KR20020038719A - Microparticles for pulmonary administration - Google Patents

Abstract

The present invention relates to biocompatible microparticles designed for inhalation comprising at least one active ingredient and at least one layer coating said active ingredient, said layer being an outer layer of said microparticles, said outer layer comprising one or more coatings do. The present invention is characterized in that the fine particles have an average diameter of 1 to 30 μm and an apparent density of 0.2 g / cm 3 to 0.8 g / cm 3, wherein the fine particles are obtained by bringing the coating agent and the active ingredient together, And introducing the supercritical fluid while stirring.

Description

[0001] MICROPARTICLES FOR PULMONARY ADMINISTRATION [0002]

Bibliographic studies show that extensive research has been conducted on this technology.

Aerosols for administering therapeutic agents to the respiratory tract have been described by Adjei, A and Garren, J. Pharm. Res., 7: 565-569 (1990); and Zanen, P. and Lamm, J.W.J. Int. J. Pharm., 114: 111-115 (1995). The respiratory tract includes the upper respiratory tract, including the larynx and mouth pharynx, and the lower respiratory tract, including the bronchial and tracheal tracts, which are the organs that extend to the fork. (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). Cardiopulmonary or alveolar (s) are the main targets of therapeutic aerosols to be inhaled and sent to the systemic route. Inhalation aerosols have already been used in the treatment of local pulmonary diseases such as asthma and cystic fibrosis (Anderson et al., Am. Rev. Respir. Dis., 140: 1317-1324 (1989)}. In addition, they can be used for systemic administration of peptides and proteins {Patton and Platt, Advanced Drug Delivery Reviews, 8: 179-196 (1992)}. However, there are various difficulties in applying the drug administration through the pulmonary route to the administration of the polymer. Among these difficulties are protein degeneration during spraying, significant loss of drug inhalation (often more than 80%), poor control of settling zone, poor regeneration due to changes in the respiratory model, too rapid drug absorption, , And phagocytosis by macrophages of the lungs.

The human lung quickly removes or emulsifies the hydrolysable product precipitated in the form of an aerosol, and this phenomenon generally occurs over several minutes to several hours. In the upper lung tract, the particles are delivered from the lungs to the mouth, and the ciliary epithelium causes a "mucociliary escalator" phenomenon (Pavia, D. "Lung Mucociliary Clearance," in Aerosols and the Lung: Clinical and Experimental Rev. Respir. Dis., 140: 1317-1324 (1989)). In cardiopulmonary resuscitation, alveolar plexus blockade Phagocytes can act on the particles immediately after precipitation.

Local and systemic treatments by inhalation generally regulate the active ingredient and release it relatively slowly {Gonda, I., Physico-chemical principles in aerosol delivery, in: Topics in Pharmaceutical Sciences 1991, D.J.A. Crommelin and K. K. Midha, Eds., Stuttgart: Medpharm Scientific Publishers, pp. 95-117 (1992). Slow release of the therapeutic aerosol prolongs the time that the administered drug remains in the lungs or vesicles and reduces the rate at which the drug enters the bloodstream. Therefore, patient tolerance is increased by reducing the number 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).

One of the disadvantages manifested by dry powder formulations is the fact that the flow and spray characteristics of the ultrafine particle powders are generally poor and the generation of aerosols entering the respiratory system is relatively slow and the inhaled aerosol parts usually settle in the mouth and throat {Gonda, I, in Topics in Pharmaceutical Sciences 1991, D. Crommelin and K. Midha, Editors, Stuttgart: Medpharm Scientific Publishers, 95-117 (1992)}.

The major problem faced by most aerosols is particulate aggregation caused by inter-particle interactions such as hydrophobicity, electrostatic and capillary interactions. Effective treatment with dry powder inhalation for local and systemic, immediate and sustained therapeutic agent release requires the use of a minimally agglomerated powder to avoid or at least delay the natural cleansing mechanism in the lung until the active ingredient is released .

Currently, there is a need for improved inhalation aerosols for releasing therapeutic agents into the lungs. Similarly, there is a need for a pharmaceutical carrier that is capable of releasing a current effective amount of the medicament into the lung tract or lung alveolar region.

There is also a need for a pharmaceutical carrier which can be used as a biodegradable inhalation aerosol and is capable of releasing the drug in a controlled manner in the closed area of the lungs and lungs and likewise has an improved spray characteristic for releasing the drug to the lungs Engraving particles are also required. It can be seen from this investigation that it is difficult to produce fine particles corresponding to the criteria for the fine particles to be used under effective conditions.

In order to exhibit sufficient effect, these microparticles should not be impaired during the transit administration in spray form. The bioavailability of these microparticles should be high enough, but the bioavailability of the microparticles of the prior art generally does not exceed 50% because of the low sedimentation level of the microparticles in the closed area.

In addition, in order to preserve these effects during administration to the lungs, the particulates once deposited in the alveoli must be sufficiently stable in the surface slime of these alveoli.

Thus, there is an interest in producing particulates for immediate or delayed release locally or systemically, but these particulates generally have an outer layer whose thickness is not significantly different from the diameter of the particle.

The present invention relates to the domain of the microparticles to be administered via the pulmonary route.

1 is an electron micrograph of the fine particles obtained in Example 2,

2 is an electron micrograph of the fine particles obtained according to Example 3. Fig.

The microparticles according to the present invention consist of a core comprising an active material coated with a coating layer deposited by supercritical fluid technology. This particular structure differs from prior art microparticles in that it is a matrix microsphere obtained using techniques of emulsification-evaporation solvents, extraction solvents with water, or spray-drying organic solvents.

Accordingly, the present invention is directed to an inhalable biocompatible particulate comprising at least one active ingredient and at least one layer coating the active ingredient, wherein said layer is an outer layer of said particulate, said outer layer comprising one or more coatings , Said fine particles having an average diameter of 1 탆 to 30 탆 and an apparent density of 0.2 g / cm 3 to 0.8 g / cm 3, said fine particles bringing together a coating agent and an active ingredient, stirring in a closed reactor, Lt; RTI ID = 0.0 > step < / RTI >

These microparticles do not aggregate upon administration and, optionally, can continuously release the active ingredient. The fine particles according to the present invention exhibit a biocompatibility of not less than 60%, preferably not less than 80%, by improving the level of precipitation of particles in the alveolar region.

Thus, by using a carefully selected biocompatible material as a coating agent and performing a method of making particles using the " supercritical fluid " technique, it is possible to control the size of the fine particles that are not aggregated in the alveolar region, Can be obtained.

The biocompatible microparticles for inhalation according to the present invention have an outer layer comprising a coating agent which prevents particles from agglomerating together. The coverage of the surface region of the particles is at least 50%, preferably at least 70%, more preferably at least 85%. The nature of this coating is inherently due to supercritical fluid technology.

The method involves two essential steps of bringing together the coating and the active ingredient, and introducing a supercritical fluid for coacervation of the coating. It is clear from the remainder of the specification that the two steps do not need to be performed in this order.

The first method for producing the microparticles according to the present invention differs from the second method in that it is not at all critical that the coating is in solution, fluid, liquid or supercritical state.

Specifically, the first method according to the present invention is carried out comprising the following steps:

Suspending the active ingredient in one or more substantially polar coating solutions in an organic solvent,

The active ingredient is insoluble in an organic solvent,

Wherein the substantially polar coating is insoluble in a fluid in a supercritical state,

Wherein the organic solvent is soluble in a supercritical fluid,

- contacting said suspension with a supercritical fluid to desolvate and coacervate the substantially polar coating in a controlled manner,

- extracting the solvent substantially with supercritical fluid and releasing the supercritical fluid / solvent mixture,

- recovering the particulate.

The fluid used to carry out the first process is preferably liquid CO ₂ or supercritical CO ₂ .

The organic solvent used to carry out this first process is generally selected from the group consisting of ketones, alcohols and esters.

A supercritical fluid is introduced into an autoclave which already contains a suspension, and a supercritical fluid is brought into contact with a suspension of the active ingredient containing the coating agent in the solution.

If the supercritical fluid is used CO _2, it can be used in the form of a liquid CO ₂ or use of CO ₂ in the supercritical state directly.

According to another variant, the suspension may be contacted with liquid CO ₂ and then the pressure and / or temperature in the autoclave may be increased to a supercritical state to extract the solvent.

When a liquid CO ₂ modification is used, the temperature is preferably 20 to 30 ° C and the pressure is preferably 80 to 150 x 10 ⁵ Pa. When a supercritical CO ₂ variant is used, the temperature is generally from 35 to 60 ° C, preferably from 35 to 50 ° C, the pressure is from 80 to 250 x 10 ⁵ Pa, preferably from 100 to 220 x 10 ⁵ Pa Is selected.

The mass of the organic solvent introduced into the autoclave represents at least 3%, preferably 3.5% to 25% of the supercritical fluid or liquid mass used to dissolve the coating. The fine particles obtained by performing this first method have an outer layer substantially free of solvent; The amount of solvent in the outer layer is actually less than 500 ppm.

Coatings that can be used to carry out this first method are, in particular,

- homopolymers and copolymers of biodegradable (co) polymers of? -hydroxycarboxylic acids, especially of lactic and glycolic acids, and in particular PLAs (poly-L-lactide) and PLGAs (poly (lacto-co- )),

- amphiphilic block polymers of the poly (lactic acid) -poly (ethylene oxide) type,

Poly (ethylene glycol), biocompatible polymers of the poly (ethylene oxide) type,

- polyanhydrides, poly (ortho esters), poly-epsilon -caprolactone and derivatives thereof,

Poly (? -Hydroxybutyrate), poly (hydroxyvalerate) and poly (? -Hydroxybutyrate-hydroxyvalerate) copolymers,

- poly (malic acid),

- polyphosphazene,

Block copolymers of the poly (ethylene oxide) -poly (propylene oxide) type,

- poly (amino acid),

- polysaccharides,

Phosphatidylglycerol, diphosphatidylglycerol (DLPG, DMPG, DPPG, DSPG) including C12 to C18 fatty acid chains, phosphatidylcholine, diphosphatidylcholine (DLPC, DMPC, DPPC, DSPC) including C12 to C18 fatty acid chains, C12 to C18 A phospholipid such as diphosphatidylethanolamine (DLPE, DMPE, DPPE, DSPE) containing a fatty acid chain, a phosphatidylserine (DLPS, DMPS, DPPS, DSPS) containing C12 to C18 chains,

- fatty acid esters such as glyceryl stearate, glyceryl laurate, cetyl palmitate, or mixtures comprising these compounds,

- a mixture comprising said compound.

A second method according to the present invention comprises suspending the active ingredient in a supercritical fluid in which one or more coating agents are dissolved and then changing the pressure and / or temperature conditions of the ambient environment to deposit a coating agent around the particles of the active ingredient And subjecting the particles to coacervation, that is, physiochemically changing the environment to coagulate the particles.

Coatings that can be used to carry out this second process are, in particular,

Phosphatidylglycerol, diphosphatidylglycerol (DLPG, DMPG, DPPG, DSPG) including C12 to C18 fatty acid chains, phosphatidylcholine, diphosphatidylcholine (DLPC, DMPC, DPPC, DSPC) including C12 to C18 fatty acid chains, C12 to C18 A phospholipid such as diphosphatidylethanolamine (DLPE, DMPE, DPPE, DSPE) containing a fatty acid chain, a phosphatidylserine (DLPS, DMPS, DPPS, DSPS) containing C12 to C18 chains,

Mono-, di-, triglycerides, and mixtures thereof, wherein the fatty acid chain is in the C4 to C22 range,

A mixture of glycerides and a mixture of esters of polyethylene glycol,

- cholesterol,

Fatty acid esters such as glyceryl stearate, glyceryl laurate and cetyl palmitate,

- a mixture comprising said compound.

Biodegradable or bioerodible polymers that are soluble in supercritical fluids may be used in this second method.

Coagulation (or coagulation) of the coating is due to a physicochemical change in the environment surrounding the active substance in the suspension in the coating solution in the solvent, which is a supercritical fluid.

The supercritical fluid preferentially used is supercritical CO ₂ (SCCO ₂ ), the typical initial functional condition of this second method is about 31-80 ° C, the pressure is 75-250 x 10 ⁵ Pa, but of course the active ingredient to be coated Or conditions that do not have a deleterious or emotional impact on the coating, higher values may be used for one or the other two parameters, or both parameters.

In addition, other fluids commonly used as supercritical fluids may be selected. In particular, the ethane is supercritical and at least 32 ℃ and 48 x 10 ⁵ Pa, nitrogen dioxide is the critical point is 36 ℃ and 72 x 10 ⁵ Pa, propane is the critical point is 96 ℃ and 42 x 10 ⁵ Pa, trifluoromethane the threshold is 26 ℃ and 47 x 10 ⁵ Pa, as chlorotrifluoroethylene critical point of methane is 29 ℃ and 39 x 10 ⁵ Pa.

This second method comprises suspending an active ingredient insoluble in a closed stirred autoclave in a supercritical fluid, wherein the supercritical fluid comprises a coating in a solute state.

The pressure and / or temperature are then varied to reduce the solubility of the coating in the fluid. Thus, the affinity of the coating to the active ingredient increases, so that the coating adsorbs around the active ingredient. Once this coating is deposited on the active component, the autoclave is depressurized and the particulate is recovered.

To carry out this second method, the active ingredient to be coated and the coating (s) are placed in an autoclave equipped with a stirrer, and the fluid present under supercritical conditions is introduced into the autoclave to pressurize the system. The temperature and / or pressure inside the autoclave is then changed in a controlled and controlled manner to gradually decrease the solubility of the coating (s). When the solubility of the (s) coating in the supercritical fluid decreases, they precipitate and are adsorbed to the surface due to the affinity of the reagent to the surface of the active ingredient. A modification of this method consists of placing the coating agent in an autoclave and introducing an active ingredient into it, or simultaneously introducing a fluid capable of passing through the active ingredient and the supercritical state. Then, when the autoclave is pressurized to a supercritical state, the coating agent will dissolve in the supercritical fluid.

According to another variant of this method, the active ingredient is placed in an autoclave equipped with a stirrer, a coating agent is placed in a second autoclave equipped with a stirrer, and a fluid capable of passing through the supercritical state is introduced into the autoclave. The temperature and pressure are increased to bring the coating into a solute state and then transferred to an autoclave containing the active ingredient.

Thus, the coating agent can be precipitated to enable the coating agent to coat the surface of the active component.

The active ingredient may be in liquid form and thus form an emulsion in a supercritical fluid of preformed solid particles, and in particular particulates already coated with, for example, monosaccharides or disaccharides. The stirring speed may range from 150 to 700 rpm for solid particles and from 600 to 1000 rpm if the effective component is a liquid.

With this agitation, the active ingredient is suspended in the supercritical fluid upon introduction of the supercritical fluid. The supercritical state is created by changing the temperature and / or pressure in the autoclave. Therefore, when the supercritical fluid is CO ₂ , the temperature of the autoclave is 35 to 80 캜, preferably 35 to 50 캜, the pressure is 100 to 250 x 10 ⁵ Pa, preferably 180 to 220 x 10 ⁵ Pa to be.

When the supercritical fluid is ethane, the temperature of the autoclave is 35 to 80 캜, preferably 35 to 50 캜, and the pressure is 50 to 200 x 10 ⁵ Pa, preferably 50 to 150 x 10 ⁵ Pa.

When the fluid is propane, the temperature of the autoclave is 45 to 80 캜, preferably 55 to 65 캜, and the pressure is 40 to 150 x 10 ⁵ Pa.

The coating is introduced into the autoclave either simultaneously with the supercritical fluid or before the supercritical fluid is introduced into the autoclave. In any case, in order for the coating to have good solubility in the supercritical fluid, the system is kept in equilibrium with stirring, establishing a suitable concentration of active ingredient and coating as the action of the desired particulate, and stirring the equilibrium for 1 hour Leave. The temperature and pressure are then changed at sufficiently low rates to completely move the coating (s) from the supercritical fluid to the surface of the active ingredient, and the system is depressurized to separate and remove the particulates from the autoclave.

The fine particles according to the present invention have a diameter of 1 탆 to 30 탆, preferably 1 탆 to 15 탆, more preferably 2 탆 to 10 탆, an apparent density of 0.02 g / cm 3 to 0.8 g / 0.05 g / cm 3 to 0.4 g / cm 3.

The active ingredient / coating mass ratio of these fine particles is preferably 95/5 to 5/95.

In the case of controlled-release fine particles, the amount of active ingredient is smaller than that of the coating, the active ingredient / coating material mass ratio is 5/95 to 20/80; On the other hand, when the coating agent stabilizes the particles, particularly when the fine particles are instant-releasing fine particles, the active ingredient / coating weight ratio is generally 95/5 to 70/30, preferably 95/5 to 80/20.

The coatings of the microparticles according to the invention are advantageously of the following group:

- homopolymers and copolymers of biodegradable (co) polymers of? -hydroxycarboxylic acids, especially of lactic and glycolic acids, and in particular PLAs (poly-L-lactide) and PLGAs (poly (lacto-co- )),

Mono-, di-, triglycerides, and mixtures thereof, wherein the fatty acid chain is in the range of C4 to C22,

A mixture of glycerides and a mixture of esters of polyethylene glycol,

- cholesterol,

- amphiphilic block polymers of the poly (lactic acid) -poly (ethylene oxide) type,

Poly (ethylene glycol), biocompatible polymers of the poly (ethylene oxide) type,

- polyanhydrides, poly (ortho esters), poly-epsilon -caprolactone and derivatives thereof,

Poly (? -Hydroxybutyrate), poly (hydroxyvalerate) and poly (? -Hydroxybutyrate-hydroxyvalerate) copolymers,

- poly (malic acid),

- polyphosphazene,

Block copolymers of the poly (ethylene oxide) -poly (propylene oxide) type,

- poly (amino acid),

- polysaccharides,

Phosphatidylglycerol, diphosphatidylglycerol (DLPG, DMPG, DPPG, DSPG) including C12 to C18 fatty acid chains, phosphatidylcholine, diphosphatidylcholine (DLPC, DMPC, DPPC, DSPC) including C12 to C18 fatty acid chains, C12 to C18 A phospholipid such as diphosphatidylethanolamine (DLPE, DMPE, DPPE, DSPE) containing a fatty acid chain, a phosphatidylserine (DLPS, DMPS, DPPS, DSPS) containing C12 to C18 chains,

- fatty acid esters such as glyceryl stearate, glyceryl laurate or cetyl palmitate,

- a mixture of two or more compounds selected from the fatty acid derivatives having suitable solubility.

Thus, depending on the solubility and the coating conditions in the coating, the supercritical fluid, the first or second method described above can be carried out.

The active ingredient may be in the form of liquid, solid powder or inert porous solid particles comprising the active ingredient on the surface.

The active ingredient employed is selected from a wide variety of therapeutic and prophylactic compounds. These include, in particular, proteins and peptides such as insulin, calcitonin, or analogs of the hormone LH-RH, polysaccharides such as heparin, budesonide, beclometasone dipropionate, Anti-asthmatics such as 17-monopropionate, bronchodilators such as beta-estradiol hormone, testosterone, albuterol, cytotoxic agents, corticoids, antigens and DNA fragments.

The following examples illustrate the scope of the invention without limiting it.

Example 1

This embodiment illustrates the first method of the present invention.

80 mg of PLGA are dissolved in 80 ml of ethyl acetate. Then, 400 mg of finely divided insulin is suspended in a solution obtained at 250 rpm, and the suspension is put into an autoclave of 1.0 liter capacity. Initially, liquid CO ₂ is introduced to increase the pressure to 100 x 10 < ⁵ > Pa, while maintaining the temperature at 28 [deg.] C.

Liquid CO ₂ is mixed with the suspension, wetting the insulin, and gradually depositing the coating.

The pressure is gradually increased to 150 x 10 < ⁵ > Pa to make the CO ₂ supercritical. The temperature is commonly maintained at 40 占 폚. Thereby, ethyl acetate is extracted. After keeping this state for 15 minutes, while maintaining the temperature in the separator to more than 35 ℃ reduced pressure to 75 x 10 ⁵ Pa to emit CO ₂ / ethyl acetate mixture. Ethyl acetate is recovered from the separator, and CO ₂ is returned to the reservoir.

Ethyl acetate is recovered, liquid CO ₂ is introduced in a continuous cycle, the supercritical state is maintained, and the CO ₂ + ethyl acetate release is repeated until the ethyl acetate is completely removed.

Make sure that the pressure is reduced through the gaseous phase so that the coating agent does not re-concentrate in the remaining ethyl acetate. After depressurization, CO ₂ is reintroduced and this operation is repeated several times to return to a pressure of 150 x 10 ⁵ Pa and a temperature of 40 ° C. Finally, the CO ₂ + solvent mixture is depressurized and extracted, the fresh CO ₂ reintroduced, and the supercritical state is obtained to completely extract the solvent. In this case, the temperature is generally 35 to 45 DEG C and the pressures are 180 and 220 x 10 < ⁵ > Pa.

Thereby, 250 mg of non-agglomerated fine particles having an average size of 3 탆, 80 to 90% by weight of insulin, and improved spray characteristics are obtained.

Example 2

This embodiment illustrates a second method of the present invention.

150 mg of spray-dried bovine serum albumin (BSA) and 600 mg of Gelucire 50/02 600 mg is placed in a compressible, stirred 0.3 liter autoclave equipped with a porous insert.

CO ₂ is introduced into the autoclave until the pressure reaches 95 x 10 ⁵ Pa for a temperature of 25 ° C. Then, the CO is in a liquid state.

Stirring is started and set at 460 rpm. The autoclave is then heated to 50 占 폚. The pressure is then 220 10 ⁵ Pa; CO ₂ is a supercritical state with a density of 0.805 g / cm 3.

This system is left to equilibrate for 1 hour. The temperature of the autoclave is then lowered from 50 ° C to 19 ° C over 38 minutes. Thus, the phase of the suspension in supercritical CO ₂ is transformed into a mixture of liquid and gaseous CO ₂ , so that the active ingredient particles are present in suspension in liquid CO ₂ . Then, the pressure was reduced to atmospheric pressure and Gelucire 0.0 > 50/2 < / RTI >

An average diameter of 10 mu m, and Gelucire 250 mg of non-agglomerated particles of BSA coated with 50/02 layer are obtained, wherein the active ingredient / coating mass ratio is about 30/70. These particulates have improved spray characteristics.

Example 3

This embodiment illustrates a second method of the present invention.

300 mg of egg white albumin (OVA) prepared by the spray-drying method and 300 mg of Gelucire Lt; RTI ID = 0.0 > 1 < / RTI > liter autoclave which is pressurizable and agitated.

CO ₂ is introduced into the autoclave until the pressure reaches 109 x 10 < ⁵ > Pa for a temperature of 23 [deg.] C. Then CO ₂ is in a liquid state.

Stirring is started and set at 340 rpm. The autoclave is then heated to 35 占 폚. Thereafter, the pressure is 180 x 10 < ⁵ > Pa and CO ₂ is in a supercritical state.

This system is left to equilibrate for 1 hour. The temperature of the autoclave is then lowered from 35 ° C to 16 ° C over 43 minutes. Thus, in supercritical CO ₂ the phase of the suspension is transformed into a mixture of liquid and gaseous CO ₂ . Thereafter, the pressure was reduced to atmospheric pressure, and Gelucire To obtain fine particles of OVA coated with 50/13.

Therefore, the spraying property was improved, the average diameter was 9 mu m, and Gelucire 300 mg of non-agglomerated particles of OVA coated with a 50/13 layer are obtained.

Example 4

This embodiment illustrates a second method of the present invention.

300 mg of beclomethasone dipropionate in the form of a glass powder prepared by the spray-drying method and 50 mg of dilauryl phosphatidylglycerol (DLPG) are placed in a pressurizable 0.3 liter autoclave equipped with a porous insert.

CO ₂ is introduced into the autoclave until the pressure is 98 x 10 < ⁵ > Pa for a temperature of 23 [deg.] C. Then, the CO is in a liquid state.

Stirring is started and set at 460 rpm. The autoclave is then heated to 60 占 폚. Thereafter, the pressure is 300 x 10 < ⁵ > Pa, CO ₂ is supercritical, and the density is 0.830 g / cm < 3 >.

This system is left to equilibrate for 1 hour. The temperature of the autoclave is then lowered to 20 ° C over 65 minutes. Thus, in supercritical CO ₂ the phase of the suspension is transformed into a mixture of liquid and gaseous CO ₂ , active ingredient particles of the suspension in liquid CO ₂ . Then, the pressure is reduced to atmospheric pressure to obtain microparticles of beclomethasone dipropionate coated with DLPG.

200 mg of non-agglomerated particles of beclomethasone dipropionate coated with a DLPG layer having an average diameter of 5 μm are obtained, wherein the active ingredient / coating mass ratio is about 90/10. These particulates have improved spray characteristics.

The microparticles according to the present invention consist of a core comprising an active material coated with a coating layer deposited by a supercritical fluid technique, wherein the specific structure is selected from the group consisting of an emulsification-vapor solvent, an extraction solvent with a water phase or a spray-dried organic solvent Gt; microparticles < / RTI > obtained using the technique of the present invention. According to the present invention, it is possible to obtain fine particles which are suitable for inhalation administration and have improved spray characteristics without aggregation.

Claims (10)

Claims 1. An inhalable biocompatible microparticle comprising at least one active ingredient and at least one layer coating the active ingredient, wherein the layer is an outer layer of microparticles, the outer layer comprises at least one coating, the average diameter of the microparticles is 1 占 퐉 To 30 占 퐉 and an apparent density of 0.02 g / cm3 to 0.8 g / cm3, bringing the coating agent and the active ingredient together, and introducing a supercritical fluid while stirring in a closed reactor Wherein the biodegradable microparticles are obtained according to the following method. The method according to claim 1, Wherein the average particle diameter of the fine particles is from 1 탆 to 15 탆, preferably from 2 탆 to 10 탆, the apparent density is from 0.05 g / cm 3 to 0.4 g / cm 3, Lt; RTI ID = 0.0 > 5/95. ≪ / RTI > 3. The method according to claim 1 or 2, The following steps: Suspending the active ingredient in one or more substantially polar coating solutions in an organic solvent, The active ingredient is insoluble in an organic solvent, Wherein the substantially polar coating is insoluble in a fluid in a supercritical state, Wherein the organic solvent is soluble in a supercritical fluid, - contacting said suspension with a supercritical fluid to desolvate and coacervate the substantially polar coating in a controlled manner, - extracting the solvent substantially with supercritical fluid and releasing the supercritical fluid / solvent mixture, - Recovering the Particles ≪ / RTI > by weight. 3. The method according to claim 1 or 2, Suspending the active ingredient in a supercritical fluid in which at least one coating agent is dissolved, and physiochemically modifying the surrounding environment to coagulate the particles. The method of claim 3, Wherein the coating comprises the following composition: - homopolymers and copolymers of biodegradable (co) polymers of? -hydroxycarboxylic acids, especially of lactic and glycolic acids, and in particular PLAs (poly-L-lactide) and PLGAs (poly (lacto-co- )), - amphiphilic block polymers of the poly (lactic acid) -poly (ethylene oxide) type, Poly (ethylene glycol), biocompatible polymers of the poly (ethylene oxide) type, - polyanhydrides, poly (ortho esters), poly-epsilon -caprolactone and derivatives thereof, Poly (? -Hydroxybutyrate), poly (hydroxyvalerate) and poly (? -Hydroxybutyrate-hydroxyvalerate) copolymers, - poly (malic acid), - polyphosphazene, Block copolymers of the poly (ethylene oxide) -poly (propylene oxide) type, - poly (amino acid), - polysaccharides, Phosphatidylglycerol, diphosphatidylglycerol (DLPG, DMPG, DPPG, DSPG) including C12 to C18 fatty acid chains, phosphatidylcholine, diphosphatidylcholine (DLPC, DMPC, DPPC, DSPC) including C12 to C18 fatty acid chains, C12 to C18 A phospholipid such as diphosphatidylethanolamine (DLPE, DMPE, DPPE, DSPE) containing a fatty acid chain, a phosphatidylserine (DLPS, DMPS, DPPS, DSPS) containing C12 to C18 chains, - fatty acid esters such as glyceryl stearate, glyceryl laurate, cetyl palmitate, or mixtures comprising these compounds, - a mixture comprising said compound ≪ / RTI > 5. The method of claim 4, Wherein the coating comprises the following composition: Phosphatidylglycerol, diphosphatidylglycerol (DLPG, DMPG, DPPG, DSPG) including C12 to C18 fatty acid chains, phosphatidylcholine, diphosphatidylcholine (DLPC, DMPC, DPPC, DSPC) including C12 to C18 fatty acid chains, C12 to C18 A phospholipid such as diphosphatidylethanolamine (DLPE, DMPE, DPPE, DSPE) containing a fatty acid chain, a phosphatidylserine (DLPS, DMPS, DPPS, DSPS) containing C12 to C18 chains, Mono-, di-, triglycerides, and mixtures thereof, wherein the fatty acid chain is in the C4 to C22 range, A mixture of glycerides and a mixture of esters of polyethylene glycol, - cholesterol, Fatty acid esters such as glyceryl stearate, glyceryl laurate and cetyl palmitate, - biodegradable or bioabsorbable polymers that are soluble in supercritical fluids, - a mixture comprising said compound ≪ / RTI > 7. The method according to any one of claims 1 to 6, Wherein said active ingredient is selected from the group consisting of proteins and peptides such as analogs of insulin, calcitonin or hormone LH-RH, polysaccharides such as heparin, budesonide, beclometasone dipropionate, An antineoplastic agent such as methadone 17-monopropionate, a bronchodilator such as beta-estradiol hormone, testosterone, albuterol, a cytotoxic agent, a corticoid, an antigen and a DNA fragment Fine particles. 3. The method of claim 2, Wherein the fine particles are immediate-release fine particles, and the effective ingredient / coating weight ratio of the particles is 95/5 to 80/20. The following steps: Suspending the active ingredient in one or more substantially polar coating solutions in an organic solvent, The active ingredient is insoluble in an organic solvent, Wherein the substantially polar coating is insoluble in a fluid in a supercritical state, Wherein the organic solvent is soluble in a supercritical fluid, - contacting said suspension with a supercritical fluid to desolvate and coacervate the substantially polar coating in a controlled manner, - extracting the solvent substantially with supercritical fluid and releasing the supercritical fluid / solvent mixture, - Recovering the Particles Wherein the microparticles are in contact with each other. Suspending an active ingredient in a supercritical fluid in which at least one coating agent is dissolved while stirring in a closed reactor, and subsequently physically chemically altering the surrounding environment to coagulate the particles.