WO2007106686A2

WO2007106686A2 - Medical apparatus and method for homogenous aerosol creation

Info

Publication number: WO2007106686A2
Application number: PCT/US2007/063451
Authority: WO
Inventors: Wiwik Watanabe; Henning Graaskov; Robert L. Clark; Victor P. Burolla; Johan Waldeck; Boris N. Valentin
Original assignee: Novo Nordisk A/S
Priority date: 2006-03-10
Filing date: 2007-03-07
Publication date: 2007-09-20
Also published as: WO2007106686A3

Abstract

The present invention provides an airway for an inhaler, comprising (a) a tubular airway portion defining a main axis and having an interior, an inlet end and an outlet end, (b) an aerosol inlet arranged at the inlet end, the airway allowing a substantially unimpeded flow along the main axis for an aerosol introduced through the aerosol inlet, and (c) air inlet means arranged in the vicinity of the distal end, wherein (d) the air inlet means is arranged to cause swirling of air introduced there through, the swirl having an axis generally along the main axis. By this arrangement a mixed swirl of air and aerosol is formed whereby the residence time of the aerosol can be prolonged which typically has a beneficial effect on creating small, fine aerosol particles, which usually results in better deposition into deep lung tissue.

Description

MEDICAL APPARATUS AND METHOD FOR EFFECTIVE AEROSOL DRUG DELIVERY

The invention relates to drug delivery generating devices and is particularly well-suited for use with inhalation devices that generate aerosols comprised of mixing particles with a gas such as air. It is suited for use with both powder and liquid based inhalation systems, including systems designed to deliver insulin.

BACKGROUND OF THE INVENTION

In a typical inhalation device, such as the AERx iDMS device described in US 5,743,250, US 5,884,620, US 5,941 ,240, US 6,167,880, and US 5,672,581 , which are hereby incorporated by reference, aerosolized compounds are mixed with hot air in an airway and then delivered to a mouthpiece for inhalation by a patient. In these devices, the aerosol is created by extruding a liquid pharmaceutical formulation thru a nozzle array. This can be done by exerting force on the liquid formulation on a container, such as a blister pack, containing the formulation. The force applied expels the liquid thru a nozzle or nozzle array, which can be incorporated into the blister pack, and into an airway. Alternatively, the aerosolized compounds may be mixed with a non-heated air.

Particle size is an important parameter in achieving the deep lung deposition that is needed when inhalers are used to deliver drugs to the lungs. Typically, the goal is to have particle size between 1 -5 microns. For liquid based aerosol, in order to create a fine aerosol, it is often necessary to first pre-heat the gas or the air stream that enters the airway. The hot gas evaporates liquid aerosol, and thus creating smaller aerosol. Even when it is unnecessary to heat the gas or air first, homogeneous mixing is important to ensure aerosol uniformity when exiting the mouthpiece.

In the AERx iDMS device, the aerosol is created by ejecting the formulation perpendicular to the flow of hot gas in the airway. This could result in a less than perfectly homogenous mix- ture. Also, hot gas must travel a certain distance before mixing with the aerosol exiting from one or more nozzles. If the distances are long and the airway is metal, such as is the case in the AERx iDMS device, regions where the aerosol is generated and mixed with the hot gas can have significant heat loss and thus inefficient heat transfer. Thus, a relatively high heat supply is needed. Moreover, it is typically observed that significant amounts of the aerosol deposit on the airway in the area where the droplets are generated and mixed with the hot gas. This not only reduces the amount of drug delivered to patients but also poses the need for the user to regularly clean the airway to avoid contamination and maintain functionality of the device.

Finally, another shortfall of the prior art inhalers, is that aerosol backflow occurs when a pa- tient accidentally exhales or coughs during aerosol delivery. This can cause foul odour because drug or biologic agents will burn on the heating elements and cause device contamination or malfunction.

Thus, there is a need for a more efficient airway that allows for greater residence time of aerosol and more uniform mixing. Also, it would be advantageous if the airway could be incorporated into a mouthpiece. In addition, to having an aerosolizing inhaler with a mouthpiece that results in lower aerosol deposition and better heat transfer (if heated air is used), it is also desirable to reduce the device size while maintaining the device performance to achieve the desired aerosol size and emitted dose. When the size of the device, i.e. air- way/mouthpiece is reduced, the residence time available for evaporation is also usually reduced. This could result in larger aerosol size, and thus smaller fine particle fraction, which relates to the amount of drug deposits in the lungs. Thus, a new optimized airway design that is smaller but provides enough residence time to evaporate the moisture in the droplets is desirable.

SUMMARY 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 an airway for an inhalation device, comprising (a) a tubular airway portion defining a main axis and having an interior, an inlet end and an outlet end, (b) an aerosol inlet arranged at the inlet end, the airway allowing a substantially unimpeded flow along the main axis for an aerosol introduced through the aerosol inlet, and (c) air inlet means arranged in the vicinity of the distal end, wherein (d) the air inlet means is arranged to cause swirling of air introduced there through, the swirl having an axis generally along the main axis. The tubular airway portion may have any suitable interior shape such as circular, oval or comprising planar portions, just as it may be generally cylin- drical or it may have varying cross-sectional shapes, e.g. funnel-shaped. In this way air introduced through the air inlet means and aerosol introduced through the aerosol inlet may mix to form a mixed swirl comprising a mixture of air and aerosol, the mixed swirl having an axis generally along the main axis. By this arrangement the residence time of the aerosol can be prolonged which typically has a beneficial effect on creating small, fine aerosol particles, which usually results in better deposition into deep lung tissue. Further, homogenous mixing of air and aerosol can be improved just as the tendency for the aerosol to stick to the inner wall of the airway may be reduced. Further, by allowing unimpeded flow of the aerosol deposition of material to surfaces are reduced.

In exemplary embodiments the air introduced through the air inlet means initially has a direction of flow substantially perpendicular to the main axis, which may be achieved by the air inlet means comprising one or more openings directing air tangentially into the tubular airway.

In a further exemplary embodiment of an airway for an inhalation device the air inlet means comprises a swirl cavity circumferentially surrounding at least a portion of the tubular airway portion, the swirl cavity comprising a cavity air inlet and a flow communication between the swirl cavity and the airway body, wherein the cavity air inlet is arranged to cause swirling of air introduced there through, the swirl having an axis generally along the main axis. The swirl cavity may be arranged to surround the inlet end of the tubular airway portion. The flow communication may be in the form of a circumferential opening between the swirl cavity and the tubular airway portion. The circumferential opening may span substantially 360 degrees or it may comprise a number of individual openings.

The airway may comprise deflecting means arranged in the tubular airway portion to deflect the swirling air introduced through the air inlet means. The deflecting means may serve to deflect the swirling air introduced through the air inlet means in a direction along the main axis, however, it may also serve to deflect the swirling air in a plane perpendicular to the main axis. The deflecting means may comprise a number of vane members surrounding the aerosol inlet and projecting generally along the main axis.

The present invention also provides an inhalation device comprising an airway as described above and further comprising aerosol generating means adapted to introduce an aerosol of a drug through the aerosol inlet. The inhalation device may further comprise means to receive a drug receptacle comprising a reservoir with a fluid drug formulation and a nozzle array in flow communication with the reservoir, and means for moving fluid drug from the reservoir through the nozzle array thereby creating an aerosol of drug particles introduced through the aerosol inlet. It may further be provided with trigger means responsive to inhalation of air through the outlet end of the airway body, the trigger means being adapted to trigger the means for moving fluid out of the reservoir, as well as means for heating the air before it is introduced into the tubular airway portion.

In a further aspect, the present invention provides for an airway comprised of an outer tube and an inner tube. The tubes may be coaxial. Heated gas is introduced into the inner portion of the outer tube. An aerosol comprised of a formulation of interest, such as for example a drug, protein or insulin, is introduced into the inner portion of the inner tube in aerosol form. The inner tube is preferably perforated so as to allow the heated gas to enter into the inner portion of the inner tube and mix with the aerosol. The aerosol can be generated in the airway or generated prior to entry into the airway. Indeed, such an airway may be provided with a swirl flow inlet as described above.

In one exemplary but non-limiting embodiment, the aerosol flows parallel to an axis of the inner tube and the hot gas enters the perforations in a somewhat perpendicular direction, or at least initially in a perpendicular direction, to the flow of the aerosolized particles. This may be achieved by, for example, having a plate with a hole through which the aerosol can be introduced covering one end of at least the inner tube. Upstream of the inner and outer tubes, a heater can be placed to heat a stream of gas or air. The heated gas or air can be introduced into the outer tube via one or more inlets. Downstream from the airway, a mouthpiece can be utilized to direct the aerosol and gas mixture to a patient. The mouthpiece can be integral with the airway.

The tubes described above can be round in cross section or have various other shapes. The shapes can be optimized based on flow characteristics of the aerosol and the hot gas. The tubes can be open at both ends or closed at one or both ends so long as there is an inlet and outlet for gas or aerosol, or the functional equivalent of an inlet or outlet. The inner tube may be designed to allow a blister pack or strip to rest against it during a process for expelling a drug from the strip. Of course the present invention would work well with other methods of aerosol generations, such as ultrasonic or pressurised gases. In some embodiments, the tube or tubes must be strong enough to support the strip (or any such container containing the formulation) during forcible removal of the medication from the strip (or container). In the AERx iDMS device this means that the airway is strong enough to withstand the extrusion forces needed to force the drug through the integral nozzle array that is part of the strip. In another aspect, the present invention may include embodiments where a one-way valve is placed upstream of the airway or mouthpiece. This configuration prevents backflow of the aerosol and prevents it from flowing back over a heater element and thus the aerosol and gas mixture can only exit into the patient's mouth.

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. In the description of the exemplary embodiments reference will be made to the use of insulin.

BRIEF DESCRIPTION OF THE DRAWINGS

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

fig. 1 shows a first embodiment of an airway in a perspective view, fig. 2 shows the airway of fig. 1 in a cross-sectional view, fig. 3 shows a second embodiment of an airway in a cross-sectional view, fig. 4 shows the airway of fig. 3 in a perspective view, fig. 5 shows the airway of fig. 4 in a vector flow simulation, fig. 6 shows, in a cross-sectional view, the airway of fig. 3 in combination with an aerosol generating device, fig. 7 shows a third embodiment of an airway in a cross-sectional view, fig. 8 shows the airway of fig. 7 in a vector flow simulation, and figs. 9-1 1 show embodiments of an airway having an inner perforated tube.

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 there relative dimensions are intended to serve illustrative purposes only.

Figs. 1 and 2 show a first embodiment of an airway for an inhalation device, having a tubular airway portion or body 10 defining a main axis and having an interior 1 1 with an interior wall 12, a proximal inlet end 13 and a distal outlet end 14 with an end opening 15 adapted to be connected in flow communication with a uses airway. An aerosol inlet opening 20 is arranged axially at the inlet end in a bottom portion 18. As appears, the tubular airway interior has no elements protruding in a non-axial direction, this allowing a substantially unimpeded flow along the main axis for an aerosol introduced through the aerosol inlet. The airway further comprises air inlet means arranged in the vicinity of the distal end, and arranged to cause swirling of air introduced there through, with the swirl having an axis generally along the main axis, see fig 5. In this way, when air is introduced through the air inlet means and aerosol is introduced through the aerosol inlet, the two flows will mix to form a mixed swirl comprising a mixture of air and aerosol, the mixed swirl having an axis generally along the main axis.

In the fig. 1 embodiment the air inlet means comprises four flow channels 30 directing air tan- gentially into the tubular airway portion, each flow channel having an inlet opening 31 and an outlet opening 32, the latter opening into the proximal end of the airway. As appears, the flow channels are arranged substantially perpendicular to the main axis, whereby air introduced through the air flow channels initially has a direction of flow substantially perpendicular to the main axis. Air will normally be drawn through the flow channels as a user starts to inhale through the end opening 15. The air may be heated or it may be ambient air.

The airway may, as shown, further comprise deflecting means arranged in the tubular airway portion serving to deflect or redirect the swirling air introduced through the air inlet means. In the shown embodiment a number of vane members projecting along the main axis surround the aerosol inlet opening 20. When the swirling air is introduced through the outlet opening 32 the outer portion will be guided along the wall 12 whereas the inner portion will hit the vane members so that the oncoming air flow is "turned" as it tries to follow the vane direction. Each one of the vanes imparts an angular velocity component to the oncoming flow which helps create the swirl. The vanes may further deflect a portion of the air towards the aerosol inlet opening allowing early mixing of air and aerosol.

When fluid aerosol particles (i.e. droplets) undertake a swirling path, the path length and mixing time between the aerosol and air is increased, and thereby droplet evaporation and parti- cle mixing. The aerosol inlet may also be placed off-centre just as more than one inlet may be used.

Figs. 3 and 4 show a second embodiment 101 of an airway for an inhalation device which, corresponding to the first embodiment, has a tubular airway portion 1 10 defining a main axis and having an interior 1 1 1 with an interior wall, a proximal inlet end 1 13 and a distal outlet end 1 14 with an end opening 1 15, as well as an aerosol inlet opening 120 arranged axially at the inlet end in a bottom portion 1 18. Instead of the flow channels 30 the second embodiment comprises a circumferential swirl chamber 150 surrounding the proximal end of the tu- bular airway portion and forming a circumferential swirl cavity 155 with a tangential cavity air inlet 151 and a flow communication 152 between the swirl cavity and the airway, whereby the cavity air inlet causes swirling of air introduced into the cavity, the swirl having an axis generally along the main axis. In the shown embodiment the flow communication between the swirl cavity and the airway is a continuous circumferential gap formed between a tubular body portion 1 10 and a bottom plate 1 18, however, it the flow communication may also comprise a number of individual openings. The airway further comprises deflecting means in the form of a ring-formed protrusion 140 surrounding the inlet opening and arranged just inside of the flow communication, the ring serving to deflect the swirling air in the axial direction towards the outlet end. The ring may also serve to prevent too early mixing of the swirl air and the aerosol, e.g. before the aerosol has been properly formed.

Fig. 5 shows the airway of figs. 3 and 4 in a vector flow simulation. When the swirling air, illustrated by small vectors 160 in the swirl cavity 155, enters the tubular airway portion it is drawn axially where it starts to mix with the aerosol which initially is introduced in an axial direction from the inlet opening. As a result, a swirling action is impacted on the aerosol particles and a mixed swirl is formed. In the simulation the resulting swirling of the aerosol particles is shown.

Fig. 6 shows an inhalation device 200 comprising an airway as described with reference to figs. 3-5. More specifically, the inhalation device comprises a durable main unit 201 comprising aerosol generating means adapted to introduce an aerosol of a drug through the aerosol inlet of a disposable airway 101 releasably attached to the main unit. In the shown embodiment the main unit is adapted to receive a receptacle strip 210 of the type described in e.g. US 6,167,880, the strip comprising a proximal handle portion 21 1 and a distal compressible blister receptacle 212 filled with a fluid drug formulation and with an associated nozzle array opening into the inlet opening of the airway. The main unit comprises a spring-loaded driving mechanism 220 for driving a piston 221 towards the receptacle when released, thereby forcing the drug out of the receptacle and through the nozzle array into the airway, thereby forming an aerosol. The travel of the piston may be settable thereby allowing a user to set how much of the drug should be expelled during an inhalation. The driving mechanism may be released manually by the user when the user has started to inhale through the airway, or it may be released automatically by a trigger mechanism 230 which is released by a given flow rate of inhaled air through the airway.

Fig. 7 shows a third embodiment 301 of an airway for an inhalation device which, corre- sponding to the second embodiment, has a tubular airway portion 310 defining a main axis and having an interior with an inner wall, an aerosol inlet opening 320 arranged axially in a bottom portion 318 at the inlet end and with a ring-formed protrusion 340, and a circumferential swirl chamber 350 surrounding the proximal end of the tubular airway portion and forming a circumferential swirl cavity with a flow communication 352 between the swirl cavity and the airway. However, in contrast to the circumferential gap of the second embodiment, the flow communication is provided with a plurality of deflecting walls 355 establishing a plurality of small flow channels 356 between the swirl cavity and the airway. The flow channels serve to accelerate the flow rate (see the vector flow simulation in fig. 8) as well as slightly directing the swirl flow towards the axially arranged slot-formed aerosol outlet.

The inhalation device 200 uses ambient non-heated air, however, it may be desirable to use heated air to evaporate carrier fluid from the fluid aerosol particles to diminish their size before entering the patient airway. To optimize heat transfer between air and aerosol particles, the contact distance between the hot gas and the aerosol is preferably minimized and the hot gas is preferably distributed in a more homogeneous manner through a large surface area.

A further embodiment of the present invention addresses these issues by placing the hot gas source proximal to where the droplets are generated. Furthermore, the hot gas can be distributed through a porous surface to provide a more homogeneous mixing of the droplets and hot gas, and thus efficient heat transfer, as well as minimizing aerosol deposition on the airway wall. The reduced amount of aerosol deposition on the wall will not only increase the amount of drug delivered to a patient but also minimize the need for users to clean the airway regularly. Fig. 9 shows an airway 401 with inner and outer coaxial cylindrical tubes 410, 420. The inner cylinder is porous (here comprising a large number of small perforations which for illustrative purposes are only shown for the end portion) and comprises an axial aerosol inlet 41 1 . The hot gas passes through the outer cylinder and enters the inner cylinder through the openings of the perforated surface to mix with the aerosol flow. The hot gas will act as a sheath gas. This configuration not only allows a homogeneous mixing of the hot gas and the aerosol but also provides minimum aerosol deposition on the airway wall. Slits or other configurations (e.g. using a woven or non-woven material) can also be used instead of perforated surface for ease of manufacturing.

Fig. 9 shows an airway comprising concentric cylinders, however, the concentric cylinders can be replaced with virtually any shaped tubes, such as square or oval tubes. The tubes can be tapered and be somewhat conical or they can have various shapes such as para- bolic, see the airways 501 , 601 of figs. 10 and 1 1. Moreover, the porous surface on the inner tube can be along the entire tube wall or located in only a region of the tube wall thus forming a mixing region within the airway. Moreover, the number or pores and size of pores need not be uniform and their locations and sizes can be optimized based upon flow parameters. Additionally, while it is described as employing hot gas, not all inhalers will require heating. In some cases ambient air will be sufficient.

As shown in fig. 9 the aerosol is introduced into the inner tube through an inlet 41 1 which may either be a nozzle generating the aerosol or an opening through which an aerosol generated by other means is introduced, the inlet being oriented parallel to the longitudinal axis of the airway. Ambient temperature air or heated gas enters the air way thru openings 521 or perforations that are in the cylindrical wall of the outer cylinder or tube. The hot gas then enters the perforated inner cylinder perpendicularly to the inner cylindrical wall via the perforations. This results in the hot gas entering perpendicular to the flow of the aerosol from the nozzle or droplet injection point 10. In the shown embodiments air enters in a perpendicular orientation but other orientations are also within the scope of the present invention.

In another embodiment of the invention, the device is designed to prevent backflow of the aerosol/gas when patient accidentally exhale/cough during aerosolization. A low resistance one-way valve may be placed upstream of the nozzle, preferably in or upstream of a mouth- piece or airway. This prevents device contamination/malfunction and generation of foul odour due to burned drug on the heating elements.

The present invention may also include embodiments where the airway is insulated so as to minimize heat loss or where the airway itself is heated. The heating can be supplemental heating in which the amount of heat added is equal to or greater than the amount of heat lost to the ambient surroundings. In some embodiments, all heating may occur within the confines of the airway.

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. 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 . An airway (1 , 101 , 301 ) for an inhalation device, comprising: a tubular airway portion (10, 1 10) defining a main axis and having an interior, an inlet end and an outlet end, an aerosol inlet (20, 120) arranged at the inlet end, the tubular airway portion allowing a substantially unimpeded flow along the main axis for an aerosol introduced through the aerosol inlet, and air inlet means (30, 150) arranged in the vicinity of the distal end, wherein the air inlet means is arranged to cause swirling of air introduced there through, the swirl having an axis generally along the main axis.

2. An airway for an inhalation device as in claim 1 , wherein air introduced through the air inlet means and aerosol introduced through the aerosol inlet mix to form a mixed swirl comprising a mixture of air and aerosol, the mixed swirl having an axis generally along the main axis.

3. An airway for an inhalation device as in claim 1 or 2, wherein air introduced through the air inlet means initially has a direction of flow substantially perpendicular to the main axis.

4. An airway for an inhalation device as in any of the previous claims, wherein the air inlet means comprises one or more openings (32, 152) directing air substantially tangentially into the tubular airway portion.

5. An airway for an inhalation device as in any of the previous claims, wherein the air inlet means comprises: a circumferential swirl cavity (155) surrounding at least a portion of the tubular airway portion, the swirl cavity comprising a cavity air inlet (151 ) and a flow communication (152) between the swirl cavity and the airway, - wherein the cavity air inlet is arranged to cause swirling of air introduced there through, the swirl having an axis generally along the main axis.

6. An airway for an inhalation device as in claim 5, wherein the swirl cavity surrounds the inlet end of the tubular airway portion.

7. An airway for an inhalation device as in claim 5 or 6, wherein the flow communication is in the form of a circumferential opening (152) between the swirl cavity and the tubular airway portion.

8. An airway for an inhalation device as in any of the previous claims, further comprising deflecting means (40, 140) arranged in the tubular airway portion, the deflecting means deflecting the swirling air introduced through the air inlet means.

9. An airway for an inhalation device as in claim 8, wherein the deflecting means serves at least partially to deflect the swirling air introduced through the air inlet means in a direction along the main axis.

10. An airway for an inhalation device as in claim 9, wherein the deflecting means comprises a number of vane members (40) surrounding the aerosol inlet and projecting generally along the main axis.

1 1 . An inhalation device comprising an airway as in any of claims 1 -10, further comprising aerosol generating means adapted to introduce an aerosol of a drug through the aerosol inlet.

12. An inhalation device as in claim 1 1 , further comprising: means to receive a drug receptacle (210) comprising a reservoir (212) with a fluid drug formulation and a nozzle array in flow communication with the reservoir, and means (220, 221 ) for moving fluid drug from the reservoir through the nozzle array thereby creating an aerosol of drug particles introduced through the aerosol inlet.

13. An inhalation device as in claim 12, further comprising trigger means (230) responsive to inhalation of air through the outlet end of the airway body, the trigger means being adapted to trigger the means for moving fluid out of the reservoir.

14. An inhalation device as in any of claims 1 1 -13, further comprising means for heating the air before it is introduced into the tubular airway portion.