Patent Description:
A known inhaler, which is a breath actuated inhaler, has a pressurised canister and a metering valve for controlling the ejection of inhalable substances from the canister. The canister is operable by a force holding unit having a cap housing attachable to a main housing of the inhaler. The metering valve includes a valve stem for transferring substances from an interior reservoir of the canister into the metering chamber and then out of the metering chamber along the valve stem in the direction of a nozzle of the inhaler. A radially directed capillary port is provided in the valve stem for communicating substances out of the interior reservoir for communication along the valve stem to the metering chamber and a similar port is provided for communicating substances out of the metering chamber and along the valve stem towards the nozzle. In use, a mouthpiece cap is opened to ready the inhaler for inhalation and then after inhalation the mouthpiece cap is closed and resets a canister fire system. It has been found that the inhaler can be left after inhalation with the mouthpiece dust cap in the opened position with the metering chamber communicating with atmosphere via the valve stem and nozzle. This can result in the variance of active ingredients in at least one subsequent dose. This means that users will sometimes remove a force holding unit cap housing from the main body of the inhaler and try to ensure that the metering chamber is sufficiently primed by firing a number of doses and this is both wasteful and may result in damage to the inhaler.

In some inhalers, when it is necessary to make changes to internal components, it is difficult to provide space and good guidance for all the necessary interior moving parts. Also, the assembly of some inhaler dose counters can be difficult.

Furthermore, in some inhalers, despite a tight connection between the valve stem and a valve stem block within the main body, blowback can occur which is leakage of substances between the valve stem block and valve stem. It can also be difficult in some inhalers to achieve reliable dose counting to reflect the number of doses actually provided by the inhaler.

<CIT> discloses metered dose inhaler for use with a removable pressurized aerosol canister, or reservoir, having a display for indicating to a user the state of the canister.

<CIT> discloses a dispenser for dispensing a medicament in a fluid propellant comprising a canister for housing the medicament; and a drug-dispensing valve. The valve is made wholly or substantially of metal, wherein the internal metal surfaces of said valve comprise a coating which enhances the surface energy thereof. The valve coating on the metal surfaces reduces the tendency of drug to adhere thereto, and improves the frictional properties thereof.

<CIT> discloses a Breath actuated inhaler (BAI) actuator, comprising: a loading element capable of being loaded with an actuation force, a breath actuated trigger mechanism arranged to counteract the actuation force of the loading element, and to fire the actuator by releasing the actuation force of the loading element in response to an inhalation breath, and actuation locking means moveable between a locked position wherein it relieves the actuation force from the trigger mechanism setting the trigger mechanism in a neutral position, and an armed position wherein the trigger mechanism is set in an armed position.

<CIT> discloses a metering valve for use with a pressurised dispensing container, the metering valve comprising a valve stem assembly co-axially slidable within an annular metering cumber defined between the valve stem assembly and a substantially cylindrical chamber body.

The present invention aims to alleviate at least to a certain extent at least one of the problems of the prior art.

Alternatively, the present invention aims to provide a useful inhaler, method of metering substances in a metering valve of a canister for a medicament inhaler and/or useful inhaler parts.

The invention provides an inhaler according to the claims.

Disclosed herein is (not separately claimed) a method of metering inhalable substances in a metering valve of a canister for a medicament inhaler, the method comprising: providing the metering valve with a metering chamber and valve stem extending from a metering chamber to an interior reservoir of the canister, with the valve stem defining a communication path between the metering chamber and the interior reservoir, the communication path including an opening configured to permit flow between a transfer space inside the valve stem and the interior reservoir; and orienting the interior reservoir above the metering chamber and replacing gas such as air located within the metering chamber with liquid from the interior reservoir.

The present inventors have worked out that the reasons why inaccurate dosing can occur include that when the metering chamber is left vented to atmosphere in some prior inhalers for as little as <NUM> minutes, a gas or air lock can form in the metering chamber and when the metering chamber is next connected for communication with the interior reservoir, due to the radial capillary port, the gas or air is trapped within the metering chamber and liquid does not enter the metering chamber reliably as the next dose. The air may enter the metering chamber from the atmosphere in the prior art. This may happen as propellant in the metering chamber evaporates and diffuses into the atmosphere. Using the presently disclosed method which involves the use of the opening configured to permit flow in a direction with an axial component along the valve stem directly between a transfer space inside the valve stem and the interior reservoir, when the interior reservoir is oriented above the metering chamber, this enables liquid from the interior reservoir to replace gas such as air located within the metering chamber and an accurate dose can be administered at the next dose.

The opening may be configured to permit flow in a direction with an axial component along the valve stem directly between the transfer space inside the valve stem and the interior reservoir.

The replacing gas located in the metering chamber with liquid from the interior reservoir may include flowing liquid under pressure through the opening, along the valve stem to a portion of the communication path communicating with the metering chamber.

The method may include flowing gas from the metering chamber, in a direction counter to a direction of liquid flow from the interior reservoir, along the communication path into the interior chamber.

The method may include providing the opening as an elongated opening.

The method may include providing a second opening to the communication path diametrically opposed to the first said opening.

The method may include providing the valve stem with at least one said opening into the interior reservoir as having an axially oriented opening portion which is oriented facing directly axially along a longitudinal axis of the valve stem into the interior reservoir, and which includes flowing liquid into the metering chamber via said axially oriented opening portion.

The method may include venting the metering chamber to atmosphere via a valve stem block and/or nozzle.

The method may include operating the metering valve and canister within a medicament inhaler and holding the valve stem depressed relative to the canister with the metering chamber vented to atmosphere so as at least partially to permit substances within the metering chamber to vaporise and to permit atmospheric air to enter the metering chamber.

Advantageously, the inhaler can be left for a long period such as <NUM> hours with the metering chamber communicating with atmosphere and then when the metering chamber is reconnected to the interior reservoir and the interior reservoir is oriented above the metering chamber the metering chamber can fully fill with liquid for the next dose. Advantageously, in a breath actuated inhaler, the features of the method mean therefore that any force holding unit and/or cap housing for the inhaler can be permanently secured or locked on to the inhaler so that users cannot tamper with the interior and there is no need to perform manual priming of the metering valve, which is a necessity in prior art inhalers, before the next dose is taken.

The method may include providing the medicament inhaler as a breath actuated inhaler, and may include, in response to air flow, firing the canister by closing communication between the metering chamber and interior reservoir and opening communication between the metering chamber and atmosphere, the valve stem being held depressed after firing.

The method may include resetting the inhaler to a reset configuration with a reset actuator so as to close communication between the metering chamber and atmosphere and open communication between the metering chamber and the interior reservoir, and carrying out the orienting of the interior reservoir above the metering chamber while the inhaler is in the reset configuration.

The method may include providing the reset actuator as a lever, press button, hinged or rotatable piece, dust cap, nasal outlet cap or mouthpiece cap for the inhaler. Closing the actuator may reset the inhaler. In the case of an oral inhaler the reset actuator may be a dust cap mouthpiece cap. In the case of a nasal inhaler, the reset actuator may take a variety of forms, including but not limited to a dust cap or a movable lever, cap or button. In this case, the carrying out of the orienting of the interior reservoir above the metering chamber being carried out once the reset actuator has been opened to a configuration suitable for inhalation or otherwise operated. Therefore, it can be ensured that right before inhalation, the metering chamber is full of liquid and any gas which may have been in the metering chamber has been drawn into the interior reservoir due to the free flowing communication pathway between metering chamber and interior reservoir.

In an alternative embodiment, the inhaler may include a dust cap or mouthpiece cap which closes communication between the metering chamber and atmosphere but does not reset the inhaler. In these cases, optionally, a separate reset actuator may be provided.

The method may include providing the medicament inhaler as a metered dose inhaler and may include applying a force to the canister to hold the valve stem depressed; and may include subsequently releasing the canister to extend the valve stem and carrying out the orienting of the interior reservoir above the metering chamber.

The method may include providing the inhalable substances as including at least one propellant.

The method may include providing at least one said propellant as a hydrofluoroalkane, such as <NUM>,<NUM>,<NUM>,<NUM>-tetrafluoroethane.

The method may include providing at least one said propellant with a surface tension at <NUM> of about <NUM> to <NUM> mN/m, typically about <NUM> to <NUM> mN/m, about <NUM> mN/m being one example.

Advantageously, it has been found that fluid with this surface tension is capable of avoiding gas or air lock in the metering chamber by flowing into the metering chamber when the features of the presently disclosed method are used.

The method may include providing the inhalable substances as including an active ingredient in suspension or in solution, such as beclomethasone dipropionate (BDP) or tiotropium bromide.

According to an aspect, the present disclosure discloses a breath actuated inhaler for the inhalation of inhalable substances, the inhaler comprising: a canister having an interior reservoir containing pressurised inhalable substances including fluid; a metering valve including a metering chamber and a valve stem defining a communication path between the metering chamber and the interior reservoir, the communication path including an opening configured to permit flow between a transfer space inside the valve stem and the interior reservoir, the interior reservoir being arranged for orientation above the metering chamber whereby gas such as air located within the metering chamber is replaced with liquid from the interior reservoir.

Advantageously, with this configuration of metering valve there is no need to manually prime the metering chamber by repeatedly firing the canister manually and an accurate next dose can be provided to the metering chamber since a gas or air lock can be avoided. This also means, advantageously, that in a breath actuated inhaler having a force holding unit or cap housing secured to a main body of the inhaler, these components may be locked together so that it is relatively difficult for a user to remove the force holding unit or cap housing and tamper with the interior components. Instead, there is no need to perform manual priming and the inhaler main housing and the cap housing can be permanently locked together enclosing the internal moving parts of the inhaler where they cannot easily be damaged.

The opening may be configured to permit flow in a direction with an axial component along the valve stem directly between a transfer space inside the valve stem and the interior reservoir.

The communication path may be configured to permit liquid to flow under pressure along the communication path to the metering chamber and gas to flow in a reverse direction therealong from the metering chamber into the interior reservoir.

The opening may comprise an elongated opening.

The inhaler may include a second opening or further openings into the communication path.

The second opening may be diametrically opposed to the first said opening.

The valve stem may have at least one opening into the interior reservoir with an axially oriented portion facing directly axially along a longitudinal axis of the valve stem into the interior reservoir for the flow of fluid directly into the communication path in an axial direction along the valve stem.

The inhaler may include a metering chamber exit port for venting the metering chamber to atmosphere via a stem block and/or nozzle.

The inhaler may include a canister fire system for ejecting inhalable substances from the inhaler in response to air flow by closing communication between the metering chamber and the interior reservoir and opening communication between the metering chamber and atmosphere. The canister fire system preferably includes a drive such as a spring for driving the canister relative to the valve stem. The inhaler may have an actuator system for operating the drive, the actuator system optionally including a vacuum chamber having a vacuum release system operable to permit the drive to drive movement of the canister relative to the valve stem. The vacuum release system may be air flow actuatable.

The actuator and/or drive may include or operate as a latch, trigger or switch and may take other forms in other embodiments such as being electromechanical.

The canister fire system may be adapted to depress the valve stem into the canister to cause inhalable substances to be ejected from the inhaler and to hold the valve stem depressed with the metering chamber communicating with atmosphere.

The canister fire system may include a reset actuator which is operable so as to extend the valve stem relative to the canister in order to close communication between atmosphere and the metering chamber and to open communication between the metering chamber and the interior reservoir.

In the case of a nasal inhaler, the reset actuator may, for example, comprise a dust cap or a lever, cap or button. In the case of an oral inhaler, the reset actuator may comprise a dust cap or mouthpiece cap for a mouthpiece of the inhaler. The mouthpiece cap may be closable to permit extension of the valve stem relative to the canister, the mouthpiece cap optionally being hingedly connected to a main housing of the inhaler for camming engagement with at least one drive rod. The drive rod may be associated with a yoke for pushing on a drive element to compress a spring of the drive.

The inhaler may include a preventer adapted, after an inhalation has taken place, to prevent a further inhalation until the reset actuator has been operated to extend the valve stem. In the case of a mouthpiece or other cap, this may comprise closing the cap.

Advantageously, the preventer may therefore ensure that the user closes the cap at some time before each inhalation and this in turn means that reliable dosing can be achieved.

The preventer may comprise a warning signaller, such as an audible or visual alarm, dose counter or warning notice, quick reference guide or instructions.

The inhaler may include inhalable substances in the interior reservoir which include at least one propellant.

At least one said propellant may comprise a hydrofluoroalkane, such as <NUM>,<NUM>,<NUM>,<NUM>-tetrafluoroethane.

At least one said propellant may have a surface tension at <NUM> of about <NUM> to <NUM> mN/m, typically about <NUM> to <NUM> mN/m, about <NUM> mN/m being on example.

The inhaler may include at least one inhalable substance in the interior reservoir as an active ingredient, for example in suspension or in solution, such as beclomethasone dipropionate or tiotropium bromide.

The inhaler may include a dose counter for counting doses, preferably for making one count with each inhalation of a dose.

The dose counter may include: (a) a tape bearing dose indicia for displaying counts and/or (b) an actuator pin for contact with the canister, or a body movable therewith, for counting doses, and preferably a dose counter chamber separated by a barrier from an inner space of the inhaler for containing the canister, the actuator pin optionally extending out of the dose counter chamber through an aperture in the wall for contact during counting with the canister (or the body movable therewith).

The inhaler may be a breath actuated inhaler.

The inhaler may be a metered dose inhaler.

The inhaler may include a reset actuator which when actuated prevents exposure of the metering chamber to atmosphere, wherein the inhaler provides <NUM> to <NUM>% of labelled claim for a dose following exposure of the metering chamber to atmosphere for a time period which is more than one minute.

In this case, the reset actuator may be a mouthpiece cap that, when closed, prevents exposure of the metering chamber to atmosphere.

The inhaler may provide <NUM> to <NUM>% of labelled claim for a dose following exposure of the metering chamber to atmosphere for a time period which is more than two minutes.

The inhaler may provide <NUM> to <NUM>% of labelled claim for a dose following exposure of the metering chamber to atmosphere for a time period which is one hour, more than one hour, <NUM> hours or more than <NUM> hours.

Operation of the inhaler may include, subsequent to closing the mouthpiece, opening the mouthpiece.

The inhaler includes a metering valve spring and an opposing canister spring for drivingly firing the canister, the metering valve spring, canister spring and metering valve being arranged in the inhaler such that an equilibrium of various forces is achieved in at least one ready-to-fire configuration of the inhaler.

In that case, the operation of the inhaler may include at least one suction force, e.g. provided by a pneumatic chamber; the suction force preferably operating against the canister spring.

Also disclosed herein is a breath actuated inhaler having a drive adapted to drive a pressurised canister so as to retract a metering valve stem into the canister to fire the canister, the canister being adapted to move during operation between <NUM> and <NUM> between end positions of its length of travel relative to the valve stem, the drive being arranged to apply a firing force of between 15N and 60N of force to the canister at a position of the canister relative to the valve stem at which the canister fires.

With this configuration of drive and canister travel, it has been surprisingly found possible to have very accurate and reliable firing of the canister, as well as accurate counting when a dose counter is provided. Furthermore, a long extent of travel of the canister to retract the valve stem can be provided to ensure that both count and fire very reliably occur.

The canister may be arranged to move between <NUM> and <NUM> between the end positions. In one example the movement between the end positions is <NUM>.

The drive may be adapted to provide the firing force as more than 40N, preferably also less than 60N.

The drive may be adapted to provide the firing force as more than 35N.

The firing force may be greater than the sum at the point of firing of opposing forces applied to the canister by a valve stem spring in the canister and a return spring for an actuator pin of a dose counter of the inhaler.

The present invention may be carried out in various ways and a number of preferred embodiments will now be described by way of example with reference to the accompanying drawings, in which:.

The following detailed description of embodiments of the inhaler and accompanying methods will be better understood when read in conjunction with the appended drawings of exemplary embodiments. It should be understood, however, that the invention is not limited to the precise arrangements and instrumentalities described in the following detailed description.

As shown in <FIG>, a breath actuated inhaler which is merely an example of an inhaler in accordance with the present invention, includes a force holding unit or cap housing <NUM>, a main body <NUM>, a mouthpiece dust cap <NUM> and a dose counter door <NUM> having a dose counter window <NUM>.

As shown by the exploded view of <FIG>, a dose counter chamber <NUM> includes a dose counter system <NUM> closed within it by the dose counter door <NUM>.

The dose counter system is shown in enlarged detail in <FIG> and includes an actuating pin <NUM> and return spring <NUM>. The dose counter can take various forms and may, for example, be as described in <CIT> or <CIT>.

As also shown in <FIG>, the inhaler <NUM> includes a force holding unit <NUM> which includes: a filter <NUM>, flap valve housing <NUM>, flap valve <NUM>, flap valve spring <NUM>, main compression spring <NUM>, retaining ring <NUM>, diaphragm <NUM> and lower cap <NUM>. The inhaler also includes a canister <NUM> with a metering valve <NUM> and a valve stem <NUM>; as well as a yoke <NUM> with drive rods or legs <NUM> having distal ends <NUM> which are driven by respective cams <NUM> on the hingedly-connected mouthpiece dust cap. The valve stem <NUM> is fitted into an inner bore <NUM> (<FIG>) of a valve stem block <NUM> which communicates with a nozzle <NUM> for ejection of inhalable substances through a central bore <NUM> (<FIG>) of a mouthpiece <NUM> (<FIG> and <FIG>) of the main body <NUM> of the inhaler <NUM>.

The force holding unit <NUM> operates substantially as disclosed with reference to <FIG> of <CIT> and the yoke <NUM> and mouthpiece dust cap <NUM> substantially as described in <CIT>, including but not limited to Figure <NUM> thereof.

In particular, with reference to <FIG>, starting from a configuration in which the mouthpiece dust cap <NUM> is closed in this configuration the liquid <NUM> in an interior reservoir <NUM> of canister <NUM> communicates with a metering chamber <NUM> which does not communicate with atmosphere through an interior bore <NUM> of the valve stem <NUM>. An opening rotation of the mouthpiece dust cap <NUM> to the configuration of <FIG> enables the distal ends <NUM> of the drive rods <NUM> and indeed the whole yoke <NUM> to be moved away from the cap housing <NUM> under the influence of the main compression spring <NUM>, the main compression spring <NUM> being reacted against as equilibrium is reached for the canister position by friction forces as well as forces provided by partial vacuum at the diaphragm, the dose counter return spring <NUM>, and metering valve spring <NUM> (<FIG>) which forms part of the metering valve <NUM>.

As the next step, the user (not shown) inhales through the mouthpiece <NUM> and the drawing out of air through the central bore <NUM> in turn draws air into the enclosure formed by the main body <NUM> and cap housing <NUM> through the series of approximately ten air inlets <NUM> formed on the cap housing <NUM>. The incoming air impinges upon the flap <NUM> which releases vacuum (i.e. a partial vacuum) from the vacuum chamber formed by the diaphragm <NUM> due to flap seal <NUM> rising off port <NUM> on diaphragm top plate <NUM>. With the vacuum released, as shown in <FIG>, as the user is inhaling air through the inhaler <NUM>, i.e. through the apertures <NUM> and all of the way along inside the cap housing <NUM> and main body <NUM> past the canister <NUM> and out through the central bore <NUM>, the main compression spring <NUM> drives the lower cap <NUM>, yoke <NUM> and canister <NUM> away from the cap housing <NUM> and towards the main body <NUM> and valve stem block <NUM> whereby the valve stem <NUM> is retracted into the canister <NUM>. This places the pressurised metering chamber <NUM> in communication with valve stem block nozzle <NUM> so fires the canister and ejects inhalable substances from the metering chamber <NUM> through the nozzle <NUM> and mouthpiece <NUM> towards the lungs (not shown) of the user. The dose counter system <NUM> also registers a count by movement of the actuating pin <NUM> by the canister ferrule <NUM>. At this time after opening and firing, the metering chamber <NUM> communicates with atmosphere. With the mouthpiece <NUM> left open such that the atmosphere communicates through the bore <NUM> and exit port <NUM> with the metering chamber <NUM>, the metering chamber <NUM> can become at least partially or fully filled with gas such as air from the atmosphere.

In other embodiments comprising nasal inhalers, the mouthpiece <NUM> may be replaced with a nose piece.

As shown in <FIG>, during closing, the mouthpiece dust cap <NUM> is rotated back to its closed position and the cams <NUM> push on the distal ends <NUM> of the drive rods <NUM> so as to push the yoke <NUM> towards the cap housing <NUM> so as to compress the main compression spring <NUM> again and the vacuum is formed again at the diaphragm <NUM>. At the same time, the canister is pushed back to its original configuration of <FIG> by the metering valve return spring <NUM>.

As shown in <FIG>, with the inhaler <NUM> in the configuration of <FIG>, the metering valve spring <NUM> keeps the valve stem <NUM> extended, the inlet port <NUM> open and the exit port <NUM> effectively closed, i.e. with the metering chamber <NUM> isolated from atmosphere. At the same time the force FYL applied as FYL/<NUM> by each of the legs or rods <NUM> of the yoke <NUM> to the lower cap <NUM> is greater than or equal to the force FFHUCS applied in the opposite direction by the spring of the force holding unit <NUM>.

As shown in <FIG>, with the inhaler then changed to the configuration of <FIG>, the canister is displaced to a representative distance Dvalve from the canister position of <FIG> where this displacement at Dvalve is less than the displacement required to actuate and fire a dose. In this <FIG> configuration, the position of the canister <NUM> is determined by an equilibrium between forces, which is: <MAT> where Fvalve CS is the force applied to the canister by the metering valve spring <NUM>, FDia is the force applied by the partial vacuum in the diaphragm <NUM> in the same direction and FFHU CS is the opposing force applied by the compression spring <NUM> of the force holding unit <NUM>. The port <NUM> is noted to be closed. The port <NUM> is open and the port <NUM> is closed.

As the user then inhales, the port <NUM> is opened by the action of air entering through the apertures <NUM> impinging on the flap <NUM>, lifting flap seal <NUM>. The equilibrium of <FIG> is therefore lost. The canister <NUM> is therefore moved to displace the valve stem <NUM> more, to the configuration of <FIG>, so that the canister is a representative distance DActuated from the valve stem block <NUM>, and where the force balance is that Fvalve CS ≤ FFHUCS in which the force applied to the lower cap <NUM> is less than or equal to the opposing force applied by the compression spring <NUM> of the force holding unit R. In this configuration, the port <NUM> has closed to isolate the metering chamber <NUM> from the interior reservoir <NUM> of the canister <NUM> and after this closure the port <NUM> has opened, thereby firing the canister <NUM> by venting pressurised contents within the metering chamber <NUM> out through the nozzle <NUM> of the valve stem block <NUM> for inhalation by the user.

The spring <NUM> is adapted such that the firing force FFHU CS is more than <NUM> N, typically less than <NUM> N. This may vary in other embodiments.

In most embodiments, the spring <NUM> is adapted in addition to device geometry such that the force exerted by the spring <NUM> on the valve/canister is equal to the sum of the opposing valve spring <NUM> and pneumatic resistance force in the FHU diaphragm <NUM> in the prepared position. Nonetheless, the spring <NUM>, unless otherwise assisted, must be able to provide sufficient force once the mechanism is triggered to actuate the canister on inhalation. The specific force values will be dependent on the componentry of the device, driven predominately by the force required to actuate the canister at a specific displacement, thus the spring <NUM> will be adapted to suit.

The metering valve <NUM> shown in <FIG> is similar to those described in <CIT> and has the metering chamber <NUM> arranged for selective communication with either the interior reservoir <NUM> of the canister <NUM> via an inlet port <NUM>, or with the interior bore <NUM> (<FIG>) of the valve stem <NUM> which communicates via the valve stem block <NUM> with the nozzle <NUM>, the valve stem <NUM> being provided with a radially configured capillary exit port <NUM> leading to the bore <NUM>. The metering chamber <NUM> is at least partly defined by a cup-shaped inner metering body <NUM> and has an inner seal <NUM> and outer seal <NUM>, as well as a location member <NUM>, a main canister seal <NUM> and a crenelated valve stem driver <NUM> which has a through bore <NUM> axially directed towards the inlet port <NUM>. The inlet port <NUM> includes two elongate openings <NUM> diametrically opposed to one another and which are defined by a pair of forked legs <NUM> which are spaced apart from one another by the elongated openings <NUM> and the open space forming the inlet port <NUM> between them. The forked legs <NUM> have substantially constant cross-section all the way along to their distal ends (not shown) which are located within the crenelated valve stem driver <NUM>. When the valve stem <NUM> is depressed into the canister <NUM> so that the inlet port <NUM> permits communication between the metering chamber <NUM> and the interior reservoir <NUM>, the communication into the interior reservoir <NUM> is at an inner side <NUM> of the inner seal <NUM> and it will be appreciated that this is a slot-shaped porting between the forked legs <NUM> from where flow can travel directly axially into our out of the interior reservoir <NUM>.

According to an alternative embodiment, the arrangement of openings in the metering valve of the present invention is similar to those described in <CIT>. In particular, the metering valve of the present invention may be similar to the embodiment shown in <FIG> of <CIT>, in which the valve body includes at least one first opening (i.e., at least one first side hole <NUM> that is arranged in a cylindrical portion of the valve body) and at least one second opening (i.e., at least one second side hole <NUM> that, as with the first hole(s), is arranged in a cylindrical portion of the valve body), the second opening(s) being axially offset relative to the first opening(s) along a longitudinal axis that extends between a first axial end and a second axial end of the valve body. The first opening(s) and second opening(s) that are axially offset from each other along the valve body enable the metering chamber to be filled and emptied.

The canister <NUM> includes inhalable substances including the active ingredient beclomethasone dipropionate and the propellant HFA134a which has a surface tension of about <NUM> mN/m as liquid at <NUM>. Other active ingredients may be used in other embodiments, such as tiotropium bromide.

If the mouthpiece dust cap <NUM> is left open such that the atmosphere communicates through the bore <NUM> and exit port <NUM> with the metering chamber <NUM>, the metering chamber can become at least partly or substantially fully filled with gas such as air from the atmosphere. When the mouthpiece dust cap <NUM> is closed, however, and when the interior reservoir <NUM> is oriented above the metering chamber <NUM>, the present inventors have discovered that the liquid phase in the interior chamber can exchange places with gas in the metering chamber <NUM>, the fluid travelling either directly through the openings <NUM> or through the throughbore <NUM>, and along through the inner seal <NUM> and into the metering chamber <NUM> and gas in the metering chamber <NUM> can travel in the reverse direction along the same path, exiting with an axial component through between the forked legs <NUM> and through the elongated openings <NUM> into the interior reservoir <NUM>. It is believed that the particular surface tension of the chosen propellant promotes this action and the higher density of the liquid than that of any gas in the metering chamber enabling the latter to rise up in and relative to the liquid.

The full filling of the metering chamber <NUM> with a dose of liquid from the interior reservoir <NUM> with any gas in the metering chamber passing in the reverse direction from the metering chamber <NUM> into the interior reservoir <NUM> is highly advantageous since with this one extension of the valve stem <NUM> from its retracted configuration after inhalation to its extended configuration with the mouthpiece dust cap <NUM> closed again ensures that the inhaler <NUM> is fully primed for use. This has overcome a significant problem.

As shown in <FIG>, the inhaler <NUM> may be provided with a preventer <NUM> for preventing the user from taking a second or further inhalation while the dust cap <NUM> is still open. The preventer <NUM> may take the form of a warning signaller <NUM> such as a warning notice as shown in the drawing stating "to reload: close before each inhalation" although in other embodiments the preventer <NUM> could take various other forms such as an alarm or audible or visual warning device to indicate that the mouthpiece dust cap <NUM> is open and needs to be closed prior to the next inhalation.

<FIG> is a graph showing a comparison of the inhaler of <FIG> with delivered dose for a prior art breath actuated inhaler with a different metering valve (not shown) in which the exit port from the interior reservoir comprises a radially oriented capillary bore which leads to an internal bore of the valve stem leading axially towards a further radially extending capillary port, such that the communication from the interior space is through the first capillary port, along the internal bore and out through the second radial capillary port into the metering chamber when the valve stem is in its extended configuration. In all cases the inhalers were held with the valve stems vertical and the canister interior reservoir above the metering chamber. After inhalation, the valve stem in each case was left in the retracted inhale configuration with the metering chamber exposed to atmosphere through the valve stem for the specified delay period and the inhaler was then reset and readied for inhalation, in the case of the present inhaler <NUM> by closing and opening the mouthpiece cap again. As shown by the graph of <FIG>, with a target of <NUM> micrograms of BDP (beclomethasone dipropionate) the diamond shaped plots <NUM> are for the prior art inhaler which began to fail to reach <NUM>% of the labelled claim for the dose after a delay of <NUM> seconds after inhalation in closing the mouthpiece cap to isolate the metering chamber from atmosphere. At all delays of <NUM> minutes or over, the prior inhaler failed to provide <NUM>% of the labelled claim of dose in <NUM>% of cases. This, the present inventors have discovered, is due to gas lock forming in the metering chamber after inhalation due to the metering chamber's exposure to atmosphere, i.e. in that when the mouthpiece cap is closed after a delay air is trapped in the metering chamber and is not replaced by liquid in the interior reservoir even when the metering chamber is connected to the interior reservoir. In contrast, the plots of crosses <NUM> in <FIG> show the performance of the inhaler of <FIG>. Here, <NUM>% of the plots are in the range of <NUM> to <NUM>% of labelled claim for the dose, even when there is no appreciable delay or a delay of one hour, twelve or twenty-four hours before closing the mouthpiece cap after inhalation. Therefore, even if the metering chamber <NUM> has been exposed to atmosphere for a relatively long time such that it is after that delay substantially full of gas due to evaporation/diffusion of substances after inhalation, this graph clearly shows that by closing the mouthpiece fully and opening it again, the gas in the metering chamber <NUM> is removed into the interior reservoir <NUM> and replaced with a correct dose very reliably.

Although <FIG> data is presented for <NUM> mcg (ex-actuator) targeted BDP HFA product, the data is representative of any formulation and formulation strength.

As shown in <FIG>, the main body <NUM> has a tubular body portion <NUM> arranged to contain the pressurised canister <NUM> for sliding motion. As shown in <FIG>, the valve stem block has a top surface <NUM> and the tubular body portion <NUM> has at least two mutually opposed guide ribs <NUM>, <NUM>. The guide ribs <NUM>, <NUM> have substantially straight guide edges <NUM>, <NUM> extending parallel to and spaced from one another, each straight guide edge <NUM>, <NUM> having an upper corner <NUM>, <NUM> where the straight guide edge meets a further surface <NUM>, <NUM> of the ribs <NUM>, <NUM> leading outwardly towards an upper rib section near an inner wall <NUM> of the tubular body portion <NUM>. At least one of the ribs <NUM>, <NUM> has its straight guide edge's upper corner <NUM>, <NUM> positioned a distance D2 in a direction parallel to an axis of the valve stem block <NUM> along away from the top surface <NUM> of the valve stem block <NUM>, a distance between the straight guide edges <NUM>, <NUM> of the ribs <NUM>, <NUM> perpendicular to the axis being ID2, and the ratio D2 divided by ID2 is <NUM>. This is smaller than in previous embodiments and can surprisingly assist in providing smooth guiding of the canister within the tubular body portion <NUM>.

The further surface <NUM>, <NUM> of at least one of the guide ribs <NUM>, <NUM> and in this case both of them extends away from the valve stem block <NUM> and terminates at a distance D3 - in the case of guide rib <NUM> - from the top surface <NUM> of the valve stem block <NUM> in the direction parallel to the axis, the ratio D3 divided by ID2 being <NUM>, the equivalent ratio for the guide rib <NUM> being <NUM>. Each guide rib meets the upper rib section <NUM>, <NUM> near the inner wall <NUM> of the tubular body portion <NUM> at an outer rib position <NUM>, <NUM> wherein the outer rib positions are a distance apart ID1 in a direction perpendicular to the axis <NUM> of the valve stem block <NUM> and the ratio ID2 divided by ID1 is <NUM>. This arrangement assists beneficially in providing sufficient space for the canister <NUM> to move within the tubular body section <NUM>.

With reference to <FIG>, a portion of the main body <NUM> is shown with the mouthpiece dust cap <NUM> and the dose counter door <NUM> and the dose counter system <NUM> not yet installed. As can be seen, the dose counter chamber <NUM> includes a recess <NUM> for location of an end <NUM> (<FIG>) of the return spring <NUM>. The recess <NUM> has a substantially flat reaction surface for pushing on the end <NUM> of the return spring <NUM>. The recess <NUM> also has a shoulder surface <NUM> adjacent the reaction surface <NUM> and an entrance mouth <NUM> into the reaction surface <NUM>. A distinct guide surface <NUM>, which is substantially planar is provided for guiding the end <NUM> of the return spring <NUM> into the recess <NUM> during assembly. The distinct guide surface <NUM> is wider than the entrance mouth <NUM> in a direction across the mouth and this assists substantially in assembling the spring <NUM> into the recess <NUM>.

The entrance mouth <NUM> also has at least a chamfered entrance lip <NUM>, an extension <NUM> of which into the guide surface forms a slanted edge <NUM> of the distinct guide surface <NUM>. At least a portion of the distinct guide surface <NUM> comprises a portion of the body <NUM> which is recessed relative to the adjacent and partially surrounding portion <NUM> of the body by an edge <NUM>. The edge <NUM> is particularly effective in catching the end <NUM> of the return spring and the wide guide surface <NUM> is effective in guiding the spring <NUM> past the chamfered entrance lip <NUM> and onto the reaction surface <NUM> where it remains once installed. A further edge <NUM> of the guide surface <NUM> is spaced from and generally parallel to the edge <NUM>. The edge <NUM> forms an intersection with an adjacent portion <NUM> of the body <NUM>.

As shown in <FIG>, the main body of the inhaler <NUM> includes a barrier <NUM> separating an interior space <NUM> defined at least partly by the tubular body portion <NUM> from the dose counter chamber <NUM>. The barrier includes a stepped upper wall area <NUM> which has four steps <NUM>, <NUM>, <NUM>, <NUM> at different levels. The steps are arcuate and have substantially flat parts <NUM>, <NUM>, <NUM>, <NUM> aligned substantially perpendicular to the axis <NUM> of the valve stem block as well a part-cylindrical risers <NUM>, <NUM>, <NUM> between the substantially flat parts <NUM>, <NUM>, <NUM>, <NUM>.

The arcuate steps <NUM>, <NUM>, <NUM>, <NUM> are substantially concentric with the axis <NUM> of the valve stem block <NUM>. The steps <NUM>, <NUM>, <NUM>, <NUM> extend around the valve block <NUM> a distance/angle of about <NUM>° although this is only approximate and may be in the region of about <NUM> to <NUM>° in various embodiments. The material forming the barrier <NUM> is of substantially constant thickness throughout the steps <NUM>, <NUM>, <NUM>, <NUM> which is advantageous for manufacturing techniques by moulding.

As shown in <FIG> which is a view into the dose counter chamber <NUM>, the dose counter chamber <NUM> is formed with two heat staking pins <NUM>, <NUM> for attaching the dose counter system <NUM> permanently into position within the dose counter chamber <NUM>. One of the heat staking pins <NUM> is directly attached to two of the steps <NUM>, <NUM>. The heat staking pin <NUM> is attached to one substantially flat step part <NUM> and to two step risers <NUM>, <NUM>, providing secure and advantageous location of the heat staking pin <NUM> in the stepped upper wall area <NUM> of the barrier <NUM>. An aperture <NUM> for the actuating pin <NUM> of the dose counter system <NUM> is formed through the second furthest step part <NUM> away from the valve stem block <NUM>.

The stepped upper wall area <NUM> is highly advantageous since it enables the accommodation of a length of movement of the canister <NUM> and in particular its ferrule <NUM> (<FIG>) within the main body <NUM>. Therefore, even with a metering valve <NUM> as used in the inhaler <NUM> which has a relatively long end-to-end travel of approximately <NUM>, the internal components can be maintained within a relatively small and compact inhaler <NUM>, while also allowing for space in the dose counter chamber <NUM> for the dose counter system <NUM> and enabling the dose counter to be heat staked firmly in place by the heat stake pins <NUM>, <NUM> including the pin <NUM> which is attached to the stepped upper wall area <NUM> of the barrier <NUM>.

As shown in <FIG>, the valve stem block <NUM> has the cylindrical inner bore <NUM> which has an inner diameter BD1 which has a first diameter, a seal <NUM> at an entrance to the inner bore <NUM> having a second diameter BD2 which is smaller than the first diameter. The seal <NUM> is inwardly convex and/or is toroidal. The first diameter BD1 is about <NUM> and is about <NUM>% larger than the second diameter BD2. The valve system <NUM> has a cylindrical outer surface <NUM> (<FIG>) with a diameter which is smaller than the first diameter BD1 but larger than the second diameter BD2 prior to introduction of the valve stem <NUM> into the inner bore <NUM> and is about <NUM>% larger. The valve stem block <NUM> also includes an annular recess <NUM> which extends more than half way around the periphery of the inner bore <NUM>, in this embodiment about <NUM>° or more. The annular recess <NUM> has an inner diameter which is about <NUM>% larger than the inner diameter BD1 of the cylindrical inner bore <NUM>. This arrangement has been found to provide extremely effective sealing against blowback which has occurred in prior designs which have a substantially greater interference fit between the exterior diameter of the valve stem and the interior diameter of the inner bore of the valve stem. Surprisingly, and advantageously, using the inwardly convex seal <NUM> to the bore <NUM>, very effective sealing without any blowback can be achieved even with a relatively small interference fit between the valve stem <NUM> and the seal <NUM>, the annular recess <NUM> assisting in providing resilience to the valve stem block <NUM> for this purpose. The small interference fit allows for good sealing even when the inhaler <NUM> is subjected to high temperatures for long periods since there is little stress to relieve. Furthermore, the seal <NUM> permits a relatively low insertion force for inserting the valve stem <NUM> into the valve stem block <NUM> and this enables accurate positioning of these two components relative to one another in an axial direction of the valve stem <NUM> so that the dose counter system <NUM> can count reliably by way of accurate actuation of its actuator pin <NUM> by the canister ferrule <NUM>.

As shown in the various sectional views of <FIG> through to 18C, a lock system <NUM> is provided for locking the cap housing or force holding unit housing <NUM> on the main body <NUM>. Helical threads <NUM>, <NUM> are provided, with male threads <NUM> on the cap housing <NUM> and female threads <NUM> on the main body <NUM>, for rotational attachment of the cap housing <NUM> on the main body <NUM> and for resisting relative longitudinal movement therebetween without rotation.

The lock system <NUM> includes a protrusion <NUM> in the region of the helical thread <NUM> on the main body <NUM> which is lockable in a recess <NUM> in the region of the helical thread <NUM> on the cap housing. As shown in <FIG>, the inhaler <NUM> includes two of the protrusions <NUM> in two of the recesses <NUM> formed at opposing locations on the inhaler, i.e. diametrically opposite to one another. As shown in <FIG>, each protrusion <NUM> has a leading ramp surface <NUM> and a trailing ramp surface <NUM>, the included angle A between the ramp and trailing surfaces <NUM>, <NUM> being <NUM>°, although a range of about <NUM> to <NUM>° is envisaged. The recesses have a similar included angle which is smaller than the angle of the protrusion <NUM> at about <NUM>°. This ensures that the protrusion <NUM> will fit securely in the recess <NUM> without any play rotationally.

The main body <NUM> has a central axis <NUM> coincident with that <NUM> of the valve stem block <NUM> and the ramp surfaces <NUM> are inclined at an angle of about <NUM>° ± <NUM>° to tangential.

The lock system <NUM> also includes a first lock member <NUM> on the cap housing <NUM> which is adapted to engage a second lock member <NUM> at a lock interface <NUM> formed by respective engagement faces thereof, the lock interface <NUM> being oriented substantially perpendicular to tangential. This therefore assists in preventing rotation. The first lock member <NUM> has a radial extent of <NUM>, although about <NUM> to <NUM> is envisaged in other embodiments or <NUM> to <NUM>. The second lock member <NUM>, it will be appreciated, has a greater radial extent. The first lock member <NUM> has a longitudinal extent parallel to the axis <NUM> of about <NUM>.

The main body <NUM> and cap housing <NUM> are formed of plastics material and the lock system <NUM> is configured so that a release torque required to overcome the locking provided by the plastics main body and cap housing at the lock interface <NUM> and at the protrusions <NUM> and recesses <NUM> is more than <NUM>. In the described example, the release torque is about <NUM>. When an information sticker is applied over the top of the interface between the main body <NUM> and cap housing <NUM> the release torque may rise to about <NUM>. This has been found to be lower than <NUM> and this is low enough that a laboratory is capable of opening up the inhaler <NUM> for inspection without significant destruction. However, this level of torque is significantly higher than likely to be tried by a user in an attempt to open the inhaler <NUM> which might result in tampering and damage to the components of the inhaler <NUM>.

In an alternative design, the radial extent of the first locking member <NUM> is significantly greater at about <NUM> and this has been found, surprisingly, to provide a removal torque which is considered too high at <NUM> for laboratory disassembly without destruction. In contrast, a design omitting the first lock member <NUM> was found to provide a removal torque of only <NUM> which is considerably too low and likely to result in users rotating the cap housing <NUM> off the main body <NUM> and potentially damaging the inhaler by investigating the contents. In fact, this was the first design attempted by the present inventors and the next step was to double up the number of protrusions <NUM> and recesses <NUM> so that there are four in total in an attempt to double the torque, at least, from <NUM>. However, surprisingly, with this design, the removal torque was only increased by about <NUM>% to <NUM>. The ideal remove torque was surprisingly achieved with only one protrusion <NUM> on each thread <NUM> and with a locking member <NUM> with only a small radial extent of <NUM>. The locking member <NUM> advantageously also includes a lead ramp <NUM> for achieving a smooth snap lock of the cap housing <NUM> onto the main body <NUM> when the cap housing <NUM> is twisted into the locked position.

<FIG> shows a modification of the inhaler <NUM> to form an inhaler <NUM> which is a metered dose inhaler having a main body <NUM> and mouthpiece dust cap <NUM> for the mouthpiece <NUM> for stopping foreign objects entering the central bore <NUM> of the mouthpiece <NUM> and for protecting the mouthpiece generally. This metered dose inhaler <NUM> does not include the cap housing <NUM> or the force holding unit <NUM> or yoke <NUM> but it does include the same dose counter chamber <NUM>, dose counter system <NUM>, canister <NUM> and metering valve <NUM> and valve stem <NUM> and valve stem block <NUM> as that in the inhaler <NUM>. If this metered dose inhaler is left with the canister <NUM> accidentally depressed, for example while squashed in luggage or clothing by mistake, such that the metering chamber is left exposed to the atmosphere for a considerable period of time, then when the inhaler <NUM> is located and turned upright for use with respective gravity with the canister allowed to extend to its rest position in which the metering chamber communicates with the interior reservoir, any gas such as air which has entered the metering chamber is easily expelled up into the interior reservoir of the canister just as in the inhaler <NUM> such that an accurate next dose is applied and the problem of gas lock is therefore avoided.

Inhalers in accordance with preferred embodiments of the present invention are suitable for the delivery of many classes of active ingredients by inhalation, and may be used for the treatment of various diseases and disorders. According to preferred embodiments, the inhaler is used for the treatment of respiratory disorders (e.g., COPD, asthma and/or cystic fibrosis). The inhaler may also be used to treat non-respiratory disorders, such as migraine. According to an embodiment, a method of treating a respiratory disease or disorder comprises actuating the inhaler to administer a therapeutically effective amount of one or more active ingredients. As described herein, the canister of the inhaler contains a drug formulation comprising one or more active ingredients in suspension or in solution. Preferably, the drug formulation comprises one or more active ingredients in propellant (e.g., HFA). The drug formulation may optionally comprise one or more excipients in combination with the active ingredient(s) and propellant.

In certain embodiments, the inhaler described herein can be used to treat patients suffering from a disease or disorder selected from asthma, chronic obstructive pulmonary disease (COPD), exacerbation of airways hyper reactivity consequent to other drug therapy, allergic rhinitis, sinusitis, pulmonary vasoconstriction, inflammation, allergies, impeded respiration, respiratory distress syndrome, pulmonary hypertension, pulmonary vasoconstriction, and any other respiratory disease, condition, trait, genotype or phenotype that can respond to the administration of, for example, a long-acting muscaric antagonist (LAMA), long-acting β2-adrenergic agonist (LABA), corticosteroid, or other active agent as described herein, whether alone or in combination with other therapies. In certain embodiments, the compositions, systems and methods described herein can be used to treat pulmonary inflammation and obstruction associated with cystic fibrosis. As used herein, the terms "COPD" and "chronic obstructive pulmonary disease" may encompass chronic obstructive lung disease (COLD), chronic obstructive airway disease (COAD), chronic airflow limitation (CAL) and chronic obstructive respiratory disease (CORD) and include chronic bronchitis, bronchiectasis, and emphysema. As used herein, the term "asthma" refers to asthma of whatever type or genesis, including intrinsic (non-allergic) asthma and extrinsic (allergic) asthma, mild asthma, moderate asthma, severe asthma, bronchitic asthma, exercise-induced asthma, occupational asthma and asthma induced following bacterial infection. Asthma is also to be understood as embracing wheezy-infant syndrome.

A range of classes of active ingredients have been developed to treat respiratory disorders and each class has differing targets and effects.

Bronchodilators are employed to dilate the bronchi and bronchioles, decreasing resistance in the airways, thereby increasing the airflow to the lungs. Bronchodilators may be short-acting or long- acting. Typically, short-acting bronchodilators provide a rapid relief from acute bronchoconstriction, whereas long-acting bronchodilators help control and prevent longer-term symptoms.

Different classes of bronchodilators target different receptors in the airways. Two commonly used classes are anticholinergics and β2-agonists.

Anticholinergics (or "antimuscarinics") block the neurotransmitter acetylcholine by selectively blocking its receptor in nerve cells. On topical application, anticholinergics act predominantly on the M3 muscarinic receptors located in the airways to produce smooth muscle relaxation, thus producing a bronchodilatory effect. Non-limiting examples of long-acting muscarinic antagonists (LAMA's) include tiotropium (bromide), oxitropium (bromide), aclidinium (bromide), ipratropium (bromide) glycopyrronium (bromide), oxybutynin (hydrochloride or hydrobromide), tolterodine (tartrate), trospium (chloride), solifenacin (succinate), fesoterodine (fumarate), darifenacin (hydrobromide) and umeclidinium (bromide). In each case, particularly preferred salt/ester forms are indicated in parentheses.

β2-Adrenergic agonists (or "β2-agonists") act upon the β2-adrenoceptors and induce smooth muscle relaxation, resulting in dilation of the bronchial passages. Non-limiting examples of long-acting β2-adrenergic agonists (LABA's) include formoterol (fumarate), salmeterol (xinafoate), indacaterol (maleate), bambuterol (hydrochloride), clenbuterol (hydrochloride), olodaterol (hydrochloride), carmoterol (hydrochloride), tulobuterol (hydrochloride) and vilanterol (triphenylacetate). Non-limiting examples of short-acting β2-agonists (SABA's) include albuterol (sulfate) and levalbuterol (tartrate). In each case, particularly preferred salt/ester forms are indicated in parentheses.

According to one embodiment, the formulation comprises albuterol (sulfate).

Another class of active ingredients employed in the treatment of respiratory disorders are inhaled corticosteroids (ICS's). ICS's are steroid hormones used in the long-term control of respiratory disorders. They function by reducing the airway inflammation. Non-limiting examples of inhaled corticosteroids include budesonide, beclomethasone (dipropionate), fluticasone (propionate), mometasone (furoate), ciclesonide and dexamethasone (sodium).

According to one embodiment, the formulation comprises beclomethasone dipropionate.

According to an embodiment, the inhaler delivers one or more active ingredients selected from the group consisting of tiotropium (bromide), oxitropium (bromide), aclidinium (bromide), ipratropium (bromide) glycopyrronium (bromide), oxybutynin (hydrochloride or hydrobromide), tolterodine (tartrate), trospium (chloride), solifenacin (succinate), fesoterodine (fumarate), darifenacin (hydrobromide), umeclidinium (bromide), formoterol (fumarate), salmeterol (xinafoate), indacaterol (maleate), bambuterol (hydrochloride), clenbuterol (hydrochloride), olodaterol (hydrochloride), carmoterol (hydrochloride), tulobuterol (hydrochloride), vilanterol (triphenylacetate), albuterol (sulfate), levalbuterol (tartrate), budesonide, beclomethasone (dipropionate), fluticasone (propionate), mometasone (furoate), ciclesonide, dexamethasone (sodium) and a combination thereof.

According to particular embodiments, the inhaler delivers a combination of at least two different active ingredients (two, three, four, etc.) which belong to the same or different classes. According to one embodiment, the inhaler delivers a "triple combination" of three different active ingredients. The three active ingredients may belong to three different active ingredient classes (e.g., LAMA, LABA, ICS); alternatively, two or three of the active ingredients may belong to the same class.

According to additional embodiments, the inhaler delivers one or more active ingredients selected from the group consisting of a long-acting muscarinic antagonist (LAMA), a long-acting β2-adrenergic agonist (LABA), an inhaled corticosteroid (ICS) and a combination thereof. Thus, the inhaler may deliver a formulation comprising one or more LAMA's, one or more LABA's and one or more ICS's. That is, the device may deliver a double combination of a LAMA and a LABA, a LAMA and an ICS, or a LABA and an ICS; or a triple combination of a LAMA, a LABA and an ICS.

According to an alternative embodiment, the inhaler delivers one or more active ingredients for the treatment of a headache disorder, such as migraine. For example, the inhaler may deliver dihydroergotamine (DHE) or a pharmaceutically acceptable salt thereof, such as dihydroergotamine mesylate.

In one embodiment the inhaler comprises a reservoir, particularly a pressurized canister, comprising an active ingredient.

Preferably the active ingredient is presented in a pharmaceutical formulation comprising a propellant, optionally a co-solvent and optionally other pharmaceutically acceptable excipients.

Preferred propellants include hydrofluroalkanes, in particular <NUM>,<NUM>,<NUM>,<NUM>-tetrafluoroethane (HFA134a), <NUM>,<NUM>,<NUM>,<NUM>,<NUM>,<NUM>,<NUM>-heptafluoropropane (HFA227), or combinations thereof. Most particular propellant is HFA134a. Most particular HFA134a concentration is from about <NUM> %w/w to <NUM> %w/w.

HFA134a has a low boiling point (-<NUM>) and correspondingly high vapor pressure (<NUM> kpa) at <NUM>.

Particular co-solvents are selected from the list of aliphatic alcohols (particularly ethanol), glycerols and glycols. Most particular co-solvent is ethanol. Most particular ethanol concentration is about <NUM> %w/w.

Ethanol is well known to be compatible with HFA-134a and increases the solubility of BDP. Ethanol (anhydrous) is used as a co-solvent to aid solubility of BDP in HFA134a. A concentration of around <NUM> %w/w of ethanol is known to provide necessary stability, preventing precipitation and achieving correct aerosol performance.

Other pharmaceutically acceptable excipients include surfactants, particularly oleic acid.

Preferably, the active ingredient is suspended in the propellant. Alternatively the active ingredient is dissolved in the propellant. The active ingredient may also be partly suspended and partly dissolved in the propellant.

A particular active ingredient is selected from the group consisting of anti-inflammatory agents, β2-adrenoreceptor agonists, anti-cholinergic agents, anti-histamines, serotonin agonists, and combinations thereof.

A particular corticosteroid is beclomethasone dipropionate (BDP).

A particular β2-adrenoreceptor agonist is salbutamol sulphate.

In a particular embodiment of the invention, the active ingredient is selected from beclomethasone dipropionate (BDP), salbutamol sulphate and dihydroergotamine.

In a particular embodiment the inhaler comprises a pressurized canister comprising beclomethasone dipropionate as active ingredient, HFA134a as propellant and ethanol as co-solvent.

In a particular embodiment the inhaler comprises a pressurized canister comprising beclomethasone dipropionate as active ingredient at about <NUM>/ml, HFA134a as propellant at about <NUM>/ml and ethanol as co-solvent at about <NUM>/ml.

In a particular embodiment the inhaler comprises a pressurized canister comprising beclomethasone dipropionate as active ingredient at about <NUM> %w/w, HFA134a as propellant at about <NUM> %w/w and ethanol as co-solvent at about <NUM> %w/w.

In a particular embodiment the inhaler comprises a pressurized canister comprising salbutamol sulphate as active ingredient, HFA134a as propellant and ethanol as co-solvent.

In a particular embodiment the inhaler comprises a pressurized canister comprising about <NUM> of salbutamol sulphate as active ingredient, about <NUM> of HFA134a as propellant and about <NUM> of ethanol as co-solvent.

One embodiment relates to an inhaler as described herein comprising an active ingredient.

One embodiment relates to an inhaler as described herein comprising an active ingredient for therapeutic use.

One embodiment relates to an inhaler as described herein comprising an active ingredient for use in the treatment or prevention of a respiratory disease, particularly COPD or Asthma.

One embodiment relates to an active ingredient for use in the treatment or prevention of a respiratory disease, particularly COPD or Asthma, wherein the active ingredient is delivered to a patient using an inhaler as described herein.

One embodiment relates to a method for the treatment or prevention of respiratory diseases, particularly COPD or Asthma, which method comprises administering an active ingredient to a human being or animal using an inhaler as described herein.

One embodiment relates to the use of an inhaler as described herein comprising an active ingredient for the treatment or prevention of respiratory diseases, particularly COPD or Asthma.

Embodiments of the present invention may be further understood by reference to the Example provided below.

According to the following example, a method of using the inhaler of the present invention comprises delivering a therapeutically effective amount of beclomethasone dipropionate HFA for the treatment of asthma, particularly for the maintenance treatment of asthma as prophylactic therapy in patients <NUM> years of age and older, wherein the inhaler is a breath-actuated inhaler (BAI) as described herein and the step of actuating the inhaler comprises inhaling through the inhaler. The breath-actuated inhaler may be used by patients to deliver at least about <NUM> mcg beclomethasone dipropionate upon each actuation, preferably twice daily, e.g., it may be used by patients <NUM> to <NUM> years old to deliver <NUM> mcg or <NUM> mcg beclomethasone dipropionate twice daily, or may be used by patients <NUM> years of age and older to deliver <NUM> mcg, <NUM> mcg, <NUM> mcg or <NUM> mcg beclomethasone dipropionate twice daily. Actuation of the breath-actuated inhaler is preferably triggered by an inspiratory flow rate of at least about <NUM> liters per minute (L/min), and includes a primeless valve so that no priming actuations are required before use. A method of treating asthma may comprise inhaling through the BAI at a flow rate of at least about <NUM>/min without priming the inhaler before use, wherein the inhaler comprises a primeless valve as described herein and wherein the mean change from baseline for FEV<NUM> between <NUM>-<NUM> weeks or between <NUM>-<NUM> weeks or between <NUM>-<NUM> weeks of using the BAI is greater than about <NUM> or greater than about <NUM>. Preferably, the mean peak plasma concentration (Cmax) of BDP is between about <NUM> pg/mL and about <NUM> pg/mL or between about <NUM> pg/mL and about <NUM> pg/mL at <NUM> minutes after inhalation of <NUM> mcg using the BAI (<NUM> inhalations of the <NUM> mcg/inhalation strength). The mean peak plasma concentration of the metabolite <NUM>-BMP is preferably between about <NUM> pg/mL and about <NUM> pg/mL or between about <NUM> pg/mL and about <NUM> pg/mL at <NUM> minutes after inhalation of <NUM> mcg of the BAI.

The breath-actuated inhaler (BAI) in this example included a canister having an interior reservoir containing pressurised inhalable substances including fluid; a "primeless" metering valve including a metering chamber and a valve stem defining a communication path between the metering chamber and the interior reservoir, the communication path including an opening configured to permit flow between a transfer space inside the valve stem and the interior reservoir, the interior reservoir being arranged for orientation above the metering chamber whereby gas such as air located within the metering chamber is replaced with liquid from the interior reservoir. Preferably, the primeless metering valve is the embodiment shown in <FIG> and described in <CIT>. Alternatively, the primeless metering valve is similar to the embodiment shown in <FIG> of <CIT>, as described herein.

Two confirmatory Phase <NUM> clinical trials were conducted comparing the above-described breath-actuated inhaler with placebo in adult and adolescent patients with persistent asthma (Trial <NUM> and Trial <NUM>).

Trial <NUM>: This randomized, double-blind, parallel-group, placebo-controlled, <NUM>-week, efficacy and safety trial compared the breath-actuated inhaler <NUM> and <NUM> mcg given as <NUM> inhalation twice daily with placebo in adult and adolescent patients with persistent symptomatic asthma despite low-dose inhaled corticosteroid or non-corticosteroid asthma therapy. Patients aged <NUM> years and older who met the entry criteria including FEV<NUM> <NUM>-<NUM> percent of predicted normal, reversible bronchoconstriction of <NUM>% with short-acting inhaled beta-agonist entered a <NUM>-<NUM> day run-in period. <NUM> patients (<NUM> previously treated with inhaled corticosteroids) who met all the randomization criteria including asthma symptoms and rescue medication use were discontinued from asthma maintenance medication and randomized equally to treatment with the breath-actuated inhaler (BAI) <NUM> mcg/day BDP, the breath-actuated inhaler <NUM> mcg/day BDP or placebo. Baseline FEV<NUM> values were similar across treatments. The primary endpoint for this trial was the standardized baseline-adjusted trough morning forced expiratory volume in <NUM> second (FEV<NUM>) area under the effect curve from time zero to <NUM> weeks [FEV<NUM> AUEC(<NUM>-12wk)]. Patients in both treatment groups had significantly greater improvements in trough FEV<NUM> compared to placebo (BAI <NUM> mcg/day, LS mean change of <NUM> and BAI <NUM> mcg/day, LS mean change of <NUM> over <NUM> weeks). In addition, the mean change from baseline for FEV<NUM> was greater than about <NUM> between week <NUM> through week <NUM> (generally between about <NUM> and about <NUM>). Both doses of BAI were effective in improving asthma control with significantly greater improvements in FEV<NUM> and morning PEF when compared to placebo. Reduction in asthma symptoms was also supportive of the efficacy of the BAI.

Trial <NUM>: This randomized, double-blind, parallel-group, placebo-controlled, <NUM>-week, efficacy and safety trial compared BAI <NUM> and <NUM> mcg BDP given as <NUM> inhalations twice daily and placebo in adult and adolescent patients with persistent symptomatic asthma despite treatment with non-corticosteroid, inhaled corticosteroids (with or without a long acting beta agonist [LABA]), or combination asthma therapy. The study also included a reference treatment group, QVAR® Inhalation Aerosol (QVAR MDI) <NUM> mcg, <NUM> inhalations twice daily. Patients aged <NUM> years and older who met the entry criteria including FEV<NUM> <NUM>-<NUM>% predicted normal, reversible bronchoconstriction of at least <NUM>% with short-acting inhaled beta-agonist discontinued baseline asthma treatment and entered a <NUM>-<NUM> week run-in period. <NUM> patients (<NUM> previously treated with ICS with or without LABA) who met all the randomization criteria including FEV<NUM> of <NUM>-<NUM>% predicted and <NUM>% reversibility with short-acting inhaled beta-agonist, and asthma symptoms were randomized equally to the BAI <NUM> mcg/day, BAI <NUM> mcg/day, QVAR MDI <NUM> mcg/day or placebo. Baseline FEV<NUM> values were similar across treatments. The primary endpoint for this trial was the standardized baseline-adjusted trough morning forced expiratory volume in <NUM> second (FEV<NUM>) area under the effect curve from time zero to <NUM> weeks [FEV<NUM> AUEC(<NUM>-6wk)]. Patients in both treatment groups had significantly greater improvements in trough FEV<NUM> compared to placebo (BAI <NUM> mcg/day, LS mean change of <NUM> and BAI <NUM> mcg/day, LS mean change of <NUM> over <NUM> weeks). Treatment with QVAR MDI was similar. The change from baseline in morning FEV<NUM> during the trial was greater than <NUM> or <NUM> between week <NUM> through week <NUM> (generally between about <NUM> and about <NUM>). Both doses of the BAI were effective in improving asthma control with significantly greater improvements in FEV<NUM>, morning PEF, weekly average of daily trough morning FEV<NUM>, reduced rescue medication use and improved asthma symptom scores than with placebo. Similar results were demonstrated with QVAR MDI.

The inhaler of the present disclosure has broad application. The apparatuses and associated methods in accordance with the present disclosure have been described with reference to particular embodiments thereof in order to illustrate the principles of operation. The above description is thus by way of illustration and not by way of relative and directional references (including: upper, lower, upward, downward, left, right, leftward, rightward, top, bottom, side, above, below, front, middle, back, vertical, horizontal, height, depth, width, and so forth) are normally given by way of example to aid the reader's understanding of the particular embodiments described herein. They should not be read to be requirements or limitations, particularly as to the position, orientation, or use of the invention unless specifically set forth in the claims. Connection references (e.g., attached, coupled, connected, joined, secured and the like) are to be construed broadly and may include intermediate members between a connection of elements and relative movement between elements. As such, connection references do not necessarily infer that two elements are directly connected and in fixed relation to each other, unless specifically set forth in the claims.

Claim 1:
An inhaler (<NUM>) for the inhalation of inhalable substances, the inhaler (<NUM>) comprising: a canister (<NUM>) having an interior reservoir (<NUM>) containing pressurised inhalable substances including fluid; a metering valve (<NUM>) including a metering chamber (<NUM>) and a valve stem (<NUM>) defining a communication path between the metering chamber (<NUM>) and the interior reservoir (<NUM>), the communication path including an opening (<NUM>) configured to permit flow between a transfer space inside the valve stem and the interior reservoir (<NUM>), the interior reservoir (<NUM>) being arranged for orientation above the metering chamber (<NUM>) whereby gas such as air located within the metering chamber (<NUM>) is replaced with liquid from the interior reservoir (<NUM>),
characterised in that the inhaler (<NUM>) includes a metering valve spring (<NUM>) and an opposing canister spring (<NUM>) for drivingly firing the canister (<NUM>), the metering valve spring (<NUM>), canister spring (<NUM>) and metering valve (<NUM>) being arranged in the inhaler (<NUM>) such that an equilibrium of various forces is achieved in at least one ready-to-fire configuration of the inhaler (<NUM>) in which the metering chamber (<NUM>) is isolated from the atmosphere and open to the interior reservoir.