MXPA99002022A - Galenic formula with extended release of milnacipran - Google Patents

Abstract

The invention concerns a galenic formula with prolonged release, for oral administration of a single daily dose of 60 to 140 mg of Milnacipran, having a multi-particulate form containing a plurality of microgranules each comprising an active microsphere containing a saccharose and/or starch nucleus of a size grade between 200 and 2000&mgr;m and containing 150 to 1000&mgr;m of Milnacipran and a binding agent, each microgranule being coated with a film, with a base of at least one polymer insoluble in water but permeable to physiological liquids, of a thickness between 20 and 100&mgr;m, the said galenic formula enabling an in vitro release corresponding to thefollowing pattern:between 10 and 55%of the dose released in 2 hours, between 40 and 75%of the dose released in 4 hours, between 70 and 90%of the dose released in 8 hours, between 80 and 100%of the dose released in 12 hours.

Description

WIDTH FORM OF MILNACIPRAN WITH PROLONGED RELEASE DESCRIPTIVE MEMORY The subject of the present invention relates to the development of a multiparticulate form of the type of controlled release mini-granules for oral administration, allowing the administration, in a single daily dose, of a particular antidepressant, namely: Milnacipran. - - The novelty of this invention is based on the design of this form of mini-granule or mini-sphere which, by a combination: - the concentration of Milnacipran per mini-granule, the physico-chemical characteristics of the coating layer, - and the thickness of this film, makes it possible to control, surprisingly, the in vitro release for several hours of a molecule whose aqueous solubility is close to 800 g / 1, thus making it possible to administer it in a single dose of this entity. The Milnacipran and its cis enantiomers exist in the form of hydrochlorides, whose aqueous solubilities are close to 800 g / 1. Currently, these extremely soluble molecules, formulated with dicalcium phosphate, calcium carboxymethylcellulose and polyvinylpyrrolidone, packaged in gelatin capsules, do not allow this goal to be achieved since the in vitro release from this form of Milnacipran 50 mg is completed in 30 minutes thus requiring the administration of a gelatin capsule in the morning and a gelatin capsule in the afternoon. By contrast and surprisingly, the present invention relates to a sustained-release dosage form, directed to oral administration in a single daily dose of 60 to 240 mg of Milnacipran, provided in a multiparticulate form by combining a plurality of mini-granules containing each an active minisphere that includes a core of sucrose and / or starch having a particle size between 200 and 2000 μ and containing 150 to 1000 μ of Milnacipran as well as a binding agent, each mini-granule being covered with a film, based on in at least one polymer insoluble in water but permeable to physiological fluids, having a thickness between 20 and 100 μ, allowing said galenic form an in vitro release corresponding to the following pattern: * between 10 and 55% of the dose released in 2 hours, * between 40 and 75% of the dose released in 4 hours, * between 70 and 90% of the dose released in 8 hours, * between 80 and 100% of the dose released in 12 hours. This minigranular form containing a dose of 60 mg to 240 mg, more precisely 120 mg of Milnacipran in racemic form, of a therapeutically equivalent dose of the derivative Dextrógira Cis, allows the therapeutic activity to be maintained over a complete period of one day and one night while adjusting the levels of plasma concentrations. First of all, it will be remembered that the Milnacipran, a new antidepressant (patents Nos. FR 2,508,035 - EP 200,638 and FR 2,640,972), exhibits a new pharmacological activity since it allows a mixed inhibition of the capture of noradrenaline and serotonin, while it does not have effect on dopamine. Its chemical structure reveals two asymmetric carbons which give the molecule a Cis and Trans isomerism, for which it has been shown that the two enantiomers Cis 3on the active forms, preferably obtained by synthesis. It has also been shown that for these two Cis derivatives the dextrorotatory form is more active than the levorotatory form. Accordingly, the subject matter of the present invention applies to both the racemic molecules of Milnacipran and to the Cis enantiomers, since the physicochemical properties involved in the diffusional processes for the form remain identical. The Milnacipran and its Cis enantiomeric forms exhibit an absolute bioavailability greater than 85% and a biological half-life of between 7 and 9 hours, these properties being entirely compatible, from the pharmacokinetic point of view, with the design of a release form prolonged one dose per day.

In general two different steps should be considered in the technical production of the extended release mini-granules, namely: - the active minisphere production phase, - the active minisphere film coating phase. Several technologies can be used for the production of the active minispheres: * assembly in a tray, which consists of splashing the active ingredient with the help of a binder on the sucrose or sucrose and starch nuclei also called sugar spheres; * mounted on a bed of fluidized air, which consists of sprinkling a solution or a dispersion of the active ingredient with the aid of a binder on the bed of sugar spheres. This spray can be executed from the top to the bottom, from the bottom to the top (rter method) or tangentially (rotor method). In the latter case, the active ingredient can be sprayed in solid form concomitantly with the wetting agent or wetting liquid, with the help of a feed hopper; * Rotating granulation, which makes it possible to obtain spherical granules from an appropriate mixture of excipients and active agent on which a solution of binders is sprayed. This technology can be developed using combined rotary granulators or in another form with a fluidised air bed; * extrusion-spheronization, which allows the production of spherical grains. This involves obtaining, starting with an appropriate excipient-active agent mixture, a plastic mass after mixing it with a binder solution. The plastic mass is then extruded using various systems which make it possible to expel and / or extrude this mass (barrel extruder, double or single screw extruder, gear, piston extruder, axial or radial extrusion). The obtained extruded material is then spheronized in an appropriate spheronizer. Conventionally, two techniques are used for the production of coated minigranules: - tray: the minispheres of uncovered active are introduced in a perforated or non-perforated tray. A coating solution or dispersion is then sprayed onto the bed of minispheres with the aid of a spray nozzle or spray gun and any other suitable system that allows the production of a uniform and reproducible continuous layer, - - fluidized air bed: depending on the mode As for the chosen spray, the film coating of the active mini-spheres can be made by "spray from above", by "spray from the bottom" or by "tangential spray". The last two techniques give a more uniform coating, more continuous and more reproducible than the first technique. The main problem faced by those skilled in the art for the development of a prolonged release form in general and of the minigranus type in particular, is the aqueous solubility of the molecule. In the present case, the Milnacipran as well as its active enantiomers are very easily soluble in water (solubility = 800 g / 1). It must be remembered that it is impossible to use the basic forms for reasons of stability. Indeed, those skilled in the art know that with such molecules, the formulator who has to develop a prolonged release form faces the following antinomic problems: * avoid the phenomenon of sudden discharge which is very frequent with this type of molecules and which, in some cases, is synonymous with side effects, * and ensure perfect control of the release of the total dose administered so that any loss of product is avoided. Some formulators have solved this problem: * combining within the same formulation several fractions of minigranules (DE-3, 941, 703), being an uncovered fraction that releases during the first minutes, and a fraction coated with a large amount of polymer that controls the diffusion during the Subsequent hours, * combining within the same formulation mini-granules with multilayer film coatings (US-4, 894,240-O-9 3097 67) or chemical compositions of coatings polymers of heterogeneous nature (EP-508 653 - EP-0 322 277 ). The present invention provides, through the design of this form of minigranules for prolonged release of Milnacipran, having an aqueous solubility equal to 800 g / 1, a solution that is less restrictive for the formulator. Indeed, the formulas that are the subject of the present invention make possible, through their design (content of active ingredient per mini-granule, film thickness and composition of the film), obtain an in vitro release which is compatible with the therapeutic objective while using only one type of minigranules per formula. Due to the absence of references, it is very difficult to describe, for a molecule with a solubility higher than 500 g / 1, what could be the design for a mini-granule form manufactured by the fluidized air and / or tray technology. By way of comparison, reference can be made to the publication "Chlorpheniramine maléate controlled release spheres, I-Effect of ethyl cellulose and dibutyl sebacate levéis", A.R. Oritz LABRADOR, E.S. CHALY (# 1146), Proceed. Intern. Symp. Control. I laughed Bioact. Mater., 20, 1993 where the authors apply up to 30% of ethylcellulose combined with dibutylsebacate to obtain a delayed release profile. In patent EP-350 246, an organic base is used as a release modulating agent.

In patent WO-953 491, inorganic bases are used as supports that control the release. In WO-9 201 446, hydrophobic substances (paraffin, waxes, stearyl alcohol) combined with a film of an acrylic nature are used to control the release of soluble active agents such as salbutanol and chlorpheniramine maleate. It is obvious to those skilled in the art that this type of formulations is very difficult to produce in and to transfer to a fluidized air bed. In the patent EP-249 949, the formulator produces a premix of soluble molecules with a non-ionic polymer and an inorganic filler, before sprinkling them on the sugar spheres, on which the insoluble film is then applied. In this example, there is in fact an intermediate layer which limits the diffusion of the active ingredient towards the backing film. The solution proposed in the context of the present invention is much simpler and more easily inrializable, as is shown particularly in the examples 13, 14 and 15 below, since it provides a mini-granule form composed of a single type of spheroids: - whose core not coated with film advantageously has a size between 710 and 850 μ, - whose content of active ingredient per mini-granule is preferably close at 510 μg, and whose coating film based on ethyl cellulose in ethanolic solution is advantageously between 4% and 12.5% which is thus to say a low thickness of 20 μ to 80 μ per mini-granule. Other features and advantages of the present invention will be understood upon reading the detailed description given below especially in consideration of the number of modalities of specific examples. The components that can be used to assemble the Milnacipran in a tray are: * Minispheres, composed of sucrose and / or starch, also called sugar spheres. These sugar spheres were obtained by successive deposits of sucrose and / or starch on a sugar crystal. The sugar spheres used here preferably contain 75% sucrose and 25% starch. The sugar spheres have different sizes ranging from 200 microns to 2 mm. The sugar spheres used preferably have a size between 500 and 1000 microns and more particularly between 710 and 850 microns. * A binding agent, sprayed in solution on a bed of mini-spheres. This binder can be a cellulose derivative such as hydroxypropylmethylcellulose, methylcellulose, hydroxypropylcellulose, carboxymethylcellulose, can be gelatin, can be a sucrose solution, can be a gum such as gum arabic, gum tragacanth, guar gum, pectins and alginates . This can be derived from polyvidone such as polyvinylpyrrolidone of different molecular weights. The amount of these binders in the wetting solution can be up to 3 to 50%, and in the final product from 0.5 to 30%. The binder used is preferably polyvinylpyrrolidone having a molecular weight of about 50000 Da (type K30) in an amount of 20% in the wetting solution and an amount of 2 to 4% in the active minispheres. * The solvent used to carry the binder can be an organic solvent of the type that includes methylene chloride, acetone, an alcohol such as isopropanol or ethanol, purified water or miscible combinations of these different solvents. The solvent used is preferably ethanol. * An agent intended to prevent the agglomeration of minigranules with one another is advantageously used by spraying it on the bed of cores. Silica derivatives, metal oxides such as titanium oxide, silicates such as talc can be used in amounts between 0.5 and 20% by weight of the active minispheres. The talc is preferably used in a co-operation between 3 and 4%.

The Milnacipran is sprinkled on the bed of cores and its amount can be between 5 and 90% in the minispheres. This amount is preferably between 45 and 55% and is preferably 51%. That is, a concentration of Milnacipran per minigrain between 450 μg and 550 μg and preferably about 510 μg since the active minisphere preferably weighs one milligram. The components used during the assembly of Milnacipran in a bed of fluidized air are: * minispheres composed of sucrose and / or starch also called sugar spheres. These sugar spheres were obtained by successively depositing sugar and / or starch on a crystal of sucrose. The sugar spheres used are preferably composed of 75% sucrose and 25% starch. The sugar spheres have various sizes ranging from 200 μ to 2mm. The sugar spheres used preferably have a size between 500 and 1000 μ and more particularly between 710 and 850 μ. * A binding agent, sprayed in solution on the bed of mini-spheres. This binder can be a cellulose derivative such as hydroxypropylmethylcellulose, methylcellulose, hydroxypropylcellulose, carboxymethylcellulose, can be gelatin, can be a sucrose solution, can be a gum such as gum arabic, gum tragacanth, guar gum, pectins and alginates . It can also be derived from polyvidone such as polyvinylpyrrolidone of different molecular weights. The amount of these binders in the wetting solution can be up to 3 to 50% and in the final product from 0.5 to 30%. The binder used is preferably polyvinyl pylorridone having a molecular weight of about 50,000 Da (type K30) in an amount of 0 to 20% and more precisely 6.7% in the wetting solution and from 5 to 25%, more precisely 15.4%, in the active mini-spheres. * The solvent used to carry the binder can be isopropanol and / or acetone, ethanol and / or acetone and is preferably isopropanol. * The Milnacipran is sprayed in the form of a dispersion in an amount of 10 to 40% in the solvent. The preferred amount is 20% in the solvent. The Milnacipran can represent 5 to 90% of the active minisphere. It is preferably between 40 and 50% and is preferably 46%. That is, a concentration of Milnacipran per minigrain between 150 and 185 μg and preferably about 170 μg when the sugar spheres have a size between 500 and 600 μ. That is, a concentration of Milnacipran per mini-granules of between 440 and 555 μg and preferably close to 510 μg when the spheres have a size between 710 and 850 μ.

That is, a concentration of Milnacipran per minigrain of between 680 and 850 μ and preferably of about 780 μg when the sugar spheres have a size of between 850 to 1000 μ. The components used during the production of active spheres during extrusion-spheronization are: * A diluent, which can be hydrophilic or hydrophobic in nature. The hydrophilic diluent component may be of a cellulosic nature, such as microcrystalline cellulose, sodium cellulose or even hydroxypropylmethylcellulose. You can also use lactose and starch. The lipophilic diluent can be a monoglyceride, a diglyceride or a triglyceride. These diluents represent 5 to 90% of the active minisphere. The diluent preferably used is microcrystalline cellulose in an amount between 25 and 75% and preferably in an amount of 50%. * A binding agent, this binding agent can be a derivative of cellulose, such as hydroxypropylmethylcellulose, methylcellulose, hydroxypropylcellulose, carboxymethylcellulose, can be gelatin, can be a sucrose solution, can be a gum such as gum arabic, gum tragacanth, guar gum, can be pectins or alginates. It can be derived from polyvidone such as polyvinylpyrrolidone of different molecular weights.

The amount of these binders in the wetting solution can be up to 0 to 50%. This binder can vary from 0 to 20% in the active minispheres. When the diluent is microcrystalline cellulose, it is not necessary to use a binder. * A solvent is used to wet the mixture of the different components and to cause it to become an extruded mass. Alcohols such as ethanol or isopropanol can be used in combination or with purified water. The purified water is preferably used to wet the particles. * The active ingredient, during this operation, is introduced in an amount of between 5 and 90% of the weight of the active spheres, preferably in an amount of between 25 and 75% of the weight of the active spheres and more particularly of 50% wax. % That is, a concentration of Milnacipran per mini-granule preferably between 250 and 750 μ and more particularly 500 μg. The components used during the production of the active spheres during the rotary granulation are: *. A diluent which can be hydrophilic or hydrophobic in nature. The hydrophilic diluent may be of a cellulosic nature, such as microcrystalline cellulose, sodium cellulose or even hydroxypropylmethylcellulose. Lactose and starch can also be used. The lipophilic diluent can be a monoglyceride, a diglyceride or a triglyceride. These diluents represent 5 to 90% of the active minisphere. The diluent preferably used is microcrystalline cellulose in an amount of between 40 and 60%, preferably in an amount of 50%. * A binding agent, this binding agent can be a cellulose derivative such as hydroxypropylmethylcellulose, methyl cellulose, hydroxypropylcellulose, carboxymethylcellulose, can be gelatin, can be a sucrose solution, can be a gum such as gum arabic, gum tragacanth, gum guar, can be pectins or alginates. They can be a derivative of polyvidone such as polyvinylpyrrolidone of different molecular weights. The amount of these binders in the wetting solution can be up to 0 to 50%. This binder can vary from 0 to 20% in the active minispheres. When the diluent is microcrystalline cellulose, it is not necessary to use a binding agent. * A solvent is used to moisten the mixture of the different components and to make them an extruded mass. Alcohols such as ethanol or isopropanol can be used in combination or otherwise with purified water.

The purified water is preferably used to wet the particles. * The active ingredient, during this operation, is introduced in an amount of between 5 and 90% of the weight of the active mini spheres, preferably in an amount of 40 and 60% of the weight of the active spheres and more particularly of about 50 %. That is, a concentration of Milnacipran per mini-granule preferably between 500 and 750 μ and more particularly 625 μg. The coating of the minispheres is composed of film-forming polymers insoluble in water but permeable to physiological fluids and which allow the Milnacipran in solution to pass through the membranes by diffusion phenomena. * The coating agents traditionally used are derivatives of acrylic copolymers, alkyl celluloses, ethyl celluloses and lacquers of natural origin such as shellac. In this invention are used the methacrylic copolymers of the type poly (ethylacrylate, methyl methacrylate) in aqueous dispersion sold under the name Eudragit NE30D, or the type of polyethylacrylate, methyl methacrylate, trimethylammoniomethyl methacrylate chloride in organic solvents (RS100 or RL100) or in aqueous dispersion RS30D / RL30D whose permeability depends on the amount of ammonium groups (RI> RS).

The polymers are used in amounts between 5 and 50% by weight of the dry polymer relative to the weight of the active minispheres. The polymer that is commercially called Eudragit RL100 or RL30D is not used in these amounts but respectively in combination with the commercially available polymers Eudragit RS100 or RS30D in amounts that can vary from 1 to 20% of the total amount of the coating polymers. * Other coating agents such as ethyl cellulose of different grades are used. In the invention, ethyl cellulose can be used in solution in a solvent such as dichloromethane, ethyl acetate, methanol and ethanol or a mixture of these solvents. Ethanol is preferably used. The amount of ethyl cellulose represents, by weight of dry polymer 2.5 to 50% of the weight of the active minispheres and is preferably between 3 and 15% and more particularly between 4 and 12.5%. Ethyl cellulose can also be in the form of an aqueous ready-to-use dispersion such as Aquacoat ECD30 or Surelease which differs, inter alia, from Aquacoat ECD30 in that the plasticizer is integrated into the dispersion. * The aqueous dispersions of ethylcellulose are used in amounts of solid substances representing 5 to 30% of the weight of the active minispheres. The amounts used preferably represent 12.5 to 17.5% of these minispheres. * It is possible to combine with these dispersions hydroxypropylmethylcelluloses of low molecular weight that are soluble in water, polyvinylpyrrolidone, low molecular weight polyethylene glycols or any other soluble substance capable of promoting the creation of pores in the membrane in amounts of between 1 and 20% of the coating layer. In the case of the present, a soluble polymer was not integrated into the formula. * The coating polymers used in this study were combined with intended plasticizers to improve film formation and qty. The plasticizers used can be dimethyl phthalate, diethyl phthalate, dibutyl phthalate, dibutyl sebacate, triethyl citrate, acetyltriethyl citrate, tributyl citrate, acetyl tributyl citrate, triacetin, polyethylene glycols, propylene glycol, glycerols, glycerides such as acetylated monoglyceride, coconut oil. and fractionated castor oil. The plasticizers are used in amounts between 0 and 50% by weight of the dry polymer. These are preferably used in amounts of between 15 and 25% by weight of the dry polymer.

The plasticizer used is preferably triethyl citrate in an amount representing 20% of the weight of the dry polymer. * Fillers such as metal oxides, silicas, silicates, in particular magnesium silicate, are used in amounts of between 10 and 100% by weight of the dry poly-iron. The amounts used with the acrylic derivatives are preferably between 50 and 100% talc while they are between 20 and 70% with ethyl cellulose in ethanolic solution and preferably equal to 50%. * Antifoaming agents, such as silicone derivatives, can be integrated into the various formulations in amounts between 0 and 0.5% of the active minispheres. The invention will be understood more clearly with the aid of the following non-limiting examples which constitute specific modalities of the various processes which refer to the various types of components according to the formula. Examples 1 to 5 describe the processes and components used for the production of the active mini-granules. Examples from 6 to 16 describe the procedures and components used for coating production of active minigranules. The technique to control the in vitro dissolution which is used to characterize these formulas is based on the USP XXIII monograph, SOLUTION, with the vane apparatus, (type 2), the speed of the vanes is set at 120 RPM, the dissolution medium can be a phosphate buffer solution (0.066 M) pH = 7.2, or purified water.

EXAMPLE 1 Example 1 describes the production of minigranules containing doses of Milnacipran using the fixation of the active ingredient in a tray. A kilogram of sugar spheres that are between 710 and 850 microns in size is placed in a solid laboratory-sized tray. A 20% ethanolic solution of polyvinylpyrrolidone K30 is sprayed to moisten the cores and make them slightly sticky. The Milnacipran, after sieving it on a sieve with a mesh opening of 600 microns, is unloaded with the help of a shovel on the bed of cores. Talc can be introduced into the core bed in the case of stickiness. The cycle is finished after a short drying which allows the Milnaeipran to fully adhere to the core. The cycles are thus repeated in succession until the Milnacipran is finished. After fixation, a proportion of talc is deposited on the surface of the mini-granule with the help of the PVP K30 solution to separate or isolate Milnacipran from external moisture. A final drying in a tray is carried out over a period of 4 hours which are in addition to the intermediate drying carried out at the end of each cycle. This fixing operation was carried out in a semi-industrial or pilot size tray. The procedure remains the same except that the quantities of raw materials are multiplied by a factor of 8 and 56. during this assembly operation, the uncovered granule concentration is close to 510 μg, leading to a 100 mg administrable dose, to a composition containing approximately 195 minigranules.

EXAMPLE The procedure used in this example is that of a fluidized air bed equipped with a sprinkler system from the bottom of the Würster type. The apparatus used is GLATT brand type GPCG1.

A 6.7% solution of PVP K30 in concentrated isopropanol is prepared. The Milnacipran is added to this solution by dispersion with the aid of an Ultra-Turrax dispersing apparatus for 10 minutes. The Milnacipran represents 20.2% of the dispersion. The dispersion is maintained with gentle agitation during the process (propeller mixer). 1 kg of cores, whose size can be between 500 and 600 μ, 710 and 850 μ or 850 and 1000 μ, is introduced in a Würster-type supply tank. The average air inlet temperature is 65 ° C, the average spray speed is 20 g / min, the air flow rate 85 m3 / h, the spray pressure 2 bar and the diameter of the spray nozzle 1 mm . Once the dispersion of Milnacipran has been completed, the minigranules are dried for 5 minutes in a bed of fluidized air at 65 ° C and then in a ventilated tank at 45 ° C for 24 hours. The procedure described above is transferred to a pilot device GPCG5 of the GLATT brand. The preparation of the dispersion of Milnacipran in the isopropanoic solution of PVP K30 is carried out under the same conditions as mentioned above multiplying the quantities used by a factor of 8.4. 8. 4 kg of cores, whose sizes are between 710 and 850 microns, are introduced in the Würster type supply tank. The average air inlet temperature is 55 ° C, the average spray speed 150 g / min, the air flow velocity 260 m3 / h, the spray pressure 3.5 bar and the diameter of the nozzle is 1.2 mm. Once the dispersion of Milnacipran has been completed, the minigranules are dried for 5 minutes in a bed of fluidized air at 55 ° C and then in a ventilated oven at 45 ° C for 24 hours. Description of the formula: During this assembly operation, the concentration per mini-granule is close to 510 μg, carrying, depending on the size of the gelatin capsule (sizes No 1 to No 00), at an administrable dose of 60 to 240 mg.

EXAMPLE 3 The Milnacipran and an excipient, microcrystalline cellulose whose commercial name is Avicel PH101, they are mixed in equal parts (150 g of each) in a urbula T2 mixer for 10 minutes, the mixture prepared in this way is moistened in a Kenwood Major type planetary mixer.The liquid used is purified water and its quantity is adjusted so that a plastic mass is obtained.The wetting time lasts 5 minutes and the kneading time is 3 minutes.The plastic mass thus obtained is extruded in a GABLER PHARMEX 35T extruder with the help of a 450 mm screw. length for a diameter of 45 mm which rotates at a speed of 50 rpm.The extrusion grid has sieves of 1 mm and is oriented on the axis of the screw.Extrusion is carried out at room temperature.The extruded material obtained is then spheronized with the help of a GABLER SPHAEROMAT SPH 250 spheronizer whose speed is set at 1000 rpm for 1 minute and then at 120 rpm for 9 minutes.The drying is done in a ventilated oven at a temperature 40 ° C until the residual moisture level is less than 3%.

The minigranules thus obtained have a particle size between 1 mm and 1.4 mm and an elongation ratio of 0.36. Description of the formula: During this assembly operation, the concentration per mini-granule is close to 500 μg, carrying, depending on the size of the gelatin capsule (sizes No 1 to Nos 00), at an administrable dose of 60 to 240 mg.

EXAMPLE The procedure used in this example is also that of: extrusion-spheronization. However, extrusion, unlike example No 3, is developed radially to the screw. The mixing of the different components which vary in quality and quantity as a function of the two formulas described is done in a LODIGE? for 5 minutes at a constant speed.

The humectant liquid is purified water which represents, depending on the formulas, 15 to 18% of the mass. The plastic mass is radially extruded and forced at a constant speed through a grid of 1 mm in diameter. The extruded material obtained is spheronized in a batch of 500 g in a Colette Marumerizer spheronizer for 5 to 10 minutes depending on the formulas. The minigranules obtained are dried for 24 hours at 40 ° C in a ventilated oven. Description of the formulas During this assembly operation, the concentration per mini-granule is 400 μg or 1160 μg, carrying, depending on the size of the gelatin capsule (sizes No 1 to Nos 00), at an administrable dose of 60 to 240 mg.

EXAMPLE 5 In the example No 5, the production of the minigranules containing Milnacipran doses is carried out by spherical granulation in a bed of fluidized air. The apparatus is characterized by a rotating disk whose distance to the wall of the supply tank makes it possible to modulate the air intake. Under the combined action of disk rotation and rising airflow, the particles follow a spiral movement. At the same time, a wetting liquid is sprayed tangentially to the mixture. The combination of these operations leads to the production of spherical particles. The mixing, composed of 250 g of Milnacipran and 250 g of Avicel PH101, is carried out in the supply tank for 3 minutes. The air is admitted at a flow rate of 100 m3 / h and the rotating disk rotates at 180 rpm. Within the same apparatus, the moistening of the mass is performed by tangential spraying of purified water. The spray speed is at 20 g / min and the disk rotation speed is increased from 180 rpm to 1080 rpm with increments of 180 rpm every minute. The air inlet temperature is 50 ° C, the spray pressure is 2 bar and the nozzle diameter is 1.2 mm. During the humidification of the mixture, the particles agglomerate, giving grains which, by rolling on the cylindrical and soft walls of the tank, become dense while they acquire a spherical aspect. Once the minigranules have been obtained, they are dried in a rotor tank for 10 minutes at 60 ° C and then for 12 hours at 40 ° C in a ventilated oven. These minigranules are characterized by a particle size distribution of between 700 and 1400 microns and an elongation factor of 0.85. Description of the formula During this assembly operation, the concentration per mini-granule is close to 625 μg, carrying, depending on the size of the gelatin capsule (sizes No 1 to Nos 00), at an administrable dose of 60 to 240 mg. Examples 6 through 16 describe the procedures and components used to perform the minigranil coating.

EXAMPLE 6 The minigranules produced by the method described in Example No 2 are coated with the aid of the same technological procedure. 180 g of a film-forming polymer, whose trade name is Eudragit RS 100, are dissolved in 1500 g of an organic solution composed of 80% isopropanol and 20% acetone. To this solution is added 27 g of diethyl phthalate, which acts as a plasticizer. 90 g of talc which acts as an anti-adherent agent are added to 750 g of an organic solution of the same composition as described above. This proportion of talc is dispersed by a polydispersing apparatus of the ultra-turrax type. This dispersion is incorporated into the Eudragit RS100 solution and maintained with agitation (propeller mixer) during the spraying. The coating preparation is maintained with agitation (propeller mixer) during the spraying. The average air inlet temperature is 45 ° C, the average spray speed is 10 g / min, the air flow speed 85 m3 / h, the spray pressure 1.5 bar and the diameter of the nozzle 0.8 mm..

Depending on the amount of coating liquid deposited on the mini-granules, the amount of dry coating polymer may represent 20%, 25% or 30% of the weight of the active mini-granules.

The dissolved percentages are the following: These formulas, whose concentration of Milnacipran per uncovered mini-granule is 510 μg and whose film thicknesses are equal to 112, 141 and 169 μ (surface masses equal to 4.74, 5.93 and 7.12 mg / cm2), did not make it possible to obtain the target mentioned above in vitro.

EXAMPLE 7 This example differs from the previous one mainly in that the film-forming polymer used is provided in the form of an aqueous dispersion whose trade name is Eudragit RS30D, in which the plasticizer is triethyl citrate and in which the sugar spheres are between 850 and 1000 micras. 19 g of triethyl citrate are incorporated in 417 g of aqueous dispersion of Eudragit RS30D, with slight agitation. 50 g of dispersed talc are introduced with the aid of a polydispersing apparatus of the ultra-Rurrax type in 400 g of purified water. Once a homogeneous dispersion of the talc is obtained, it is added to the first preparation and the gentle agitation is maintained during the entire duration of the spraying. The air inlet temperature is between 50 and 55 ° C, the average spray speed is 10 g / min, the air flow rate is 85 m3 / h, the spray pressure 2 bar and the nozzle diameter 0.8 mm.

Depending on the amount of coating liquid deposited on the mini-granules, the amount of coating polymers may represent 20 or 25% of the weight of the mini-granules uncovered.

The dissolved percentages are as follows: These formulas, whose concentration of Milnacipran per uncovered mini-granule is 780 μg and whose film thicknesses are equal to 151 and 188 μ (surface masses equal to 5.5 t 6. 85 mg / cm), they do not make it possible to obtain the aforementioned goal in vitro.

EXAMPLE 8 This example differs from the previous one in that the film-forming polymer used is Eudragit NE30D instead of Eudragit RS30D, in which the plasticizer is not used since the glass transition temperature of the polymer is low and in which 75% talc is used relative to the weight of the dry polymer and in which the sugar spheres have a size between 710 and 850 microns. 65.6 g of talc are dispersed with the help of a polydispersing apparatus of the ultra-turrax type in 323.2 g of purified water. Once the homogeneous dispersion has been obtained, it is incorporated in 291.7 g of Eudragit NE30D with gentle agitation (propeller mixer). The dispersion thus obtained is maintained with agitation during the spraying. The average air inlet temperature is 35 ° C, the average spray speed is 10 g / min, the average air flow speed 110 m3 / h, the spray pressure 2 bar and the diameter of the nozzle 0.8 mm .

Depending on the amount of coating liquid deposited on the mini-granules, the amount of dry coating polymers may represent 10, 12.5, 15, 17.5% of the weight of the mini-granules uncovered.

The dissolved percentages are the following: The formulas containing 10 and 17.5% of polymer whose concentration of Milnacipran per uncovered mini-granule is 510 μg and whose film thicknesses are equal to 81 and 89 μ (surface masses equal to 2.15 and 3.94 mg / cm2), do not make it possible Obtaining the aforementioned objective in vitro. On the other hand, surprisingly, with the formulas containing 12.5% and 15% polymer, which have a concentration of Milnacipran per uncovered mini particle of 510 μ, whose film thickness is close to 63 and 76 μ (equal surface masses) at 2.81 and 3.37 mg / cm2), the aforementioned objective was obtained in vitro. These formulas containing dose units of 60 to 240 mg, and more particularly of 100 mg and 150 mg of Milnacipran, can be placed in gelatin capsule of sizes No 1 or No 0+.

EXAMPLE 9 Example No. 9 differs from the previous examples mainly in that the coating polymer is no longer acrylic copolymer of meta and ethacrylic acids but that it is ethyl cellulose provided in the form of an aqueous dispersion in an amount of between 24.5 and 29.5%. This dispersion is sold under the name Acuacoat ECD30 and is also composed of ur. surfactant, sodium lauryl sulfate, in an amount between 0.9 and 1.7% and a stabilizing agent, cetyl alcohol, in an amount between 1.7 and 3.3%. 334 g of Aquacoat ECD are incorporated into 246 g of purified water, with gentle agitation (propeller mixer), and then 20 g of plasticizer, triethyl citrate, are added to the dispersion. To allow a good distribution of the plasticizer, the agitation is continued for 30 minutes before starting the spray during which the agitation is maintained. The average air inlet temperature is 52.5 ° C, the average spray speed is 10 g / min, the air flow speed is 85 rrr / h, the spray pressure is 2 bar and the nozzle diameter is 0.8 mm . Depending on the amount of coating liquid deposited on the microgranules, the amount of dry coating polymer may represent 10, 15 or 20% of the weight of the uncovered microgranules. At the end of the spray, the drying in a bed of fluidized air is carried out at 40 ° C for 5 minutes. The minigranules are then unloaded and dried for 24 hours at 40 ° C in a ventilated oven. Depending on the amount of coating liquid deposited on the microgranules, the amount of dry coating polymer may represent 10, 15 or 20% of the weight of the uncovered mz-nigranules.

The dissolved percentages are the following: These formulas, whose concentration of Milnacipran per mini-granule is 510 μg and whose film thicknesses are equal to 75, 113 and 150 μ (surface masses equal to 2.74, 4.11 and . 48 mg / cm), they do not make it possible to obtain the aforementioned goal in vitro.

EXAMPLE 10 This example differs from the previous example in that the aqueous dispersion of ethylcellulose is sold under the name Surelease and in that its composition is different from Aquacoat ECD30. This dispersion is composed of ethylcellulose, a plasticizer which can be dibutyl sebacate or fractionated coconut oil also called miglyol, an oleic acid stabilizing co-stabilizer and an aqueous ammonium hydroxide base. In this particular example the plasticizer is dibutyl sebacate. The preparation of the coating dispersion is carried out by incorporating 400 g of Surelease E-7-7050, with gentle agitation (propeller mixer), into 915 g of purified water. Depending on the amount of coating liquid deposited on the microgranules, the amount of dry coating polymer may represent 10, 15 or 20% of the weight of the uncovered microgranules.

The coating operation as well as the drying of the minigranules are carried out in the same manner as in example 10.

The dissolved percentages are the following: The formulas containing 10 and 20% of polymer whose concentrations of Milnacipran per uncovered mini-granule is 510 μg and whose film thicknesses are equal to 52 and 103 μ, (surface masses equal to 2.27 and 4.54 mg / cm), do not make it possible to achieve the aforementioned goal in vitro. On the other hand, surprisingly, the formula containing 15% polymer, which has a concentration of Milnacipran per minigranum without cover of 510 μg, whose film thickness is equal to 77.5 μ (surface mass equal to 3.41 mg / cm "), achieves the aforementioned objective in vitro.These formulas contain dose units from 60 to 240 mg, and more particularly of 110 mg and 220 mg of Milnacipran, can be placed in gelatin capsules of sizes No. No. 00.

EXAMPLE 11 This example differs from examples Nos. 9 and 10 in that the coating polymer, ethylcellulose, is no longer provided in the form of a dispersion but in the form of an ethanolic solution of the film-forming polymer. 50 g of ethylcellulose are gradually incorporated into 900 grams of ethanol, with vigorous agitation (propeller mixer). The mixture is maintained with stirring for one hour. 25 grams of talc are dispersed in 300 grams of ethanol with the aid of a polispersing apparatus of the Ultra-turrax type for the time required for the homogenization of the dispersion. 10 grams of plasticizer, dibutyl sebacate, and talc dispersion are added to the ethanolic ethylcellulose solution, with gentle agitation (propeller mixer). This agitation is maintained during the spraying. During the coating operation, the average air inlet temperature is 40 ° C, the average spray speed is 11 g / min, the average air flow speed 85 m3 / h, the spray pressure 2 bar and the diameter of the mouthpiece 0. 8 mm. The minigranules are then dried in a bed of fluidized air at 35 ° C for 5 minutes. An additional drying in a ventilated oven is carried out for 24 hours at 40 ° C. Depending on the amount of coating liquid deposited on the microgranules, the amount of dry coating polymer may represent 5, 7.5 or 10% of the weight of the uncovered microgranules.

Description of: .as formulas: IJOS dissolved percentages are the following: The formula that contains 10% of the polymer whose concentration of Milnacipran per mini-granule without covering is of 510 μg and whose film thickness is 54 μ (surface mass equal to 2.32 mg / cm), does not make it possible to obtain the aforementioned objective in vitro. On the other hand, surprisingly, the formulas containing 5% and 7.5% polymer, which has a concentration of Milnacipran per uncovered mini particle of 510 μg, whose film thicknesses are equal to 27 and 40 μ (surface masses equal to 1.16 and 1.74 mg / cm), achieve the aforementioned goal in vitro. These formulas containing dosage units of 60 to 240 mg, and more particularly 60 mg and 120 mg of Milnacipran, can be placed in gelatin capsules of sizes No. 3 or No. 1.

EXAMPLE 12 This example differs from example 11 in that the sugar spheres used in the operation for fixing F2207 in a bed of fluidized air have a size between 500 and 600 microns and not between 710 and 800 microns and in that the plasticizer is dibutyl sebacate and not triethyl citrate. Depending on the amount of coating liquid deposited on the microgranules, the amount of dry coating polymer may represent 5, 7.5 or 10% of the weight of the uncovered iricrogranules.

Description of the formulas: The dissolved percentages are the following: The formula that contains 5% of polymer whose concentration of Milnacipran per mini-granule is 175 μg and whose film thickness is equal to 12 μ (surface mass equal to 0. 77 mg / cm), does not make it possible to obtain the aforementioned objective in vitro. On the other hand, surprisingly, the formulas containing 7.5 and 10% polymer, which have a Milnacipran concentration per minigrang of 175 μg, whose film thicknesses are equal to 18 and 28 μ (surface masses equal to 1.15 and 1.54 mg / cm), achieve the aforementioned goal in vitro ,. These formulas containing dose units of 60 to 240 mg and more particularly of 120 mg of Milnacipran, can be placed in gelatin capsules of sizes No. 1 or No. 0+.

EXAMPLE 13 This example differs from the previous examples in that the fixation of Milnacipran is developed according to example No. 1 and not according to example No. 2. On the other hand, the composition of the coating is identical to that described in example No. 11. The operating conditions are modified to the level of the average air inlet temperature which is set. Depending on the amount of coating liquid deposited on the microgranules, the amount of dry rewind polymer can represent 5, 7.5 and 10% of the weight of the microgranules without covering.

Description of the formulas: The dissolved percentages are the following: Surprisingly, the formula FEW73 containing 5, 7.5 and 10% ethylcellulose, having a concentration of Milnacepran per mini-granule of 510 μg, whose film thickness is equal to 28, 43 and 57 μ, (surface masses equal to 1.19, 1.79 and 2.38 mg / cm2), achieve the aforementioned goal in vitro. The average kinetic curves for solution in phosphate buffer at pH 7.2 are indicated below in accompanying figure No. 1. These formulas contain the dose units of 60 to 240 mg, and more particularly 60 mg and 240 mg of Milnacipran , can be placed in gelatin capsules of sizes No. 3 or No. 00.

EXAMPLE 14 This example differs from the previous one in that the operation to coat the mini-granules is developed in a pilot device type GLATT GPCG5. The proportions of the various components are multiplied by the factor of 15. The average air inlet temperature is set at 52 ° C, the average spray speed is 110 g / min, the average air flow velocity is 300 m / h, the spray pressure is 3 bar and the diameter of the nozzle is 1.2 mm. Depending on the amount of the coating liquid deposited on the mini-granules, the amount of dry coating polymer may represent 5, 7.5 and 10% of the weight of the mini-granules uncovered.

Description of the formulas: The dissolved percentages are the following: Surprisingly, the formula 9584 containing 5, 7.5 and 10% ethyl cellulose, having a concentration of Milnacepran per uncovered mini-granule of 510 μg, whose film thicknesses are equal to 27, 43 and 57 μ (surface masses equal to 1.19, 1.79 and 2.38 mg / cm2), achieve the aforementioned goal in vitro. The average dissolution curves in vitro in phosphate buffer at pH 7.2 are given in the accompanying figure 2. These formulas, which contain the dose unit of 60 to 240 mg, and more particularly of 100 mg and 180 mg of Milnacipran, They can be placed in gelatin capsules of sizes No. 1 or No. 0+. In addition, these formulas, packaged in bubble packs of PVC (250μm) / PVDC (40 g / m2), aluminum (20μ) are stable for at least 6 months at 30 ° C / 70% RH.

EXAMPLE 15 This example differs from the previous one in that the operation to coat the minigranules is carried out in a semi-industrial apparatus type GLATT GPCG120. The proportions of the various components are multiplied by a factor of 3.6 compared to that of Example No. 14 and by a factor of 54 compared to Example 13. The various operating parameters are adjusted accordingly.

Depending on the quality of the coating liquid deposited on the minigranules, the amount of the dry coating polymer may represent 7.5 and 10% of the weight of the uncovered minigranules.

The dissolved percentages are the following: Surprisingly, batches 9658 / E1 and 9673 / E1 containing a Milnacipran concentration of 510 μg per uncoated mini-granule achieve the aforementioned purpose in vitro. The corresponding average kinetic curves for dissolution are given in the accompanying figure 3. These formulas, which contain dose units of 60 to 240 mg, and more particularly of 60, 120 and 240 mg. of Milnacipran, can be placed in gelatin capsules of sizes no. 3) No. 1 or not. 00 EXAMPLE 16 Example No. 16 differs from all previous examples in that the active microgranules are produced according to example no. 3, which is say by axial extrusion followed by spheronization. The preparation of the coating solution as well as that of the coating operation are developed according to the above examples.

Description of the formulas: The dissolved percentages are the following: Surprisingly, formula FE 61 containing 7.5% and 10% polymer, which has a concentration of Milnacipran per minigrang of 500 μg, whose film thicknesses are equal to 21 and 28 μ (surface masses equal to 1.25 and 1.67 mg / cm2), achieve the aforementioned goal in vitro. These formulas, which contain dosage units of 60 to 240 mg, and more particularly 60 mg and 180 mg of Milnacipran, can be placed in non-sized gelatin capsules. 3 and no. 0 + -.

EXAMPLE . 17 This example differs from the previous examples in that the active microgranules were produced according to example no. 5, ie by rotogranulation in a bed of fluidized air. The preparation of the coating dispersion as well as the coating operation are developed according to example no. 10, knowing that in these cases Surelease E-7-7060 whose plasticizer is Miglyol and not Dibutyl sebacate is used. Depending on the amount of coating liquid deposited on the mini-granules, the amount of dry coating polymer may represent 15 and 20% of the weight of the uncovered minigranules.

Description of the formulas: The dissolved percentages are the following: The formulas that contain 15% and contain 20% polymer, whose concentration of Milnacipran per mini-granule is 500 μg and whose film thicknesses are equal to 65 μ and 87.5 μ (surface masses equal to 3.13 and 4.2 mg / cm2), do not make it possible to achieve the aforementioned goal in vitro.

Claims (27)

NOVELTY OF THE INVENTION CLAIMS

1. - Long-lasting dosage form, designed for oral administration in a single daily dose of 60 to 240 mg of Milnacipran, provided in a multiparticulate form that combines a plurality of mini-granules each containing an active minisphere comprising a core of sucrose or / and starch having a particle size between 200 and 2000 μ and containing 150 to 1000 μg of Milnacipran as well as a binding agent, each mini-granule being coated with a film, based on at least one water-insoluble but permeable polymer. physiological fluids, which has a thickness of between 20 and 100 μ, allowing said galenic form an in vitro release corresponding to the following pattern: between 10 and 55% of the dose released in two hours, between 40 and 75% of the dose released in 4 hours; between 70 and 90% of the dose released in 8 hours; between 80 and 100% of the dose released in 12 hours.

2. A galenic form according to claim 1, further characterized in that the unit of administrable dose of Milnacipran is more particularly between 60 and 240 mg and more particularly 120 mg.

3. A galenic form according to either claim 1 and 2, further characterized in that Milnacipran is used in the form of a therapeutically equivalent dose of its Cis-D enantiomer.

4. A galenic form according to one of claims 1 to 3, further characterized in that the active uncoated minispheres, manufactured in a tray or in a fluidised air bed, are obtained from spheres of sugar. which have a size between 200 and 2000 μ, more precisely between 500 and 1000 μ.

5. A galenic form according to claim 4, further characterized in that the sugar spheres are composed of sucrose and / or starch, preferably a mixture of about 75% sucrose and about 25% starch.

6. - Galenic form according to one of claims 1 to 3, further characterized in that the uncoated active minigranules are obtained by extrusion-spheronization.

7. A galenic form according to claim 6, further characterized in that, during the extrusion-spheronization operation, a binder is used, which is chosen from microcrystalline cellulose, hydroxypropylcellulose, carboxymethylcellulose, gelatin, lactose, starch, a mono-, di- or triglyceride, guar gum, gum arabic, gum tragacanth, pectins, alginates and mixtures thereof.

8. - A galenic form ", according to claim 7, further characterized in that the binder used is microcrystalline cellulose in proportions by mass of between 25 and 75%, more precisely equal to 50%.

9. - Galenic form according to one of claims 6 to 8, further characterized in that, during the extrusion-spheronization operation, a humectant solvent is used, which is chosen from purified water, ethanol, isopropanol and mixtures thereof. respective.

10. A galenic form according to claim 4, further characterized in that the binding agent used is PVP with a molecular weight of about 50,000 Da in solution in ethanol, CH 2 Cl 2, acetone, isopropanol and mixtures thereof, representing the mass from PVP 3 to 50%, preferably about 20% of the mass of wetting solution and preferably 2 to 4% of the mass of the uncoated active minispheres.

11. A galenic form according to claim 10, further characterized in that the spheres contain, in addition, an anti-adherent agent such as talc in an amount of 0.5 to 20%, preferably 3 to 4% by weight relative to the weight of the microspheres active uncoated

12. - Galenic form according to claim 4, further characterized in that the binder used is chosen from hydroxypropylmethylcellulose, methylcellulose or hydroxypropylcellulose, carboxymethylcellulose, gelatin, gum arabic, gum tragacanth, guar gum, pectins, alginates, a sucrose solution, and mixtures thereof.

13. - Galenic form according to one of claims 1 to 4 and 10 to 12, further characterized in that the Milnacipran in dispersion in isopropanol in a mass amount of 10 to 40%, preferably 20%, is sprayed on the spheres of aziicar in a mass amount of 40 to 50%, more precisely 46%.

14. A galenic form according to claim 13, further characterized in that by using sugar spheriε having a size of between 710 and 850 μ, active uncoated minispheres containing 440 to 555 μg of Milnacipran are obtained.

15. A galenic form according to claim 13, further characterized in that by using sugar spheres having a size between 850 and 1000 μ, uncoated active minispheres containing 680 to 850 μg of Milnacipran are obtained.

16. A galenic form according to claim 13, further characterized in that by using sugar spheres having a size of between 500 and 600 μ, active uncoated minispheres containing from 150 to 185 μg, more precisely 170 μg, are obtained. of Milnacipran.

17. A galenical form of non-conformity with one of claims 1 to 16, further characterized in that the film for coating the mini-granules is obtained with the aid of a coating agent consisting of one or more methacrylic copolymers of the type poly (ethacrylate, methyl methacrylate) in dispersion aqueous or of the type poly (ethyl acrylate, methyl methacrylate, trimethylammonium chloride, methyl methacrylate) in an organic solvent or in an aqueous dispersion, the mass of the dry polymer preferably being between 5 and 50% of the mass of the mini-granules.

18. A galenic form according to claim 16, further characterized in that the coating agent consists of alkyl cellulose in aqueous solution whose dry extract represents 5 to 30% of the weight of the mini-granules.

19. A galenic form according to claim 16, further characterized in that the coating agent consists of alkyl cellulose in solution in a solvent or mixture of organic solvents, the dry extract of which represents 2.5 to 50% of the weight of the minigranules.

20. A galenic form according to claim 17, further characterized in that the coating agent contains an anti-adherent agent chosen from talc, metal oxides or silica.

21. A galenic form according to one of claims 17 to 20, further characterized in that the coating agent contains a plasticizer, which is chosen from triethyl citrate, dibutyl sebacate, dibutyl phthalate, diethyl phthalate, acetyltriethyl citrate. , tributyl citrate, acetyltriethyl citrate, triacetin, polyethylene glycols, propylene glycol, glycerol, coconut oil and fractionated castor oil.

22. A galenic form according to one of claims 1 to 16, for which the reverse operation carried out in a fluidized air bed involves a coating agent of the ethyl cellulose type in ethanolic solution to a dry polymer level relative to the weight of the minispheres of between 3 and 15% and preferably between 4 and 12.5%, leading to a film thickness of between 20 and 80.

23. - A galenic form according to claim 22, further characterized in that the coating film based on ethylcellulose includes a plasticizer, triethyl citrate or dibutyl sebacate, in an expressed amount relative to the weight of the dried polymer of between 15 and 25% and preferably equal to about 20%. A galenic form according to claim 23, further characterized in that the coating film based on ethyl cellulose comprises a filler agent such as talc whose relative expressed amount the weight of dry polymer is between 20 and 70% and preferably equal to 50%. 25. A galenic form according to one of claims 1 to 16, for which the film coating operation carried out a. in a bed of fluidized air involves a coating agent of the ethyl cellulose type in aqueous suspension, at a dry polymer level relative to the weight of the minispheres of between 5 and 30%, preferably between 12.5% and 17.5%, leading to a Film thickness between 60 and 90 μ. 26. A galenic form according to one of claims 1 to 16, for which the coating operation carried out in a fluidized air bed comprises a coating agent of the polyethylacrylate-methyl methacrylate type in aqueous dispersion , at a level of dry polymer relative to the weight of the minispheres of between 10 and 20% and more particularly between 12.5% and 15%, ie a film thickness of between 60 and 80 μ. 27. A galenic form according to any of claims 25 and 26, further characterized in that the coating film comprises a filler, in particular talc, at a level expressed in relation to the dry weight of the polymeric coating agent between 20 and 70%, preferably equal to about 50%.