MXPA06010903A - Pharmaceutical compositions - Google Patents

Abstract

A process for micronization of pharmaceutically active agents.

Description

PHARMACEUTICAL COMPOSITIONS The present invention relates to a process for the preparation of small particles of pharmaceutically active agent, for example having an average particle size from less than about 7 microns, to particles of pharmaceutically active agents prepared by this process, and to pharmaceutical compositions which they comprise the mentioned particles. The controlled production of particles of pharmaceutically active agents having a defined particle size in the range of sizes in low microns or sub-microns, presents specific technical difficulties. The conventional processes of crushing, milling, as well as wet and dry milling, are often associated with more or less severe operating problems, or with poor product quality due, for example, to heavy metal contamination when handling compounds Organic pharmaceuticals and active agents. For example, grinding techniques are often used in industrial practice to reduce the size of the solids particles. However, dry milling techniques can cause unacceptable levels of dust, which require sophisticated safety precautions to be taken during the milling operation. Moreover, in many cases, dry milling increases the amorphous content in the particle formulations of pharmaceutically active agents, which may not be convenient, or which may, entail weakened or even adverse therapeutic effects. Dry grinding processes often suffer from a significant loss of product, or operational problems, such as product jamming or equipment clogging. The latter is often observed when sticky and sticky powders are handled in conventional dry grinding equipment. The main limitation of the technology of wet milling is the contamination with heavy metal, due to the direct physical contact of the particles with the grinding medium, as well as the wear of the wall. Other technical problems observed in the dry and wet trituration of pharmaceutically active agents are thermal and chemical degradation due, for example, to high local temperatures in the grinding equipment, to the non-uniform characteristics of the product, and to the variability of the batch to batch Spray and freeze drying techniques, or particle formation using supercritical fluids, have been employed as alternative processes to produce micronized dry powders. However, the three technologies hardly meet the requirements with respect to the average particle size. Moreover, thermally labile molecules can be susceptible to decomposition or degradation after being exposed to elevated temperatures, which are typically used in spray drying. In a similar manner, a frequently undesired increase in amorphous content in the formulation is often observed, such as spray drying and freezing, as in the formation of particles with supercritical fluids. There is a need to provide robust and simple processes for the industrial production of particle sizes in microns or sub-microns of pharmaceutically active agents difficult to crush, with a controlled average particle size, and with a controlled particle size distribution (PSD). ), that overcome these technical problems. The present invention provides a process that eliminates or minimizes the above technical problems. In one aspect, the present invention provides a process for the controlled micronization of the pharmaceutically active agent, for example having an average particle size of less than about 7 microns, for example from about 0.1 or 0.5 to about 1, 2, 3, 4, 5, 5.5, 6, or 6.5 microns, which comprises: (a) suspending the pharmaceutically active agent in a compressed or propellant gas; (b) process the suspension by high pressure homogenization, and (c) obtain dry powder from the process after depressurization. In another aspect, the present invention provides a process for the controlled micronization of the pharmaceutically active agent, for example having an average particle size of less than 7 microns, for example from about 0.1 or 0.5 to about 1, 2, 3, 4 , 5, 5.5, 6, or 6.5 microns, which comprises: (a) suspending the pharmaceutically active agent in a propellant, (b) processing the suspension by high pressure homogenization, and (c) obtaining a suspension of the pharmaceutically active agent. micronized in a propellant. The pharmaceutically active agent can be suspended in a compressed or propellant gas, and optionally one or more pharmaceutically acceptable excipients can be used to form the suspension medium. The invention can be practiced with a wide variety of pharmaceutically active agents. The drug substance is preferably present in an essentially pure form. The powder particle size of the drug substance is reduced by the process of the invention to an average particle size of less than about 7 microns, for example from about 0.1 or 0.5 to about 1, 2, 3, 4, 5 , 5.5, 6, or 6.5 microns, for example from about 0.5 to about 5.0 microns, from a coarse starting material with average particle sizes of between about 10 and 200 microns, preferably between about 10 and 40 microns. The process of the present invention can preferably be used to micronise high-aspect, spicular, or needle-like crystals. Particles that exhibit this or a similar morphology often cause severe operation problems in conventional milling equipment. In particular, a clogging or malfunction of the equipment is often observed due to the formation of a voluminous powder cake compressed inside the mill. Additionally, the process of the present invention is particularly suitable for micronizing very sticky or sticky drug substances, which often involve similar or similar problems of operation. For the purpose of the invention, "pharmaceutically active agent" means all substances that produce a pharmaceutical or therapeutic effect. Examples of the pharmaceutically active agents include, but are not limited to, the active agents poorly soluble in water and / or thermally or chemically unstable, such as, for example, phenytoin (5,5-diphenylhydantoin), adrenoceptor agonists. -2-receptor, such as the compounds (in free or salt or solvate form) of Formula I of International Publication Number WO 2000/075114, preferably the compounds of the examples thereof, especially a compound of the Formula: and pharmaceutically acceptable salts thereof, as well as the compounds (in free or salt or solvate form) of Formula I of International Publication Number WO 2004/016601, preferably the compounds of the examples thereof, especially those of Examples 1, 3, 4, 5, and 79; corticosteroids, such as the compounds (in free or salt or solvate form) of Formula I of International Publication Number WO 2002/000679, preferably the compounds of the examples thereof, especially those of Examples 3, 11, 14, 17, 19, 26, 34, 37, 39, 51, 60, 67, 72, 73, 90, 99, and 101; anti-muscarinic agonists, such as the compounds (in salt or zwitterionic form) of Formula I of International Patent Application Number PCT / EP2004 / 004605, preferably the compounds of the examples thereof, especially those of the examples 17, 34, 52, 54, 71, 76, 96, 114, 138, 159, 170, 190, 209, 221, 242, and 244; pimecrolimus (33-epichloro-33-deoxy-ascomycin), as described, for example, in European Patent Number EP 427680; N-benzoyl-staurosporine, as described, for example, in European Patent Number EP 296110; proteins; peptides; vitamins; steroids; corticosteroids, and bronchodilators. Other pharmaceutically active agents may include, but are not limited to, oxcarbazepine, carbamazepine, 1- (2,6-difluoro-benzyl) -1 H- [1,2,3] -triazole-4-carboxylic acid amide; pyrimidyl-amino-benzamides, such as the compounds of Formula I of International Publication Number WO 04/005281, preferably the compounds of the examples thereof, especially those of Example 92; selective inhibitors of Cox-2, for example 5-methyl-2- (2'-chloro-6'-fluoro-anilino) -phenyl-acetic acid, as described, for example, in Publication I International No. WO 99/1 1605; a derivative of ptotecin that has the following structure, known as Compound A: Com Item A Compound A may be in free or pharmaceutically acceptable salt form, and may be prepared as described in U.S. Patent No. 6,424,457. Compound A may be in the form of its possible enantiomers, diastereoisomers, and related mixtures, the pharmaceutically acceptable salts thereof, and their active metabolites. The pharmaceutically acceptable excipient may be a surfactant. Suitable surfactants include acetylated monoglycerides, such as, for example, the active ingredient known and commercially available under the tradename Myvacet® 9-08, (Fiedler, loc. Cit., Page 1 167), perfluorocarboxylic acid, sterol- polyethylene glycol esters (PEG), for example PEG 200, 300, 400, or 600 (Fiedler, loc. cit., page 1 348), sorbitan fatty acid esters of polyethylene oxide, for example Tween® 20, 40, 60, 65, 80 ,. u 85 (Fiedler loe. cit., page 1 754), sorbitan esters, for example sorbitan mono-laurate, sorbitan mono-oleate, sorbitan tri-oleate, or sorbitan mono-palmitate, propylene glycol, and oleic acid . Optionally, a combination of one or more surfactants can be used. In another aspect of the invention, the excipient can be a vehicle. The carriers can be composed of one or more crystalline sugars, for example from one or more sugar alcohols or polyols. Preferably, lactose or glucose can be used. In a further aspect of the invention, the excipient may be an anti-friction or anti-adhesion agent, such as a lubricant. Suitable lubricants include leucine, lecithin, magnesium stearate, stearic acid, sodium lauryl sulfate, sodium stearyl fumarate, stearyl alcohol, sucrose mono-p.alinate, menthol, colloidal silicon dioxide, for example as is commercially available available under the trade name Aerosil® 200, and sodium benzoate, or a combination thereof. In a further aspect, the excipients may include antimicrobial agents, for example, benzalkonium chloride, acidifiers, for example citric acid, antioxidants, for example ascorbic acid, chelating agents, for example disodium EDTA. The excipients may include a combination of one or more additives.

The details of excipients suitable for use in the process of the invention are described in Fiedler's "Lexikon der Hilfsstoffe'S 5th Edition, ECV Aulendorf 2002, and in the "Handbook of Pharmaceutical Excipients, "Rowe, Sheskey and Weller, 4th Edition 2003, which are incorporated herein by reference In one embodiment of the invention, the powder of the pharmaceutically active agent used in the process of the present invention is suspended. in a compressed gas The amount of active agent suspended in a compressed gas can range from about 0.1 percent grams per liter (0.01 percent by volume) to about 250 grams per liter (25 percent by volume) A class of compressed gases includes CO2, ethane, propane, butane, dimethyl ether, and nitrogen.A combination of compressed gases can also be used.Co2 can preferably be used.Another class of compressed gases are propellants, including hydro-fluoro-alkanes (HFA), for example 1,1,1,2-tetrafluoro-ethane (HFA 134a), and 1,1,1,3,3,3-heptafluoro-propane (HFA 227). HFA 134a, and HFA 227 are qualified for human use, and in contrast to the chlorofluoro-carbon (CFC) propellants, they have no consumer effect on the ozone layer. Other examples of the hydro-fluoro-alkane propellants are perfluoro-ethane, monochloro-difluoro-methane, and difluoro-ethane. A combination of propellants can also be used.

For the purpose of the invention, "suspension" means a two-phase system consisting of a finely divided solid dispersed in a continuous gas phase, for example compressed. The suspension can be prepared by loading the coarse starting material into a stirred pressure vessel. The container can be sealed and hermetically sealed to allow operation at elevated pressure, and the compressed gas can be added to form the suspension. The operating pressure in the stirred vessel may depend on the compressed gas. Typical operating pressures at room temperature according to the invention, may be in the range from 1.5 to 2 bar, up to about 300 bar, for example from about 10 to about 30 bar for some hydrofluoroalkanes, for example about 55 to about 60 bar for carbon dioxide, and, for example, from about 200 bar to about 300 bar for nitrogen. The operating pressures may be in the range of from about 2 to about 5 bar in the case of hydrofluoroalkanes, if the operating temperature is significantly below room temperature, for example from about 0 ° C to 5 ° C. Suitable operating temperatures for the proposed process may be in the range of from about -30 ° C to about 50 ° C. The whole process can be carried out in hermetically sealed and sealed equipment, pressure-proof. High pressure homogenization is an established technology for preparing o / w, w / o, s / o / w, or w / o / w emulsions, solid-lipid nanoparticles, stabilized suspensions, and for the deagglomeration of solids - dispersed in aqueous suspensions. In the suspensions of solids or liquids for conventional high-pressure homogenization, the liquids are first formed and then processed in the homogenization unit at high pressures of up to several thousand bar. In accordance with the present invention, high pressure homogenization of the suspensions in compressed gas can be an effective technology for producing micronized particles of a pharmaceutically active agent, for example with a defined product particle size of less than about 7 microns, for example from about 1 or 2 to about 3, 4, 5, 5.5, 6, or 6.5 microns, from a coarse starting material with average particle sizes of about 10 to about 200 microns. The average particle size and the particle size distribution of the product, which can be harvested as a dry powder after depressurization of the unit, or as a suspension in compressed gas, can be efficiently controlled by close control of the parameters characteristic of the proposed micronization process. The homogenization pressure, the suspension density and solids concentration, the operating temperature, the choice of the interaction geometries, and the number of passes through the equipment (which is largely equivalent to time) can be used. of total processing), or combinations of these main operating parameters, to closely control the quality of the product. The process of the invention can be used to generate narrow particle size distributions, in the size range of less than 7 microns, for example from about 1 or 2 to about 3, 4, 5, 5.5 6, or 6.5 microns. The size range of about 1 to about 5 microns may be particularly suitable for application in formulations for therapeutic inhalation, for example in dry powder inhalers (DPI), or in metered dose inhalers (MDI), or in pressurized metered dose inhalers (pMDI). In a further aspect, the present invention provides an apparatus for the micronization of pharmaceutically active agents, which comprises one or two stirred pressure vessels, a high pressure homogenizer, and a fluid conduit interconnecting the stirred pressure vessel or the pressure vessels stirred with the high pressure homogenization unit. The agitated pressure vessel used to prepare the suspension of the starting material can be connected to a line that supplies sufficient quantities of compressed gas, which itself can be connected to one or several submerged or gas cylinders, or to a tank. of waves containing the pressurized gas. The desired operating pressure can be established and controlled by the addition of compressed gas through a pump, until the set point is reached. The high pressure homogenization unit can include an intensifying pump, and one or multiple interaction chambers, where the reduction of particle sizes or micronization takes place due to particle-particle and particle-wall collisions, to the forces of tearing, and to the cavitation of the fluid. The intensifier pump, the line connecting the agitated pressure vessel, and the intensifier pump of the high pressure homogenization unit, can be cooled to prevent the accumulation of compressible gas bubbles in the inlet section of the intensifier pump. The high pressure homogenization unit can include an additional intensifier pump. The homogenization can be achieved by adjusting a defined pressure drop of less than, for example, 1,500 bar, for example 200, 500, 750, 1,000 or 1,500 bar, through a high pressure gap or geometry valve static A dynamic high pressure homogenization valve can be used. This valve overcomes some of the major drawbacks of static interaction geometries, such as clogging at high concentrations of solids. In the case of a blockage, the valve is opened, and the desired pressure drop can be readjusted manually or automatically, using an appropriate pressure control device. Interaction chambers can provide a flow divider and an impact chamber. The flow of compressed gas, the non-solvent containing the solid particles, and optionally the pharmaceutically acceptable excipients, can be divided into two sub-flows in the flow divider, and these two streams can be reattached in the flow chamber. mpactation. The primary forces that cause the micronization of the solid particles in the high pressure homogenizer, can be tearing forces, turbulent flow, acceleration, and change of speed in the direction of flow; impact forces, which involve the collision of the processed particles with solid elements of the homogenizer, and collision between the particles that are being processed; and cavitation forces, which involve a greater change in velocity with a reduced change in pressure, and turbulent flow. An additional force can be attributed to wear, that is, friction grinding. If micronization is achieved by releasing the pressure through a defined gap, such as, for example, a high-pressure valve, the primary forces that cause micronization can be cavitation, tearing forces, turbulence, impact forces that involve collision of the particles processed with the solid elements of the homogenizer, and the collision between the particles that are being processed, as well as the wear. In one embodiment of the present invention, the process can be carried out in an apparatus consisting of a stirred pressure vessel and a high pressure homogenization unit. The output of the homogenizer can be connected to the agitated pressure vessel containing the suspension. The processed suspension is reintroduced into the container containing the unprocessed suspension. The total processing time can be used to control the average particle size of the particulate product or particles in the compressed gas suspension. The operation of the high pressure homogenizer can be started after a suspension of the active agent has formed in the compressed gas in the pressure vessel. The homogenizer can operate as follows: the homogenizer, which has an inlet and an outlet, is supported by a high-pressure pump, which is designed to supply the desired pressure at a constant rate to the product flow. The pump delivers the product at constant pressure through the microchannels of fixed geometry defined within the interaction chamber. The reduction of the particle sizes and the homogenization of the previously formed suspension in the stirred pressure vessel are presented within the interaction chamber. The block of the injection interaction chamber makes use of three different forces: claw, impaction, and cavitation. The high pressure homogenization provides a rather uniform particle size reduction, for example, the micronization and deagglomeration of the pharmaceutically active agent. In another embodiment of the invention, referring to Figure 1, the apparatus may consist of two stirred pressure vessels (10), which are provided with an agitator element (16), and a high pressure homogenization unit (12) . The inlet and the outlet of the homogenizer (12) can be connected by high pressure pipe (15) to both stirred pressure vessels (10), and all connections can be closed individually by the operation of a high three-way valve pressure (11), or high pressure valves (17), in a manual or automatic way. The suspension of the starting material can be formed in one of the two stirred pressure vessels, and then the homogenization can be started. The output of the homogenizer can be connected to the second pressure vessel, which is initially empty. If the first agitated pressure vessel is empty, and the second agitated pressure vessel is filled with homogenized suspension, the valves can be operated in such a manner that the content of the second agitated pressure vessel containing the homogenized suspension is redirected, through the homogenizer, and the suspension is collected twice homogenized in the first stirred pressure vessel. The advantage of this embodiment of the invention is a more efficient control of the average particle size, by controlling the residence time through the number of passes through the equipment. The average particle size in this modality, is controlled by a total number of passes through the homogenizer, and the typical numbers of passes in practice are in the range from about 3 to 25, to reach an average particle size of less than about 7 microns, for example, from about 0.1 or 0.5 to about 1, 2, 3, 4, 5, 5.5, 6, or 6.5 microns. If the total number of passes through the homogenizer is reached, the suspension can be stored in a storage tank (14). In this embodiment of the invention, both static interaction geometries and dynamic high pressure relaxation valves can be used for homogenization. The high pressure homogenizer that provides the static interaction geometries can be, for example, a closed system, for example a Microfluidics Model M-110Y Microfluidizer®. The apparatus and method of operation of a Microfluidizer® is further described in U.S. Patent Number 4,533,254, and in U.S. Patent No. 4,908,154, which are incorporated herein by reference. Membrane pumps can also be used in conjunction with the interaction geometries of the Microfluidics M-110Y Microfluidizer®, instead of the original high-pressure piston pump. A dynamic high-pressure homogenizer can be, for example, a system comprising a high-pressure boost pump, for example a membrane metering pump LEWA, LDE / 1V M211S, and a suitable high pressure valve with the opening or gap of the adjustable valve, and the seat and valve body are preferably made of cavitation resistant materials, such as, for example, zirconium oxide, tungsten carbide or materials of a similar quality. The material of the needle or plunger of the valve can preferably be made of a material harder than the valve seat. The dynamic high pressure valve can be operated in a manual or automatic way, by using appropriate downstream pressure control elements. In another aspect of the invention, the process of the present invention provides dry particles are solvent and moisture free of the pharmaceutically active agent, having an average particle size of less than about 7 microns, for example from about 1 or 2 microns to about 3, 4, 5, 5.5, 6, or 6.5 microns, obtained by depressurizing the system. The powder particles of pharmaceutically active agent of a size of about 1 to about 5 microns can be used for the dry powder inhaler (DPI) formulations without further processing. In a further aspect of the invention, the process provides particles of the pharmaceutically active agent, which have an average particle size of less than about 7 microns, for example from about 0.1 or 0.5 microns to about 1, 2, 3, 4, 5 , 5.5, 6, or 6.5 microns, finely dispersed in a propellant qualified for human use, in order to form a suspension. The suspension comprising particles of a size from about 0.5 to about 5 microns can be filled directly into suitable inhalation devices, and then used in formulations and metered dose inhaler (MDI) or pressurized metered dose (pMDI) without processing additional back some. An advantage of the present invention is that the suspension of the pharmaceutically active agent in the propellant or in the compressed gas can be micronized in a one-step process, eliminating the need for any additional steps subsequent to processing. After depressurization of the compressed gas or propellant, dry powder of the pharmaceutically active agent is obtained, which can be used for the inhalation formulation without further processing. The process is easy to apply and to carry out under light and inert conditions. Through the process of the present invention, technical problems are eliminated, such as high amounts of solvents, increased amorphous content, pollution, and wear. In a further aspect, the invention provides a pharmaceutical composition comprising micronized pharmaceutically active agent particles, obtained by the process of the present invention, and pharmaceutically acceptable excipients. The pharmaceutically acceptable excipients, as described above, include surfactants, vehicles, and / or lubricants, and can be used to produce a pharmaceutical composition, for example in solid dosage forms, such as capsules, tablets, or sachets. In a further aspect, the invention provides micronized particles of an active pharmaceutical agent, for use in an ointment or in a formulation of eye drops. In another aspect, the invention provides micronized particles of a pharmaceutically active agent, for use in parenteral formulations. In another aspect, the invention provides micronized particles of a pharmaceutically active agent, for use in oral formulations. In another aspect, the invention provides micronized particles of a pharmaceutically active agent, for use in topical formulations. In a further aspect, the invention provides a package comprising a composition of the invention together with instructions for its use. The structure and advantages of the present invention will become further apparent after consideration of the following non-limiting description of various embodiments of the present invention, in conjunction with the accompanying drawings. Below is a non-limiting description by way of example. Example 1 Pimecrolimus is suspended in the propellant HFA227 (1,1, 1, 2,3,3, 3-heptafluoro-propane), and homogenized in a Microfluidics Microfluidizer M-110YMR. A pressure vessel is used, and the total processing time is 60 minutes. The operating pressure in the stirred vessel is about 3 bar, and the maximum homogenization pressure is about 500 bar. The input temperature is 0 ° C, and the output temperature is about 30 ° C. The pressure vessel is depressurized after 60 m processing hours, and the dried powder product is analyzed using conventional off-line analytical tools. Example 2 Pimecrolimus is suspended in the propellant HFA227 (1, 1, 1, 2, 3,3, 3-heptafluoro-propane), and homogenized in a Microfluidics Microfluidizer M-1 1YYM R. Two pressure vessels are used, and the number of passes through is used. of the equipment to control the average particle size of the product. The operating pressure is about 3 bar, and the maximum homogenization pressure is about 500 bar. The inlet temperature is about 0 ° C, and the outlet temperature is about 30 ° C. After the tenth pass, the system is depressurized, and the dry powder product is analyzed using conventional off-line analytical tools. Example 3 Pimecrolimus is suspended in the propellant H FA1 34 (1,1,1-trifluoro-ethane) and homogenized through a high-pressure valve in a tightly controlled pressure drop. A pressure vessel is used, and the total processing time is 1 80 minutes. The operating pressure is about 10 bar, and the maximum homogenization pressure is about 750 bar, thus utilizing a pressure drop of about 740 bar through the relaxation valve. The inlet temperature is about 0 ° C, and the outlet temperature is about 30 ° C. The pressure vessel is depressurized after 180 minutes of processing, and the dried powder product is analyzed using analytical tools outside. conventional line. The pimecrolimus particles obtained in Examples 1, 2, and 3 are redispersed in water containing Tween 20 at about 0.1 percent to form a suspension, and then ultrasonically for typically 60 seconds before measuring the size of the suspension. the particles using the particle calibrator by laser light diffraction Sympatec Helos. The results of the measurement of the particle sizes are illustrated in Table 1. The processing time is 60 minutes in the continuous mode of the test, as described in Example 1, and the average particle size by volume ( x5o) is 2.7 microns, and x90 is 11.4 microns. In the test described in Example 2, the sample is processed in batch mode, and the results are reported after 10 passes. In this case, x5o is 5.3 (5.5) micras, and x90 is 19.2 (20.6) micras.

Table 1 Example 4 Phenytoin (5,5-diphenylhydantoin) is suspended in the propellant H FA134 (1,1,1-trifluoro-ethane) and homogenized through a high-pressure valve with a tightly controlled pressure drop. A pressure vessel is used, and the total processing time is 240 minutes. The operating pressure is approximately 1.0 bar, and the maximum homogenization pressure is approximately 750 bar. The inlet temperature is about 0 ° C, and the outlet temperature is about 30 ° C. The pressure vessel is depressurized after 240 minutes of processing, and the dried powder product is analyzed using conventional off-line analytical tools. The particle size distribution of the phenytoin microparticles produced in Example 4 is illustrated in Figure 2.

Example 5 Phenytoin (5,5-diphenylhydantoin) is suspended in carbon dioxide, and homogenized through a high pressure valve with tightly controlled pressure drop. A pressure vessel is used, and the total processing time is 240 minutes. The operating pressure is about 57 bar, and the maximum homogenization pressure is about 800 bar. The inlet temperature is about 0 ° C, and the outlet temperature is about 30 ° C. The pressure vessel is depressurized after 240 minutes of processing, and the dried powder product is analyzed using conventional off-line analytical tools. The particle size distribution of the phenytoin microparticles produced in Example 5 is illustrated in Figure 3. The phenytoin particles obtained in Examples 4 and 5 are redispersed in water containing Tween 20 at about 0.1. percent to form a suspension, and then ultrasonic for typically 60 seconds before measuring the particle sizes using a particle gauge by laser beam light diffraction Sympatec Helos. The results of the measurement of the particle sizes are illustrated in Table 2. The processing time is 240 minutes in the continuous mode in the tests described in Examples 4 and 5, and the average particle size by volume (x50 ) is 1.48 and 1.46 microns, respectively, and x90 is 3.57 and 3.02 microns, respectively. Table 2 BRIEF DESCRIPTION OF THE DRAWINGS Figure 1 is a schematic drawing of a continuous cycle closed apparatus comprising two stirred pressure vessels according to the invention. The apparatus consists of two stirred pressure vessels (10), which are provided with an agitator element (16), a high pressure homogenization unit (12), and a storage tank (14). The inlet and the outlet of the homogenizer (1 2) are connected by high pressure pipe (1 5) with both stirred pressure vessels (10), and all the connections are closed individually by the operation of a three way valve. high pressure (1 1), or high pressure valves (17), in a manual or automatic way. Figure 2 is an example of phenytoin microparticles produced using a process of the invention. In Example 4, the particle size distribution measured using a particle calibrator by Sympatec Helos laser light diffraction is as follows: x1 0 = 0.72 microns, x5o = 1 -48 microns, and x90 = 3.57 microns. Figure 3 is an example of the phenytoin microparticles produced using a process of the invention. In Example 5, the particle size distribution measured using a Simpatec Helos laser light diffraction particle calibrator is as follows: X? 0 = 0.73 microns, x5o = 1-46 microns, and x90 = 3.02 microns.

Claims (22)

1. CLAIMS 1. A process for the micronization of a pharmaceutically active agent, which comprises: (a) suspending the pharmaceutically active agent in a propellant or in a compressed gas, (b) processing this suspension by high pressure homogenization, and (c) obtaining Dry powder after depressurization.
2. 2. A process for the micronization of a pharmaceutically active agent, which comprises: (a) suspending the pharmaceutically active agent in a propellant, (b) processing this suspension by high pressure homogenization, and (c) obtaining a suspension of the pharmaceutically active agent micronized in a propellant.
3. 3. The process according to claim 1 or 2, wherein the pharmaceutically active agent micronized by the aforementioned process has an average particle size of between about 0. 1 and about 7.0 microns.
4. 4. The process according to any of the preceding claims, wherein the pharmaceutically active agent micronized by the aforementioned process has an average particle size of from about 0.5 to about 5.0 microns.
5. The process according to any of the preceding claims, wherein the suspension formed by the active pharmaceutical agent and the compressed or propellant gas, comprises one or more pharmaceutically acceptable excipients.
6. The process according to any of the preceding claims, wherein the active pharmaceutical agent is poorly soluble in water and / or chemically or thermally unstable.
7. The process according to any of the preceding claims, wherein the pharmaceutically active agent is selected from at least one of pimecrolimus (33-epichloro-33-deoxy-ascomycin), 5 - [(R) -2- (5,6-diethyl-indan-2-yl-amino) -1-hydroxy-ethyl] -8-hydroxy- (1H) -quinolin-2-one, (6S, 9R, 10S, 11S, 13S, 16R, 17 R) -9-clo ro-6-f luoro-11-hydroxy-17-methoxy-carbonyl-10,13, 16-trimethyl-3-oxo-6,7,8,9,10-11,12 , 13,14,15,16,17-dodecahydro-3H-cyclopenta- [a] -phenanthren-17-yl-ester of 3-methyl-thiophene-2-carboxylic acid, N-benzoyl-staurosporine, oxcarbazepine, carbamazepine, 1- (2,6-difluoro-benzyl) -1H- [1,2,3] -triazole-4-carboxylic acid amide, cox-2 inhibitors, pyrimidyl-amino-benzamides, camptothecin derivatives, proteins, peptides , vitamins, steroids, bronchodilators.
8. The process according to any of the preceding claims, wherein the compressed gas is selected from at least one of carbon dioxide, nitrogen, dimethyl ether, ethane, propane, and butane.
9. 9. The process according to any of the preceding claims, wherein the compressed gas is a HFA propellant qualified for human use.
10. 10. The process according to any of the preceding claims, wherein the compressed gas is selected from at least one of HFA134a and HFA227.
11. 11. The process according to claim 5, wherein the pharmaceutically active excipient is selected from at least one of a surfactant, vehicle, and lubricant. .
12. 12. The process according to claim 11, wherein the surfactant is selected from at least one of acetylated monoglycerides, perfluorocarboxylic acid, polyethylene glycol sterol esters (PEG), poly sorbitan fatty acid esters, ethylene oxide, sorbitan esters, sorbitan mono-laurate, sorbitan mono-oleate, sorbitan tri-oleate, sorbitan monopalmitate, propylene glycol, and oleic acid.
13. The process according to any of the preceding claims, wherein the suspension of the pharmaceutically active agent in a propellant or compressed gas, is processed by homogenization, using the static geometries.
14. The process according to any of the preceding claims, wherein the suspension of the pharmaceutically active agent in a propellant or compressed gas, is processed by homogenization, using a dynamic valve.
15. 15. The process according to any one of the preceding claims, wherein the suspension of the pharmaceutically active agent and the compressed or propellant gas is formed in a first agitated container, and is stored in a second agitated container after the process of molding. icronization.
16. 16. A pharmaceutically active, pharmaceutically active agent obtained by the process of any of the preceding claims.
17. 17. A pharmaceutical composition comprising a pharmaceutically active, pharmaceutically active agent obtained by the process of claim 1 6, and pharmaceutically acceptable excipients.
18. 18. A package comprising a composition according to claim 17, and instructions for its use. 9.
19. A process according to any of claims 1 to 15, wherein the pharmaceutically active pharmaceutically active agent is prepared in situ in a device for inhalation.
20. 20. The use of a micronized pharmaceutically active agent obtained by the process of claims 1 to 1 5, in formulations for inhalation. twenty-one .
21. The use of a micronized pharmaceutically active agent obtained by the process of any of claims 1 to 15, in parenteral formulations.
22. 22. An apparatus for the micronization of a pharmaceutically active agent, comprising: two stirred pressure vessels, a high pressure homogenizer, a fluid conduit interconnecting the stirred pressure vessels and the high pressure homogenizer.