RU2039554C1 - Process for manufacture of galenic form - Google Patents

Abstract

FIELD: medicine; chemico-pharmaceutical industry. SUBSTANCE: essence of this process resides in adsorption of active ingredient in the form of particles and selecting active ingredient from either therapeutic or cosmetic preparations. Medicinal preparation is based on hard porous matrix made from physiologically acceptable material by freezing, sublimation drying and compression. EFFECT: higher specific activity of ingredient. 6 cl, 1 tbl

Description

 The invention relates to the production of a galenic form, in particular to the production of a galenic form containing a porous filter matrix with particles of the active substance deposited on it, possibly encapsulated.

 It is known to retain by filtration of submicron particles of polyalkyl acrylate coated with a biologically active substance (EP-A-0064967) through fritted glass. However, fritted glass is not a physiologically acceptable matrix.

Millipore ^R type filter membranes are also known that hold very fine particles and are made of organic polymeric substances, for example, cellulose esters, polyacrylates and polyacrylic substances, polyvinylidene fluorides, polytetraethylene fluoride, polyethylene, polypropylene and mixtures thereof. However, retained particles are analyzed by burning to the carbon residue of the membrane and therefore only those that are not susceptible to burning can be held particles, i.e., these filter membranes are not suitable for organic active substances.

 Currently, there is a need for filter materials that can absorb (hold) submicron particles used in therapy and cosmetics. It is known that submicron particles of active substances are not susceptible to enzymatic destruction and, in addition, those of these substances that cannot be transported at the level of cell membranes could be introduced into the body by purely physical means.

 The industrial production of submicron particles is a complex and delicate operation due to the fact that, being in Brownian motion, it is very difficult to capture and concentrate them. In addition, aerosol spraying of certain substances is of great danger to the body, since when inhaled they can cause undesirable physiological reactions or cause toxicity, sometimes even more acute, the smaller the particle size.

 The objective of the invention is to develop such a method of obtaining galenic forms for submicron particles of the active substance, which would be devoid of the above disadvantages and would be easier to implement.

 The galenic form obtained according to the invention allows, in addition, to improve the effectiveness of the active principle, presented in the form of submicron particles, in some cases coated with a shell.

 The galenic form according to the invention is a matrix of a solid porous filtering physiologically acceptable material onto which submicron particles of the active substance are absorbed, sometimes in an encapsulated form.

A method of obtaining a galenic form according to the invention consists in the following operations:
1) obtaining a preparation of the active ingredient in a liquid medium, wherein said active ingredient is either soluble or insoluble in said liquid medium and its concentration in the liquid medium is lower than or equal to 10% (total / volume);
2) spraying the resulting preparation to obtain an aerosol transported in a gaseous carrier fluid stream;
3) evaporation of the aerosol liquid medium to obtain microparticles transported by a gaseous carrier fluid;
4) filtering a gaseous carrier fluid containing the active ingredient in the form of microparticles through a filter containing filter elements from a solid and porous material obtained in the dry state by freezing, grinding, freeze-drying and compressing to absorb the active substance on the filter element .

 The obtained galenic form is suitable in therapy and in cosmetics and contains microparticles of the active substance either soluble or insoluble in water, on the one hand, can be coated, whatever their water solubility, on the other hand, with an average particle size distribution of 5-0, 01 μm. Of these particles, those that have an average particle size distribution of less than or equal to 2.5 μm and better less than or equal to 1 μm are preferred.

 The galenical matrix is obtained from the specified filter element.

 As a material for the filter element, water-soluble or microdispersible substances are used, namely polysaccharide substances, such as dextran, carboxymethyl cellulose, hydroxypropyl cellulose; mono- or disaccharide materials such as glucose, lactose, maltose, sucrose; polyvinyl materials such as polyvinyl alcohol; polyacrylic materials, such as salts or esters of polyacrylic polymethacrylic acids, polyvinylpyrrolidones, and mixtures thereof, especially milk powder, which is a product comprising lactose, casein and other protein and polypeptide substances, and milk extracts. Alternatively, you can use a material that is not soluble in water, but soluble in a conventional, appropriate organic solvent.

According to the invention, freeze-dried or lyophilized material is used as a porous filter element. Freeze-drying or lyophilization is a freeze-drying, ie. E. An operation which comprises the freeze preparation containing a solvent, diluting or dispersing liquid, especially at a temperature of -40 ^o C or -80 ^{° C,} then evaporating the frozen liquid by sublimation under a vacuum. This operation results in porous products having a relatively large specific surface area [expressed especially in cm ² / cm ³ ] and which can retain their porous structure until they are in contact with one of their solvents.

 Pressing (compression), which is carried out to improve the mechanical stability of a solid filter material during the passage of gaseous fluids through its thickness, is a kind of frying of a material having a porous structure obtained by foaming during freeze-drying.

 According to the invention, the filter element is compressed after freeze-drying with a compression ratio of from about 1.1 to about 5. Preferably, the above compression ratio is 1.2-4 and preferably 1.25-3.60.

 The filter element, which is obtained by freezing, crushing (to obtain granulate with a granulometry of the order of about 1-3 mm), freeze-drying, then compressing, has the advantage that it is relatively light and can easily dissolve or disperse easily in very small amounts of appropriate solvents after passing through it filtered gaseous fluids.

 For applying to the matrix of the active substance, the filter element, crushed, lyophilized and compressed, is placed in the path of a circulating gaseous fluid containing, for example, particles of micron or submicron size. Due to the very large porosity of this material, gas circulates there very easily, without noticeable pressure loss. Moreover, a very fine structure of the material causes the capture of solid individual elements, which can be deposited there due to collision, Brownian motion, adsorption or due to electrostatic forces. On this basis, lyophilized and compressed material behaves like a high-efficiency filter.

 The coating of the microparticles of the active unit is carried out in order to change the leaching conditions of the specified active ingredient in the body, especially orally.

 This coating especially allows you to smooth out the so-called negative properties, such as a bitter aftertaste, pronounced bitterness or too rapid solubilization of the active ingredient under normal conditions of administration. The coating also, forming a shell, layer or film enveloping these microparticles, allows you to protect the active ingredient. This sheath can remain intact as long as it is in contact or in circulation in a body-specific or corresponding fluid.

 The coating in this way can disappear due to destruction or dissolution at a certain 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. The coating may finally serve to favor the assimilation of microparticles in the body, according to the “masking” effect or “liposome” effect, according to the preferred embodiment of the invention, especially when the average particle size or average particle size distribution resulting from coating the microparticle shell is of the order of a micrometer or better less than a micrometer.

To implement the method of obtaining the galenic form according to the invention, it is preferable that the content of the active ingredient in a solution or dispersion in water or an organic solvent in stage 1 be lower than or equal to 5% [wt./volume]
The atomization carried out in stage 2 is carried out to obtain liquid aerosol microparticles having an appropriate average diameter in order to give, after evaporation of the solvent or dispersion liquid, solid microparticles with an average particle size of 5 to 0.01 μm, preferably with an average particle size lower than or equal to 2.5 μm and better with an average particle size lower than or equal to 1 μm.

 A gaseous carrier fluid that is suitable according to the invention is a gas inert to the active ingredient and the matrix formed by a filter element, for example nitrogen, argon and, if desired, dried air.

Evaporation in step 3 is carried out at an appropriate temperature so as not to damage the active ingredient, especially at a temperature of 25-90 ° ^C. Preferably, working at 30-65 ° ^C. In case it is possible to use an increasing or decreasing temperature gradient.

The filtration in stage 4 is carried out with a pressure loss of from about 80 to about 10,000 Pa. The pressure loss, which especially depends on the thickness of the filter element, the degree of compression (the ratio of the thickness of the material to compression in the thickness of the specified material after compression) and porosity, as well as the pressure of the filtered gaseous fluids, is usually from 1 cm H ₂ O (about 98 , 06 Pa) up to 100 cm H ₂ O (about 9806 Pa), or more precisely from 2 cm H ₂ O (about 196.1 Pa) for a thickness of 8 mm of filter material with a compression ratio of 1.25 for a gaseous fluid with a flow rate of 300 l / min, related to normal conditions of temperature and pressure, up to 76 cm H ₂ O (or about 7 451.5 Pa) for a thickness of 14 mm of filter material with a compression ratio of 3.6 for gaseous fluid with a flow rate of 4 l / min, referring to normal conditions of temperature and pressure.

 After filtering in step 4, the method also includes, in order to obtain an appreciably homogeneous galenical form, step 5, called the mixing step, according to which the filter element is thoroughly mixed with microparticles that are absorbed by the specified filter element in stage 4. Thus, as a result of filtration , the largest part of the absorbed microparticles is located in the thickness of the filter element near the surface in contact with the gaseous fluid containing solid microparticles, which They want to collect.

If the active ingredient is insoluble in water, has a size of 5-0.01 μm, then the production method then includes the following steps:
obtaining a solution in an organic solvent of the active ingredient insoluble in water, so that the concentration of the active ingredient in the solution is lower than or equal to 10% (wt./volume);
spraying the solution thus obtained in the form of a liquid aerosol using a gaseous carrier fluid;
evaporation of the solvent from the active ingredient in the carrier gas stream so that the solid microparticles resulting from drying the aerosol liquid microparticles are transported by the carrier gas;
filtering a gaseous carrier fluid containing an active ingredient in the form of microparticles with an average particle size of 5-0.01 μm, on the one hand, and a solvent of the active ingredient in the form of steam, on the other hand, using a filter including a solid, porous filter element and water-soluble material obtained in the dry state by freezing, crushing, freeze-drying and compression.

 If necessary, microparticles of the active water-insoluble ingredient can be separated by dissolving in water a matrix on which the microparticles are absorbed.

When the active ingredient is water soluble, the process for preparing the galenic form comprises the following steps:
obtaining a solution of the active ingredient in water, so that the concentration of the active ingredient in the solution is lower or equal to 10% (wt / vol);
spraying the resulting solution in the form of a liquid aerosol in a gaseous carrier fluid stream;
evaporating water from the carrier gas stream to form the above solid microparticles in the carrier gas;
filtering a gaseous carrier fluid containing the active ingredient mainly in the form of microparticles with an average particle size of 5-0.01 μm, on the one hand, and the solvent of the active ingredient in the form of steam, on the other hand, using a filter including a solid filter element and porous material, which is obtained in the dry state by freezing, grinding, freeze-drying and compression.

When the active ingredient is in the form of coated microparticles, the method is characterized in that it comprises the following steps:
obtaining a suspension of microparticles of the active ingredient in a liquid medium containing dissolved coating material, wherein the active ingredient is insoluble in said liquid medium and its concentration in the liquid medium is lower than or equal to 10% (w / v);
spraying the resulting suspension to obtain an aerosol in a gaseous carrier fluid stream;
evaporation of the aerosol liquid medium in such a way that the microparticle coating obtained by drying the aerosol is transferred by the gaseous carrier fluid;
filtering a gaseous carrier fluid containing the active ingredient mainly in the form of microparticles coated with a coating material using a filter including a solid and porous material as a filter element, which is obtained in the dry state by freezing, grinding, freeze-drying and compression, obtaining coated microparticles on the filter element.

To obtain coated microparticles, a method is provided that includes:
spraying a solution of the active ingredient in water or an organic solvent;
drying the resulting aerosol in a gaseous carrier fluid or vector;
filtering gaseous fluid with a filter element obtained by freezing, grinding, freeze-drying, then compression;
dissolving the specified filter element in a solvent, where the coating material is soluble, on the one hand, and the microparticles of the ingredient are insoluble, on the other hand;
spraying the resulting dispersion or suspension;
drying the aerosol transported in a gaseous carrier fluid, and
filtration on a filter element obtained by freezing, grinding, freeze-drying, then compression.

According to a better embodiment of the invention, the method for producing coated microparticles is characterized in that it comprises the following steps:
(a) obtaining a solution of the active ingredient in the first solvent, so that the concentration of the specified active ingredient in the first solvent is less than or equal to 10% (wt./volume) and preferably less than or equal to 5% (wt./volume);
(b) spraying the resulting solution in the form of a liquid aerosol in a gaseous carrier fluid stream;
(c) evaporating the solvent of the active ingredient in said carrier gas stream, so that the solid microparticles resulting from drying the aerosol microparticles are transferred by the carrier gas;
(d) filtering a gaseous carrier fluid containing the active ingredient mainly in the form of microparticles with an average particle size of 5-0.01 μm, on the one hand, and a solvent of the active ingredient in the form of steam, on the other hand, using a filter including as a filter element, a solid and porous material that is obtained in the dry state due to freezing, grinding, freeze-drying and compression;
(e) dissolving the filter element used in step (d) in a second solvent, in which (1) the active ingredient is insoluble, and (P) the coating material is soluble to obtain a liquid medium formed by said second solvent, where the coating material is dissolved and where dispersed coated microparticles;
(e) spraying the resulting suspension to obtain an aerosol in a gaseous carrier fluid stream;
(g) evaporation of the solvent of the liquid medium for drying the aerosol, so that the microparticle coating resulting from the drying of the aerosol is transferred by the carrier gas;
(h) filtering a gaseous carrier fluid containing a shell of a particle of the active ingredient with a filter comprising, as a filter element, a solid and porous material that is obtained in the dry state by freezing, grinding, freeze-drying and compression.

 The coating material that is suitable according to the invention is an organic film-forming substance, soluble in an ordinary specific solvent and insoluble in other ordinary, non-specific solvents. The coating material usually has a polymer nature. Particularly suitable are polymers and copolymers of derivatives of acrylic acid, such as polyacrylic acids, polymethacrylic acids, their salts and their esters; cellulose derivatives, glycerides, fatty acid polyglycerides, lecithins, hydrogenated oils, polyoxyalkylene glycols such as polyoxyethylene glycols and polyoxypropylene glycols, polyacids such as polylactic acids, and mixtures thereof.

 In general, waxes, fats, and other physiologically acceptable coating agents that are used in the galenical region are suitable as a coating material.

 Microparticles according to the invention, which can be coated or not coated, and, if necessary, are recovered by dissolving the matrix, which was used as a filter element in the filtration process in step 4. This dissolution is realized in an appropriate solvent, in which said microparticles, if coating, insoluble.

 PRI me R 1. Obtaining a matrix.

An aqueous solution is prepared containing dextran 70 (4%), hydroxypropyl methylcellulose (4%) of the brand Pharmacoat 603 and sucrose (0.0125%). The clarified solution was poured into a rectangular metal plates, pre-siliconized, a height of 10 mm, then slowly frozen at -50 ° ^C.

At a temperature of -50 ^{° C} frozen solution was removed from the mold, then the cold plate pulverized using a hammer mill until a homogeneous granulate with a grain size of about 2-3 mm, which is then lyophilized under vacuum 1, 333 Pa, is then brought to atmospheric pressure and room temperature by removing the vacuum in an atmosphere of neutral and dry gas (nitrogen).

 After lyophilization, the obtained granulate is placed in a cylindrical filter holder, closed in its lower part with a fine lattice located on a circular diaphragm.

 Lyophilized granulate is poured into the filter holder to a total height of 50 mm, or 25 mm, then they are all placed together on a stand that allows you to install a cylindrical piston at the top of the filter holder. Carry out a controlled compression of the granulate to reduce the total thickness to a predetermined value.

 In this way, a “fritted” filter is obtained in the form of a very homogeneous and crack-free compact disk with hydrophilic properties.

 The resulting filter is installed in the filter device so that the gaseous fluid transporting the particles of the filtered substance passes through the filter.

 To assess the effectiveness of the filter, the filtering device is placed between the generator of the analyzed particles in the form of an aerosol calibrated to a size of 0.017-0.350-1.091 μm and a laser particle counter after filtration.

 Gaseous fluid (air) containing aerosol particles of the filtered substance is continuously blown through the system, and the air leaving the filter is analyzed.

 The results are shown in the table.

 These results show that it is possible, using rationally lyophilized material in the form of a "fritted" filter and controlling the compression ratio, to obtain a matrix that completely retains the smallest particles from the gaseous vector of the submicron aerosol stream.

PRI me R 2. A lyophilized compressed filter is obtained according to example 1 from an aqueous solution containing dextran 70 (4%), Pharmacoat 603 (4%), sucrose (0.0125%). A stream of microparticles is passed through the filter by a generator in the form of an aerosol in a gaseous fluid. Microparticles are obtained from a 2.5% (w / v) solution of nifedipine (1,4-dihydro-2,6-dimethyl-4- / 2-nitrophenyl / -3,5-pyridinecarboxylic acid dimethyl ether) in chloroform, which is injected into the nitrogen flow into the atomizer, where it forms a spray pressure of 4 bar, at a temperature of ²⁵ ° C and under a feed of 300 l [normal conditions] gas / min. The resulting spray dried at ³⁰ ° C and the resulting microparticles collected on lyophilized filter identical to that described in example 1, with a final thickness of 8 mm after a small pressing with initially th layer of granulate 10 mm thick.

 Under these conditions, the pressure loss at the filter level is insignificant (2 cm water column, i.e. 196.1 Pa), and it is noted that the particles are absorbed in the first three millimeters of the filter, which turns yellow, on which it can be absorbed in 10 minutes 4, 5 g of active product with a total weight of filter material 115 g.

 The filter matrix is removed and homogenized to give a galenic form with 3.9% nifedipine in the form of submicron particles.

 The following examples 3-5 relate to the preparation of submicron particles of active principles insoluble in water.

PRI me R 3. A 2.5% (w / v) solution of nifedipine in chloroform is sprayed under a pressure of 4 bar in a dry nitrogen carrier stream. Then, the resulting spray dried at 30 ^{° C} by circulating in a metal ring, the wall of which is heated electrically. The aerosol of solid microparticles thus obtained is directed to a filter, which is prepared as described in Example 1 by moderate compression of the lyophilized granulate obtained from an aqueous composition with 4% (w / v) dextran 70.4% (w / v) Pharmacoat 603 and 0.0125% (w / v) sucrose. Under optimal conditions of use, the filter retains the completely obtained microparticles, the gaseous carrier fluid, nitrogen enriched in chloroform vapors and escaping after filtration are sent to the treatment plant, where it is purified by cryogenic condensation, which allows the solvent to be separated from it, and then the gaseous fluid is recirculated carrier.

 At the end of the operation, the active ingredient, nifedipine, is completely in the form of submicron particles "trapped" in the upper part of the lyophized and compressed filter. Then the filter is removed and homogenized in order to obtain a galenic form enriched with the active product in the form of very small particles. This galenic form can be used as it is, or can serve as an intermediate in other galenic operations.

PRI me R 4. Spray 700 g of a 2.5% (w / v) chloroform solution of nifedipine in a carrier gas, dry nitrogen. The carrier gas is heated at a temperature of 30-35 ^about C, for about 50-70 minutes, so that solid microparticles are formed due to the evaporation of chloroform.

 Microparticles of nifedipine are collected per 60 g of filter, in the form of a disk, prepared as described in example 3.

 Quantitative determination of nifedipine shows that a) near the surface called the filter inlet: 2.4% wt./nifedipine; b) near the base (i.e., the exit surface of the filter): 0.09 wt. nifedipine; and c) after homogenization, the average nifedipine content in the matrix is 0.58 wt.

 In addition, the residual solvent content is below 900 ppm (about 800-900 ppm) before homogenization, and below 400 ppm after homogenization.

 Photographs taken with an electronic scanning microscope show that the microparticles have an average particle size distribution of 0.2-1μ m.

Example 5. A compressed lyophilized filter was obtained as described above in Example 3 from an aqueous solution containing dextran 70 (4%), Pharmacoat 603 (4%), sucrose (0.0125%). The filter is placed in a stream of microparticles leaving the microparticle generator. Microparticles prepared from 2.5% solution (wt. / Vol) nifedipine in chloroform, which was injected into the nitrogen flow into the atomizer, wherein a pressure of 4 bar, at a temperature of ²⁵ ° C and under a feed of 300 l (STP) of gas / min microparticles are formed. The thus obtained spray dried at ³⁰ ° C and the resulting solid lyophilized microparticles were collected on a filter and compressed to a final thickness of 8 mm, after a short initial pressing at 10 mm layer of granulate.

 Under these conditions, the pressure loss at the filter level is insignificant (about 196.1 Pa), and it turns out that all particles are trapped in the first three millimeters of the filter, which turns yellow and absorbs 4.5 g of the active product per 10 minutes, calculated for the total weight of the filter material 115 g.

 The filter is removed and homogenized in order to obtain a galenic form having a content of 3.9% nifedipine in submicron form.

 The following examples 6-9 illustrate the preparation of submicron particles of active ingredients that are soluble in water, on the one hand, and coated submicron particles of active principles, on the other hand.

PRI me R 6. Prepare an aqueous 5% (wt./vol.) Solution of Buflomedil hydrochloride. Spray 100 g of this solution under a pressure of 3-4 bar in a stream of dry nitrogen. The resulting liquid spray dried for 50 minutes at a temperature gradient of 44 ^{° C} (start of drying) to 50 ^{° C} ending drying. The obtained microparticles are filtered off on 45 g of a filter element from polyvinylpyrrolidone obtained by freeze-drying, then pressing.

Quantitative analysis of the filter element allows us to establish that the amount of Buflomedil hydrochloride fixed on the filter is 4%
Photographs that are significant with an electronic scanning microscope show the size of the hit points on the order of 0.1-0.2 m, which indicates that particles with a particle size distribution of less than 0.1 μm can be obtained.

PRI me R 7. Do as described in example 6, spraying 100 g of an aqueous 2% (wt./vol.) Heparin solution, drying the resulting aerosol for 60 minutes with a temperature gradient of 60 ^about (the beginning of drying), 50 ^about C (the end of drying), then collecting the obtained microparticles for 40 g subjected to freeze-drying and pressing the filter from polyvinylpyrrolidone.

 By quantitative analysis using flame photometry, the amount of sodium in the filter corresponds to a fixation expressed as sodium heparin of the order of 1%. Photographs taken with an electronic scanning microscope show uniform particles of the order of 0.1-0.5 μm, whereas the initial particles during dissolution in water were very heterogeneous 10-100 μm or more.

 PRI me R 8. Do as indicated in example 7, with an aqueous 5% (wt./vol.) Heparin solution, that is, a more concentrated solution than that of example 7.

 Electron microscopic examination of the filter surface sample confirms well that the heparin particles that are obtained are of the order of 0.1-0.5 μm.

 PRI me R 9. Do as described in example 7, spraying 400 g of an aqueous 5% (wt./vol.) Heparin solution, which is collected on a filter of polyvinylpyrrolidone (PNP) obtained by freezing, grinding, freeze-drying and compression.

 The filter is dissolved in 500 ml of chloroform, then the composition of glycerides and partial polyglycerides of fatty acids, commercially available under the name GELUCIRE, is dissolved in the resulting mixture. The resulting suspension is sprayed and the microparticle coating is collected on a PVP filter. Said heparin microparticle coatings thus obtained have an average particle size distribution below 1 μm; they may, if necessary, be associated with GELUCIRE microparticles.

Claims (6)

1. METHOD FOR PRODUCING A GALENA FORM, comprising absorbing the active ingredient in the form of submicron particles on a filter element, characterized in that the active ingredient in a concentration of 2.5% (weight / volume) is dissolved either in water or in a solvent, or a suspension of microparticles in an encapsulating solution agent, spray it in the carrier gas stream to obtain a liquid aerosol, followed by drying it at 30-60 ^o C to obtain solid particles of the active ingredient in the carrier gas stream and then direct the resulting stream to adsorption to the filter a solidifying element representing a solid porous matrix obtained by freezing, cryo-drying, grinding and pressing a physiologically acceptable product.  2. The method according to claim 1, characterized in that a physiologically acceptable matrix is obtained by freezing, grinding and freeze-drying an aqueous solution containing 4% (weight / volume) dextran, 4% (weight / volume) hydroxypropylmethyl cellulose and 0.0125% (weight / volume) sucrose, and then pressing the resulting material to a compression ratio of from 2 to 3.6.  3. The method according to claim 1, characterized in that polyvinylpyrrolidone is used as a physiologically acceptable product.  4. The method according to claim 1, characterized in that a solution of the active ingredient in an organic solvent is prepared if it is insoluble in water.  5. The method according to claim 1, characterized in that an aqueous solution of the active ingredient is prepared if the latter is soluble in water.  6. The method according to claim 1, characterized in that to obtain the galenic form with the encapsulated active ingredient, a suspension of the active ingredient is prepared in a liquid medium in which the encapsulating agent is dissolved, but in which the active ingredient is insoluble, and after filtration, the filter matrix with the absorbed active ingredient dissolved in a solvent in which the active ingredient is insoluble, but soluble the coating material of the active ingredient, to obtain a liquid dispersion of the active ingredient, then spray the resulting dis Persia to obtain an aerosol using a gaseous carrier fluid, the solvent of the liquid medium for drying the aerosol is evaporated to obtain coated microparticles transported by the gaseous carrier fluid and filtered gaseous carrier fluid containing the coated particles of the active ingredient on the filter element obtained by freezing, grinding, freeze-drying and compression of physiologically acceptable material.

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