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WO2008101991A1 - Mécanisme de libération activé par la respiration destiné à un dispositif de génération d'aérosol - Google Patents

Mécanisme de libération activé par la respiration destiné à un dispositif de génération d'aérosol Download PDF

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Publication number
WO2008101991A1
WO2008101991A1 PCT/EP2008/052136 EP2008052136W WO2008101991A1 WO 2008101991 A1 WO2008101991 A1 WO 2008101991A1 EP 2008052136 W EP2008052136 W EP 2008052136W WO 2008101991 A1 WO2008101991 A1 WO 2008101991A1
Authority
WO
WIPO (PCT)
Prior art keywords
receptacle
air
cavity
airway
flow
Prior art date
Application number
PCT/EP2008/052136
Other languages
English (en)
Inventor
Claes Johan Friberg
Kristian GLEJBØL
Original Assignee
Novo Nordisk A/S
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Novo Nordisk A/S filed Critical Novo Nordisk A/S
Publication of WO2008101991A1 publication Critical patent/WO2008101991A1/fr

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M15/00—Inhalators
    • A61M15/0091—Inhalators mechanically breath-triggered
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M15/00—Inhalators
    • A61M15/0028—Inhalators using prepacked dosages, one for each application, e.g. capsules to be perforated or broken-up
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M15/00—Inhalators
    • A61M15/0028—Inhalators using prepacked dosages, one for each application, e.g. capsules to be perforated or broken-up
    • A61M15/003—Inhalators using prepacked dosages, one for each application, e.g. capsules to be perforated or broken-up using capsules, e.g. to be perforated or broken-up
    • A61M15/0043—Non-destructive separation of the package, e.g. peeling
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M15/00—Inhalators
    • A61M15/0028—Inhalators using prepacked dosages, one for each application, e.g. capsules to be perforated or broken-up
    • A61M15/0045—Inhalators using prepacked dosages, one for each application, e.g. capsules to be perforated or broken-up using multiple prepacked dosages on a same carrier, e.g. blisters
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M15/00—Inhalators
    • A61M15/0028—Inhalators using prepacked dosages, one for each application, e.g. capsules to be perforated or broken-up
    • A61M15/0045—Inhalators using prepacked dosages, one for each application, e.g. capsules to be perforated or broken-up using multiple prepacked dosages on a same carrier, e.g. blisters
    • A61M15/0046—Inhalators using prepacked dosages, one for each application, e.g. capsules to be perforated or broken-up using multiple prepacked dosages on a same carrier, e.g. blisters characterized by the type of carrier
    • A61M15/0051—Inhalators using prepacked dosages, one for each application, e.g. capsules to be perforated or broken-up using multiple prepacked dosages on a same carrier, e.g. blisters characterized by the type of carrier the dosages being arranged on a tape, e.g. strips
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M15/00—Inhalators
    • A61M15/0028—Inhalators using prepacked dosages, one for each application, e.g. capsules to be perforated or broken-up
    • A61M15/0045—Inhalators using prepacked dosages, one for each application, e.g. capsules to be perforated or broken-up using multiple prepacked dosages on a same carrier, e.g. blisters
    • A61M15/0053—Inhalators using prepacked dosages, one for each application, e.g. capsules to be perforated or broken-up using multiple prepacked dosages on a same carrier, e.g. blisters characterized by the type or way of disposal
    • A61M15/0055—Inhalators using prepacked dosages, one for each application, e.g. capsules to be perforated or broken-up using multiple prepacked dosages on a same carrier, e.g. blisters characterized by the type or way of disposal the used dosages being coiled
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M15/00—Inhalators
    • A61M15/0091—Inhalators mechanically breath-triggered
    • A61M15/0093—Inhalators mechanically breath-triggered without arming or cocking, e.g. acting directly on the delivery valve
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M16/00—Devices for influencing the respiratory system of patients by gas treatment, e.g. ventilators; Tracheal tubes
    • A61M16/20—Valves specially adapted to medical respiratory devices
    • A61M16/201—Controlled valves
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M2202/00—Special media to be introduced, removed or treated
    • A61M2202/06—Solids
    • A61M2202/064—Powder
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M2206/00—Characteristics of a physical parameter; associated device therefor
    • A61M2206/10—Flow characteristics
    • A61M2206/16—Rotating swirling helical flow, e.g. by tangential inflows

Definitions

  • 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.
  • 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.
  • one convenient method is the oral delivery of pills, capsules and the like.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • a carrier either as a single-dose carrier or a multi-dose carrier.
  • 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.
  • the user's inhalation may also be used to actuate the device, e.g. as shown in WO 01/85245 in which a MDI device is actuated by the patient's inhalation moving a triggering membrane a small distance.
  • a challenge in utilizing the patient's inspired gases is that the inspiration flow rate can drastically 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, 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. It is a further problem that patients may not use the device in a consistent and correct way, this both applying to a group of users as well as to an individual user.
  • 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 enhance 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.
  • the present invention provides a breath actuation mechanism for an aerosol generating device, comprising an air inlet, an air outlet adapted to be connected to the airway of a patient, a variable-volume chamber connected to the air outlet and having an initial volume, valve means associated with the air inlet and having an initial closed state preventing a flow of air from the outside through the air inlet to the air outlet, and actuatable trig- gering means responsive to evacuation of a volume of air from the chamber through the air outlet, wherein the pre-defined volume of air is at least 25 ml, and wherein actuation of the triggering means opens the valve means thereby allowing a flow of air through the air inlet to the air outlet.
  • the initial inhalation can proceed essentially unimpeded until the whole of the definite pre-defined volume has been emptied.
  • the lungs are slightly expanded and thus made ready for inhalation of an aerosol.
  • the point in time when inhalation is shifted from evacuating air from the chamber and inhalation through the air inlet will in most cases be sensed by the user as a change in flow resistance, this indicating that the mechanism has been actuated.
  • the definite volume may be fixedly pre-set or it may be pre-set individually for each user. For an adult the volume may be in the 50-200 ml range.
  • the breath actuation mechanism may be incorporated in any desirable type of aerosol generating device in which breath actuation is desirable, e.g.
  • valve means in a MDI or in an inhaler in which powder is provided in bulk or in pre-metered doses.
  • the valve means When the valve means is closed the user may inhale air solely from the chamber, however, the breath actuation mechanism or the device in which it is integrated may comprise additional air inlet means allowing a by- pass flow of air during the period of time in which the chamber is evacuated from the predefined volume of air. Such a leak flow may also be provided by "unintentional" leakage between components due to production tolerances.
  • the breath actuation mechanism may comprise a rigid chamber (e.g. a cylinder) and a moveable member arranged therein (e.g. a piston), the rigid chamber and the moveable member defining the variable-volume chamber.
  • the moveable member may be a flexible membrane.
  • the triggering means may be actuated by movement of the moveable member or by a vacuum created by a patient when the variable-volume chamber has been evacuated.
  • the breath actuation mechanism is part of an aerosol generating device comprising means for receiving an amount of an aerosolizeable drug formulation, and which may comprise a releasable mechanism actuatable by the triggering means.
  • the aero- sol generating device may comprise or may be adapted to receive one or more receptacles containing an aerosolizeable drug formulation, as well as means for moving the receptacle from a first position to a second position, the second position allowing a flow of air to extract drug formulation from the receptacle, wherein the means for moving the receptacle is actuated by the triggering means.
  • the aerosol generating device may further comprise a valve controlling the air flow between the air inlet and the air outlet, and a receptacle containing an aerosolizeable drug formulation.
  • the valve is then operatable between a first closed condition in which there is no flow communication between the air inlet and the receptacle, and a second open condition in which there is established flow communication between the air inlet and the receptacle, thereby allowing a flow of air between the air inlet and the air outlet extracting drug formulation from the receptacle, wherein the valve is actuated from the first to the second condition by the triggering means.
  • the aerosol generating device may alternatively comprise a chamber for receiving a dose of an aerosolizeable drug formulation in communication with the air outlet, and aerosolization means to assist aerosolization of a dose of the drug formulation, which means is operable by a patient-independent energy output source, wherein the aerosolization means is actuated by the triggering means.
  • the patient-independent energy output is derived from a source se- lected from the group consisting of a spring, or other biasable resilient energy storage means, a battery and a source of compressed or liquefied gas.
  • an aerosol generating device comprises a breath actuation mechanism as disclosed above, and further comprises 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 communica- tion 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.
  • 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.
  • tangential 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.
  • 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 ⁇ m or less than 5 ⁇ m depending on the kind of drug and the intended place of deposition.
  • 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.
  • 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.
  • 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 out- let, e.g. a mechanical member as a membrane or flap, or an electronic pressure or flow transducer.
  • the actuatable triggering means will serve to actuate both the valve means and the drive means.
  • the aerosol generating device includes a drug carrier compris- ing 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 allowing 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.
  • 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.
  • the outlet may be arranged generally tangentially.
  • 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.
  • an aerosol generating device adapted to receive a receptacle member 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.
  • a method comprising the steps of (a) providing an aerosol generating device comprising an air inlet, an air outlet adapted to be connected to the airway of a patient, a variable-volume chamber connected to the air outlet and having an initial volume, and valve means associated with the air inlet and having an initial closed state preventing a flow of air from the air inlet to the air outlet, (b) evacuating a volume of at least 25 ml of air from the chamber through the air outlet, and (c) in response to the evacuation of at least 25 ml of air from the chamber opening the valve means thereby allowing a flow of air through the air inlet to the air outlet.
  • the method may comprise the further step of establishing flow communication between the air outlet and a receptacle contain- ing an aerosolizeable drug formulation, e.g. as described in detail above.
  • 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.
  • 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 a partial cross-section of a further aerosol generating device
  • fig. 6 shows a yet further aerosol generating device, fig.
  • FIG. 7 shows an exploded view of the aerosol generating device of fig. 6
  • figs. 8A and 8B show cross-sectional views of the aerosol generating device of fig. 6 in different conditions of use
  • figs. 9A and 9B show further cross-sectional views of the aerosol generating device of fig. 6 in different conditions of use
  • figs. 1 OA, 10B and 10C show cross-sectional views of parts of the aerosol generating device of fig. 6 in different conditions of use
  • fig. 11 shows a multi dose peel mechanism
  • figs. 11A and 1 1 B show a further multi dose peel mechanism.
  • aerosol generating devices or "inhalers" will be described which may be used in combination with the breath actuation mechanism of the present invention. Aerosol generating devices incorporating the breath actuation principle of the present invention will be described with reference to figs. 5-10.
  • 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 portion 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.
  • the sealed container In an initial condition (not shown) the sealed container is arranged outside the airway cavity open- ing 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.
  • the angle between the tubular airway cavity and the drug carrier is approximately 20 degrees, however, it may vary between 0 and 180 degrees (i.e. the recep- tacle and the air flow may move against each other). Further, the receptacle may be moved transversely relative the airway cavity, e.g. when using a rotationally arranged disc-formed carrier comprising a plurality of powder-filled cavities.
  • the inhaler 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.
  • 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 extracts powder drug from the receptacle as air revolves between the airway cavity and the receptacle cavity.
  • one or more tangential air inlets 32 may be provided as shown in fig. 1 B.
  • 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.
  • the carrier is represented by a blister member 120 (i.e. corre- sponding to receptacle member 51 of fig. 1A) comprising a lower base portion 125 in which the receptacle cavity 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.
  • a lower part 115 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 1 10 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 connec- tion to a mouthpiece.
  • 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 1 18 used for peeling and supporting the blister lid foil is connected to the lower part.
  • a blister member 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • the same relative movement takes place as in the above described first embodiment.
  • 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.
  • the blister member as a sliding valve controlling the airflow through the swirl chamber.
  • 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.
  • the surface portion serves as a closed valve when the receptacle member is in its initial position
  • the opening or cut-out portion serves as an open valve when the receptacle member is in an actuated position.
  • 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.
  • Fig. 5 shows an embodiment of an aerosol generating device 201 incorporating a breath actuation mechanism. More specifically, the device comprises a housing 210 in which a slidable spring-biased carrier 220 is arranged.
  • the housing comprises a generally oblong airway cavity of the same general design as shown in figs. 2-4.
  • a variable-volume chamber 240 is connected to the air outlet 235 via a conduit and the airway cavity and comprises a rigid cylindrical chamber 242 and a slidable piston 243 mounted therein, the cylinder and piston defining the variable-volume chamber.
  • a bellows seal 244 is provided between the piston and the cylindrical chamber.
  • variable-volume chamber is associated with actuatable trig- gering means 245 responsive to evacuation of a volume of air from the chamber whereby actuation of the triggering means releases the carrier 220 which subsequently opens a valve (not shown) thereby allowing a flow of air through an air inlet to the air outlet.
  • the slidable carrier 220 comprises a generally oblong receptacle (either formed in the carrier or by a blister member arranged in the carrier) containing the aerosolizeable powder drug formulation and has an upper opening closed by a peelable foil lid. A free portion of the foil lid is wrapped around a stationary wedge portion (as in fig. 3) and fixed thereto.
  • the upper surface of the carrier serves as closure means for the airway cavity opening, whereas the foil lid serves as the closure means for the receptacle.
  • the carrier is actuated and starts to move the foil is peeled from the receptacle as shown in fig. 3.
  • Fig. 7 shows in an exploded view an embodiment of an aerosol generating device 301 incorporating a further breath actuation mechanism. More specifically, the device comprises a main housing portion 310 with an air outlet 335, a lower portion 315, an upper blister holder portion 350, a piston 343, a sledge 360, a releasable lock 325, and a biasing spring 368.
  • Fig. 6 shows the device 301 in an assembled state.
  • a blister member 370 with a peelable lid 378 is arranged, see fig. 8A. As seen in fig.
  • a generally closed square-cylindrical cavity is formed in which the square piston is slidably mounted, a variable-volume chamber 340 being formed between the upper surface of the piston and the cavity, a bellows seal 344 being provided between the periphery of the piston and the lower portion.
  • the piston comprises a release member 345 projecting from its upper surface and being guided in an opening 352 in the blister holder portion.
  • the main portion comprises an airway cavity 330 with a lower opening 331 which initially is in flow communication with the chamber 340.
  • the blister holder portion 350 comprises a generally planar lower portion 351 and an upper tubular portion 355 in which the sledge 360 is slidingly mounted.
  • the lower portion comprises a left-most wedge edge 366 around which the peel foil 328 is mounted, and on the lower surface a gripping flange 353 is arranged which in combination with gripping flanges 311 , 312 on the main housing portion serves to hold the blister member yet allowing it to be moved in a controlled manner, see fig. 8A.
  • Below the flange 353 an air inlet 354 in communication with the exterior is arranged.
  • the sledge 360 has a right-most tube portion with an upper slot 361 along its length, this al- lowing a spring support member 356 of the blister holder portion to project into the sledge tube portion, the springs 368 being mounted in an initially compressed state between the spring support member and a pin 362 attached to the right-most end of the sledge.
  • the sledge further has a left-most main portion 365 comprising a releasable lock 325 which initially engages the opening 352 in the blister holding portion, as well as it serves to hold the proximal end 379 of the peelable foil lid 378 (see below).
  • the blister member 370 comprises a base sheet 375 in which an oblong receptacle cavity 371 with an opening 372 is formed, the remaining of the base sheet forming a generally planar circumferential portion comprising first and second cut-out portions 373, 374 (see fig. 9A).
  • the peelable lid 378 comprises a distal portion attached to the circumferential portion thereby covering the receptacle cavity to form a sealed blister cavity containing an amount of an aerosolizable drug powder formulation, as well as a proximal portion arranged around the wedge edge and attached to the main portion of the sledge.
  • FIGs. 8A, 9A and 1OA show the device in its initial condition.
  • air is evacuated from the chamber 340 via the airway cavity 330 through the lower opening 331 which initially is in flow communication with the chamber 340.
  • Fig. 10A shows the blister holder 350 and the blister member 370 in the initial condition with the other components removed.
  • the free proximal portion of the peelable lid 378 is wrapped around the stationary wedge edge 366 with upstanding proximal end of the lid foil mounted in the main portion 365 of the sledge 360, see fig. 8A.
  • the foil is peeled off the base sheet, whereby the blister is opened and moved to the left (see figs. 10B and 10C) and thereby into flow communication with the airway cavity.
  • the blister member As the blister member is moved it also serves to open and close airway openings. In the initial position as seen in fig. 9A the airway cavity is in flow communication with the variable- volume chamber through cavity opening 331 , and the air inlet openings 332 and 354 are closed by the blister member.
  • the cavity opening is closed and the air inlet openings 332 and 354 are opened (by moving the first cut-out portion 373 into register with the inlet 332 and moving the blister member out of register with the inlet 354), this providing that air is drawn through the air inlet opening 354, the variable-volume chamber 340 and the air inlet opening 332 before it enters the airway cavity through a U- shaped channel-formed air inlet portion arranged in front of the wedge (this as best shown in fig. 4B) and here creates a swirl before it is inhaled by the patient.
  • the receptacle is moved into flow communication, this allowing the airway swirl to generate a secondary swirl in the receptacle cavity, thereby extracting powder formulation from the receptacle.
  • the powder is moved in the receptacle cavity and the airway cavity by the swirling air it is subjected to high shear forces whereby it is de- agglomerated before it exits through the air outlet 335.
  • the blister member continues to move this resulting in the first cut-out portion 373 being moved out of register with the air inlet 332 whereby the inlet is closed by the planar portion of the blister member, and the second cut-out portion 374 being moved into regis- ter with the airway cavity opening 331 , this resulting in a secondary flow of air flushing the airway cavity.
  • the combined flow resistance is lower for the sec- ondary flow.
  • it is important that a good seal is provided between the upper surface of the blister member and the lower surface of the blister holder.
  • the air inlet opening for the flushing air flow is provided by the opening also used for the receptacle cavity, however the inlet opening for the flushing air flow could be provided as a separate inlet opening.
  • a multi dose peel mechanism 400 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.
  • 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.
  • a loading mechanism 435 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 pre- vented from turning by a trigger that may be either manual or released by the user's inhalation.
  • the spring can be loaded 1 through 5 steps (clicks) corresponding to the desired number of doses.
  • 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.
  • the oblong cavities are arranged transversely on the receptacle member.
  • the blister tape may also be provided with openings or cut-out portions controlling the flow of air.
  • 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.
  • 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.
  • 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.
  • the receptacle member may be a continuous band as above, however, this would imply cutting off the used receptacle portion.
  • the peel mechanism is activated by turning the priming wheel thereby loading the peel mechanism.
  • the peel wheel When the trigger mechanism is released the peel wheel is allowed to turn a given angle corresponding to the peeling and forwarding of an individual receptacle member.
  • the receptacle member When integrated into an inhaler, the receptacle member will be moved past an airway cavity as shown schematically in fig. 1A, 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.
  • the blister tapes shown in figs. 11 and 1 1A may be provided with valve means in the form openings and/or cut-out portions formed in the receptacle member(s) as described above with reference to figs. 4-9, e.g. corresponding to cut-out portions 124, 373.
  • the lid foil may be formed without corresponding openings.
  • the lid foil may be provided with "camera" perforations allowing the lid foil to be pulled by a peeling mechanism, the blister part of the tape comprising no such perforations.
  • the airway cavity has a generally oblong or tubular con- figuration in which the generated swirl has an axis along the length of the cavity and cham- ber.
  • the airway cavity could also have other configurations, for example a disc- formed configuration.

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Abstract

L'invention concerne un mécanisme de libération activé par la respiration destiné à un dispositif de génération d'aérosol (201), comprenant un orifice d'admission de l'air, un orifice de sortie de l'air (235) conçu pour être connecté aux voies respiratoires d'un patient, une chambre à volume variable (240) connectée à l'orifice de sortie de l'air et possédant un volume initial, un agencement de soupape associé à l'orifice d'admission de l'air et possédant un état initial fermé, un moyen de déclenchement actionnable (245) réagissant à l'évacuation d'un volume d'air défini de la chambre, où l'actionnement du moyen de déclenchement ouvre le mécanisme de soupape, ce qui permet à l'air de s'écouler par l'orifice d'admission de l'air en directionde l'orifice de sortie de l'air. Au départ, l'inhalation se fait sensiblement librement jusqu'à libération de l'ensemble du volume défini. Les poumons sont ainsi légèrement ouverts et prêts pour l'inhalation d'un aérosol.
PCT/EP2008/052136 2007-02-21 2008-02-21 Mécanisme de libération activé par la respiration destiné à un dispositif de génération d'aérosol WO2008101991A1 (fr)

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EP07102780 2007-02-21

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WO2008101991A1 true WO2008101991A1 (fr) 2008-08-28

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Citations (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1992004068A1 (fr) * 1990-08-30 1992-03-19 Boehringer Ingelheim Kg Inhalateur sans gaz propulseur a courant d'air exterieur
US5297542A (en) * 1989-06-22 1994-03-29 Raymond J. Bacon Aerosol dispensing device
WO1995005208A1 (fr) * 1993-08-18 1995-02-23 Fisons Plc Inhalateur pourvu d'un systeme de regulation du debit d'air
FR2751883A1 (fr) * 1996-08-01 1998-02-06 Cieutat Bertrand Dispositif de commande d'un generateur d'aerosol pneumatique
WO2001085245A1 (fr) * 2000-05-09 2001-11-15 Iep Pharmaceutical Devices Inc. Inhalateur respiratoire a commande pneumatique
WO2002002168A1 (fr) * 2000-07-05 2002-01-10 Ml Laboratories Plc Actionneur comprenant une membrane mobile
US6606992B1 (en) * 1999-06-30 2003-08-19 Nektar Therapeutics Systems and methods for aerosolizing pharmaceutical formulations
EP1386630A1 (fr) * 2002-07-31 2004-02-04 CHIESI FARMACEUTICI S.p.A. Inhalateur de poudre
WO2004103445A1 (fr) * 2003-05-21 2004-12-02 Jean-Marc Aiache Dispositif d'inhalation de poudre
EP1488819A1 (fr) * 2003-06-16 2004-12-22 Rijksuniversiteit te Groningen Inhalateur de poudre sèche et procédé d'inhalation pulmonaire de poudre sèche

Patent Citations (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5297542A (en) * 1989-06-22 1994-03-29 Raymond J. Bacon Aerosol dispensing device
WO1992004068A1 (fr) * 1990-08-30 1992-03-19 Boehringer Ingelheim Kg Inhalateur sans gaz propulseur a courant d'air exterieur
WO1995005208A1 (fr) * 1993-08-18 1995-02-23 Fisons Plc Inhalateur pourvu d'un systeme de regulation du debit d'air
FR2751883A1 (fr) * 1996-08-01 1998-02-06 Cieutat Bertrand Dispositif de commande d'un generateur d'aerosol pneumatique
US6606992B1 (en) * 1999-06-30 2003-08-19 Nektar Therapeutics Systems and methods for aerosolizing pharmaceutical formulations
WO2001085245A1 (fr) * 2000-05-09 2001-11-15 Iep Pharmaceutical Devices Inc. Inhalateur respiratoire a commande pneumatique
WO2002002168A1 (fr) * 2000-07-05 2002-01-10 Ml Laboratories Plc Actionneur comprenant une membrane mobile
EP1386630A1 (fr) * 2002-07-31 2004-02-04 CHIESI FARMACEUTICI S.p.A. Inhalateur de poudre
WO2004103445A1 (fr) * 2003-05-21 2004-12-02 Jean-Marc Aiache Dispositif d'inhalation de poudre
EP1488819A1 (fr) * 2003-06-16 2004-12-22 Rijksuniversiteit te Groningen Inhalateur de poudre sèche et procédé d'inhalation pulmonaire de poudre sèche

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