JP2003506479A - Fine particles for pulmonary administration - Google Patents

Abstract

(57) Abstract: The present invention relates to a fine particle comprising at least one active ingredient and at least one layer covering the active ingredient, wherein this layer is an outer layer of the fine particle, and the outer layer comprises at least one type of fine particle. Biocompatible microparticles designed for inhalation, including coatings. The present invention, this particle has an apparent density of average particle size and the range of 0.02g / cm ³ ~0.8g / cm ³ in the range of 1 to 30 [mu] m, a step of combining the active ingredient with the coating agent and sealed reaction The method is characterized by being obtained by a method including, as an essential step, a step of introducing a supercritical fluid while stirring in a vessel.

Description

Detailed Description of the Invention

[0001]   The present invention relates to the field of microparticles for administration via the pulmonary route.

It has been possible to clarify from the literature reviews that much research has been done on this technology. Aerosols for the release of therapeutic agents into the respiratory tract include, for example, Adjei, A and Garren, J. Ph.
arm.Res., 7: 565-569 (1990); and Zanen, P. and Lamm, JWJ Int. J. Pharm.,
114: 111-115 (1995). The airways consist of the upper airways, which include the larynx and oropharynx, and the lower airways, which include the trachea extending to the bifurcation: bronchi and bronchioles. The terminal bronchi then divide into respiratory bronchioles, which lead to the final regions of the respiratory system, the alveoli (also known as the deep lung) (Gonda, I. “Aerosols for therapeutic and diagnostic supply in the respiratory tract” Critical. Reviews in Therapeutic Drug Carrier Syste
ms, 6: 273-313 (1990)). The deep lung, or alveoli, is the main target for therapeutic aerosol by inhalation for the systemic route. Aerosols for inhalation have already been used for the treatment of localized lung diseases such as asthma and cystic fibrosis (Anderson et al., Am. Re.
v. Respir. Dis., 140: 1317-1324 (1989)). Furthermore, they can be used for systemic release of peptides and proteins (Patton and Platz, Advanced D
rug Delivery Reviews, 8: 179-196 (1992)). However, when trying to apply the release of drugs by the pulmonary route to the release of macromolecules, some difficulties are encountered. These difficulties include protein denaturation during nebulization, significant loss of inhaled drug dose in the oropharynx (often> 80%), difficulty in controlling deposition area, and reproducibility of treatment results due to variability in respiratory model. Poor sex, excessive absorption of drug, local toxic effects, and phagocytosis by pulmonary macrophages.

The human lungs are able to rapidly remove or degrade hydrolyzable products deposited in the form of aerosols, a phenomenon that generally occurs for minutes to hours.
In the upper lung airways, the ciliated epithelium contributes to the `` mucociliary escalator '' phenomenon in which particles are guided from the lung airways to the mouth (Pavia, D.
Mucociliary clearance in the lung "Aerosols and the Lung: Clinical and Experimen
tal Aspects, Clarke, SW and Pavia, D. Ed., London, Butterworth, 1984;
Anderson et al., Am. Rev. Respir. Dis., 140: 1317-1324 (1989)). When particles are deposited in the deep lung, they are immediately taken up by alveolar macrophages (phagocytosis).
be able to.

Topical and systemic treatments by inhalation generally allow a controlled and relatively slow release of the active ingredient (Gonda, I., "Physicochemical principles of aerosol delivery" Topics in Pharmaceutical Science 1991 , DJACrommelin and KKMidha
Editor, Stuttgart: Medpharm Scientific Publishers, pp.95-117 (1992)
). The slow release of the therapeutic aerosol can increase the time that the administered drug remains in the pulmonary airways or lobules and reduce the rate of drug inflow into the bloodstream. Therefore, decreasing the frequency of dosing increases patient tolerance (Langer
, R., Science, 249: 1527-1533 (1990); Gonda, I. "Aerosol for therapeutic and diagnostic delivery to the respiratory tract" Critical Reviews in Therapeutic Drug Carrier Sys
tems, 6: 273-313 (1990)).

A drawback caused by dry powder formulations is that ultrafine powders generally have poor flow and nebulization properties, which leads to the production of aerosol fractions that are administered relatively slowly to the respiratory system, These fractions of inhaled aerosols are generally deposited in the mouth and throat (Gonda, I., Topics in Pharma
ceutical Science 1991, edited by D. Crommelin and K. Midha, Stuttgart: Me
dpharm Scientific Publishers, 95-117 (1992)).

A major problem with most aerosols is agglomeration of particles caused by particle-particle interactions such as hydrophobic, electrostatic and capillary interactions. Effective treatment by inhalation of dry powder for immediate and sustained release of therapeutic agents both locally and systemically avoids the natural lung clearance mechanism or at least releases the active ingredient It is necessary to use a powder with minimal agglomeration that allows it to be stopped until time.

There is currently a need for improved inhalation aerosols for the release of therapeutic agents to the lung. There is also a current need for a pharmaceutical carrier that is capable of releasing an effective amount of the drug into the respiratory tract of the lung or the alveolar region of the lung.

[0008] Furthermore, there is a need for a pharmaceutical carrier that is biodegradable and that can be used as an inhalation aerosol that enables the pharmaceutical to be released into the alveolar regions of the respiratory tract and lungs in a controlled manner, as well. There is a need for particles for the release of pharmaceuticals in the lung that have improved spraying properties. These studies tend to indicate that it is difficult to produce microparticles that meet the criteria imposed on them by using them under effective conditions.

In order to be fully effective, these microparticles, when in atomized form, must not be damaged during administration. The bioavailability of these microparticles must reach sufficiently high values. However, the bioavailability of conventional microparticles generally does not exceed 50% because the microparticles deposit at low levels in the alveolar region.

Furthermore, in order to retain their effectiveness during pulmonary administration, the microparticles, once deposited in the alveoli, must be sufficiently stable in the mucus on the surface of these alveoli. Therefore, it may prove advantageous to produce microparticles for immediate or sustained release, either locally or systemically. However, these particles generally have an outer layer whose thickness relative to the particle size of the particles is not insignificant.

The microparticles of the present invention consist of a core containing the active substance coated with a layer of coating material deposited by supercritical fluid technology. This particular structure distinguishes the microparticles of the invention from conventional microparticles, which are matrix microspheres obtained using the techniques of solvent emulsification-evaporation, solvent extraction in the aqueous phase, or organic solvent spray-drying. To be done.

[0012]   Accordingly, the present invention covers at least one active ingredient and the active ingredient.
A microparticle comprising at least one layer, the layer being an outer layer of the microparticle,
The outer layer is a biocompatible microparticle for inhalation containing at least one coating
, The average particle diameter of these fine particles is in the range of 1 μm to 30 μm, and the apparent density is 0.02 g / cm. ³ ~ 0.8g / cm³The process of combining the coating with the active ingredient and the closure reaction
By a method that includes a step of introducing a supercritical fluid while stirring in a vessel as an essential step
A biocompatible microparticle for inhalation, characterized in that it can be obtained.

These microparticles do not aggregate when administered and may, in some cases, allow a sustained release of the active ingredient. The microparticles of the present invention exhibit a bioavailability of 60% or more, preferably 80% or more, by improving the amount of particles deposited in the alveolar region of the lung.

A method of preparing microparticles by the “supercritical fluid” technique using a suitably selected biocompatible material as a coating is carried out and has a controlled size such that the microparticles do not aggregate and form lungs. It was thus demonstrated that it is possible to obtain microparticles that are surface-finished to deposit in the alveolar region.

The biocompatible microparticles for inhalation of the present invention have an outer layer containing a coating that prevents these particles from aggregating with each other. The coverage of the surface area of the particles is at least 50% or more, preferably 70% or more, more preferably 85% or more. The nature of this coating is essentially due to supercritical fluid technology.

The method comprises two essential steps: combining the coating and the active ingredient and introducing a supercritical fluid to ensure the coacervation of the coating. It will be clear from the following description of the specification that these two steps do not have to be performed in this order.

The first method of producing the microparticles of the present invention differs from the second method in that the coating agent is not present in solution in the liquid or supercritical fluid at any time. Specifically, the first implementation of the method of the present invention comprises the steps of: suspending the active ingredient in a solution of at least one substantially polar coating agent in an organic solvent; Is insoluble in the organic solvent, the substantially polar coating is insoluble in the supercritical fluid, the organic solvent is soluble in the supercritical fluid, and the substantially polar coating is Contacting this suspension with a fluid in the supercritical state so as to desolvate it in a controlled manner and ensure its coacervation; And extracting the supercritical fluid / solvent mixture, and collecting fine particles.

The fluid used for carrying out this first method is preferably liquid CO ₂ or CO ₂ in the supercritical state. The organic solvent used for carrying out this first method is generally selected from the group consisting of ketones, alcohols and esters.

The supercritical fluid is brought into contact with this suspension by introducing the supercritical fluid into an autoclave which already contains a suspension of the active ingredient containing the coating agent in solution. When the supercritical fluid used is CO _2, it is possible to use CO ₂ in liquid form or to use CO ₂ directly in the supercritical state.

According to another approach, the suspension is contacted with liquid CO ₂ and then the liquid CO ₂ is brought to a supercritical state by increasing the pressure and / or temperature in the autoclave in order to extract the solvent. It is also possible.

[0021]   Liquid CO₂When selecting the method described above, the temperature is preferably in the range of 20 to 30 ° C.
Power is 80 ~ 150 × 10^FiveIt is in the range of Pa. Supercritical CO₂When using the method of
It is generally in the range of 35 to 60 ° C, preferably 35 to 50 ° C, and the pressure is 80 to 250 × 10 ^Five Pa, preferably 100-220 x 10^FivePa.

The mass of organic solvent charged to the autoclave is at least 3%, preferably 3.5% to 25% of the mass of the supercritical fluid or liquid used to effect the desolvation of the coating.
Is. The microparticles obtained by carrying out this first method have an outer layer that is substantially free of solvent, the amount of solvent in the outer layer being in fact less than 500 ppm.

The coating agents which can be used for carrying out this first method are more particularly: biodegradable (co) polymers of α-hydroxycarboxylic acids, in particular lactic acid and glycolic acid. Homopolymers and copolymers of PLA (poly-L-lactide
) And PLGA (lactic acid-glycolic acid copolymer), -poly (lactic acid) -poly (ethylene oxide) type amphiphilic block polymer, -poly (ethylene glycol), poly (ethylene oxide) type biocompatibility Polymers, -polyanhydrides, poly (orthoesters), poly-ε-caprolactone and their derivatives, -poly (β-hydroxybutyrate), poly (hydroxyvalerates) and poly (β-hydroxybutyrate-hydroxy) (Valerate) copolymer, -poly (malic acid), -polyphosphazene, -poly (ethylene oxide) -poly (propylene oxide) type block copolymer, -poly (amino acid), -polysaccharide, -phosphatidylglycerol , Diphosphatidylglycerol containing C12-C18 fatty acid chains (DLPG, DMPG, DPPG, DSPG), phosphatidylcholine, C12 C18
Diphosphatidylcholine containing fatty acid chains (DLPC, DMPC, DPPC, DSPC), C12 ~
Diphosphatidylethanolamine containing fatty acid chains of C18 (DLPE, DMPE, DPPE,
DSPE), diphosphatidylserine containing C12-C18 chains (DLPS, DMPS, DPPS, DSPS
) And mixtures containing these phospholipids; -glycerin stearates, lauric glycerin esters, fatty acid esters such as cetyl palmitate and mixtures containing these compounds, -mixtures containing the above compounds.

The practice of the second method of the present invention involves suspending the active ingredient in a supercritical fluid containing at least one coating agent dissolved therein and then depositing the coating agent around the particles of the active ingredient. This consists of modifying the conditions of pressure and / or temperature of the environment so as to ensure the coacervation of the particles, ie the physicochemical changes of the environment.

The coating agents which can be used for carrying out this second method are more particularly: phosphatidyl glycerol, diphosphatidyl glycerol containing C12 to C18 fatty acid chains (DLPG, DMPG, DPPG, DSPG). ), Phosphatidylcholine, C12-C18
Diphosphatidylcholine containing fatty acid chains (DLPC, DMPC, DPPC, DSPC), C12 ~
Diphosphatidylethanolamine containing fatty acid chains of C18 (DLPE, DMPE, DPPE,
DSPE), diphosphatidylserine containing C12-C18 chains (DLPS, DMPS, DPPS, DSPS
) Such as phospholipids and mixtures containing these phospholipids; -mono-, di-, triglycerides with fatty acid chains of C4 to C22 and mixtures containing them-mixtures of glycerides and esters of poly (ethylene glycol),-cholesterol Fatty acid esters such as glyceryl stearate, glyceryl laurate, cetyl palmitate, and mixtures containing the above compounds.

In the second method, a biodegradable or biodegradable substance soluble in a supercritical fluid is used.
(Bioerodible) polymers may be used. Coacervation (or agglomeration) of the coating is caused by a physico-chemical modification of the environment containing the active ingredient in suspension in a solution of the coating in a solvent that is a supercritical fluid.

The supercritical fluid preferably used is supercritical CO ₂ (SCCO ₂ ), typical initial working conditions of this second method are about 31-80 ° C. and pressures of 75-250 × 10 5. It will be ⁵ Pa. However, one or the other of the two parameters, provided that higher values do not have a detrimental or degrading effect on the active ingredient or coating to be coated,
Alternatively, higher values may be used for both.

Furthermore, it is possible to select other fluids that are commonly used as supercritical fluids. In particular, ethane and critical points that become supercritical above 32 ° C and 48 × 10 ⁵ Pa
36 ℃, 72 × 10 ⁵ Pa nitrogen dioxide, 96 ° C, 42 × 10 ⁵ Pa propane, critical point 26 ° C, 47 × 10 ⁵ Pa trifluoromethane, and critical point 29 ° C ,
An example is chlorotrifluoromethane, which is 39 × 10 ⁵ Pa.

This second method involves suspending the active ingredient insoluble in the supercritical fluid in a closed closed autoclave with stirring, the supercritical fluid containing the coating in the solute state.

The pressure and / or temperature is then changed to reduce the solubility of the coating in the fluid. In this way, the affinity of the coating agent for the active ingredient is improved and the coating agent is adsorbed around the active ingredient. After the coating agent is deposited on the active ingredient, the autoclave is depressurized to collect fine particles.

In order to carry out this second method, the active ingredient to be coated and the coating agent are placed in an autoclave equipped with a stirrer and then the supercritical fluid is placed in this autoclave. Pressurize the system. The temperature and / or pressure in the autoclave is then changed in a controlled and regulated manner to gradually reduce the solubility of the coating. When the solubility of these coating (s) in the supercritical fluid decreases, they (these) precipitate and the coating's affinity for the surface of the active ingredient causes the coating to adsorb to the surface of the active ingredient. A variant of this method consists of putting the coating in the autoclave before putting the active ingredient in the autoclave or at the same time with the active ingredient and the fluid which may be in the supercritical state at the same time. Pressurization of the autoclave to create the supercritical fluid state will then dissolve the coating in this supercritical fluid.

According to another variant, the active ingredient is placed in an autoclave equipped with a stirrer and the coating material is placed in a second autoclave equipped with a stirrer into which a fluid which can be in a supercritical state is introduced. To do. The coating is soluted by increasing the temperature and pressure and then transferred into an autoclave containing the active ingredient.

In this way, the coating agent is deposited so that the coating agent covers the surface of the active ingredient. The active ingredient may be in liquid form, which may form an emulsion in a supercritical fluid, and may also be preformed solid particles, in particular optionally already coated (e.g. monosaccharides and disaccharides). In) It may be in the form of fine particles. The stirring speed may be in the range of 150 to 700 rpm in the case of solid particles, and in the range of 600 to 1,000 rpm in the case of the liquid active ingredient.

Such agitation ensures that the active ingredient is suspended in the supercritical fluid when the supercritical fluid is introduced. The supercritical state is created by changing the temperature and / or pressure inside the autoclave. Therefore, when the supercritical fluid is CO ₂ , the temperature of the autoclave is in the range of 35-80 ° C, preferably 35-50 ° C, and the pressure is 100-250.
× 10 ⁵ Pa, preferably 180 to 220 × 10 ⁵ Pa.

When the supercritical fluid is ethane, the temperature of the autoclave is 35-80 ° C., preferably 35-50 ° C., the pressure is 50-200 × 10 ⁵ Pa, preferably 50-150 × 10 ⁵ Pa. is there.

When the supercritical fluid is propane, the temperature of the autoclave is 45-80 ° C., preferably 55-65 ° C., and the pressure is 40-150 × 10 ⁵ Pa. The coating agent is introduced into the autoclave at the same time as the supercritical fluid or before the supercritical fluid is put into the autoclave. At the very least, in order to ensure good solubilization of the coating in the supercritical fluid, the system is kept in equilibrium with stirring and a suitable concentration of active ingredient and coating is applied to the desired microparticles. Establish as a function and hold this equilibrium for 1 hour with stirring. The temperature and pressure are then changed at a rate slow enough to completely transfer the coating from the supercritical fluid to the surface of the active ingredient, the system is depressurized to separate the particles and the particles are removed from the autoclave.

The fine particles of the present invention have a particle size of 1 μm to 30 μm, preferably 1 μm to 15 μm, more preferably 2 μm to 10 μm, and an apparent density of 0.02 g / cm ^{3 to} 0.8 g / cm ³ , preferably 0.05 g. / cm ^{3 to} 0.4 g / cm ³ .

The mass ratio of the active ingredient / coating agent of these fine particles is preferably 95/5 to 5/95. In the case of controlled release fine particles, the amount of the active ingredient is smaller than that of the coating agent, and
The mass ratio of the coating agent is 5/95 to 20/80. On the other hand, when it is desired to stabilize the particles in the coating, especially when the particles are immediate release particles, the mass ratio of active ingredient / coating agent is generally 95/5 to 70/30, preferably 95/5 to 80. / 20.

The coatings of the microparticles according to the invention are preferably of the following group: biodegradable (co) polymers of α-hydroxycarboxylic acids, in particular homopolymers and copolymers of lactic acid and glycolic acid. Polymer, more specifically PLA (poly-L-lactide
) And PLGA (lactic acid-glycolic acid copolymer),-mono-, di-, and triglycerides whose fatty acid chain is C4 to C22 and mixtures containing them-glyceride mixtures and mixtures of esters of poly (ethylene glycol),-cholesterol, -poly (Lactic acid) -poly (ethylene oxide) type amphiphilic block polymer, -poly (ethylene glycol), poly (ethylene oxide) type biocompatible polymer, -polyanhydride, poly (orthoester), poly -ε-caprolactone and derivatives thereof, -poly (β-hydroxybutyrate), poly (hydroxyvalerate) and poly (β-hydroxybutyrate-hydroxyvalerate) copolymer, -poly (malic acid),- Block copolymerization of polyphosphazene, -poly (ethylene oxide) -poly (propylene oxide) type , - poly (amino acids), - a polysaccharide, - phosphatidylglycerol, diphosphatidylglycerol containing fatty acid chains of C12 ~C18 (DLPG, DMPG, DPPG, DSPG), phosphatidyl choline, C12 -C18
Diphosphatidylcholine containing fatty acid chains (DLPC, DMPC, DPPC, DSPC), C12 ~
Diphosphatidylethanolamine containing fatty acid chains of C18 (DLPE, DMPE, DPPE,
DSPE), diphosphatidylserine containing C12-C18 chains (DLPS, DMPS, DPPS, DSPS
) And mixtures containing these phospholipids, fatty acid esters such as glyceryl stearate, glyceryl laurate, cetyl palmitate, at least 2 having a suitable solubility selected from the above fatty acid derivatives. A mixture of seed compounds.

The above first and second methods can be carried out depending on the coating agent, the solubility in the supercritical fluid, and the coating conditions. The active ingredient may be in liquid form, solid powder form, or inert porous solid particles containing the active ingredient on the surface thereof.

The active ingredient used is selected from various therapeutic and prophylactic compounds. These are more preferably proteins and peptides such as insulin, calcitonin or analogues of the hormone LH-RH, polysaccharides such as heparin, budesonide (budeso).
nide), beclometasone dipropionate and its active metabolite 17-beclometasone 17-mon monopropionate
selected from anti-asthma drugs such as opropionate, bronchodilators such as β-estradiol hormone, testosterone, albuterol, cytotoxic drugs, corticoids, antigens and DNA fragments.

The present invention is illustrated by the following examples, which do not limit its scope.

[0043]

Example 1 This example illustrates a first method of practicing the invention. Solubilize 80 mg PLGA in 80 ml ethyl acetate. 400 mg of micronised insulin are suspended in the solution obtained at 250 rpm and the suspension is placed in an autoclave with a volume of 1.0 l. First, the pressure is raised to 100 × 10 ⁵ Pa by introducing liquid CO ₂ , and at the same time, it is maintained at a constant temperature of 28 ° C.

CO _{2 in the} liquid state mixes with the suspension, which makes it possible to wet the insulin and gradually deposit the coating. CO ₂ is brought into a supercritical state by gradually increasing the pressure to 150 × 10 ⁵ Pa.
At the same time maintain the temperature at 40 ° C. The ethyl acetate is extracted in this way. These conditions are maintained for 15 minutes, then the CO ₂ / ethyl acetate mixture is discharged to the separator by reducing the pressure to 75 × 10 ⁵ Pa, while keeping the temperature above 35 ° C. Ethyl acetate is collected in this separator and CO ₂ is returned to the storage tank.

A continuous cycle of recovering ethyl acetate and introducing liquid CO ₂ , bringing it to a supercritical state and venting CO ₂ and ethyl acetate is repeated until the ethyl acetate is completely removed.

The vacuum is always carried out via the gas phase so that the coating agent is not reconcentrated in the residual ethyl acetate. After the depressurization step, the operation of reintroducing CO ₂ to bring the pressure back to 150 × 10 ⁵ Pa and the temperature back to 40 ° C. may be repeated several times. Finally, decompression and CO ₂ +
After extraction of the solvent mixture, fresh CO ₂ is reintroduced into the supercritical state to completely extract the solvent. In this case, the temperature is generally 35-45 ° C and the pressure is 180-220 × 10 ⁵ Pa.
Is.

250 mg of non-aggregated microparticles are thus obtained, which has an average size of 3 μm and contains 80-90% by weight of insulin and has improved spraying properties.

[0048]

Example 2 This example illustrates a second method of practicing the present invention. 150 mg bovine serum albumin (BSA) prepared by spray-drying and 600 mg chip-like Gelucire ^™ 50/02 600 mg are placed in a pressurizable 0.3 l autoclave equipped with a porous insert with stirring.

CO ₂ is placed in the autoclave until a pressure of 95 × 10 ⁵ Pa is obtained for a temperature of 25 ° C. At this time, CO ₂ is in a liquid state. Start stirring and set to 460 rpm. The autoclave is then heated to 50 ° C.
At that time, the pressure is 220 × 10 ⁵ Pa, CO ₂ is in a supercritical state, and has a density of 0.805 g / cm ³ .

The system is held in equilibrium for 1 hour. Next, the temperature of the autoclave is started from 50 ° C. and lowered to 19 ° C. over 38 minutes. The phase in suspension of supercritical CO ₂ is thus transformed into a liquid and gaseous CO ₂ mixture and the particles of active ingredient are present in suspension in liquid CO ₂ . Subsequent depressurization to atmospheric pressure gives fine particles of BSA coated with Gelucire ^™ 50/02.

Non-agglomerated with an average particle size of 10 μm and coated with a layer of Gelucire ^™ 50/02
250 mg of BSA particles are obtained, whose active ingredient / coating mass ratio is about 30/70.
These microparticles have improved spraying properties.

[0052]

Example 3 This example illustrates a second method of practicing the invention. 300 mg of ovalbumin (OVA) prepared by spray drying and gelsia in the form of chips
(Gelucire ^™ ) 50/13 300 mg is put into a pressurizable 1 l autoclave with stirring.

CO ₂ is placed in the autoclave until a pressure of 109 × 10 ⁵ Pa is obtained for a temperature of 23 ° C. At this time, CO ₂ is in a liquid state. Start stirring and set at 340 rpm. The autoclave is then heated to 35 ° C.
At that time, the pressure is 180 × 10 ⁵ Pa, and CO ₂ becomes a supercritical state.

The system is allowed to equilibrate for 1 hour. Next, the temperature of the autoclave is started from 35 ° C. and lowered to 16 ° C. over 43 minutes. Thus the suspended phase in supercritical CO ₂ is transformed into a liquid and gaseous CO ₂ mixture. Then, by depressurizing to atmospheric pressure, Gelu
OVA particles coated with a layer of cire ^™ 50/13 are obtained.

Non-agglomerated with an average particle size of 9 μm and coated with a layer of Gelucire ^™ 50/13
300 mg of OVA particles are obtained, which have improved spraying properties.

[0056]

Example 4 This example illustrates a second method of practicing the invention. Beclomethasone dipropionate in the form of free powder prepared by spray drying
300 mg and 50 mg dilauroylphosphatidylglycerol (DLPG) are placed in a pressurizable 0.3 l autoclave equipped with a porous insert.

CO ₂ is placed in the autoclave until a pressure of 98 × 10 ⁵ Pa is obtained for a temperature of 23 ° C. At this time, CO ₂ is in a liquid state. Start stirring and set to 460 rpm. The autoclave is then heated to 60 ° C.
At that time, the pressure is 300 × 10 ⁵ Pa, CO ₂ is in a supercritical state, and has a density of 0.830 g / cm ³ .

The system is allowed to equilibrate for 1 hour. Next, let the autoclave temperature take 65 minutes.
Reduce to 20 ° C. Thus, the suspended phase in supercritical CO ₂ is transformed into a liquid and gaseous CO ₂ mixture, and the particles of the active ingredient are suspended in liquid CO ₂ . Then, the pressure is reduced to atmospheric pressure to obtain beclomethasone dipropionate particles coated with DLPG.

200 mg of non-agglomerated beclomethasone dipropionate particles with an average particle size of 5 μm and coated with a layer of DLPG are obtained, the active ingredient / coating mass ratio of which is about 90/10. These microparticles have improved spraying properties.

[Brief description of drawings]

[Figure 1]   5 is an electron micrograph of fine particles obtained in Example 2.

[Fig. 2]   5 is an electron micrograph of fine particles obtained in Example 3.

─────────────────────────────────────────────────── ─── Continuation of front page (51) Int.Cl. ⁷ Identification code FI theme code (reference) A61K 31/58 A61K 31/58 31/711 31/711 31/727 31/727 38/22 45/00 38 / 23 47/14 38/28 47/24 45/00 47/34 47/14 47/36 47/24 47/42 47/34 A61P 5/22 47/36 5/50 47/42 11/00 A61P 5 / 22 11/06 5/50 11/08 11/00 B01J 3/00 A 11/06 A61M 13/00 11/08 A61K 37/24 B01J 3/00 37/26 13/08 37/30 // A61M 13 / 00 B01J 13/02 F (81) Designated countries EP (AT, BE, CH, CY, DE, DK, ES, FI, FR, GB, GR, IE, IT, LU, MC, NL, PT, SE ), OA (BF, BJ, CF, CG, CI, CM, GA, GN, GW, ML, MR, NE, SN, TD, TG), AP (GH, GM, KE) LS, MW, MZ, SD, SL, SZ, TZ, UG, ZW), EA (AM, AZ, BY, KG, KZ, MD, RU, TJ, TM), AE, AG, AL, AM, AT, AU, AZ, BA, BB, BG, BR, BY, BZ, CA, CH, CN, CR, CU, CZ, DE, DK, DM, DZ, EE, ES, FI, GB, GD, GE, GH , GM, HR, HU, ID, IL, IN, IS, JP, KE, KG, KP, KR, KZ, LC, LK, LR, LS, LT, LU, LV, MA, MD, MG, MK, MN, MW, MX, MZ, NO, NZ, PL, PT, RO, RU, SD, SE, SG, SI, SK, SL, TJ, TM, TR, TT, TZ, UA, UG, US, UZ , VN, YU, ZA, ZW (72) Inventor Le Murre, Dominique France, 49100 Ngé, Abnune du General Lamoliere, 17 (72) Inventor Benoit, Jean-Pierre France, 49240 Abril, Are de Chattenier, 45 F Term (reference) 4C076 AA30 AA93 BB27 CC15 CC26 CC30 DD46 DD63 EE23 EE24 EE25 EE30 EE41 FF03 FF04 FF05 FF07 FF68 GG08 GG28 4C084 AA03 AA17 BA44 DB01 DB31 DB34 MA05 MA13 MA56 NA10 NA13 ZA591 ZA611 ZB211 ZC031 ZA03 MA21 MA01 MAA21 NA03 ZA21 MA16 MA12 MA16 MA12 MA16 MA12 MA16 MA12 MA16 MA12 AA02 FA14 MA03 MA05 MA13 MA56 NA10 NA13 ZA59 ZA61 ZB21 ZC03 ZC06 4G005 AA01 AB15 AB21 BA06 BB01 BB13 BB17 DA04W DB05Z DB12X DB12Z DB22X DB24X DC15Z DC18Z DC32.

Claims (10)

[Claims] 1. A microparticle comprising at least one active ingredient and at least one layer coating the active ingredient, the layer being an outer layer of the microparticle, the outer layer comprising at least one coating agent. in biocompatible microparticles for inhalation, the microparticles have an apparent density of average particle size and the range of 0.02g / cm ³ ~0.8g / cm ³ in the range of 1 to 30 [mu] m, together the active ingredient and a coating agent And biocompatible fine particles for inhalation, which can be obtained by a method including, as an essential step, the step of introducing the supercritical fluid into the sealed reactor while stirring. 2. An active ingredient / coating agent of particles having an average particle size in the range of 1 μm to 15 μm, more preferably 2 μm to 10 μm, and an apparent density in the range of 0.05 g / cm ^{3 to} 0.4 g / cm ^3. The fine particles according to claim 1, characterized in that the mass ratio thereof is in the range of 95/5 to 5/95. 3. Microparticles according to claim 1 or 2 obtainable using a method comprising the steps of: -active substance suspended in a solution of at least one substantially polar coating agent in an organic solvent. The active ingredient is insoluble in the organic solvent, the substantially polar coating is insoluble in the supercritical fluid, the organic solvent is soluble in the supercritical fluid, and-is substantially The suspension is contacted with a fluid in the supercritical state so as to desolvate the polar coating material in a controlled manner and ensure its coacervation; Is substantially extracted, the supercritical fluid / solvent mixture is drained, and the fine particles are recovered. 4. A method comprising suspending an active ingredient in a supercritical fluid containing at least one coating in solution and then ensuring physicochemical modification of the environment to ensure particle coacervation. The fine particles according to claim 1 or 2, which can be obtained by using. 5. The coating material is selected from the group consisting of:
Microparticles according to claim 3, -Biodegradable (co) polymers of α-hydroxycarboxylic acids, more particularly homopolymers and copolymers of lactic acid and glycolic acid, more particularly PLA (poly-L-lactide).
) And PLGA (lactic acid-glycolic acid copolymer), -poly (lactic acid) -poly (ethylene oxide) type amphiphilic block polymer, -poly (ethylene glycol), poly (ethylene oxide) type biocompatibility Polymers, -polyanhydrides, poly (orthoesters), poly-ε-caprolactone and their derivatives, -poly (β-hydroxybutyrate), poly (hydroxyvalerates) and poly (β-hydroxybutyrate-hydroxy) (Valerate) copolymer, -poly (malic acid), -polyphosphazene, -poly (ethylene oxide) -poly (propylene oxide) type block copolymer, -poly (amino acid), -polysaccharide, -phosphatidylglycerol , Diphosphatidylglycerol containing C12-C18 fatty acid chains (DLPG, DMPG, DPPG, DSPG), phosphatidylcholine, C12 C18
Diphosphatidylcholine containing fatty acid chains (DLPC, DMPC, DPPC, DSPC), C12 ~
Diphosphatidylethanolamine containing fatty acid chains of C18 (DLPE, DMPE, DPPE,
DSPE), diphosphatidylserine containing C12-C18 chains (DLPS, DMPS, DPPS, DSPS
) And mixtures containing these phospholipids; -glycerin stearates, lauric glycerin esters, fatty acid esters such as cetyl palmitate and mixtures containing these compounds, -mixtures containing the above compounds. 6. The coating material is selected from the group consisting of:
Microparticles according to claim 4, -phosphatidylglycerol, diphosphatidylglycerol containing fatty acid chains of C12-C18 (DLPG, DMPG, DPPG, DSPG), phosphatidylcholine, C12-C18.
Diphosphatidylcholine containing fatty acid chains (DLPC, DMPC, DPPC, DSPC), C12 ~
Diphosphatidylethanolamine containing fatty acid chains of C18 (DLPE, DMPE, DPPE,
DSPE), diphosphatidylserine containing C12-C18 chains (DLPS, DMPS, DPPS, DSPS
) Such as phospholipids and mixtures containing these phospholipids; -mono-, di-, triglycerides with fatty acid chains of C4 to C22 and mixtures containing them-mixtures of glycerides and esters of poly (ethylene glycol),-cholesterol Fatty acid esters such as glyceryl stearate, glyceryl laurate, cetyl palmitate, biodegradable or biodegradable polymers soluble in supercritical fluids, mixtures containing the above compounds. 7. The active ingredient is insulin, calcitonin or the hormone LH-R.
Proteins and peptides such as analogues of H, polysaccharides such as heparin, anti-asthma drugs such as budesonide, beclomethasone dipropionate (becl)
ometasone dipropionate) and its active metabolite beclomethasone 17-monopropionate, bronchodilators such as β-estradiol hormone, testosterone, albuterol, cytotoxic drugs, corticoids, antigens The microparticle according to any one of claims 1 to 6, which is selected from the group consisting of: and a DNA fragment. 8. The fine particles according to claim 2, wherein the fine particles are immediate release type fine particles, and the mass ratio of the active ingredient / coating agent of the particles is 95/5 to 80/20. 9. A method for producing fine particles for inhalation, which comprises the steps of: suspending the active ingredient in a solution of at least one substantially polar coating agent in an organic solvent, the active ingredient being the organic solvent. Insoluble, the substantially polar coating is insoluble in the supercritical fluid, the organic solvent is soluble in the supercritical fluid, and the substantially polar coating is controlled The suspension is contacted with a fluid in the supercritical state so as to desolvate in the process and ensure its coacervation, and the solvent is substantially extracted using the fluid in the supercritical state, Drain the critical fluid / solvent mixture and-collect fine particles. 10. At least one coating agent with stirring in a closed reactor. The active ingredient is suspended in a supercritical fluid that is dissolved and contained, and then the physicochemical change of the environment In addition, the production of fine particles for inhalation, including more ensuring particle coacervation How to build.