JP2009533104A - Metering device - Google Patents

Abstract

  A metering device (1) for metering powder (2) as a spray (3) is disclosed. The metering device has a duct (5) so that the gas can be metered through the duct by gas pressure to deagglomerate the powder. The duct is angled at least about 90 ° at the turning portion (12) and / or is turned in two opposite directions at the bifurcated portion (15), resulting in powder Impinges on the solid surface (14) to cause deagglomeration of the powder.

Description

  The present invention relates to a metering device for metering a powder according to the preamble of claim 1.

  Drugs administered via metered dose devices, particularly inhalers, are optimally targeted to specific sites in the respiratory system. These sites include intranasal passages, throat (pharynx) and various locations in the lung, such as bronchi, bronchioles and alveolar regions. Whether a drug can be administered to a target area depends, among other things, on the aerodynamic size of the particles. As currently believed to be understood, particles with an aerodynamic diameter of less than 2 μm are considered potentially optimal for deposition within the alveolar region of the lung. Particles with an aerodynamic diameter of 2 μm to about 5 μm may be more suitable for administration to the bronchiole or bronchial region. Particles with an aerodynamic size range of greater than 6 μm, more preferably greater than 10 μm are suitable for administration to the laryngeal region, throat, or intranasal passage.

  In most cases, it is desirable to achieve a high inhalable rate and high dosing efficiency, i.e., a high rate of reaching the desired area, particularly in the lung. This depends on various factors, in particular the nature of the resulting spray plume, such as the plume propagation speed, particle size and distribution, the fraction of fine particles, the proportion of gas, and the like. In the present invention, the desired spray plume properties are preferably small particle size, high proportion of drug particles with a diameter of 6 μm or less, low propagation speed, long spray generation duration, and / or possible A long duration of inhalation and / or a small amount of gas required to meter a certain amount of powder.

  In particular, the present invention relates to a dry powder inhaler for administering a drug to the lung. Many dry powder inhalers are on the market or have been proposed. There are two major types: passive and active. In a passive inhaler, all of the energy required to deagglomerate the powder and transfer the powder to the lungs is obtained by user or patient breathing. In an active inhaler, there is an additional energy source that helps to deagglomerate the powder.

  Most powder inhalers are passive, where the powder is inhaled by the patient without the aid of an additional energy source. The problem with passive inhalers is that the inhalable fraction or proportion of powder that actually enters the lungs is primarily dependent on the patient's breathing. The deagglomeration of the powder and hence the inhalable fraction is a function of the flow rate of the inhalation air through the inhalation device, and therefore varies greatly from patient to patient.

  Dry powder inhalers are subdivided into single dose inhalers and multiple dose inhalers. Multi-dose inhalers are further subdivided into pre-metered inhalers in which doses are stored individually and metered inhalers in which powder doses are metered in the inhaler.

  Multi-dose pre-metered inhalers have the advantage that individual doses are metered under strict factory conditions and the powder can be isolated very easily from the atmosphere. In many applications, the active duct powder is mixed with a carrier, such as lactose, which tends to absorb moisture from the atmosphere, making them difficult to stick together and deagglomerate.

  The present invention particularly relates to an active, gas-powered, pre-metered multi-dose or single-dose device for metering a powder containing a drug or a powder comprising a drug.

  WO 92/127799 (A1), which forms the starting point of the present invention, discloses a pre-metering device that converts a fluid flow into a fine particle size spray, in which an annular The flow is caused by a velocity gradient in the flow that is sufficient to break the flow through the stem filled with the powder, due to the shear forces between the components of the flow, to the state of the spray. A chevron duct extends from the exit of the stem to the exit orifice of the spray head.

International Publication No. 92/12799 (A1) Pamphlet

  However, the known devices are not optimal for deagglomerating the powder or creating a slow spray plume with the desired properties.

  It is an object of the present invention to provide an improved metering device that provides good deagglomeration of the powder.

  This object is achieved by a metering device as defined in claim 1. Preferred embodiments are the subject-matter of the dependent claims.

  One major aspect of the present invention is that the duct is angled at least about 90 ° at the turning portion and / or is turned in two opposite directions at the bifurcated portion so that the powder is solid. It is intended to cause powder deagglomeration by colliding with the surface (impact or deflecting surface). As a result of the impact of the powder particles against the surface or wall, a surprisingly good deagglomeration of the powder particles occurs. The explanation is that a very large shearing force is generated by the collision or deflection of the powder particles. The use of a turning portion and / or a bifurcated portion for collision and powder deagglomeration according to the present invention has not been recognized in the prior art.

  According to a preferred embodiment, the duct has a number of turning portions and / or a number of bifurcated portions to further promote powder deagglomeration. In particular, the duct impinges the powder against the two solid surfaces or multiple solid surfaces or surface portions of the duct wall in the vicinity of the turning portion and / or the bifurcated portion, particularly for powder deagglomeration. Designed to be

  Preferably, the ducts are alternately bent in opposite directions and / or angled. This makes it possible to obtain a compact design with very good powder deagglomeration.

  According to a preferred embodiment, the duct is a capillary. This results in a very effective collision of the powder particles against the solid surface and thus a good powder deagglomeration. Preferably, the duct is located at the mouthpiece inlet and / or exits into the mouthpiece with no flow restriction behind the duct.

  Preferably, the duct has a flat cross section. The powder is pushed into the duct by the pressurized gas, causing the powder to deagglomerate and produce a spray containing fine powder particles. The ratio of the longest side to the shortest side of the flat cross section of the duct is at least 2.0. Surprisingly, very good deagglomeration and finer particles can be achieved with a small amount of gas, especially for a given volume or mass of powder than with a circular or pseudo-circular duct. This effect can be explained by providing a longer perimeter (perimeter) for a given cross-sectional area than for a cross-section where a flat cross-section is not desired. As a result of this long perimeter, a wide duct surface in contact with the gas and powder is obtained, so that it is high without changing the cross-sectional area (hydraulic diameter), i.e. without significantly changing the flow resistance or mass flow. Good deagglomeration can be achieved due to shear forces.

  Preferably, the ratio of the longest side to the shortest side of the flat cross section is 3 to 50, most preferably about 5 to 30. Thus, a high power of a powder with good deagglomeration as a spray containing a small powder particle size can be achieved with a relatively low gas pressure, a relatively low gas volume and a relatively low gas flow rate. The metering device produces a plume deagglomerated dry powder with a high inhalable fraction and with the desired spray plume properties.

  It has been found that when the average particle size of the fine powder is less than 5 μm, a substantially rectangular duct of typically 75 μm × 1500 μm works well. When the average particle diameter of the powder exceeds 30 μm, a duct of 200 μm × 1500 μm typically works well. Non-circular ducts should preferably have a hydraulic diameter of 20 μm to 1000 μm, depending on the particle size of the powder. The duct may be made of any drug compatible material, such as plastic or metal. Two or more non-circular ducts may be used in parallel.

  The duct preferably has a hydraulic diameter of at least 5 or 10 in length, and preferably has a hydraulic diameter of 10 to 60 (the hydraulic diameter is obtained by dividing four cross-sectional areas by the duct circumference. Defined ratio). For a given pressure, the longer the non-circular duct, the slower the powder administered to the patient. However, if the duct is too long, the speed in the storage and mixing chamber may be reduced to such an extent that the mixing chamber is not emptied.

  In particular, it is possible to push the powder into the duct with a gas pressure of less than 300 kPa to deagglomerate the powder and produce a fine particle size spray. Thus, optimal spray plume characteristics, particularly low propagation speeds, can be generated.

  It is advantageous to minimize gas and powder outlet velocities to minimize powder impingement in the mouth and upper airways. However, the higher the exit speed, the better the powder crushing or deagglomeration. One solution to this is gas at the duct outlet by using two or more impinging ducts or a powder jet that impinges preferably at an angle of 30 ° to 180 °, preferably at an angle of 90 ° to 150 °. And slow the outlet speed of the powder mixture. This is another aspect of the present invention. In particular, a large number of at least two powder spray jets are struck, i.e. such powder spray jets hit each other to reduce the spray propagation speed and / or deagglomerate the powder. This supports the desired spray plume characteristics described above. As a variant, the flow of gas and powder at the outlet of the duct may be decelerated using a diffuser with an increasing cross section.

  Any gas can be used. For example, liquefied gases such as HFA 134a and HFA 227 can be used. In such an instrument, the gas is stored in a pressurized canister containing a metering valve with means for connection to a powder reservoir. As a variant, for example, the atmosphere may be pressurized using a piston cylinder device, bellows or any other gas pump. With such devices, the user or patient needs to prepare or prime the metering device prior to use. For single dose devices, a pre-pressurized canister with compressed air may be used.

The amount of gas required to completely empty the storage chamber (reservoir) and / or the mixing chamber depends on the volume or mass of the powder. When the mass of the powder is from 0.1 mg to 50 mg, an amount of gas from 0.2 mg to 300 mg is required. For example, in the case of 5 mg powder having an average particle size of 4 μm, when the mass of air is about 20 mg to 60 mg, compressed air of 100 kPa to 200 kPa needs 10 cm ³ to 20 cm ³ . In the case of a coarse powder, the energy required for deagglomeration is small, so that typically the amount of gas required in a low pressure state below 100 kPa gauge pressure is small.

The volume of the storage chamber (reservoir), and optionally the mixing chamber, required to expel all powder depends on the volume or mass of the powder. Such volume is preferably required to be from 0.002 cm ³ depending on the dose of the powder is 0.2 cm ^3. The higher the dose of powder, the larger the reservoir / mixing chamber needs to be. For example, if the powder dose is 5 mg, a volume of 0.015 cm ³ to 0.03 cm ³ is required for complete mixing. Preferably, the ratio of chamber volume (storage chamber volume and optional mixing chamber volume) to powder volume should be between 1.2 and 4.

  The reservoir should preferably be cylindrical with no sharp edges. The reason is that these sharp edges can attract powder deposits. The one or more gas inlets should preferably be positioned so that the gas sweeps all of the chamber surface and prevents powder from depositing on the chamber surface. Preferably, the inlet should be located near the end of the chamber farthest away from the outlet, i.e. near the non-circular duct. The relative positions of the inlet and outlet of the reservoir and mixing chamber are such that the gas powder mixture forms a turbulent vortex in the chamber to maximize deagglomeration, or a smooth non-turbulent flow is achieved in the chamber. It is good to set by way.

  Preferably, the surface area after the non-circular duct is minimized to minimize powder adherence or loss to the surface. The present invention has the advantage that little or no powder is retained in the device after inhalation and therefore the weighed mass and the dispensed (delivered) mass are approximately the same.

  Preferably, the powder is forced into a duct or nozzle or the like with a relatively low gas pressure of less than 300 kPa, thereby causing the powder to deagglomerate and / or produce a spray. Experimental results show that such low pressure is sufficient to achieve good deagglomeration and is optimal to achieve slow spraying.

  Other aspects, advantages and features of the present invention will become apparent from the appended claims and the following detailed description of the preferred embodiments.

  In the drawings, the same reference numerals are used for the same or similar components, and in this case, the same property, or similar properties, features, or advantages are realized even if the repeated description is omitted. Or achieved, or feasible, or achievable. Furthermore, the features and aspects of the different embodiments may be combined in any desired manner and / or used in other metering devices or methods of metering the powder as desired.

  FIG. 1 shows a metered dose device 1 of the present invention in a schematic partial cross-sectional view and not to scale for illustrative purposes. The metering device 1 is in particular gas-operated. Preferably, the metering device 1 is an inhaler for a user or patient (not shown), in particular a dry powder inhaler.

  The metering device 1 is designed to meter powder 2, which powder comprises in particular at least one powder or consists of at least one drug. The powder 2 may be a pure drug or a mixture of at least two kinds of drugs. In addition, the powder 2 may contain at least one other substance, in particular a carrier such as lactose.

  Preferably, the average diameter of the powder particles is about 2 μm to 7 μm, in particular 6 μm or less. This is especially true when the powder 2 does not contain any carrier such as lactose, for example.

  When powder 2 contains a carrier, such as lactose, and at least one drug, powder 2 may have a particle size of 20 μm to 300 μm, in particular about 30 μm to 60 μm. However, as a result of the deagglomeration described in detail below, even in this case, a spray 3 having a small particle size of, for example, about 10 μm or less is obtained. In particular, during deagglomeration, the drug can be separated from the carrier, so when the metering device is used as an inhaler, the drug is inhaled mainly due to the small particle size of about 2 μm to 6 μm, Large carriers will be swallowed. Alternatively or additionally, crushing or cracking of the carrier is possible during deagglomeration.

  The above mentioned and below mentioned diameters should be understood as most medium aerodynamic diameters and / or can be applied to the particle size or fraction of the spray 3 particles.

  FIG. 1 very schematically shows a metering device 1 when metering a powder 2 as a spray 3. The spray 3 includes fine particles (powder particles), that is, preferably has a fine particle size of 6 μm or less. In particular, the spray 3 has the desired spray plume characteristics described above.

  The metering device 1 is adapted to receive a storage device 4 for storing the powder 2 or has a storage device 4 for storing the powder 2. The storage device 4 may be integrated into the metering device 1 or may be part of the metering device 1. As a variant, the storage device 4 may be a separate part, in particular a container, a cartridge, a blister or the like, which can be inserted into the metering device 1 or connected to the metering device 1 and optionally exchangeable.

  The metering device 1 or the storage device 4 preferably has a duct 5 and the powder 2 is metered through the duct 5 to deagglomerate the powder 2 and / or to form a spray 3. The

  The duct 5 preferably has a nozzle or a stop (not shown) provided at the outlet 6.

  The metering device 1 preferably uses pressurized gas to push the powder 2 into the duct 5 to deagglomerate the powder 2 and / or produce a fine particle size spray 3. Preferably, the dosing device 1 has means for providing a pressurized gas, in this embodiment preferably an air pump which can be actuated as indicated by the handle or actuator 8 or which can be operated manually. Specifically, the air pump 7 is made of a bellows or formed by a bellows. However, the air pump may be a piston cylinder device. Instead of the air pump 7, the means for providing the pressurized gas is a capsule, container or the like containing pressurized or liquefied gas for powering the metering device 1, ie for metering the powder 2 as desired. There may be.

  The air pump 7 can provide a gas pressure of less than 300 kPa, in particular a gas pressure of about 50 kPa to 200 kPa. This is preferably sufficient to operate the dosing device 1. When using a container containing liquefied gas or pressurized gas, the range of gas pressure may be from 100 kPa to about 700 kPa. In this case, before supplying the gas into the storage device 4, in particular into its storage chamber 10, this pressure may be reduced or suppressed to a preferred pressure range, for example by means of regulation or control means 9. Optional adjustment or control means 9 include, in particular, valves, flow restrictors, capillaries, which regulate, throttle (suppress) and / or control gas flow rate and / or gas pressure. Etc.

  Preferably, all pressure values stated in the specification and claims are gauge pressures, i.e. pressure differences. All pressure values relate to the pressure in a gas storage means, for example a container with pressurized or liquefied gas, or the pressure provided by the air pump 7 or in the chamber 10 and / or in the duct 5 Regarding working pressure.

  The metering device 1 or the storage device 4 preferably has at least one storage chamber 10 containing a single dose of powder 2 to be metered in a single metering operation.

  For metered administration, gas is supplied to the storage chamber 10 / powder 2 under pressure via a gas source or inlet 11 or the like. Preferably, the inlet 11 is connected to or connectable to means for providing a pressurized gas, ie in particular the air pump 7 or the regulation or control means 9. The gas causes a respective flow in the storage chamber 10 to push at least essentially all the powder 2 into the duct 5.

  As gas is supplied to the storage chamber 10, each dose of powder 2 is metered with the gas, ie, pushed into the duct 5 in a mixed state with the gas, and spray 3 as shown in FIG. Released as.

  Preferably, the storage device 4, in particular the chamber 10, does not have sharp edges, corners, etc., and has a smooth contour, so that the gas sweeps the entire chamber surface and powder 2 Can be prevented from depositing on the surface of the chamber, and the complete release of the powder 2 can be ensured or the complete release of the powder 2 can be made possible. In particular, the gas inlet 11 is arranged on the opposite side of the duct 5 with respect to the axial direction or the outlet direction.

  The storage device 4 may comprise only one storage chamber 10 for a single dose, in which case the storage device 4 is dedicated to a single dose, or the storage device 4 can be used for multiple storages. It may have a cavity 10 and thus contain a number of doses of powder 2 that can be metered one after the other.

  The gas supply provided by the metering device 1, in particular by the air pump 7, is preferably in a suitable manner, only temporarily when a metering operation is required, in the respective storage device 4 or storage chamber 1, In particular, each gas inlet 11 can be coupled. For example, by pushing the penetrating element, the coupling element, etc., in particular such elements are inserted through the respective sealing elements, diaphragms, membranes, wall parts etc. to open or allow the gas supply to the respective storage chamber 10 Thus, the gas inlet 11 may be fluidly coupled to the respective storage chamber 10.

  FIG. 2 is an enlarged cross-sectional view of FIG. 1 and in particular an enlarged cross-sectional view of the duct design of the metering device 1 described in FIG. In this case, the duct 5 is angled at least about 90 ° at the at least one turning portion 12. In this embodiment, the duct has a number of turning portions 12.

  The powder 2 that has flowed into the duct 5 at the inlet 13 collides with the solid surface (collision region) 14 at each turning portion 12 as shown in FIG. In this embodiment, the ducts 5 are alternately bent in opposite directions and / or preferably angled. The duct 5 has a total of six impact points or regions 14 in the embodiment of FIGS. The duct 5 is preferably angled approximately 90 ° at each turning portion 12.

  In FIG. 3, the duct 5 preferably follows a serpentine pattern. However, other designs are possible, in particular folding designs.

  The deagglomeration of the powder 2 is preferably assisted or further facilitated by the powder 2 being preferably deagglomerated through the thin duct 5 or the flat duct 5.

  FIG. 3 shows another embodiment of the duct 5 of the metering device 1 of the present invention. In this case, the duct 5 is additionally or alternatively used as a reservoir for the powder 2 (storage chamber 10). In this case, a separate storage chamber 10 or an additional storage chamber 10 is not necessary. Instead, the duct 5 is set to allow sufficient mixing of the gas and the powder 2 so that sufficient deagglomeration of the powder 2 can be achieved.

  Preferably, the first part located adjacent to the inlet 13 of the duct 5 forms the storage chamber 10 and / or is filled with the powder 2.

  In the embodiment of FIG. 3, ten turning portions 12 and thus ten impact points or solid surfaces 14 are formed.

  FIG. 4 shows another embodiment, which preferably has a zigzag duct shape or a staggered duct shape. In this case, the duct 5 has at least two turning portions 12, the duct 5 being angled greater than 90 °, in particular angled greater than 135 °, preferably about 150 °. It is angled, resulting in very good powder deagglomeration.

  FIG. 5 shows another embodiment of the duct 5 of the metering device 1 of the present invention. In this case, the duct 5 is divided in two opposite directions at the bifurcated portion 15, so that the powder 2 hits the two solid surfaces 14 and the powder is deagglomerated. Specifically, the duct 4 is divided or branched into two separate branches or ducts 5a, 5b. Each branch 5a, 5b has the direction change part 12 as mentioned above. Specifically, the exit directions of the two branches 5a, 5b are essentially parallel to each other in the embodiment of FIG. However, other ducts or outlet configurations are possible.

  In the embodiment of FIG. 5, the powder particles are hit, thus forming three impact points 14 where deagglomeration occurs.

  FIG. 6 shows a similar embodiment. In this case, the duct branches 5a, 5b are angled at greater than 90 ° at the respective turning portions 12 and then bent in opposite directions so that the exit directions are angled or inclined. In addition, (or) a diffuser 16 is formed at or in the duct or the outlet 6 of the channel 5 to reduce the outlet speed.

  FIG. 7 shows another embodiment in which the branches 5a, 5b of the duct 5 exit in at least substantially parallel outlet directions similar to the embodiment of FIG. 5, but close to each other.

  FIG. 8 shows another similar embodiment in which the two branches 5 a, 5 b of the duct 5 are joined together at the outlet 6. FIG. 9 shows another embodiment similar to FIG. 8, in which the diffuser 16 is formed at the common outlet 6 of the branches 5a, 5b.

  FIG. 10 shows another embodiment of the duct 5 of the metering device 1 of the present invention. In this case, the duct 5 is substantially a repetition of the two duct structures of FIG. The interconnecting portion 17 forms an outlet of the first duct structure and an inlet of the second duct structure, and the outlet and the inlet are continuously connected.

  In this embodiment, the duct 5 has a large number, ie at least two bifurcated portions 5, which are divided in two directions, preferably in opposite directions or divided. Yes.

  It should be noted that different duct structures and / or different features of the duct structure can be combined in any suitable manner.

  FIG. 11 shows, in schematic cross-section, another duct structure with means for reducing the speed, said means forming a number of powder jet spray impingement means 18. Said means 18 form a large number of at least two powder spray jets P which collide with each other as shown in FIG. In this embodiment, the duct 5 is divided into two parts 5a and 5b, and these parts 5a and 5b have an opening or a powder jet P ejected from the parts 5a and 5b with the outlet 6 being inclined with respect to each other. Designed to collide with each other at an angle. For example, as shown in FIG. 11, in order to form at least two portions 5 a and 5 b of the duct 5, a flow divider 19 or an arbitrary guide means may be provided in the flow path.

  The collision angle α between the powder jets P is 30 ° to 180 °, preferably at least 90 °, in particular about 90 ° to 150 °. As a result of the impingement of the powder jet P, the speed of the spray 3 decreases and / or the deagglomeration of the powder 2 occurs and / or the separation of drug particles from the carrier occurs and / or Good focusing of the spray 3 is obtained. These functions and effects are determined by the collision angle α. When the collision angle α is large, the effect is improved as a result. In contrast to a liquid jet, the collision angle α can and is preferably 90 ° or more. These angles also apply to the following embodiments.

  The duct 5 is preferably connected at least tangentially to the storage chamber 10 in the embodiment shown in FIG. Preferably, the duct 5 is connected to the mixing chamber 10 at one axial end of the cylindrical chamber 14 and the gas inlet 11 is connected to the other axial end of the chamber 10. In particular, the gas inlet 11 is also tangentially connected to the storage chamber 10 so that when it enters the gas, a swirl is produced, the swirl direction assisting the discharge of the mixture of gas and powder 2 through the duct 5, and the swirl direction Is connected tangentially to the direction of swirl rotation.

  FIG. 12 shows another embodiment of the powder jet impinging means 18 in a schematic cross-sectional view. In this case, the two or three or more ducts 5 have inclined portions or outlet portions 5c, and these inclined portions or outlet portions are arranged such that the powder jets P ejected from the outlet portion 5c are mutually connected. They are tilted with respect to each other so that they collide.

  The embodiment of FIGS. 11 and 12 is also suitable for impinging three or more powder jets P. For example, it is possible to provide substantially the same structure in a cross-sectional plane perpendicular to the plane of the drawing so that the four outlet directions and the powder jet P are arranged on the surface of the conus. However, many other structures with similar effects are possible.

  It should be added that the cross sections of the duct portions 5a-5c are preferably not necessarily rectangular or flat, and can take any suitable cross sectional shape.

  Preferably, the gas inlet 11 or gas supply has a smaller cross-sectional area than the duct 5 or outlet 6, so that the gas flow rate is not by the outlet side during metering, ie by the duct 5 or outlet 6. Rather than being determined by the entrance. In this case, the mixture of gas and powder 2 is pushed into the duct 5 and / or any other suitable outlet, for example the outlet 6, with a relatively low gas pressure, the gas flow rate during this phase. Controlled at least primarily by the gas inlet 11 or any other throttle cross section upstream of the gas inlet 11. Since the gas pressure releasing the powder 2 through the duct 5 and / or the outlet 6 is relatively low, a low discharge rate of the spray 3 and thus a low propagation velocity can be achieved. In addition, if the means for reducing the propagation speed of the spray 3, specifically, the powder jet impinging means 18 is used, the propagation speed of the spray 3 can be further reduced.

  Preferably, the average speed of spray 3 (average speed measured 10 cm away from the outlet / mouthpiece) is less than 2 m / s, in particular less than 1 m / s. Preferably, the average duration of the spray 3 is at least 0.2 seconds or 0.3 seconds, in particular from about 0.5 seconds to 2 seconds.

  Preferably, the duct 5 has a flat (inner) cross section. FIGS. 13 a to 13 c show a possible cross section of the duct 5. FIG. 13a shows a substantially rectangular cross section. FIG. 13b shows a flat cross section with two opposite straight sides connected to each other by two curved portions. FIG. 13c shows an oval or elliptical cross section.

  In the present invention, a cross-section is considered flat if the longest side of the cross-section or the ratio of the side d1 to the shortest side or the side d2 is at least 2.0. Preferably the ratio is from 3 to 50, in particular from about 5 to 70. It is pointed out that the cross section shown in FIG. 6 is not to scale.

  The longest side d1 is preferably from 0.5 mm to 5 mm, in particular from 1 mm to 3 mm. Most preferably, the longest side d1 and the fine particle size (desired particle size) (the average diameter of most of the powder particles or drug particles of the spray 3) is less than 500, preferably less than 300, especially about 30 to 300.

  The shortest side d2 is preferably from 0.05 mm to 0.5 mm, in particular from about 0.07 mm to 0.25 mm. Most preferably, the shortest side d2 and the fine particle size (desired particle size) (the average diameter of most of the powder particles or drug particles of the spray 3) is less than 50, preferably less than 30, especially about 3 to 20 It is.

  The length of the duct 5 preferably means the length of a flat cross section. Thus, the duct 5 may have a large length, i.e. another cross-sectional shape and / or another part with a large cross-sectional area, so that these for the mixture of gas and powder 2 The influence of the other parts is low compared to the part of the duct 5 having a flat cross section. However, the cross-sectional area and / or shape of the flat cross section may vary throughout the length of the duct 5 (the portion having the flat cross section). Thus, the cross-sectional area of the duct 5 can taper from the inlet to the outlet, or vice versa.

  Most preferably, the duct 5 has a constant cross-sectional area, ie, at least a portion of a flat cross-section with a constant diameter and / or shape.

  The length of the duct 5, i.e. the part having a flat cross section, is from 3 mm to 80 mm, in particular from 5 mm to 15 mm. Preferably, the duct length is matched to the average hydraulic diameter of the duct 5, so that the ratio of the length of the duct 5 to the average hydraulic diameter is at least 5, in particular about 10, preferably 20 to 60 or more. In this case, the hydraulic diameter is defined as a ratio obtained by dividing four cross-sectional areas by the duct circumference.

  The diameter of the preferably circular or cylindrical or conical chamber 10 is determined by the volume or mass of each dose of powder 2. A single dose may be, for example, 1 mg to 2 mg (pure drug without carrier) or 2 mg to 10 mg (drug and carrier, especially lactose blend). In the first case, the diameter range is preferably 1.5 mm to 2.5 mm. In the second case, the diameter range is preferably 2 mm to 5 mm. Preferably, the cross section of the duct 5 varies as well. For example, the shortest side d2 is about 0.07 mm to 0.1 mm in the first case, and about 0.15 mm to 0.25 mm in the second case. The larger (inner) side d1 does not depend very strongly on the size or particle size of the powder. Preferably, the larger side is about 1 mm to 2 mm in the first case and about 1 mm to 3 mm in the second case.

  The average hydraulic diameter of the duct 5 is preferably less than 1 mm, in particular from 0.1 mm to 0.6 mm.

  Preferably, the duct 5 is formed and / or formed by a flat groove with a cover.

  The metering device 1 or the storage device 4 administers one dose of the powder 2 simultaneously, in particular increasing the total mass flow or output of the metered powder 2 so that the desired dose is as desired and / or ), May have a number of outlets 5 that can be released in a sufficiently short period of time or can be administered as required.

  FIG. 14 shows another embodiment of the metering device 1 in a very schematic cross-sectional view. In this embodiment, the storage device 4 is preferably a cartridge, container, blister or the like on a disc with multiple storage cavities. The storage device 4 can be rotated or indexed in stages, so that the powder 2 can be dispensed one after another from the storage cavity 10. In this embodiment, the gas may be supplied axially and the gas and powder 2 mixture may be metered radially into the mouthpiece 20 especially for the user or patient (not shown). Preferably, the powder 2 is administered directly into the mouthpiece 20 via the at least one duct 5 and / or the outlet 6. Most preferably, the duct 5 and the outlet 6 are arranged in the mouthpiece 20, in particular in a retracted state with respect to the opening of the mouthpiece 20. This is preferably also the case for the metering device 1 shown in FIGS.

  It should be noted that the present invention, specifically the metering device 1 and / or the storage device 4 is a single drug, a blend of multiple drugs, or at least two or three. Can be used to meter different drugs. In the latter case, separate drugs are stored in separate storage chambers 10 and the drugs are mixed with the gas either in a common mixing chamber or in their respective storage chambers 10 during metered dose operations. Furthermore, different medicaments can be discharged through the common duct 5 or outlet 6 or the separate duct 5 or outlet 6. In the latter case, the separate medicaments will be mixed after leaving the separate duct 5 and outlet 6 or in the mouthpiece 31 or in any other suitable (additional) mixing chamber. Become. It is also possible to mix different drugs by colliding powder jets of different drugs. For metering different drugs, it is possible to use a common gas supply or means for pressurizing the gas, eg air pump 7, or means for providing a separate gas supply / pressurized gas. .

  In the following, two embodiments showing the effects of the present invention will be described.

  Example 1 A blend of 90.0 wt% lactose 200, 9.7 wt% microlactose and 0.3 wt% tiotropium was used. The average particle diameter of lactose 200 was about 45 μm, the average particle diameter of microlactose was about 4 μm, and the average particle diameter of tiotropium was about 4 μm. Approximately 5.5 mg of the blend was stored as powder 2 in the storage and mixing chamber 10. Such storage and mixing chambers had a substantially cylindrical shape with a diameter of 3 mm and an axial length of 3 mm. 5 ml (5 milliliters) of compressed air was fed into the chamber 10 from a gas inlet having an inlet orifice of 0.5 mm with a gauge pressure of about 100 kPa. Powder 2 was dosed via a duct 5 having a substantially rectangular cross section with the shortest side of about 0.18 mm and the longest side of about 1.5 mm. The duct 5 is divided into two duct parts 5a, 5b (specifically shown in FIG. 11), each part having a shortest side of about 0.18 mm and a longest side of about 0.2 mm. It had a substantially rectangular cross section of 75 mm. The total length of the duct 5 including the portions 5a and 5b was about 8 mm. As a result, 100% of the weighed mass, ie all of the powder 2 in the chamber 10 was dispensed. Approximately 50% of the average diameter and most of the average microfractions were measured by Anderson Cascade Impactor at both 30 l (30 liters) / min and 60 l (60 liters) / min.

  Example 2: Fenoterol having an average particle diameter of 4 μm is placed in a storage and mixing chamber 10 as about 1.5 mg powder 2, which is substantially 2 mm in diameter and 2 mm in axial length. It had a cylindrical shape. 5 ml (5 milliliters) of compressed air was fed into the chamber 10 from a gas inlet having an inlet orifice of 0.5 mm with a gauge pressure of about 150 kPa. Powder 2 was dosed via a duct 5 having a substantially rectangular cross section with the shortest side of about 0.075 mm and the longest side of about 1.5 mm. The duct 5 is divided into two duct parts 5a, 5b (specifically shown in FIG. 11), each part having a shortest side of about 0.075 mm and a longest side of about 0.05 mm. It had a substantially rectangular cross section of 75 mm. The total length of the duct 5 including the portions 5a and 5b was about 8 mm. As a result, 100% of the weighed mass, ie all of the powder 2 in the chamber 10 was dispensed. Approximately 45% of the average diameter and most average microfractions were measured by an Anderson Cascade Impactor at both 30 l (30 liters) / min and 60 l (60 liters) / min.

  The powder 2 or drug may comprise any one of the following substances or any mixture of these substances. The powder 2 or medicament may preferably comprise an additional pharmacologically active substance or mixture of substances selected from the following group:

Anticholinergics :
The anticholinergic is preferably tiotropium, tiotropium bromide, oxitropium bromide, furtropium bromide, ipratropium bromide, glycopyrronium salt, trospium chloride, tolterodine, 2,2-diphenylpropion acid tropenol ester- Metobromide, 2,2-diphenylpropion acid scopine ester-methobromide, 2-fluoro-2,2-diphenylacetic acid scopine ester-methobromide, 2-fluoro-2,2-diphenylacetic acid tropenol ester-methobromide, 3,3 ', 4,4'-Tetrafluorobenzyl acid tropenol ester-methobromide, 3,3', 4,4'-tetrafluorobenzyl acid scopine ester-methobromide, 4,4'-difluoro Nyl acid tropenol ester-methobromide, 4,4'-difluorobenzyl acid scopine ester-methobromide, 3,3'-difluorobenzyl acid tropenol ester-methobromide, 3,3'-difluorobenzyl acid scopine ester-methobromide 9-hydroxy-fluorene-9-carboxylic acid tropenol ester-methobromide, 9-fluoro-fluorene-9-carboxylic acid tropenol ester-methobromide, 9-hydroxy-fluorene-9-carboxylic acid scopine ester-methobromide, 9 -Fluoro-fluorene-9-carboxylic acid scopine ester-methobromide, 9-methyl-fluorene-9-carboxylic acid tropenol ester-methobromide, 9-methyl- Luolene-9-carboxylic acid scopine ester-methobromide, benzyl acid cyclopropyl tropine ester-methobromide, 2,2-diphenylpropion acid cyclopropyl tropine ester-methobromide, 9-hydroxy-xanthene-9-carboxylic acid cyclopropyl tropine ester- Metobromide, 9-methyl-fluorene-9-carboxylic acid cyclopropyl tropine ester-methobromide, 9-methyl-xanthene-9-carboxylic acid cyclopropyl tropine ester-methobromide, 9-hydroxy-fluorene-9-carboxylic acid cyclopropyl tropine ester -Metobromide, 4,4'-difluorobenzyl acid methyl ester cyclopropyl tropine ester-Metobromi 9-hydroxy-xanthene-9-carboxylic acid tropenol ester-methobromide, 9-hydroxy-xanthene-9-carboxylic acid scopine ester-methobromide, 9-methyl-xanthene-9-carboxylic acid scopine ester-methobromide, 9-methyl-xanthene-9-carboxylic acid tropenol ester-methobromide, 9-ethyl-xanthene-9-carboxylic acid tropenol ester-methobromide, 9-difluoromethyl-xanthene-9-carboxylic acid tropenol ester-methobromide, 9 -Hydroxymethyl-xanthene-9-carboxylic acid scopine ester-methobromide, and optionally, racemates, enantiomers, diastereomeric forms, and options Pharmacologically acceptable acid addition salts, and include the hydrates thereof.

Beta-exchange neurostimulants :
The beta-exchange neurostimulants are preferably albuterol, bambuterol, vitorterol, broxaterol, carbuterol, clenbuterol, fenoterol, formoterol, hexoprenalin, ibuterol, inductolol, isoetarine, isoprenaline, levosalbutamol, mabuterol, meladolol, , Ortiprenaline, pyrbuterol, procaterol, reproterol, limiterol, ritodrine, salmeterol, salmefamol, soterenot, sulfonterol, thiaramide, terbutaline, tolbuterol, CHF-1035, HOKU-81, KUL-1248, 3- (4- {6- [2 -Hydroxy-2- (4-hydroxy-3-hydroxymethyl-phenyl) -ethylamino ] -Hexyloxy} -butyl) -benzolsulfonamide, 5- [2- (5,6-diethyl-indan-2-ylamino) -1-hydroxy-ethyl] -8-hydroxy-1H-quinolin-2-one 4-hydroxy-7- [2-{[2-{[3- (2-phenylethoxy) propyl] sulfonyl} ethyl] -amino} ethyl] -2 (3H) -benzothiazolone, 1- (2-fluoro- 4-hydroxyphenyl) -2- [4- (1-benzimidazolyl) 2-methyl-2-butylamino] ethanol, 1- [3- (4-methoxybenzyl-amino) -4-hydroxyphenyl] -2- [ 4- (1-Benzimidazolyl) -2-methyl-2-butylamino] ethanol, 1- [2H-5-hydroxy-3-oxo-4H-1,4-benzoxazine- -Yl] -2- [3- (4-N, N-dimethylaminophenyl) -2-methyl-2-propylamino] ethanol, 1- [2H-5-hydroxy-3-oxo-4H-1,4 -Benzoxazin-8-yl] -2- [3- (4-methoxyphenyl) -2-methyl-2-propylamino] ethanol, 1- [2H-5-hydroxy-3-oxo-4H-1,4- Benzoxazin-8-yl] -2- [3- (4-n-butyroxyphenyl) -2-methyl-2-propylamino] ethanol, 1- [2H-5-hydroxy-3-oxo-4H-1, 4-Benzoxazin 8-yl] -2- {4- [3- (4-methoxyphenyl) -1,2,4-triazol-3-yl] -2-methyl-2-butylamino} ethanol, 5-hydroxy -8- (1-Hydro Xyl-2-isopropylaminobutyl) -2H-1,4-benzoxazin-3- (4H) -one, 1- (4-amino-3-chloro-5-trifluoromethylphenyl) -2-ter-butylamino ) Ethanol and 1- (4-ethoxycarbonylamino-3-cyano-5-fluorophenyl) -2- (ter-butylamino) ethanol and, optionally, their racemates, enantiomers, diastereomeric forms, And optionally selected from these pharmacologically acceptable acid addition salts and hydrate forms.

Steroid :
The steroid is preferably prednisolone, prednisone, butyxocortopropionate, RPR-106541, flunisolide, beclomethasone, triamcinolone, budesonide, fluticasone, mometasone, ciclesonide, rofleponide, ST-126, dexamethasone, 6α, 17α-difluoro -[(2-Furanylcarbonyl) oxy] -11β-hydroxy-16α-methyl-3-oxo-androst-1,4-diene-17β-carbothione acid (S) -fluoromethyl ester, 6α, 9α- Difluoro-11β-hydroxy-16α-methyl-3-oxo-17α-propionyloxy-androst-1,4-diene-17β-carbothion acid (S)-(2-oxo-tetrahydrofuran-3S-yl) Ter and etipredonol-dichloroacetate (BNP-166), and optionally their racemic, enantiomeric, diastereomeric forms, and optionally their pharmacologically acceptable acid addition salts and water It is selected from Japanese forms.

PDEIV inhibitors :
PDEIV inhibitors are preferably enprofylline, theophylline, roflumilast, ariflo (tyromylast), CP-325,366, BY343, D-4396 (Sch-355191), AWD-12-281 (GW-842470), N -(3,5-dichloro-1-oxo-pyridin-4-yl) -4-difluoromethoxy-3-cyclopropylmethoxybenzamide, NCS-613, pumafentin, (-) p-[(4aR ^* , 10bS ^* ] -9-Ethoxy-1,2,3,4,4a, 10b-hexahydro-8-methoxy-2-methylbenzo [s] [1,6] naphthyridin-6-yl] -N, N-diisopropylbenzamide , (R)-(+)-1- (4-bromobenzyl) -4- [3-cyclopentyloxy] -4-methoxy Phenyl] -2-pyrrolidone, 3- (cyclopentyloxy-4-methoxyphenyl) -1- (4-N ′-[N-2-cyano-S-methyl-isothioureido] benzyl) -2-pyrrolidone, cis [ 4-cyano-4- (3-cyclopentyloxy-4-methoxyphenyl) cyclohexane-carbon acid], 2-carbomethoxy-4-cyano-4- (3-cyclopropylmethoxy-4-difluoromethoxyphenyl) cyclohexane- 1-one, cis [4-cyano-4- (3-cyclopropyl-methoxy-4-difluoromethoxyphenyl) cyclohexane-1-ol], (R)-(+)-ethyl [4- (3-cyclopentyl) Roxy-4-methoxyphenyl) pyrrolidin-2-ylidene] acetate, (S)-(−)-ethyl [4- (3-cyclopentyl Xyl] -4-methoxyphenyl) pyrrolidine-2-ylidone] acetate, CDP840, Bay-198004, D-4418, PD-168787, T-440, T2585, allophylline, atizolane, V-11294A, C1-1018 , CDC-801, CDC-3052, D-22888, YM-58997, Z-15370, 9-cyclopentyl-5,6-dihydro-7-ethyl-3 (2-thienyl) -9H-pyrazolo [3,4 c] -1,2,4-triazolo [4,3-a] pyridine and 9-cyclopentyl-5,6-dihydro-7-ethyl-3- (ter-butyl) -9H-pyrazolo [3,4] -C] -1,2,4-triazolo [4,3-a] pyridine, and optionally these racemates, It is selected among the forms of nanthiomers, diastereomers, and optionally these pharmacologically acceptable acid addition salts and hydrates.

LTD4 antagonist :
The LTD4 antagonist is preferably montelukast, 1-(((R)-(3- (2- (6,7-difluoro-2-quinolinyl) ethenyl) phenyl) -3- (2- (2-hydroxy- 2-propyl) phenyl) thio) methylcyclopropane-acetic acid, 1-(((1 (R) -3 (3- (2- (2,3-dichlorothieno [3,2-b] pyridin-5-yl) )-(E) ethenyl) phenyl) -3- (2- (1-hydroxy-1-methylethyl) phenyl) propyl) thio) methyl) cyclopropane-acetic acid, pranlukast, zafirlukast, [2-[[2- (4-ter-butyl-2-thiazolyl) -5-benzofuranyl] oxymethyl] phenyl] acetic acid, MCC-847 (ZD-3523), MN-001, MEN-91507 (LM-1507), V F-5078, VUF-K-8707 and L-733321 and, optionally, their racemic, enantiomeric, diastereomeric forms, and, optionally, their pharmacologically acceptable acid addition salts, and , Selected from hydrate forms.

EGFR kinase inhibitors :
The EGFR kinase inhibitor is preferably cetuximab, trastuzumab, ABX-EGF, Mab ICR-62, 4-[(3-chloro-4-fluorophenyl) amino] -6- { [4- (Morphonin-4-yl) -1-oxo-2-buten-1-yl] amino} -7-cyclopropylmethoxy-quinazoline, 4-[(R)-(1-phenyl-ethyl) amino] -6-{[4- (morpholin-4-yl) -1-oxo-2-buten-1-yl] amino} -7-cyclopentyloxy-quinazoline, 4-[(3-chloro-4-fluoro -Phenyl) amino] -6-{[4-((R) -6-methyl-2-oxo-morpholin-4-yl) -1-oxo-2-buten-1-yl] amino} -7- [(S)-(Tetra Drofuran-3-yl) oxy] -quinazoline, 4-[(3-chloro-4-fluoro-phenyl) amino] -6- [2-((S) -6-methyl-2-oxo-2-morpholine -4-yl) -ethoxy] -7-methoxy-quinazoline, 4-[(3-chloro-4-fluorophenyl) amino] -6-({4- [N- (2-methoxy-ethyl) -N- Methyl-amino] -1-oxo-2-buten-1-yl} amino) -7-cyclopropylmethoxy-quinazoline, 4-[(R)-(1-phenyl-ethyl) amino] -6-({4 -[N- (tetrahydropyran-4-yl) -N-methyl-amino] -1-oxo-2-buten-1-yl} amino) -7-cyclopropylmethoxy-quinazoline, 4-[(3-chloro -4-fluorophenyl) amino ] -6-({4- [N- (2-methoxy-ethyl) -N-methyl-amino] -1-oxo-2-buten-1-yl} amino) -7-cyclopentyloxy-quinazoline, 4 -[(3-Chloro-4-fluorophenyl) amino] -6-{[4- (N, N-dimethylamino) -1-oxo-2-buten-1-yl] amino} -7-[(R )-(Tetrahydrofuran-2-yl) methoxy] -quinazoline, 4-[(3-ethynyl-phenyl) amino] -6,7-bis- (2-methoxy-ethoxy) -quinazoline, 4-[(R)- (1-phenyl-ethyl) amino] -6- (4-hydroxy-phenyl) -7H-pyrrolo [2,3-d] pyrimidine, 3-cyano-4-[(3-chloro-4-fluorophenyl) amino ] -6-{[4- (N, N-dimethyl Mino) -1-oxo-2-buten-1-yl] amino} -7-ethoxy-quinoline, 4-[(R)-(1-phenyl-ethyl) amino] -6-{[4-((R ) -6-Methyl-2-oxo-morpholin-4-yl) -1-oxo-2-buten-1-yl] amino} -7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro) Phenyl) amino] -6-{[4- (morpholin-4-yl) -1-oxo-2-buten-1-yl] amino} -7-[(tetrahydrofuran-2-yl) methoxy] -quinazoline, 4-[(3-Ethynyl-phenyl) amino] -6-{[4- (5,5-dimethyl-2-oxo-morpholin-4-yl) -1-oxo-2-buten-1-yl] Amino} -quinazoline, 4-[(3-chloro-4-fluoro Phenyl) amino] -6- {2- [4- (2-oxo-morpholin-4-yl) -piperidin-1-yl] -ethoxy} -7-methoxy-quinazoline, 4-[(3-chloro- 4-Fluoro-phenyl) amino] -6- (trans-4-amino-cyclohexane-1-yloxy) -7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl) amino] -6 (Trans-4-metanesulphonylamino-cyclohexane-1-yloxy) -7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl) amino] -6- (tetrahydropyran-3-yloxy] -7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl) amino] -6- {1-[(morpholin-4-yl) carbonyl ] -Piperidin-4-yloxy} -7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl) amino] -6- (piperidin-3-yloxy) -7-methoxy-quinazoline, 4- [(3-Chloro-4-fluoro-phenyl) amino] -6- [1- (2-acetylamino-ethyl) -piperidin-4-yloxy] -7-methoxy-quinazoline, 4-[(3-chloro- 4-fluoro-phenyl) amino] -6- (tetrahydropyran-4-yloxy) -7-ethoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl) amino] -6- {trans-4- [(Morpholin-4-yl) carbonylamino] -cyclohexane-1-yloxy} -7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro Phenyl) amino] -6- {1-[(piperidin-1-yl) carbonyl] -piperidin-4-yloxy} -7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl) amino] -6- (cis-4- {N-[(morpholin-4-yl) carbonyl] -N-methyl-amino} -cyclohexane-1-yloxy) -7-methoxy-quinazoline, 4-[(3-chloro -4-fluoro-phenyl) amino] -6- (trans-4-ethanesulfonylamino-cyclohexane-1-yloxy) -7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl) amino] -6- (1-Methanesulfonyl-piperidin-4-yloxy) -7- (2-methoxy-ethoxy) -quinazoline, 4-[(3-chloro-4 Fluoro-phenyl) amino] -6- {1- (2-methoxy-acetyl) -piperidin-4-yloxy] -7- (2-methoxy-ethoxy) -quinazoline, 4-[(3-ethynyl-phenyl) amino ] -6- (Tetrahydropyran-4-yloxy] -7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl) amino] -6- (cis-4- {N-[(piperidine- 1-yl) carbonyl] -N-methyl-amino} -cyclohexane-1-yloxy) -7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl) amino] -6- {cis-4 -[(Morpholin-4-yl) carbonylamino] -cyclohexane-1-yloxy} -7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-fluoro Enyl) amino] -6- {1- [2- (2-oxopyrrolidin-1-yl) ethyl] -piperidin-4-yloxy} -7-methoxy-quinazoline, 4-[(3-ethynyl-phenyl) amino ] -6- (1-acetyl-piperidin-4-yloxy) -7-methoxy-quinazoline, 4-[(3-ethynyl-phenyl) amino] -6- (1-methyl-piperidin-4-yloxy) -7 -Methoxy-quinazoline, 4-[(3-ethynyl-phenyl) amino] -6- (1-methanesulfonyl-piperidin-4-yloxy) -7-methoxy-quinazoline, 4-[(3-chloro-4- Fluoro-phenyl) amino] -6- (1-methyl-piperidin-4-yloxy) -7 (2-methoxy-ethoxy) -quinazoline, 4-[(3-ethynyl-phen L) amino] -6- {1-[(morpholin-4-yl) carbonyl] -piperidin-4-yloxy} -7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)- Amino] -6- {1- [N-methyl-N-2-methoxyethyl-amino] carbonyl] -piperidin-4-yloxy} -7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro- Phenyl) amino] -6- (1-ethyl-piperidin-4-yloxy) -7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl) amino] -6- [cis-4- ( N-methanesulfonyl-N-methyl-amino) -cyclohexane-1-yloxy] -7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl) amino]- -[Cis-4- (N-acetyl-N-methyl-amino) -cyclohexane-1-yloxy] -7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl) amino] -6 (Trans-4-methylamino-cyclohexane-1-yloxy) -7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl) amino] -6- [trans-4- (N-methane) Sulfonyl-N-methyl-amino) -cyclohexane-1-yloxy] -7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl) amino] -6- (trans-4-dimethylamino-cyclohexane -1-yloxy) -7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl) amino] -6- (trans-4- {N-[(morpholin-4-yl) carbonyl] -N-methyl-amino} -cyclohexane-1-yloxy) -7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl) amino ] -6- [2- (2,2-dimethyl-6-oxo-morpholin-4-yl) -ethoxy] -7-[(S)-(tetrahydrofuran-2-yl) methoxy] -quinazoline, 4- [(3-Chloro-4-fluoro-phenyl) amino] -6- (1-methanesulfonyl-piperidin-4-yloxy) -7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl) ) Amino] -6- (1-cyano-piperidin-4-yloxy) -7-methoxy-quinazoline and 4-[(3-chloro-4-fluoro-phenyl) amino] -6 1-[(2-methoxyethyl) carbonyl] -piperidine-4-ethoxy} -7-methoxy-quinazoline and, optionally, their racemic, enantiomeric, diastereomeric forms, and optionally these It is selected from among pharmacologically acceptable acid addition salts and hydrate forms.

  In addition, the compounds may be in the form of betamimetic (s), bacqua alkaloid derivatives, triptans, CGRP antagonists, phosphodiesterase V inhibitors, optionally racemic, enantiomeric, or diastereomeric forms and options Or a pharmacologically acceptable acid addition salt and a hydrate thereof.

  Acid addition salts containing pharmacologically acceptable acids include, for example, hydrochloride (hydrochloride), hydrobromide (hydrobromide), hydriodide (hydroiodic acid), hydrosulfate (bisulfate), Hydrophosphate, hydromethanesulfonate, hydronitrate, hydromaleate, hydroacetate, hydrobenzoate, hydrocitrate, hydrofumarate, hydrotartrate, hydrooxalate, hydrosuccinate, hydrobenzoate and hydro-p-tolu Orthosulfonates, preferably hydrochloride, hydrobromide, hydrosulfate, hydrophosphate, hydrofumarate and hydromethanesulfonate.

  Antiallergic agents include disodium cromoglycate and nedocromil.

  Examples of the alkaloid derivative include dihydroergotamine and ergotamine.

  Furthermore, inhalable macromolecules can be used as pharmacologically effective substances, as disclosed in EP 1,003,478.

  For inhalation purposes, the medicaments, pharmaceutical preparations and mixtures thereof containing the pharmacologically active substances mentioned above can be used and these pharmacologically active substances, salts, esters, and It is possible to use combinations of these pharmacologically effective substances, salts and esters.

  Furthermore, inhalable macromolecules can be used as pharmacologically effective substances, as disclosed in EP 1,003,478.

1 is a schematic cross-sectional view of a metering device as one embodiment of the present invention. It is a schematic sectional drawing of the duct of the metering administration instrument of FIG. It is a schematic sectional drawing of the duct of the metering administration device as another embodiment. It is a schematic sectional drawing of the duct of the metering administration device as another embodiment. It is a schematic sectional drawing of the duct of the metering administration device as another embodiment. It is a schematic sectional drawing of the duct of the metering administration device as another embodiment. It is a schematic sectional drawing of the duct of the metering administration device as another embodiment. It is a schematic sectional drawing of the duct of the metering administration device as another embodiment. It is a schematic sectional drawing of the duct of the metering administration device as another embodiment. It is a schematic sectional drawing of the duct of the metering administration device as another embodiment. It is a schematic sectional drawing of the duct of the metering administration device as another embodiment. It is a schematic sectional drawing of the duct of the metering administration device as another embodiment. It is sectional drawing of the duct provided with one cross section. It is sectional drawing of the duct provided with another cross section. It is sectional drawing of the duct provided with another cross section. It is a schematic sectional drawing of the metering administration device as another embodiment.

Claims (20)

In particular, a metering device (1) for metering a powder containing a drug or a powder (2) comprising a drug as a spray (3) containing fine powder particles, the metering device (1) comprising a duct (5) A metering device wherein the powder can be metered through the duct by gas pressure to deagglomerate the powder (2),
The duct (5) is angled at least about 90 ° at the turning portion (12) so that the powder (2) impinges on the solid surface (14) to cause deagglomeration of the powder ( Or) a metering device characterized in that it is turned in two opposite directions at the bifurcated part (15).   2. Metering device according to claim 1, characterized in that the duct (5) has a number of turning parts (12).   3. Metering device according to claim 1 or 2, characterized in that the duct (5) has a number of bifurcated parts (15).   The duct (5) is designed such that the powder (2) impinges on a number of solid surfaces or surface portions (14) to cause deagglomeration of the powder. A metering device according to any one of the above.   5. Metering device according to any one of the preceding claims, characterized in that the duct (5) is alternately bent in opposite directions and / or angled. .   6. Metering device according to any one of the preceding claims, characterized in that the duct (5) is a capillary.   7. Metering device according to any one of the preceding claims, characterized in that the duct (5) extends directly into the mouthpiece (20) of the metering device (1). .   The duct (5) has a flat cross section, preferably the ratio of the longest side (d1) to the shortest side (d2) of the flat cross section is at least 2.0. The metering device according to any one of claims 1 to 7.   The longest side (d1) is 0.5 mm to 5 mm, preferably about 1 mm to 3 mm, and (or) the shortest side (d2) is 0.05 mm to 0.5 mm, 9. Metering according to claim 8, characterized in that it is preferably about 0.07 mm to 0.25 mm and / or the flat cross section is substantially oval or rectangular. Instruments.   The metering device (1) pushes the powder (2) into the duct (5) and / or provides a pressurized gas, in particular air, for metering the powder (2) The metering device according to any one of claims 1 to 9, characterized in that   11. The metering device (1) has an air pump (7) as means for providing a pressurized gas, the air pump (7) preferably being manually operable. A metering device according to any one of the above.   The metering device (1) contains a single dose of powder (2) or separate multiple doses of powder (7) so that multiple doses can be metered one after the other. 12. The storage device (4) according to any of the preceding claims, characterized in that it is preferably adapted to receive or exchangeable storage devices (4). The metering device according to one item.   13. Storage device (4), characterized in that each dose of powder (2) is configured to be metered through a separate duct (5) or outlet (6). The metering device described.   14. Metering device according to claim 12 or 13, characterized in that the storage device (4) is a cartridge, blister, capsule or container.   Said metering device (1) has a number of ducts (5) for metering a batch of powder (2) simultaneously, in particular to increase the total mass flow rate of powder (2) to be metered. The metering device according to any one of claims 1 to 14.   The metering device (1) and / or the storage device (4) is such that each dose of powder (2) is metered through a separate duct (5) or an unused duct (5). A metering device according to any one of the preceding claims, characterized in that it is configured to be administered.   The metering device (1) is preferably provided at the outlet of the duct (5) and comprises means, in particular a diffuser (16), for reducing the propagation speed of the spray (3). The metering administration device according to any one of claims 1 to 16.   The metering device (1) further deagglomerates the powder (2) and / or reduces the propagation speed of the spray (3) and / or mixes separate powders (2). 18. A metering device according to any one of the preceding claims, characterized in that it comprises powder jet impingement means (18) for impinging at least two powder jets (P) to do so.   The average particle size of the powder particles is 2 μm to 7 μm when the powder (2) is a pure drug or a blend of drugs, or the average particle size of the powder particles is that of the powder (2) 19. Metering device according to any one of the preceding claims, characterized in that when it is a carrier, for example a blend of lactose and at least one drug, it is from 20m to 300m.   20. The metering device according to any one of the preceding claims, characterized in that the metering device (1) is a dry powder inhaler.

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