WO2009112539A2

WO2009112539A2 - A closure

Info

Publication number: WO2009112539A2
Application number: PCT/EP2009/052892
Authority: WO
Inventors: Joseph Paul Marino Jr
Original assignee: Glaxo Group Limited
Priority date: 2008-03-12
Filing date: 2009-03-12
Publication date: 2009-09-17
Also published as: WO2009112539A3

Abstract

One aspect provides a closure (716) for use with an article (1) having an outlet (14), the closure comprising a closure part (716a) for closing the outlet, a connector part (716b) for connecting the closure to the article, and a hinge (719) between the closure and connector parts to enable the closure part to be hinged relative to the connector part, wherein the closure is configured and arranged so that hinging of the closure part relative to the connector part in an opening direction (O) is to a limit whereupon the closure part couples to the connector part so that the closure and connector parts thereafter have to move in unison in the opening direction.

Description

A CLOSURE

Related Applications

The present application claims priority from U. S Provisional Application No. 61/035,872 filed 12 March 2008, the entire original content of which is incorporated herein by reference.

The disclosures of the following U.S. Provisional Applications are incorporated herein by reference in their entirety: U. S Provisional Application Nos. 60/823,134, 60/823,139, 60/823,141 , 60/823,143, 60/823,146, 60/823,151 and 60/823,154, all filed on 22 August 2006; U.S. Provisional Application No. 60/956,950 filed on 21 August 2007; U.S. Provisional Application No. 60/894,537 filed on 13 March 2007; U.S. Provisional Application No. 60/956,947 filed on 21 August 2007; and US Provisional Application No. 61/029,458 filed on 18 February 2008.

The disclosures of US (PCT) Patent Application Nos. 12/377,403 (WO-A- 2008/023018), 12/377,412 (WO-A-2008/023019), 12/377,416 (WO-A-2008/023017), 12/377,418 (WO-A-2008/023015), 12/377,422 (WO-A-2008/023014), 12/377,427 (WO-A-2008/023013) and International Patent Application No. PCT/US2007/076347 (WO-A-2008/024728), which designates the United States of America, and claim priority from the aforementioned U.S. Provisional Application Nos. 60/823,134, 60/823,139, 60/823,141 , 60/823,143, 60/823,146, 60/823,151 and 60/823,154, are all also incorporated herein by reference in their entirety.

Also hereby incorporated herein by reference is the disclosure of International (PCT) Patent Application No. PCT/EP2008/052967 (WO-A-2008/110584) which designates the United State of America and claims priority from the aforementioned U.S. Provisional Application Nos. 60/894,537 and 60/956,947.

Field of the Invention

The present invention relates to a closure for closing an opening of an article, for instance a dispensing opening of a dispenser, such as a mouthpiece of an inhaler. The present invention further relates to an article including such a closure. Background of the Invention

In WO-A-2007/028992 there is disclosed a closure, in the form of a dust cap, for use with a pressurised metered dose inhaler (MDI) to close the dispensing outlet (e.g. mouthpiece) thereof. The MDI has a housing in which is movably mounted an aerosol container unit, movement of the container unit relative to the housing resulting in a dose of pressurised medicament formulation to be released from the container unit and discharged through the dispensing outlet. The closure is rotatably mounted on the inhaler for movement between a closed position, in which the closure closes the dispensing outlet, and an open position, in which the dispensing outlet is open. The closure further comprises a revolvable element comprising a restricting member, the revolvable element being adapted to revolve about an axis on movement of the closure between its closed and open positions, and the revolvable element being placed in first and second positions when the closure is in its open and closed positions respectively. The first position places the restricting member in a non-restricting position which does not restrict relative movement between the container unit and the housing for dispensing of the dose of the medicament formulation, and the second position places the restricting member in a restricting position which does restrict relative movement between the container unit and the housing such that dispensing of the dose of the medicament formulation is prevented. Thus, the closure carries a lock-out for selectively locking out the MDI depending on whether the closure is closed or open.

The aim of the present invention is to provide a closure with advantageous novel attributes and which may, without limitation, be useful in an inhaler, for instance an MDI.

Summary of the Invention

According to a first aspect of the invention there is provided a closure for use with an article having an outlet, the closure comprising: a closure part for closing the outlet, a connector part for connecting the closure to the article, and a hinge between the closure and connector parts to enable the closure part to be hinged relative to the connector part, wherein the closure is configured and arranged so that hinging of the closure part relative to the connector part in an opening direction is to a limit whereupon the closure part couples to the connector part so that the closure and connector parts thereafter have to move in unison in the opening direction.

In embodiments of the invention, including those disclosed hereinafter with reference to the Figures, the connecting part is adapted to be rotatably connected to the article such that, in use, said movement in unison of the closure and connector parts is a rotary movement.

In embodiments of the invention, including those disclosed hereinafter with reference to the Figures, the connecting part has a mounting for mounting to an axle of the article for rotation thereabout.

In embodiments of the invention, including those disclosed hereinafter with reference to the Figures, the closure comprises an angle limiter which acts to limit the angle of hinging of the closure part relative to the connector part.

In embodiments of the invention, including those disclosed hereinafter with reference to the Figures, the angle limiter is provided on the connector part.

In embodiments of the invention, including those disclosed hereinafter with reference to the Figures, the closure part has a control surface which is brought into engagement with a stop surface of the angle limiter on hinging of the closure part relative to the connector part by a predetermined angle in the opening direction thereby to prevent further hinging of the closure part relative to the connector part in the opening direction.

In embodiments of the invention, including those disclosed hereinafter with reference to the Figures, the control and stop surfaces are oriented parallel to the axis of the hinge.

In embodiments of the invention, including those disclosed hereinafter with reference to the Figures, the closure and connector parts are hinged together by male and female connectors.

In embodiments of the invention, including those disclosed hereinafter with reference to the Figures, the male and female connectors are pin-and-hole connectors. In embodiments of the invention, including those disclosed hereinafter with reference to the Figures, the connector part presents a lock member adapted in use to lock operation of the article when the closure closes the opening and to unlock the article for operation thereof when the closure is moved in the open direction to an open position.

According to a second aspect of the invention there is provided an article having an opening and a closure in accordance with the invention, wherein the connector part is connected to the article such that the closure is movable in the opening direction from a closed position, in which the closure part closes the opening, to an open position, in which the closure part is spaced from the outlet for opening thereof.

In embodiments of the invention, including those disclosed hereinafter with reference to the Figures, the closure is movable from its closed position to the open position by sequentially hinging the closure part relative to the connector part in the opening direction to the limit and then moving the closure and connector parts in unison in the opening direction.

In embodiments of the invention, including those disclosed hereinafter with reference to the Figures, the closure is still at least partially closed by the closure part when the closure part is at the hinge limit in the opening direction.

In embodiments of the invention, including those disclosed hereinafter with reference to the Figures, the article includes an obstruction for obstructing movement of the closure in the opening direction.

In embodiments of the invention, including those disclosed hereinafter with reference to the Figures, the obstruction obstructs movement of the closure in the opening direction only once the closure part is at the hinge limit.

In embodiments of the invention, including those disclosed hereinafter with reference to the Figures, the obstruction obstructs movement of the closure when the closure and connector parts move in unison in the opening direction.

In embodiments of the invention, including those disclosed hereinafter with reference to the Figures, the obstruction is adapted to obstructively engage the connector part. In embodiments of the invention, including those disclosed hereinafter with reference to the Figures, the obstruction obstructs movement of the closure when the opening is still at least partially closed by the closure part.

According to a third aspect of the invention there is provided an article comprising: an opening, a closure mounted to the article for movement in an opening direction from a closed position, in which the closure closes the opening, to an open position, in which the opening is open, and an obstruction for obstructing movement of the closure in the opening direction.

In embodiments of the invention, including those disclosed hereinafter with reference to the Figures, the obstruction obstructs movement of the closure when the closure has moved a predetermined distance in the opening direction at which the closure still at least partially closes the opening.

In embodiments of the invention, including those disclosed hereinafter with reference to the Figures, only when the closure is past the obstruction in the opening direction is the opening fully open.

In embodiments of the invention, including those disclosed hereinafter with reference to the Figures, the closure presents a lock member adapted in use to lock operation of the article when the closure closes the opening and to unlock the article for operation thereof when the closure is moved in the open direction to the open position.

In embodiments of the invention, including those disclosed hereinafter with reference to the Figures, the lock member unlocks the article for operation thereof only when the closure is past the obstruction in the opening direction.

In embodiments of the invention, including those disclosed hereinafter with reference to the Figures, the closure is mounted to the article for rotation from the closed position to the open position. In embodiments of the invention, including those disclosed hereinafter with reference to the Figures, the article is a dispenser and the opening is a dispensing opening of the dispenser.

In embodiments of the invention, including those disclosed hereinafter with reference to the Figures, the dispenser is an inhaler and the opening is a mouthpiece or nasal nozzle.

In embodiments of the invention, including those disclosed hereinafter with reference to the Figures, the dispenser has a housing and a dispensing member movably mounted in the housing for dispensing from the dispenser.

In embodiments of the invention, including those disclosed hereinafter with reference to the Figures, the lock member selectively locks and unlocks the dispensing member for movement for dispensing from the dispenser.

In embodiments of the invention, including those disclosed hereinafter with reference to the Figures, the lock member presents a surface configured to restrict movement of the dispensing member when the closure is in the closed position and to not restrict said movement of the dispensing member when the closure is in the open position.

In embodiments of the invention, including those disclosed hereinafter with reference to the Figures, the article is an inhaler.

In embodiments of the invention, including those disclosed hereinafter with reference to the Figures, the article is a pressurised metered dose inhaler and the dispensing member is an aerosol canister unit.

The article of the invention may be a dispenser, suitably a drug dispenser and more suitably an inhaler, especially of the well-known "metered dose inhaler" (MDI) type, and yet more suitably a hand-held, hand-operable breath-coordinated MDI. In such a MDI, the patient manually actuates the MDI for release of the drug therefrom while concurrently inhaling at the outlet (e.g. mouthpiece). Thus inhalation and actuation are coordinated. This is in distinction from breath-operated MDIs, where the inhalation event itself actuates the MDI so that no coordination is required. In accordance with the present invention, each aspect thereof can be combined with one or more of the other aspects or one or more of the features of one or more of the other aspects.

Additional aspects and features of the present invention are set forth in the claims and in the description of exemplary embodiments of the present invention which now follow with reference to the accompanying Figures of drawings. It should be appreciated that the exemplary embodiments are set forth to illustrate the invention, and that the invention is not limited to these embodiments.

Brief Description of the Figures

Figure 1 shows a perspective view of a hand-held, hand-operable, breath coordinated drug dispenser device of the MDI type in the 'at rest' position;

Figure 2 shows a perspective view of the drug dispenser device of Figure 1 with upper front cover part, actuation counter, front plate, mouthpiece and mouthpiece cover removed and the lower front cover part shown in cut-away section, the device again being shown in the 'at rest' position;

Figures 3a to 3b show front views of the drug dispenser device of Figure 1 with upper front cover part, actuation counter, front plate and mouthpiece cover removed and the left lower front cover part and left-side of mouthpiece shown in cut-away section, the device respectively being shown in 'at rest' and first stage of actuation positions;

Figures 4a to 4c show front views of the drug dispenser device of Figure 1 with upper front cover part, actuation counter, front plate, mouthpiece cover and left lever removed and the left lower front cover part and left-side of mouthpiece shown in cutaway section, the device respectively being shown in second, third and fourth stages of actuation positions;

Figure 5 shows an exploded view from the front of part of the internal mechanism of the drug dispenser device of Figure 1 with front plate removed;

Figure 6 shows a schematic view of part of the internal mechanism of the drug dispenser device of Figure 1 with front plate removed, and in particular, the 'interlock' mechanism provided to block actuation thereof when the mouthpiece is covered by the mouthpiece cover; Figure 7 shows a perspective view of the drug dispenser device of Figure 1 with the mouthpiece cover removed from the mouthpiece and thus, in a 'ready to use' position;

Figure 8 shows a perspective view of the drug dispenser device of Figure 1 with the mouthpiece cover removed from the mouthpiece and the levers depressed and thus in the 'in use' position;

Figure 9 illustrates a perspective view of a first half of the drug dispenser of Figure 1 showing air flow into the housing in the 'in use' position thereof;

Figure 10 illustrates a perspective cut-away view of a second half of the drug dispenser device of Figure 1 (with actuation counter and details of internal mechanism omitted) showing air flow through the chambers of the housing in the 'in use' position thereof;

Figure 1 1 illustrates a perspective cut-away view of a second half of a drug dispenser device that is a slight variation of that drug dispenser device of Figure 1 (with actuation counter and details of internal mechanism omitted) showing air flow through the inhaler body in the 'in use' position thereof;

Figure 12 shows an exploded view of an actuation counter herein arranged for receipt within the upper front cover part of the first drug dispenser of Figure 1 or second drug dispenser device of Figure 11 ;

Figures 13a and 13b respectively show underside and top views of the actuation counter of Figure 12 received in the upper front cover part;

Figures 14a and 14b show cut-away views of the actuation counter of Figure 12 at respectively 'count 120' and 'count 119' positions;

Figures 15a and 15b respectively show cut-away views corresponding to Figures 14a and 14b of the actuation counter of Figure 12 absent the decimals count wheel;

Figures 16a and 16b respectively show cut-away views corresponding to Figures 14a and 14b of the actuation counter of Figure 12 absent the numerals count wheel; Figures 17a and 17b show cut-away views of the actuation counter of Figure 12 at respectively 'count _0' and 'shuttered' positions;

Figures 18a and 18b respectively show cut-away views corresponding to Figures 17a and 17b of the actuation counter of Figure 12 absent the numerals count wheel;

Figure 19 shows a front view of the drug dispenser device of Figure 1 with upper front cover part and actuation counter removed, the device being in the 'at rest' position;

Figure 20 shows a perspective view of the drug dispenser device of Figure 1 with the upper front cover part and actuation counter disposed therein shown detached from the remainder of the device, the device being shown in an 'at rest' position;

Figure 21 shows a plan view of the inner side of the upper front cover part of the drug dispenser device of Figure 1 and showing the actuation counter disposed therein;

Figures 22 and 23 show perspective views of a container collar part for use in an alternative internal mechanism for use with the drug dispenser device herein, as respectively shown in upright and inverted configurations;

Figures 24 and 25 respectively show perspective underside and top views of an extension collar part for use in an alternative internal mechanism for use with the drug dispenser device herein;

Figures 26a to 26c show perspective views of sequential steps in the assembly of an alternative internal mechanism for use with the drug dispenser device herein, and employing the container collar of Figures 22 and 23 and the extension collar of Figures 24 and 25;

Figures 27a to 27c show sectional side views of interaction of key parts of the container collar of Figures 22 and 23 with the extension collar of Figures 24 and 25 during sequential operational steps of the alternative mechanism assembled as shown in Figures 26a to 26c;

Figure 28 shows a perspective view from above of the lower housing part and mouthpiece assembly (shown separated) of the drug dispenser device of Figure 1 ; Figures 29a and 29b show an alternative 'two part form' lower housing part, as respectively shown separated and as assembled, for use with the drug dispenser device of Figure 1 ;

Figures 30a to 3Oo respectively show front views of mouthpiece forms which may be employed in the drug dispenser devices of Figures 1 or 1 1 as an alternative to the mouthpieces thereof;

Figures 31 a and 31 b respectively show back and front views of a front (driver) plate for use with a modified version of the actuation counter of Figures 12 to 18b;

Figures 32a to 32g and Figures 33a to 33g respectively show corresponding plan and perspective views of sequential operation steps of key parts of a modified version of the actuation counter of Figures 12 to 18b incorporating the driver plate of Figures 31 a to 31 b;

Figures 34a and 34b respectively show perspective underside and top views of a numerals wheel for use in the modified actuation counter of Figures 32a to 33g;

Figures 35a and 35b respectively show perspective underside and top views of a decimals wheel for use in the modified actuation counter of Figures 32a to 33g;

Figures 36a to 36o respectively show front views of further alternative mouthpiece forms which may be employed in the drug dispenser devices of Figures 1 and 11 as an alternative to the mouthpieces thereof;

Figures 37a and 37b are respectively a rear perspective view and a rear view of the mouthpiece of Figure 36a showing bracing ribs provided thereto;

Figures 38a to 38e are schematic, part-sectional views of the lower housing part of the drug dispenser device of Figure 1 showing a mouthpiece cover for the mouthpiece in accordance with the present invention in its various stages of opening thereof;

Figures 39a and 39b are respectively a side view and a front view (on arrow A in Figure 39a) of a mouthpiece closure part of the mouthpiece cover of Figures 38a to 38e;

Figures 39c and 39d are respectively plan and side views of a connector part of the mouthpiece cover of Figures 38a to 38e; Figure 39e is a view on section l-l in Figure 39c;

Figure 40a is an underneath view of the lower housing part shown in Figures 38a to 38e;

Figure 40b is a view on section J-J in Figure 40a;

Figure 41 shows a front view of a mouthpiece cover in accordance with the present invention; and

Figure 42 is a schematic, part-sectional view of a lower part of a drug dispenser device comprising a mouthpiece and a mouthpiece cover for the mouthpiece which is in accordance with the present invention.

Detailed Description of the Figures

For the convenience of the reader, in the following description like reference numerals are used to designate like features in the alternative/different embodiments.

Turning now to the drawings, Figure 1 shows a drug dispenser device 1 which is in the form of a hand-held, hand-operable, breath coordinated pressurised metered dose inhaler (MDI). This type of device requires a patient to coordinate their inhalation at a dispensing outlet of the device (in this embodiment, a mouthpiece 14, see Figure 7) with manual actuation of the device so that the inhalation is coordinated with release of drug from the device so that drug is entrained by the inhalation airflow to the target location in the respiratory tract (in this case, the lungs) of the patient.

The device 1 comprises a housing defined in combination by front 10a and rear 10b upper housing parts and lower housing part 12, all of which are, in this embodiment, formed from plastic, for example of ABS (acrylonitrile butadiene styrene). It will be noted that the overall form of the housing is arranged for ease of receipt by a user's hand such that in general terms the rear of lower housing part 12 is received by the user's palm. Mouthpiece 14 (not visible in Figure 1 , but see Figure 7) is protected by removeable mouthpiece cover 16, and extends from the front of lower housing part 12 and is arranged in use, for insertion into the mouth of a patient for inhalation therethrough. The mouthpiece 14 may be made from polypropylene (PP). A ledge 13a, 13b is provided to the base of the lower housing part 12 such that the device may be arranged to 'stand upright' on the ledges 13a, 13b and mouthpiece cover 16, when cover 16 covers the mouthpiece 14. As will be understood from Figure 7, when the cover 16 is moved to its 'mouthpiece uncovered' position, the device is able to 'stand upright' on the end face 16a of the cover 16 itself, with the ledges 13a, 13b and mouthpiece cover 16 optionally being provided with releasable complementary connectors, e.g. complementary male and female snap-fit connectors, (not shown) to releasably connect the mouthpiece cover 16 to the ledges 13a, 13b in the position shown in Figure 7. Such complementary connectors may be respectively provided on the outer surface of the ledges 13a, 13b and the inner surface of the mouthpiece cover 16.

A viewing window 216 is provided to the front upper housing part 10a for viewing of count indicia displayed by a counter 201 locating within that part 10a and described in more detail hereinafter with reference to Figures 12 to 21 or (ii) one of the modified counters described in more detail hereinafter with reference to Figures 31 to 35.

Opposing levers 20a, 20b protrude from apertures 1 1 a, 11 b provided to the front 10a and rear 10b upper housing parts. The levers 20a, 20b are shaped such as to respectively accommodate the finger(s) and thumb of a patient in use, thereby facilitating one-handed operation of the device. The levers may be made from ABS.

Figure 28 shows the lower housing part 12 and mouthpiece 14 (shown separated from each other, in this view) of the drug dispenser device of Figure 1. Provided to the lower housing part 12 is stem block 8, which is arranged to receive valve stem 7 of an aerosol canister 5 (see also Figure 2). The stem block 8 also includes a passage 9, which in use acts such as to guide discharged aerosolized drug from the valve stem 7 to the mouthpiece 14. Step portions 18a, 18b, 18c, the purpose of which will be described in more detail in the later description, are also provided to the lower housing part 12.

Figures 29a and 29b show an alternative 'two part form' lower housing part 412, as respectively shown separated and as assembled, for use with the drug dispenser device of Figure 1 as an alternative to the lower housing part 12 of Figure 28. This two part form comprises lower housing part 412, which is arranged to receive separate stem block part 490. That separate stem block part 490 includes stem block 408 and stem block passage 409. As before, the lower housing part 412 defines step portions 418a, 418b, 418c. During assembly the separate parts 412, 490 are brought together and sockets 494a, 494b, 494c on the stem block part 490 aligned with posts 492a, 492b, 492c on the lower housing part. The parts 412, 490 are then joined to each other by means of heat welding ('heat staking') at each respective post 492a, 492b, 492c to socket 494a, 494b, 494c mating point.

Advantages of using the alternative 'two part form' lower housing part 412 and stem block part 490 assembly are that the precision features of the stem block part 490 are easier to produce and inspect. Additionally, the lower housing part 412 and the stem block part 490 may be made from different plastics/polymer materials (typically by moulding), each material being particularly suited to the particular function(s) of the lower housing part 412 and the stem block 408. The stem block part 490 is generally made from a plastics/polymer selected for ease of drug delivery, and in particular suitable for contact with the drug propellant formulation which will, in use, be discharged through the stem block 408. To this end, polypropylene (PP) may be used to form the stem block part 490, especially when the propellant is HFA-134a or HFA 227 infra. The lower housing part 412, on the other hand, may be formed of ABS or another plastics/polymer material which equally provides rigidity to the step portions 418a, 418b, 418c to thereby facilitate disengagement of flexible support legs 34a, 34b therefrom in actuation of the device 1 , as described in more detail hereinafter.

It will be appreciated that the stem block part and lower housing part may have different complementary forms and connections than shown in Figures 29a and 29b without departing from the raison d'etre for the two-part form for the lower housing part of the device 1.

Details of the inner workings of the device 1 of Figure 1 may be appreciated by reference to Figure 2, in which the upper 10a front housing part and mouthpiece cover 16 have been removed. It will be seen that each opposing lever 20a, 20b pivotally connects to the upper housing part 10a, 10b by means of pivot connector 22a, 22b. The positioning of the pivotal connection is selected to facilitate the desired finger-thumb operability of the levers 20a, 20b by a squeezing movement. It will also be seen that the lower ends 21a, 21 b of each lever 20a, 20b mesh together, thereby tending to the couple the motion of each respective lever 20a, 20b one to the other.

Although not shown, each lever 20a, 20b has a lower end 21a, 21 b on either side thereof providing a generally U-shape to each lever 20a, 20b at its lower end in plan view. Provided to the housing, but largely obscured from view by container collar 30, there is provided a drug discharge device, which takes the form of cylindrical valved aerosol canister 5 of the type commonly known for use in an MDI. A valve stem 7 of the drug discharge device is received within the stem block 8 provided to the housing, which stem block 8 includes the passage 9 which acts such as to guide discharged aerosolized drug from the valve stem 7 to the mouthpiece 14.

The levers 20a, 20b are arranged in the device such that the lower ends 21a, 21 b of each lever 20a, 20b are disposed on opposing sides (front and rear) of the drug discharge device.

In this particular embodiment, and referring to Figure 5, the canister 5 has a body 6 made of metal, for instance of stainless steel or, more preferably, of aluminium or an aluminium alloy. The canister contains a pressurised drug aerosol formulation. The formulation comprises the drug (one or more drug actives) and a fluid propellant, and optionally one or more excipients and/or adjuvants. The drug is in solution or suspension in the formulation. The propellant is typically a CFC-free propellant, suitably a liquid propellant, and preferably is a HFA propellant, such as HFA-134a or HFA-227 or a combination thereof. The drug active(s) is typically of the type for use in treatment of a respiratory disease or condition, such as asthma or chronic obstructive pulmonary disease (COPD). The active(s) may also be for prophylaxis or palliation of a respiratory disease or condition.

The canister 5 may have its inner surface coated with a fluorocarbon polymer, optionally in a blend with a non-fluorocarbon polymer, such as a blend of polytetrafluoroethylene and polyethersulphone (PTFE-PES), as disclosed in US patent Nos. 6,143,277; 6,511 ,653; 6,253,762; 6,532,955; and 6,546,928. This is particularly preferred if the drug is in suspension in the formulation, and especially if the suspension formulation is composed only, or substantially only, of the drug and HFA propellant.

The valve stem 7 forms part of a metering valve (not shown) mounted in the canister 5, as will be understood by the skilled person in the art, and as commercially available from manufacturers well known in the aerosol industry, for example, from Valois, France (e.g. DF10, DF30, DF60), Bespak pic, UK (e.g. BK300, BK356, BK357) and 3M-Neotechnic Ltd, UK (e.g. Spraymiser^M) jh_e metering chamber of the metering valve may be coated with a fluorinated polymer coating, such as formed from perfluoro-hexane, for instance by cold plasma polymerisation, as detailed in US- A-2003/0101993.

As may be further understood with reference also to Figure 5, which shows an exploded view of key parts of the internal mechanism, the container collar 30 permanently engages via split-ring collar 33 with the neck 5a of the canister 5 such that the so-engaged parts are moveable together relative to the housing in a direction defined by the longitudinal axis L-L of the canister 5 (i.e. generally up and down when the device 1 is upright). The split-ring collar 33 permanently engages the container collar 30 to the canister 5 as described in US patent application Nos. 10/110,611 (WO-A-01/28887) and US-A-2006/0082039, hereby incorporated herein by reference.

The container collar 30 connects via closed coil extension springs 50a, 50b and respective spring connection points 31 a, 31 b and 41 a, 41 b to extension collar 40, which is provided at its lower end with a ramp 44. This multi-collar arrangement is such that the extension collar 40 is moveable with respect to the container collar 30 (and hence the canister 5) along the longitudinal axis L-L of the drug discharge device.

The container collar 30. split-ring collar 33 and extension collar 40 may all be made from acetal.

The springs 50a, 50b will typically be formed of metal, for instance stainless steel, such as 302 grade stainless steel.

As shown in Figure 5, the extension collar 40 includes an actuating portion, in the form of shelf 42, on opposing sides which are arranged for interaction with the lower ends 21 a, 21 b of the opposing levers 20a, 20b such that when the levers are squeezed together (i.e. inwards relative to the housing) the shelf 42 and hence, extension collar 40 are pushed downwards (i.e. towards the stem block 8).

In this particular embodiment, the levers 20a, 20b have an asymmetric arrangement in that, for each lever 20a, 20b, one of the lower ends (i.e. lower end 21 b of lever 20b) extends further towards the other lever than the other lower end, and in this case the longer lower end (i.e. lower end 21 b of lever 20b) extends across the central axis H-H of the device 1. Only the longer lower end of each lever 20a, 20b acts on the actuating portion/shelf 42 of the extension collar 40, whereby only one lever 20b acts through its longer lower end 21 b on the front side of the actuating portion 42 and only the other lever 20a acts on the rear side of the actuating portion 42 through its longer lower end. As regards the shorter lower ends of each lever 20a, 20b, these link the levers 20a, 20b together at their lower ends, as can be seen most clearly in Figure 2.

In a modification, however, the levers 20a, 20b may adopt a symmetrical arrangement in which the lower ends 21 a, 21 b of each lever 20a, 20b have the same extent and both act directly on opposing sides of the actuating portion 42 of the extension collar 40. In this case, the lower ends 21a, 21 b would typically not extend across the central axis H-H. The mechanical advantage of this symmetrical arrangement may provide a larger mechanical advantage (e.g. 4:1 ) than the asymmetrical arrangement (e.g. 1.4-1.5:1 ). The selection of an asymmetric or symmetric arrangement may depend on various factors, including the force needed to open the valve and/or the spring force of the springs 50a, 50b.

The container collar 30 is further provided with flexible support legs 34a, 34b each of which is provided with a protruding foot 35a, 35b for latching engagement with a respective step 18a, 18b provided to the housing (see Figure 2). Each leg 34a, 34b also has a shaped head 36a, 36b the purpose of which will become clearer from the later description.

In the 'at rest' position of Figures 2 and 3a, each foot 35a, 35b is slightly spaced from its respective step 18a, 18b on the housing. A third flexible support leg (not visible, but associated with third step 18c as visible on Figure 28) locates at the rear of the container collar (i.e. there are three flexible support legs 34a, 34b). In one embodiment, the two support legs 34a, 34b on either side of the mouthpiece 14 are spaced at 1 13.4° intervals relative to a third support leg (not visible) which locates rearwards to the mouthpiece 14.

The container collar 30 is further provided with downward protrusions 38a, 38b, the purpose of which will become clear from the later description.

In general operational terms, referring now also to Figure 3a, the opposing levers 20a, 20b are moveable transversely with respect to the longitudinal axis L-L of the drug discharge device to apply a force to the shelf 42 of the extension collar 40 to move the extension collar 40 downwards along that longitudinal axis (i.e. towards stem block 8 and mouthpiece 14). The closed coil extension springs 50a, 50b that connect the container collar 30 via connector points 31a, 31 b with the extension collar 40 act as a biasing mechanism to store biasing energy on moving the extension collar 40 downwards along the longitudinal axis L-L in response to squeezing of the levers 20a, 20b. In embodiments, an initial biasing tension - inherent in the closed coil form thereof - is present in the closed coil extension springs 50a, 50b even when in their 'at rest' state.

The flexible support legs 34a, 34b act to provide a pre-load mechanism to prevent transfer of that biasing energy to the container collar 30 to move the canister 5 downwards along the longitudinal axis L-L to actuate the valve 7 thereof (and hence, to fire the aerosolized drug dose) until a pre-determined threshold force is overcome.

Further details of the operation of the device 1 (which results from an effective user actuation thereof) may be appreciated by making reference to Figures 3a to 4c, in which for clarity only selected parts relevant to the particular stage of operation represented are labelled.

Figure 3a shows how the device 1 is configured in the 'at rest' position, in this instance also with the mouthpiece 14 covered by the mouthpiece cover 16. The levers 20a, 20b are splayed apart and catch retainers 24a, 24b provided to an inner part of the protruding end 23a, 23b of each respective lever 20a, 20b locate close to 'stop' positions defined by notches 15a, 15b provided to the top parts 10a, 10b of the housing. The lower ends 21a, 21 b of each lever 20a, 20b seat against the shelf 42 of the extension collar 40 but no force acts on the extension collar 40. The closed coil extension springs 50a, 50b are therefore in their 'at rest' state with no externally- applied (i.e. by lever 20a, 20b actuation) biasing energy stored therein (but only any initial biasing tension - inherent in the closed coil form of the extension springs 50a, 50b - present). Each foot 35a, 35b of the flexible support legs 34a, 34b is slightly spaced from its respective step 18a, 18b on the housing.

In Figure 3b, the device is shown at a first early stage of operation, after removal of the mouthpiece cover 16 from the mouthpiece 14, in which the levers 20a, 20b have been squeezed very slightly together. The lower ends 21a, 21 b of each lever 20a, 20b push slightly down on the shelf 42 of the extension collar 40 such that the extension collar 40 is moved slightly downwards. That downwards movement of the extension collar 40 is transferred via the extension springs 50a, 50b to the container collar 30, which also moves slightly downwards. Importantly, this downwards movement of the container collar 30 brings each foot 35a, 35b of the flexible support legs 34a, 34b into latching engagement with its respective step 18a, 18b on the housing. As a result of this latching engagement, further downwards movement of the container collar 30 is impeded.

In Figure 4a, the device is shown at a second stage of operation, in which the levers 20a, 20b have been squeezed further together. The lower ends 21a, 21 b of each lever 20a, 20b push further down on the shelf 42 of the extension collar 40 such that the extension collar 40 is moved downwards. That downwards movement of the extension collar 40 however, cannot now be transferred via the extension springs 50a, 50b to the container collar 30 because of the latching engagement of each foot 35a, 35b of the flexible support legs 34a, 34b with its respective step 18a, 18b on the housing. That latching engagement impedes the downwards movement of the container collar 30. The downwards movement of the extension collar 40 therefore results in the extending of each closed coil extension spring 50a, 50b, thereby resulting in biasing energy being stored in the now-extended springs 50a, 50b.

In Figure 4b, the device is shown at a third stage of operation, in which the levers 20a, 20b have been squeezed even further together. The lower ends 21a, 21 b of each lever 20a, 20b push even further down on the shelf 42 of the extension collar 40 such that the extension collar 40 is moved even further downwards. That further downwards movement of the extension collar 40 still cannot now be transferred via the extension springs 50a, 50b to the container collar 30 because of the latching engagement of each foot 35a, 35b of the flexible support legs 34a, 34b with its respective step 18a, 18b on the housing. The further downwards movement of the extension collar 40 therefore results in further extension of each extension spring 50a, 50b, thereby resulting in further biasing energy being stored in the now well- extended springs 50a, 50b.

Further, in the position shown in Figure 4b, ramps 44 provided to the extension collar 40 respectively engage with the shaped heads 36a, 36b of the flexible legs 34a, 34b and act on the already-tensed flexible legs 34a, 34b such that each foot thereof 35a, 35b is at the point of becoming displaced from its respective step 18a, 18b. In essence, the ramp 44 acts to 'guide' the displacement action. Thus, Figure 4b corresponds to the position at which the latching engagement of the flexible legs 34a, 34b with their steps 18a, 18b is just about to be overcome for release of the biasing energy stored in the extension springs 50a, 50b. This position therefore corresponds to the threshold (or 'tipping point') of the pre-load / stored biasing energy system defined by the components of the device. Applying any further squeeze force to the levers 20a, 20b will result in that threshold being exceeded, and effective user actuation of the device 1.

Conveniently, the device 1 is adapted such that the threshold is only exceeded preferably by the user applying at least a total grip force of 15 to 25N, more conveniently 20-25N, to the levers 20a, 20b. In other words, this is the minimum total grip force that the user needs to apply for actuation of the device 1. In practice, this would typically means applying half the total grip force to each lever 20a, 20b or all the total grip force to one lever 20a, 20b (noting that the levers 20a, 20b are coupled so that movement of one causes movement of the other). However, the total grip force could also be applied by other unequal application of forces to the levers 20a, 20b. Of course, the actual pre-load threshold force for unlatching the collar legs 34a, 34b and releasing the stored energy in the springs 50a, 50b would be greater than the minimum total grip force due to the use of a pair of levers 20a, 20b which each provide a mechanical advantage. This makes it easier for the user to "fire" the device 1 than would otherwise be the case, although not so easy to "fire" unintentionally.

In Figure 4c, which corresponds to a fourth stage of operation, such further force has been applied to the levers 20a, 20b. The protruding end 23a, 23b (see also Fig. 3a) of each respective lever 20a, 20b touches off one against the other, thereby preventing any further lever 20a, 20b travel. Most importantly, the flexible legs 34a, 34b have become displaced from their respective steps 18a, 18b through the action of the ramps 44. The container collar 30 may now move freely downwards and indeed, will do so as a result of its experience of the biasing energy stored in the extension springs 50a, 50b. The container collar 30 and canister 5 in permanent engagement therewith move rapidly downwards propelled by the stored biasing energy of the springs 50a, 50b. The valve of the canister 5 is thereby opened to release aerosolized drug through the passage 9 in the stem block 8 which guides that discharged aerosolized drug to the mouthpiece 14 for inhalation by the patient.

It will be appreciated that once the threshold force has been overcome (i.e. just past the 'tipping point' of the device) a uniform actuating force resulting from the energy stored in the springs 50a, 50b is experienced by the container collar 30 and canister 5 regardless of how much extra force is applied by the patient to the levers 20a, 20b. A consistent actuation (opening) of the valve 7 of the canister 5 is thereby enabled by the configuration of the device 1. The springs 50a, 50b are adapted to store sufficient energy therein as to overcome the force for opening the metering valve 7 when released. For a typical standard force of approximately 4ON for opening a MDI metering valve, each spring would be configured to produce an equal force which is marginally greater than one-half the metering valve opening force. If a 55N force was needed to open the metering valve 7, each spring may be selected to produce a nominal 29N force.

Following actuation, the coiled coil extension springs 50a, 50b return to their 'at rest' state (i.e. with no externally-applied biasing energy, but only any initial biasing tension inherent in the closed coil form of the extension springs 50a, 50b present). As will be appreciated by the skilled reader in the art, the return spring (not shown) of the valve of the valved canister provides energy to move the canister 5, container collar 30, extension collar 40 and levers 20a, 20b back to the 'at rest' position as shown in Figure 2. Further actuating operations may therefore be conducted until the canister 5 is exhausted of its drug formulation contents.

Figure 6 shows a particular detail of the first drug dispenser device of Figures 1 to 5. For succinctness, only those parts relevant to this detail are now described further.

As previously described, the container collar 30 is provided at its underside with two downward protrusions 38a, 38b. The mouthpiece cover 16 is further provided with P- shaped cam interference elements 17a, 17b joined together by bridge element 18 and joining to the mouthpiece cover 16 by means of living hinge 19 about which the bridged interference elements 17a, 17b may pivot. When, as shown in Figure 6, the mouthpiece cover 16 engages with the body 12 of the dispenser device 1 to close the mouthpiece 14 (i.e. in the mouthpiece-closed position) the interference elements 17a, 17b adopt a position in which they locate underneath the downward protrusions 38a, 38b in close proximity or abutment therewith to thereby prevent any downward movement of the container collar 30. See also Figure 3a. Unintended movement of the container collar 30, and hence unintended actuation of the dispenser device 1 , is prevented.

In a subtle point, it is noted that when the mouthpiece cover 16 is in place such that the interference elements 17a, 17b prevent the downward movement of the container collar 30, the levers 20a, 20b, extension springs 50a, 50b and extension collar 40 are not locked and are therefore free to move. The levers 20a, 20b may thus still be compressed to the point at which their protruding ends 23a, 23b touch off, but without any movement of the container collar 30 and actuation of the dispenser device 1. When the protruding ends 23a, 23b are so touched off the user will also not be able to apply further, potentially damaging, force to the interference elements 17a, 17b or to the stem block 8.

The relative positioning of the interference elements 17a, 17b and the collar protrusions 38a, 38b in the various stages of operation of the device 1 is shown in Figures 3 and 4. Figure 3a shows the spatial relationship when the mouthpiece cover 16 is in the mouthpiece-closed position, whilst Figures 3b and 4a-4c show the spatial relationship with the cover 16 removed and the levers being depressed inwardly to fire the device 1.

The mouthpiece cover 16 may take one of the particular forms described in US Patent Application No. 12/066,048, derived from PCT Patent Application No. WO-A- 2007/028992, which claims priority from UK patent application No. 0 518 355 filed 8 September 2005, the entire content of which applications are incorporated herein by reference.

In Figures 38-40 there is shown an embodiment of the present invention which is a modification of the drug dispenser device 1 or 101. In this embodiment, a modified mouthpiece cover 716 in accordance with the present invention is provided for use in place of the mouthpiece cover 16 previously described. The modified mouthpiece cover 716 has the same function as the other mouthpiece cover 16, namely to close and cover the mouthpiece 14, and also to provide a lock-out function to prevent actuating movement of the container collar 30 (but not movement of the levers 20a, 20b and the extension collar 40). Accordingly, like reference numerals are used to designate like features between the two mouthpiece covers 16, 716.

The modified mouthpiece cover is comprised of a closure part 716a and a connector part 716b which includes the P-shaped cam interference elements 717a, 717b which are rotatably mounted on an axle presented by the lower housing part 12 (as before) which defines the axis of rotation of the mouthpiece cover 716 on the device 1 , which axis of rotation is generally perpendicular to the housing axis H-H. Whereas the first mouthpiece cover 16 is integrally formed (e.g. of polypropylene (PP)), thereby forming the living hinge 19, the closure and connector parts 716a, 716b are separately formed components which are hingeably connected (about axis 719) through complementary male 719a and female 719b features, in this case pin-and- hole connectors. In this embodiment, the closure and connector parts 716a, 716b are formed respectively from ABS and polypropylene (PP). In Figure 38a, the modified mouthpiece cover 716 is shown in a closed position in which the closure part 716a closes the mouthpiece 14 and the interference elements 717a, 717b are positioned to lock-out actuation of the device 1 by blocking action with the downward protrusions 38a, 38b of the container collar 30. As shown in Figures 38a and 39b, the inside surface of the end wall of the closure part 716a carries a rib structure 728. When the mouthpiece cover 716 closes the mouthpiece 14, the rib structure 728 forms an interference fit with the inside surfaces of the mouthpiece 14 to help maintain the closure part 716a in the closed position. However, the interference fit is such as to allow the closure part 716a to be removed from the mouthpiece 14 when sufficient force is applied thereto, which force is selected to be achievable by a wide range of users (young, elderly, etc).

As shown in Figure 38b, to open the mouthpiece 14 the user has to firstly hinge the closure part 716a in an opening direction (arrow O) relative to the connector part 716b. As indicated by the circle P1 in Figure 38b, once the closure part 716a has been hinged open a predetermined angle, a surface of a bridging element 723 of the closure part 716a abuts a surface of an angle limiter 724 provided on the bridging element 718 of the connector part 716b. These bridging element and angle limiter surfaces extend in directions which are essentially parallel to one another and also to the axis of the hinge 719. This abutment limits the angle by which the closure part 716a is able to be hinged relative to the connector part 716b in the opening direction O (the "hinge limit"). It is to be noted that at the hinge limit, shown in Figure 38b, the closure part 716a still partially closes the mouthpiece 14 and the interference elements 717a, 717b still lock-out actuation of the device 1.

Once the hinge limit is reached, the closure and connector parts 716a, b are coupled whereby, as shown in Figure 38c, further onward movement of the closure part 716a in the opening direction O causes the closure and connector parts 716a, b to rotate in unison in the opening direction O. This results in the closure part 716a further opening the mouthpiece 14 and rotation of the interference elements 717a, 717b towards an unlocking position where they will no longer block downward movement of the container collar 30 through blocking interaction with the downward protrusions 38a, 38b thereof.

However, as indicated by the circle P2 in Figure 38c, before the mouthpiece cover 716 is fully opened, and the interference elements 717a, 717b brought to the unlocking position, the bridging element 718 of the connector part 716b is obstructed by an obstruction 725 (in this case a ramp or tooth-profile rib) which is provided to the base of the lower housing part 12, as shown in Figures 40a and 40b which are views of the base of the lower housing part 12 (with the mouthpiece cover 716 in an opened position immediately prior to the closure part 716a being hinged into the position shown in Figure 39e where it is connected with the ledges 13a, 13b on the base).

As shown in Figures 38d and 38e, only if the user applies a sufficient force to the mouthpiece cover 716 is the connector part 716b able to pass the obstruction 725 and the mouthpiece cover 716 move to its end position where the closure part 716a is connected to the base of the lower housing part 12 through complementary snap- fittings 727a, 727b (here male fittings 727a on the closure part 716a and female fittings 727b on the ledges 13a, 13b), as before.

An advantage of the modified mouthpiece cover 716 and modified lower housing part 12 is that the hinge limit and obstruction 725 intuitively guide the user to move the mouthpiece cover to at least a position where the interference elements 717a, 717b adopt an unlocking position. This is because the mouthpiece 14 will not be open until the hinge limit is firstly reached and then the obstruction 725 passed (see Figure 38d) so the patient is compelled to move the mouthpiece cover beyond the obstruction 725 to gain lip access to the mouthpiece 14. Once the mouthpiece cover 716 is past the obstruction 725, the connector part 716b has rotated sufficiently in the opening direction O such that, even if the mouthpiece cover 716 is left hanging downwardly in a position immediately adjacent the obstruction 725, such as shown in Figure 38d, the cam profile 726 of the interference elements 717a, 717b is oriented such as not to provide an impediment to downward movement of the container collar 30 in response to user actuation of the levers 20a, 20b, since the downward protrusions 38a of the container collar 30 will act directly on the cam profile 726 to cam the mouthpiece cover 716 further in the opening direction O.

Expressed another way, the top dead centre (TDC) 726a of the cam profile 726 is only at an inclined angle on the opening side (here the left-hand side as viewed in the Figures) to an axis which is parallel with the longitudinal axis L-L (or H-H) - in the Figures, a vertical axis - after the obstruction 725 is overcome. Otherwise, the TDC 726a is inclined to the axis on the closing (here, right-hand) side thereof or coextensive with the axis, e.g. as indicated by the circle P in Figure 38a (see also Figures 38b and 38c). Thus, when the TDC 726a is to the closing side of, or coextensive with, the axis, the interference elements 717a, 717b block the downward protrusions 38a, 38b of the container collar 30 to prevent firing of the device 1. However, when the TDC 726a is inclined to the opening side of the axis, no blocking occurs, since even if the interference elements 717a, 717b are contacted by the downward protrusions 38a, 38b (as in the case of Figure 38d, but not so in Figure 38e when the mouthpiece cover 716 is fully opened) the mouthpiece cover 716 is cammed out of the way, as described above.

Thus, once the mouthpiece cover 716 is opened, either to the position shown in Figure 38d or, ideally, the position shown in Figure 38e (where the device 1 can then be stood up on the end face of the closure part 716a, as in Figure 7), the device 1 is ready to be actuated through the levers 20a, 20b. The mouthpiece cover 716 is able to be moved back to its closing position of Figure 38a, to lock-out the device 1 and prevent ingress of dirt etc. into the mouthpiece 14, by reversing the hinging and rotating steps, this time in an opposite, closing direction. The obstruction 725 will also need to be overcome in the closing direction. The opening and closing of the mouthpiece cover 716 can be repeated as often as necessary until the content of the aerosol canister 5 is exhausted through actuations of the device 1 in accordance with the prescribed dosage regime for the drug formulation contained in the canister 5.

When the mouthpiece cover 716 is in its closed position, the levers 20a, 20b and extension collar 40 are still free to be displaced, as before for the mouthpiece cover 16.

It will be appreciated that the hinge 719 and obstruction 725 prevent the inhaler device 1 being inadvertently unlocked, e.g. through playing with the closure part 716a, since no rotation of the connector part 716b (and hence the interference elements 717a, 717b) takes place until after the hinge limit is met and, even when the obstruction 725 is encountered, the interference elements 717a, 717b are still in a locking position (Figure 38c).

However, the obstruction 725 may be dispensed with, for example if it is desired to make it easier for the mouthpiece cover 716 to be moved to its open position. This applies equally to other embodiments of the invention, including those others described with reference to the Figures hereof (e.g. Figure 42). A further potential advantage of the modified mouthpiece cover 716 is the improved strength of the hinge 719 compared to a living hinge.

It will be appreciated that the modified mouthpiece cover 716 and modification to the lower housing 12 are also suitable for use in the drug dispenser device 101 of Figure 11 and may also be used in any of the other variants of the drug dispenser devices 1 ; 101 disclosed herein. It will further be appreciated that the drug dispenser devices incorporating the modified mouthpiece cover and modification to the lower housing part are also in accordance with the present invention.

If the mouthpiece 14 has a rectangular form, such as shown in Figures 36 and 37, a mouthpiece cover 816 as shown in Figure 41 may be used, which cover 816 corresponds to the cover 716 other than having a rectangular form.

Figures 7 to 10 illustrate aspects of the air flow into and through the housing of the drug dispenser device of Figure 1 during use thereof. For succinctness, only those parts of the drug dispenser relevant to these aspects are now described.

Figure 7 shows the drug dispenser device 1 of Figure 1 in a 'ready to use' position with the mouthpiece cover 16 removed from the mouthpiece 14. It will be noted that in this position, the mouthpiece cover 16 is pivoted to a position underneath the lower housing part 12. The opposing levers 20a, 20b, which protrude from apertures 1 1a, 11 b provided to the front 10a and rear 10b upper housing parts, are in their rest position. It will also be noted that in this position, the opposing levers 20a, 20b act to block off the apertures 11a, 1 1 b such as to prevent ingress of dirt particles or other debris into the body of the device 1.

Figure 8 shows the drug dispenser device 1 of Figure 1 in the 'in use' position, in which the opposing levers 20a, 20b have been moved towards each other, typically in response to a patient finger and thumb squeezing action. In this position, the opposing levers 20a, 20b no longer act to block off the apertures 11 a, 1 1 b such that air 60a, 60b may flow through the opened up apertures 11 a, 1 1 b into the upper housing part 10a, 10b in response to patient inhalation 61 through the mouthpiece 14.

The air flow 'in use' through the device 1 is now described in more detail with reference to Figures 9 and 10. Figure 9 shows one half of the device 1 of Figure 1 in the 'in use' position, in which the mouthpiece 14 is revealed, and in which lever 20b has been pushed inwards to open up aperture 11 b. External air 60b may thus now be drawn into the body of the device housing through this aperture 1 1 b (and also similarly through aperture 11 a on the other side) in response to patient inhalation 61 through the mouthpiece 14. In other words, the patient coordinates their inhalation 61 at the mouthpiece 14 to depression of the levers 20a, 20b so that the resulting airflow through the housing 10a, 10b, which enters via the opened apertures 1 1a, 11 b and exits through the mouthpiece 14, is coincident with the release of the drug from the canister 5 caused through actuation of the levers 20a, 20b. The airflow thus entrains the drug into the respiratory tract of the patient.

Figure 10 illustrates in more detail, the air flow 60a, 62 through the body of the device 1 during use thereof (i.e. again with the device 1 in the 'in use' position of Figures 8 and 9).

Referring to Figure 10 in more detail, the device 1 may be seen to comprise a discharge assembly in the form of a stem block assembly 3 which is integrally formed with the lower body part 12 and provides for the delivery of an aerosol spray of a drug on actuation of the inhaler. Mouthpiece 14 is a separately formed part which is fitted to the lower body part 12 (see Figure 28) and in use is gripped in the lips of the user to facilitate oral inhalation. Received within the enclosed chamber defined by the housing parts 10a, 10b, 12 there is provided aerosol canister 5 which contains drug to be delivered on actuation of the inhaler and is fitted in the main body and fluidly connected to the stem block assembly 3.

The mouthpiece 14 comprises an external section 15 which is configured to be gripped in the lips of a subject and defines a substantially cylindrical, open forward end through which an aerosol spray of a drug is in use delivered on actuation of the inhaler, an essentially 'bucket-shaped' open chamber form internal section 17 which has a closed rear section (other than air holes 66 and spray orifice 72 described hereinafter), and a discharge outlet in the form of a nozzle outlet 70 which is coupled to a rear end of the internal section 17, such as to provide for the delivery of an aerosol spray 64 into and through the internal section 17. In response to patient inhalation, air 60a is drawn down the rear part 10b of the body of the device 1 past around the stem block assembly 3 and towards the rear of the internal section 17 of the mouthpiece 14, which is provided with a duality of slot-like air holes 66 at the rear (i.e. base of the 'bucket') thereof arranged about spray orifice 72. The air holes 66 may be equi-spaced from the spray orifice 72. As may be seen, when the air 60a is drawn through these dual air holes 66 a duality of air flows 62 is defined within the mouthpiece 14. This provides for a partly annular air flow at the inner peripheral surface of the mouthpiece 14, which partly sheaths the aerosol spray 64 as delivered from the spray orifice 72 of the nozzle outlet 70, thereby partly entraining the aerosol spray 64 and reducing deposition at the internal surface of the mouthpiece 14.

In this embodiment the rear of the internal section 17 has a generally flat shape, which forms the base of the 'bucket'. The edges of the base curve outwards such that the internal section 17 has an increasing internal dimension in a direction away from the stem block assembly 3.

The nozzle outlet 70 includes the spray orifice 72 which provides for the delivery of an aerosol spray through the internal section 17 of the mouthpiece 14 and a delivery channel 74 which fluidly connects the delivery passage 9 of the stem block assembly 3 to the spray orifice 72.

In this embodiment the delivery channel 74 is a tapering channel which narrows towards the spray orifice 72. In this embodiment the delivery channel 74 has straight wall sections.

In this embodiment, the stem block assembly 3 comprises the stem block 8 for receiving the valve stem 7 of the canister 5, and the nozzle outlet 70 of the mouthpiece 14 which is fluidly connected to the stem block 8, such as to provide for the delivery of an aerosol spray through the mouthpiece 14. The stem block 8 may be integrally formed with the lower body part 12.

The stem block 8 includes a tubular bore 76 for receiving the valve stem 7 of the canister 5, which in this embodiment is co-axial with the longitudinal axis H-H of the housing (Figure 3a), which housing axis H-H in this embodiment is coincident with the longitudinal axis L-L of the drug discharge device when mounted in the drug dispenser device 1. The tubular bore 76 is open at one, the upper, end thereof and includes an upper section 77 which has an internal dimension which is substantially the same as the outer dimension of the valve stem 7 of the canister 5 and a lower section 78 which has a smaller dimension, which sections 77, 78 together define an annular seat for the distal end of the valve stem 7.

In this embodiment, the stem block 8 includes a lateral cavity 80 which slidingly receives the nozzle outlet 70 of the mouthpiece 14 and is fluidly connected to the tubular bore 76 thereof. The nozzle outlet 70 is configured to be a tight friction fit in the lateral cavity 80 in the stem block 8. Desirably, the tight friction fit provides a gas- tight seal. In other embodiments, other types of sealing method, also preferably arranged to provide a gas-tight seal, may be employed.

With this configuration of the stem block assembly 3, the nozzle outlet 70 (or mouthpiece 14) and the nozzle block 8 (or lower housing part 12) can be formed of different materials and to different specifications which are specifically suited to their purposes.

Figure 11 shows a variation 101 of the drug dispenser device of Figures 1 to 10, with like features being identified with like reference numerals. The device 101 of Figure 11 is identical to the embodiment of Figures 1 to 10 in all aspects other than that the dual horizontal slot-like air holes 66 visible in Figure 10 are replaced by an arrangement of four circular air holes 166 (only three visible in Figure 11 ) about the spray orifice 172 at the rear (i.e. base of the 'bucket') of the internal section 1 17 of the mouthpiece 114. It may be seen that the four air holes 166 are arranged in a generally circular arrangement about the spray orifice 172, in this embodiment being at 90° angular displacement relative to each other. The spray orifice 172 may be centrally located in the circular arrangement of the air holes 166. As may be seen in Figure 11 , when external air 160a is drawn through these plural spaced air holes 166 a plurality of air flows 162 is defined within the mouthpiece 114. This provides for an essentially annular air flow at the inner peripheral surface of the mouthpiece 1 14, which essentially sheaths the aerosol spray 164 as delivered from the spray orifice 172 of the nozzle outlet 170, thereby entraining the aerosol spray and reducing deposition at the internal surface of the mouthpiece 114.

Figures 30a to 3Oo show other mouthpiece forms 514a to 514o, which may be employed in the drug dispenser device of Figures 1 and 11 as an alternative to the mouthpieces 14, 1 14 thereof. These alternative mouthpiece forms 514a to 514o differ only in the size, shape and number of respective air holes 566a to 566o provided to the rear of the internal section 517a to 517o of these alternative mouthpiece forms 514a to 514o, which air holes 566a to 566o are as before, arranged about a spray orifice 572a to 572o.

Thus, Figures 30a to 3Od and 3Oi show different arrangements of four circular air holes 566a to 566d and 566i; Figures 3Oe and 3Of show different arrangements of three slot-like air holes 566e, 566f; Figures 3Og 3Oh and 3Oo show different arrangements of six slot-like air holes 566g, 566h and 566o; Figure 3Oj shows an arrangement of many circular air holes 566j; Figure 30k shows an arrangement of six curved slot air holes 566k arranged in two concentric rings; Figures 3Ol to 3On show different arrangements of three curved slot air holes 566I to 566n arranged in a ring pattern.

Figures 36a to 36o show yet further alternative mouthpiece forms 614a to 614o which may be employed in the drug dispenser device of Figures 1 and 11 as an alternative to the mouthpieces 14, 1 14 thereof. These further alternative mouthpiece forms 614a to 614o correspond closely to the respective mouthpiece forms 514a to 514o, in particular sharing the same air flow arrangements, and like reference numerals being used to indicate like features. However, it will be observed that the further alternative mouthpiece forms 614a to 614o have a subtly different shape and configuration than the mouthpiece forms 14; 114; 514a to 514o, in particular having a generally rectangular front aspect.

Referring to Figures 37a and 37b, this shows the mouthpiece 614a of Figure 36a provided with bracing ribs 673 to its the rear side to strengthen the mouthpiece 14; 114; 514; 614. Features in common with the mouthpiece 14 are provided with like reference numerals (cf. Figure 10). Similar bracing ribs may be provided to the other mouthpiece forms 14; 1 14; 514a-o and 614b-o herein described and may be particularly advantageous when the mouthpiece 14; 114; 514a-o; 614a-o has a large number of air holes 66; 166; 566a-o; 666a-o.

Other air flow pathways through the drug dispenser device are possible, for instance such as those described in U.S. Provisional Application No. 60/823,146 and International (PCT) Patent Application PCT/EP2007/058670 (WO-A-2008/023014) supra . The upper front part 10a of the drug dispenser device 1 , 101 of Figures 1 and 11 is arranged for receipt and housing of an actuation counter. Figures 12 to 18b provide details of the workings of a suitable actuation counter 201. Figures 19 to 21 show more details of the interaction of the actuation counter 201 with the actuating mechanism of the drug dispenser device 1 , 101.

Referring now to Figure 12, this shows an actuation counter 201 for use with the drug dispenser device 1 , 101 herein. Figures 13a and 13b respectively show underside and top views of the actuation counter 201. The actuation counter 201 is of the form disclosed in Applicant's US Patent Application No. 10/597551 derived from International (PCT) Patent Application WO-A-2007/104964, the contents of each of which are incorporated herein by reference.

The actuation counter 201 is comprised within upper front part 10a of the drug dispenser device 1 (or 101 ) which provides first 212 and second 214 spindle mountings, each capable of defining an axis of rotation, and a circumferential wall 218 defining a bezel form retainer 219. A viewing window 216 is provided to the housing to enable the viewing of the count. As will be understood by a comparison of Figure 1 with Figure 13b, the oval-shaped front face 101 of the upper front part 10a is covered with a correspondingly shaped label 103 (e.g. of a polymeric material) to cover the apertures in the front face 101 shown in Figure 13b, but not the viewing window 216. In other words, the label has an aperture 105 which registers with the viewing window 216. In an alternative embodiment, the label 103 may itself have a transparent portion in place of the aperture 105 to enable observation of the viewing window 216.

Now describing the workings of the actuation counter in more detail: First, discshaped count wheel 220 has 'units' (i.e. numerals) count indicia 222 provided at spaced intervals on a top face thereof. The first count wheel 220 is provided with a central aperture 226 and a circular cavity 223 that is arranged for disposed receipt of ratchet wheel 250. Ratchet drive receipt teeth 224 are arranged about the inner circumferential wall 225 of the cavity for ratcheted drive interaction with the ratchet wheel 250. The ratchet wheel 250 itself is sized and shaped for receipt by the circular cavity 223 of the first count wheel 220 and is provided with two oppositely-located drive tongues 252a, 252b for ratcheted drive interaction with the ratchet drive receipt teeth 224. The ratchet wheel 250 is also provided with a drive-receiving protrusion 254 arranged in use for drivable rotation of the ratchet wheel 250. As will be described in more detail hereinafter with reference to Figures 19 to 21 , the drive-receiving protrusion 254 receives drive in response to drive interaction with downward drive slot 82 provided to front plate 80 in which the drive-receiving protrusion 254 is located. The front plate 80 is permanently fixed to the container collar 30 so as to move in tandem/unison therewith. In this embodiment, the front plate 80 is permanently fixed to the container collar 30 by ultrasonic welding.

Noting that the front plate 80 moves on a linear path (along axis L-L) on actuation of the drug dispenser device 1 , 101 and that the ratchet wheel 250 rotates, the drive slot 82 allows for the transverse component of motion of the drive-receiving protrusion 254 therein as the ratchet wheel 250 rotates upon the drive-receiving protrusion 254 being driven by the drive slot 82.

Second, ring form count wheel 230 also has 'tens of units' (i.e. decimals) count indicia 232 provided at spaced intervals on a top face 237 thereof and a set of teeth 234 provided in annular arrangement to the underside thereof. It may be noted that at stop position 238, two of the teeth 234 have been removed and further that the outer circumferential edge of top face 237 is formed with a series of equally spaced notches or indentations 236. The reasons for these features will become clear from the later description. The second count wheel 230 is also provided with a protruding shutter 280, the function of which will also be described later.

Kick wheel 240 has kick teeth 244 provided in annular arrangement around the circumference thereof.

As may be best seen at Figure 13a, when assembled, second count wheel 230 is received for rotation within the bezel form retainer 219 of the housing; and first count wheel 220 is received within the inner ring void 235 defined by ring-shaped second count wheel 230 and its central aperture 226 by first spindle 212 such that clearance exists between the first 220 and second 230 count wheels. Thus, the first 220 and second 230 count wheels are in concentric relationship, but the level of the second count wheel 230 is slightly raised relative to that of the first count wheel 220 to enable shutter 280 to protrude over and above the first count wheel 220. Ratchet wheel 250 is received within the circular cavity 223 of the first count wheel 220 such that drive tongues 252a, 252b engage with the ratchet drive receipt teeth 224. Both wheels 220, 230 and the ratchet wheel 250 are rotatable about a common first axis of rotation F-F defined by the axis of first spindle 212. The drive-receiving protrusion 254 is offset from the first axis F-F, as is the drive slot 82. Moreover, the protrusion 254 and drive slot 82 are both offset to the longitudinal axis L-L.

Kick wheel 240 is received by second spindle 214 for rotation about a second axis of rotation S-S defined by the second spindle 214 and therefore offset from the first axis of rotation F-F. It will be appreciated that the second axis of rotation S-S is spaced from the first axis of rotation F-F to be outside the path of rotation defined by the outwardly-facing teeth 234 of the second count wheel 230. Moreover, the first and second axes F-F, S-S are parallel, or substantially parallel, to each other.

The set of kick teeth 244 of the kick wheel 240 are in meshed relationship with the set of teeth 234 of the second count wheel 230 such that rotary motion of the kick wheel 240 results in rotary motion of the second count wheel 230. In turn, ratchet drive tongues 252a, 252b of ratchet wheel 250 mesh with the ratchet drive receipt teeth 224 of the first count wheel 220 for drivable rotation of the first count wheel 220.

As will be described in more detail hereinafter, when the actuation counter 201 is disposed in the drug dispenser 1 ,101 , the ratchet wheel 250 is in turn drivably rotatable about the first axis F-F by the drive-receiving interaction of protrusion 254 with downward drive slot 82 provided to front plate 80. The front plate 80 fixes to the container collar 30, which is itself drivable downwards in response to effective user actuation of the drug dispenser device 1 , 101.

First count wheel 220 may also be seen to be provided at its periphery with a pair of fixed index teeth 228a, 228b (as may be best seen in Figure 15a) arranged for intermittent meshing with the kick teeth 244 of the kick wheel 240 such that rotary motion of the kick wheel 240 results from rotary motion of the first count wheel 220 only when said intermittent meshing occurs.

In a subtle aspect, it may be seen that the profile of certain teeth 234, 228a, 228b, has a flanged form, which is selected to optimise the various toothed engagements necessary for effective gearing and inter-operability of the parts of the counter.

In a further subtle aspect, the counter 201 is arranged to count down from '120' to a 'shuttered position'. The second count wheel 230 is thus arranged to define fourteen equal pitches allied to twenty-six (calculated as (2 x 14) - 2) teeth 234 plus two missing teeth at stop position 238. The number of pitches is defined as x + 2, wherein x is the highest numeral on the second count (i.e. decimals) wheel, which in turn corresponds to a highest count of 10 times x (i.e. 10 x 12 = 120, in this embodiment). The '+ 2' part of the sum determining the number of pitches relates to one coloured portion 282 and one shutter portion 280, as are described in more detail later.

Overall, it may be noted that the actuation counter 201 has a relatively compact form to assist its receipt within the upper front housing part 10a of the drug dispenser device 1 , 101. In particular, the counter 201 extends upwards in the direction of the axes F-F, S-S to only a minor extent.

Operation of the actuation counter 201 is now described with additional reference to Figures 14a to 16b, in which only the most relevant features to the described operation are labelled. The actuation counter 201 is arranged to count down and thus, to illustrate a count operation, Figures 14a, 15a and 16a show the actuation counter 201 at a 'count 120' position and Figures 14b, 15b and 16b show the actuation counter 201 at a 'count 119' position (i.e. just after counting down from 120).

It will be appreciated that the 'count' of the dose counter 201 referred to herein is the count number collectively presented by the count wheels 220, 230 in the window 216.

To initiate a general count operation, ratchet wheel 250 is rotated in response to effective user actuation of the drug dispenser device 1 , 101 by squeezing the levers 20a, 20b together as described with reference to Figures 1 to 7 above. This results in the drive slot 82 driving the ratchet wheel protrusion 254 to rotate the ratchet wheel 250 in a first rotary sense (clockwise in Figures 12 and 13a). This, in turn, results in rotation of the first count wheel 220 in the first rotary sense by the meshed interaction of drive tongues 252a, 252b with ratchet drive receipt teeth 224. The ratchet wheel 250 and first count wheel 220 are configured and arranged such that when indexed first count wheel 220 rotates by 36° such that a single indicium 222 thereon is advanced (i.e. the 'units' count moves down one unit).

Where the pre-count operation visible count is xθ (e.g. 120 with 'x = 12', as shown at Figures 14a, 15a and 16a), the counting action resulting from the use operation is subtly different. Once again, ratchet wheel 250 is rotated in response to effective user actuation of the drug dispenser device 1 , 101 causing rotation of the first count wheel 220 by 36° such that the 'unit' indicium 222 moves on from '0' to '9' (as shown at Figures 14b and 15b). This rotation of the first count wheel 220 however, also brings the pair of index teeth 228a, 228b into meshed relationship with the kick teeth 244 of kick wheel 240 such that the kick wheel 240 rotates and in turn causes the second count wheel 230 to rotate through meshing of their respective teeth 234, 244. The wheels 220, 230, 240 are configured and arranged such that the resultant rotation of the second count wheel 230 is by 360/14° (that is to say by 360/n° wherein n is the number of number spacings, where in this case n = 14 because there are twelve decimals indicia 232; one shutter portion 280 and one coloured portion 282) such that a single indicium 232 thereon is advanced (i.e. the 'tens' count moves down exactly one unit). In this instance, the decimal indicium 232 moves down from '12' to '1 1 ', as shown in Figures 14a and 14b.

Where the previous visible count was 10 (i.e. x=1 ), the counting action resulting from the use operation is again subtly different in that the kick wheel 240 action, as described above, results in the coloured (e.g. red) portion 282 of the second count wheel 230 being advanced into place in the window 216 such that the next display is 'red 9' (i.e. coloured portion 282; and numerals indicia 222 is number 9).

As shown at Figures 17a and 18a, where the previous visible count was 'red 0' (i.e. x=0), the counting action resulting from the use operation is still again subtly different in that the kick wheel 240 action, as described above, results in the shutter portion 280 of the second count wheel 230 being advanced into place in the window 216 such that the next display is fully shuttered off (i.e. no indicia 222, 232 visible at all, as shown at Figures 17b and 18b). Additionally, the stop position 238 in the set of second count wheel teeth 234 is brought into opposed relation with the kick teeth 244 whereby the kick teeth 244 and the teeth 234 no longer mesh. Thus, if the first count wheel 220 continues to rotate, e.g. in response to continued user operation of the drug dispenser device 1 , 101 into which the actuation counter 201 is incorporated, notwithstanding that all drug doses in the prescribed dosing regime have been dispensed (although surplus doses may remain in the canister 5 for patient administration in accordance with regulatory requirements, as understood by the skilled person in the art), the index teeth 228a, 228b of the first count wheel 220 will still intermittently mesh with the kick teeth 244 to cause the kick wheel 240 to rotate. However, this rotation of the kick wheel 240 will not be transmitted to the second count wheel 230, due to the missing teeth of stop position 238, and the shutter 280 remains in the shuttering position in the window 216 so that the underlying 'units' indicium 222 remains unseen.

In this embodiment, the second count wheel 230 is integrally formed with the shutter portion 280.

The shutter portion 280 may be coloured, for instance be of the same colour (e.g. red) as the coloured portion.

To further illustrate the countdown display of the counter 201 , the reader's attention is drawn to Table 1 below. Table 1 shows the sequential countdown for each of the units (first) and decimals (second) count wheels 220, 230 upon succeeding use operations or actuations of the counter 201 , and also indicates which of these two count wheels 220, 230 indexes to bring the counter 201 to its new counter display. As shown in Table 1 , the first (units) count wheel 220 indexes on each counter actuation, whereas the second (decimals) count wheel 230 only indexes (through the kick wheel 240 supra) each time the units indicium 222 of the first (units) count wheel 220 in the window 216 decrements from '0' to '9'. At the end of the countdown, when the display is shuttered, the first count wheel 220 is still free to rotate, underneath the shutter 280 so as not to be visible, and no further indexing of the second count wheel 230 occurs due to the stop position 238 providing for disengagement of the teeth 234, 244 of the second count wheel 230 and the kick wheel 240.

Table 1

Sequential Decimals Units Wheel Indexing of Units Indexing of

Counter Wheel Count Count in Wheel to this Decimal Wheel

Display in in Window Window Count? to this Count?

Window

120 12 0

119 1 1 9 Yes Yes

118-110 1 1 8 to O Yes No

109 10 9 Yes Yes

108-100 10 8 to O Yes No

99 9 9 Yes Yes

98-90 9 8 to O Yes No

89 8 9 Yes Yes

88-80 8 8 to O Yes No

79 7 9 Yes Yes

78-70 7 8 to O Yes No

69 6 9 Yes Yes

68-60 6 8 to O Yes No

59 5 9 Yes Yes

58-50 5 8 to O Yes No

49 4 9 Yes Yes

48-40 4 8 to O Yes No

39 3 9 Yes Yes

38-30 3 8 to O Yes No

29 2 9 Yes Yes

28-20 2 8 to O Yes No

19 1 9 Yes Yes

18-10 1 8 to O Yes No

9 'Red' 9 Yes Yes

8-0 'Red' 8 to O Yes No

Shuttered Shuttered Shuttered Yes Yes

After effective user actuation of the drug dispenser device 1 , 101 and registration of the count, the levers 20a, 20b are released to return to their outward rest position and to allow the container collar 30 to return to its rest position. This results in the ratchet wheel 250 reversing, to reset it in its starting position for the next counting event, through interaction of the drive slot 82 with the drive-receiving protrusion 254.

Thus, the ratchet wheel 250 is adapted to not only rotate in the cavity 223 of the first count wheel 220 in the first rotary sense (clockwise as viewed in Figures 12 and 13a), but also to rotate in an opposite, second rotary sense (anti-clockwise as viewed in Figures 12 and 13a) in the first count wheel cavity 223.

However, while rotation of the ratchet wheel 250 in the first rotary sense drivably rotates the first count wheel 220 in the first rotary sense for indexing of the units count 222 in the window 216, rotation of the ratchet wheel 250 in the opposite, second rotary sense is relative to the first count wheel 220; i.e. the first count wheel 220 remains stationary so that the units indicia 222 in the window 216 remains unchanged. That is to say, frictional engagement between the respective wheels 220, 250 does not result in reverse rotation of the first count wheel 220, except for tolerance adjustments as discussed below.

To this end, the first count wheel 220 is provided with a pair of diametrically opposed resilient tongues or pawls 227 which co-operate with a serrated circumferential surface 211 of the first spindle 212a. The serrated surface 21 1 comprises plural ratchet teeth 215 with which the free ends 227a of the pawls 227 engage. As the skilled person will understand, as the first count wheel 220 is driven by the ratchet wheel 250 to rotate in the first sense, the free ends 227a of the pawls 227 ride over the respective ratchet tooth 215 presently engaged with and drop onto the next adjacent ratchet tooth 215 in the first sense, there being a step between adjacent teeth 215. This then indexes the first count wheel 220 in its new position, at which the next units indicia 222 in the count sequence registers with the window 216. However, the step between the adjacent ratchet teeth 215 prevents the first count wheel 220 rotating back in the opposite, second sense as the ratchet wheel 250 so rotates as the pawl free ends 227a cannot pass thereover.

As will also be appreciated by the skilled person, the ratchet teeth 215 provide tolerances in the indexing rotation of the first count wheel 220 by the ratchet wheel 250. In other words, the first count wheel 220 can be slightly over-rotated in the first sense, but as the ratchet wheel 250 rotates back in the opposite, second sense it carries the first count wheel 220 in the same sense, through frictional forces, until the pawl free ends 227a engage the step between the ratchet teeth 215 which then prevents further reverse rotation of the first count wheel 220 and indexes the units indicia 222 in the window 216.

As shown in Figures 12 and 13b, for example, the upper front part 210 of the drug dispenser device 1 , 201 further provides a resilient pawl 217. The pawl 217 has a free end 217a which engages the indentations 236 in the outer circumferential surface of the top face 237 of the second count wheel 230, as shown in Figures 14a and 14b, for instance. There is one indentation 236 for each count or index position of the second count wheel 230, so the free end 217a of the pawl 217 and the indentations 236 provide an indexing function which provides for accurate alignment of the decimals indicia 234 in the window 216 and inhibits or prevents reverse rotation of the second count wheel 230.

The indentations 236 in this embodiment have a symmetrical shape, more particularly a generally U-shape. However, other shapes could be used. Moreover, asymmetric shapes could also be used. For instance, it may be useful for the flanks of the indentations 236 to present different angles, for example for the trailing (rear) flanks of the indentations 236 (relative to the direction of rotation of the second count wheel 230, e.g. anti-clockwise in Figures 14a and 14b) to form a greater angle with a central radial line through the indentations 236 than the leading (forward) flanks. This means there is less resistance to the pawl 217 releasing from the indentations 236 as the second count wheel 230 is driven by the kick wheel 240.

It will be appreciated that the above usage of the actuation counter has been described in terms of a counter assembly 201 arranged to count downwards (i.e. to count on from 'n +1 ' to 'n' on indexing), but that the counter assembly may be straightforwardly modified to count upwards (i.e. instead to count on from 'n' to 'n + 1 ' on indexing).

Alternatively, other indicators than a complete countdown/count-up could be employed to indicate the amount of drug content left in the canister 5, such as the use of colour scales, line or block scales or letters/words on the count wheels 220, 230.

The components of the actuation counter 201 and any assemblies and sub- assemblies described above may be made from any suitable materials such as plastic polymer materials (e.g. acetal or ABS or styrene polymers). In particular, the count wheels 220, 230 may be of ABS while the kick wheel 240 and the ratchet wheel 250 may be of acetal.

In a modification of the counter 201 (not shown), the friction resistance between the kick wheel 240 and its spindle mounting 214 may be increased to provide a dragging or braking effect which retards the speed of rotation of the kick wheel 240 when driven by the first count wheel 220. One possible way to achieve this is through the provision of axially-oriented splines about the outer periphery of the spindle mounting 214. This may prevent or inhibit any tendency for the second count wheel 230 to be misaligned or over-indexed by a fast moving kick wheel 240.

The interrelationship between the actuation counter 201 and the drug dispenser device 1 is now described in more detail with reference to Figures 19 to 21. For clarity and succinctness, only relevant parts of Figures 19 to 21 are labelled.

Figures 19 shows the drug dispenser device 1 with upper front cover part 10a and actuation counter 201 removed. The device 1 is in the 'at rest' position with the levers 20a, 20b not depressed.

Figure 20 shows the drug dispenser device 1 with the upper front cover part 10a and actuation counter 201 disposed therein shown detached from the remainder of the device 1. The drug dispenser device 1 is again in the 'at rest' position with the levers 20a, 20b not depressed. Figure 21 shows further details of the actuation counter 201 disposed in the upper front cover part 10a of the drug dispenser device 1.

Arrow A of Figure 20 indicates the direction of reciprocal movement of the container collar 30 and front plate 80 attached thereto resulting from effective user actuation of the drug dispenser device. Arrow B of Figure 20 indicates the resulting interaction between the downward drive slot 82 of the front plate 80 and the drive-receiving protrusion 254 of the ratchet wheel 250 of the actuation counter 201.

Detailed aspects of the drug dispenser device 1 and actuation counter 201 of Figures 19 to 21 correspond to those already described by reference to Figures 1 to 11 and Figures 12 to 18b respectively, and for succinctness these are not described further.

Registration of a count is now described. In use, following effective user actuation of the drug dispenser device 1 by squeezing the levers 20a, 20b together, as described hereinabove with reference to Figures 1 to 7, the container collar 30 and front plate 80 move downwards in tandem/unison. The downward drive slot 82 on the front plate 80 drivably engages the drive-receiving protrusion 254 to drive on the ratchet wheel 250 of the actuation counter 201 thereby resulting in registration of a count. As described previously, effective user actuation which results in the downward movement of the container collar 30 (and actuation of drug release from the canister 5) occurs only once a pre-load threshold ('tipping') force has been overcome (by that effective user actuation). Thus, it will also be appreciated that a count is only registered by the actuation counter 201 in response to such an effective user actuation. The registered count thus fully ties in with the number of occurrences of drug release.

The actuation counter 201 may be modified as described in US Provisional Application No. 61/029,458 supra, in particular as now described with reference to, Figures 31 to 35 hereof.

Figures 31 a and 31 b respectively show back and front views of a front plate 690 (hereinafter in the description of this modification the "driver plate") for use with a modified version 601 of the actuation counter 201 of Figures 12 to 21. The modified actuation counter 601 will be appreciated to have a generally similar mode of usage to that of the unmodified counter 201 , but also includes features to prevent 'overrun' of the count. The operation of the modified counter 601 is described below in more detail with reference to Figures 32a to 35b.

The driver plate 690 of Figures 31 a and 31 b may be appreciated to have the same outline form (i.e. l-form) as that of front plate 80 of Figures 19 to 20 as previously described in relation to use with the drug dispenser device 1 of Figure 1. It will be appreciated from the following description that the driver plate 690 and the modified actuation counter 601 of Figures 32a to 35b are also arranged to be suitable for use with the drug dispenser device 1 , 101 of Figures 1 and 1 1.

Thus, the driver plate 690 is arranged in use, to be permanently fixed to the container collar 30 of the drug dispenser device 1 , 101 so as to move in tandem therewith. In embodiments, the driver plate 690 is permanently fixed to the container collar 30 by ultrasonic welding. Whilst in alternative embodiments the driver plate 690 and container collar 30 may be provided as an integral part there are advantages associated with forming them as separate parts, which are then fixed (e.g. ultrasonically welded) together. In particular, the welding of the driver plate 690 to the container collar 30 as part of a final assembly process allows the positioning of the driver plate 690 relative to the container collar 30 to be effectively tailored to each container collar 30 and device 1 , 101 to ensure effective actuation counter 601 operation. Thus, manufacturing tolerance variations across a variety of components of the device 1 , 101 and/or counter 601 may effectively be compensated for.

The driver plate 690 is provided with a driver feature in the form of a downward drive slot 692 that is arranged in use, for driving interaction with a drive-receiving feature (e.g. drive-receiving protrusion 254 of the actuation counter 201 of Figure 12) for driving on of the actuation counter 601 to register a count. The driver plate 690 differs from that front plate 80 of Figures 19 to 20 in that a protruding brake element 694 is provided to the upper front part thereof. As will become clear from the later description, the brake element 694 is arranged to selectively interact with the first counter wheel 620 and/or second count wheel 630 of the modified actuation counter 601 to prevent overrun thereof when registering a count of an actuation of the drug dispenser device 1 , 101.

Figures 32a to 32g and Figures 33a to 33g show corresponding plan and perspective views of sequential operation steps of key parts of the modified actuation counter 601. Those key parts are the driver plate 690; first (units) count wheel 620; second (decimals) count wheel 630; kick wheel 640 and ratchet wheel 250). All other parts of the modified actuation counter 601 (e.g. including the housing 10a with spindle mountings 212, 214) correspond to those of the unmodified actuation counter 201 of Figures 12 to 18b).

Figures 34a and 34b respectively show perspective underside and top views of the first count wheel 620 for use in the modified actuation counter 601. Thus, discshaped first count wheel 620 has 'units' (i.e. numerals) count indicia 622 provided at spaced intervals on a top face thereof. Alignment holes 622a, 622b and notches 622e, 662f are provided adjacent indicia '6' and 7' and '8' and '9' respectively, and also alignment holes 622c, 622d adjacent indicia '3' and '8' for alignment of the first count wheel 620 with the second count wheel 630 during assembly of the counter 601. The first count wheel 620 is provided with a central aperture 626 and a circular cavity 623 that is arranged for disposed receipt of ratchet wheel 250 (not shown, but see e.g. Figures 12 and 21 ). Ratchet drive receipt teeth 624 are arranged about the inner circumferential wall 625 of the cavity for ratcheted drive interaction with the ratchet wheel 250. With reference also to Figures 12 and 21 , the ratchet wheel 250 itself, is sized and shaped for receipt by the circular cavity 623 of the first count wheel 620 and is provided with two oppositely-located drive tongues 252a, 252b for ratcheted drive interaction with the ratchet drive receipt teeth 224. The ratchet wheel 250 is also provided with a drive-receiving protrusion 254 arranged in use, for drivable rotation of the ratchet wheel 250 in response to drive interaction with downward drive slot 692 of the driver plate 690 in which slot 692 the drive-receiving protrusion 254 locates, in use.

The first count wheel 620 is also provided with a pair of diametrically opposed resilient tongues or pawls 627 which co-operate with a serrated circumferential surface 211 of the first spindle 212a (not shown, but see Figure 12). The serrated surface 211 comprises plural ratchet teeth 215 with which the free ends 627a of the pawls 627 engage. As before, as the first count wheel 620 is driven by the ratchet wheel 250 to rotate in the first sense (anti-clockwise as viewed in Figures 32 to 33, as shown by arrow A in Figures 32b and 33b) the free ends 627a of the pawls 627 ride over the respective ratchet tooth 215 presently engaged with and drop onto the next adjacent ratchet tooth 215 in the first sense, there being a step between adjacent teeth 215. This then indexes the first count wheel 620 in its new position, at which the next units indicia 622 in the count sequence registers with the window 616. However, the step between the adjacent ratchet teeth 215 prevents the first count wheel 620 rotating back in the opposite, second sense as the ratchet wheel 250 so rotates as the pawl free ends 627a cannot pass thereover.

First count wheel 620 may also be seen to be provided with a pair of fixed index teeth 628a, 628b arranged for intermittent meshing with the kick teeth 644 of the kick wheel 640 such that rotary motion of the kick wheel 640 results from rotary motion of the first count wheel 620 only when said intermittent meshing occurs (see Figures 32a to 33g and also Figures 15a and 15b showing corresponding index teeth 228a, 228b of the unmodified actuation counter). The first count wheel 620 is further provided with a peripheral flanged portion 621. Notch 621 is provided to this flanged portion adjacent to fixed index tooth 628b to prevent the kick teeth 644 of the kick wheel 640 snagging the peripheral flange of the first count wheel 620. The peripheral flanged portion 621 of the first count wheel 620 also includes at equally-angularly spaced-apart intervals on the outer circumference thereof a series of shaped notches or saw-tooth indentations 629 ( e.g. 'crenellations') provided with near-radial lead faces 629a and arranged for selective interaction with the brake element 694 of the driver plate 690, as will be described in more detail later. The saw-tooth indentations 629 may be noted to have an asymmetrical shape, more particularly an offset U- shape with near-radial lead face (flank) 629a.

Figures 35a and 35b respectively show perspective underside and top views of the second count wheel 630 for use in the modified actuation counter 601. The second, ring form count wheel 630 has 'tens of units' (i.e. decimals) count indicia 632 provided at spaced intervals on a top face 637 thereof and a set of drive teeth 634 provided in annular arrangement to the underside thereof. Alignment notches 632a, 632b are provided adjacent indicia '3' and '4' and '8' and '9' respectively for alignment of the first counter wheel 620 with the second count wheel 630 during assembly of the counter 601. It may be noted that at stop position 638, a couple of the teeth 634 have been removed. It will also be noted that the outer circumferential edge of top face 637 is formed with a series of equally-angularly spaced-apart notches or saw-tooth indentations 636 (e.g. 'crenellations') provided with near-radial lead faces 636a and arranged in one aspect, for selective interaction with the brake element 694 of the driver plate 690, as will be described in more detail later. The saw-tooth indentations 636 may be noted to have an asymmetrical shape, more particularly an offset U-shape with near-radial lead face (flank) 636a. The second count wheel 630 is also provided with a protruding shutter 680, which is coloured, the function of which is identical to that of the shutter 280 of the second count wheel 630 of the unmodified counter 201 and the operation of which, for succinctness, will not be described in detail. The second count wheel 630 also has coloured portion 682, the function of which is identical to that of coloured portion 282 of the unmodified counter 201 , and which again will therefore not be described in detail. The colour of the shutter 680 and coloured portion preferably corresponds (e.g. both are red).

Referring now to Figures 32a to 32g and Figures 33a to 33g, the key parts (driver plate 690; first count wheel 620; second count wheel 630; kick wheel 640 and ratchet wheel 250) of the modified counter 601 are shown in the configuration which they would adopt in the full counter arrangement. Kick wheel 640 may be seen to have kick teeth 644 provided in annular arrangement around the circumference thereof. Figures 32a to 32g also show resilient pawl 217 (refer also to Figure 12). The pawl 217 has a pawl portion 217a which trails the saw-tooth indentations 636 in the outer circumferential surface of the top face 637 of the second count wheel 630 to align the dose count. There is one indentation 636 for each count or index position of the second count wheel 630, so the free end 217a of the pawl 217 and the saw-tooth indentations 636 provide an indexing function which provides for accurate alignment of the decimals indicia 634 in the window 616 (see also Figures 14a and 14b, which show corresponding features of the unmodified counter 201 ) and inhibits or prevents reverse rotation of the second count wheel 630. The ratchet wheel 250 has identical form to that ratchet wheel 250 of the unmodified counter 201 of Figures 12 to 21 save that a V-groove feature 256 has been added at the front for assembly alignment purposes.

Sequential operation of the modified actuation counter 601 is now described by reference to Figures 32a to 32g, and 33a to 33g. For succinctness only specifically referred-to parts of the Figures showing later aspects of the operation are labelled.

At Figures 32a and 33a, the modified actuation counter 601 is shown at rest with a count of 71 ' registering in the count window 616. The brake element 694 of the driver plate 690 is spaced from both count wheels 620, 630. This configuration corresponds to when the aerosol canister 5 is in its rest or return position in the drug dispenser device 1 , 101 (e.g. before initiating actuation of the device 1 by squeezing the levers 20a, 20b).

At Figures 32b and 33b, the drug dispenser device 1 , 101 has been actuated by squeezing the levers 20a, 20b towards one another. Thus, ratchet wheel 250 has been rotated in response to effective user actuation of the drug dispenser device 1 , 101 by squeezing the levers 20a, 20b together as previously described with reference to Figures 1 to 7 above. This results in the driver plate 690 starting to move on a linear downwards path and the drive slot 692 driving the ratchet wheel protrusion 254 to rotate the ratchet wheel 250 in a first rotary sense. This, in turn, results in rotation of the first count wheel 620 in the first rotary sense by the meshed interaction of drive tongues 252a, 252b with ratchet drive receipt teeth 624. The ratchet wheel 250 and first count wheel 620 are configured and arranged such that when indexed first count wheel 620 rotates by 36° in the direction of Arrow A such that a single indicium 622 thereon is advanced (i.e. as shown the 'units' count moves down one unit from indicia T to indicia O'). Since this is not a 'tens' counting down, the kick wheel 640 and second count wheel 630 do not move. It will be noted that the spacing of the brake element 694 from the count wheels 620, 630 has also been reduced.

At Figures 32c and 33c, the drug dispenser device 1 , 101 has been fully actuated and as a result the driver plate 690 moved fully along its linear downwards path. The drive slot 692 has transferred further drive to the drive-receiving protrusion 254 of the ratchet wheel 250, which causes the first count wheel 620 to rotate sufficiently in an anti-clockwise sense that the numerals indicia '0' registers in the viewing window 616 such that a count of 70' is registered thereat. Further, brake element 694 has been brought into blocking interaction with one of the saw-tooth indentations 629 of the first count wheel 620 (and also into blocking interaction with one of the saw-tooth indentations 636 of the second count wheel 630). The effect of this blocking interaction is that further rotation of the first count wheel 620 is prevented and thus, any overrun thereof (e.g. associated with a particularly extreme actuating movement) beyond the 70' count position is prevented. In more detail, the intent is that the lead face 629a of that one of the saw-tooth indentations 629 of the first count wheel 620 only physically abuts up against the brake element 694 to prevent count overrun by over-rotation of the first count wheel 620 in an extreme circumstance.

After effective user actuation of the drug dispenser device 1 , 101 and registration of the count, the levers 20a, 20b are released to return to their outward rest position and to allow the container collar 30 and driver plate 692 carried thereon to return to the rest position. This 'return' of the driver plate 690 to its start (i.e. non-downwardly displaced) position happens (as previously described in relation to the non-modified actuation counter 201 ) under the influence of the return biasing force of the valve spring of the valve canister 5. As a result, the ratchet wheel 250 reverses, to reset it in its starting position for the next counting event, through interaction of the drive slot 692 with the drive-receiving protrusion 254. Thus, as shown at Figures 32d and 33d, the driver plate 690 of the modified counter 601 has been returned to its start position with the brake element 694 of the driver plate 690 spaced from both count wheels 620, 630. The count of 70' still registers in the count window 616.

In a detail element, it may be appreciated that the inclusion of brake element 694 onto the driver plate 690 ensures that part (i.e. driver plate 690) that initiates the drive interaction for the actuation counting operation (i.e. by drive slot 692 acting on drive- receiving portion 254) also effectively finishes that action (i.e. by blocking action of the brake element 694). Thus, the drive stroke is by effectively controlled by the action of different fixed parts 692, 694 of a single driver feature 690, thereby minimizing the tolerance loop.

Each actuation of the drug dispenser device 1 , 101 resulting in only the first (units) count wheel indexing results in the counter operation as described above, whereby the braking element is positioned in a different indentation 629 of the first count wheel 620 (and also in an indentation 636 of the second count wheel) in the downward stroke of the driver plate 690 to prevent overrun of the first count wheel 620.

Where the pre-count operation visible count is xθ (e.g. 70 with 'x = 7', as shown at Figures 32d and 33d), the counting action resulting from the next use operation is subtly different. Thus, at Figures 32e and 33e, the drug dispenser device 1 , 101 has been actuated for a second time in the manner as described previously. Once again, driver plate 690 starts to move on a linear downwards path. As before, the drive slot 692 thereof transfers drive to the drive-receiving protrusion 254 of the ratchet wheel 250, which is rotated in response to effective user actuation of the drug dispenser device 1 , 101 causing rotation of the first count wheel 620 by 36° in the direction of Arrow A such that the 'unit' indicium 622 starts to move on from O' to '9'. This rotation of the first count wheel 620 however, also brings the pair of index teeth 628a, 628b into meshed relationship with the kick teeth 644 of kick wheel 640 such that the kick wheel 640 rotates and in turn, causes the second count wheel 630 to rotate through meshing of their respective teeth 634, 644. The wheels 620, 630, 640 are configured and arranged such that the resultant rotation in the direction of Arrow B of the second count wheel 630 is by 360/14° (that is to say by 360/n° wherein n is the number of number spacings, where in this case n = 14 because there are twelve decimals indicia 632; one shutter portion 680 and one coloured portion 682) such that a single indicium 632 thereon is advanced (i.e. the 'tens' count moves down exactly one unit). In this instance, the decimal indicium 632 moves starts to move down from '7' to '6', as shown in Figures 32e and 33e. The spacing of the brake element 694 from the count wheels 620, 630 has also been reduced.

At Figures 32f and 33f, the drug dispenser device 1 , 101 has been fully actuated and as a result the driver plate 690 moved fully along its linear downwards path. The drive slot 692 has transferred further drive to the drive-receiving protrusion 254 of the ratchet wheel 250, which has caused the first count wheel 620 to rotate sufficiently in an anti-clockwise (first) sense that the numerals indicia '9' registers in the viewing window. Further, the kick wheel 640 has acted on the second count wheel 630 to rotate that second count wheel sufficiently in an anti-clockwise (the first) sense that the decimals indicia '6' registers in the viewing window 616. Thus, overall a count of '69' is registered thereat. Further, brake element 694 has been brought into blocking interaction with one of the saw-tooth indentations 629 of the first count wheel 620 and also into blocking interaction with one of the saw-tooth indentations 636 of the second count wheel. The effect of this blocking interaction is that further rotation of both the first count wheel 620 and the second count wheel 630 is prevented and thus, any overrun thereof beyond the '69' count position is prevented. In more detail, the intent is that the lead faces 629a, 636a of that one of the saw-tooth indentations 629, 636 of the first 620 and/or second 630 count wheels only physically abut up against the brake element 694 to prevent count overrun by over-rotation of the first 620 and/or second 630 count wheels in an extreme circumstance. Alignment of the count wheels 620, 630 is by action of the resilient pawl 217 with the relevant indentation 636 of the second count wheel 630. The brake element 694 provides no such count wheel 620, 630 alignment function.

At Figures 32g and 33g, the driver plate 690 of the modified counter 601 has been returned to its start position with the brake element 694 of the driver plate 690 spaced from both count wheels 620, 630. This 'return' of the driver plate to its start (i.e. non-downwardly displaced) position happens, as previously described in relation to the non-modified actuation counter 201 , as a result of the return biasing force of the valve spring of the valve canister 5. The count of '69' still registers in the count window 616.

Each actuation of the drug dispenser device 1 , 101 resulting in both the first (units) and second (tens/decimals) count wheels indexing results in the counter operation as described above, whereby the braking element is positioned in a different indentation 629, 636 of the first and second count wheels 620, 630 in the downward stroke of the drive plate 690 to prevent overrun of the first and second count wheels 620, 630.

It will be understood that, as with the unmodified actuation counter 201 , the countdown sequence of the modified actuation counter 601 is as shown in Table 1 supra, although the start number for the countdown sequence of both the modified and unmodified counters 201 ; 601 (as shown in window 216; 616) can be varied by appropriate pre-setting of the position of the count wheels 220, 230; 620, 630. It will also be understood that the number of numerals on the second (tens/decimal) count wheel 230; 630 can be different to that shown in the respective so that the starting countdown number in the window 216; 616 is different. It will be further understood that, as with the unmodified actuation counter 201 , at the end of the countdown sequence with the modified actuation counter 601 no drive is transmissible from the kick-wheel 640 to the second count wheel 630 as a result of the missing teeth at the stop position 638, so that, while the first count wheel 620 can continue to be indexed on continued user actuation of the drug dispenser device 1 , 101 (for access to surplus doses therein), the shutter 680 still shutters the window 616 so that the units indicium is not visible .

One particular advantage of the 'count overrun' preventing action of the brake element 694 is that effective counting with no overrun can be assured even where particularly high dispenser device 1 , 101 actuating forces and speeds are employed. Thus, the modified counter 601 may be used with dispenser devices 1 , 101 designed for use with a broad range of actuating and valve forces (e.g. more robust forces than usual) and accommodate a broad range of actuating speeds (e.g. relating to different user actuation behaviours and/or profiles).

The modified counter 601 may itself be revised as described in International (PCT) Patent Application No. PCT/EP2009/051876, filed 17 February 2009, which designates the United States of America and is hereby incorporated herein by reference.

Figures 22 to 27c show different aspects of key parts of an alternative internal mechanism for use with the drug dispenser device 1 and canister 5 as hereinbefore described. This alternative mechanism may be appreciated to be a slight variation of that previously described, mainly in relation to Figure 5.

Details of the container collar 330 of the alternative internal mechanism are shown at Figures 22 and 23. Details of the extension collar 340 of the alternative internal mechanism are shown at Figures 24 and 25. Assembly steps relating to the alternative internal mechanism are illustrated at Figures 26a to 26c, and key operational aspects at Figures 27a to 27c.

As before, the container collar 330 permanently engages via split-ring collar 333 with the neck 305a of the canister 305 such that the so-engaged parts are moveable together (i.e. in unison) relative to the housing in a direction defined by the longitudinal axis L-L of the canister 305 (i.e. generally up and down when the device 1 is upright). The split-ring collar 333 permanently engages the container collar 330 to the canister 305 as will be understood from US patent application Nos. 10/1 10,61 1 (WO-A-01/28887) and US-A-2006/0082039.

Again, as before the container collar 330 connects via closed coil extension springs 350a (only one visible in Figure 26c) and respective spring connection points 331 a, 331 b and 341 a, 341 b to extension collar 340, which is provided at its lower end with an outer ramp 344, and also with an inner ramp 343. This multi-collar arrangement is such that the extension collar 340 is moveable with respect to the container collar 330 along the longitudinal axis L-L of the drug discharge device.

The extension collar 340 includes an actuating portion in the form of shelf 342, which is arranged for interaction with the lower ends 21 a, 21 b of the opposing levers 20a, 20b such that when the levers 20a, 20b of the device 1 are squeezed together (i.e. inwards relative to the housing) the shelf 342, and hence extension collar 340, are pushed downwards. The container collar 330 is further provided with flexible support legs 334a, 334b, 334c which as before, act to provide a pre-load mechanism to prevent transfer of that biasing energy to the container collar 330 to move the canister 5 downwards along the longitudinal axis L-L to actuate the valve 5 thereof (and hence, to fire the aerosolized drug dose) until a pre-determined threshold force is overcome. Again, as before, each flexible support leg 334a, 334b, 334c is arranged for interaction with a respective step 18a, 18b on the housing. However, in this variation each flexible support leg 334a, 334b, 334c is provided with a protruding inner foot 335a, 335b, 335c and protruding outer foot 336a, 336b (only two visible) the purpose of which will become clearer from the later description.

Assembly steps relating to those key parts of the alternative internal mechanism are illustrated at Figures 26a to 26c. The split-ring collar 333, which generally comprises a plastic polymer material, is used to permanently fix the container collar 330 to the neck 305a of the canister 305 by ultrasonic welding, as generally described in US patent application Nos. 10/110,611 (WO-A-01/28887) and US-A-2006/0082039.

The welding process may use two sonotrodes (ultrasonic welding heads) each with three small conical projections to focus the weld energy. During the welding process the conical projections are plunged into the outer surface of the container collar 330 allowing the ultrasonic energy to create a pool of molten material to form the bond (welds) between inside surface of the container collar 330 and the outer surface of the split-ring collar 333, which is wedged between the neck 305a of the container 305 and the inside surface of the container collar 330. In a subtle variation of that ultrasonic welding process, the inner surface of the container collar 330 is provided with plural (e.g. two sets of three) spaced longitudinal ribs (not visible). During this variation of the welding process one or more plural pronged (e.g. three pronged) ultrasonic welding heads (not shown) are arranged about the container collar 330 with their prongs aligned one to each rib (which abut with the split-ring collar 333 which is wedged between the container neck 305a and the ribs) and ultrasonic energy applied to form welds between the inside surface of the container collar 330 and the outside surface of the split-ring collar 333 using the rib material.

This alternative welding process, which is known as an 'energy director' method avoids any 'splash back' of particulate weld material which may otherwise occur where some of the molten material may be displaced onto the outside surface of the container collar 330 to form a 'splash' thereon which can subsequently detach. Such 'splash back' is disadvantageous because any particulates resulting therefrom may potentially lodge within the dispenser and possibly be inhaled by the user. As the alternative process focuses the weld energy at the internal ribs, the sonotrode(s) no longer has the conical projections and, as the ribs are sandwiched between the container collar 330 and the split-ring collar 333, most if not all extraneous molten material will be encapsulated and therefore unable (or less able) to become detached.

As shown at Figure 26a, in a first step of the assembly process, the canister 305 with split-ring collar 333 located about its neck 305a is aligned above the container collar 330 and extension collar 340. In a next step, as shown at Figure 26b, the canister 305 with split-ring collar 333 is inserted into the container collar 330, the split-ring collar 333 is adjusted to be wedged between the neck 305a and the inside surface of the container collar 330 and then the container collar 330 and the split-ring collar 333 are permanently joined by one of the afore-described welding processes to thereby permanently fix the container collar 330 to the canister 305. The so-engaged parts 305, 330, 333 are moveable together (i.e. in unison) relative to the housing in a direction defined by the longitudinal axis L-L of the canister 305 (i.e. generally up and down when the device 1 is upright).

The canister 305 and container collar 330 assembly is then inserted into the extension collar 340. The container collar 330 is connected via closed coil extension springs 350a (only one visible) and respective spring connection points 331a, 331 b and 341 a, 341 b to the extension collar 340, as shown at Figure 26c. When so- connected, the extension collar 340 is moveable with respect to the container collar 330 along the longitudinal axis L-L of the drug discharge device.

It will be appreciated that the overall form of the alternative internal mechanism is very similar to that previously described in relation to Figure 5 other than that the shaping of the flexible support legs 334a, 334b, 334c differs slightly from those legs 34a, 34b of the internal mechanism of Figure 5, and that correspondingly the ramp 44 thereof is replaced in the alternative internal mechanism by both an inner 343 and outer 344 ramp. The operational effect of these slight variations is described in greater detail below in relation to Figures 27a to 27c. Other than these slight variations, the general principles of operation of the device 1 with the alternative internal mechanism of Figures 22 to 27c correspond to those previously described with reference to Figures 3a to 4c.

Thus, in general operational terms, referring now also to Figures 27a to 27c, the opposing levers 20a, 20b of the device 1 are moveable transversely with respect to the longitudinal axis L-L of the drug discharge device to apply a force to the shelf 342 of the extension collar 340 to move the extension collar 340 downwards along that longitudinal axis (i.e. towards stem block 8 and mouthpiece 14 of the device 1 ).

The closed coil extension springs 350a that connect the container collar 330 via connector points 331a, 331 b with the extension collar 340 act as a biasing mechanism to store biasing energy on moving the extension collar 340 downwards along the longitudinal axis L-L in response to squeezing of the levers 20a, 20b. In embodiments, an initial biasing tension - inherent in the closed coil form thereof - is present in the closed coil extension springs 350a even when in their 'at rest' state.

The flexible support legs 334a, 334b, 334c act to provide a pre-load mechanism to prevent transfer of that biasing energy to the container collar 330 to move the canister 305 downwards along the longitudinal axis L-L to actuate the valve thereof (and hence to fire the aerosolized drug dose) until a pre-determined threshold force is overcome.

Figures 27a to 27c illustrate details of the relationship between a flexible support leg 334a of container collar 330 and an inner 343 and outer ramp 344 of the extension collar 340 during operation of the device 1. Figure 27a shows details of this relationship when the device 1 is in the 'at rest' position (i.e. corresponding to previous Figure 3a). That is to say, with no downward force applied by the levers 20a, 20b to the shelf 342 of the extension collar 340. The flexible support leg 334a of the container collar 330 protrudes down between the inner 343 and outer 344 ramps of the extension collar 340, and interacts at its bottom end with a respective step 18a, 18b on the housing.

Figure 27b shows details of this relationship when the device 1 is in a 'tipping point' configuration (i.e. roughly corresponding to previous Figure 4c). In this position, significant downward force has been applied by the levers 20a, 20b of the device 1 to the shelf 342 of the extension collar 340. The outer ramp 344 of the extension collar 340 has been brought down on the protruding outer foot 336a of the flexible leg support 334a, thereby causing the flexible leg support 334a to flex inwards and to be displaced interiorly to the outer ramp 344. In consequence, noting that this interaction happens concurrently with the other pairs of outer ramps 344 and outer feet 336b, 336c, the container collar 330 may now move freely downwards and, indeed, will do so as a result of its experience of biasing energy stored in the extension springs 350a. The container collar 330 and canister 305 in permanent engagement therewith move rapidly downwards propelled by the stored biasing energy of the springs 350a. The valve 306 of the canister 305 is thereby activated to release aerosolized drug for inhalation by the patient.

As before, it will be appreciated that once the threshold force has been overcome (i.e. just past the 'tipping point' of the device 1 ) a uniform actuating force resulting from the energy stored in the springs 350a is experienced by the container collar 330 and canister 305 regardless of how much extra force is applied by the patient to the levers 20a, 20b. A consistent actuation of the valve of the canister 305 is thereby, enabled.

Following actuation, the coiled coil extension springs 350a return to their 'at rest' state (i.e. with no externally-applied biasing energy, but only any initial biasing tension inherent in the closed coil form of the extension springs 350a present). As will be appreciated by the skilled reader in the art, the return spring (not shown) of the valve 306 of the valved canister 305 provides energy to move the canister 305, container collar 330, extension collar 340 and levers 20a, 20b back to the 'at rest' position. As shown at Figure 27c, during this return operation the inner protruding foot 335a of the flexible leg 334a interacts with the inner ramp 343 of the extension collar 340, the effect of this interaction being to push the flexible leg 334a outwards to the 'at rest' state of Figure 27a, in which the flexible leg 334a is un-flexed.

In Figure 42 there is shown a further embodiment of the present invention which is drug dispenser device 901 in the form of a hand-held, hand-operable breath- coordinated metered dose inhaler (MDI) which incorporates a mouthpiece cover 916 corresponding closely to that of Figures 38 to 40. Accordingly, like reference numerals are used to designate like features between the two mouthpiece covers 716, 916 and other features in common with the previously described devices 1 ; 101 , to which the reader is directed.

The mouthpiece cover 916 thus has the same function as the other mouthpiece cover 716, namely to close and cover a mouthpiece 914, and also to provide a lockout function to prevent actuating movement of an aerosol canister 5 movably mounted in a housing, of which the lower housing part 912 is shown.

However, unlike the drug dispenser device 1 , 101 , there is no collar arrangement 30, 40, 50a, b mounted to the aerosol canister 5. Rather, the canister 5 forms part of a canister unit with an actuation counter 991 , which is permanently fixed to the valve end of the canister 5 as described in US patent application Nos. 10/110,611 (WO-A- 01/28887) and US-A-2006/0082039 supra. The counter 991 is described in detail in U.S. Patent No. 7500444 with reference to the Figures thereof, which U.S. Patent is hereby incorporated herein by reference, and a component part of MDIs marketed by the GlaxoSmithKline group of companies under inter alia the names ADVAIR® HFA, SERETIDE® HFA and VENTOLIN® HFA.

When the canister unit is depressed downwardly (as indicated by the arrow in Figure 42) sufficiently far, the valve (not shown, but see previously) is caused to open to release a metered dose through the mouthpiece 914. Moreover, the counter 991 mechanically registers the release and causes a display (not shown, but see U.S. Patent No. 7500444 supra) to advance, typically to decrement.

However, as will be understood from Figure 42, such downward depression of the canister unit is not possible when the mouthpiece cover 916 covers the mouthpiece 914 through the blocking action of interference elements 917a located underneath the canister unit, more specifically underneath the actuation counter 991. In this regard, the shape of the interference elements 917a differs somewhat from that of the previously described mouthpiece cover 716, but this is simply so that the interference elements 917a are correctly positioned with reference to the actuation counter 991 to provide the lock-out function.

So, as before, only once the mouthpiece cover 916 has been moved to the open position is the user able to operate the drug dispenser device 901 to depress the canister unit. In this regard, the canister unit may be by depressed by any means known in the art, including simple manual application of the actuating force (e.g. by a finger or thumb) directly to the canister base.

In this embodiment, the closure and connector parts 916a, 916b may again be formed respectively from ABS and polypropylene (PP).

Where not stated, the components of the drug dispenser devices herein may be made from conventional engineering materials, especially conventional engineering plastics materials, more especially those which allow moulding of the component. Where plastics materials have been stated for manufacture of a component, such component would typically be formed by injection moulding.

The illustrated drug dispenser devices and mouthpiece covers in accordance with the present invention have the advantage of providing a lock-out which prevents inadvertent firing of the device, but which is also configured and arranged such that the user is intuitively prompted to open the mouthpiece cover to a position which results in unlocking the lock-out when the user prepares for actuating or firing the device.

Each of the above-described embodiments may be modified to incorporate one or more features disclosed in the U.S. Provisional, and/or US (PCT) and/or International Patent Applications incorporated herein by reference in the second to fourth paragraphs hereof.

It will be appreciated that the mouthpiece 14; 914 in the exemplary embodiments could be configured instead as a nasal nozzle for insertion in a nostril of a human being, so that the drug formulation is deliverable to the nasal cavity of the human being. The drug dispenser device herein is suitable for dispensing of a drug formulation to a patient. The drug formulation may take any suitable form and include other suitable ingredients such as diluents, solvents, carriers and propellants.

Administration of drug may be indicated for the treatment of mild, moderate or severe acute or chronic symptoms or for prophylactic treatment. It will be appreciated that the precise dose administered will depend on the age and condition of the patient, the particular drug used and the frequency of administration and will ultimately be at the discretion of the attendant physician. Embodiments are envisaged in which combinations of drugs are employed.

Appropriate drugs may thus be selected from, for example, analgesics, e.g., codeine, dihydromorphine, ergotamine, fentanyl or morphine; anginal preparations, e.g., diltiazem; antiallergics, e.g., cromoglycate (e.g. as the sodium salt), ketotifen or nedocromil (e.g. as the sodium salt); antiinfectives e.g., cephalosporins, penicillins, streptomycin, sulphonamides, tetracyclines and pentamidine; antihistamines, e.g., methapyrilene; anti- inflammatories, e.g., beclomethasone (e.g. as the dipropionate ester), fluticasone (e.g. as the propionate or furoate ester), flunisolide, budesonide, rofleponide, mometasone e.g. as the furoate ester), ciclesonide, triamcinolone (e.g. as the acetonide) or 6α, 9α-difluoro-11 β-hydroxy-16α-methyl-3-oxo-17α- propionyloxy-androsta-1 ,4-diene-17β-carbothioic acid S-(2-oxo-tetrahydro-furan-3-yl) ester; antitussives, e.g., noscapine; bronchodilators, e.g., albuterol (e.g. as free base or sulphate), salmeterol (e.g. as xinafoate), ephedrine, adrenaline, fenoterol (e.g. as hydrobromide), salmefamol, carbuterol, mabuterol, etanterol, naminterol, clenbuterol, flerbuterol, bambuterol, indacaterol, formoterol (e.g. as fumarate), isoprenaline, metaproterenol, phenylephrine, phenylpropanolamine, pirbuterol (e.g. as acetate), reproterol (e.g. as hydrochloride), rimiterol, terbutaline (e.g. as sulphate), isoetharine, tulobuterol or 4-hydroxy-7-[2-[[2-[[3-(2-phenylethoxy)propyl]sulfonyl]ethyl]amino]ethyl- 2(3H)-benzothiazolone; adenosine 2a agonists, e.g. 2R,3R,4S,5R)-2-[6-Amino-2- (1 S-hydroxymethyl-2-phenyl-ethylamino)-purin-9-yl]-5-(2-ethyl-2H-tetrazol-5-yl)- tetrahydro-furan-3,4-diol (e.g. as maleate); α₄ integrin inhibitors e.g. (2S)-3-[4-({[4- (aminocarbonyl)-1-piperidinyl]carbonyl}oxy)phenyl]-2-[((2S)-4-methyl-2-{[2-(2- methylphenoxy) acetyl]amino}pentanoyl)amino] propanoic acid (e.g. as free acid or potassium salt), diuretics, e.g., amiloride; anticholinergics, e.g., ipratropium (e.g. as bromide), tiotropium, atropine or oxitropium; hormones, e.g., cortisone, hydrocortisone or prednisolone; xanthines, e.g., aminophylline, choline theophyllinate, lysine theophyllinate or theophylline; therapeutic proteins and peptides, e.g., insulin or glucagon; vaccines, diagnostics, and gene therapies. It will be clear to a person skilled in the art that, where appropriate, the drugs may be used 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) to optimise the activity and/or stability of the drug.

The drug formulation may in embodiments, be a mono-therapy (i.e. single active drug containing) product or it may be a combination therapy (i.e. plural active drugs containing) product.

Suitable drugs or drug components of a combination therapy product are typically selected from the group consisting of anti-inflammatory agents (for example a corticosteroid or an NSAID), anticholinergic agents (for example, an M₁, M₂, M₁ZM₂ or M₃ receptor antagonist), other β₂-adrenoreceptor agonists, antiinfective agents (e.g. an antibiotic or an antiviral), and antihistamines. All suitable combinations are envisaged.

Suitable anti-inflammatory agents include corticosteroids and NSAIDs. Suitable corticosteroids which may be used in combination with the compounds of the invention are those oral and inhaled corticosteroids and their pro-drugs which have anti-inflammatory activity. Examples include methyl prednisolone, prednisolone, dexamethasone, fluticasone propionate, 6α,9α-difluoro-17α-[(2-furanylcarbonyl)oxy]- 11 β-hydroxy-16α-methyl-3-oxo-androsta-1 ,4-diene-17β-carbothioic acid S- fluoromethyl ester (fluticasone furoate), 6α,9α-difluoro-1 1β-hydroxy-16α-methyl-3- oxo-17α-propionyloxy- androsta-1 ,4-diene-17β-carbothioic acid S-(2-oxo-tetrahydro- furan-3S-yl) ester, beclomethasone esters (e.g. the 17-propionate ester or the 17,21- dipropionate ester), budesonide, flunisolide, mometasone esters (e.g. the furoate ester), triamcinolone acetonide, rofleponide, ciclesonide, butixocort propionate, RPR- 106541 , and ST-126. Preferred corticosteroids include fluticasone propionate, 6α,9α-difluoro-11 β-hydroxy-16α-methyl-17α-[(4-methyl-1 ,3-thiazole-5-carbonyl)oxy]- 3-oxo-androsta-1 ,4-diene-17β-carbothioic acid S-fluoromethyl ester, 6α,9α-difluoro- 17α-[(2-furanylcarbonyl)oxy]-1 1 β-hydroxy-16α-methyl-3-oxo-androsta-1 ,4-diene-17β- carbothioic acid S-fluoromethyl ester (fluticasone furoate), 6α,9α-difluoro-1 1 β- hydroxy-16α-methyl-3-oxo-17α-(2,2,3,3-tetramethycyclopropylcarbonyl)oxy-androsta- 1 ,4-diene-17β-carbothioic acid S-cyanomethyl ester, 6α,9α-difluoro-11 β-hydroxy- 16α-methyl-17α-(1 -methycyclopropylcarbony^oxy-S-oxo-androsta-i ,4-diene-17β- carbothioic acid S-fluoromethyl ester and 9α, 21 dichloro-1 1 β, 17α methyl-1 ,4 pregnadiene 3, 20 dione-17-[2'] furoate (mometasone furoate).

Further corticosteroids are described in WO02/088167, WO02/100879, WO02/12265, WO02/12266, WO05/005451 , WO05/005452, WO06/072599 and WO06/072600.

Non-steroidal compounds having glucocorticoid agonism that may possess selectivity for transrepression over transactivation and that may be useful are disclosed WO03/082827, WO98/54159, WO04/005229, WO04/009017, WO04/018429, WO03/104195, WO03/082787, WO03/082280, WO03/059899, WO03/101932, WO02/02565, WO01/16128, WO00/66590, WO03/086294, WO04/026248, WO03/061651 , WO03/08277, WO06/000401 , WO06/000398 and WO06/015870.

Suitable NSAIDs include sodium cromoglycate, nedocromil sodium, phosphodiesterase (PDE) inhibitors (e.g. theophylline, PDE4 inhibitors or mixed PDE3/PDE4 inhibitors), leukotriene antagonists, inhibitors of leukotriene synthesis, iNOS inhibitors, tryptase and elastase inhibitors, beta-2 integrin antagonists and adenosine receptor agonists or antagonists (e.g. adenosine 2a agonists), cytokine antagonists (e.g. chemokine antagonists), inhibitors of cytokine synthesis or 5- lipoxygenase inhibitors. Examples of iNOS inhibitors include those disclosed in WO93/13055, WO98/30537, WO02/50021 , WO95/34534 and WO99/62875. Examples of CCR3 inhibitors include those disclosed in WO02/26722.

Suitable bronchodilators are β₂-adrenoreceptor agonists, including salmeterol (which may be a racemate or a single enantiomer, such as the R-enantiomer), for instance salmeterol xinafoate, salbutamol (which may be a racemate or a single enantiomer, such as the R-enantiomer), for instance salbutamol sulphate or as the free base, formoterol (which may be a racemate or a single diastereomer, such as the R, R- diastereomer), for instance formoterol fumarate or terbutaline and salts thereof. Other suitable β₂-adrenoreceptor agonists are 3-(4-{[6-({(2R)-2-hydroxy-2-[4-hydroxy- 3-(hydroxymethyl)phenyl]ethyl}amino)hexyl] oxy} butyl) benzenesulfonamide, 3-(3- {[7-({(2R)-2-hydroxy-2-[4-hydroxy-3-hydroxymethyl) phenyl] ethyl}-amino) heptyl] oxy} propyl) benzenesulfonamide, 4-{(1 R)-2-[(6-{2-[(2, 6-dichlorobenzyl) oxy] ethoxy} hexyl) amino]-1-hydroxyethyl}-2-(hydroxymethyl) phenol, 4-{(1 f?)-2-[(6-{4-[3- (cyclopentylsulfonyl)phenyl]butoxy}hexyl)amino]-1-hydroxyethyl}-2-(hydroxymethyl) phenol, N-[2-hydroxyl-5-[(1 R)-1-hydroxy-2-[[2-4-[[(2R)-2-hydroxy-2- phenylethyl]amino]phenyl]ethyl]amino]ethyl]phenyl]formamide, and N-2{2-[4-(3- phenyl-4-methoxyphenyl)aminophenyl]ethyl}-2-hydroxy-2-(8-hydroxy-2(1 H)- quinolinon-5-yl)ethylamine, and 5-[(/?)-2-(2-{4-[4-(2-amino-2-methyl-propoxy)- phenylamino]-phenyl}-ethylamino)-1-hydroxy-ethyl]-8-hydroxy-1 H-quinolin-2-one. Preferably, the β₂-adrenoreceptor agonist is a long acting β₂-adrenoreceptor agonist (LABA), for example a compound which provides effective bronchodilation for about 12 hours or longer.

Other β₂-adrenoreceptor agonists include those described in WO 02/066422, WO

02/070490, WO 02/076933, WO 03/024439, WO 03/072539, WO 03/091204, WO 04/016578, WO 2004/022547, WO 2004/037807, WO 2004/037773, WO 2004/037768, WO 2004/039762, WO 2004/039766, WO01/42193 and WO03/042160.

Preferred phosphodiesterase 4 (PDE4) inhibitors are cis 4-cyano-4-(3- cyclopentyloxy-4-methoxyphenyl)cyclohexan-1-carboxylic acid, 2-carbomethoxy-4- cyano-4-(3-cyclopropylmethoxy-4-difluoromethoxyphenyl)cyclohexan-1-one and cis- [4-cyano-4-(3-cyclopropylmethoxy-4-difluoromethoxyphenyl)cyclohexan-1-ol].

Other suitable drug compounds include: c/s-4-cyano-4-[3-(cyclopentyloxy)-4- methoxyphenyl]cyclohexane-1-carboxylic acid (also known as cilomalast) disclosed in U.S. patent 5,552,438 and its salts, esters, pro-drugs or physical forms; AWD-12- 281 from elbion (Hofgen, N. et al. 15th EFMC lnt Symp Med Chem (Sept 6-10, Edinburgh) 1998, Abst P.98; CAS reference No. 247584020-9); a 9-benzyladenine derivative nominated NCS-613 (INSERM); D-4418 from Chiroscience and Schering- Plough; a benzodiazepine PDE4 inhibitor identified as CI-1018 (PD- 168787) and attributed to Pfizer; a benzodioxole derivative disclosed by Kyowa Hakko in WO99/16766; K-34 from Kyowa Hakko; V-1 1294A from Napp (Landells, LJ. et al. Eur Resp J [Annu Cong Eur Resp Soc (Sept 19-23, Geneva) 1998] 1998, 12 (Suppl. 28): Abst P2393); roflumilast (CAS reference No 162401-32-3) and a pthalazinone (WO99/47505, the disclosure of which is hereby incorporated by reference) from Byk-Gulden; Pumafentrine, (-)-p-[(4aR^*, 10bS^*)-9-ethoxy-1 , 2, 3,4,4a, 10b-hexahydro- 8-methoxy-2-methylbenzo[c][1 ,6]naphthyridin-6-yl]-N,N-diisopropylbenzamide which is a mixed PDE3/PDE4 inhibitor which has been prepared and published on by Byk- Gulden, now Altana; arofylline under development by Almirall-Prodesfarma; VM554/UM565 from Vernalis; or T-440 (Tanabe Seiyaku; Fuji, K. et al. J Pharmacol Exp Ther,1998, 284(1 ): 162), and T2585.

Further compounds are disclosed in WO04/024728, WO04/056823 and WO04/103998, all of Glaxo Group Limited.

Suitable anticholinergic agents are those compounds that act as antagonists at the muscarinic receptor, in particular those compounds, which are antagonists of the M₁ or M₃ receptors, dual antagonists of the M₁ZM₃ or M₂/M₃, receptors or pan-antagonists of the M-ι/M₂/M₃ receptors. Exemplary compounds include the alkaloids of the belladonna plants as illustrated by the likes of atropine, scopolamine, homatropine, hyoscyamine; these compounds are normally administered as a salt, being tertiary amines.

Other suitable anti-cholinergics are muscarinic antagonists, such as (3-enc/o)-3-(2,2- di-2-thienylethenyl)-8,8-dimethyl-8-azoniabicyclo[3.2.1] octane iodide, (3-enc/o)-3-(2- cyano^^-diphenylethyO-δ.δ-dimethyl-δ-azoniabicycIo [3.2.1] octane bromide, 4- [hydroxy(diphenyl)methyl]-1-{2-[(phenylmethyl)oxy]ethyl}-1-azonia bicyclo[2.2.2] octane bromide, (1 R,5S)-3-(2-cyano-2,2-diphenylethyl)-8-methyl-8-{2-

[(phenylmethyl)oxy]ethyl}-8-azoniabicyclo[3.2.1] octane bromide, (enc/o)-3-(2- methoxy^^-di-thiophen^-yl-ethyO-δ.δ-dimethyl-δ-azonia-bicyclo^^.iloctane iodide, (enc/o)-3-(2-cyano-2,2-diphenyl-ethyl)-8,δ-dimethyl-δ-azonia-bicyclo

[3.2.1]octane iodide, (enc/o)-3-(2-carbamoyl-2,2-diphenyl-ethyl)-8,8-dimethyl-8- azonia-bicyclo[3.2.1]octane iodide, (enc/o)-3-(2-cyano-2,2-di-thiophen-2-yl-ethyl)-8,8- dimethyl-8-azonia-bicyclo[3.2.1]octane iodide, and (enc/o )-3-{2,2-diphenyl-3-[(1- phenyl-methanoyl)-amino]-propyl}-8,8-dimethyl-8-azonia-bicyclo[3.2.1] octane bromide.

Particularly suitable anticholinergics include ipratropium (e.g. as the bromide), sold under the name Atrovent, oxitropium (e.g. as the bromide) and tiotropium (e.g. as the bromide) (CAS- 139404-48-1 ). Also of interest are: methantheline (CAS-53-46-3), propantheline bromide (CAS- 50-34-9), anisotropine methyl bromide or Valpin 50 (CAS- 80-50-2), clidinium bromide (Quarzan, CAS-3485-62-9), copyrrolate (Robinul), isopropamide iodide (CAS-71-81-8), mepenzolate bromide (U.S. patent 2,918,408), tridihexethyl chloride (Pathilone, CAS-4310-35-4), and hexocyclium methylsulfate (Tral, CAS-1 15-63-9). See also cyclopentolate hydrochloride (CAS-5870-29-1 ), tropicamide (CAS-1508-75-4), trihexyphenidyl hydrochloride (CAS- 144- 11-6), pirenzepine (CAS-29868-97-1 ), telenzepine (CAS-80880-90-9), AF-DX 1 16, or methoctramine, and the compounds disclosed in WO01/041 18. Also of interest are revatropate (for example, as the hydrobromide, CAS 262586-79-8) and LAS-34273 which is disclosed in WO01/041 18, darifenacin (CAS 133099-04-4, or CAS 133099- 07-7 for the hydrobromide sold under the name Enablex), oxybutynin (CAS 5633-20- 5, sold under the name Ditropan), terodiline (CAS 15793-40-5), tolterodine (CAS 124937-51-5, or CAS 124937-52-6 for the tartrate, sold under the name Detrol), otilonium (for example, as the bromide, CAS 26095-59-0, sold under the name Spasmomen), trospium chloride (CAS 10405-02-4) and solifenacin (CAS 242478-37- 1 , or CAS 242478-38-2 for the succinate also known as YM-905 and sold under the name Vesicare).

Other anticholinergic agents include compounds disclosed in USSN 60/487,981 and USSN 60/51 1 ,009.

Suitable antihistamines (also referred to as H-i-receptor antagonists) include any one or more of the numerous antagonists known which inhibit Hi-receptors, and are safe for human use. All are reversible, competitive inhibitors of the interaction of histamine with Hi-receptors. Examples include ethanolamines, ethylenediamines, and alkylamines. In addition, other first generation antihistamines include those which can be characterized as based on piperizine and phenothiazines. Second generation antagonists, which are non-sedating, have a similar structure-activity relationship in that they retain the core ethylene group (the alkylamines) or mimic the tertiary amine group with piperizine or piperidine.

Examples of H1 antagonists include, without limitation, amelexanox, astemizole, azatadine, azelastine, acrivastine, brompheniramine, cetirizine, levocetirizine, efletirizine, chlorpheniramine, clemastine, cyclizine, carebastine, cyproheptadine, carbinoxamine, descarboethoxyloratadine, doxylamine, dimethindene, ebastine, epinastine, efletirizine, fexofenadine, hydroxyzine, ketotifen, loratadine, levocabastine, mizolastine, mequitazine, mianserin, noberastine, meclizine, norastemizole, olopatadine, picumast, pyrilamine, promethazine, terfenadine, tripelennamine, temelastine, trimeprazine and triprolidine, particularly cetirizine, levocetirizine, efletirizine and fexofenadine.

Exemplary H1 antagonists are as follows: Ethanolamines: carbinoxamine maleate, clemastine fumarate, diphenylhydramine hydrochloride, and dimenhydrinate.

Ethylenediamines: pyrilamine amleate, tripelennamine HCI, and tripelennamine citrate.

Alkylamines: chlropheniramine and its salts such as the maleate salt, and acrivastine.

Piperazines: hydroxyzine HCI, hydroxyzine pamoate, cyclizine HCI, cyclizine lactate, meclizine HCI, and cetirizine HCI.

Piperidines: Astemizole, levocabastine HCI, loratadine or its descarboethoxy analogue, and terfenadine and fexofenadine hydrochloride or another pharmaceutically acceptable salt.

Azelastine hydrochloride is yet another H₁ receptor antagonist which may be used in combination with a PDE4 inhibitor.

The drug, or one of the drugs, may be an H3 antagonist (and/or inverse agonist). Examples of H3 antagonists include, for example, those compounds disclosed in WO2004/035556 and in WO2006/045416.

Other histamine receptor antagonists which may be used include antagonists (and/or inverse agonists) of the H4 receptor, for example, the compounds disclosed in Jablonowski et al., J. Med. Chem. 46:3957-3960 (2003).

Suitably, the drug formulation includes one or more of a β₂-adrenoreceptor agonist, a corticosteroid, a PDE-4 inhibitor and an anti-cholinergic.

Generally, powdered drug particles suitable for delivery to the bronchial or alveolar region of the lung have an aerodynamic diameter of less than 10 micrometers, preferably from 1-6 micrometers. Other sized particles may be used if delivery to other portions of the respiratory tract is desired, such as the nasal cavity, mouth or throat.

The amount of any particular drug or a pharmaceutically acceptable salt, solvate or physiologically functional derivative thereof which is required to achieve a therapeutic effect will, of course, vary with the particular compound, the route of administration, the subject under treatment, and the particular disorder or disease being treated. The drugs for treatment of respiratory disorders herein may for example, be administered by inhalation at a dose of from 0.0005mg to 10 mg, preferably 0.005mg to 0.5mg. The dose range for adult humans is generally from 0.0005 mg to 100mg per day and preferably 0.01 mg to 1.5mg per day.

In one embodiment, the drug is formulated as any suitable aerosol formulation, optionally containing other pharmaceutically acceptable additive components. In embodiments, the aerosol formulation comprises a suspension of a drug in a propellant. In embodiments, the propellant is a fluorocarbon or hydrogen-containing chlorofluorocarbon propellant.

Suitable propellants include, for example, C-|_4hydrogen-containing chlorofluorocarbons such as CH₂CIF, CCIF₂CHCIF, CF₃CHCIF, CHF₂CCIF₂, CHCIFCHF₂, CF₃CH₂CI and CCIF₂CH₃; C-| ^hydrogen-containing fluorocarbons such as CHF₂CHF₂, CF₃CH₂F, CHF₂CH₃ and CF₃CHFCF₃; and perfluorocarbons such as CF₃CF₃ and CF₃CF₂CF₃.

Where mixtures of the fluorocarbons or hydrogen-containing chlorofluorocarbons are employed they may be mixtures of the above-identified compounds or mixtures, preferably binary mixtures, with other fluorocarbons or hydrogen-containing chlorofluorocarbons for example CHCIF₂, CH₂F₂ and CF₃CH₃. Preferably a single fluorocarbon or hydrogen-containing chlorofluorocarbon is employed as the propellant. Particularly preferred as propellants are C-_| ^hydrogen-containing fluorocarbons such as 1 ,1 ,1 ,2- tetrafluoroethane (CF₃CH₂F) and 1 ,1 ,1 ,2,3,3,3- heptafluoro-n-propane (CF₃CHFCF₃) or mixtures thereof.

The drug formulations are preferably substantially free of chlorofluorocarbons such as CCI₃F, CCI₂F₂ and CF₃CCI₃. Preferably, the propellant is liquefied HFA134a or

HFA-227 or mixtures thereof.

The propellant may additionally contain a volatile adjuvant such as a saturated hydrocarbon for example propane, n-butane, liquefied, pentane and isopentane or a dialkyl ether for example dimethyl ether. In general, up to 50% w/w of the propellant may comprise a volatile hydrocarbon, for example 1 to 30% w/w. However, formulations, which are free or substantially free of volatile adjuvants are preferred. In certain cases, it may be desirable to include appropriate amounts of water, which can be advantageous in modifying the dielectric properties of the propellant.

A polar co-solvent such as C2-6 aliphatic alcohols and polyols e.g. ethanol, isopropanol and propylene glycol, preferably ethanol, may be included in the drug formulation in the desired amount to improve the dispersion of the formulation, either as the only excipient or in addition to other excipients such as surfactants. In embodiments, the drug formulation may contain 0.01 to 5% w/w based on the propellant of a polar co-solvent e.g. ethanol, preferably 0.1 to 5% w/w e.g. about 0.1 to 1% w/w. In embodiments herein, the solvent is added in sufficient quantities to solubilise part or all of the drug component, such formulations being commonly referred to as 'solution' aerosol drug formulations.

A surfactant may also be employed in the aerosol formulation. Examples of conventional surfactants are disclosed in EP-A-372,777. The amount of surfactant employed is desirable in the range 0.0001% to 50% weight to weight ratio relative to the drug, in particular, 0.05 to 10% weight to weight ratio.

The aerosol drug formulation desirably contains 0.005-10% w/w, preferably 0.005 to 5% w/w, especially 0.01 to 2% w/w, of drug relative to the total weight of the formulation.

In another embodiment, the drug is formulated as any suitable fluid formulation, particularly a solution (e.g. aqueous) formulation or a suspension formulation, optionally containing other pharmaceutically acceptable additive components.

Suitable formulations (e.g. solution or suspension) may be stabilised (e.g. using hydrochloric acid or sodium hydroxide) by appropriate selection of pH. Typically, the pH will be adjusted to between 4.5 and 7.5, preferably between 5.0 and 7.0, especially around 6 to 6.5.

Suitable formulations (e.g. solution or suspension) may comprise one or more excipients. By the term "excipient", herein, is meant substantially inert materials that are nontoxic and do not interact with other components of a composition in a deleterious manner including, but not limited to, pharmaceutical grades of carbohydrates, organic and inorganic salts, polymers, amino acids, phospholipids, wetting agents, emulsifiers, surfactants, poloxamers, pluronics, and ion exchange resins, and combinations thereof.

Suitable carbohydrates include monosaccharides include fructose; disaccharides, such as, but not limited to lactose, and combinations and derivatives thereof; polysaccharides, such as, but not limited to, cellulose and combinations and derivatives thereof; oligosaccharides, such as, but not limited to, dextrins, and combinations and derivatives thereof; polyols, such as but not limited to sorbitol, and combinations and derivatives thereof.

Suitable organic and inorganic salts include sodium or calcium phosphates, magnesium stearate, and combinations and derivatives thereof.

Suitable polymers include natural biodegradable protein polymers, including, but not limited to, gelatin and combinations and derivatives thereof; natural biodegradable polysaccharide polymers, including, but not limited to, chitin and starch, crosslinked starch and combinations and derivatives thereof; semisynthetic biodegradable polymers, including, but not limited to, derivatives of chitosan; and synthetic biodegradable polymers, including, but not limited to, polyethylene glycols (PEG), polylactic acid (PLA), synthetic polymers including but not limited to polyvinyl alcohol and combinations and derivatives thereof;

Suitable amino acids include non-polar amino acids, such as leucine and combinations and derivatives thereof. Suitable phospholipids include lecithins and combinations and derivatives thereof.

Suitable wetting agents, surfactants and/or emulsifiers include gum acacia, cholesterol, fatty acids including combinations and derivatives thereof. Suitable poloxamers and/or Pluronics include poloxamer 188, Pluronic® F-108, and combinations and derivations thereof. Suitable ion exchange resins include amberlite IR120 and combinations and derivatives thereof;

Suitable solution formulations may comprise a solubilising agent such as a surfactant. Suitable surfactants include α-[4-(1 ,1 ,3,3-tetramethylbutyl)phenyl]-ω- hydroxypoly(oxy-1 ,2-ethanediyl) polymers including those of the Triton series e.g. Triton X-100, Triton X-114 and Triton X-305 in which the X number is broadly indicative of the average number of ethoxy repeating units in the polymer (typically around 7-70, particularly around 7-30 especially around 7-10) and 4-(1 , 1 ,3,3- tetramethylbutyl)phenol polymers with formaldehyde and oxirane such as those having a relative molecular weight of 3500-5000 especially 4000-4700, particularly Tyloxapol. The surfactant is typically employed in a concentration of around 0.5-10%, preferably around 2-5% w/w based on weight of formulation.

Suitable solution formulations may also comprise hydroxyl containing organic co- solvating agents include glycols such as polyethylene glycols (e.g. PEG 200) and propylene glycol; sugars such as dextrose; and ethanol. Dextrose and polyethylene glycol (e.g. PEG 200) are preferred, particularly dextrose. Propylene glycol is preferably used in an amount of no more than 20%, especially no more than 10% and is most preferably avoided altogether. Ethanol is preferably avoided. The hydroxyl containing organic co-solvating agents are typically employed at a concentration of 0.1-20% e.g. 0.5-10%, e.g. around 1-5% w/w based on weight of formulation.

Suitable solution formulations may also comprise solublising agents such as polysorbate, glycerine, benzyl alcohol, polyoxyethylene castor oils derivatives, polyethylene glycol and polyoxyethylene alkyl ethers (e.g. Cremophors, Brij).

Suitable solution formulations may also comprise one or more of the following components: viscosity enhancing agents; preservatives; and isotonicity adjusting agents.

Suitable viscosity enhancing agents include carboxymethylcellulose, veegum, tragacanth, bentonite, hydroxypropylmethylcellulose, hydroxypropylcellulose, hydroxyethylcellulose, poloxamers (e.g. poloxamer 407), polyethylene glycols, alginates xanthym gums, carageenans and carbopols.

Suitable preservatives include quaternary ammonium compounds (e.g. benzalkonium chloride, benzethonium chloride, cetrimide and cetylpyridinium chloride), mercurial agents (e.g. phenylmercuric nitrate, phenylmercuric acetate and thimerosal), alcoholic agents (e.g. chlorobutanol, phenylethyl alcohol and benzyl alcohol), antibacterial esters (e.g. esters of para-hydroxybenzoic acid), chelating agents such as disodium edetate (EDTA) and other anti-microbial agents such as chlorhexidine, chlorocresol, sorbic acid and its salts and polymyxin. Suitable isotonicity adjusting agents act such as to achieve isotonicity with body fluids (e.g. fluids of the nasal cavity), resulting in reduced levels of irritancy associated with many nasal formulations. Examples of suitable isotonicity adjusting agents are sodium chloride, dextrose and calcium chloride.

Suitable suspension formulations comprise an aqueous suspension of particulate drug and optionally suspending agents, preservatives, wetting agents or isotonicity adjusting agents.

Suitable suspending agents include carboxymethylcellulose, veegum, tragacanth, bentonite, methylcellulose and polyethylene glycols.

Suitable wetting agents function to wet the particles of drug to facilitate dispersion thereof in the aqueous phase of the composition. Examples of wetting agents that can be used are fatty alcohols, esters and ethers. Preferably, the wetting agent is a hydrophilic, non-ionic surfactant, most preferably polyoxyethylene (20) sorbitan monooleate (supplied as the branded product Polysorbate 80).

Suitable preservatives and isotonicity adjusting agents are as described above in relation to solution formulations.

The drug dispenser device herein is in one embodiment suitable for dispensing aerosolized drug (e.g. for inhalation via the mouth) for the treatment of respiratory disorders such as disorders of the lungs and bronchial tracts including asthma and chronic obstructive pulmonary disorder (COPD). In another embodiment, the invention is suitable for dispensing aerosolized drug (e.g. for inhalation via the mouth) for the treatment of a condition requiring treatment by the systemic circulation of drug, for example migraine, diabetes, pain relief e.g. inhaled morphine.

Administration of drug in aerosolized form may be indicated for the treatment of mild, moderate or severe acute or chronic symptoms or for prophylactic treatment. It will be appreciated that the precise dose administered will depend on the age and condition of the patient, the particular particulate drug used and the frequency of administration and will ultimately be at the discretion of the attendant physician. When combinations of drugs are employed the dose of each component of the combination will in general be that employed for each component when used alone. Typically, administration may be one or more times, for example from 1 to 8 times per day, giving for example 1 , 2, 3 or 4 aerosol puffs each time. Each valve actuation, for example, may deliver 5μg, 50μg, 100μg, 200μg or 250μg of a drug. Typically, each filled canister for use in a metered dose inhaler contains 60, 100, 120 or 200 metered doses or puffs of drug; the dosage of each drug is either known or readily ascertainable by those skilled in the art.

In another embodiment, the drug dispenser device herein is suitable for dispensing fluid drug formulations for the treatment of inflammatory and/or allergic conditions of the nasal passages such as rhinitis e.g. seasonal and perennial rhinitis as well as other local inflammatory conditions such as asthma, COPD and dermatitis. A suitable dosing regime would be for the patient to inhale slowly through the nose subsequent to the nasal cavity being cleared. During inhalation the formulation would be applied to one nostril while the other is manually compressed. This procedure would then be repeated for the other nostril. Typically, one or two inhalations per nostril would be administered by the above procedure up to three times each day, ideally once daily. Each dose, for example, may deliver 5μg, 50μg, 100μg, 200μg or 250μg of active drug. The precise dosage is either known or readily ascertainable by those skilled in the art.

It will be understood that the present invention has been described above by way of example only and that the above description can be modified in many different ways without departing from the scope of the invention as defined by the appended claims.

All publications, patents, and patent applications cited herein, and any US patent family equivalent to any such patent or patent application, are hereby incorporated herein by reference to their entirety to the same extent as if each publication, patent, or patent application was specifically and individually indicated to be incorporated by reference.

It must be noted that, as used in the specification and appended claims, the singular forms "a", "an", "the" and "one" include plural referents unless the content clearly dictates otherwise.

The application of which this description and claims form part may be used as a basis for priority in respect of any subsequent application. The claims of such subsequent application may be directed to any feature or combination of features described therein. They may take the form of product, method or use claims and may include, by way of example and without limitation, one or more of the following claims.

Claims

1. A closure for use with an article having an outlet, the closure comprising: a closure part for closing the outlet, a connector part for connecting the closure to the article, and a hinge between the closure and connector parts to enable the closure part to be hinged relative to the connector part, wherein the closure is configured and arranged so that hinging of the closure part relative to the connector part in an opening direction is to a limit whereupon the closure part couples to the connector part so that the closure and connector parts thereafter have to move in unison in the opening direction.

2. The closure according to claim 1 wherein the connecting part is adapted to be rotatably connected to the article such that, in use, said movement in unison of the closure and connector parts is a rotary movement.

3. The closure according to claim 1 or claim 2 wherein the connecting part has a mounting for mounting to an axle of the article for rotation thereabout.

4. The closure according to claim 1 , 2 or 3 comprising an angle limiter which acts to limit the angle of hinging of the closure part relative to the connector part.

5. The closure according to claim 4, wherein the angle limiter is provided on the connector part.

6. The closure according to claim 5, wherein the closure part has a control surface which is brought into engagement with a stop surface of the angle limiter on hinging of the closure part relative to the connector part by a predetermined angle in the opening direction thereby to prevent further hinging of the closure part relative to the connector part in the opening direction.

7. The closure according to claim 6, wherein the control and stop surfaces are oriented parallel to the axis of the hinge.

8. The closure according to any of the preceding claims wherein the closure and connector parts are hinged together by male and female connectors.

9. The closure according to claim 8 wherein the male and female connectors are pin-and-hole connectors.

10. The closure according to any of the preceding claims, wherein the connector part presents a lock member adapted in use to lock operation of the article when the closure closes the opening and to unlock the article for operation thereof when the closure is moved in the open direction to an open position.

11. The closure according to any of the preceding claims wherein the article is a dispenser and the opening is a dispensing opening of the dispenser.

12. The closure according to any of the preceding claims, wherein the dispenser is an inhaler and the opening is a mouthpiece or nasal nozzle.

13. An article having an opening and a closure according to any of the preceding claims, wherein the connector part is connected to the article such that the closure is movable in the opening direction from a closed position, in which the closure part closes the opening, to an open position, in which the closure part is spaced from the outlet for opening thereof.

14. The article according to claim 13, wherein the closure is movable from its closed position to the open position by sequentially hinging the closure part relative to the connector part in the opening direction to the limit and then moving the closure and connector parts in unison in the opening direction.

15. The article according to claim 14, wherein the closure is still at least partially closed by the closure part when the closure part is at the hinge limit in the opening direction.

16. The article according to any of claims 13 to 15 including an obstruction for obstructing movement of the closure in the opening direction.

17. The article according to claim 16, wherein the obstruction obstructs movement of the closure in the opening direction only once the closure part is at the hinge limit.

18. The article according to claim 17, wherein the obstruction obstructs movement of the closure when the closure and connector parts move in unison in the opening direction.

19. The article according to claim 16, 17 or 18, wherein the obstruction is adapted to obstructively engage the connector part.

20. The article according to any of claims 16 to 19, wherein the obstruction obstructs movement of the closure when the opening is still at least partially closed by the closure part.

21. The article according to any of claims 16 to 20, wherein only when the closure is past the obstruction in the opening direction is the opening fully open.

22. The article according to any of claims 16 to 20 when appended directly or indirectly to claim 10, wherein the lock member unlocks the article for operation thereof only when the closure is past the obstruction in the opening direction.

23. The article according to any of claims 16 to 22, wherein the article is a dispenser and the opening is a dispensing opening of the dispenser.

24. The article according to claim 23, wherein the dispenser has a housing and a dispensing member movably mounted in the housing for dispensing from the dispenser.

25. The article according to claims 22 and 24, wherein the lock member selectively locks and unlocks the dispensing member for movement for dispensing from the dispenser.

26. The article according to claim 25, wherein the lock member presents a surface configured to restrict movement of the dispensing member when the closure is in the closed position and to not restrict said movement of the dispensing member when the closure is in the open position.

27. The article according to claim 24, 25 or 26, wherein the article is an inhaler.

28. The article according to claim 27 which is a pressurised metered dose inhaler and the dispensing member is an aerosol canister unit.

29. An article comprising: an opening, a closure mounted to the article for movement in an opening direction from a closed position, in which the closure closes the opening, to an open position, in which the opening is open, and an obstruction for obstructing movement of the closure in the opening direction.

30. The article according to claim 29, wherein the obstruction obstructs movement of the closure when the closure has moved a predetermined distance in the opening direction at which the closure still at least partially closes the opening.

31. The article according to claim 29 or 30, wherein only when the closure is past the obstruction in the opening direction is the opening fully open.

32. The article according to claim 29, 30 or 31 , wherein the closure presents a lock member adapted in use to lock operation of the article when the closure closes the opening and to unlock the article for operation thereof when the closure is moved in the open direction to the open position.

33. The article according to claim 32, wherein the lock member unlocks the article for operation thereof only when the closure is past the obstruction in the opening direction.

34. The article according to any of claims 29 to 33, wherein the closure is mounted to the article for rotation from the closed position to the open position.

35. The article according to any of claims 29 to 34, wherein the article is a dispenser and the opening is a dispensing opening of the dispenser.

36. The article according to claim 35, wherein the dispenser is an inhaler and the opening is a mouthpiece or nasal nozzle.

37. The article according to claim 35 or 36, wherein the dispenser has a housing and a dispensing member movably mounted in the housing for dispensing from the dispenser.

38. The article according to claim 37 when appended directly or indirectly on claim 32, wherein the lock member selectively locks and unlocks the dispensing member for movement for dispensing from the dispenser.

39. The article according to claim 38, wherein the lock member presents a surface configured to restrict movement of the dispensing member when the closure is in the closed position and to not restrict said movement of the dispensing member when the closure is in the open position.

40. The article according to any of claims 37 to 39 which is a pressurised metered dose inhaler and the dispensing member is an aerosol canister unit.

41. A closure for use with an article substantially as herein described with reference to, and illustrated by, Figures 38 to 42 of the accompanying drawings.

42. An article substantially as herein described with reference to, and illustrated by, Figures 38 to 42 of the accompanying drawings.