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
  • A61M15/0028—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
  • A61M15/0001—Details of inhalators; Constructional features thereof
  • A61M15/0003—Details of inhalators; Constructional features thereof with means for dispensing more than one drug
• • 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
  • A61M15/0001—Details of inhalators; Constructional features thereof
  • A61M15/0021—Mouthpieces therefor
  • A61M15/0025—Mouthpieces therefor with caps
  • A61M15/0026—Hinged caps
• • 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
  • A61M15/0033—Details of the piercing or cutting means
• • 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
  • A61M15/005—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 cylindrical surface
• • 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
  • A61M15/0065—Inhalators with dosage or measuring devices
  • A61M15/0068—Indicating or counting the number of dispensed doses or of remaining doses
  • A61M15/007—Mechanical counters
  • A61M15/0071—Mechanical counters having a display or indicator
  • A61M15/0075—Mechanical counters having a display or indicator on a disc
• • 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
  • A61M15/0091—Inhalators mechanically breath-triggered
  • A61M15/0096—Hindering inhalation before activation of the dispenser
• • 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
  • A61M2205/00—General characteristics of the apparatus
  • A61M2205/58—Means for facilitating use, e.g. by people with impaired vision
  • A61M2205/581—Means for facilitating use, e.g. by people with impaired vision by audible feedback
• • 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
  • A61M2205/00—General characteristics of the apparatus
  • A61M2205/58—Means for facilitating use, e.g. by people with impaired vision
  • A61M2205/582—Means for facilitating use, e.g. by people with impaired vision by tactile feedback
• • 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
  • A61M2205/00—General characteristics of the apparatus
  • A61M2205/82—Internal energy supply devices
  • A61M2205/8218—Gas operated

Definitions

• This invention relates generally to inhalation devices comprising two or more hermetically sealed receptacles, each holding a single pre-metered dose of pressurized liquefied propellant-based formulation.
• Pressurized metered dose inhalers have been used for over forty years for the treatment of asthma and other respiratory conditions.
• Pressurized metered dose inhalers comprise a container filled with many doses of propellant-based formulation, together with a metering valve for dispensing individual metered doses upon demand.
• One of the disadvantages of conventional metered dose inhalers is the difficulty in providing a low number of doses (e.g. less than thirty) that is appropriate for some therapy regimes.
• hermetically sealed receptacles each containing a single dose of a pressurized formulation comprising a pharmaceutically active ingredient and a liquefied aerosol propellant consisting of 1 ,1 ,1 ,2-tetrafluoroethane (HFA 134a), 1,1,1 ,2,3,3,3-heptafluoropropane (HFA 227) or a mixture thereof (as the sole propellant component) and wherein at least a portion of the receptacle is perforable (i.e.
• an inhalation device in which upon actuation of the device and thus perforation of a receptacle, an aerosol is generated allowing for delivery of the pharmaceutically active ingredient to the lung.
• the generated aerosol for inhalation advantageously comprises fine droplets of liquefied propellant together with pharmaceutically active ingredient allowing for reliable delivery and transport of the active ingredient to the patient's lungs.
• the present invention provides an inhalation device comprising two or more hermetically sealed receptacles, each containing a single dose of a pressurized formulation comprising a pharmaceutically active ingredient and a liquefied aerosol propellant consisting of HFA 134a, HFA 227 or a mixture thereof and wherein at least a portion of each receptacle is perforable.
• the device is to be provided with sufficiently high vapor pressure at room temperature such that proactive delivery means vaporize thoroughly upon activation (providing a hard aerosol with just active ingredient) and similar to the devices disclosed in US'914 much of the medicament will simply be immediately deposited on surfaces of the device and/or retained within the device.
• the receptacles of the devices described herein preferably have relatively low internal pressure within the receptacle at ambient temperature (22 0 C), e.g. at most 7 atmospheres pressure absolute. This is advantageous inter alia in terms of cost effectiveness and ease in manufacture, in that the receptacle need not be spheroid in shape (a form typically necessary for containers having a high internal pressure).
• Receptacles also desirably have an internal volume of less than 0.3 ml. The volume of the pressurized formulation is typically 150 ⁇ l at most.
• Devices in accordance with the invention preferably further comprise a firing pin for perforating the receptacle, more preferably two or more firing pins, wherein each receptacle is in operative association with a firing pin.
• the device includes a corresponding number of firing pins to the number of receptacles, so that each receptacle is associated with its own operatively associated firing pin. This is advantageous in that for the perforation of each receptacle a fresh firing pin is used and thus any potential problems of blunting and/or occlusion upon a repetitive use of a single firing pin may be avoided.
• Each firing pin comprises a channel having an opening at both ends; more desirably the channel is defined by an internal surface of the firing pin.
• the at least perforable portion of the receptacle may be provided as a substantially planar portion to help avoid deflection or skidding of the firing pin used to perforate the receptacle. Such perforation is preferably rapid, in order to avoid or minimize unwanted aerosol leakage during perforation.
• the receptacle to-be-fired and firing pin are desirably mutually displaced, through the use of a triggering mechanism that is released upon actuation to act on the receptacle and/or firing pin as the case may be, to cause the firing pin to perforate the receptacle at said at least perforable portion and to cause aerosol formulation to pass through said channel from the first end to the second end of the channel and through to the patient.
• the term "mutually displaced" means that the receptacle is displaced towards the firing pin, or the firing pin is displaced towards the receptacle, or both the receptacle and firing pin are displaced towards each other.
• the firing pin is held fixed at the time of actuation and the receptacle to-be-fired is displaced towards the firing pin, for example through the use of a triggering mechanism including a mechanically or pneumatically loaded impactor that is released upon actuation to act on the receptacle displacing it towards the firing pin to cause the firing pin to perforate the receptacle at said at least perforable portion.
• the device is arranged such that upon perforation of said at least perforable portion of the receptacle by the firing pin, the first end of the channel of the firing pin passes into a liquid portion of the pressurized formulation.
• the outer surface of the portion of the firing pin (e.g. the tip thereof) that passes into the receptacle is conical in shape.
• the channel is preferably not provided in the form of a capillary tube.
• the internal surface of the said firing pin channel may be arranged to provide an expansion chamber, i.e. a chamber through which the expanding aerosol passes after its release from the perforated receptacle and before its subsequent passage through a more restrictive region such as a spray break-up orifice.
• the internal surface of said channel may advantageously be generally conical from the first end to the second end.
• the channel of the firing pin extends generally along a single axis.
• the outermost surface of the firing pin e.g.
• the outermost portion of the tip of the firing pin is provided with a piercer capable of perforating the at least perforable portion of the receptacle.
• a piercer capable of perforating the at least perforable portion of the receptacle.
• Devices described herein desirably further comprise a carrier wherein the receptacles are mounted on the carrier.
• the carrier may be in the form of a carousel, wherein the receptacles are mounted onto the carousel such that the at least perforable portion of each receptacle is positioned radially outwardly.
• the firing pins may also be mounted on the carrier, for example such that the first end of the channel of each individual firing pin is positioned towards the at least perforable portion of its associated receptacle.
• a portion of the device comprising the carrier and mounted receptacles (and in preferred embodiments their associated firings pin) may advantageously be reversibly removable from the device.
• This portion may be suitably provided in the form of a cassette.
• devices described herein may be provided in the form of a kit-of-parts comprising a body portion and a cassette including receptacles (and in preferred embodiments their associated firing pins) and optionally one or more such cassettes as replacement cassettes.
• Devices described herein suitably further comprise a patient outlet adapted for insertion into a patient's mouth or nose (nostril or nostrils) having a passageway.
• Devices described herein desirably further comprise an advancing mechanism, in particular a mechanical advancing mechanism, wherein the advancing mechanism is arranged such that prior to actuation of the device, the receptacle to be fired (and in preferred embodiments its associated firing pin) is (are) advanced to a registered position in alignment with the patient-outlet in preparation for actuation, more desirably, the advancing mechanism is arranged, such that an advancement of any subsequent receptacle to the registered position is prohibited until the preceding advanced receptacle has been actuated (i.e. fired).
• the device further comprises a patient-outlet cover and said cover is coupled to the advancing mechanism, such that upon opening the cover the receptacle to be fired (and in preferred embodiments its associated firing pin) is (are) advanced to the registered position, more particularly such cover is coupled to the advancing mechanism, such that if the receptacle advanced to the registered position upon opening of the outlet cover has not been actuated (i.e. fired) then upon closing the outlet cover said receptacle (and if applicable its associated firing pin) is (are) returned to its pre-advanced position so that when the cover is subsequently opened said receptacle (if applicable together with its associated firing pin) is (are) advanced again to the registered position.
• a patient-outlet cover and said cover is coupled to the advancing mechanism, such that upon opening the cover the receptacle to be fired (and in preferred embodiments its associated firing pin) is (are) advanced to the registered position, more particularly such cover is coupled to the advancing mechanism, such that if the recepta
• the perforation of the receptacle preferably via the use of a firing pin and a triggering mechanism as described herein, to cause aerosol formulation to pass out of the receptacle and through to the patient is generally referred to in abbreviation as actuating the receptacle or firing the receptacle.
• Devices described herein may be actuated either manually (e.g. by pressing a button or lever) or by inhaling (i.e. by breath-actuation). Breath-actuation is preferred.
• the delivery of a pharmaceutically active ingredient for treatment of a systemic disease will tend to require the aerosol to penetrate the deep lung (e.g. to the alveolar regions). This requires good coordination of dose release with the early part of the patient's inspiratory manoeuvre.
• Breath-actuation provides a reliable way of ensuring such coordination, particularly for patients using an inhaler for the first time or for patients using an inhaler infrequently.
• Figures 1 to 3 show perspective views of an exemplary embodiment of a device in accordance with the present invention.
• Figures 4, 5 and Figure 13 represent exploded diagrams of particular sub- assemblies of the embodiment shown in Figures 1 to 3.
• Figures 6 to 9 represent schematic interior views of the embodiment shown in Figures 1 to 3 in its rest position, primed position, in an intermediate position of actuation and in its fired position, respectively, while Figure 10 represents schematic interior view of the opposite side of the embodiment in its fired position.
• Figures 11 and 12 represent schematic interior views of the embodiment shown in Figures 1 to 3 in two intermediate positions upon return to its rest position after actuation.
• Figure 14 represents a perspective view of another exemplary embodiment of a device in accordance with the present invention.
• Figure 15 represents a perspective view of a portion of the exemplary embodiment shown in Figure 14.
• Figures 16 to 24 represent schematic interior views of the embodiment shown in Figure 14 at various stages of the operation of a dose advancing mechanism
• Figure 25 represents an exploded diagram of a sub-assembly of the dose advancing mechanism.
• Figure 26 represents an enlarged, schematic cross-section of a preferred formation of a portion of a tip of a firing pin for both the exemplary embodiments shown in Figures 1 to 13 and 14 to 25, respectively.
• Figure 27 represents an enlarged, schematic cross-section of an alternative preferred formation of a portion of a tip of a firing pin for both the exemplary embodiments shown in Figures 1 to 13 and 14 to 25, respectively.
• Figure 28a and b represent schematic interior views of a portion of yet another exemplary embodiment.
• Figures 1 to 13 illustrate a first exemplary embodiment in accordance with the present invention.
• This exemplary embodiment is a refillable breath-actuated device.
• the exemplary device (1) comprises a reusable body portion (2) and a replaceable cassette (5) containing a plurality of receptacles (39).
• the device comprises an outlet (3) adapted for insertion into a patient's mouth.
• the outlet may be adapted for insertion into a patient's nasal cavity (e.g. for delivery of a pharmaceutically active ingredient to nasal mucosa).
• the outlet adapted for insertion into a patient's mouth or nasal cavity or cavities will generally be referred to under the term patient-outlet.
• the device may include a hinged outlet cover (4) that can be used by the patient to cover the patient-outlet (3) when the inhaler is not in use, thereby protecting the device against dirt and moisture ingress.
• the outlet cover (4) is shown in its open position in Figure 1 and in its closed position in Figures 2 and 3.
• the device may be provided with a tactile and/or audible feedback for the patient indicating that the device or outlet is fully opened or fully closed, for example by providing small pips (not shown) on the outlet cover (4) and small indentations (not shown) on the body portion (2) which give a "click" interaction when the patient opens or shuts the outlet cover.
• the patient-outlet (3) is a push-fit into the body portion (2), so that it can be detached for the patient to wash it.
• Figures 2 and 3 show the receptacle-containing cassette (5) removed from the body portion (2) of the exemplary device (1), e.g. for replacement with a fresh cassette. Removal and replacement of cassettes typically involve simple sliding motions, the cassette being held in place by conventional "snap-fit" features (not shown).
• the cassette (5) typically includes a number of openings, such as a mounting hole (73), a cassette driving opening (53) and a cassette impact opening (44).
• the cassette When the cassette (5) is inserted into the body portion (4), components located within the body portion (see Figure 2), such as a C-shaped mounting post (10) and an impactor (13) having a head (43) and a hollow shaft (54) with a cam (55) (the function of these components will be explained below), can be received by the cassette through the respective openings of the cassette.
• the cassette also includes a front opening (51) (see Figure 3) that is positioned towards the patient-outlet (3) facing a spray inlet (52) of the patient-outlet when the cassette is inserted into the body portion.
• visible through the front opening (51) is a carousel (50) containing the receptacles
• visible through the impactor opening (44) is a bottom surface of another receptacle (39).
• the profile (4a in Figure 1) of the outlet cover (4) is suitably configured such that the cassette (5) can only be removed or replaced when the cover (4) is in its closed position, and thus the device is in its rest position (explained in more detail below), in order to ensure that the impactor (13) is not in a position (e.g. its fired position)_where it would cause an obstruction and possible damage.
• the cam (55) on the driving shaft (54) of the impactor is in a position where it cannot pass through the cassette driving opening (53, see Figure 5) and thus the cam also helps to facilitate the retention of the cassette (5) in the body portion (2) when the impactor is in its fired position.
• the cassette includes outer (16) and inner (17) casing halves.
• the exemplary device includes twelve hermetically sealed receptacles (39), each comprising at least a perforable portion (39a).
• the receptacles may be provided on an elongated strip (19) and mounted in a carousel (50), whereby the carousel comprising two housing halves (18,20).
• each receptacle may advantageously be in the form of a foil (see e.g. component 39b in Figure 5).
• a foil may be e.g. laser welded (as described in our co-pending application GB 0418738 filed August 23, 2004, incorporated herein by reference) onto a receptacle body (see e.g. component 39c in Figure 5).
• the receptacle or any of its components, e.g. a foil or a receptacle body may be made of metal such as stainless steel or aluminum.
• the perforable portion of the receptacle may be provided as a substantially planar portion, so as to minimize skidding or deflection of a firing pin (discussed below) as the firing pin contacts the portion.
• the at least perforable portion of the receptacle suitably has a thickness of at most 250 ⁇ m.
• a thickness of at least 25 ⁇ m is favorable for the at least perforable portion.
• a thickness of at least 38 ⁇ m is desirable, more desirably of at least 50 ⁇ m.
• a thickness of at most 150 ⁇ m is desirable, more desirably of at most 100 ⁇ m, most desirably of at most 75 ⁇ m.
• the receptacles for example onto a carousel within the device, in the general form of a circle with the at least perforable portions of the receptacles facing radial outwardly from the center point of the circle.
• Each receptacle contains a single dose of a pressurized formulation comprising a pharmaceutically active ingredient and a liquefied aerosol propellant consisting of HFA 134a, HFA 227 or a mixture thereof.
• Receptacles used in inhalation devices described herein are desirably free of elastomeric seals and diaphragms and/or dispensing valves, which is advantageous in avoiding leaking during storage as well as any ingress of air or moisture from the outside environment and/or any undesirable interaction with seal and/or diaphragm materials.
• the receptacles are desirably appropriately dimensioned (e.g.
• the receptacle desirably has an internal volume of less than 0.3 ml, more desirably 0.2 ml or less, even more desirably 0.15 ml or less, most desirably about 0.15 ml.
• the internal volume of the receptacle is at least 0.1 ml.
• the volume of pressurized formulation is typically 150 ⁇ l at most, and more desirably about 100 ⁇ l at most, and most desirably about 80 ⁇ l at most.
• the pressurized formulation has a volume of at least about 25 ⁇ l, and more desirably at least about 40 ⁇ l and most desirably at least about 50 ⁇ l.
• the internal pressure within the receptacle is desirably at most 7 atmospheres absolute at ambient temperature, more desirably at most about 6.5 atmospheres absolute, even more desirably from about 3 to about 6.5 atmospheres absolute, most desirably from about 4 to about 6.5 atmospheres absolute.
• each receptacle (39) is in operative association with a firing pin (21).
• the exemplary device includes twelve individual firing pins.
• the firing pins may be suitably mounted onto a carrier, e.g. onto the carousel (50), such that the perforable portion (39a) of each receptacle (39) is positioned facing towards its associated firing pin (21), in particular to a piercer capable of perforating the perforable portion provided on the tip (21a) of the firing pin.
• Each firing pin desirably has an internal surface defining a channel, wherein the channel has an opening at its first end, positioned towards the receptacle at least at the time of actuation, and an opening at its second end, positioned towards the patient outlet at least at the time of actuation.
• the channel of the firing pin defines substantially a single axis and the outlet passageway extends substantially along or substantially parallel to that axis at the time of actuation of the device.
• the channel may be generally conical from the first end to the second end.
• the outermost surface of the firing pin is suitably provided with a piercer, e.g. in the form of a sharp point.
• a piercer e.g. in the form of a sharp point.
• the outer surface of the tip of the firing pin, positioned towards the receptacle at least at the time of actuation, is conical in shape.
• the first end (60a) of the channel (60) is advantageously slightly set back from the outermost surface of the firing pin and positioned adjacent to said piercer (21b).
• FIG 27 shows an enlargement of an alternative tip (21a), in which the internal surface defining the channel (60) is arranged as to provide an expansion chamber (62) with a spray break-up orifice (64).
• the firing pin or the tip thereto is suitably made of a material, e.g. a material comprising a metal or a polymeric material, allowing perforation of the at least perforable portion of the receptacle.
• injection molded polymeric firing pins such as those comprising polybutyleneterephthalate, acetal and/or polycarbonate, can be used to effectively perforate perforable portions of hermetically sealed receptacles, even when said portions are formed from metal (e.g. stainless steel or aluminum), e.g. metallic foil (such as 50 ⁇ m thick stainless steel foil).
• Alternative forms of piercer, such as oblique-cut stainless steel points are also suitable.
• the cassette also comprises a gear (22), an indexing yoke (23), an indexing arm (24), and a torsion spring (25).
• the body portion includes besides the removable patient-outlet (3), the outlet cover (4) formed from two components (8,9) and the impactor (13), a housing made of two outer casing halves (6, 7), a vane (11), a rocker (12) an impactor spring (14) and a drive gear (15).
• the function of these components will be explained below.
• the triggering mechanism of the device which comprises the vane (11), rocker (12), impactor (13), and impactor spring (14), is stable, due to the slight "over centre” direction of action of the force of the impactor spring (14) about the pivot point (38) of the rocker (12).
• the triggering mechanism can however readily be released by inhalation through the patient-outlet (3), due to "mechanical advantage” provided by preferable geometries of the vane (11) and the rocker (12).
• the vane (11) continues to rotate (counterclockwise) further (as shown in Figure 9), and the rocker (12) in turn rotates sufficiently for its large hook (30) to release the protrusion (29) on the impactor (13).
• the impactor (13) freely rotates (clockwise in Figure 9) at high speed such that the impactor (13) strikes the receptacle (39-1) that is aligned with the patient-outlet (3).
• the receptacle In particular as the head (43; not clearly visible in Figure 9) of the impactor (13) strikes the base of the receptacle (39-1), the receptacle is displaced (pushed) towards its associated firing pin, such the top surface of the receptacle comprising the perforable portion strikes against its associated firing pin (21a), causing the latter to puncture the perforable portion.
• the outer surface of the firing pin the tip thereof
• the dose of medicament formulation inside the receptacle (39-1) passes through the channel of the firing pin (21-1) and out through the inlet (52) and passageway of the patient-outlet (3) to the patient.
• the patient-outlet may include an inner spacer portion (40) (between inlet (52 in Figure 1) and the generally cylindrical outer portion (3a) of the patient-outlet) provided with air-inlets (34) to create an annular air-jacket around the emerging aerosol.
• the internal surface of the inner spacer portion (40) of the patient-inlet is desirably generally conical. Due to the characteristic positioning of the arm (28) of the impactor (13) in the fired position of the device, the arm (which might be advantageous brightly colored) may be suitably used as an indicator to appear in a window (26 in Figure 4) in the device, thereby indicating to the patient that the mechanism has been triggered (i.e. that a dose has been released).
• the front edge (41) of the impactor (13) may be suitably shaped to match the contour of the internal front wall (42) against which the cassette rests. By virtue of these matching contours, the energy of the moving impactor (13) would be safely dissipated across a wide area if the inhaler were to be triggered without a cassette being present.
• the upper surface of the reset arm (27) may be suitably profiled such that during the final part of the reset process (from the position shown in Figure 12 to that shown in Figure 6), the interaction of the reset arm (27) with the impactor (13) causes the forces to "go over centre". In other words the force of the impactor spring (14) then tends to bias the impactor (13) and the outlet cover (4) slightly towards their respective “at rest” positions (as shown in Figure 6). Finally, the impactor (13) moves slightly away from the rocker (12), thus "unloading" the rocker (12) and vane (11) mechanism at the rest position of the device.
• a dose advancing mechanism including an indexing yoke (23), an indexing arm (24), a torsion spring (25), a gear (22) and a drive gear (15) moves appropriately the carousel (50) and thus the receptacle to-be-fired and its associated firing pin. Since the second exemplary embodiment incorporates a similar dose advancing mechanism, said mechanism and its operation will be described with reference to the second exemplary embodiment shown in Figures 14 to 25.
• Figure 13 shows further features of the first exemplary embodiment.
• tamper prevention means are provided to ensure that the patient does not move the carousel between doses, i.e. to a position where a receptacle (39) will be out of registration with the patient outlet (3) (in particular the inlet (52) to the patient-outlet).
• These tamper prevention means take the form of a small clip (not shown) that prevents movement of the indexing yoke (23) when the cassette (5) is out of the body portion (2).
• the clip is mounted on an integral spring mounting (71) that is cantilevered out from the wall of the outer case (16) of the cassette.
• a tall post 70 in Figure 5
• another, C-profiled, post (10 in Figure 2) in the body portion (2) passes through an access hole (73 in Figure 3) into the cassette (5), and meets the tall post (70) end-to-end.
• the first exemplary embodiment also includes components for centering the carousel (50).
• the inner casing (17) is provided with an integral springy finger (72) that interacts with a series of recesses or dimples (45) - one for each receptacle - on the top surface of the carousel (see Figure 5).
• These recesses (45) individually co-operating with the springy finger upon dose advancement provide the required degree of self-centering alignment or quantization of the carousel parking position.
• a tactile and/or audible feedback from the finger and recess arrangement may desirably provide an indication to the patient that the next dose has been advanced successfully.
• FIGs 14 to 25 illustrate a second exemplary embodiment in accordance with the present invention.
• This exemplary embodiment is a non-refillable breath- actuated device.
• This exemplary device is similar to the device shown in Figures 1 to 13 with a major difference being that the device is non-refillable and thus the device includes a body (2) that is fully enclosed.
• the device (1) comprises a body (2), a patient-outlet in the form of a mouthpiece (3), and a hinged outlet cover (4) provided with a reset arm (27).
• the patient-outlet (3) is provided with a screw-fit with a definite stop position to facilitate good contact between the outlet and the carousel (50, not visible in Figure 14) in which the receptacles and firing pins are mounted.
• a grill (65) may be provided across most of the width of the frontal air inlet (31) in order to e.g. prevent the intrusion of patient fingers.
• this second exemplary embodiment includes like the first exemplary embodiment a triggering mechanism (comprising an impactor (13)
• Molded onto the underside of the clip (63), but not visible in Figure 15, is a protruding V-shaped pip, which co-operates with small recesses (e.g. 46) on the carousel (50), one recess associated with each receptacle (39) to provide an additional positive centering of the position of the carousel (50), and hence of each receptacle (39), after each dose advancement.
• Tactile and/or audible feedback from the pip and recess arrangement also desirably provides a signal to the patient that the next receptacle has been advanced successfully and thus is in position for actuation.
• the dose advancing mechanism of the exemplary device advances the carousel to bring the next receptacle to-be-fired into its registered position (i.e. in alignment with the patient-outlet (and the inlet thereof)), and thus ready for actuation, when the patient-outlet cover is opened, in particular on the condition that the previous receptacle was impacted and thus fired.
• Figure 16 shows an interior view of the exemplary device (1) in its rest position, with the outlet cover (4) closed.
• the receptacle and firing pin-containing carousel (50) is clipped onto a central boss (66) in the device, and is held in place by the retaining clip (63).
• an indexing yoke (23) Also mounted on the central boss (66), but free to rotate relative to the carousel (50), is an indexing yoke (23), the teeth of which are engaged with those of a gear (22).
• Clipped onto a peg (49) molded on the indexing yoke (23) sits an indexing arm (24).
• a torsion spring (25) is held between the indexing arm (24) and a spring stop (59) on the indexing yoke (23), such that the indexing arm (24) is biased outwardly (i.e. pivoted clockwise around peg (49) in Figure 16), with its indexing tooth (57) engaged in one of a sequence of carousel advancement recesses (56) inside the rim of the carousel (50).
• One such recess corresponds to each of the twelve dose-containing receptacles in the carousel (50).
• a curved bias link (67) may be anchored to a point (67a) on the internal surface of the body (2) and to a point (67b) on an extension (23a) provided on the indexing yoke (23).
• the anchor points (67a, 67b) allow some rotational movement of the ends of the bias link (67) but are spaced so that the bias link is not loose.
• the gear (22) is provided with a shaft (22a).
• the shaft (22a) is inserted into the hollow impactor shaft (54) having a cam (55) of the impactor (13, not completely shown).
• the cam (55) will in certain situations (described in detail below) interact with a pawl (36) provided on the indexing arm (24).
• the teeth of the gear (22) are engaged with those of the indexing yoke (23).
• the teeth of the gear (22) are also engaged with the teeth of a drive gear (15).
• the drive gear is in turn engaged with a square peg (58, not visible (see Figure 4 showing the square peg in the first exemplary embodiment)) provided on the internal surface of the outlet cover (4).
• Figures 17 to 19 provide schematic representations of the interior of device when the outlet cover (4) is partially opened (at about 65°), almost completely open (at about 120°) and completely open (at about 130°).
• the bias link (67) thus provides an advantageous "positive open - positive close” feature, as it serves to bias the outlet cover (4) to either its fully open or fully closed position, thereby helping to ensure full advancement of receptacles and their correct registration with the impactor and the patient-outlet.
• This arrangement also provides tactile feedback to the patient that the outlet cover (4) has been correctly opened or closed. It also prevents the outlet cover (4) from flapping loosely when fully opened.
• This arrangement provides for the to-be-fired receptacle to be positioned ready, for perforation, in advance of the start of inhalation, thereby ensuring that receptacle advancement imposes no delay on, and takes no energy from, the triggering mechanism.
• the patient at this point in time may decide not to use the device and close the outlet cover.
• devices described herein advantageously provide an advancing mechanism in which the next receptacle to be fired is not advanced until the previous receptacle has been fired.
• the advancing mechanism is configured and coupled to the outlet cover such that if the receptacle advanced upon opening of the outlet cover has not been actuated (fired), then upon closing the outlet cover said receptacle is returned to its original pre-advanced position.
• Figure 20 schematically shows the interior of the device in the case that the device has not been used (i.e. there has been no breath actuation of the device and thus the receptacle has not been actuated), but the patient has started to re-close the outlet cover.
• the outlet cover (4) has been closed to a position of about 125°.
• the gears (15, 22).
• the advancing mechanism is configured such that upon closing the outlet cover, the expended receptacle remains in the registered position and then upon a sequential opening of the outlet cover, the next receptacle to-be-fired is then advanced to the registered position.
• the device is ready for actuation and the indexing tooth (57) of the indexing arm (24) is disengaged from the carousel advancement recess (56-1). Also referring to Figure 19, it can be noted that the rotation of the indexing arm against the force of the torsion spring causing the disengagement of the indexing tooth (57) from the recess (56-1) also causes a corresponding movement of the pawl (36) of the indexing arm (24) away from the impactor shaft cam (55).
• Figure 21 shows a view after actuation of the device allowing the triggering mechanism to fire the device, in particular allowing the impactor to rotate and thus strike the base of the receptacle to displace the receptacle to the firing pin for perforation and thus release of the dose (as discussed in detail in connection with the first exemplary embodiment).
• Figure 25 provides an exploded diagram of the indexing yoke (23), indexing arm (24), torsion spring (25), and bias link (67) used in the second exemplary embodiment.
• the first exemplary embodiment shown in Figures 1 to 13 includes the same advancing components and arrangement as the second exemplary embodiment shown in Figures 14 to 25, with the exception of the presence of a bias link, and thus the dose advancing mechanism of the first exemplary embodiment operates in a similar manner to that of the second exemplary embodiment.
• the first exemplary embodiment may also be provided with a curved bias link (67) similar to that shown in the second exemplary embodiment, providing a third exemplary embodiment.
• Figures 28a and b show interior views of (just) the advancing mechanism of such an embodiment showing the positions of the mechanism when the outlet cover (4) is closed and opened, respectively.
• the bias link (67) may be anchored to a point (67a) on the internal surface of the outer housing (16) of the cassette (5) and to a point (67b) on an extension (23a) provided on the indexing yoke (23).
• the advancing mechanism operates in the same manner as described for the second exemplary embodiment. It is to be understood that the description concerning dose advancement in the second exemplary embodiment applies appropriately or completely to the first and third exemplary embodiments, respectively.
• the third embodiment (as well as the first embodiment) may also include a window (69) in the outer casing (16) of the cassette (5) allowing the patient to view the carousel and any appropriate dose count indicia provided on the carousel.
• the axis of rotation of the carousel may be parallel to the direction of impaction of the receptacles rather than perpendicular to it, and/or the impactor head (comprising a circular impaction ring with a through-hole in it) may strike a firing pin, which may be re-usably part of the impactor or may be associated with the individual receptacle, against the front (dose release) side of the receptacle, spray thereby passing through the hole in the impactor head.
• a firing pin which may be re-usably part of the impactor or may be associated with the individual receptacle, against the front (dose release) side of the receptacle, spray thereby passing through the hole in the impactor head.
• Inhalation devices described herein comprise two or more hermetically sealed receptacles.
• Devices described herein are particularly suitable for containing three or more, more particularly four or more and most particularly five or more hermetically sealed receptacles.
• the total number of receptacles provided within the device depends in part of the particular targeted use of the device and in part on size considerations, for example the dimensions of each individual receptacle and the dimensions of the inhalation device. In regard to the latter considerations, preferable the inhalation device is a hand-held device.
• Devices described herein will typically include 30 individual receptacles at most.
• the total number of receptacles may be appropriately selected for the particular therapy. For example for a particular therapy requiring one dose of medicament per day over a period of a week, 10 days, two weeks or three weeks, the device may appropriately include seven, ten, fourteen or twenty one receptacles, respectively.
• Devices may be refillable.
• the device may include an access panel whereby the patient or a pharmacist can refill the device with fresh receptacles (and for preferred embodiments their associated firing pins).
• devices may be provided as a kit-of-parts including a body portion and a cassette comprising receptacles (and in preferred embodiments their associated firing pins) and optionally one or more such cassettes as replacement cassettes.
• the body portion would desirably include a patient outlet (favorably a reversibly detachable outlet for washing) and/or a triggering mechanism and/or if applicable an outlet cover, e.g. as described herein.
• Such a kit may for example include the appropriate number of cassettes (and thus receptacles) for a particular therapy. For example for a 3-week therapy of two doses per day, the kit may include 3 cassettes each with 14 receptacles. Alternatively e.g. for long-term therapies, such cassettes may be provided separately, so that a patient may obtain e.g. through the pharmacist, fresh cassettes as needed for re-filling.
• each receptacle comprising a pharmaceutically active ingredient and a liquefied aerosol propellant consisting of 1 ,1 ,1 ,2-tetrafluoroethane (HFA 134a), 1 ,1 ,1 , 2,3,3, 3-heptafluoropropane (HFA 227) or a mixture thereof may optionally comprise one or more suitable pharmaceutical non-propellant and non-gaseous excipients, such as surfactants, preservatives, flavorings, antioxidants, anti-aggregating agents and co-solvents, e.g. ethanol.
• suitable pharmaceutical non-propellant and non-gaseous excipients such as surfactants, preservatives, flavorings, antioxidants, anti-aggregating agents and co-solvents, e.g. ethanol.
• excipients as used herein means chemical agents having little or no pharmacological activity (for the quantities used) but which may enhance the pharmaceutical formulation or the performance of the inhalation device.
• non-propellant excipient is to be understood that the excipient is not a propellant.
• Propellant used herein means an inert liquid with a boiling point from about 25°C to -43°C which exerts a high vapor pressure at room temperature, e.g. a hydrocarbon (such as propane, butane, isobutane), a chlorofluorocarbon or a hydrogenated-chlorofluorocarbon.
• non-gaseous excipient is to be understood that the excipient is not a gas (i.e. a substance having a boiling point less than -43°C, e.g. carbon dioxide, oxygen, nitrogen).
• the pharmaceutical pressurized formulation for use in the invention may contain a single pharmaceutically active ingredient or a combination two or more other pharmaceutically active ingredients.
• Such pharmaceutically active ingredients may be selected from any suitable medicaments used in inhalation therapy.
• Appropriate medicaments may thus be selected from, for example, analgesics, e.g. codeine, dihydromorphine, ergotamine, fentanyl or morphine; anginal preparations, e.g. diltiazem, nitroglycerin; antiallergics, e.g. cromoglycate, ketotifen or nedocromil; a nti infectives e.g. cephalosporins, penicillins, streptomycin, sulphonamides, tetracyclines and pentamidine; antihistamines, e.g.
• anti-inflammatories e.g. corticosteroids, such as beclomethasone (e.g. the dipropionate), betamethasone, flunisolide, budesonide, ciclesonide, mometasone
• corticosteroids such as beclomethasone (e.g. the dipropionate), betamethasone, flunisolide, budesonide, ciclesonide, mometasone
• bronchodilators e.g. the fuorate, fluticasone (e.g. the propionate), triamcinolone acetonide, cortisone, dexamethasone, hydrocortisone, methylprednisolone, prednisolone or prednisone; antitussives, e.g. noscapine; bronchodilators, e.g.
• the medicaments may be used as a free base or in a physiologically acceptable form, e.g. in the form of salts (e.g. as alkali metal or amine salts or as acid addition salts) or as esters (e.g. lower alkyl esters) or as solvates (e.g. hydrates).
• salts e.g. as alkali metal or amine salts or as acid addition salts
• esters e.g. lower alkyl esters
• solvates e.g. hydrates
• Inhalation devices in accordance with the present invention are advantageous for use in providing a plurality of single doses of very expensive and/or very sensitive pharmaceutically active ingredients cost-effectively, e.g. especially for therapies including macromolecules (e.g. proteins and peptides) or other biological products.
• macromolecules e.g. proteins and peptides
• the pharmaceutically active ingredient may advantageously be selected from insulin, glucagon, g-csf (granulite colony simulating factor), erythropoietin, growth hormone, alpha-interferon, beta-interferon, calcitonin, alpha-1-anti-trypsin, oxytosin, somatostatin, parathyroid hormone, tnf (tumor- necrosis-factor)-alpha, Dnase, vasopressins (e.g. arginine vasopressin and ornithine vasopressin), LHRH analog, bovine-lgG, ferritin, gene transfer or therapy preparations (e.g.
• recombinant vectors viral or non-viral
• virus naked or complex plasmids
• virus producing cells in vitro genetically modified cells
• in vitro genetically modified cells or portions of nucleic acids (e.g. for anti-sense type therapy)), somatic cell therapy preparations, molecules issued from rDNA and vaccines.
• each receptacle may contain a different pharmaceutical active ingredient or combination of pharmaceutical active ingredients.
• a device may include four receptacles, each containing a different vaccine formulation, so that a single inhalation device (e.g. a disposable inhalation device) may be used to administer to a patient sequentially four different vaccines.
• a single inhalation device e.g. a disposable inhalation device
• the devices described herein advantageously allow actuation of the receptacles contained therein in sequence, the devices can be particularly useful for therapies in which the dosage of a pharmaceutically active ingredient is tapered down (e.g. anti-infectives/antibiotics) or ramped up during therapy.
• the dosage of the pharmaceutically active ingredient in one receptacle may be either higher or lower (as desired or needed) than the dosage of the pharmaceutically active ingredient in another receptacle.
• the receptacles may be provided in a prescribed order, wherein the dosage of pharmaceutically active ingredient in said receptacles in said prescribed order decreases continuously or intermediately (e.g. stepwise) or decreases to a constant plateau.
• the dosage of pharmaceutically active ingredient in said receptacles in said prescribed order may increase continuously or intermediately (e.g. stepwise) or increase to a constant plateau.
• Devices described herein are also particularly advantageous for therapies administrating two or more pharmaceutically active ingredients sequentially, e.g. where one active ingredient is desirably administered before another active ingredient (e.g. a bronchodilator administered shortly before an anti-inflammatory, to assure that the anti-inflammatory reaches its target site in the lungs) or where the selected active ingredients can be not be combined in a single formulation.
• the device advantageously comprises an even number of receptacles (e.g. 2n where n is 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 , 12, 13, 14 or 15), wherein the odd numbered receptacles in the sequence (e.g.
• 1 st to (2n-1) th receptacle each contain a first formulation comprising a first active ingredient and the even numbered receptacles in the sequence (e.g. 2 nd to (2n) th receptacle) contain a second formulation comprising a second active ingredient.
• One active ingredient may be a bronchodilator, a xanthine or a leukotriene modifier, while the other active ingredient may be an anti- inflammatory, in particular a corticosteroid.
• a bronchodilator and an anti-inflammatory in particular a corticosteroid
• a xanthine and an antiinflammatory in particular a corticosteroid
• the anti-inflamatory is the second active ingredient (i.e. the anti-inflammatory is to be administered after the bronchodilator or xanthine).
• the anti-inflammatory can be either the first or second active ingredient.
• the first and/or second formulations may comprise additional active ingredients as desired or needed.
• a three medicament combination therapy with a bronchodilator and an anti- inflammatory in particular a corticosteroid
• a leukotriene modifier is formulated with either the bronchodilator or the anti-inflammatory, preferably with the anti-inflammatory, and more preferably with the bronchodilator being the first active ingredient (i.e. to be administered before the anti-inflammatory and leukotriene modifier).
• the device may include 3n number of receptacles (e.g.
• n is an integer greater than or equal to 1 , in particular n is 1 , 2, 3, 4, 5, 6, 7, 8, 9 or 10) and wherein the first receptacle in each sequence of three contains a first active ingredient, the second receptacle in each sequence of three contains second active ingredient and the third receptacle in each sequence of three contains a third active ingredient.
• bronchodilator leukotriene modifier, anti-inflammatory combination, preferably the bronchodilator is the first active ingredient.

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• 2004
  • 2004-12-23 GB GBGB0428169.7A patent/GB0428169D0/en not_active Ceased
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