MXPA02001520A - Microparticles for pulmonary administration. - Google Patents

Abstract

The invention relates to a biocompatible microparticle designed to be inhaled comprising at least one active principle and at least one layer coating said active particle which is the outer layer of the microparticle, the outer layer comprising at least one coating agent; The invention is characterized in that said microparticle has an average diameter that varies between 1μm and 30μm, an apparent density ranging between 0.02 g / cm3 and 0.8 g / cm3 and can be obtained by a method comprising the essential steps consisting of in joining a coating agent and an active principle and introducing a supercritical fluid, under agitation in a reactor closed

Description

MICROPARTICLES FOR PULMONARY ADMINISTRATION The present invention relates to the domain of microparticles that are intended to be administered via the pulmonary route. A bibliographical study made it possible to demonstrate that a great research has been carried out with reference to this technology. Aerosols have been described for therapeutic release agents in respiratory tracts in, for example (Adjei, A and Garren, J. Pharm. Res., 7: 565-569 (1990); and Zanen, P. And Lamm, JWJ Int. J. Pharm., 114: 111-115 (1995)). The respiratory tracts comprise the upper respiratory tracts, which include the larynx and oropharynx and the lower respiratory tracts, which include the trachea that extends into bifurcations: the bronchi and bronchioles. The terminal bronchioles are then divided into respiratory bronchioles which lead to the last zone of the respiratory system, the pulmonary alveoli, also named in the deep lung (Gonda, I. "Aerosols for delivery of therapeutic and diagnostic agents in the respiratory tract", in Critical Reviews in Therapeutic Drug Carrier Systems, 6: 273-313 (1990)). The deep lung, or alveoli, is (are) the main target for the systemic route. Aerosols intended to be inhaled have already been used for the treatment of local lung disorders, such as asthma and cystic fibrosis (Anderson et al., Am. Rev. Respir Dis., 140: 1317-1324 (1989)). In addition, they can be used for the systemic release of peptides and proteins (Paton and Platz, Advanced Drug Delivery Reviews, 8: 179-196 (1992)). However, a number of difficulties are encountered when the intention is to apply the release of medicinal products through the pulmonary route for the release of macromolecules. Among these difficulties, there is denaturation of the protein during nebulization, a significant loss of the amount of medicinal products inhaled in the oropharynx (which often exceeds 80%), poor control of the deposit area, poor reproductive capacity of the therapeutic results due to the variations in respiratory models, a very fast absorption of the medicinal products, generation of local toxic effects and phagocytosis by the macrophages of the lung. The human lung can rapidly eliminate or degrade hydrolysable products deposited in the form of aerosols, this phenomenon usually occurring for a period of between a few minutes and a few hours. In the upper lung tracts, the ciliated epithelium contributes to the phenomenon of "mucociliary ladder" by which the particles are driven from the pulmonary tracts to the mouth (Pavia, D. "Lung Mucocliary Clearance, in" Aerosols and the Lung: Clinical and Experimental Aspects ", Clarke, SW and Pavia, D., Eds.r Butterworths, London, 1984; Anderson et al., Am. Rev. Respir Dis., 140: 1317-1324 (1989).) In the deep lung, alveolar macrophages are able to phagocytose particles immediately after they have been deposited.

Local and systemic therapies by inhalation generally allow the controlled and relatively slow release of the active principle (Gonda, I., "Physico-chemical principles in aerosol delivery", in: Topics: Pharmaceutical Sciences 1991, DJA Crommelin and KK Mida, Eds ., Stuttgart: Medpharm Scientific Publishers, pp. 95-117 (1992)). The slow release of the therapeutic aerosol can prolong the time for which the medical product administered remains in the lung tracts or in the acini, and decreases the rate of entry of medical products into the bloodstream. Therefore, patient tolerance is increased by reducing the frequency of administrations (Langer, R .; Science, 249: 1527-1533 (1990); and Gonda, I. "Aerosols for delivery of therapeutic and diagnostic agents to the respiratory tract ", in Critical Reviews in Therapeutic Drug Carrier Systems 6: 273-313 (1990)). Among the disadvantages represented by dry powder formulations, there is the fact that ultrafine particle powders have flow and nebulization properties that are generally poor, leading to the production of aerosol fractions that are admitted into the relatively slow respiratory system, these fractions of the inhaled aerosol being deposited generally in the mouth and in the throat (Gonda, I.; in Topics in Pharmaceutical Sciences 1991, D. Cromelin and K. Mida, Editors, Stuttgart: Medpharm Scientific Publishers, 92-117 (1992)). The main problem encountered with most aerosols is the aggregation of particles generated by interparticle interactions, such as electrostatic and capillary interactions. An effective therapy by inhalation of dry powder both for the immediate and sustained release of therapeutic agents, both locally and systemically, requires the use of a powder that has minimal aggregation that makes it possible to avoid or at least suspend the mechanisms of natural lung evacuation until the moment when the active substance is released. Currently there is a need for improved inhalation aerosols which is intended for the pulmonary release of therapeutic agents. Similarly, there is currently a need for medical product supports that are capable of delivering the medical product in an effective amount in the lung tracts or in the alveolar regions of the lungs. In addition, there is also a need for supports for medicinal products that can be used as inhalation aerosols that are biodegradable and which make it possible to release the medicinal products in a controlled manner in the respiratory tracts and the alveolar region of the lungs, and similarly, there is the need for particles for the release of medicinal product in the lungs, which have improved misting properties. These investigations tend to show that it is difficult to prepare microparticles that correspond to the criteria imposed on them being used under effective conditions. In order to exhibit sufficient effectiveness, these microparticles should not be damaged during administration, when they pass in nebulized form. The bioavailability of these microparticles should reach a sufficiently high value; however, the bioavailability of the microparticles of the prior art generally does not exceed 50%, due to a low level of deposits of the microparticles in the alveolar lung regions. Furthermore, in order to preserve its effectiveness during pulmonary administration, the microparticles, once deposited in the alveoli, must be sufficiently stable in the mucus of the surface of these alveoli. Therefore, it may prove interesting to prepare microparticles for immediate or delayed release, either locally or systemically; however, these microparticles generally have an outer layer, the thickness of which, in relation to the diameter of said particle, is not insignificant. The microparticles according to the invention consist of a core containing the active material coated with a layer of coating agent deposited by the supercritical fluid technique. This particular structure distinguishes them from the microparticles of the prior art, which are matrix microspheres obtained using emulsification-solvent evaporation techniques, solvent extraction with aqueous or nebulization-drying phases of the organic solvent. Accordingly, the present invention relates to biocompatible microparticles that are intended to be inhaled, comprising at least one active principle and at least one layer that coats this active principle, which is the outer layer of said microparticles, said outer layer that contains at least one coating agent, the microparticles having a mean diameter of between 1 μ? ? 30 μp? and an apparent density of between 0.2 g / cm 3 and 0.8 g / cm 3, and it being possible to obtain them according to a method comprising the essential steps that bind a coating agent and an active principle and introduce a supercritical fluid, with agitation in a closed reactor. These microparticles do not aggregate when administered and, optionally, may allow sustained release of the active ingredient. The microparticles according to the invention exhibit a bioavailability greater than 60%, and preferably greater than 80%, due to an improvement in the level of deposition of the particles in the alveolar lung regions. It has therefore been demonstrated that the implementation of a method for preparing microparticles using a "supercritical fluid" technique using, as a coating agent, the judiciously chosen biocompatible materials, makes it possible to obtain microparticles of controlled size and having a Surface finished so that the microparticles do not aggregate and deposit in the alveolar lung regions. The biocompatible microparticles which are intended for inhalation according to the invention have an outer layer comprising a coating agent which prevents these particles from being added to each other. The degree of coverage of the surface area of the particles is at least greater than 50%, preferably greater than 70%, even more preferably greater than 85%. The quality of this coating is essentially due to the supercritical fluid technique. Said method comprises two essential steps that unite a coating agent and an active principle and introduce a supercritical fluid in order to ensure the coacervation of the coating agent. It clearly emerges from the rest of the description as to why these two steps do not have to be carried out in the established order. The first method for preparing the microparticles according to the invention differs from the second method by the fact that the coating agent is at no time in solution in the fluid in the liquid or supercritical state. Specifically, a first implementation of the method according to the invention comprises the following steps: suspending an active ingredient in a solution of at least one substantially polar agent in an organic solvent, said active principle being insoluble in the organic solvent, said principle active being insoluble in the organic solvent, said substantially polar coating agent being insoluble in a fluid in the supercritical state, said organic solvent being insoluble in a fluid in the supercritical state, - placing the suspension in contact with a fluid in the supercritical state , so as to de-solder in a controlled manner the substantially polar coating agent and ensure its coacervation, - substantially remove the solvent using a fluid in the supercritical state and discharge the supercritical fluid / solvent mixture; - recover the microparticles. The fluid used for the implementation of this first method is preferably liquid CO2 or CO2 in the supercritical state. The organic solvent used for the implementation of this first method is generally chosen from the group consisting of ketones, alcohols and esters. The supercritical fluid is contacted with the active ingredient suspension by coating the coating agent in solution by introducing the supercritical fluid into an autoclave containing the suspension. When the supercritical fluid used is C02, it is possible to use C02 in the liquid form or use CO2 in the supercritical state. According to another variant, it is also possible to put the suspension in contact with liquid CO2 which then enters the supercritical state by increasing the pressure and / or the temperature in the autoclave in order to extract the solvent. When liquid C02 is used, the variant is chosen, the temperature preferably chosen between 20 and 30 ° C and the pressure between 80 and 150 105 Pa.

When the supercritical CO2 variant is used, the temperature is generally chosen between 35 and 60 ° C, preferably between 35 and 50 ° C, and the pressure between 80 and 250 105 Pa, preferably between 100 and 220 105 Pa. The mass of The organic solvent introduced into the autoclave represents at least 3%, preferably between 3.5% and 25%, of the mass of the supercritical fluid or liquid used to cause the dissolvation of the coating agent. The microparticles obtained by implementing this first method have an external layer virtually free of solvent; the amount of solvent in the outer layer, in fact, is less than 50 ppm. The coating agents that can be used for the implementation of this first method are more particularly: biodegradable (co) polymers of α-hydroxycarboxylic acids, in particular homopolymers and copolymers of lactic acid and glycolic acid, and more particularly PLAs ( poly-L-lactide) and PLGAs (poly (lactic acid-co-glycolic acid)), amphiphilic block polymers of the poly (lactic acid) -poly (ethylene oxide) type, - biocompatible polymers of the poly (ethylene glycol) type ), poly (ethylene oxide, - polyanhydrides, poly (orthoesters), poly-s-caprolactones and derivatives thereof, - copolymers of poly- (p-hydroxybutyrate), poly (hydroxyvalerate) and poly (hydroxybutyrate-hydroxyvalerate) , -poly (mellic acid), -polyphosphazenes, -block copolymers of the type of poly (ethylene oxide) -poly (propylene oxide), -poly (amino acids), -polysaccharides, -polyprospholipids such as phosphatidyl glycerols, glycerols of diposfat idyl containing chains of C12 to C18 fatty acids (DLPG, DMPG, DPDG, DSPG), phosphatidylcholines, diphosphatidylcholines containing C12 to C18 fatty acid chains (DLPC, DMPC, DPPC, DSPC), diphosphatidylethanolamines containing acid chains C12 to C18 fatty acids (DLPE, DMPE, DPPE, DSPE), diphosphatidylserine containing C12 to C18 chains (DLPS, DMPS, DPPS, DSPS), and mixtures containing the aforementioned phospholipids, - fatty acid esters such as stearates of glyceryl, glyceryl laurate, cetyl palmitate, or mixtures containing these compounds, - mixtures containing the aforementioned compounds. The implementation of the second method according to the invention consists of suspending an active ingredient in a supercritical fluid containing at least one coating agent dissolved therein and then modifying the conditions of pressure and / or temperature of the environment so that ensure the coacervation of the particles, by precipitation of the coating agent around the particles of active principle, that is, ensure the coacervation of the particles by physical-chemical modification of the environment. The coating agents that can be used for the implementation of this second method are more particularly: phospholipids such as phosphatidyl glycerol, diphosphatidyl glycerol containing chains of C12 to C18 fatty acids (DLPG, DMPG, DPPG, DSPG), phosphatidylcholines, diphosphatidylcholines containing C12 to C18 fatty acid chains (DLPC, DMPC, DPPC, DSPC), diphosphatidylethanolamines containing C12 to C18 fatty acid chains (DLPE, DMPE, DPPE, DSPE), diphosphatidyisine containing C12 chains at C18 (DLPS, DMPS, DPPS, DSPS), and mixtures containing the aforementioned phospholipids, - mono-, di-, triglycerides in which the fatty acid chains vary from C4 to C22, and mixtures containing them, - mixtures of glycerides and polyethylene glycol esters, - cholesterol. - ethers of fatty acids such as glyceryl stearates, glyceryl laurate or cetyl palmitate, - mixtures containing the aforementioned compounds. Biodegradable or biodegradable polymers soluble in a supercritical fluid can also be used in this second method.

The coacervation (or aggregation) of a coating agent is caused by physicochemical modification of an environment containing an active substance in suspension in a solution of a coating agent in a solvent, said solvent being a supercritical fluid. The supercritical fluid preferentially used is supercritical CO2 (SCCO2), the initial operating conditions of this second method will be approximately 31 to 80 ° C and the pressures will be 75 to 250 105 Pa, although higher values can be used for one or the other of the two parameters, or both, of course, with the condition that higher values have no harmful or degrading effect on the active principle that will be covered or on the coating agents. However, it is also possible to choose other fluids commonly used as supercritical fluids. Particular mention should be made of ethane, which becomes supercritical above 32 ° C and 40 105 Pa, nitrogen dioxide, the critical point of which is 36 ° C and 42 105 Pa, trifluoromethane, the critical point of which is 26 ° C and 47 105 Pa, and chlorotrifluoromethane, the critical point of which is 20 ° C and 10 105 Pa. This second method involves suspending, in a closed agitated autoclave, an active principle that is insoluble in the supercritical fluid, said fluid supercritical containing a coating agent that is in the state of a solute. The pressure and / or the temperature are then modified so as to decrease the solubility of the coating agent in the fluid. Therefore, the affinity of the coating agent for the active ingredient is increased in such a way that this coating is adsorbed around the active principle. Once this coating agent is deposited on the active principle, the autoclave is depressurized and the microparticles are recovered. To implement this second method, the active ingredient to be covered and the coating agent (s) are placed in an autoclave equipped with a stirrer, and then the system is pressurized by introducing into the autoclave a fluid presented under supercritical conditions. The temperature and / or pressure within the autoclave are modified in a controlled and regulated manner so as to gradually decrease the solubility of the coating agent (s). When the solubility of this or these coating agent (s) decreases in the supercritical fluid, it (them) is precipitated (n) and the affinity of these agents for the surface of the active principle leads them to adsorb on this surface. A variant of this method consists of placing the coating agent in the autoclave before introducing the active principle therein or while simultaneously introducing therein the active principle and a fluid capable of passing in the supercritical state. Pressurizing the autoclave to produce a supercritical fluid state will cause the coating agent to dissolve in said supercritical fluid. According to another variant of the method, the active principle is placed in an autoclave equipped with a stirrer, and the coating agent is placed in a second autoclave equipped with an agitator, in which the fluid capable of passing in the state is introduced. supercritical. The coating agent is brought into the state of a solute by increasing the temperature and pressure and then transferring in the autoclave what contains the active principle. The coating agent is then deposited such that this agent covers the surface of the active principle. The active principle can have the form of a liquid which can thus form an emulsion in the supercritical fluid, of preformed solid particles, and in particular of microparticles optionally optionally coated, for example, with mono- or disaccharides. The stirring speeds can vary between 150 and 700 rpm for solid particles and between 600 and 1000 rpm when the active principle is a liquid. Said agitation ensures that the active principle is suspended in the supercritical fluid when the latter is introduced. The supercritical conditions are produced by modifying the temperature and / or the pressure inside the autoclave. ThusWhen the supercritical fluid is CO2, the temperature of the autoclave is between 35 and 80 ° C, preferably between 35 and 50 ° C, and the pressure is between 100 and 250 105 Pa, and preferably between 50 and 150 105 Pa ,. When the fluid is propane, the temperature of the autoclave is between 45 and 80 ° C, preferably between 55 and 65 ° C, and the pressure is between 40 and 150 105 Pa.

The coating agent is introduced into the autoclave at the same time as the supercritical fluid or before the supercritical fluid is introduced into the autoclave. In any case, in order to ensure good solubilization of the coating agent in the supercritical fluid, the system is kept in equilibrium with stirring, the appropriate concentration of the active ingredient and coating agent is established as a function of the desired microparticles and this balance is left for an hour with agitation. The temperature and pressure are then modulated at a sufficiently slow rate to completely transfer the coating agent (s) of the supercritical fluid to the surface of the active principle, and the system is depressurized in order to isolate the microparticles, that are removed from the autoclave. The microparticles according to the present invention have a diameter between 1 μ? and 30 μ? t ?, preferably between 1 μ? and 15μ ??, and even more preferably between 2μ? t? and 10 μ? t ?, and a bulk density of between 0.02 g / cm3 and 0.8 g / cm3, and preferably between 0.05 g / cm3 and 0.4 g / cm3. The mass ratio of active ingredient / coating agent of these microparticles is preferably between 95/5 and 5/95. In the case of controlled release microparticles, the amount of active ingredient is small compared to the coating agent, and the mass ratio of active ingredient / coating agent is between 5/95 and 20/80; on the other hand, when it is intended to stabilize the particle, in particular, when the microparticle is an immediate release microparticle, the mass ratio of active ingredient / coating agent is generally between 95/5 and 70/30, and preferably between 95 / 5 and 80/20. The coating agents of the microparticles according to the invention advantageously belong to the following families: biodegradable (co) polymers of α-hydroxycarboxylic acids, in particular homopolymers and copolymers of lactic acid and glycolic acid, and more particularly PLAs (polymers) L-lactide) and PLGAs (poly (lactic acid-co-glycolic acid)), - mono-, di-, or triglycerides in which the fatty acid chains vary from C4 to C22, and mixtures containing them, - mixtures of glycerides and polyethylene glycol esters, - cholesterol, - amphiphilic block polymers of the poly (lactic acid) -poly (ethylene oxide) type, - biocompatible polymers of the poly (ethylene glycol) type, poly (ethylene oxide) , - polyanhydrides, poly (orthoesters), ??? - e-caprolactones and derivatives thereof, - copolymers of poly- (p-hydroxybutyrate), poly (hydroxyvalerate) and poly (p-hydroxybutyrate-hydroxyvalerate), -poly ( malic acid), -polyps Fazenos, block copolymers of the poly (ethylene oxide) -poly (propylene oxide) type, - poly (amino acids), - polysaccharides, - polyphospholipids such as phosphatidyl glycerol, diphosphatidyl glycerol containing acid chains C12 to C18 fatty acids (DLPG, DMPG, DPPG, DSPG), phosphatidylcholines, diphosphatidylcholines containing C12 to C18 fatty acid chains (DLPC, DMPC, DPPC, DSPC), diphosphatidylethanolamines containing fatty acid chains of C12 to C18 ( DLPE, DMPE, DPPE, DSPE), diphosphatidylserine containing C12 to C18 chains (DLPS, DMPS, DPPS, DSPS), and mixtures containing the aforementioned phospholipids, - fatty acid esters such as glyceryl stearates, glyceryl laurate, cetyl palmitate, - mixtures of at least two compounds chosen from the fatty derivatives mentioned above and in such a way that they have adequate solubility. Depending on the coating agent, the solubility in the supercritical fluids and the coating conditions, then the first and second methods described above can be implemented.

Said active principle may be in the form of a liquid, a solid powder or an inert solid porous particle, comprising, on its surface, an active principle. The active ingredients used are chosen from very varied therapeutic and prophylactic compounds. They are chosen more particularly from proteins and peptides, such as insulin, calcitonin or hormones of the hormone LH-RH, polysaccharides such as heparin, anti-asthmatic agents, such as budesonide, beclomethasone dipropionate and its active metabolite 17-beclomethasone monopropionate, beta-estradiol hormones, testosterone, bronchodilators, such as albuterol, cytotoxic agents, corticosteroids, antigens and DNA fragments. Figure 1 is an electron microphotograph of a microparticle obtained according to example 2. Figure 2 is an electronic microphoto photograph of microparticles obtained according to example 3. The following examples illustrate the invention without limiting the scope thereof.

EXAMPLE 1 This example illustrates the first method of implementation of the invention. 80 mg of PLGA are solubilized in 80 ml of ethyl acetate. 400 gm of micronized insulin are suspended in the solution obtained at 250 rpm and the suspension is placed in an autoclave with a capacity of 1.0 1. Initially, the pressure is increased to 100 105 Pa by introducing the liquid C02, while at the same time remaining a constant temperature of 20! C. The C02 in the liquid state is mixed with the suspension, making it possible to wet the insulin and also making it possible to produce the gradual precipitation of the coating agent. The C02 is brought to the supercritical state by gradually increasing the pressure to 150 105 Pa. The temperature is maintained together at 40 ° C. In this way the ethyl acetate is extracted. These conditions are maintained for 15 minutes and then the mixture of CC ethyl acetate is discharged, decompressing at 75-105 Pa, in a separator, while maintaining the temperature at a value greater than 35 ° C. The ethyl acetate is recovered in this separator and the C02 returns to a tank. The ethyl acetate is recovered and the successive cycles to introduce the liquid C02, bringing it to the supercritical state and the discharge of the C02 + ethyl acetate are repeated until the ethyl acetate is completely eliminated.

The decompression is necessarily carried out via the gas phase so that no further concentration of the coating agent is concentrated in the remaining ethyl acetate. After the decompression phase, the operation can be repeated several times by reintroducing C02 in order to return to a pressure of 150-105 Pa and a temperature of 40 ° C. Finally, after depressurization and extraction of the C02 + solvent mixture, fresh C02 is reintroduced and brought to the supercritical state in order to completely extract the solvent. The temperature in this case is generally between 35 and 45 ° C and the pressure between 180 and 220 10 Pa. Therefore 250 mg of non-aggregated microparticles are obtained, which can have an average size of 3 μ? T ?, comprising 80 to 90% by weight of insulin and has improved misting properties.

EXAMPLE 2 This example illustrates the second method of implementation of the invention. 150 mg of bovine serum albumin (BSA) prepared by spray-drying and 600 mg of Gelucire® 50/20 in the form of flakes are placed in a pressurized and agitated autoclave at 0.3 I equipped with a porous insert.

CO2 is introduced into the autoclave until a pressure of 95 105 Pa is obtained for a temperature of 25 ° C. The C02 is then in the liquid state. Stirring begins and is fixed at 460 rpm. The autoclave is then heated to 50 ° C. The pressure is then 220 105 Pa; C02 is then in the supercritical state and has a density of 0.805 g / cm3. The system is allowed to equilibrate for one hour. The autoclave temperature then decreases to 19 ° C for a period of 30 minutes starting at 50 ° C. The suspended phase in the supercritical C02 thus transforms into a mixture of liquid and gaseous CO2, the particles of active principle being suspended in the liquid C02. Depressurizing then at atmospheric pressure, BSA microparticles covered with Gelucire® 50/20 are obtained. 250 mg of non-aggregated particles of BSA are obtained, with an average diameter equal to 10 μ ??, coated with a layer of Gelucire® 50/02, the mass ratio of the active ingredient / coating agent of which is approximately 30. / 79. These microparticles have improved misting properties.

EXAMPLE 3 This example illustrates the second method of implementation of the invention. 300 mg of ovalbumin (OVA) prepared by spraying-drying and 300 mg of Gelucire® 50/13 in the form of flakes are placed in a pressurized and stirred autoclave at 1 I equipped with a porous insert. C02 is introduced into the autoclave until a pressure of 109 105 Pa is obtained for a temperature of 23 ° C. The CO2 is then in the liquid state. Stirring begins and is fixed at 340 rpm. The autoclave is then heated to 35 ° C. The pressure is then 180 105 Pa; C02 is then in the supercritical state. The system is allowed to equilibrate for one hour. The temperature of the autoclave then decreases to 16 ° C for a period of 43 minutes starting at 35 ° C. The suspended phase in the supercritical CO2 thus transforms into a mixture of liquid and gaseous CO2, the particles of active principle being suspended in the liquid C02. Depressurizing then at atmospheric pressure, OVA microparticles covered with Gelucire® 50/13 are obtained. 300 mg of non-aggregated OVA particles are obtained, with an average diameter equal to 9 μ ??, coated with a layer of Gelucire® 50/13, which have improved misting properties.

EXAMPLE 4 This example illustrates the second method of implementation of the invention. 300 mg of beclomethasone dipropionate in the form of free powder prepared by spray-drying and 50 mg of dilauroyl phosphatidyl glycerol (DLPG) are placed in a pressurized and agitated autoclave at 0.3 I equipped with a porous insert. CO2 is introduced into the autoclave until a pressure of 98-105 Pa is obtained for a temperature of 23 ° C. The CO2 is then in the liquid state. Stirring begins and is fixed at 460 rpm. The autoclave is then heated to 60 ° C. The pressure is then 300 105 Pa; CO2 is then in the supercritical state and has a density of 0.830 g / cm3. The system is allowed to equilibrate for one hour. The autoclave temperature then decreases to 20CC for 65 minutes. The suspended phase in the supercritical CO2 thus transforms into a mixture of liquid and gaseous CO2, the particles of active principle being suspended in the liquid CO2. Depressurizing then at atmospheric pressure, beclometazone dipropionate microparticles covered with DLPG are obtained. 200 mg of non-aggregated particles of beclomethasone dipropionate are obtained, with an average diameter equal to 5 μ ??, coated with a layer of DLPG, the mass ratio of the active ingredient / coating agent of which is approximately 90/10 . These microparticles have improved misting properties.

Claims (10)

NOVELTY OF THE INVENTION CLAIMS

1. A biocompatible microparticle that is intended to be inhaled, comprising at least one active ingredient and at least one layer coated with this active principle, which is an outer layer of the microparticle, the outer layer containing at least one active agent. coating, characterized in that the microparticle has a mean diameter of between 1 μ? t? and 30 μ ?? and an apparent density of between 0.02 g / cm3 and 0.8 g / cm3, and in which it is possible to obtain according to a method comprising the essential steps for joining a coating agent and an active principle and introducing a supercritical fluid, with agitation in a closed reactor.

2. The microparticle according to claim 1, characterized in that it has a mean diameter of between 1 μ? and 15 μ? t ?, and even more preferably between 2 μ? t? and 10 μ ??, and an apparent density of between 0.05 g / cm3 and 0.4 g / cm3, and in which the mass ratio of the active ingredient / coating agent of this particle is between 95/5 and 5/95.

3. The microparticle according to claim 1 or 2, which can be obtained by using a method comprising the following steps: suspending an active ingredient in a solution of at least one substantially polar agent in an organic solvent, said active principle being insoluble in the organic solvent, said active ingredient being insoluble in the organic solvent, said substantially polar coating agent being insoluble in a fluid in the supercritical state, said organic solvent being insoluble in a fluid in the supercritical state, - putting the suspension in contact with a fluid in the supercritical state, so as to de-solder in a controlled manner the substantially polar coating agent and ensure its coacervation, - substantially remove the solvent using a fluid in the supercritical state and discharge the percritical fluid mixture. sun - recover the microparticles.

4. The microparticle according to claim 1 or 2, characterized in that it can be obtained by using a method consisting of suspending an active ingredient in a supercritical fluid containing at least one coating agent dissolved therein and then ensuring coacervation of the particles by physical-chemical modification of the environment.

5. The microparticle according to claim 3, further characterized in that the coating agent is selected from the group consisting of biodegradable (co) polymers of α-hydroxycarboxylic acids, in particular homopolymers and copolymers of lactic acid and glycolic acid, and more particularly PLAs (poly-L-lactide) and PLGAs (poly (lactic-co-glycolic acid)), amphiphilic block polymers of the poly (lactic acid) -poly (ethylene oxide) type, - biocompatible polymers of the type of poly (ethylene glycol), poly (ethylene oxide, - polyanhydrides, poly (orthoesters), poly-s-caprolactones and derivatives thereof, - copolymers of poly- (P-hydroxybutyrate), poly (hydroxyvalerate) and poly (p-) hydroxybutyrate-hydroxyvalerate), -poly (mellic acid), -polyposphazenes, - block copolymers of the poly (ethylene oxide) -poly (propylene oxide) type, - poly (amino acids), - polysaccharides, - polyphospholipids as phosphatidyl glycerol, glyce roles of diphosphatidyl containing C12 to C18 fatty acid chains (DLPG, DMPG, DPDG, DSPG), phosphatidylcholines, diphosphatidylcholines containing C12 to C18 fatty acid chains (DLPC, DMPC, DPPC, DSPC), diphosphatidylethanolamines containing chains of fatty acids of C12 to C18 (DLPE, DMPE, DPPE, DSPE), diphosphatidylserine containing C12 to C18 chains (DLPS, D PS, DPPS, DSPS), and mixtures containing the aforementioned phospholipids, fatty acid esters such such as glyceryl stearates, glyceryl laurate, cetyl palmitate, or mixtures containing these compounds, mixtures containing the compounds mentioned above.

6. The microparticle according to claim 4, further characterized in that the coating agent is selected from the group consisting of - phospholipids such as phosphatidyl glycerols, diphosphatidyl glycerols containing chains of C12 to C18 fatty acids (DLPG, DMPG, DPPG, DSPG), phosphatidylcholines, diphosphatidylcholines containing fatty acid chains of C12 to C18 (DLPC, DMPC, DPPC, DSPC), diphosphatidylethanolamines containing C12 to C18 fatty acid chains (DLPE, DMPE, DPPE, DSPE), diphosphatidylserine containing C12 to C18 chains (DLPS, DMPS, DPPS, DSPS), and mixtures containing the aforementioned phospholipids, - mono-, di-, triglycerides in which the fatty acid chains vary from C4 to C22, and mixtures containing them, - mixtures of glycerides and asters of polyethylene glycol, - cholesterol, - ethers of fatty acids such as glyceryl stearates, glyceryl laurate or cetyl palmitate, - mixtures containing the compounds mentioned above. The microparticle according to any of claims 1 to 6, characterized in that the active principle is chosen from the group consisting of proteins and peptides, such as insulin, calcitonin, or analogs of the hormone LH-RH, polysaccharides such as heparin, anti-asthmatic agents, such as budesonide, beclomethasone dipropionate and its active metabolite 17-beclomethasone monopropionate, beta-estradiol hormones, testosterone, bronchodilators such as albuterol, cytotoxic agents, corticosteroids, antigens and DNA fragments. The microparticle according to claim 2, characterized in that the microparticle is an immediate release microparticle and that the mass ratio of active ingredient / coating agent of this particle is between 95/5 and 80/20. 9. A method for preparing microparticles that are intended to be inhaled, and comprising the following steps: suspending an active ingredient in a solution of at least one substantially polar agent in an organic solvent, said active ingredient being insoluble in the organic solvent , said active principle being insoluble in the organic solvent, said substantially polar coating agent being insoluble in a fluid in the supercritical state, said organic solvent being insoluble in a fluid in the supercritical state, - placing the suspension in contact with a fluid in the fluid. the supercritical state, so as to de-solder in a controlled manner the substantially polar coating agent and ensure its coacervation, - substantially remove the solvent using a fluid in the supercritical state and discharge the supercritical fluid / solvent mixture; - recover the microparticles. 10. A method for preparing microparticles that are intended to be inhaled, consisting of suspending, with agitation in a closed reactor, an active ingredient in a supercritical fluid containing at least one coating agent dissolved therein, and then ensuring the coacervation of the particles by physical-chemical modification of the modality.