FR2620026A2 - Pharmaceutical dosage form comprising microparticles and process for preparing it - Google Patents

Abstract

The present addition relates to a pharmaceutical dosage form comprising a matrix and an active ingredient and which is characterised in that: A) the physiologically acceptable matrix is a solid and porous material which has been obtained in the dry state by cryodesiccation and compression to impart sufficient mechanical strength to the aforementioned material to prevent it, in the main, from cracking when a gaseous fluid is passed through its thickness; and B) the active ingredient combined with the abovementioned matrix consists essentially of microparticles having an average particle size of between 5 mu m and 0.01 mu m, and is chosen from substances which are 1 water-soluble or 2 coated. It also relates to the process for preparing this pharmaceutical dosage form.

Description

GALENIC FORM COMPRISING MICROPARTICLES
AND PROCESS FOR THE PREPARATION THEREOF
The present invention, which is a second certificate of addition attached to main patent Jo 87 09 696 of July 8, 1987, relates to a new dosage form comprising water-soluble and / or coated microparticles which are in particular of submicron size. It also relates to the process for the preparation of this new galenical form and to its use in particular in therapeutics and cosmetics.

THE MAIN PATENT
A technical solution has been described in the main patent to which this present addition is attached to solve the problem of filtration of gaseous fluids with a view to retaining, for separation, analytical and / or preparative purposes, gaseous products or fine particles contained in said gaseous fluids.

 This technical solution used the use of a freeze-dried or lyophilized material then compressed as a porous filter element. It was based on the fact that cryodessication or lyophilization (ie freezing of a preparation containing a liquid of solvation, dilution or dispersion, in particular at a temperature of -40 C and / or - 80 C, then evaporation of said frozen liquid by sublimation under vacuum), leads to porous products having a relatively large specific surface (expressed in particular in cm @ / cm @) and capable of retaining their porous texture until they have been brought into contact with one of their solvents.

 This solution therefore made it possible to obtain a filter comprising a lyophilized filter element and compressed in the form of a porous layer. Advantageously, the freeze-dried or lyophilized material was ground before being compressed to form said porous filtering layer.

THE FREKIER CERTIFICATE OF ADDITION
The first certificate of addition No 87 Il 468 of August 12, 1987 attached to said main patent related to a dosage form or composition comprising in combination (i) a physiologically acceptable matrix and (ii) at least one active ingredient in the particulate form and chosen from therapeutic and cosmetic active ingredients, where A) the physiologically acceptable matrix is a solid and porous material which has been obtained in the dry state by cryodessication and compression to give said material sufficient mechanical strength to essentially prevent it from becoming crack when a gaseous fluid passes through its thickness; and,
B) the active ingredient associated with said matrix is insoluble in water and consists essentially of microparticles having an average particle size of between 5 μm and 0.01 μm.

The first certificate of addition recommended a process for the preparation of said dosage form or composition comprising the following steps
1) obtaining a solution in an organic solvent of said active ingredient insoluble in water. so that the concentration of said active ingredient in said solution is less than or equal to 10 'Z (weight / volume)
2-) nebulization of said solution thus obtained, in the form of liquid aerosol entered into a stream of carrier gas fluid
3) evaporation of the solvent of the active ingredient in said stream of carrier gaseous fluid, so that the solid microparticles resulting from the drying of the liquid microparticles of the aerosol are carried by said carrier gaseous fluid
4 ′) filtration of said carrier gas fluid containing the active ingredient essentially in the form of microparticles having an average particle size of between 5 μm and 0.01 μm, on the one hand, and the solvent of said active ingredient in the form of vapor, on the other hand, by means of a filter comprising, as filtering element, a solid, porous and water-soluble material which has been obtained in the dry state by cryodessication and compression to give said material sufficient mechanical strength to essentially prevent it from becoming crack when a gaseous fluid passes through its thickness.

PURPOSE OF IF EXTIOX
There is a need for particles of micron size and better of submicron size for therapeutic or cosmetic use.

 In particular, it is seriously believed that with submicronic particles, the enzymatic degradation could, in particular, be avoided and that certain compounds not having transporters at the level of the cellular membranes could nevertheless be administered to the organism by incorporation according to processes purely physical similar to pynocytosis.

 Pilot and a fortiori industrial manufacture of submicron particles is a delicate operation if one takes into account the fact that in gas suspension they only follow molecular or browmian agitation movements and are therefore very difficult to collect. and to focus. In addition, it should be added that in aerosol, most of them are very aggressive towards the organism, their entry into the respiratory tract can in certain cases lead to catastrophic physiological reactions and even have a very high toxicity, all the more acute the smaller the particle size.

 It is therefore sought to obtain particles of submicron size using an appropriate, perfectly reliable and reproducible technology which makes it possible to overcome the aforementioned difficulties relating to microparticles, such as in particular particles of submicron size, in particular with a view to improving efficiency and / or the bioavailability of the active ingredients constituted by said submicron particles.

 According to a first aspect of the invention, it is proposed to obtain a dosage form analogous to that of the first certificate of addition but comprising at least one water-soluble or water-dispersible active ingredient.

 According to a second aspect of the invention, it is proposed to obtain a dosage form comprising at least one active ingredient (soluble or insoluble in water) in the form of coated microparticles.

 According to yet another aspect of the invention, there is provided a process for preparing the above-mentioned dosage forms which is useful in particular for isolating said microparticles and in particular those which have been coated.

OBJECT OF IJVEJTIOJ
Therefore, according to the invention, as a new industrial product, a dosage form or composition is recommended, said dosage form comprising in combination (i) a physiologically acceptable matrix and (ii) at least one active ingredient in particulate form and chosen from therapeutic and cosmetic active ingredients, and it is characterized in that
A) the physiologically acceptable matrix is a solid and porous material which has been obtained in the dry state by cryodessication and compression to give said material sufficient mechanical strength to essentially prevent it from cracking during the passage from a gaseous fluid to through its thickness; and,
B) the active ingredient associated with said matrix consists essentially of microparticles having an average particle size of between 5 μm and 0.01 μm, and chosen from substances which are (1) soluble in water or (2) coated.

 We therefore aim here a dosage form or composition in which the active principle is in the form of microparticles and soluble in water, on the one hand or coated whatever its solubility in water, on the other hand.

A method of preparing such a dosage form or composition is also recommended, or the active ingredient is water-soluble, said method being characterized in that it comprises the following steps
1 ') obtaining a solution of said active ingredient in water, so that the concentration of said active ingredient in said solution is less than or equal to 1C% <w / v)
2 ') nebulization of said solution, thus obtained, in the form of a liquid aerosol entrained in a stream of gaseous carrier fluid
3 ') evaporation of water, solvent for the active ingredient. in said carrier gas stream, so that the solid microparticles resulting from the drying of the liquid microparticles of the aerosol are carried by said carrier gas fluid
4-) filtration of said carrier gas fluid containing the active ingredient essentially in the form of microparticles having an average particle size between 5 Hm and 0.01 pm, on the one hand, and the solvent of said active ingredient in the form of vapor, on the other hand, by means of a filter comprising, as a filtering element, a solid and porous material which has been obtained in the dry state by cryodessication and compression to give said material sufficient mechanical strength to essentially prevent it from cracking during of the passage of a gaseous fluid through its thickness.

We also recommend a process for preparing such a dosage form or composition in which the active ingredient is in the form of coated microparticles, said process being characterized in that it comprises the following steps
1 ') obtaining a suspension of microparticles of the active ingredient in a liquid medium containing a dissolved-coating material, said active ingredient being insoluble in said liquid medium and its concentration in said liquid medium being less than or equal to 10 'b (w / v)
2 ') nebulization of the resulting suspension in order to obtain an aerosol entrained in a stream of gaseous carrier fluid
3 ') evaporation of the liquid medium from the aerosol, so that the coated microparticles which result from the drying of said aerosol are carried by said gaseous carrier fluid
4 ′) filtration of said carrier gaseous fluid containing the active ingredient essentially in the form of microparticles coated with the coating material by means of a filter comprising, as filter element, a solid and porous material which has been obtained in the state dry by cryodessication and compression to give said material sufficient mechanical strength to essentially prevent it from cracking when a gaseous fluid passes through its thickness, to collect said coated microparticles on the filter element.

DETAILED DESCRIPTIOJ OF IVEXTIOJ
The dosage form or composition according to the invention, which is useful in therapy and in cosmetics, contains microparticles (either soluble in water, or coated whatever its water solubility) having an average particle size of between 5 Hm and 0.01 ym. Among these particles, preference is given to those which have an average particle size less than or equal to 2.5 μm and better still less than or equal to 1 μm.

 The matrix according to the present addition is prepared as indicated in the main patent from an appropriate material soluble or, if necessary, microdispersible in water, in particular polysaccharide materials such as dextran, carboxymethylcellulose, hydroxypropylcellulose, hydroxypropylmetbylcellulose, mono- or disaccharide materials such as glucose, lactose, maltose, sucrose, polyvinyl materials such as polyvinyl alcohol and polyvinylpyrrolidone, polyacrylic materials such as polyacrylate and polymethacrylate salts and esters, and, mixtures thereof, in particular milk powder (which is a product containing in particular lactose, casein and other protein and polypeptide substances) and milk extracts.

 The matrix of the dosage form is obtained from the filter element of the filter according to the main patent. This filter element which is in the form of a porous layer which consists of a solid material obtained in the dry state (i) by cryodessication, then (ii) by compression so as to give it sufficient mechanical strength to essentially prevent '' it cracks during the passage of a gaseous fluid through its thickness.

 The compression which is carried out to improve the mechanical resistance of the solid filtering material to the passage of the gaseous fluid through its thickness, constitutes a kind of sintering having a porous structure resulting from the porous structure obtained by expansion during cryodessication.

 The compression ratio is between approximately 1.1 and approximately 5. Advantageously, said compression ratio will be between 1.2 and 4, and better still between 1.25 and 3.60.

 To have a better porosity after compression, it may be advantageous to disaggregate or even grind (by means of a hammer mill in particular) the material which has been obtained by freeze-drying or lyophilization, before undertaking said compression. In other words, according to an alternative embodiment, the filter element which is in the form of a porous layer is made up of a solid material obtained in the dry state (a) by cryodessication, (b) by grinding, then (c) by coinpressure.

 To practically avoid any cracking of the filter element during the passage of the gaseous fluid which it is desired to filter, it is recommended to incorporate into the mass of the solid material constituting said filter element a suitable cohesion agent, as indicated in the main patent. .

 The microparticles of the active ingredient are coated in order to modify the disintegration conditions of said active ingredient in the body, in particular by oral route. It makes it possible in particular to overcome so-called negative properties, such as bitter aftertaste, pronounced bitterness or too rapid solubilization of the active ingredient under normal conditions of administration.

The coating also makes it possible, by forming an essentially continuous envelope, layer or film around said microparticles, to protect the active ingredient. This envelope can remain intact until it is in contact with or circulating in a specific or appropriate body fluid. The coating can thus disappear by degradation or dissolution at a determined level of the digestive tract in order to release the active ingredient, for example at the level of the intestinal mucosa in the case of a gastro or acid-resistant coating. finally serve to promote the assimilation of microparticles in the organism, according to a * mask effect "or an Nliposome effect", according to a preferred mode of the invention, especially when the average size or particle size of the particles which result from the coating microparticles is of the order of a micrometer or better submicron.

 For the implementation of the process for the preparation of the dosage form according to the invention, it is preferred that the content of active ingredient in the solution or dispersion in water or the organic solvent of step 1) is less than or equal to 5% (w / v).

 The nebulization, implemented in step 2), is carried out so as to obtain liquid aerosol microparticles having an average diameter suitable for giving, after evaporation of the solvent for dissolving or dispersing, solid microparticles having an average particle size between 5 μm and 0.01 μm, preferably an average particle size less than or equal to 2.5 μm, and better still an average particle size less than or equal to 1 μm.

 The gaseous carrier fluid which is suitable according to the invention is an inert gas with respect to the active ingredient and the matrix formed by the filtering element, for example nitrogen, argon and, where appropriate, air dried up.

 Evaporation from step 3) is carried out at an appropriate temperature so as not to deteriorate the active ingredient, in particular at a temperature between 25 and 90 C. Advantageously, the operation will be carried out at a temperature between 30 'and 65 'C. If necessary, an increasing or decreasing temperature gradient can be used.

 The filtration of step 4) is carried out with a pressure drop of between approximately 80 and approximately 10,000 Fa. The pressure drop, which is in particular a function of the thickness of the filter element, of its compression ratio ( ratio of the thickness of the material before compression to the thickness of said material after compression) and the resulting porosity, as well as the pressure of the gaseous fluid to be filtered, generally between 1 cm HO (approximately 98.06 Pa) and 100 cm HO (approximately 9806 Fa), or more precisely between 2 cm HO (approximately 196.1 Paw for a thickness of 8 mm of filter material at a compression ratio of 1.25 for a gaseous fluid having a flow rate of 300 1 / min compared to normal temperature and pressure conditions, and 76 cm H2O (or approximately 7,452.5 Fa) for a thickness of 14 mm of filter material at a compression ratio of 3.6 for a gaseous fluid having a flow rate of 4 1 / min related to normal temperature and pressure conditions.

 After the filtration of step 4), the process of the invention further comprises, for obtaining a substantially homogeneous dosage form, a step 5) called kneading, according to which the filter element and the microparticles which have been retained by said filter element in step 4 '). Indeed, due to the filtration mode, most of the retained microparticles are gathered in the thickness of the filter element in the vicinity of the inlet face of said filter element receiving the gaseous fluid containing the solid microparticles that l 'we want to collect.

For obtaining coated microparticles, a method is recommended according to the invention which comprises
- nebulization of a solution of the active ingredient
in water or an organic solvent,
- drying of the resulting aerosol entrained in a
carrier or carrier gas fluid,
- filtration of said gaseous fluid by means of a
filter element according to the main patent,
- dissolving said filter element in a solvent
where the coating material is soluble, on the one hand, and
the ingredient microparticles are insoluble,
- nebulization of the dispersion or suspension
resulting,
- drying of the aerosol entrained in a fluid
carrier gas as indicated above;
and
- filtration on a filter element according to
main patent.

According to a preferred embodiment of the invention, the process for preparing coated microparticles is characterized in that it comprises the following steps
(a) obtaining a solution of the active ingredient in a first solvent, so that the concentration of said active ingredient in said first solvent is less than or equal to 10 X (w / v) and preferably less than or equal to 5 % (w / v)
(b) nebulization of said solution, thus obtained, in the form of a liquid aerosol entrained in a stream of gaseous carrier fluid
(c) evaporation of the solvent of the active ingredient in said stream of gaseous carrier fluid, so that the solid microparticles resulting from the desiccation of the liquid microparticles of the aerosol are carried by said gaseous carrier fluid
(d) filtration of said carrier gaseous fluid containing the active ingredient essentially in the form of microparticles having an average particle size of between 5 Hm and 0.01 pm, on the one hand, and the solvent of said active ingredient in the form of vapor, d on the other hand, by means of a filter comprising, as a filtering element, a solid and porous material which has been obtained in the dry state by cryodessication and compression to give said material sufficient mechanical strength to essentially prevent it from cracking when a gaseous fluid passes through its thickness.

(e) solubilization of the filter element used in step (d) in a second solvent in which (i) the active ingredient is insoluble, and (ii) the coating material is soluble, in order to obtain a liquid medium constituted by said second solvent in which the coating material is dissolved and in which the microparticles to be coated are dispersed
(f) nebulization of the resulting suspension to obtain an aerosol entrained in a stream of gaseous carrier fluid
(g) evaporation of the solvent from the liquid medium for drying the aerosol, so that the coated microparticles which result from the drying of said aerosol are carried by said gaseous carrier fluid
(h) filtration of said gaseous carrier fluid containing the particles of active ingredient coated by means of a filter comprising, as filter element, a solid and porous material which has been obtained in the dry state by cryodessication and compression to confer on said material sufficient mechanical strength to essentially prevent it from cracking when a gaseous fluid passes through its thickness.

 The coating material which is suitable according to the invention is an organic film-forming substance. soluble in a solvent and generally of a polymeric nature. Particularly suitable are polymers and copolymers derived from acrylic acid such as polyacrylic acids, polymethacrylic acids, their salts and their esters, cellulose derivatives, glycerides, polyglycidides of fatty acids, lecithins, hydrogenated oils . polyoxyalkylene glycols such as polyoxyethylene glycols and polyoxypropylene glycols, polyacids such as polylactic and polygluconic acids, and mixtures thereof.

 Generally suitable, physiologically acceptable waxes, fats and other coating means which are typically used or usable in galenics, for example a 1/1 weight mixture of ethylcellulose (product marketed under the brand name AQUACOAT "by the company called SEPPIC) and hydroxypropylmethylcellulose (product marketed under the name of wPHARXACOAT 603" by the company called SEPPIC).

 The microparticles according to the invention whether coated or uncoated can, if necessary, be recovered by dissolving the matrix which was used as a filtering element during the filtration of step 4). This dissolution is carried out in an appropriate solvent in which the said microparticles, if any coated, are insoluble.

 Other advantages and characteristics of the invention will be better understood on reading which will follow from examples of preparation which are in no way limitative but given by way of illustration.

EXAMPLE 1
An aqueous solution of Buflomedil hydrochloride at% Cp / v) is prepared. .00 g of this solution is nebulized under a pressure of 3-4 bars in a stream of nitrogen se #. The resulting liquid aerosol is dried for 50 minutes under a temperature gradient from 44 ° C. at the start of drying) to 50 ° C. (end of drying). The resulting microparticles are filtered through 45 g of polyvinylpyrrolidone filter element obtained by cryodessication and then compression according to the main patent.

 The dosage of the filter element shows that the amount of Buflomedil hydrochloride attached to the filter is 4%.

 The photographs taken with a scanning electron microscope show impact points of the order of 0.1 Hm to 0.2 μm, which implies that particles with a particle size of less than 0.1 μm can be obtained.

BIHIPLE 2
The procedure is as indicated in Example 1 above, by nebulizing 100 g of a 2 × (w / v) aqueous solution of heparin, drying the aerosol obtained for 60 minutes with a temperature gradient of 60 ° C. (start of drying) at 50 ° C. (end of drying) then by collecting the microparticles obtained on 40 g of cryodried and compressed polyvinylpyrrolidone filter.

 By determination by flame photometry, the quantity of sodium found on the filter media corresponds to a fixation expressed in heparin sodium of the order of 1 Z. The photographs obtained by scanning electron microscopy show regular particles of the order of 0.1 d 0.5 pm. while the starting particles were. during dissolution in water, very heterogeneous from 10 to 100 m and more.

EXAMPLE 3
The procedure is as indicated in Example 2 above with a 5% (w / v) aqueous heparin solution, that is to say more concentrated.
Examination with an electron microscope of a sample from the surface of the filter confirms that the particles obtained are of the order of 0.1 to 0.5 μm.

EXAMPLE 4
The procedure is as indicated in Example 2 by nebulizing 400 g of an aqueous solution of heparin at 5% (w / v) which is collected on a polyvinylpyrrolidone (PVP) filter according to the main patent.

The filter is solubilized in soe ml of chloroform, then solubilized in the resulting mixture a composition of glycerides and partial polyglycides of fatty acids marketed under the brand name of GELUÇIRH. The resulting suspension is nebulized and the coated microparticles are collected on a PVP filter in accordance with the main patent. Said coated heparin microparticles thus obtained have an average particle size of less than 1 μm; they can be, if necessary, associated with microparticles of
GELUCIRE.

 By combining the teaching of the main patent. from the first certificate of addition and from this second certificate of addition there are obtained, if desired, microparticles soluble or insoluble in water, which subsequently can each be coated with a continuous protective envelope or film.

Claims (14)

 B) the active ingredient associated with said matrix consists essentially of microparticles having an average particle size of between 5 m and 0.01 pm. and selected from substances which are (1) water soluble or (2) coated.  A) the physiologically acceptable matrix is a solid and porous material which has been obtained in the dry state by cryodessication and co-pressure to give said material sufficient mechanical strength to essentially prevent it from cracking when passing from a gaseous fluid to through its thickness; and,  1. Use of a filter according to claim I of the main patent for the production of a dosage form comprising in combination (i) a physiologically acceptable matrix and (ii) at least one active ingredient in particulate form and chosen from the active ingredients , therapeutic and cosmetic, said dosage form being characterized in that  2. Use according to claim 1 for la- realization of a dosage form, characterized in that the active ingredient is soluble in water.  3. Use according to claim 1, characterized in that the active ingredient is in the form of coated microparticles.  4. Use according to claim 1 for the realization of a dosage form, characterized in that the physiologically acceptable matrix is a solid and porous material which has been obtained by cryodessication then co # pressure at a rate of between approximately 1.1 and about 5.  5. Use according to claim 1 for the production of a dosage form, characterized in that the physiologically acceptable matrix has been obtained by cryodessicatinn of an aqueous solution containing 4% (w / v) of dextran, 4% (w / v) hydroxypropylcellulose and 0.0125% (w / v) sucrose. pul compression of the resulting lyophilisate at a rate between about 1.1 and about 5, preferably between 1.2 and 4 and better between 1.25 and 3.60.  6. Use according to claim 1 for the production of a dosage form, characterized in that the physiologically acceptable matrix has been obtained by cryodessication of a solution containing polyvinylpyrrolidone, then compression of the resulting lyophilisate at a rate of between approximately 1 , 1 and about 5, preferably between 1.2 and 4 and they between 1.25 and 3.60.  4 ′) filtration of said carrier gas fluid containing the active ingredient essentially in the form of microparticles having an average particle size of between 5 and 0.01 μm, on the one hand, and the solvent of said active ingredient in the form of vapor. on the other hand, by means of a filter comprising, as a filtering element, a solid and porous material which has been obtained in the dry state by cryodessication and compression in order to confer on said material a sufficient mechanical strength to prevent essentially that 'it cracks when a gaseous fluid passes through its thickness.  3 ′) evaporation of the water, solvent for the active ingredient, in said stream of carrier gaseous fluid, so that the solid licroparticles resulting from the drying of the liquid zicroparticles of the aerosol are transported by said gaseous carrier fluid  2) nebulization of said solution, thus obtained in the form of a liquid aerosol entrained in a stream of carrier gas fluid  1 ') obtaining a solution of said active ingredient in water, so that the concentration of said active ingredient in said solution is less than or equal to 10% <w / v)  7. A method of preparing a dosage form according to claim 2, characterized in that it comprises the following props  8. A method of preparing a dosage form according to claim 3 wherein the active ingredient is in the form of coated microparticles, said method being characterized in that it comprises the following steps  1 ') obtaining a suspension of microparticles of the active ingredient in a liquid medium containing a dissolved coating material, said active ingredient being insoluble in said liquid medium and its concentration in said liquid medium being less than or equal to 10% (w / v)  2 ') nebulization of the resulting suspension in order to obtain an aerosol entrained in a stream of gaseous carrier fluid  3 ′) evaporation of the liquid medium from the aerosol, so that the coated microparticles which result from the drying of said aerosol are carried by said gaseous carrier fluid  4-) filtration of said carrier gaseous fluid containing the active ingredient essentially in the form of microparticles coated with the coating material by means of a filter comprising, as filter element, a solid and porous material which has been obtained in the state dry by cryodessication and compression to give said material sufficient mechanical strength to essentially prevent it from cracking when a gaseous fluid passes through its thickness, to collect said coated microparticles on the filter element.  9. Method according to any one of claims 7 and 8. characterized in that one prepares in 1 'step 1') a liquid preparation having an active ingredient content less than or equal to 5% (w / v).  10. Method according to any one of claims 7, s and 9, characterized in that the nebulization of step 2) is carried out so as to obtain aerosol particles having a suitable average diameter to give after evaporation of the solvent of the liquid preparation, solid microparticles having an average particle size of between 5 μm and 0.01 μm.  11. Method according to any one of claims 7 and 8, characterized in that the evaporation of step 3 ') is carried out at an appropriate temperature so as not to deteriorate the active ingredient, in particular at a temperature comprised between 25 'and its C.  12. Method according to any one of claims 7 and 8, characterized in that it further comprises the step of kneading the assembly comprising the filter element and the microparticles of active ingredient, which results from filtration from step 4 ').  13. The method of claim 8 for the preparation of a dosage form comprising coated active ingredient microparticles, characterized in that it comprises the following steps  (A) obtaining a solution of the active ingredient in a first solvent, so that the concentration of said active ingredient in said first solvent is less than or equal to 10 'h (pzv) and preferably less than or equal to s' Xe (w / V) ::  (b) nebulization of said solution, thus obtained, in the form of a liquid aerosol entrained in a dying carrier gas fluid  (c) evaporation of the solvent from the active ingredient in said stream of carrier gaseous fluid. so that the solid microparticles resulting from the drying of the liquid microparticles of the aerosol are transported by said gaseous carrier fluid  (d) Filtration of the carrier gas fluid containing the active ingredient essentially in the form of microparticles having an average particle size of between 5 and 0.01 Hm, on the one hand, and the solvent of said active ingredient in the form of vapor, on the other hand, by means of a filter comprising, as a filtering element, a solid and porous material which has been obtained in the dry state by cryodessication and compression to give said material sufficient mechanical strength to essentially prevent it from cracking during of the passage of a gaseous fluid through its thickness.  (h) filtration of said carrier gas fluid containing the ingredient particles. active coated with a filter comprising. course element #Iltrant. ur solid and porous material which has been obtained in the dry state by cryodessication and compression to give said material sufficient mechanical strength to essentially prevent it from cracking when a gaseous fluid passes through its thickness.  ç evaporation of the solvent from the liquid medium for drying the aerosol, so that the coated microparticles which result from the drying of said aerosol are transported by said gaseous carrier fluid: and  (f) nebulization of the resulting suspension to obtain an aerosol entrained in a stream of gaseous carrier fluid  (e) solubilization of the filter element used in step (d) in a second solvent in which (i) the active ingredient is insoluble, and (ii) the coating material is soluble. in order to obtain a liquid medium constituted by said second solvent in which the coating material is dissolved and in which the microparticles to be coated are dispersed  14. Use of the method according to any one of claims 7 and 8, characterized in that the microparticles of the active ingredient are collected, where appropriate coated, by dissolution of the matrix, which is associated with it and which has was used as a filtering element during the filtration of step 4), in an appropriate solvent which does not dissolve said microparticles, if appropriate coated.