CA2642862A1

CA2642862A1 - Dispensing device

Info

Publication number: CA2642862A1
Application number: CA002642862A
Authority: CA
Inventors: Stephen Terence Dunne
Original assignee: Boehringer Ingelheim Microparts GmbH
Current assignee: Individual
Priority date: 2006-04-13
Filing date: 2006-04-13
Publication date: 2007-10-25
Also published as: EP2004258A1; JP2009533104A; WO2007118490A1

Abstract

A dispensing device (1) for dispensing powder (2) as a spray (3) is disclosed. The dispensing device comprises a duct (5) through which the powder is dispensible by gas pressure for de-agglomerating the powder. The duct is angled by at least about 90 degrees at a diversion portion (12) and/or diverted into two opposite directions at a fork portion (15) so that the powder is impacted on to a solid surface (14) for powder de-agglomeration.

Description

Dispensing Device The present invention relates to a dispensing device for dispensing powder ac-cording to the preamble of claim 1.
Powder drugs delivered through dispensing devices, in particular inhalers, are intended to optimally target specific sites in the pulmonary system. These sites include the nasal passages, the throat, and various locations within the lungs, such as the bronchi, bronchioles and alveolar regions. The ability to deliver drugs to a target area depends inter alia on the aerodynamic sizes of the parti-cles. As currently believed to be understood, particles having an aerodynamic diameter of less than 2 m are considered to be potentially optimal for deposi-tion in the alveolar region of the lung. Particles that have an aerodynamic di-ameter of between 2 and approximately 5[tm may be more suitable for deliv-ery to the bronchiole or bronchi regions. Particles with an aerodynamic size range greater than 6 m, and more preferably 10 m, are typically suitable for delivery to the laryngeal region, throat or nasal passages.

In most cases, it is desired to achieve a high inhalable fraction and high deliv-ery efficiency, i.e. the fraction that reaches the desired region, in particular in the lung. This depends on various factors, in particular on the characteristics of the generated spray plume, such as propagation velocity of the plume, par-ticle size and its distribution, fraction of small particles, fraction of gas and the like. In the present invention, the desired spray plume characteristics include preferably a small particle size, a high fraction of drug particles with a diame-ter of 6 m or less, a low propagation velocity, a long duration of spray gen-eration and/or possible inhalation, and/or a low amount of gas volume re-quired for dispensing a certain amount of powder.

In particular, the present invention is concerned with dry powder inhalers for the delivery of drugs to the lungs. Many dry powder inhalers are on the mar-ket or have been proposed. There are two main types, namely the passive ones and the active ones. In passive inhalers all the energy required for de-agglomerating the powder and transferring the powder to the lungs is provided CONFIRMATION COPY

by the breathing of a user or patient. In active inhalers there is an additional source of energy to help to de-agglomerate the powder.

Most powder inhalers are of the passive type 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 the proportion of powder that actually enters the lungs, is largely dependant on the breathing of the patient.
The de-agglomeration of the powder and hence the inhalable fraction is a function of the flow rate of inhaled air through the device and, therefore, var-ies greatly from patient to patient.

Dry powder inhalers are subdivided into single dose devices and multi-dose inhalers. Multi-dose inhalers are further subdivided into pre-metered types where the doses are stored individually and into metering inhalers where the powder dose is metered in the device.

Multi dose pre-metered inhalers have the advantage that the single doses are metered under strict factory conditions and the powder can quite easily be iso-lated from the atmosphere. In many applications the active duct powder is mixed with a carrier such as lactose which tends to absorb humidity from the atmosphere which makes it stick together and difficult to de-agglomerate.

The present invention relates in particular to an active, gas powered, pre-metered multi- or single-dose dispensing device for dispensing powder con-taining or consisting of a drug, such as a dry powder inhaler.

WO 92/12799 Al, which forms the starting point of the present invention, discloses a pre-metered dispensing device for transforming a flow of fluid into a spray of fine particle size, wherein an annular flow is caused through a stem filled with powder with a velocity gradient within that flow sufficient to cause sheer forces between components of the flow to break the flow up into a spray. An angled duct leads from the outlet of the stem to an outlet orifice in a spray head. However, the known device is not optimal for de-agglomerating the powder and for generating a slow spray plume with the desired character-istics.

Object of the present invention is to provide an improved dispensing device with better de-agglomeration of the powder.

The above object is achieved by a dispensing device according to claim 1.
s Preferred embodiments are subject of the subclaims.

One main aspect of the present invention is that the duct is angled by at least about 90 degrees at a diversion portion and/or is diverted into two opposite di-rections at a fork portion so that the powder is impacted on to a solid surface (impaction or deflection surface) for powder de-agglomeration. The impaction of the powder particles on the surface or wall results in a surprisingly good de-agglomeration of the powder particles. An explanation may be that very high shear forces are generated by the impaction or deflection of the powder parti-cles. The use of a diversion portion and/or fork portion has not been recog-nized in the prior art for the impaction and powder de-agglomeration accord-ing to the present invention.

According to a preferred embodiment, the duct comprises multiple diversion portions and/or fork portions in order to further enhance powder de-agglomeration. In particular, the duct is designed such that the powder is im-pacted on two multiple solid surfaces or surface portions - in particular of the duct wall in the regions of the diversion portions and/or fork portions - for powder de-agglomeration.

Preferably, the duct is bent and/or angled alternately in opposite directions.
This enables a compact design with very good powder de-agglomeration.
According to a preferred embodiment, the duct is a capillary. This leads to a very effective impaction of the powder particles to the solid surface and, thus, to good powder de-agglomeration. Preferably the duct is located at a mouth-piece entrance and/or exits into a mouthpiece with no flow restrictions after the duct.

Preferably, the duct comprises a flat cross section. The powder is forced through the duct by pressurized gas to de-agglomerate the powder and to gen-erate a spray including fine powder particles. The ratio of the largest side to the smallest side of the flat cross section of the duct is at least 2Ø
Surpris-ingly a much better de-agglomeration and finer particles can be achieved, in particular with a lower amount of gas for a given volume or mass of powder, than by a circular or quasi circular duct. This effect may be explained in that the flat cross section provides a larger perimeter for a given cross sectional area than a non-flat cross section. This larger perimeter results in a larger duct surface that is in contact with the gas and powder so that better de-agglomeration can be achieved due to higher sheer forces without changing the cross sectional area (hydraulic diameter), i.e. without changing the flow resistance or mass flow significantly.

Preferably, the ratio of the largest side to the smallest side of the flat cross sec-tion is between 3 to 50, most preferably about 5 to 30. Thus, a high output of powder with good de-agglomeration as a spray with small powder particles size can be achieved by a comparatively low gas pressure, low gas volume, and low gas flow rate. The dispensing device produces a plume of de-agglomerated dry powder with a high inhalable fraction and with the desired spray plume characteristics.

It was found that with fine powders of mean particles of fewer than 5 m a substantially rectangular duct of typically 75 m by 1500 m works well.
With powders of mean particle size above 30 m a duct of typically 200 m by 1500 m works well. The non circular duct should preferably have a hy-draulic diameter of between 20 to 1000 m depending on the particle size of the powder. It can be made of any material that is drug compatible including plastics or metals. More than one non circular duct may be used in parallel.
The duct preferably has a length of at least 5 or 10, preferably between 10 and 60, hydraulic diameters (the hydraulic diameter is defined as the ratio of 4 cross sectional areas over the duct perimeter). For any given pressure the longer the non circular duct the slower is the powder delivery to the patent.
However if the duct is too long the velocity in the storing / mixing chamber may be reduced to an extent that the mixing chamber is not emptied.

In particular, it is possible to force the powder through the duct by a gas pres-sure of less than 300 kPa to de-agglomerate the powder and to generate the spray with fine particle size. So optimal spray plume characteristics, in par-ticular a low propagation velocity, can be achieved.

It is advantageous to minimize the exit velocity of the gas and powder in order to minimize powder impaction in the mouth and upper respiratory tract. How-ever the higher the exit velocity the better is the powder break up or de-agglomeration.. One solution to this is to slow the exit velocity of the gas and powder mixture at the duct exit by using two or more impinging ducts or powder jets preferably impinging at an angle of between 30 and 180, prefera-bly 90 and 150, degrees. This is another aspect of the present invention. In particular, multiple - at least two - powder spray jets are impinged, i.e. hit each other, to slow down the propagation velocity of the spray and/or to de-agglomerate the powder. This supports the desired spray plume characteristics as mentioned above. Alternatively a diffuser with an increasing cross section may be used to decelerate the gas and powder flow at the exit of the duct.

Any gas may be used. For instance liquefied gases such as HFA134a and HFA227 may be used. In such a device the gas is stored in a pressurized can-ister containing a metering valve with connecting means to the powder reser-voir(s). Alternatively a piston cylinder arrangement, a bellows or any other gas pump may be used to pressurize e.g. atmospheric air. In such a device the user or patient needs to cock or prime the device prior to use. Further, com-pressed gas may be used. For single doses devices a pre-pressurized canister of compressed air may be used.
The volume of gas needed to completely empty a storage chamber (reservoir) and/or mixing chamber depends on the powder volume or mass. For powder masses of 0.1 to 50 mg, gas masses of between 0.2 and 300 mg are required.
For instance 5 mg of powder with a mean particle size of 4 m requires be-tween 10 and 20 cm3 of compressed air at between 100 kPa and 200 kPa with a mass of approximately 20 to 60 mg of air. For coarser powders less gas vol-ume is needed at lower pressure typically under 100 kPa gauges as less energy for de-agglomeration is required.

The volume of the storage chamber (reservoir) and optional mixing chamber needed to expel all the powder depends on the powder volume or mass. It should preferably have a volume of between 0.002 and 0.2 cm3 depending on powder dose. The larger the powder dose the larger the reservoir/mixing chamber should be. For instance with a powder dose of 5 mg a volume of be-tween 0.015 and 0.03 cm3 is needed for thorough mixing. Preferably, the ratio of the chamber volume (volume of the storage chamber and of the optional mixing chamber) to the powder volume should be between 1.2 and 4.

The reservoir should preferably be of cylindrical shape with no sharp edges as these can attract powder deposits. The gas inlet or inlets should preferably be positioned so that the gas sweeps all the chamber surfaces to prevent powder accumulating on said surfaces. Preferably the inlet(s) should be placed near the chamber end furthest from the outlet, i.e. the non circular duct. The rela-tive positions of the entry(s) and outlet in the reservoir and mixing chamber may be arranged in such a way that the gas powder mixture forms turbulent eddies within the chamber to maximize de-agglomeration or that a smooth non turbulent flow is achieved in the chamber(s).

Preferably surface areas after the non circular duct are minimized to minimize powder adherence or loss on said surfaces. The invention has the advantage that little or no powder is retained in the device after inhalation and hence the metered and delivered masses are almost the same.

Preferably, the powder is forced through the duct or a nozzle or the like by a comparatively low gas pressure of less than 300 kPa to de-agglomerate the powder and/or to generate the spray. Experiments have shown that such low pressures are sufficient for achieving good de-agglomeration and optimal for achieving a slow spray.

Further aspects, advantages and features of the present invention will be an apparent from the claims and following detailed description of preferred em-bodiments. In the drawings show:

Fig. 1 a schematic sectional view of a dispensing device accord-ing to one embodiment of the present invention;

Fig. 2 a schematic sectional view of a duct of the dispensing de-vice according to Fig. 1;

Fig. 3 a schematic sectional view of a duct of a dispensing device according to another embodiment;

Fig. 4 a schematic sectional view of a duct of a dispensing device according to another embodiment;

Fig. 5 a schematic sectional view of a duct of a dispensing device according to another embodiment;

Fig. 6 a schematic sectional view of a duct of a dispensing device according to another embodiment;
Fig. 7 a schematic sectional view of a duct of a dispensing device according to another embodiment;

Fig. 8 a schematic sectional view of a duct of a dispensing device according to another embodiment;

Fig. 9 a schematic sectional view of a duct of a dispensing device according to another embodiment;

Fig. 10 a schematic sectional view of a duct of a dispensing device according to another embodiment;

Fig. 11 a schematic sectional view of a duct of a dispensing device according to another embodiment;
Fig. 12 a schematic sectional view of a duct of a dispensing device according to another embodiment;

Fig. 13a - 13c cross sectional views of ducts with different cross sections;
and Fig. 14 a schematic sectional view of a dispensing device accord-ing to another embodiment.

In the Fig., the same reference signs are used for same or similar components, wherein same or similar characteristics, features or advantages are or can be realized or achieved even if a repeated discussion is omitted. Further, the fea-tures and aspects of the different embodiments can be combined in any de-sired manner and/or used for other dispensing devices or methods for dispens-ing powder as desired.

Fig. 1 shows in a schematic cross section - for illustration purposes not in scale - a dispensing device 1 according to the present invention. The dispens-ing device 1 is an active device, in particular gas powered. Preferably, the dis-pensing device 1 is an inhaler, in particular a dry powder inhaler, for a user or patient (not shown).

The dispensing device 1 is designed to dispense powder 2 which in particular 1s contains or consists of at least one drug. The powder 2 may be a pure drug or a mixture of at least two drugs. In addition, the powder 2 may contain at least one other material, in particular a carrier such as lactose.

Preferably the mean diameter of the powder particles is about 2 to 7 m, in particular 6 m or less. This applies in particular if the powder 2 does not con-tain any carrier such as lactose.

If the powder 2 contains a carrier, such as lactose, and at least one drug, the powder 2 may have a particle size of 20 to 300 m, in particular about 30 to 60 m. However, the de-agglomeration, which will be described later in more detail, may result even in this case in a spray 3 with a smaller particle size, e.g. of about 10 m or less. In particular, the drug may be separated form the carrier during de-agglomeration so that primarily the drug will be inhaled due to its small particle size of about 2 to 6 m and the larger carrier will be swal-lowed when using the dispensing device as an inhaler. Alternatively or addi-tionally, breaking or opening of the carrier is possible during de-agglomeration.

The above diameters mentioned above and below may be understood as mass medium aerodynamic diameters andlor may apply to the particle size or a fraction of the particles of the spray 3.

Fig. 1 shows the dispensing device 1 when dispensing the powder 2 as a spray 3 in a very schematic manner. The spray 3 comprises fine (powder) particles, i.e. has fine particle size of preferably 6 m or less. In particular, the spray 3 has the desired spray plume characteristics as described above.

The dispensing device 1 is adapted to receive or comprises a storage device 4 for storing the powder 2. The storage device 4 may be integrated into the dis-pensing device 1 or form part of the dispensing device 1. Alternatively, the storage device 4 may be a separate part, in particular a container, cartridge, blister or the like that can be inserted or connected with the dispensing device 1 and optionally replaced.

The dispensing device 1 or the storage device 4 preferably comprises a duct 5 through which the powder 2 is dispensed for de-agglomerating the powder 2 and/or forming the spray 3.

The duct 5 can comprise a nozzle or restriction (not shown) preferably at the outlet 6.
The dispensing device 1 uses preferably pressurized gas to force the powder 2 through the duct 5 to de-agglomerate the powder 2 and/or to generate the spray 3 with fine particle size. Preferably, the dispensing device 1 comprises a means for providing pressurized gas, in the present embodiment an air pump 7 which can preferably be actuated or operated manually as indicated by handle or actuator 8. In particular, the air pump 7 comprises or is formed by a bel-lows. But, it could be also a piston-cylinder-arrangement. Instead of the air pump 7, the means for providing pressurized gas can be e.g. a capsule, con-tainer or the like containing pressurized or liquefied gas for powering the dis-pensing device 1, i.e. dispensing the powder 2 as desired.

The air pump 7 may provide a gas pressure of less than 300 kPa, in particular about 50 to 200 kPa. This is preferably sufficient for operating the dispensing device 1. If liquefied gas or a container with pressurized gas is used, the gas pressures might range from 100 kPa to about 700 kPa. Then, the pressure may be reduced or throttled to the preferred pressure range - e.g. by a regulation or control means 9 - before supplying the gas to the storage device 4, in particu-lar its storage chamber 10. The optional regulation or control means 9 is in particular a valve, a flow restrictor, a capillary tube or the like, for regulating, throttling and/or controlling the gas flow and/or pressure.

Preferably, all pressure values mentioned in the present description and the claims are gauge pressures, i.e. pressure differences. All pressure values relate to the pressure in a gas storage such as a container with pressurized or lique-fied gas or provided by air pump 7 or relate to the pressures acting in the chamber 10 and/or in the duct 5.

The dispensing device 1 or storage device 4 comprises preferably at least one storage chamber 10 containing a single dose of powder 2 that shall be dis-pensed in one dispensing operation.
For dispensing, the gas is supplied under pressure to the storage chamber 10 /
powder 2 via a gas supply or inlet 11 or the like. Preferably, the inlet 11 is connected or connectable to the means for providing pressurized gas, i.e. in particular the air pump 7, or to the regulation or control means 9. The gas generates a respective flow in the storage chamber 10 to force at least essen-tially all powder 2 through the duct 5.

When gas is supplied to the storage chamber 10, the respective dose of pow-der 2 is dispensed, namely mixed with the gas, forced through the duct 5 and discharged as spray 3 as shown in Fig. 1.

Preferably, the storage device 4, in particular the chamber 10, is formed with no sharp edges, corners or the like, but have a smooth contour so that the gas can sweep all chamber surfaces to prevent powder 2 accumulating on said sur-faces and to ensure or allow complete discharge of the powder 2. In particular, the gas inlet 11 is located opposite to the duct 5 with regard to the axial or out-let direction.

The storage device 4 may comprise only one storage chamber 10 for a single dose, in this case the storage device 4 is for single dose only, or may comprise multiple storage cavities 10 and, thus, contain multiple doses of powder 2, which can be dispensed subsequently.

The gas supply provided by the dispensing device 1, in particular air pump 7, can be connected in any suitable manner to the respective storage device 4 or storage chamber 1, in particular to the respective gas inlet 11, preferably only temporarily when required for a dispensing operation. For example, a piercing element, connecting element or the like can be fluidically connected with gas inlet 11 / the respective storage chamber 10, in particular by pushing it through a respective sealing element, diaphragm, membrane, wall portion or the like to open or enable gas supply to the respective storage chamber 10.
Fig. 2 shows an enlarged sectional view of Fig. 1, in particular of the duct de-sign of the dispensing device 1 according to Fig. 1. Here, the duct 5 is angled at least ones by at least about 90 degrees at at least one diversion portion 12.
In this embodiment, the duct comprises multiple diversion portions 12.

The powder 2 entering the duct 5 at its inlet 13 impacts on to a solid surface (impaction region) 14 at each diversion portion 12 as indicated in Fig. 2. In the present embodiment, the duct 5 is bent and/or angled preferably alternately in opposite directions. In total, the duct 5 comprises six impaction points or regions 14 in the embodiment according to Fig. I and Fig. 2. The duct 5 is preferably angled by about 90 degrees at each diversion portion 12.

In Fig. 3, the duct 5 follows preferably a meander-like pattern. However, other in particular folded designs are possible as well.

The de-agglomeration of the powder 2 is preferably supported or further en-hanced by de-agglomeration of the powder 2 by flowing through the prefera-bly narrow or flat duct 5.

Fig. 3 shows an other embodiment of the duct 5 of the dispensing device 1 ac-cording to the present invention. Here, the duct 5 is additionally or alterna-tively used as a reservoir (storage chamber 10) for the powder 2. In this case, the separate or additional storage chamber 10 is not required. Instead, the duct is designed to enable sufficient mixing of the gas with the powder 2, and sufficient de-agglomeration of the powder 2 can be achieved.

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

In the embodiment according to Fig. 3, ten diversion portions 12 and, thus, ten impaction points or solid surfaces 14 are formed.

Fig. 4 shows another embodiment with a preferably zigzag-like or staggering duct configuration. Here, the duct 5 comprises at least two diversion portions 12 where the duct 5 is angled by more than 90 degrees, in particular more than 135 degrees, preferably about 150 degrees, resulting in very good powder de-agglomeration.
Fig. 5 shows another embodiment of the duct 5 of the dispensing device 1 ac-cording to the present invention. Here, the duct 5 is diverted into two opposite directions at a fork portion 15 so that the powder 2 is impacted on two solid surfaces 14 for powder de-agglomeration. In particular, the duct 4 is diverted or branched into two separate branches or ducts 5a and 5b. Each branch 5a, 5b comprises a diversion portion 12 as discussed above. In particular, the outlet directions of the two branches 5a, 5b are essentially parallel in the embodi-ment according to Fig. 5. However, other duct or outlet configurations are possible as well.
In the embodiment according to Fig. 5, three impaction points 14 are formed where the powder particles hit and, thus, de-agglomeration takes place.

Fig. 6 shows a similar embodiment. Here, the duct branches 5a and 5b are an-gled by more than 90 degrees at the respective diversion portions 12 and, then, bent in opposite directions so that the outlet directions are angled or inclined by each other and/or that a diffuser 16 is formed at or in the outlet 6 of the channel 5 in order to slow the exit velocity.

Fig. 7 shows another embodiment, where the branches 5a and 5b of the duct 5 exit with at least substantially parallel outlet direction similar to the embodi-ment according to Fig. 5, but closer together.

Fig. 8 shows another, similar embodiment where the two branches 5a and 5b of the duct 5 are joined at the outlet 6.

Fig. 9 shows a further embodiment similar to Fig. 8, wherein the diffuser 16 is formed at the common outlet 6 of the branches 5a and 5b.
Fig. 10 shows a further embodiment of the duct 5 of the dispensing device 1 according to the present invention. In this case, the duct 5 is substantially a sequence of two duct arrangements according to Fig. 8. The interconnection 17 forms the outlet of the first duct arrangement and the inlet of the second duct arrangement which are connected in series.

In this embodiment, the duct 5 comprises multiple, namely at least two fork portions 5 where the duct 5 is respectively diverted or split up into two, pref-erably directly opposite directions.
It has to be noted that the different duct arrangements and/or different features of the duct arrangements can be combined in any suitable manner.

Fig. 11 shows in a schematic sectional view another duct arrangement with a means for slowing down the velocity which forms a multiple powder jet spray impinging means 18. The means 18 forms multiple - at least two - powder spray jets P which impinge, i.e. hit each other as indicated in Fig. 11. In this embodiment, the duct 5 divides into two sections 5a and 5b that are designed such that the openings or outlets 6 are inclined to each other so that the pow-der jets P ejecting from the portions 5a and 5b are inclined to each other and impinge. For example, a flow divider 19 or any guiding means can be located in the flow path to form the at least two sections 5a and 5b of the duct 5 as shown in Fig. 11.

The impinging angle a between the powder jets P is between 30 to 180 , preferably at least 90 , in particular about 90 to 150 . The impinging of the powder jets P results in a decrease of the velocity of the spray 3 and/or in a de-agglomeration of the powder 2 andJor in separation of drug particles from a carrier and/or in better focusing of the spray 3. These effects depend on the impinging angle a. A larger impinging angle a results in better effects. In contrast to liquid jets, an impinging angle a of 90 and more is possible and preferred. These angles also apply for the following embodiments.

The duct 5 is preferably at least tangentially connected to the storage chamber in the embodiment shown in Fig. 11. Preferably, the duct 5 is connected to 10 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 particu-lar, the gas inlet 11 is connected also tangentially to the storage chamber 10, such that swirls are generated when entering the gas with a swirl direction supporting discharge of the mixture of gas and powder 2 through the duct 5 which connects tangentially to the rotational direction of the swirl.

Fig. 12 shows in a schematic sectional view another embodiment of the pow-der jet impinging means 18. Here, two or more ducts 5 comprise inclined or outlet sections 5c which are inclined to each other so that the powder jets P
ejected from outlet sections 5c impinge with each other.

The embodiments according to Fig. 11 to 12 are also suitable for impinging more than two powder jets P. For example, it is possible to have similar ar-rangements in the cross sectional planes perpendicular to the drawing plane resulting in four outlet directions and powder jets P arranged on the surface of a conus. However, multiple other arrangements with similar effects are possi-ble.

It has to be added that the cross sections of the duct sections 5a to 5c are pref-erably not necessarily rectangular or flat, but can have any suitable cross sec-tional shape.

Preferably, the gas inlet 11 or the gas supply comprises a smaller cross sec-tional area than the duct 5 or outlet 6 so that the gas flow is determined by the inlet and not by the outlet side, i.e. not by the duct 5 or outlet 6, during dis-pensing. Then, the mixture of gas and powder 2 is forced by a comparatively low gas pressure through the duct 5 and/or any other suitable outlet such as outlet 6, wherein the gas flow is controlled during this phase at least mainly by the cross section of the gas inlet 11 or any other restriction stream up of gas inlet 11. Due to the comparatively low gas pressure for discharging the pow-der 2 through duct 5 and/or outlet 6 a low discharge velocity and, thus, a low propagation velocity of the spray 3 can be achieved. In addition, the means for slowing down the propagation velocity of the spray 3, in particular the powder jet impinging means 18, can be used to further decrease the propagation ve-locity of the spray 3.
Preferably, the spray 3 has a mean velocity (taken 10 cm from the outlet /
mouthpiece) of less than 2 m/s, in particular less than 1 m/s. Preferably, the mean duration of the spray 3 is at least 0.2 or 0.3 s, in particular about 0.5 to 2.
Preferably the duct 5 has a flat (inner) cross section. Fig. 13a to 13c show po-tential cross sections 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 by two curved portions. Fig. 13c shows an oval or elliptical cross section.

In the present invention, a cross section is considered to be flat when the ratio of the largest side dl to the smallest side d2 of the cross section is at least 2Ø
Preferably, the ratio is between 3 to 50 and in particular about 5 to 70. It is pointed out that the cross sections shown in Fig. 6 are not in scale.

The largest side dl is preferably between 0.5 to 5 mm, in particular 1 to 3 mm.
Most preferably, the ratio of the largest side dl to the (desired) fine particle size (mass mean diameter of the powder particles or drug particles of the spray 3) is less than 500, preferably less than 300, in particular about 30 to 300.

The smallest side d2 is preferably between 0.05 to 0.5 mm, in particular about 0.07 to 0.25 mm. Most preferably, the ratio of the smallest side d2 to the mass mean (desired) fine particle size (mass mean diameter of the powder particles / drug particles of the spray 3) is less than 50, preferably less than 30, in par-ticular about 3 to 20.

The length of the duct 5 preferably means the length with the flat cross sec-tion. Thus, the duct 5 can have a larger length, i.e. further portions with an-other cross sectional shape and/or with a larger cross sectional area so that the influence of these other portions is low on the mixture of gas and powder 2 in comparison to the portion of the duct 5 with the flat cross section. However, the cross sectional area and/or the shape of the flat cross section may vary over the length of the duct 5 (the portion with the flat cross section). Thus, it is possible that the cross sectional area of the duct 5 tapers from the inlet to the outlet or vice versa.

Most preferably, the duct 5 comprises at least one portion of flat cross section with constant cross section area, i.e. constant diameter and/or shape.

The length of the duct 5 - i.e. the portion with flat cross section - may be in the range of 3 mm to 80 mm, in particular 5 to 15 mm. Preferably, the duct length is adapted to the mean hydraulic diameter of the duct 5 such that the ra-tio of the length of the duct 5 to the mean hydraulic diameter is at least 5, in particular about 10, preferably 20 to 60, or more, wherein the hydraulic di-ameter is defined as the ratio of four cross sectional areas over the duct pe-rimeter.

The diameter of the preferably circular or cylindrical or conical chamber 10 - depends on the volume of mass of the respective dose of powder 2. A single dose may have e.g. 1 to 2 mg (pure drug without carrier) or 2 to 10 mg (blend of drug with carrier, in particular lactose). In the first case, the range of the di-ameter is preferably 1.5 to 2.5 mm. In the second case, the range of the diame-ter is preferably between 2 and 5 mm. Preferably, the cross section of the duct 5 varies in a similar manner. For example, the smallest side d2 is about 0.07 to 0.1 mm in the first case and about 0.15 to 0.25 mm in the second case. The larger (inner) side dl does not depend so strongly on the powder or particle size. Preferably, it is in the range of about 1 to 2 mm in the first case and 1 to 3 mm in the second case.

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

Preferably, the duct 5 is moulded and/or formed by a flat groove with a cover.
The dispensing device 1 or storage device 4 may comprise multiple ducts 5 for dispensing simultaneously one dose of powder 2, in particular for increas-ing the total mass flow or output of dispensed powder 2 so that a desired dose can be discharged or dispensed in a sufficiently short time as desired and/or required.

Fig. 14 shows another embodiment of the dispensing device 1 in a very sche-matic sectional view. In this embodiment, the storage device 4 is a preferably disc-like cartridge, container, blister or the like with multiple storage cavities.
The storage device 4 can be rotated or indexed stepwise so that the powder 2 can be dispensed from the storage cavities 10 one after the other. In this em-bodiment, the gas may be supplied axially, and the mixture of gas and powder 2 may be dispensed radially, in particular into the mouthpiece 20 for a user or patient (not shown). Preferably, the powder 2 is dispensed through at least one duct 5 and/or a outlet 6 directly into a mouthpiece 20. Most preferably, the duct 5 / outlet 6 is located within the mouthpiece 20 and, in particular, set back with regard to the opening of the mouthpiece 20. This applies preferably also to the dispensing device I shown in Fig. 1 and 2.

It has to be noted, that the present invention, in particular the dispensing de-vice 1 and/or the storage device 4, can be used for dispensing one drug, a blend of drugs or at least two or three separate drugs. In the latter case, the separate drugs are stored in separate storage chambers 10 and, during the dis-pensing operation, the drugs are mixed either in a common mixing chamber or in their respective storage chambers 10 with the gas. Further, the separate drugs can be discharged through a common duct 5 or outlet 6 or through sepa-rate ducts 5 or outlets 6. In the latter case, the separate drugs will be mixed af-ter leaving the separate ducts 5 / outlets 6 or in the mouthpiece 31 or in any other suitable (additional) mixing chamber. It is also possible to mix the sepa-rate drugs by impinging powder jets of the separate drugs. For dispensing the separate drugs, it is possible to use a common gas supply or means for pres-surizing gas such as the air pump 7 or separate gas supplies / means for pro-viding pressurized gas.

In the following, two examples are described which show the effect of the present invention.

Example 1: A blend of 90.0 % by weight of lactose 200, of 9.7 % by weight of fine lactose, and of 0.3 % by weight of Tiotropium was used. The mean parti-cle diameter of lactose 200 was about 45 gm, of fine lactose about 4 m and of Tiotropium about 4 m. About 5.5 mg of the blend was positioned as pow-der 2 in the storage and mixing chamber 10 which had a substantially cylin-drical shape with a diameter of 3 mm and an axial length of 3 mm. 5 ml of compressed air was supplied via the gas inlet having an inlet orifice of 0.5 mm into the chamber 10 with a gauge pressure of about 100 kPa. The powder 2 was dispensed via duct 5 of substantially rectangular cross section having a smallest side of about 0.18 mm and a largest side of about 1.5 mm. The duct 5 divided into two duct sections 5a and 5b (in particular as shown in Fig. 11), wherein each section had a substantially rectangular cross section with a smallest side of about 0.18 mm and the largest side of about 0.75 mm. The to-tal length of the duct 5 including the sections 5a, 5b was about 8 mm. The re-sult was that 100 % of the metered mass, i.e. all powder 2 in chamber 10, was dispensed. Approximately 50% of both diameter mean and mass mean fine fraction was measured on a Anderson Cascade Impactor at both 30 and 60 1/min.

Example 2: About 1.5 mg of Fenoterol with a mean particle diameter of 4 m was positioned as powder 2 in the storage and mixing chamber 10 which had a substantially cylindrical shape with a diameter of 2 mm and an axial length of 2 mm. 5 ml of compressed air was supplied via the gas inlet having an inlet orifice of 0.5 mm into the chamber 10 with a gauge pressure of about 150 kPa.
The powder 2 was dispensed via a duct 5 of substantially rectangular cross section having a smallest side of 0.075 mm and a largest side of 1.5 mm. The duct 5 divided into two duct sections 5a and 5b (in particular as shown in fig.

11), wherein each section had a substantially rectangular cross section with a smallest side of about 0.075 mm and the largest side of about 0.75 mm. The total length of the channel including the sections 5a, 5b was about 8 mm. The result was that 100 % of the metered mass, i.e. all powder 2 in chamber 10, was dispensed. Approximately 45% of both diameter mean and mass mean fine fraction was measured on a Anderson Cascade Impactor at both 30 and 60 1/min.

The powder 2 or drug may contain any one of the following substances or any mixtures thereof. It might contain additional pharmacologically active sub-stances or mixtures of substances, preferably selected from those groups:

Anticholinergica:
Anticholinergica preferably selected from the group consisting of tiotropium, tiotropiumbromide, oxitropiumbromide, flutropiumbromide, ipratropiumbro-mide, glycopyrroniumsalts, trospiumchloride, tolterodin, 2,2-diphenylpropi-onacidtropenolester-methobromide, 2,2-diphenylpropionacidscopinester-methobromide, 2-fluoro-2,2-diphenylacidicacidscopinester-methobromide, 2-fluoro-2,2-diphenylacidicacidtropenolester-methobromide, 3,3',4,4'-tetrafluor-benzilacidtropenolester-methobromide, 3,3',4,4'-tetrafluorbenzilacidscopi-nester-methobromide, 4,4'-difluorbenzilacidtropenolester-methobromide, 4,4'-difluorbenzilacidscopinester-methobromide, 3,3'-difluorobenzilacidtropeno-lester-methobromide, 3,3'-difluorobenzilacidscopinester-methobromide, 9-hy-droxy-fluoren-9-carbonacidtropenolester -methobromide, 9-fluoro-fluoren-9-carbonacidtropenolester -methobromide, 9-hydroxy-fluoren-9-carbonacid-scopinester -methobromide, 9-fluoro-fluoren-9-carbonacidscopinester-metho-bromide, 9-methyl-fluoren-9-carbonacidtropenoleste- methobromide, 9-methyl-fluoren-9-carbonacidscopineste- methobromide, benzilacidcyclopro-pyltropinester-methobromide, 2,2-diphenylpropionacidcyclopropyltropinester -methobromide, 9-hydroxy-xanthen-9-carbonacidcyclopropyltropinester-methobromide, 9-methyl-fluoren-9-carbonacidcyclopropyltropinester-metho-bromide, 9-methyl-xanthen-9-carbonacidcyclopropyltropinester -methobro-mide, 9-hydroxy-fluoren-9-carbonacidcyclopropyltropinester -methobromide, 4,4'-difluorbenzilacidmethylestercyclopropyltropinester -methobromide, 9-hydroxy-xanthen-9-carbonacidtropenolester -methobromide, 9-hydroxy-xan-then-9-carbonacidscopinester methobromide, 9-methyl-xanthen-9-carbo-nacidtropenolester -methobromide, 9-methyl-xanthen-9-carbonacidscopine-ster -methobromide, 9-ethyl-xanthen-9-carbonacidtropenolester methobro-mide, 9-difluormethyl-xanthen-9-carbonacidtropenolester -methobromide, 9-hydroxymethyl-xanthen-9-carbonacidscopinester -methobromide, optionally in the form of the racemates, the enantiomers, the diastereomers and option-ally the pharmacologically acceptable acid addition salts and the hydrates thereof.

Beta-sympathomimetica:
Beta-sympathomimetica preferably selected from the group consisting of al-buterol, bambuterol, bitolterol, broxaterol, carbuterol, clenbuterol, fenoterol, formoterol, hexoprenaline, ibuterol, indacterol, isoetharine, isoprenaline, levosalbutamol, mabuterol, meluadrine, metaproterenol, orciprenaline, pir-buterol, procaterol, reproterol, rimiterol, ritodrine, salmeterol, salmefamol, so-terenot, sulphonterol, tiaramide, terbutaline, tolubuterol, CHF-1035, HOKU-81, KUL-1248, 3-(4-{6-[2-hydroxy-2-(4-hydroxy-3-hydroxymethyl-phenyl)-ethylamino]-hexyloxy}-butyl)-benzenesulfoneamide, 5-[2-(5,6-Diethyl-indan-2-ylamino)-1-hydroxy-ethyl]-8-hydroxy-lH-quinolin-2-one, 4-hydroxy-7-[2-{ [2- { [3-(2-phenylethoxy)propyl]sulphonyl } ethyl]-amino} ethyl]-2(3H)-2o benzothiazolone, 1-(2-fluoro-4-hydroxyphenyl)-2-[4-(1-benzimidazolyl)-2-methyl-2-butylamino]ethanol , 1-[3-(4-methoxybenzyl-amino)-4-hydroxy-phenyl]-2-[4-(1-benzimidazolyl)-2-methyl-2-butylamino]ethanol , 1-[2H-5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-y1]-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-butyloxyphenyl)-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-hydroxy-2-isopropylaminobutyl)-2H-1,4-benzoxazin-3-(4H)-one, 1-(4-amino-3-chloro-5-trifluormethylphenyl)-2-tert.-butylamino)ethanol und 1-(4-ethoxycarbonylamino-3-cyano-5-fluorophenyl)-2-(tert.-butylamino)ethanol, optionally in the form of the race-mates, the enantiomers, the diastereomers and optionally the pharmacologi-cally acceptable acid addition salts and the hydrates thereof.

Steroids:

Steroids preferably selected from the group consisting of prednisolone, pred-nisone, butixocortpropionate, RPR-106541, flunisolide, beclomethasone, triamcinolone, budesonide, fluticasone, mometasone, ciclesonide, rofleponide, ST- 126, dexamethasone, 6a,9a-difluoro-l7a-[(2-furanylcarbonyl)oxy]-11 b-s hydroxy-16a-methyl-3-oxo-androsta-1,4-dien-17b-carbothionacid (S)-fluoromethylester, 6a,9a-difluoro-1 lb-hydroxy-16a-methyl-3-oxo-l7a-propionyloxy-androsta-1,4-dien-l7b-carbothionacid (S)-(2-oxo-tetrahydro-furan-3 S-yl)ester and etiprednol-dichloroacetat (BNP-166), optionally in the form of the racemates, the enantiomers, the diastereomers and optionally the pharmacologically acceptable acid addition salts and the hydrates thereof.
PDEIV-inhibitors:
PDE IV-inhibitor preferably selected from the group consisting of enprofyllin, theophyllin, roflumilast, ariflo (cilomilast), CP-325,366, BY343, D-4396 (Sch-351591), AWD-12-281 (GW-842470), N-(3,5-Dichloro-l-oxo-pyridin-4-yl)-4-difluoromethoxy-3-cyclopropylmethoxybenzamide, NCS-613, pu-mafentine, (-)p-[(4aR*, l ObS*)-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-methoxyphenyl]-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)cyclohexan-l-carbonacid], 2-carbomethoxy-4-cyano-4-(3-cyclopropylmethoxy-4-difluoromethoxyphenyl)cyclohexane-l-on, cis[4-cyano-4-(3-cyclopropylmethoxy-4-difluoromethoxyphenyl)cyclohexane-l-o1], (R)-(+)-ethyl [4-(3 -cyclopentyloxy-4-methoxyphenyl)pyrrolidin-2-yliden] acetate, (S)-(-)-ethyl [4-(3-cyclopentyloxy-4-methoxyphenyl)pyrrolidin-2-yliden] acetate, CDP840, Bay-198004, D-4418, PD-168787, T-440, T-2585, arofyllin, atizo-ram, V-11294A, Cl-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]pyridin and 9-cyclopentyl-5,6-dihydro-7-ethyl-3-(tert-butyl)-9H-pyrazolo[3,4-c]-1,2,4-triazolo[4,3-a]pyridine, optionally in the form of the racemates, the enantiomers, the diastereomers and optionally the phar-macologically acceptable acid addition salts and the hydrates thereof.
LTD4-Antagonists:

LTD4-antagonist preferably selected from the group consisting of montelu-kast, 1-(((R)-(3-(2-(6,7-difluoro-2-quinolinyl)ethenyl)phenyl)-3-(2-(2- hy-droxy-2-propyl)phenyl)thio)methylcyclopropan-acidicacid, 1-(((1(R)-3(3-(2-(2,3 -dichlorothieno[3,2-b]pyridin-5-yI)-(E)-ethenyl)phenyl)-3-(2-(1-hydroxy-1-methylethyl)phenyl)propyl)thio)methyl)cyclopropanacidicacid, pranlukast, zafirlukast, [2-[[2-(4-tert-butyl-2-thiazolyl)-5-benzofuranyl]oxymethyl]phenyl]acidicacid, MCC-847 (ZD-3523), MN-001, MEN-91507 (LM-1507), VUF-5078, VUF-K-8707 und L-733321, option-ally in the form of the racemates, the enantiomers, the diastereomers and op-to tionally the pharmacologically acceptable acid addition salts and the hydrates thereof.

EGFR-Kinase-Inhibitors:
cetuximab, trastuzumab, ABX-EGF, Mab ICR-62, 4-[(3-Chlor-4-fluorophenyl)amino]-6- { [4-(rnorpholin-4-yl)-1-oxo-2-buten-1-yl] amino } -7-cyclopropylmethoxy-chinazolin, 4-[(R)-(1-phenyl-ethyl)amino]-6-{[4-(morpholin-4-yl)-1-oxo-2-buten-l-yl]amino}-7-cyclopentyloxy-chinazolin, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{ [4-((R)-6-methyl-2-oxo-morpholin-4-yl)-1-oxo-2-buten-l-yl]amino}-7-[(S)-(tetrahydrofurane-3-yl)oxy]-chinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-[2-((S)-6-methyl-2-oxo-morpholine-4-yl)-ethoxy]-7-methoxy-chinazolin, 4-[(3-chloro-4-fluorophenyl)amino]-6-( {4-[N-(2-methoxy-ethyl)-N-methyl-amino]-1-oxo-2-buten-1-yl}amino)-7-cyclopropylmethoxy-chinazoline, 4-[(R)-(1-Phenyl-ethyl)amino]-6-( {4-[N-(tetrahydropyrane-4-yl)-N-methyl-amino]-1-oxo-2-buten-1-yl}amino)-7-cyclopropylmethoxy-chinazoline, 4-[(3-chloro-4-fluorophenyl)amino]-6-( {4-[N-(2-methoxy-ethyl)-N-methyl-amino]-1-oxo-2-buten-1-yl}amino)-7-cyclopentyloxy-chinazoline, 4-[(3-chloro-4-fluorophenyl)amino]-6- { [4-(N,N-dimethylamino)-1-oxo-2-buten-l-yl]amino}-7-[(R)-(tetrahydrofuran-2-yl)methoxy]-chinazolin, 4-[(3-Ethinyl-phenyl)amino]-6,7-bis-(2-methoxy-ethoxy)-chinazoline, 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-dimethylamino)-1-oxo-2-buten-1-yl]amino}-7-ethoxy-chinoline, 4-[(R)-(1-phenyl-ethyl)amino]-6-{[4-((R)-6-methyl-2-oxo-morpholin-4-yl)-1-oxo-2-buten-l-yl]amino}-7-methoxy-chinazoline, 4-[(3-chloro-4-fluorophenyl)amino]-6- { [4-(morpholine-4-yl)-1-oxo-2-buten-l-yl]amino}-7-[(tetrahydrofurane-2-yl)methoxy]-chinazoline, 4-[(3-ethinyl-phenyl)amino]-6-{[4-(5,5-dimethyl-2-oxo-morpholin-4-yl)-1-oxo-2-buten-l-yl]amino}-chinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{2-[4-(2-oxo-morpholine-4-y1)-piperidine-l-yl]-ethoxy }-7-methoxy-chinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(trans-4-amino-cyclohexan-l-yloxy)-7-methoxy-chinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(trans-4-methansulfonylamino-cyclohexan-1-yloxy)-7-methoxy-chinazoline, 4-[(3-chloro-4-fluorc-pheny 1)am ino]-6-(tetrahydropyrane-3 -yloxy)-7-methoxy-chinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{ 1-[(morpholine-4-yl)carbonyl]-piperidin-4-yloxy }-7-methoxy-chinazoline, 4-[(3-chloro-4-1o fluoro-phenyl)amino]-6-(piperidine-3-yloxy)-7-methoxy-chinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-[ 1-(2-acetylamino-ethyl)-piperidin-4-yloxy]-7-methoxy-chinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(tetrahydropyran-4-yloxy)-7-ethoxy-chinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6- {trans-4-[(morpholin-4-yl)carbonylamino]-cyclohexan-l-yloxy}-7-methoxy-chinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6- { 1-[(piperidin-1-yl)carbonyl]-piperidin-4-yloxy }-7-methoxy-chinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(cis-4- {N- [(morpholin-4-yl)carbonyl]-N-methyl-amino } -cyclohexan-1-yloxy)-7-methoxy-chinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(trans-4-ethansulfonylamino-cyclohexan-l-yloxy)-7-methoxy-chinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-methansulfonyl-piperidin-4-yloxy)-7-(2-methoxy-ethoxy)-chinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-[ 1-(2-methoxy-acetyl)-piperidin-4-yloxy]-7-(2-methoxy-ethoxy)-chinazoline, 4-[(3-ethinyl-phenyl)amino]-6-(tetrahydropyran-4-yloxy]-7-methoxy-chinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(cis-4- {N- [(piperidin-1-yl)carbonyl]-N-methyl-amino }-cyclohexan-1-yloxy)-7-methoxy-chinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6- { cis-4-[(morpholin-4-yl)carbonylamino]-cyclohexan-l-yloxy}-7-methoxy-chinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{ 1-[2-(2-oxopyrrolidin-1-yl)ethyl]-piperidin-4-yloxy }-7-rnethoxy-chinazoline, 4-[(3 -ethinyl-pheny l)amino] -6-(1-acetyl-piperi din-4-yloxy )-7-methoxy-chinazoline, 4-[(3-ethinyl-phenyl)amino]-6-(1-methyl-piperidin-4-yloxy)-7-methoxy-chinazoline, 4-[(3-ethinyl-phenyl)amino]-6-(1-methansulfonyl-piperidin-4-yloxy)-7-methoxy-chinazolin, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-methyl-piperidin-4-yloxy)-7(2-methoxy-ethoxy)-chinazoline, 4-[(3-ethinyl-phenyl)amino]-6-{ 1-[(morpholin-4-yl)carbonyl]-piperidin-4-yloxy }-7-methoxy-chinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{ 1-[(N-methyl-N-2-methoxyethyl-amino)carbonyl]-piperidin-4-yloxy}-7-methoxy-chinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-ethyl-piperidin-4-yloxy)-7-methoxy-chinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-[cis-4-(N-methansulfonyl-N-methyl-amino)-cyclohexan-1-yloxy]-7-methoxy-chinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-[cis-4-(N-acetyl-N-methyl-amino)-cyclohexan-l-yloxy]-7-methoxy-chinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(trans-4-methylamino-cyclohexan-1-yloxy)-7-methoxy-chinazoline, 4-[(3-chloro-4-to fluoro-phenyl)amino]-6-[trans-4-(N-methansulfonyl-N-methyl-amino)-cyclohexan-1-yloxy]-7-methoxy-chinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(trans-4-dimethylamino-cyclohexan-1-yloxy)-7-methoxy-chinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(trans-4-{N-[(morpholin-4-yl)carbonyl]-N-methyl-amino} -cyclohexan-1-yloxy)-7-methoxy-t 5 chinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-[2-(2,2-dimethyl-6-oxo-morpholin-4-yl)-ethoxy]-7-[(S)-(tetrahydrofuran-2-yl)methoxy]-chinazoline, 4- [(3 -chloro-4-fluoro-pheny 1)amino]-6-(1-methansulfonyl-piperidin-4-yloxy)-7-methoxy-chinazoline, 4-[(3-chlor-4-fluoro-phenyl)amino]-6-(1-cyano-piperidin-4-yloxy)-7-methoxy-chinazoline, und 4-[(3-chloro-4-fluoro-20 phenyl)amino]-6-{ 1-[(2-methoxyethyl)carbonyl]-piperidin-4-yloxy}-7-methoxy-chinazoline, optionally in the form of the racemates, the enanti-omers, the diastereomers and optionally the pharmacologically acceptable acid addition salts and the hydrates thereof.

25 Moreover, the compound could be from the group of betamimetika, antialler-gika, derivates of ergotalcaloids, triptane, CGRP-antagonists, phosphodi-esterase-V-inhibitores, optionally in the form of the racemates, the enanti-omers, the diastereomers and optionally the pharmacologically acceptable acid addition salts and the hydrates therof.
The pharmacologically acceptable acid addition salts could be from the group of hydrochloride, hydrobromide, hydroiodide, hydrosulfate, hydrophosphate, hydromethansulfonate, hydronitrate, hydromaleate, hydroacetate, hydroben-zoate, hydrocitrate, hydrofumarate, hydrotartrate, hydrooxalate, hydrosucci-nate, hydrobenzoate und hydro-p-toluolsulfonate, preferably hydrochloride, hydrobromide, hydrosulfate, hydrophosphate, hydrofumarate and hy-dromethansulfonate.

As antiallergika: disodiumcromoglicate, nedocromil.
As derivates of alkaloides: dihydroergotamine, ergotamine.

Moreover, inhalable macromolecules can be used as pharmacologically active substances, as disclosed in EP 1 003 478.
For inhalation purposes pharmaceuticals, formulations and mixtures of phar-maceuticals with the above named pharmacologically active substances can be used, as well as their pharmacologically active salts, esters and combinations of the pharmacologically active substances, salts and esters.
Moreover, inhalable macromolecules can be used as pharmacologically active substances, as disclosed in EP 1 003 478.

Claims

1. Dispensing device (1) for dispensing powder (2), in particular containing or consisting of a drug, as a spray (3) including fine powder particles, the dis-pensing device (1) comprising a duct (5) through which the powder (2) is dis-pensable by gas pressure for de-agglomerating the powder (2), characterized in that the duct (5) is angled by at least about 90 degrees at a diversion portion (12) und/or diverted into two opposite directions at a fork portion (15) so that the powder (2) is impacted on to a solid surface (14) for powder de-agglomeration.

2. Dispensing device according to claim 1, characterized in that the duct (5) comprises multiple diversion portions (12).

3. Dispensing device according to claim 1 or 2, characterized in that the duct (5) comprises multiple fork portions (15).

4. Dispensing device according to any one of the preceding claims, charac-terized in that the duct (5) is designed such that the powder (2) is impacted on to multiple solid surfaces or surface portions (14) for powder de-agglomeration.

5. Dispensing device according to any one of the preceding claims, charac-terized in that the duct (5) is bent and/or angled alternately in opposite direc-tions.

6. Dispensing device according to any one of the preceding claims, charac-terized in that the duct (5) is a capillary.

7. Dispensing device according to any one of the preceding claims, charac-terized in that the duct (5) directly exits into a mouthpiece (20) of the dispens-ing device (1).

8. Dispensing device according to any one of the preceding claims, charac-terized in that the duct (5) has a flat cross section, preferably wherein the ratio of the largest side (d1) to the smallest side (d2) of the flat cross section is at least 2Ø

9. Dispensing device according to claim 8, characterized in that the largest side (d1) is between 0.5 to 5 mm, preferably about 1 to 3 mm, and/or that the smallest side (d2) is between 0.05 to 0.5 mm, preferably about 0.07 to 0.25 mm, and/or that the flat cross section is substantially oval or rectangular.

10. Dispensing device according to any one of the preceding claims, charac-terized in that the dispensing device (1) comprises means for providing pres-surized gas, in particular air, for forcing the powder (2) through the duct (5) and/or dispensing the powder (2).

11. Dispensing device according to any one of the proceeding claims, charac-terized in that the dispensing device (1) comprises an air pump (7) as means for providing pressurized gas, wherein the air pump (7) is preferably manually operated.

12. Dispensing device according to any one of the preceding claims, charac-terized in that the dispensing device (1) is adapted to receive or comprises a preferably replaceable storage device (4) with a single dose of powder (2) or with multiple separate doses of powder (7), so that the doses are dispensable subsequently.

13. Dispensing device according claim 12, characterized in that the storage device (4) is constructed such that each dose of powder (2) is dispensed through a separate duct (5) or outlet (6).

14. Dispensing device according to claim 12 or 13, characterized in that the storage device (4) is a cartridge, blister, capsule or container.

15. Dispensing device according to any one of the preceding claims, charac-terized in that the dispensing device (1) comprises multiple ducts (5) for dis-pensing simultaneously one dose of powder (2), in particular for increasing the total mass flow of dispensed powder (2).

16. Dispensing device according to any one of the preceding claims, charac-terized in that the dispensing device (1) and/or the storage device (4) is con-structed such that each dose of powder (2) is dispensed through a separate or unused duct (5).

17. Dispensing device according to any one of the preceding claims, charac-terized in that the dispensing device (1) comprises a means for slowing down the propagation velocity of the spray (3), in particular a diffuser (16), prefera-bly at the exit of the duct (5).

18. Dispensing device according to any one of the preceding claims, charac-terized in that the dispensing device (1) comprises a powder jet impinging means (18) for impinging at least two powder jets (P) to further de-agglomerate the powder (2) and/or to slow down the propagation velocity of the spray (3) and/or to mix separate powders (2).

19. Dispensing device according to any one of the preceding claims, charac-terized in that the mean size of the powder particles is 2 to 7 µm when the powder (2) is a pure drug or a blend of drugs, or that the mean size of the powder particles is 20 to 300 µm when the powder (2) is a blend of a carrier, such as lactose, with at least one drug.

20. Dispensing device according to any one of the preceding claims, charac-terized in that the dispensing device (1) is a dry powder an inhaler.