WO2008092864A1

WO2008092864A1 - Method and devices for aerosolizing a drug formulation

Info

Publication number: WO2008092864A1
Application number: PCT/EP2008/051052
Authority: WO
Inventors: Kristian GLEJBØL; Dan Nørtoft SØRENSEN; Frank Daniel Mersebach; Martin VON BÜLOW; Thomas Ørts PEDERSEN; Ulrik Ullum; Sigurd Ove Frederiksen; Erik Stentoft
Original assignee: Novo Nordisk A/S
Priority date: 2007-01-29
Filing date: 2008-01-29
Publication date: 2008-08-07

Abstract

The present invention provides a method of aerosolizing powder, comprising the steps of providing a receptacle member (51) having a receptacle cavity (52) containing powder drug, providing a device (1) with an airway cavity (30) comprising a tangential air inlet (32) and an air outlet (35), the airway cavity comprising an opening (31) having a closed state and an open state in which it is in flow communication with the receptacle cavity, providing a flow of air through the air inlet when the airway cavity is in its closed state, thereby creating a swirl of air in a portion of the airway, and arranging the receptacle cavity in flow communication with the • airway cavity. The swirl of air in the airway cavity hereby creates a flow of air in the receptacle cavity, the combined flow of air in the airway cavity and in the receptacle cavity resulting in powder de-agglomeration and transport of the de-agglomerated powder.

Description

METHOD AND DEVICES FOR AEROSOLIZING A DRUG FORMULATION

The invention relates to devices, technologies and methods for the administration of a substance by inhalation, especially for administering medicaments to the lungs of a patient by the aerosolization of pharmaceutical formulations using energy created by patient inhalation. The pharmaceutical formulations may be in the form of a powder formulation.

BACKGROUND OF THE INVENTION

In the disclosure of the present invention reference is mostly made to the treatment of diabetes by the administration of blood glucose controlling drugs such as insulin or GLP-1 as well as their analogues, however, this is only an exemplary use of the present invention.

Effective drug delivery to a patient is a critical aspect of any successful drug therapy, and a variety of drug delivery techniques have been proposed. For example, one convenient method is the oral delivery of pills, capsules and the like. However, oral delivery can in some cases be undesirable in that many drugs are degraded in the digestive tract before they can be absorbed. Another technique is subcutaneous injection as traditionally used for the administration of insulin which for the time being cannot be administered orally. One disadvan- tage to this approach is low patient acceptance, for which reason it has been proposed to use pulmonary delivery also for insulin.

Of particular interest to the invention are pulmonary delivery techniques which rely on the inhalation of a pharmaceutical formulation by the patient so that the active drug within the dispersion can reach the distal (alveolar) regions of the lung. A variety of aerosolization systems have been proposed to disperse pharmaceutical formulations. For example, US 5,785,049 and US 5,740,794, the disclosures of which are herein incorporated by reference, describe exemplary powder dispersion devices which utilize a compressed gas to aerosolize a powder. Other types of aerosolization systems include so-called MDI's (which typically have a drug that is stored in a propellant), nebulizers (which aerosolize liquids using compressed gas, usually air), and the like.

Another technique which is of interest to the invention is the use of inspired gases to disperse the pharmaceutical formulation. In this way, the patient is able to provide the energy needed to aerosolize the formulation by the patient's own inhalation. This insures that aerosol generation and inhalation are properly synchronized just as it may be possible to provide a device which is simpler to manufacture and more economical in use. Utilization of the patient's inspired gases can be challenging in several respects.

A challenge in utilizing the patient's inspired gases is that the inspiration flow rate can drasti- cally vary between individuals. Such variability may affect the ability of the formulation to be dispersed within a gas stream, the ability to de-agglomerate a powdered formulation, the ability to effectively empty a given powder dose, and/or the ability of the aerosolized formulation to adequately reach the deep lung, see e.g. US 6,606,992 which are hereby incorporated by reference.

The powder may be provided in bulk form from where a desired amount of powder can be metered and moved into flow communication with the airway through which the patient is inhaling air to the lungs, this allowing the powder to be de-agglomerated and aerosolized. The powder may also be provided in pre-metered doses, the doses typically being contained in sealed containers formed in a carrier, either as a single-dose carrier or a multi-dose carrier. For example, US 6,1 16,239 discloses inhalation devices using a rotationally arranged disc- formed carrier comprising a plurality of powder-filled cavities, whereby rotation of the disc brings a new dose to be inhaled into flow communication with the airway. US 5,873,360 and US 7,171 ,965, which are hereby incorporated by reference, disclose inhalation devices for use with a medicament pack in which a plurality of powder-filled containers (or blisters) is defined between two strip-formed sheets peelable secured to each other. The device comprises means for peeling the sheets apart to open the containers consecutively, and an airway with an outlet communicating with the opened container, through which a user can inhale medicament in powder form from the opened container.

Having regard to the above, it is the object of the present invention to provide devices and methods for regulating and managing the flow of inspired gases that may be utilized when dispersing a pharmaceutical formulation and which assures one or more of the following: enhancing the ability of a formulation to be dispersed within a gas stream produced by patient inhalation, enhancing the ability to de-agglomerate a powdered formulation, enhancing the ability for the patient to use the device in a consistent and correct way, thereby contributing to enhancing the ability of the aerosolized formulation to adequately reach the deep lungs of the patient. It is a further object to provide devices and methods which are user-friendly thereby promoting correct and consistent use of the device.

DISCLOSURE OF THE INVENTION In the disclosure of the present invention, embodiments and aspects will be described which will address one or more of the above objects or which will address objects apparent from the below disclosure as well as from the description of exemplary embodiments.

Thus, in a first aspect, the present invention provides a method of aerosolizing a drug formulation, comprising the steps of (a) providing a receptacle member having a receptacle cavity containing a powder drug, (b) providing a device with an airway cavity comprising a tangential air inlet and an air outlet, the airway cavity comprising an opening having a closed state and an open state in which it is in flow communication with the receptacle cavity, (c) providing a flow of air through the air inlet when the airway cavity is in its closed state, thereby creating a swirl of air in a portion of the airway, and (d) arranging the receptacle cavity in flow communication with the airway cavity. The swirl of air in the airway cavity hereby creates a flow of air in the receptacle cavity, whereby the combined flow of air in the airway cavity and in the receptacle cavity results in powder de-agglomeration and transport of the de- agglomerated powder towards the air outlet.

When in the context of the present invention the term tangential is used, this is not to be understood as a strictly tangential structure but merely as a structure having a tangential com- ponent providing the desired functionality. In the context of the present invention the term de- agglomeration is used for the process in which a powder comprising larger particles (and/or aggregates and/or agglomerates) is processed into an aerosol comprising fine particles suitable for inhalation. This process is also described as de-aggregation just as other terms may be used. The aerosol may comprise particles generally having a diameter of less than 10 μm or less than 5 μm depending on the kind of drug and the intended place of deposition.

In the open state the flow communication between the airway cavity and the receptacle cavity may be gradually enlarged, this allowing a secondary swirl of air to build up in the receptacle before full flow communication is established between the airway cavity and the recep- tacle cavity. To enhance air movement in the receptacle cavity it may open directly into the airway cavity.

The device may be operated manually, however, it may further comprise means for shifting the opening between the closed state and the open state, the shifting means being actuated in response to inhalation through the air outlet, this ensuring that a primary swirl of air is generated before the receptacle cavity opens into the airway cavity. In exemplary embodiments the receptacle member comprises a closure portion and a receptacle cavity portion (and optionally a plurality thereof), the closure portion engaging the airway cavity opening in the closed state, thereby serving as a closure for the airway cavity opening. In such a design the receptacle member and the airway cavity are moveable relative to each other from a first position in which the closure portion closes the airway cavity opening, and a second position in which the airway cavity is in flow communication with the receptacle cavity. As indicated above, such a device may be provided with means for moving the receptacle member between the first and second position, wherein the means for moving the receptacle member is actuated in response to a users inhalation through the air outlet.

As mentioned above, a primary swirl of air may be created in the airway cavity and a secondary swirl of air may be created in the receptacle. The secondary swirl may have a swirl axis which is perpendicular or non-perpendicular to the primary swirl axis.

In a second aspect of the invention an aerosol generating device is provided comprising a receptacle member having a receptacle cavity containing a powder drug, and an airway cavity comprising a tangential air inlet and an air outlet adapted to be connected to the airway of a patient, the airway cavity comprising an opening having a first closed state and a second open state in which it is in flow communication with the receptacle cavity. The device is designed such that a flow of air introduced through the tangential air inlet when the airway cavity opening is in its closed state creates a swirl of air in a portion of the airway, and, when the receptacle cavity is in flow communication with the airway cavity, the swirl of air in the airway cavity creates a flow of air in the receptacle cavity, the combined flow of air in the airway cav- ity and in the receptacle cavity result in powder de-agglomeration and transport of the de- agglomerated powder towards the air outlet. In the open state the flow communication between the airway cavity and the receptacle cavity can be gradually enlarged, just as means for transforming the opening between its first and second state may be provided, wherein the transforming means is actuated in response to inhalation through the air outlet.

In exemplary embodiments the receptacle member comprises a closure portion and a receptacle cavity portion (and optionally a plurality thereof), the closure portion engaging the airway cavity opening in the closed state, thereby serving as a closure for the airway cavity opening. In such a design the receptacle member and the airway cavity are moveable rela- tive to each other from a first position in which the closure portion closes the airway cavity opening, and a second position in which the airway cavity is in flow communication with the receptacle cavity. As indicated above, such a device may be provided with means for moving the receptacle member between the first and second position, wherein the means for moving the receptacle member is actuated in response to a users inhalation through the air outlet.

The means for moving the receptacle member may comprise actuatable drive means for moving the receptacle, and actuatable triggering means for actuating the drive means, the triggering means comprising an element responsive to patient inspiration through the air outlet, e.g. a mechanical member as a membrane or flap, or an electronic pressure or flow transducer.

In an exemplary embodiment the aerosol generating device includes a drug carrier comprising a receptacle member having a receptacle cavity containing a powder drug, and a lid peelably attached to the receptacle member thereby defining a container, the lid comprising a lower surface facing the receptacle member and an opposed upper surface. The device further comprises a peel structure (e.g. a sharp or rounded edge) engaging the upper surface of the peelable lid in sliding engagement therewith, wherein the aerosol generating device is adapted in such a way that pulling the peelable lid results in sliding movement between the peelable lid and the peel structure, thereby opening the container and bringing the receptacle cavity in flow communication with the airway cavity. Such a device may further comprise a guide for guiding the drug carrier, the guide comprising a first portion adapted to engage a portion of the upper surface of the lid, and a second portion comprising the airway cavity opening, the second portion adapted to engage an upper surface portion of the receptacle member, wherein a peel edge is formed between the first portion and the support surface. The peel edge may form a portion of the circumference of the airway cavity opening, this al- lowing the lower surface of the lid foil to be exposed in the airway cavity.

The device may comprise a plurality of individual receptacle members peelably attached to the lid along the length thereof, thereby defining a plurality of containers, or it may comprise an elongate receptacle member having a plurality of receptacle cavities arranged along the length thereof and being peelably attached to the lid, thereby defining a plurality of containers.

In exemplary embodiments the air outlet comprises means for at least partially transforming the air swirl into an axial flow of air. The airway cavity may have a general axis defining a general axis for the generated swirl, with the air outlet being arranged generally co-axially with the airway cavity. Alternatively the outlet may be arranged generally tangentially. In embodiments in which the receptacle cavity and the airway cavity are moveable relative to each other corresponding to a reference plane and where the airway cavity has a configuration generating a swirl of air having a general swirl axis, the airway cavity may have an axis angle relative to the reference plane which may vary between 0-180 degrees in two planes. The actual design may be optimized for e.g. de-agglomeration efficiency, flow resistance and/or device packaging.

In a further embodiment an aerosol generating device adapted to receive a receptacle mem- ber having a receptacle cavity containing a powder drug is provided, e.g. essentially a device as described above but adapted to be used with a separate drug carrier. Such a device comprises an airway cavity comprising a tangential air inlet and an air outlet adapted to be connected to the airway of a patient, wherein the airway cavity comprises an opening adapted to have a first closed state and a second open state in which it can be brought in flow commu- nication with the receptacle cavity. When a flow of air is introduced through the tangential air inlet when the airway cavity opening is in its closed state a swirl of air is created in a portion of the airway, and, when the receptacle cavity is in flow communication with the airway cavity, the swirl of air in the airway cavity creates a flow of air in the receptacle cavity, the combined flow of air in the airway cavity and in the receptacle cavity result in powder de- agglomeration and transport of the de-agglomerated powder towards the air outlet. In exemplary embodiments the device may be modified as described above for the device comprising a drug carrier.

In a yet further aspect an alternative aerosol generating device is provided comprising an air- way cavity comprising a tangential air inlet and an air outlet, a receptacle containing an aero- solizeable drug formulation, wherein, in a situation of use, the receptacle can be arranged in flow communication with the airway cavity, the flow communication being established by an opening between the airway cavity and the receptacle, whereby the airway cavity and the receptacle, corresponding to the flow communication, forms a combined swirl chamber allow- ing a flow of air introduced through the tangential air inlet to create a swirl in the combined cyclone chamber, the swirl thereby extracting drug formulation from the receptacle as air revolves between the airway cavity and the receptacle portion of the airway cavity.

By this arrangement the airway cavity and the receptacle, corresponding to the flow commu- nication, forms a combined swirl chamber allowing a flow of air introduced through the air inlet to create a swirl in the combined swirl chamber, the swirl sweeping at least a portion of the receptacle thereby extracting drug formulation from the receptacle. As appears, this embodiment is not based upon the generation of a secondary swirl in the receptacle, but merely a common swirl. This concept may be realized e.g. when the air flow rate is low or when the receptacle is arranged (fully) in flow communication with the airway cavity before the flow of air is generated.

The combined swirl chamber may have a generally tubular configuration defining a swirl axis and with the air inlet and outlet arranged generally opposed to each other, or it may have a generally disc-formed configuration defining the swirl axis. By the sweeping action of the cy- clone it is secured that for a given flow of air though the airway cavity the rotating air will travel through the cavity a plurality of times and pick up drug formulation before it leaves the airway cavity, this aiding in emptying the receptacle.

The aerosol generating device may be operatable between a first condition in which there is no flow communication between the airway cavity and the receptacle, and a second condition in which there is established flow communication between at least a portion of the airway cavity and at least a portion of the receptacle. The receptacle and the airway cavity may be arranged in alignment with each other in the first condition, the aerosol generating device further comprising closure means between the receptacle and the airway cavity, the closure means being closed corresponding to the first condition and at least partially open corresponding to the second condition. The closure means may be formed from a peelable lid attached to the receptacle.

Many of the features for the above-described aerosol generating device may also be used in such an alternative device, e.g. it may comprise user releasable actuation means for operating the device between the first and second condition. The actuation means may released by a user inhalation applied to the air outlet.

For any of the above-described embodiments the aerosol generating device may further comprise a valve controlling the flow through the airway cavity. The valve may be controlled by the relative movement between the drug carrier and the airway cavity. For example, the receptacle member or the lid foil may be provided with openings arranged to a control a flow of air through regulated openings.

Above an aerosol generating device comprising a receptacle containing an aerosolizeable drug formulation has been described, however, in a further aspect the present invention also provides an aerosol generating device per se for use with a receptacle containing an aerosol- izeable drug formulation, comprising an airway cavity comprising an air inlet and an air outlet, and means for receiving the receptacle. Inn a situation of use, the receptacle can be arranged in flow communication with the airway cavity, whereby the airway cavity and the re- ceptacle, corresponding to the flow communication, forms a combined cyclone chamber allowing a flow of air introduced through the air inlet to create a cyclone in the combined cyclone chamber, the cyclone having an axis and sweeping at least a portion of the receptacle thereby extracting drug formulation from the receptacle. The aerosol generating device may comprise one or more of the different device-related features described above.

In a yet further aspect the present invention provides a method of aerosolizing a drug formulation, comprising the steps of (i) providing an airway cavity comprising an air inlet and an air outlet, (ii) providing a receptacle containing an aerosolizeable drug formulation, (iii) arranging the receptacle in flow communication with the airway cavity, whereby the airway cavity and the receptacle, corresponding to the flow communication, forms a combined swirl chamber, and (iv) providing a flow of air through the air inlet to create a swirl in the combined swirl chamber, the swirl sweeping at least a portion of the receptacle thereby extracting drug formulation from the receptacle. The method may be adapted in accordance with the above- described different embodiments of an aerosol generating device.

As used herein, the term "drug" is meant to encompass any drug-containing formulation capable of being aerosolized. Representative drugs include pharmaceuticals such as peptides, proteins, and hormones, biologically derived or active agents, hormonal and gene based agents, nutritional formulas and other substances.

BRIEF DESCRIPTION OF THE DRAWINGS

In the following the invention will be further described with references to the drawings, wherein

fig. 1A shows a schematic cross-sectional representation of an aerosol generating device in a situation of use, fig. 1 B shows a schematic cross-sectional view an the inlet end of an airway cavity, fig. 2 shows a further embodiment of an aerosol generating device in an unassembled state, fig. 3 shows in a schematic cross-sectional representation an embodiment of an aerosol generating device in a situation of use, figs. 4A-4D show different states of use for an aerosol generating device of the type shown in fig. 2, a portion of the device being removed, fig. 5 shows an exploded view of an aerosol generating device, fig.6 shows from below a view into the airway cavity of the device of fig. 5, fig. 7 shows a cross-sectional view of the airway cavity of fig. 6, figs. 8A-8D show in cross-sectional views different states of use for the aerosol generating device shown in fig. 5, fig. 9 shows a cross-sectional view of an airway cavity of a further aerosol generating device, fig. 10 shows a multi dose peel mechanism, figs. 11A and 1 1 B show a further multi dose peel mechanism, and figs. 12 and 13 show a yet further multi dose peel mechanism.

In the figures like structures are mainly identified by like reference numerals.

DESCRIPTION OF EXEMPLARY EMBODIMENTS

When in the following terms such as "upper" and "lower", "right" and "left", "horizontal" and "vertical" or similar relative expressions are used, these only refer to the appended figures and not to an actual situation of use. The shown figures are schematic representations for which reason the configuration of the different structures as well as their relative dimensions are intended to serve illustrative purposes only.

Firstly, with reference to fig. 1A an aerosol generating device 1 (or "inhaler") will be described. The housing 10 comprises a generally oblong and generally tubular airway cavity 30 having a lower opening 31 along its length and comprising an air inlet 32 and an opposed (i.e. downstream) air outlet 35 adapted to be connected to the airway of a patient. The air inlet has a generally tangential orientation thereby creating a swirling air flow in the airway cavity as air is drawn through the cavity from the air inlet to the air outlet (see below). The housing further comprises a support surface 40 for supporting an upper surface of a free por- tion of a peelable lid in sliding engagement therewith (see below).

The inhaler is provided with a drug carrier 50 comprising a receptacle member 51 having a receptacle cavity 52 containing a powder drug, and a foil lid 55 peelably attached to the receptacle member thereby defining a sealed container 54, the lid comprising a lower surface facing the receptacle member and an opposed upper surface, wherein the lower surface corresponding to the receptacle cavity faces the powder drug in an initial sealed condition of the container. The two layers will typically be formed from aluminium-polymer laminates. In an initial condition (not shown) the sealed container is arranged outside the airway cavity opening 31 with a leading portion 53 of the receptacle member slidingly engaging and closing the airway cavity opening. A free portion 56 of the lid is slidingly guided around a peeling edge 41 and subsequently supported on the support surface 40. An end portion of the lid is connected to a peeling mechanism (not shown) for pulling the lid. The lid may also be pulled manually as in the embodiment shown in figs. 2-4. How the moving receptacle member can serve to control flow communication between the receptacle cavity and the airway cavity will be described in greater detail with reference to figs. 2-4 and figs. 5-9.

In the fig. 1A embodiment the angle between the tubular airway cavity and the drug carrier is approximately 20 degrees, however, it may vary between 0 and 180 degrees (see below).

When a flow of air has been generated between the air inlet and outlet, and thereby a swirl- ing air flow in the airway cavity, the inhaler is actuated either manually or automatically (e.g. triggered by the users inhalation) and the lid is pulled in the direction indicated by arrow 81 , this resulting in the receptacle member moving in the direction indicated by arrow 82, and the container being peeled open, whereby the receptacle cavity is moved into flow communication with the airway cavity. As the receptacle cavity starts to come into flow communication with the airway cavity, the airway swirl will start to generate a secondary swirl in the receptacle cavity generally in the plane of the opening. From experiments conducted it has been found that this secondary swirl is created very early when only a small portion of the receptacle cavity is in direct flow communication with the airway cavity. This situation can be compared with a situation in which two gear wheels are in engagement with each other. Even when the receptacle cavity is in full flow communication with the airway cavity as seen in fig. 1A, it has been found that a secondary swirl is still present in the receptacle cavity. Indeed, in the border region between the receptacle cavity and the airway cavity a complex mixed flow will exist which will bring the powder into the airway cavity swirl and towards the air outlet. From experiments it appears that the majority of de-agglomeration takes place in the recep- tacle cavity.

As appears from fig. 1A the air inlet 32 is arranged to provide a flow of air past the exposed lower surface of the peelable lid and through the receptacle cavity, the flow of air thereby removing powder drug from the peelable lid and the receptacle cavity. As shown in fig. 3 the air inlet and the airway cavity are configured in such a way that the flow of air creates a swirling air flow in a portion of the airway in flow communication with the receptacle cavity, whereby the rotating motion of air in the swirl sweeps the exposed lower surface of the peelable lid thereby removing powder drug, and whereby the rotating motion of air in the swirl extracts powder drug from the receptacle as air revolves between the airway cavity and the receptacle cavity.

To create the swirl one or more tangential air inlets 32 may be provided as shown in fig. 1 B. Although a swirling air flow is created in the airway cavity to provide de-agglomeration of the powder, it may be desirable that the aerosol flow leaving the inhaler has a predominantly axial flow to avoid uneven particle distribution in the inhaled air. This may be achieved by the provision of generally axially oriented vanes 36 arranged in the airway outlet as indicated in fig. 1A. Alternatively, counter-rotating additional air inlets that straighten the flow downstream of the swirl chamber may be provided.

In figs. 2 and 3 an alternative, fully manual and thus simple design for an inhaler 100 is shown. In this embodiment the carrier is represented by a blister member 120 (i.e. corresponding to receptacle member 51 of fig. 1 ) comprising a lower base portion 125 in which the receptacle 121 is formed, the receptacle being closed by a peelable lid foil 128. The inhaler can be designed such that it consists of only one foldable mechanical part and one aluminium/ aluminium blister. The mechanical part containing airway inlet and outlet, swirl chamber (i.e. corresponding to the airway cavity 30 of fig. 1 ), lid support, sliding groove and connection for a mouthpiece is depicted in fig. 3. More specifically, a lower part 1 15 serves as lid and includes an opening 132 for the airway inlet and a groove 1 16 for slidingly receive the receptacle. A top part 110 includes an oblong swirl chamber 130 with an opening 131 , a U- shaped channel portion 133 to be arranged in front of a wedge in an assembled state and serving as part of the tangential air-inlet, and the air-outlet 135 adapted for connection to a mouthpiece. In the shown embodiment the outlet is tangential relative to the airway chamber but alternatively it may be axial as in the fig. 1A embodiment. A wedge-formed lid support 118 used for peeling and supporting the blister lid foil is connected to the lower part. When assembling the inhaler, a blister member is placed on the lower part with the receptacle arranged in the groove, where after the wedge section is folded over. A freely extending portion 129 of the lid foil of the blister unit is then folded backwards over the wedge section. Final assembly is achieved by folding the top part hereby locking the folded assembly with a tab portion of the lid foil protruding from the inhaler. In the fig. 3 embodiment air enters from the top of the housing and not from the bottom as in the embodiment shown in figs. 2 and 4A-4D. With reference to figs. 4A-4D use of a device of the type shown in fig. 2 will be described. In the figures a portion of the housing is cut away, this allowing a view to the air inlet 132, the airway cavity 130, the lid support 118 and the blister member 120 comprising the receptacle 121 and a surrounding planner portion 123 with a cut-out portion 124. The specific design of an air inlet 132 controlled by a cut-out portion in the blister member is only an example of how the flow of air and the movement of the blister member can be synchronized and is not part of the present invention.

In a situation of use the patient starts to inhale through the mouthpiece, either freely through the air inlet or against a closed valve as shown, thus feeling a resistance to inhalation, this as shown in fig. 4A showing the device in an initial situation. When inhaling or attempting to inhale the user starts to pull the tab 129 whereby the lid will be pulled around the front peel edge of the lid support 118, this resulting in the cut-out portion 124 being moved into register with the inlet opening 132 whereby air is sucked through the U-shaped channel and tangen- tially into the airway cavity where it creates a swirl 138 before leaving the device through the mouthpiece 136, see fig. 4B. Just after the swirl is established in the airway cavity the receptacle is moved into flow communication with the airway cavity, this allowing a flow of air introduced through the air inlet 132, 133 to create a swirl in the receptacle cavity as it is moved into flow communication, thereby de-agglomerating and extracting powder formulation from the receptacle, see fig. 4C. As appears, the air inlet 133 is designed so that air is directed over the peeled lower surface of the foil lid, this cleaning the lid foil for powder sticking thereto. As the powder is moved in the receptacle cavity and in the swirl chamber by the swirling air it is subjected to high shear forces whereby it is de-agglomerated before it exits through the air outlet and mouth piece 136. Thus, in respect of the receptacle and the airway cavity the same relative movement takes place as in the above described first embodiment. After the receptacle has been emptied the receptacle may be moved further forwards (not shown) this allowing a second cut-out portion in the blister member to be moved into register with the airway cavity, this resulting in a secondary flow of air via the groove 1 16 flushing the cavity.

As appears, by appropriate design of the air inlet it is possible to use the blister member as a sliding valve controlling the airflow through the swirl chamber. As shown, the blister may be provided with a circumferential portion 123 comprising a surface portion and an opening or cut-out portion, wherein the surface portion serves as a closed valve when the receptacle member is in its initial position, and the opening or cut-out portion serves as an open valve when the receptacle member is in an actuated position. As can be seen in fig. 4B a valve opening (here: a cut out portion 124) in the blister is designed to open the air inlet a little prior to the point in time when the receptacle is moved into communication with the airway cavity, this allowing a swirl to be formed in the airway cavity before the combined swirl chamber is created.

With reference to figs. 5-8D an aerosol generating device (or unit) 200 designed for laboratory test purposes will be described. The device in fig. 5 comprises a housing 210, a lid support member 220, a bottom member 230, a drug carrier 201 comprising a peelable foil lid 240 attached to a receptacle member 250 formed from a base foil, and a clamp member 260 for holding together the different parts.

The lid support member 220 comprises an upper guide surface 221 , a cavity guide surface 222, a lower guide surface 223, and a peel edge 224 formed between the cavity guide sur- face and the lower guide surface.

The receptacle member 250 comprises a closure portion 251 and a receptacle cavity portion 252 with a receptacle cavity 253 (or "blister") formed therein. The lid 240 comprises a first portion 241 which initially is peelably attached to receptacle cavity portion, thereby sealing the receptacle cavity to form a container in which a powder drug is enclosed, and a second free portion 242, the lid comprising a lower surface facing the receptacle member (corresponding to the first portion) and an opposed upper surface.

The bottom member 230 comprises a lower guide surface 231 with an axial groove 232, the guide surface being adapted to slidingly support the lower surface of the receptacle member with the receptacle cavity arranged in the groove. When the bottom member is attached to the housing the two guide surfaces form a channel in which the drug carrier is slidingly guided. In the shown experimental embodiment the groove prevents the blister from sliding along the length of the housing, however, in multi-blister version (see below) the groove will be open at both ends.

Referring to figs. 6 and 8A, the housing 210 comprises a lower surface with a generally planar upper guide surface 219 defining a guide plane, and a tubular portion 21 1 arranged at an angle of about 20 degrees relative to the guide plane. The housing is adapted to receive the lid support member 220 whereby an airway cavity 212 is formed by the proximal portion of the tubular portion and the cavity guide surface 222. The cavity has an opening 213 opening on the upper guide surface, and a generally tangential air inlet 214 in flow communication with an air inlet tube 215 via an air inlet channel 216. Between the airway cavity and the air outlet 218 a number of generally axially oriented vanes 217 are arranged serving to at least partially transforming a swirling air flow in the airway cavity into an axial flow of air. Between the upper surface of the lid support member 220 and the housing a lid guide channel 225 is formed. Fig. 7 shows in a transverse cross-sectional view the proximal-most portion of the airway cavity with the cavity guide surface 222, the air inlet 214, the air inlet channel 216, and the receptacle cavity 253.

Fig. 8A shows a longitudinal cross-section through a partially assembled device in an initial state. As in fig. 6 the lid support member 220 has been arranged in housing 210, however, in addition the drug carrier 201 has been attached and arranged in sliding engagement with the upper guide surface 219. More specifically, the closure portion 251 has been arranged against the upper guide surface corresponding to the airway cavity opening, thereby closing the opening, and the receptacle cavity portion 252 with the attached first portion of the lid has been arranged against the lower guide surface 223 of the lid support member 220. The free lid portion has been arranged in the lid guide channel 225 with the free end extending from the device, this allowing the lid to be pulled by a peeling mechanism (not shown). As appears, the lid foil is guided around the peel edge 224 and is supported on the cavity guide surface 222, a portion of the lower lid surface thereby forming a part of the airway cavity. As indicated above, when the device is fully assembled the drug carrier will guided in a channel formed between the housing and the bottom member.

Fig. 8A shows the device in an initial condition with the airway cavity opening closed. In an experimental set-up a pressure transducer is connected to the inlet tube, a peel mechanism is connected to the free end of the lid foil, and a vacuum source and powder collector is connected to the air outlet. When a given vacuum or flow rate is measured in the inlet tube (and thereby a swirl is generated in the airway cavity), the peel mechanism is released and starts to pull the lid foil, this moving the receptacle cavity forwards and into flow communication with the airway cavity as seen in fig. 8B. The graduate opening of the container is further illustrated in figs. 8C and 8D. For the experimental embodiment fig. 8D shows a final position of the blister, however, in a multi-blister version the drug carrier will be forwarded further until a new closure portion 251 is closing the airway cavity opening. The used receptacle may be collected in the device (see fig. 10) or ejected from the device (see fig. 1 1A). In the fig. 5 embodiment the airway cavity axis was arranged at an angle of approximately 20 degrees relative to the guide plane in the plane of the paper, however, the angle may be varied between 0-180 degrees, e.g. the flow of air may be in the opposite direction of blister movement.

Correspondingly, fig. 9 shows a further embodiment in which the airway cavity axis is arranged perpendicularly relative to the guide plane, i.e. at 90 degrees. In the fig. 5-8 embodiment the sideway opening 213, the non-perfectly circular airway cavity and the single air inlet result in a swirl which is not perfectly symmetrical with an axis corresponding to the axis of the tube 211 , however, the design of the fig. 9 embodiment allows a more symmetrical swirl to be created.

Fig. 9 shows in cross-section an aerosol generating device 300 of the same general design as in fig. 5, i.e. comprising a housing 310, a lid support member 320, a bottom member 330, a drug carrier 301 comprising a peelable foil lid (not shown) attached to a receptacle member 350 formed from a base foil, and a clamp member (not shown) for holding together the different parts. However, in contrast to the inclined airway cavity shown in fig. 5 the airway cavity 312 in fig. 9 has a general tubular configuration with an axis arranged substantially perpendicularly to the guide plane and an opening 313 at the "end" of the tube 311. In contrast to the single inherently asymmetrical air inlet of the above described embodiments, this embodiment is well suited for a plurality of tangential air inlets 314 arranged circumferentially in the lower-most part of the airway cavity. A further difference is that the peel edge 324 and the lid support are arranged outside the airway cavity, however, it may also form part of the airway cavity as in the figs. 5-8 embodiment.

Although the swirl created in the airway cavity 312 is generally perpendicular relative to the guide plane, the device has been found to essentially function in the same way as when the airway cavity is inclined relative to the guide plane, i.e. a primary swirl will be created in the airway cavity which, when the receptacle cavity begins to open into the airway cavity, will generate a secondary swirl in the receptacle cavity in a "gear wheel fashion". The axis of the secondary swirl will initially be parallel with the primary swirl, but it is not until the receptacle cavity is arranged in register with airway cavity that the two swirls can be expected to be co- parallel.

In the figs. 1-9 embodiments the airway cavity axis is arranged in a plane defined by the axial movement of the blister, however, the blister may also be moved transversely across the blister cavity or at any desired angle. Further, the airway cavity axis may also be "tilted" out of the plane of the paper. In the shown embodiments the airway cavity has a generally cylindrical form, however, it may have other more angular forms just as it may be provided with projections or irregularities which may aid in de-agglomeration of the powder. Further, the airway cavity does not have to be straight but may be curved or comprise portions arranged at an angle relative to each other.

With reference to fig. 10 a multi dose peel mechanism 400 will be described, whereby peeling and conveying a blister tape can be carried out by a mechanism using a spring as the power source. The mechanism is designed to peel a blister tape of the type described in US 5,873,360 which is hereby incorporated by reference. The shown embodiment is a prototype mounted on a board 401 and designed to test the peeling mechanism for which reason an airway is not provided.

The blister tape 410, comprising an elongate receptacle member 411 having a plurality of receptacle cavities 412 arranged along the length and a peelable lid foil layer 413, is kept coiled up in a first chamber 421 , led out of the chamber around a driving wheel 430 and into a second chamber 422. In the shown embodiment the cavities have a longitudinal configuration arranged transversely on the blister tape but they may have any desirable configuration. Further, two cavities could be arranged side-by-side, e.g. comprising two different powders. The lid foil is separated from the blister tape at a peeling pin 431 and wound up on a peeling wheel 432 to which it is attached. When a loading mechanism 435 is turned counter clock wise a spring wheel 436 is turned and a spring (not shown) mounted inside the spring wheel is loaded and held in an actuated condition until released. The spring wheel has ratchet arms that click inside the driving wheel when the loading arm is turned. The driving wheel is prevented from turning by a trigger that may be either manual or released by the user's inhalation. In a dial-a-dose embodiment the spring can be loaded 1 through 5 steps (clicks) corresponding to the desired number of doses. Hereby the driving wheel is allowed to turn which again turns the peeling wheel by means of gear wheels 437, 438. The motion continues until the spring wheel meets a spring wheel stop. A tape support member 439 keeps the cavities on the blister tape close to the driving wheel to ensure contact. The airway cavity and air flow channels are not shown but are to be positioned in the area where the cavities are opened. As appears, in this embodiment the oblong cavities are arranged transversely on the receptacle member. Corresponding to the above-described single-blister embodiments, the blister tape may also be provided with openings or cut-out portions controlling the flow of air. With reference to figs. 11A and 1 1 B a further multi dose peel mechanism 500 will be described, whereby peeling and conveying a blister tape can be carried out by a mechanism using a spring as the power source. The shown embodiment is a prototype designed to test the peeling mechanism.

In this embodiment the blister tape 510 comprises a plurality of individual receptacle members 51 1 each having a receptacle cavity 512 and being peelably attached to a strip-formed lid foil member 513 along the length thereof, thereby defining a plurality of containers. The mechanism comprises a blister tape storage 521 , a peeling station 530 with a peeling edge (i.e. corresponding to the above-described embodiments), a spring-loaded peeling mechanism 540 with a peeling wheel 541 for taking up the lid foil 513, a priming wheel 542 and an airway 550 with a vacuum-actuated trigger membrane for actuating the triggering mechanism (arranged inside the peeling wheel) for the peeling mechanism. An advantage of using an inhalation controlled triggering mechanism is that the receptacle is opened during inhalation only, this minimizing the risk of an opened blister being left in the device. As appears, in contrast to the fig. 5 embodiment only the lid foil is collected on the peel wheel whereas the individual receptacle member is discarded from the inhaler when it has been fully peeled off the lid foil. Alternatively, the receptacle member may be a continuous band as above, however, this would imply cutting off the used receptacle portion. In a situation of use the peel mecha- nism is activated by turning the priming wheel thereby loading the peel mechanism. When a given flow of air (or a given vacuum) is created in the airway the trigger mechanism is released and the peel wheel is allowed to turn a given angle corresponding to the peeling and forwarding of an individual receptacle member. When integrated into an inhaler, the receptacle member will be moved past an airway cavity as shown schematically in fig. 1 , a flow of air cleaning the lower surface of the lid foil and emptying the receptacle cavity for powder before the empty receptacle member is discarded.

With reference to figs. 12 and 13 a further multi dose peel mechanism will be described, whereby peeling and conveying a blister tape can be carried out by a mechanism using a spring as the power source. The shown embodiment is a prototype incorporating an aerosol generating unit similar to that of fig. 5, however, the prototype is designed to primarily test the peeling mechanism.

The device 600 comprises a base member (or chassis) 601 on which the further components are mounted, an aerosol generating unit 610, a vacuum-actuated trigger unit 620, a spring- actuated index and transport unit 630 for the blister lid, and a blister lid take-up unit 640. A multi-blister tape (not shown) is to be arranged above the trigger unit. For the shown embodiment the lid foil will be provided with transport perforations along its edges.

The aerosol generating unit comprises a guide plane 619 with an opening 613 to the airway cavity, a peel edge 617, an air outlet 61 1 , and a vacuum outlet 618 adapted to be connected to the vacuum inlet 621 on the trigger unit. The trigger unit comprises a vacuum chamber and a moveable membrane connected to a bi-stable trigger mechanism. The transport unit 630 comprises a cylindrical transport and index wheel 631 with upper and lower circumferential rows of projections 632 adapted to engage and pull the lid foil, as well as an actuatable drive coil spring arranged between the base member and the wheel. The transport wheel comprises a first gear wheel 635 which is in toothed engagement with a second gear wheel 645 on the take-up wheel 641 to which the end of the lid foil is attached, e.g. by means of projections 642. The second gear wheel is further in toothed engagement with a damping unit 650 which controls the speed of blister transport. When the drive spring is actuated by lever 635 the spring and an associated ratchet will be rotated corresponding to the advancement of one blister member (see fig. 11A). This will tend to rotate the drive wheel and thereby the take-up wheel, however, a releasable stop (locking arm 646 in fig. 13) is arranged on the take-up wheel, the stop engaging the base member and being released when the trigger mechanism is actuated by the generated vacuum.

When a blister tape is mounted the lid foil is threaded around the peel edge, out through the opposed side of the aerosol generating unit, around the drive wheel (on the side facing away from the trigger unit), for being attached to the take-up wheel.

In the cross-sectional view of fig. 13 the trigger mechanism is shown in greater detail. The trigger mechanism comprises a vacuum chamber 622 with a trigger membrane 623 move- able by the generated vacuum. From the other side of the membrane a pin projects, the pin comprising an opening 625 through which a bi-stable spring 626 is arranged. The spring is mounted in a housing 627 with a free end 628 of the spring projecting there from, the spring being designed to "flip" between the shown initial state and a reversed actuated state when actuated. When the membrane is moved downwardly by the vacuum generated by the user's inhalation the pin will act on the spring, and if the vacuum generated is sufficient the bi-staple spring will be actuated and "flip", this resulting in the free end of the spring moving upwards where it then engages the locking arm 646 and moves it out of engagement with the base member, this allowing the drive wheel to rotate and pull the blister lid, whereby a receptacle cavity is moved into flow communication with the airway cavity. As the effective diameter of the take-up wheel will increase as lid foil is collected, rotation of the take-up wheel varies by means of a ratchet mechanism 643 arranged between the second gear wheel 645 and the take-up wheel 641 , this allowing the gear wheel to be "over-rotated".

In the above description of the preferred embodiments, the different structures and means providing the described functionality for the different components have been described to a degree to which the concept of the present invention will be apparent to the skilled reader. For example, instead of a blister tape the drug carrier could be in the form of a rotatable disc member comprising a number of drug-filled cavities, e.g. as shown in US 6,116,239. Alterna- tive, the opening between a receptacle cavity and the airway cavity could be controlled by a "shutter" aperture, this allowing a receptacle to be emptied to be arranged under the airway cavity before flow communication is established by movement of the shutter member. The peeling mechanism could also be based on a flap as in e.g. US 2005/0081851 , just as the drive wheel could push the lid foil into a compartment instead of winding it up.

The detailed construction and specification for the different components are considered the object of a normal design procedure performed by the skilled person along the lines set out in the present specification.

Claims

1. A method of aerosolizing a drug formulation, comprising the steps of: providing a receptacle member (51 , 250) having a receptacle cavity (52, 253) con- taining a powder drug, providing a device (1 , 100, 200, 300) with an airway cavity (30, 212) comprising a tangential air inlet (32, 214) and an air outlet (35, 211 ), the airway cavity comprising an opening (31 , 213) having a closed state and an open state in which it is in flow communication with the receptacle cavity, - providing a flow of air through the air inlet when the airway cavity is in its closed state, thereby creating a swirl of air in a portion of the airway, when a swirl of air has been created, arranging the receptacle cavity in flow communication with the airway cavity, the swirl of air in the airway cavity thereby creating a flow of air in the receptacle cavity, the combined flow of air in the airway cavity and in the recep- tacle cavity resulting in powder de-agglomeration and transport of the de-agglomerated powder towards the air outlet.

2. A method as in claim 1 , wherein in the open state the flow communication between the airway cavity and the receptacle cavity is gradually enlarged.

3. A method as in claim 1 or 2, wherein the device further comprises means (242, 630, 620) for shifting the opening between the closed state and the open state, the shifting means being actuated in response to inhalation through the air outlet.

4. A method as in claim 1 or 2, wherein: the receptacle member (250) comprises a closure portion (251 ) and a receptacle cavity portion (252), the closure portion engaging the airway cavity opening in the closed state, thereby serving as a closure for the airway cavity opening, the receptacle member and the airway cavity being moveable relative to each other from a first position in which the closure portion closes the airway cavity opening, and a second position in which the airway cavity is in flow communication with the receptacle cavity.

5. A method as in claim 4, wherein the device further comprises means (242, 630, 620) for moving the receptacle member between the first and second position, the means for mov- ing the receptacle member being actuated in response to a users inhalation through the air outlet.

6. A method as in any of claims 1-5, wherein a primary swirl of air is created in the airway cavity and a secondary swirl of air is created in the receptacle.

7. A method as in claim 6, wherein the secondary swirl has a swirl axis non- perpendicular to the primary swirl axis.

8. A method as in any of claims 1-7, wherein the receptacle cavity opens directly into the airway cavity.

9. A method as in any of claims 1-8, wherein the device comprises: a) a drug carrier (201 ) comprising: a receptacle member (250) having a receptacle cavity (253) containing a powder drug, - a lid (240) peelably attached to the receptacle member thereby defining a container, the lid comprising a lower surface facing the receptacle member and an opposed upper surface, b) a peel structure (224) engaging the upper surface of the peelable lid in sliding engagement therewith, - wherein the aerosol generating device is adapted in such a way that pulling the peelable lid opens the container and brings the receptacle cavity in flow communication with the airway cavity.

10. An aerosol generating device (1 , 100, 200, 300), comprising: - a receptacle member (51 , 250) having a receptacle cavity (52, 253) containing a powder drug, an airway cavity (30, 212, 312) comprising a tangential air inlet (32, 214, 314) and an air outlet (35, 218, 318) adapted to be connected to the airway of a patient, the airway cavity comprising an opening (31 , 213, 313) having a first closed state and a second open state in which it is in flow communication with the receptacle cavity, wherein a flow of air introduced through the tangential air inlet when the airway cavity opening is in its closed state creates a swirl of air in a portion of the airway, wherein, when the receptacle cavity is in flow communication with the airway cavity, the swirl of air in the airway cavity creates a flow of air in the receptacle cavity, the combined flow of air in the airway cavity and in the receptacle cavity result in powder de-agglomeration and transport of the de-agglomerated powder towards the air outlet, and wherein the opening is controlled in response to a users inhalation through the air outlet.

11. A device as in claim 10, wherein in the open state the flow communication between the airway cavity and the receptacle cavity can be gradually enlarged.

12. A device as in claim 10 or 1 1 , further comprising means (242, 630, 620) for transforming the opening between its first and second state, wherein the transforming means is actuated in response to a users inhalation through the air outlet.

13. A device as in claim 10 or 1 1 , wherein: the receptacle member (250) comprises a closure portion (251 ) and a receptacle cavity portion (252), the closure portion engaging the airway cavity opening in the closed state, thereby serving as a closure for the airway cavity opening, and - the receptacle member and the airway cavity are moveable relative to each other from a first position in which the closure portion closes the airway cavity opening, and a second position in which the airway cavity is in flow communication with the receptacle cavity.

14. A device as in claim 13, further comprising means (242, 630, 620) for moving the receptacle member between the first and second position, the means for moving the receptacle member being actuated in response to a users inhalation through the air outlet.

15. A device as in claim 14, wherein the means for moving the receptacle member comprises: - actuatable drive means (630) for moving the receptacle, and actuatable triggering means (620) for actuating the drive means, the triggering means comprising an element (623) responsive to patient inspiration through the air outlet.

16. A device as in any of claims 10-15, comprising: a) a drug carrier comprising: a receptacle member (250) having a receptacle cavity (253) containing a powder drug, a lid (240) peelably attached to the receptacle member thereby defining a container, the lid comprising a lower surface facing the receptacle member and an opposed upper surface, b) a peel structure (41 , 224, 324) engaging the upper surface of the peelable lid in sliding engagement therewith, wherein the aerosol generating device is adapted in such a way that pulling the peelable lid results in sliding movement between the peelable lid and the peel structure, thereby opening the container and bringing the receptacle cavity in flow communication with the airway cavity.

17. A device as in claim 16, further comprising a guide for guiding the drug carrier, the guide comprising: - a first portion (223) adapted to engage a portion of the upper surface of the lid, and a second portion (219) comprising the airway cavity opening (213), the second portion adapted to engage an upper surface portion (251 ) of the receptacle member, wherein a peel edge is formed between the first portion and the support surface.

18. A device as in claim 17, wherein the peel edge (224) forms a portion of the circumference of the airway cavity opening (213).

19. An aerosol generating device as in any of claims 16-18, comprising a plurality of individual receptacle members (51 1 ) peelably attached to the lid (513) along the length thereof, thereby defining a plurality of containers (512).

20. An aerosol generating device as in any of claim 16-18, comprising an elongate receptacle member (41 1 ) having a plurality of receptacle cavities (412) arranged along the length thereof and being peelably attached to the lid (413), thereby defining a plurality of con- tainers.

21. A device as in any of the previous claims, wherein the air outlet comprises means (36, 217, 317) for at least partially transforming the air swirl into an axial flow of air.

22. A device as in any of the previous claims, wherein the airway cavity has a general axis defining a general axis for the generated swirl, the air outlet being arranged generally co-axially with the airway cavity.

23. A device as in any of the previous claims, wherein: - the receptacle cavity and the airway cavity are moveable relative to each other corresponding to a reference plane, the airway cavity has a configuration generating a swirl of air having a swirl axis, and the swirl axis is generally non-perpendicular to the reference plane.

24. An aerosol generating device adapted to receive a receptacle member having a re- ceptacle cavity containing a powder drug, comprising: an airway cavity comprising a tangential air inlet and an air outlet adapted to be connected to the airway of a patient, the airway cavity comprising an opening adapted to have a first closed state and a second open state in which it can be brought in flow communication with the receptacle cavity, - wherein a flow of air introduced through the tangential air inlet when the airway cavity opening is in its closed state creates a swirl of air in a portion of the airway, and wherein, when the receptacle cavity is in flow communication with the airway cavity, the swirl of air in the airway cavity creates a flow of air in the receptacle cavity, the combined flow of air in the airway cavity and in the receptacle cavity result in powder de-agglomeration and transport of the de-agglomerated powder towards the air outlet.