of claims 1 to 9, characterized in that Said galenic forming step involving mechanical stress is chosen from compression.

23. Galenical form according to claim 22, characterized in that The galenic forming step involving mechanical stress is compaction.

24. The galenical form according to any one of claims 1 to 9, characterized in that The active drug is a therapeutic substance or a prophylactic substance.

25. A method for producing a galenical form according to any one of claims 1 to 24, comprising at least: a) a step of preparing the lipid composition; b) a step of mixing and encapsulating at least one active drug or food substance with the lipid composition prepared in step a) to obtain the controlled release composition, and c) a step of galenically shaping the controlled release composition prepared in step b), which involves mechanical stress, wherein the galenically shaping step is selected from compression, extrusion, and pelletization.

26. The manufacturing method according to claim 25, characterized in that: The mixing and encapsulation step b) comprises: - a first sub-step: heating the lipid composition prepared in step a) to a temperature 10°C to 15°C higher than the highest melting point of the various components of the lipid composition, so as to melt the lipid composition, - a second sub-step of mixing the molten lipid composition with said at least one active drug or food substance in dispersed or molten form, and - Third sub-step: spraying the composition obtained in the second sub-step into ambient air or cooled air or into a cooled liquid in order to obtain solidified particles of the controlled release composition.

27. The manufacturing method according to claim 25 or 26, characterized in that: Said galenic forming step involving mechanical stress is chosen from compression.

28. The manufacturing method according to claim 27, characterized in that: The galenic forming step involving mechanical stress is compaction.

29. The manufacturing method according to claim 25 or 26, characterized in that: The active drug is a therapeutic substance or a prophylactic substance.

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