CN1972670B - pharmaceutical composition - Google Patents

Abstract

A process for micronization of pharmaceutically active agents.

Description

pharmaceutical composition

The present invention relates to a process for the preparation of small particles of a pharmaceutically active agent, such as small particles having an average particle size of less than about 7 microns, to small particles of a pharmaceutically active agent prepared by said method, and to pharmaceutical compositions comprising said particles . the

The controlled production of particles of pharmaceutically active agents with a defined particle size in the low micron or submicron size range presents particular technical difficulties. When handling organic pharmaceutical compounds and active agents, conventional crushing, milling, and wet and dry milling methods are often accompanied by operational problems of varying severity or poor product quality due to, for example, heavy metal caused by pollution. the

For example, grinding techniques are often used in industrial practice to reduce the particle size of solids. However, dry grinding techniques can create unacceptable levels of dust, which require complex safety precautions to be taken during grinding operations. Furthermore, in many cases, dry milling increases the amorphous content of the granular formulation of the pharmaceutically active agent, which may be disadvantageous or lead to a diminished or even poor therapeutic effect. Dry milling often suffers from significant product loss or suffers from operational problems such as product agglomeration or equipment plugging. The latter is often observed when tacky, cohesive powders are handled in conventional dry milling equipment. The main limitations of wet grinding techniques are heavy metal contamination due to direct physical contact of the particles with the grinding media and wear of the walls. Other technical problems observed in dry and wet comminution of pharmaceutically active agents are thermal and chemical degradation, non-uniform product properties and batch-to-batch variations due to, for example, localized high temperatures of the milling equipment. the

Spray and freeze drying techniques or particle formation using supercritical fluids have been used as alternative methods for producing micronized dry powders. However, all three techniques barely meet the requirements in terms of average particle size. In addition, thermally labile molecules may be prone to decomposition or degradation when exposed to elevated temperatures (commonly used in spray drying). Similarly, an often undesired increase in the amorphous content of the formulation is often observed in spray and freeze drying, as well as in particle formation using supercritical fluids. the

There is a need to provide a robust and simple process for the industrial production of micron or submicron sized particles of refractory pharmaceutically active agents with controlled mean particle size and controlled particle size distribution (PSD) that overcomes these technical problems. The present invention provides a method that can avoid or minimize the above technical problems. the

In one aspect, the invention provides a method for the controlled micronization of a pharmaceutically active agent, e.g., having a particle size of less than about 7 microns, e.g. 6 or 6.5 micron average particle size, the method comprising (a) suspending the pharmaceutically active agent in a compressed gas or propellant, (b) treating the suspension by high pressure homogenization, and (c) decompressing the suspension from the Method to obtain dry powder. the

In another aspect, the present invention provides a method for the controlled micronization of a pharmaceutically active agent, e.g. , an average particle size of 6 or 6.5 microns, the process comprising (a) suspending a pharmaceutically active agent in a propellant, (b) processing the suspension by high pressure homogenization, and (c) obtaining a micronized pharmaceutically active agent Suspensions in propellants. the

The pharmaceutically active agent can be suspended in a compressed gas or propellant, optionally with one or more pharmaceutically acceptable excipients to form a suspension medium. the

The present invention can be practiced with various pharmaceutically active agents. The drug is preferably present in substantially pure form. The particle size of the pharmaceutical powder is reduced by the method of the present invention from a raw material having an average particle size of about 10 to 200 microns, preferably about 10 to 40 microns, 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, such as from about 0.5 to about 5.0 microns. The method of the present invention can preferably be used to micronize needle-like or needle-like crystals of high aspect ratio. Particles exhibiting this or similar morphology often cause serious operational problems in conventional milling equipment. In particular, equipment blockages or mechanical failures due to the formation of compressed large powder agglomerates within the mill are often observed. Furthermore, the method of the present invention is particularly suitable for micronization of sticky or highly cohesive drugs that often pose similar or other handling problems. the

For the purposes of the present invention, "pharmaceutically active agent" means any substance that produces a pharmacological or therapeutic effect. Examples of pharmaceutically active agents include, but are not limited to, poorly water soluble and/or thermally or chemically labile agents such as phenytoin (5,5-diphenylhydantoin), _β2 -adrenoceptor agonists Agents such as the compound of formula I in WO2000/075114 (free form or salt form or solvate form), preferably the compounds of its examples, especially the compounds of the following formula and their pharmaceutically acceptable salts,

And the compound of formula I in WO2004/016601 (free form or salt form or solvate form), the compound of preferred embodiment thereof, especially the compound of embodiment 1,3,4,5 and 79; Corticosteroid such as WO2002/ Compounds of formula I in 000679 (free form or salt form or solvate form), preferably the compounds of its examples, especially examples 3, 11, 14, 17, 19, 26, 34, 37, 39, 51, Compounds of 60, 67, 72, 73, 90, 99 and 101; antimuscarinic antagonists such as compounds of formula I (salt or zwitterion form) in PCT/EP2004/004605, compounds of preferred embodiments thereof, especially are the compounds of Examples 17, 34, 52, 54, 71, 76, 96, 114, 138, 159, 170, 190, 209, 221, 242 and 244; pimecrolimus (33 - epichloro-33-deoxy-ascomycin); N-benzoyl staurosporine as described eg in EP296110; proteins; peptides; vitamins; steroids; corticosteroids and bronchodilators. the

Other pharmaceutically active agents may include, but are not limited to, oxcarbazepine, carbamazepine, 1-(2,6-difluoro-benzyl)-1H-[1,2,3]triazole-4-carboxylic acid amide; pyrimidine Pyrimidyalaminobenzamide (pyrimidyalaminobenzamide) such as the compound of formula I in WO04/005281, preferably the compound of its embodiment, especially the compound of embodiment 92; Cox-2 selective inhibitor is for example described in WO99/11605 5-Methyl-2-(2'-chloro-6'-fluoroanilino)phenylacetic acid; a camptothecin derivative known as Compound A having the following structure:

化合物A 

Compound A

Compound A may be in free form or in the form of a pharmaceutically acceptable salt, and may be prepared as described in US Patent No. 6,424,457. Compound A may be in the form of its possible enantiomers, diastereomers and relative mixtures, its pharmaceutically acceptable salts and its active metabolites. the

9-08(Fiedler loc.cit.，p1167)商购获得的表面活性剂、全氟代羧酸(perfluorocarboxilic acid)、聚乙二醇(PEG)固醇酯例如PEG 200，300，400或600(Fiedler loc.cit.，p1348)、聚氧乙烯失水山梨醇脂肪酸酯例如Tween

20，40，60，65，80或85(Fiedlerloc.cit.PP1754)、失水山梨醇酯例如失水山梨醇单月桂酸酯、失水山梨醇单油酸酯、失水山梨醇三油酸酯或失水山梨醇单棕榈酸酯、丙二醇和油酸。任选地可以使用一种或多种表面活性剂的组合。 Pharmaceutically acceptable excipients may be surfactants. Suitable surfactants include acetylated monoglycerides such as are known and available under the trade name Myvacet

9-08 (Fiedler loc.cit., p1167) commercially available surfactants, perfluorocarboxylic acid (perfluorocarboxililic acid), polyethylene glycol (PEG) sterol esters such as PEG 200, 300, 400 or 600 ( Fiedler loc.cit., p1348), polyoxyethylene sorbitan fatty acid esters such as Tween

20, 40, 60, 65, 80 or 85 (Fiedlerloc.cit.PP1754), sorbitan esters such as sorbitan monolaurate, sorbitan monooleate, sorbitan trioleate Esters or Sorbitan Monopalmitate, Propylene Glycol and Oleic Acid. Optionally a combination of one or more surfactants can be used.

In another aspect of the invention, the excipient may be a carrier. The carrier may include one or more crystalline sugars, such as one or more sugar alcohols or polyols. Preferably, lactose or glucose can be used. the

200商购获得的胶态二氧化硅以及苯甲酸钠或它们的组合。 In another aspect of the invention, the excipient may be an anti-friction agent or an anti-sticking agent such as a lubricant. Suitable lubricants include leucine, lecithin, magnesium stearate, stearic acid, sodium lauryl sulfate, sodium stearyl fumarate, stearyl alcohol, sucrose monopalmitate (sucrosemono palinate) ), menthol, colloidal silicon dioxide, for example available under the trade name Aerosil

200 Commercially available colloidal silicon dioxide and sodium benzoate or combinations thereof.

In another aspect, excipients may include antimicrobial agents such as benzalkonium chloride, acidifying agents such as citric acid, antioxidants such as ascorbic acid, chelating agents such as disodium EDTA. the

Excipients may include one or a combination of additives. the

Details of suitable excipients for use in the methods of the invention are found in Fiedler, "Lexikonder Hilfsstoffe", 5th edition, ECV Aulendorf 2002 and "Handbook of Pharmaceutical Excipients", Rowe, Sheskey and Weller, 4th edition, 2003. description, which documents are incorporated herein by reference. the

In one embodiment of the invention, the powder of the pharmaceutically active agent used in the method of the invention is suspended in a compressed gas. The amount of active agent suspended in the compressed gas may range from 0.1% g/L (0.01% per volume) to about 250 g/L (25% per volume). the

One class of compressed gases includes _CO2 , ethane, propane, butane, dimethyl ether, and nitrogen. Combinations of compressed gases may also be used. Preferably, CO ₂ can be used.

Another class of compressed gases are propellants, including hydrofluoroalkanes (HFAs) such as 1,1,1,2-tetrafluoroethane (HFA 134a) and 1,1,1,2,3,3,3-heptafluoropropane ( HFA 227). HFA 134a and HFA 227 are safe for use on humans and, unlike chlorofluorocarbon (CFC) propellants, are not ozone depleting. Other examples of hydrofluoroalkane propellants are perfluoroethane, chlorodifluoromethane and difluoroethane. Combinations of propellants may also be used. the

For the purposes of the present invention, "suspension" means a two-phase system consisting of finely divided solids dispersed in a continuous, eg compressed, gas phase. the

Suspensions can be prepared by filling the crude material into a stirred pressure vessel. The container can be closed or hermetically sealed to allow handling under elevated pressure and compressed gas can be added to form the suspension. The operating pressure in the stirred vessel can rely on compressed gas. Typical operating pressures at room temperature according to the invention may be from 1.5 to 2 bar to about 300 bar, for example from about 10 to about 30 bar for some hydrofluoroalkanes, for example from about 55 to about 60 bar for carbon dioxide bar, for example from about 200 bar to about 300 bar for nitrogen. If the operating temperature is significantly below room temperature, for example about 0 to 5°C, the operating pressure may be about 2 to about 5 bar in the case of hydrofluoroalkanes. For the proposed process, a suitable operating temperature may be from about -30°C to about 50°C. The entire method can be carried out in a strongly closed and sealed, pressure-resistant device. the

High-pressure homogenization is a method for preparing o/w, w/o, s/o/w or w/o/w emulsions, solid-lipid nanoparticles, stable suspensions and dispersing Prior Art for Deagglomeration of Solids in Aqueous Suspensions. In conventional high-pressure homogenization, a solid or liquid-in-liquid suspension is first formed, which is then processed in a homogenization unit at elevated pressures of up to several thousand bar. the

According to the present invention, high-pressure homogenization of compressed gas suspensions may be a method for producing micronized pharmaceutically active agent particles from coarse feedstocks having an average particle size of from about 10 to about 200 microns, for example having a particle size of less than about 7 microns, such as about Effective techniques for defining product particle size particles of 1 or 2 to about 3, 4, 5, 5.5, 6 or 6.5 microns. By closely controlling the process parameters characteristic of the proposed micronization process, it is possible to effectively control the average particle size and particle size distribution of the product, which can be prepared as a dry powder or as a compressed gas suspension after depressurizing the unit. reward. Homogenization pressure, suspension density and solids concentration, operating temperature, choice of interaction geometries and total number of passes through the device (which largely correspond to total processing time) or these main operations can be used The combination of parameters to closely control the product quality. The method of the invention can be used to produce a narrow particle size distribution in the size range of less than 7 microns, for example about 1 or 2 to about 3, 4, 5, 5.5, 6 or 6.5 microns. A size range of about 1 to about 5 microns may be particularly suitable for use in therapeutic inhalation formulations, for example in dry powder inhalers (DPI) or in metered dose inhalers (MDI) or pressurized metered dose inhalers (pMDI). the

In another aspect, the present invention provides a device for micronizing pharmaceutically active agents, which includes one or two stirred pressure vessels, a high-pressure homogenizer, and the one or two stirred pressure vessels connected to the high-pressure homogenizer. Fluid conduits for chemical units. Stirred pressure vessels for the preparation of stock suspensions may be connected to a line supplying sufficient compressed gas, which itself may be connected to one or several dip-tubes or gas cylinders or containing Balance tank connection for pressurized gas. The desired operating pressure can be set and controlled by pumping compressed gas until the set point is reached. The high pressure homogenization unit may include an intensifier pump and one or more interaction chambers in which particles due to particle-particle and particle-wall collisions, shear forces and fluid cavitation (fluid cavitation) and particle size reduction or micronization. The booster pump, the line of the booster pump connecting the stirred pressure vessel and the high-pressure homogenization unit may be cooled to avoid the accumulation of compressible gas bubbles in the inlet portion of the booster pump. The high pressure homogenization unit can include an additional booster pump. Homogenization may be achieved by adjusting a determined pressure drop across a high pressure gap or valve of the static geometry to be less than, for example, 1500 bar, for example to 200, 500, 750, 1000 or 1500 bar. A dynamic high pressure homogenizing valve can be used. The valve overcomes some of the major disadvantages of static interaction geometries, such as clogging at elevated solids concentrations. In the event of clogging, the valve is opened and the required pressure drop can be readjusted manually or automatically using suitable pressure control equipment. the

Interaction chambers can provide stream splitters and impact chambers. The stream of compressed gas, non-solvent containing solid particles and optional pharmaceutically acceptable excipients can be divided into two sub-streams in a stream splitter, and the two streams can be recombined in an impingement chamber. The main forces that lead to the micronization of solid particles in a high-pressure homogenizer may be shear, turbulence, acceleration and velocity changes in the flow direction; impact forces, including the collision of the particles being processed with the solid elements of the homogenizer and the collisions between particles; and cavitation forces, including changes in velocity increase associated with changes in pressure decrease, and turbulent flow. Other forces may be friction, ie grinding due to friction. the

If micronization is achieved by releasing pressure across a defined opening such as a high pressure valve, the main forces leading to micronization may be cavitation, shear, turbulence, impact (including contact between the particles being processed and the homogenizer). Collisions of solid elements and collisions between the particles being processed) and friction. the

In one embodiment of the invention, the process may be carried out in an apparatus comprising a stirred pressure vessel and a high pressure homogenization unit. The outlet of the homogenizer can be connected to a stirred pressure vessel containing the suspension. The treated suspension is reintroduced into the container containing the untreated suspension. The total processing time can be used to control the average particle size of the granular product or the particles in the compressed gas suspension. Operation of the high pressure homogenizer can be started after a suspension of active agent in compressed gas has been formed in the pressure vessel. A homogenizer can be operated as follows: A homogenizer with an inlet and an outlet relies on a high pressure pump designed to supply the product stream with the required pressure at a constant rate. The pump delivers product at constant pressure through fixed geometry microchannels defined within the interaction chamber. Both particle size reduction and homogenization of the suspension previously formed in the stirred pressure vessel take place within the interaction chamber. The jet interaction chamber assembly utilizes three different forces: shear, impact and cavitation. High pressure homogenization provides a fairly uniform particle size reduction such as micronization and deagglomeration of the pharmaceutically active agent. the

In another embodiment of the invention (cf. FIG. 1 ), the apparatus may comprise two stirred pressure vessels (10) with a stirrer (16) and a high pressure homogenization unit (12). The inlet and outlet of the homogenizer (12) can be connected with two stirring pressure vessels (10) through high-pressure pipes (15), and all connections can be made through manual or automatic operation of high-pressure three-way valve (11) or high-pressure valve (17) are closed separately. A suspension of raw material can be formed in one of two stirred pressure vessels, after which homogenization can begin. The outlet of the homogenizer can be connected to a second pressure vessel which is initially empty. If the first stirred pressure vessel is empty and the second stirred pressure vessel contains the homogenized suspension, the valve can be operated e.g. to readjust the second stirred pressure vessel containing the homogenized suspension Pass the contents through the direction of the homogenizer and collect the twice homogenized suspension in the first stirred pressure vessel. An advantage of this embodiment of the invention is the more effective control of the average particle size by controlling the residence time controlled by the number of passes through the apparatus. In this embodiment, the average particle size is controlled by the total number of passes through the homogenizer, typically about 3 to 25 passes to achieve less than about 7 microns, such as about 0.1 or 0.5 to about 1, Average particle size of 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 geometry and dynamic high pressure relaxation valves can be used for homogenization. the

。Microfluidizer

的装置和操作方法在美国专利No.4,533,254和美国专利No.4,908,154中有进一步的描述，将这两篇文献引入本文作为参考。也可以用隔膜泵代替原来的高压活塞泵与Microfluidics M-110Y Microfluidizer相互作用几何结构相连接。 A high-pressure homogenizer characterized by a static interaction geometry can be, for example, a closed system such as the Microfluidics Model M-110Y Microfluidizer

. Microfluidizer

The apparatus and method of operation are further described in US Patent No. 4,533,254 and US Patent No. 4,908,154, both of which are incorporated herein by reference. Diaphragm pumps can also be used to replace the original high-pressure piston pumps with Microfluidics M-110Y Microfluidizer The interacting geometry is connected.

The dynamic high-pressure homogenizer can be, for example, a system comprising a high-pressure booster pump such as a LEWA LDE/1VM211S membrane dosage pump (membrane dosage pump) and a suitable high-pressure valve with an adjustable valve port or opening, and the valve seat and valve The body is preferably made of a cavitation resistant material such as zirconia, tungsten carbide or a material of similar nature. The material of the valve needle or plunger may preferably be made of a harder material than the valve seat. Dynamic high pressure valves can be operated manually or automatically through the use of suitable downstream pressure control means. the

In another aspect of the present invention, the method of the present invention provides an average particle diameter obtained by depressurizing the system having a particle size of less than about 7 microns, such as about 1 or 2 microns to about 3, 4, 5, 5.5, 6 or 6.5 microns. Particle-sized dry granules of pharmaceutically active agents free of solvents and moisture. The pharmaceutically active agent powder particles with a size of about 1 to about 5 microns can be used in dry powder inhaler (DPI) formulations without any further processing. the

In another aspect of the invention, the method provides finely dispersed in a human-acceptable propellant to form a suspension having , 5, 5.5, 6 or 6.5 micron average particle size of the pharmaceutically active agent. Suspensions comprising particles of about 0.5 to about 5 micron in size can be filled directly into suitable inhalation devices and then used in metered dose inhaler (MDI) or pressurized metered dose inhaler (pMDI) formulations without any further processing middle. the

An advantage of the present invention is that suspensions of pharmaceutically active agents in propellants or compressed gases can be micronized in a single step process without any additional post-processing steps. Dry powders of the pharmaceutically active agent are obtained after decompression of the compressed gas or propellant, which can be used in inhalation formulations without any further treatment. The method is easy to apply and is performed under mild and inert conditions. The method of the present invention avoids many technical problems such as the use of large amounts of solvents, the increase of amorphous content, contamination and abrasion. the

In another aspect, the present invention provides a pharmaceutical composition comprising micronized particles of a pharmaceutically active agent obtained by the method of the present invention and a pharmaceutically acceptable excipient. The aforementioned pharmaceutically acceptable excipients include surfactants, carriers and/or lubricants, and can be used in the manufacture of pharmaceutical compositions, for example in the form of solid dosage forms such as capsules, tablets or sachets. the

In another aspect, the present invention provides micronized particles of a pharmaceutically active agent for use in ointments or eye drops. the

In another aspect, the present invention provides micronized particles of a pharmaceutically active agent for use in parenteral formulations. the

In another aspect, the present invention provides micronized particles of a pharmaceutically active agent for use in oral formulations. the

In another aspect, the present invention provides micronized particles of a pharmaceutically active agent for use in topical formulations. the

In another aspect, the present invention provides a kit comprising the composition of the present invention and instructions for use. the

The structure and advantages of the present invention will become more apparent with reference to the following non-limiting description of various embodiments of the invention, together with the accompanying drawings. the

The following are non-limiting descriptions by way of example. the

Example 1

Pimecrolimus was suspended in propellant HFA227 (1,1,1,2,3,3,3-heptafluoropropane) and homogenized in a Microfluidics Microfluidizer M-110Y ^™ . Using one pressure vessel, the total processing time was 60 minutes. The operating pressure in the stirred vessel is about 3 bar, the maximum homogenization pressure is about 500 bar. The inlet temperature was 0°C and the outlet temperature was about 30°C. After 60 minutes of treatment, the pressure vessel was depressurized and the dry product powder was analyzed using standard off-line analysis tools.

Example 2

Pimecrolimus was suspended in propellant HFA227 (1,1,1,2,3,3,3-heptafluoropropane) and homogenized in a Microfluidics Microfluidizer M-110Y ^™ . Using two pressure vessels, the average particle size of the product is controlled with the number of passes through the equipment. The operating pressure is about 3 bar and the maximum homogenization pressure is about 500 bar. The inlet temperature was about 0°C and the outlet temperature was about 30°C. After the 10th pass, the system was depressurized and the dry product powder was analyzed using standard off-line analysis tools.

Example 3

Pimecrolimus was suspended in propellant HFA134 (1,1,1-trifluoroethane) and homogenized across a high pressure valve under tightly controlled pressure drop. Using one pressure vessel, the total processing time was 180 minutes. The operating pressure was about 10 bar and the maximum homogenization pressure was about 750 bar, so a pressure drop of about 740 bar across the relief valve was used. The inlet temperature was about 0°C and the outlet temperature was about 30°C. After 180 minutes of treatment, the pressure vessel was depressurized and the dry product powder was analyzed using standard off-line analysis tools. the

The pimecrolimus particles obtained in Examples 1, 2 and 3 were redispersed in water containing about 0.1% Tween 20 to form a suspension, then sonicated, usually for 60 seconds, after which the particle size was diffracted with a Sympatec Helos laser The analyzer measures particle size. The results of particle size measurement are shown in Table 1. In the run described in Example 1, with a treatment time of 60 minutes and in a continuous manner, the average particle size by volume ( _X50 ) was 2.7 microns and _X90 was 11.4 microns. In the run described in Example 2, samples were processed in batches and results were reported after 10 passes. In this case, the X ₅₀ is 5.3 (5.5) microns and the X ₉₀ is 19.2 (20.6) microns.

Table 1

Running number/measurement number Processing method X₁₀[μm] X₅₀[μm] X₉₀[μm] 1/1 60 minutes 0.9 2.7 11.4 1/2 60 minutes 0.9 2.7 11.7 2/1 10 times 1.1 5.5 20.6 2/2 10 times 1.0 5.3 19.2 3/1 180 minutes 0.89 2.13 6.07

Example 4

Phenytoin (5,5-diphenylhydantoin) was suspended in propellant HFA134 (1,1,1-trifluoroethane) and homogenized across a high pressure valve under tightly controlled pressure drop. Using one pressure vessel, the total processing time was 240 minutes. The operating pressure is about 10 bar and the maximum homogenization pressure is about 750 bar. The inlet temperature was about 0°C and the outlet temperature was about 30°C. After 240 minutes of treatment, the pressure vessel was depressurized and the dry product powder was analyzed using standard off-line analysis tools. The particle size distribution of the phenytoin microparticles produced in Example 4 is shown in FIG. 2 . the

Example 5

Phenytoin (5,5-diphenylhydantoin) was suspended in carbon dioxide and homogenized across a high pressure valve under tightly controlled pressure drop. Using one pressure vessel, the total processing time was 240 minutes. The operating pressure is about 57 bar and the maximum homogenization pressure is about 800 bar. The inlet temperature was about 0°C and the outlet temperature was about 30°C. After 240 minutes of treatment, the pressure vessel was depressurized and the dry product powder was analyzed using standard off-line analysis tools. The particle size distribution of the phenytoin microparticles produced in Example 5 is shown in Figure 3. the

The phenytoin particles obtained in Examples 4 and 5 were redispersed in water containing about 0.1% Tween20 to form a suspension, and then ultrasonically treated, usually for 60 seconds, after which the particle size was measured with a Sympatec Helos laser diffraction particle size analyzer. The results of particle size measurement are shown in Table 2. In the runs described in Examples 4 and 5, with a treatment time of 240 minutes and in a continuous manner, the mean particle sizes by volume (X ₅₀ ) were 1.48 and 1.46 microns, and X ₉₀ were 3.57 and 3.02 microns, respectively.

Table 2

Running number/measurement number Processing method X₁₀[μm] X₅₀[μm] X₉₀[μm] 4 240 minutes 0.72 1.48 3.57 5 240 minutes 0.73 1.46 3.02

Figure 2 is an example of phenytoin microparticles produced using the method of the present invention. In Example 4, the particle size distribution measured by a Sympatec Helos laser diffraction particle size analyzer is as follows: X ₁₀ =0.72 μm, X ₅₀ =1.48 μm, X ₉₀ =3.57 μm.

Figure 3 is an example of phenytoin microparticles produced using the method of the present invention. In Example 5, the particle size distribution measured by a Sympatec Helos laser diffraction particle size analyzer is as follows: X ₁₀ =0.73 μm, X ₅₀ =1.46 μm, X ₉₀ =3.02 μm.

Claims (24)

1. with the micronized method of forms of pharmacologically active agents, it comprises

(a) forms of pharmacologically active agents is suspended in the Compressed Gas,

(b) by the high pressure homogenize handle this suspensoid and

(c) the decompression back obtains dry powder,

The binary system that wherein said suspensoid is made up of the solid that is dispersed in the fine segmentation in the continuous gas phase.

2. with the micronized method of forms of pharmacologically active agents, it comprises

(a) forms of pharmacologically active agents is suspended in the gas propellant,

(b) by the high pressure homogenize handle this suspensoid and

(c) obtain the suspensoid of micronized forms of pharmacologically active agents in the gas propellant,

The binary system that wherein said suspensoid is made up of the solid that is dispersed in the fine segmentation in the continuous gas phase.

3. method according to claim 1 and 2 is wherein had about 0.1 to about 7.0 microns particle mean size by the micronized forms of pharmacologically active agents of described method.

4. method according to claim 1 and 2 is wherein had about 0.5 to about 5.0 microns particle mean size by the micronized forms of pharmacologically active agents of described method.

5. method according to claim 1, wherein the suspensoid that is formed by forms of pharmacologically active agents and Compressed Gas comprises one or more pharmaceutically useful excipient.

6. method according to claim 1 and 2, wherein forms of pharmacologically active agents poorly soluble and/or chemical or thermally labile in water.

7. method according to claim 1 and 2, wherein forms of pharmacologically active agents is selected from pimecrolimus; 5-[(R)-2-(5,6-diethyl-indane-2-base is amino)-1-hydroxyl-ethyl]-the 8-hydroxyl-(1H)-quinoline-2-one-; 3 methyl thiophene-2-carboxylic acid (6S; 9R; 10S, 11S, 13S; 16R; 17R)-and 9-chloro-6-fluoro-11-hydroxyl-17-methoxycarbonyl-10,13,16-trimethyl-3-oxo-6; 7; 8,9,10; 11; 12,13,14; 15; 16,17-ten dihydros-3H-cyclopenta [α] phenanthrene-17-base ester; N-benzoyl staurosporin; oxcarbazepine; carbamazepine; 1-(2,6-two fluoro-benzyls)-1H-[1; 2,3] triazole-4-carboxylic acid amide; the cox-2 inhibitor; pyrimidylaminobenzamderivatives; camptothecin derivative; protein; peptide; vitamin; steroid; at least a in the bronchodilator.

8. method according to claim 1, wherein Compressed Gas is selected from least a in carbon dioxide, nitrogen, dimethyl ether, ethane, propane and the butane.

9. method according to claim 1, wherein Compressed Gas is the HFA propellant that can be used for the people.

10. method according to claim 2, wherein the gas propellant is the HFA propellant that can be used for the people.

11. method according to claim 1, wherein Compressed Gas is selected from least a among HFA134a and the HFA227.

12. method according to claim 2, wherein the gas propellant is selected from least a among HFA134a and the HFA227.

13. method according to claim 5, wherein pharmaceutically useful excipient are selected from least a in surfactant, carrier and the lubricant.

14. method according to claim 13, wherein surfactant is selected from least a in acetylated monoglycerides, perfluorinated substituted carboxylic acids, Polyethylene Glycol sterol ester, polyoxyethylene sorbitan fatty acid ester, sorbitan ester, sorbitan mono-laurate, sorbitan monooleate, sorbitan trioleate, anhydrous sorbitol monopalmitate, propylene glycol and the oleic acid.

15. method according to claim 1, wherein the suspensoid of forms of pharmacologically active agents in Compressed Gas is to be that the high-pressure homogenizer of feature is handled in order to static state interaction geometry.

16. method according to claim 1, wherein the suspensoid of forms of pharmacologically active agents in Compressed Gas is to handle with the high-pressure homogenizer with dynamic high-pressure graduated release valve.

17. method according to claim 1, wherein the suspensoid of forms of pharmacologically active agents and Compressed Gas forms in first stirred vessel and is stored in after micronization process in second stirred vessel.

18. the micronized forms of pharmacologically active agents that obtains with the method for claim 1 or 2.

19. a pharmaceutical composition, it comprises the micronized forms of pharmacologically active agents and the pharmaceutically useful excipient of claim 18.

20. a packaging kit, it comprises the compositions and the operation instructions of claim 19.

21. method according to claim 2, wherein said suspensoid is filled in the suction apparatus.

22. the micronized forms of pharmacologically active agents that obtains with the method for claim 1 or 2 sucks purposes in the preparation in preparation.

23. the purposes of micronized forms of pharmacologically active agents in the preparation parenteral formulation that obtains with the method for claim 1 or 2.

24. according to any described method in the claim 1,5,8,9,15,16 or 17, wherein said Compressed Gas is the gas propellant.

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