HK1182033B

HK1182033B - Metered-dose inhaler actuator, metered-dose inhaler

Info

Publication number: HK1182033B
Application number: HK13109298.5A
Authority: HK
Inventors: G．布拉姆比拉; D．A．刘易斯; R.约翰森
Original assignee: 奇斯药制品公司
Priority date: 2010-09-06
Filing date: 2011-09-05
Publication date: 2017-01-20

Description

Metered dose inhaler actuator, metered dose inhaler

Technical Field

The present invention relates to a metered dose inhaler actuator, a metered dose inhaler and a method of using the same.

Background

Among the devices that can be used to deliver drugs to the lungs, Metered Dose Inhalers (MDIs) are widely used.

Metered dose inhalers are aerosol delivery systems designed to deliver a medicament formulated with a solvent, such as a compressed low boiling point liquefied gas propellant. Metered dose inhalers are designed to meter a predetermined amount of a medicament either completely dissolved (in solution) or suspended in a formulation and dispense the dose in the form of a cloud or plume of breathable aerosol.

A conventional metered-dose inhaler 100 is shown in fig. 40. The metered-dose inhaler 100 comprises an actuator 101 in which actuator 101 a canister 102 is positioned. The canister 102 contains a formulation in which the drug is in solution or suspension with a low boiling point propellant. The canister 102 is typically provided with a metering valve having a hollow valve stem 103 for measuring discrete doses of a medicament formulation. The dose is dispensed in the form of a respirable cloud or plume 104.

The typical actuator 101 has a nozzle or valve stem block 105, the nozzle or valve stem block 105 receiving the hollow valve stem 103 of the aerosol canister 102. The valve stem block 105 defines the walls of the valve stem receptacle, the expansion chamber 106 and the orifice 107. The orifice 107 is used to push the aerosol formulation toward the mouthpiece opening 110 and assist in aerosolizing the aerosol formulation. Conventionally, the orifice 107 is arranged such that its longitudinal axis is aligned with the longitudinal axis 109 of the actuator mouthpiece portion, so that aerosol exits the orifice in an average direction towards the mouthpiece opening 110. That is, the orifice 107 in the valve stem block 105 is typically positioned at an angle of about 90 ° to about 110 ° from the direction of the hollow valve stem 103) such that when the canister 102 is actuated, the propellant-containing formulation moves down the stem 103 and expands within the expansion chamber 106 before being ejected through the orifice 107 toward the mouthpiece opening 110. The formulation is aerosolized in a direction that extends at an angle of about 90 ° to about 110 ° to the longitudinal direction of the aerosol canister 102. An example of arranging the valve stem block 105 in an actuator housing as illustrated in fig. 40 is described, for example, in WO2009/003657a 1.

In a conventional actuator design as shown in fig. 40, the manufacturing process constrains the possible shapes of the orifice 107, enabling the orifice 107 to be implemented in the valve stem block 105. For example, in a conventional molding process, pins may be provided in the mold to allow for the formation of the apertures 107. When it is desired to withdraw the pin from the opening after the actuator has been molded, the orifice design may be limited to a cylindrical shape or a shape that flares outward toward the interface opening 110. For example, the flared portion 108 may be formed on an exterior face of the valve stem block 105 and around the outlet of the orifice 107.

Modification of the orifice design is limited due to the orientation of the orifice 107 and expansion chamber 106 within the stem block 105. For example, certain modifications may be made to take advantage of the effects of different orifice diameters and orifice lengths of the cylindrical orifice 107. However, it would be desirable to have a more flexible orifice design.

While it is desirable to achieve a more flexible orifice design, the actuator performance should at least be similar to, or even better than, conventional designs in terms of certain characteristics. For example, it may be desirable to allow greater flexibility in orifice design while reducing the proportion of non-respirable particles or droplets dispensed from the actuator.

The effect of airflow patterns on actuator characteristics has been discussed in various contexts in the art. For purposes of illustration, US4,972,830 describes an inhaler in which the channel that directs the pressurised medicament from the canister to the mouthpiece opening is of a particular configuration to reduce the ejection rate and improve dispersion of the medicament in the airflow. The inhaler of US4,972,830 has a conventional arrangement of orifices oriented at a 90 ° angle to the valve stem axis, which makes the use of orifice shapes that taper towards the mouthpiece opening challenging in conventional mass production techniques.

In view of the above, there remains a need in the art for a metered-dose inhaler actuator and metered-dose inhaler that meet some of the above needs. In particular, there remains a need for metered dose inhaler actuators and metered dose inhalers that allow for a wider variety of orifice shapes to be achieved. There is also a need for an actuator and metered dose inhaler that allows for the removal of a substantial portion of the non-respirable particles or droplets from the aerosol cloud prior to dispensing the aerosol cloud through the mouthpiece opening.

Disclosure of Invention

These and other needs are met by a metered-dose inhaler actuator, a metered-dose inhaler and a method of using the same, as defined in claims 1, 14 and 15. The dependent claims define embodiments.

According to one aspect, a metered dose inhaler actuator is provided. The actuator includes a housing having an interface portion and a canister receiving portion configured to receive a canister. The housing extends from an opening for receiving a medicament canister to a mouthpiece opening. The actuator also includes a member disposed within the housing and defining a valve stem receptacle configured to receive a valve stem of the canister. An orifice is formed in the member in fluid communication with the valve stem receptacle and extending to a face of the member opposite the valve stem receptacle. The longitudinal axis of the orifice is aligned with the longitudinal axis of the valve stem receptacle. At least one air inlet port is disposed in the housing of the housing in spaced relation to the opening for receiving the medicament canister and the mouthpiece opening, the at least one air inlet port being in fluid communication with the mouthpiece opening.

As used herein, the term "aligned" when referring to two axes means "coincident or parallel to each other".

In the actuator, a longitudinal axis of the orifice is aligned with a longitudinal axis of the valve stem receptacle. This allows a wider variety of orifice shapes to be achieved even when using conventional actuator manufacturing techniques. The orientation of the longitudinal axis of the orifice allows a wider variety of orifice shapes to be achieved without the need for a member defining an orifice that is manufactured separately from the housing of the actuator. The non-respirable particles or droplets may impinge on the inner surface of the actuator housing such that a majority of the non-respirable particles or droplets may be removed prior to dispensing the aerosol cloud or plume from the actuator. For example, an orifice may be formed having a tapered portion that tapers in a direction away from the valve stem receptacle. At least one air inlet opening provided in the housing shell allows an air flow to be formed in the housing, which air flow carries particles or liquid droplets when the actuator is put into use.

The actuator is designed such that the atomised spray can be ejected from an orifice whose longitudinal axis coincides with the longitudinal axis of the valve stem receptacle and, in use of the device, with the longitudinal axis of the can.

The at least one air inlet may be provided in a portion of the housing extending from the member defining the valve stem receptacle towards the interface opening. Thereby, a gas flow may be formed, which allows for the transport of a high fine particle fraction.

The mouthpiece portion may have a longitudinal axis and the housing may have a wall oriented at an angle relative to the longitudinal axis of the mouthpiece portion (i.e., the wall is not parallel to the longitudinal axis of the mouthpiece portion). An inlet of the at least one inlet may be provided in the wall. The wall may extend substantially parallel to the longitudinal axis of the aperture. The wall may be a rear wall of the canister receiving portion. Thereby, an air flow may be established, which allows to deliver a high fine particle fraction.

The air inlet may be positioned such that it is visible through the interface opening for at least one viewing direction. The plurality of air inlets may be positioned such that the air inlets are visible through the interface opening for at least one viewing direction. Thereby, an airflow pattern can be established during use of the actuator, wherein the airflow interacts with the aerosol plume. Respirable particles or droplets can be efficiently transported in the airflow mode towards the interface opening.

The air inlet may be positioned in a base of the actuator, the base being defined by a boundary of the interface portion, the boundary being a lower boundary of the interface portion in operation of the actuator. A plurality of air inlets may be positioned in the base of the actuator. By positioning one or more air inlets in the base of the actuator, an air flow is created which has an almost opposite direction to the direction of the plume in the vicinity of the air inlets. Actuator deposition may thereby be reduced. This may improve aerosol performance. A high fine particle fraction can be obtained. For the air inlet port(s) positioned on the actuator base, the distance between the aperture and the air inlet port(s) may be greater than for the air inlet port(s) positioned in the actuator sidewall. The number and location of the air inlet(s) may be selected according to the distance between the aperture and the actuator base.

At least one of the air inlet port(s) formed in the base of the actuator may be positioned towards the rear wall of the actuator relative to the point of impact of the plume. That is, the intersection of the longitudinal axis of the orifice with the actuator base may be at a distance from the mouthpiece opening that is less than the distance of the at least one air inlet in the base from the mouthpiece opening, the distances being measured along a line parallel to the longitudinal axis of the mouthpiece portion, respectively.

If more than one air inlet opening is positioned in the actuator base, the offset between the air inlet openings in a direction transverse to the longitudinal axis of the mouthpiece portion may be set to correspond to the width of the plume as it impinges on the actuator base.

Additionally or alternatively, several air inlets may be positioned in the actuator base near the intersection of the longitudinal axis of the aperture and the actuator base.

The air inlet may be positioned on a line parallel to the longitudinal axis of the mouthpiece portion and passing through the mouthpiece opening. The actuator may be configured such that a straight line passes through the hollow interior of the housing without passing through any solid actuator components. This allows for establishing an airflow pattern during use of the actuator, wherein respirable particles or droplets can be efficiently transported towards the interface opening.

The member and the air inlet may be configured such that all air output via the interface opening during use of the actuator is drawn into the housing interior through the at least one air inlet. This allows the airflow pattern in the housing to be controlled via the position of the at least one air inlet.

The member may extend across a cross-sectional area of the canister receiving portion. This allows the member to provide adequate support to the canister during use of the actuator, while the arrangement of the orifice with its longitudinal axis in register with the axial axis of the valve stem receptacle can be implemented in a simple geometry.

The member may be configured to prevent gas from passing through the member radially outward of the bore. That is, the member may be configured such that gas may only exit from the face opposite the valve stem receptacle through the aperture. During use of the actuator, air flow directed along the longitudinal axis of the canister receiving portion and facing towards the actuator base may be reduced or inhibited.

The interface portion may define a base of the actuator, and the member may be arranged spaced apart from the base. The member may particularly be arranged in the canister receiving portion such that it is not visible through the interface opening. Thereby, the influence of the component on the air flow pattern from the at least one air inlet to the mouthpiece opening may be reduced or inhibited.

The distance between the plane of the face of the member in which the orifice outlet is located and the actuator base measured along the actuator rear wall may define a reference height. The reference height may be in the range of 8mm to 52 mm. The reference height may specifically be in the range of 12mm to 32 mm. The reference height may specifically be in the range of 12mm to 22 mm. The reference height may in particular be 22 mm. For this reference height, a high fine particle dose can be obtained.

The aperture may have at least one portion that tapers towards a face of the member opposite the receiving portion. Thus, the aerosolization of aerosol formulations comprising high concentrations of polar low volatility compounds, which may be one or more polar co-solvents such as ethanol, water or ethylene glycol, may be improved.

The maximum diameter of the conical portion of the orifice may match the outer diameter of the valve stem. Thereby, the deposition of the drug within the valve stem may be reduced.

The maximum diameter of the conical portion of the orifice may match the internal diameter of the valve stem. Thereby, the formation of vortices directly below the valve stem may be reduced and the deposition of medicament within the valve stem may be reduced.

An expansion chamber may be formed in the member. The expansion chamber may be in fluid communication with the orifice and the valve stem receptacle, and may have a longitudinal axis aligned with a longitudinal axis of the valve stem receptacle. Thus, the internal expansion chamber may be combined with the valve stem receptacle and the orifice in an in-line configuration according to the requirements dictated by the aerosol formulation to be delivered. The expansion chamber may have at least one portion that tapers towards a face of the member opposite the valve stem receiving portion. The tapered portion of the expansion chamber may provide a smooth transition to the orifice.

The longitudinal axis of the orifice may be arranged at an angle equal to or greater than 90 ° with respect to the longitudinal axis of the interface portion. Such a configuration may help to allow a greater amount of fine particles or droplets to be carried in the airflow through the base of the actuator.

In any of the embodiments, the longitudinal axis of the orifice may coincide with the longitudinal axis of the valve stem receptacle. If the expansion chamber is incorporated in the member, the longitudinal axis of the expansion chamber may coincide with the longitudinal axis of the valve stem receptacle.

The actuator may be configured to act as an actuator for a breath-actuated inhaler (BAI). This allows the use of an actuator in a system that eliminates the need for manual coordination by automatically actuating the release of a dose of aerosol when the patient inhales with his/her lips in contact with the mouthpiece.

When the actuator is configured as an actuator for a breath-actuated inhaler, the actuator may be configured such that the airflow is initiated prior to actuation of the valve assembly (i.e. prior to dispensing a dose from the canister). Whereby a good response can be obtained.

The actuator may comprise means for automatically actuating the release of a dose from the medicament container when the patient inhales with his/her lips in contact with the mouthpiece. With an actuator configured as such, a single inhalation by the patient can deliver a dose of aerosol and can cause the respirable particles and non-respirable particles of the plume to separate.

According to another aspect, a metered dose inhaler is provided. A metered dose inhaler comprises an actuator of any aspect or embodiment described herein and a canister having a metering valve. The canister includes a valve stem to be fitted into a valve stem receiving portion formed in a member of the actuator. The canister contains an aerosol formulation.

The aerosol formulation may be an aerosol solution formulation or an aerosol suspension formulation. Aerosol formulations may contain at least one active ingredient in a propellant or propellant/solvent system and optionally other excipients.

The metered dose inhaler may be a breath actuated inhaler. This configuration eliminates the need for manual coordination when using the inhaler by automatically actuating to release a dose of aerosol when the patient inhales with his/her lips in contact with the mouthpiece. Moreover, a single inhalation by the patient may deliver a dose of aerosol and may cause the respirable particles and non-respirable particles of the plume to separate.

According to another aspect, there is provided a method of using the actuator of any one of the aspects or embodiments described herein for dispensing an aerosol formulation from a canister. The method may be used to dispense aerosol formulations without interaction with the human or animal body. The method may be used, for example, to dispense aerosol formulations when the metered dose inhaler is actuated.

According to another aspect, a metered dose inhaler actuator is provided. The actuator includes a housing having an interface portion and a canister receiving portion configured to receive a canister. The actuator also includes a member disposed within the housing and defining a valve stem receptacle configured to receive a valve stem of the canister. An orifice is formed in the member in fluid communication with the valve stem receptacle and extending to a face of the member opposite the valve stem receptacle. The aperture formed in the member has a portion that tapers toward a face of the member disposed opposite the receiving portion.

With the actuator according to the other aspect, atomization of an aerosol formulation containing a high concentration of a polar compound can be improved.

In an actuator according to other aspects, a longitudinal axis of the orifice may be aligned with a longitudinal axis of the valve stem receptacle. If the expansion chamber is formed in the member, the longitudinal axis of the expansion chamber may also be aligned with the longitudinal axis of the valve stem receptacle. This configuration allows the tapered portion to be easily formed when the actuator is manufactured.

In an actuator according to other aspects, the at least one air inlet may be provided in an outer shell of the housing.

According to another aspect, a method of manufacturing a metered dose inhaler actuator is provided. The method includes forming a housing having a mouthpiece portion and a canister receiving portion configured to receive a canister, wherein the housing extends from an opening for receiving a medicament canister to the mouthpiece opening. The method includes forming a member disposed within a housing and defining a valve stem receptacle configured to receive a valve stem of a canister, wherein an orifice is formed in the member such that the orifice is in fluid communication with the valve stem receptacle and extends to a face of the member opposite the valve stem receptacle. The member is formed such that a longitudinal axis of the orifice is aligned with a longitudinal axis of the valve stem receptacle. At least one air inlet port is formed in the housing of the housing in spaced relation to the opening for receiving the medicament canister and the mouthpiece opening, the at least one air inlet port being formed in fluid communication with the mouthpiece opening.

The member may be formed such that the outlet of the aperture is located at a distance from the actuator base. The position of the at least one air inlet may be selected in dependence on said distance. The number of air inlets comprised by the at least one air inlet may be selected in dependence on the distance between the outlet of the aperture and the actuator base.

Various effects can be obtained with the actuator, metered-dose inhaler and method of embodiments. For example, an actuator according to embodiments may be designed to reduce the deposition of a drug in the oropharyngeal region.

The above and other effects will be further explained with reference to the exemplary embodiments described with reference to the drawings.

Drawings

FIG. 1 is a schematic cross-sectional view of a metered-dose inhaler including an embodiment of an actuator;

FIG. 2 is a schematic front view of the metered-dose inhaler of FIG. 1;

FIG. 3 is a schematic cross-sectional view of a metered-dose inhaler including another embodiment of an actuator;

FIG. 4 is a schematic cross-sectional view of a metered-dose inhaler including another embodiment of an actuator;

FIG. 5 is a schematic cross-sectional view of a metered-dose inhaler including another embodiment of an actuator;

FIG. 6 is a graph representing delivered dose for various actuator designs;

fig. 7 is a diagram illustrating an external configuration of a metered-dose inhaler having an actuator according to an embodiment (right side) as compared with a sectional view (left side) of a conventional metered-dose inhaler;

FIG. 8 is a graph representing delivered dose for various actuator designs;

fig. 9 to 14 illustrate an orifice design in an actuator according to an embodiment;

FIG. 15 is a schematic cross-sectional view of a metered-dose inhaler including another embodiment of an actuator;

FIG. 16 is a schematic view illustrating an actuator base of an actuator according to another embodiment;

FIG. 17 is a schematic view illustrating various configurations of air intakes;

18A and 18B are schematic views illustrating the configuration of air inlets positioned on the actuator rear wall and the actuator base, respectively;

FIG. 19 is a schematic view of an apparatus for measuring pressure drop;

20A, 20B, and 20C are graphs representing delivery characteristics for actuators having air inlets in the base of the actuator according to various embodiments for three different formulations;

21A, 21B, and 21C are graphs representing delivery characteristics for an actuator having an air inlet in the rear wall of the actuator according to various embodiments for three different formulations;

FIG. 22A is a graph illustrating pressure drop for an actuator having an air inlet in the base of the actuator according to various embodiments, and FIG. 22B is a graph illustrating pressure drop for an actuator having an air inlet in the back wall of the actuator according to various embodiments;

FIG. 23 is a graph representing delivery characteristics of an actuator having one air inlet in the base of the actuator according to various embodiments for different diameters of the air inlet;

FIG. 24 is a graph representing the delivery characteristics of an actuator according to various embodiments for different arrangements and different sizes of air inlets;

FIG. 25 is a graph representing delivery characteristics of an actuator having two air inlets in the base of the actuator according to various embodiments for different diameters of the air inlets;

FIG. 26 is a schematic diagram illustrating additional configurations of air inlets for actuators according to other embodiments;

27A and 27B are graphs respectively representing delivery characteristics of actuators having two or three air inlets in the base of the actuator, according to various embodiments;

FIG. 28 is a schematic diagram illustrating additional configurations of air inlets for actuators according to other embodiments;

FIG. 29 is a graph representing the delivery characteristics of an actuator having two air inlets in the base of the actuator according to various embodiments for different separation distances between the centers of the air inlets;

FIG. 30 is a graph representing delivery characteristics for an actuator having one or two air inlets in the actuator base according to various embodiments for different distances of the valve stem block orifice from the actuator base;

FIG. 31 is a graph representing the delivery characteristics of an actuator having two or three air inlets in the base of the actuator according to various embodiments, as compared to the delivery characteristics of an actuator according to embodiments having additional air inlets in the rear wall of the actuator;

FIG. 32 is a graph representing the transport characteristics of an actuator according to an embodiment measured with an Andersen multistage impactor (ASI);

FIG. 33 is a graph representing the delivery characteristics of an actuator according to an embodiment measured with an Andersen multistage impactor (ASI) for another formulation;

FIG. 34 is a graph representing the transport characteristics of an actuator according to an embodiment measured with an Andersen multistage impactor (ASI) for yet another formulation;

FIG. 35 is a graph representing particle size distributions measured for actuators according to various embodiments as compared to particle size distributions of conventional actuators;

FIG. 36 is a graph representing the delivery characteristics of an actuator according to an embodiment for an ethanol-containing suspension formulation measured with an Andersen multistage impactor (ASI);

FIG. 37 is a graph representing particle size distributions measured for actuators according to an embodiment when delivering an ethanol-containing suspension formulation compared to particle size distributions measured for control actuators;

FIG. 38 is a graph representing delivered dose as a function of volumetric flow rate through an actuator in accordance with an embodiment;

FIG. 39 is a graph representing actuator deposition as a function of volumetric flow rate through the actuator for an actuator in accordance with an embodiment;

fig. 40 is a schematic cross-sectional view of a metered-dose inhaler including a conventional actuator.

Detailed Description

Exemplary embodiments of the present invention will now be described with reference to the accompanying drawings. Features of the embodiments may be combined with each other, unless otherwise specified.

FIG. 1 is a schematic cross-sectional view of a Metered Dose Inhaler (MDI). The cross-sectional view is taken along the central symmetry plane of the metered-dose inhaler. Fig. 4 of the drawing in fig. 1 shows a detailed view of the valve stem block. Fig. 2 is a front view of the metered-dose inhaler as viewed along the longitudinal axis of the mouthpiece portion.

The metered-dose inhaler 1 comprises a canister 2 and an actuator 11. Canister 2 contains an aerosol formulation. The aerosol formulation may be an aerosol solution formulation or an aerosol suspension formulation. Aerosol formulations may contain at least one active ingredient in a propellant or propellant/solvent system and optionally other excipients. The canister may be configured as a conventional canister for a pressurized metered dose inhaler (pMDI). The canister 2 is provided with a valve having a valve stem 3. The valve may be a metering valve which allows a metered dose to be dispensed through the hollow valve stem 3 upon actuation.

The actuator 11 has a housing defining a canister receiving portion 12 and an interface portion 13. The canister receiving portion 12 is configured to receive a canister 2, which canister 2 is at least partially inserted into the housing of the actuator 11 through an opening 21 for receiving the canister. The mouthpiece portion 13 defines an mouthpiece opening 22 through which the aerosol cloud can be dispensed 22.

The actuator 11 includes a valve stem block 14. The valve stem block 14 may be integrally formed with the housing of the actuator 11. The valve stem block 14 defines a valve stem receiving portion 15, and the front end of the valve stem 3 of the canister 2 is received in the valve stem receiving portion 15. An orifice 16 is formed in the valve stem block 14. The orifice 16 extends to a face 19 of the valve stem block 14 opposite the face in which the valve stem receptacle 15 is formed. The shape of the orifice 16 may be selected from a variety of shapes. For purposes of illustration, a cylindrical orifice 16 is shown in FIG. 1.

To administer the medicament through the metered-dose inhaler, the patient presses the end of the mouthpiece portion 13 against his lips and actuates the metered-dose inhaler by pressing the canister 2 into the actuator 11. Alternatively, the metered-dose inhaler may be a breath-actuated inhaler (BAI) configured to automatically actuate delivery of a dose of aerosol without additional manual actuation when the patient inhales with his lips in contact with the mouthpiece. Upon actuation, a metered dose measured by the valve is ejected from the valve stem 3. The ejected dose passes through an internal nozzle passage formed by an orifice 16 in the valve stem block 14. Upon passage through the orifice 16, the aerosol formulation is aerosolized. The patient initiates inhalation through the mouthpiece upon release of a metered dose following actuation of the metered dose inhaler.

In the actuator 11, the valve stem block 14 is arranged spaced apart from the actuator base, which is defined by the lower boundary of the mouthpiece portion 13 when the metered-dose inhaler 1 is held in its use position, as shown in fig. 1 and 2. The valve stem block 14 is disposed above the longitudinal axis 25 of the interface portion 13. In the illustrated embodiment, the valve stem block 14 is disposed a distance 27 from the actuator base. The distance 27 is greater than the height 26 of the interface opening 22 measured upward from the base of the actuator. The valve stem block 14 is thereby arranged such that the valve stem block 14 cannot be seen when the metered-dose inhaler is viewed from the mouthpiece opening 22 in a viewing direction parallel to the longitudinal axis 25 of the mouthpiece portion 13.

Distance 27 represents a reference height 27, which reference height 27 is the distance between face 19 of valve stem block 14 and the actuator base. The reference height may be defined as the distance between the plane in which the outlet of the orifice 16 lies and the actuator base, measured along the actuator rear wall.

As best seen in inset 4 of fig. 1, the orifice 16 is formed in the valve stem block 14 such that a longitudinal axis 18 of the orifice 16 is aligned with a longitudinal axis 17 of the valve stem receptacle 15. The longitudinal axis 17 of the valve stem receiving portion may coincide with the longitudinal axis 24 of the container receiving portion. As used herein, the term "longitudinal axis" refers to the central longitudinal axis of the respective concavity or component.

A valve stem block 14 is provided in the housing so as to extend through the inner cross-sectional area of the actuator except for an orifice 16. The valve stem block 14 is configured to prevent gas from passing through the valve stem block 14 at any location radially outward of the orifice 16. In particular, the valve stem block 14 does not comprise any vent holes allowing passage through the valve stem block 14 when the valve stem 3 is received in the valve stem receiving portion. When the canister 2 is inserted into the canister receiving portion 12 and the valve stem 3 is received in the valve stem receiving portion 15, air is substantially prevented from passing from the container receiving opening 21 toward the mouthpiece opening 22.

An air inlet or inlets 20 or vents 20 are formed in the housing of the actuator housing. The terms air vent and air inlet will be used synonymously. During use of the metered-dose inhaler, an inflow of air 23 will be established through the air inlet 20 by the patient's inspiratory effort. The air inlet 20 is disposed at a location that is spaced apart from both the container receiving opening 21 and the interface opening 22.

In the actuator 11, the air inlet 20 is provided on the portion of the actuator housing extending from the stem block 14 towards the mouthpiece opening 22, i.e. the air inlet 20 is provided downstream of the outlet of the orifice 16, so that during use of the metered-dose inhaler, respirable particles or droplets may be entrained in the air stream 23 of moving air which passes through the air inlet 20 into the actuator interior during inhalation.

By way of example, three air inlets 20 are shown in fig. 2. However, the number, shape and arrangement of the air inlets may vary within wide ranges. Embodiments of the present invention are not limited to the specific number, shape, and arrangement of air inlets 20 illustrated. Rather, a wide and varied number, geometry, size and location of air inlets may be implemented in embodiments.

In the actuator 11, the air inlet 20 is provided on the rear wall of the actuator housing and in the vicinity of the actuator base. The term "rear wall" refers to the wall located opposite the interface opening 22. The intake ports 20 are arranged such that each of the intake ports 20 is in direct communication with the interface opening 22. A line 29 parallel to the longitudinal axis 25 of the mouthpiece and passing through one of the air inlets 20 intersects the mouthpiece opening 22 without passing through any solid part or element of the actuator.

When the metered-dose inhaler 1 is used to dispense an aerosol formulation from a canister 2, an atomized spray is emitted from the orifice 16 along a longitudinal axis 18 of the orifice 16, said longitudinal axis 18 coinciding with the longitudinal axis 17 of the valve stem receptacle and the valve stem 3. Air is drawn into the actuator housing through the air inlet 20 by the patient's inspiratory effort during inhalation. An air flow 23 of motive air is generated, said air flow 23 passing through the actuator base. Respirable particles or droplets generated from the aerosolized formulation when canister 2 is pressed against actuator 11 are carried into the airflow. Non-respirable particles or droplets are not easily carried by the airflow and are more likely to impinge on the actuator base.

In the actuator 11, the air inlet 20 allows respirable particles or droplets generated from the atomized spray to be entrained, while at the same time the non-respirable particles or droplets are more likely to impinge on the inner actuator wall and remain within the actuator. The ratio of respirable particles or droplets to non-respirable particles or droplets may be enhanced by this configuration.

Various modifications of the actuator 11 may be implemented in other embodiments. For example, other numbers, sizes, geometries, or arrangements of air inlets 20 may be implemented. For further illustration, the angle between the longitudinal axis 25 of the mouthpiece portion 13 and the longitudinal axis 24 of the canister receiving portion 12 may be comprised in the interval 90 ° to 180 °. The angle between the mouthpiece portion 13 and the longitudinal axis 24 of the canister receiving portion 12 may preferably be in the range of 90 ° to 130 °, and more preferably in the range of 90 ° to 110 °.

Also, although the cylindrical orifice 16 is formed in the valve stem block 14, other shapes of orifices may be implemented in other embodiments. The arrangement of the orifice 16, wherein the longitudinal axis of the orifice 16 is aligned with the valve stem longitudinal axis, allows for an orifice design having a shape that tapers towards the face 19 of the valve stem block 14.

FIG. 3 is a schematic cross-sectional view of a metered-dose inhaler (MDI). The cross-sectional view is taken along a central symmetry plane of the metered-dose inhaler. Elements or features which correspond in construction and/or function to elements or features of the metered-dose inhaler 1 of figures 1 and 2 are indicated by the same reference numerals.

The metered dose inhaler comprises a canister 2 and an actuator 31. Canister 2 contains an aerosol formulation. The canister 2 has a valve assembly 32 comprising a valve stem 3.

The actuator 31 has a valve stem block 14, the valve stem block 14 defining a valve stem receptacle and an orifice. The valve stem block 14 extends through the inner cross-sectional area of the actuator so as to prevent the passage of gas through the valve stem block 14 at all locations outside the bore. The longitudinal axes of the valve stem receptacle and the orifice are aligned with one another. The orifice has a tapered portion. The tapered portion, which may be frustoconical, tapers in a direction away from the valve stem receptacle (i.e., in a downward direction in fig. 3), i.e., in a downstream direction of the aerosol flow path. The arrangement in which the longitudinal axis of the orifice is aligned with the longitudinal axis of the valve stem receptacle facilitates production of an actuator in which the orifice tapers in the downstream direction of the aerosol flow.

One or more air inlets 20 are formed in the housing of the actuator housing. The air inlet port 20 is spaced from the actuator base and is disposed adjacent the valve stem block 14. An air inlet 20 is formed in the rear wall of the actuator housing which extends cylindrically around the longitudinal axis of the valve stem receptacle and the longitudinal axis 18 of the orifice.

The actuator 31 is configured such that the angle 33 between the longitudinal axis of the mouthpiece portion 12 and the longitudinal axis 18 of the orifice is equal to or greater than 90 °, said longitudinal axis 18 corresponding to the longitudinal axis of the canister 2 when the canister 2 is inserted into the actuator 31.

FIG. 4 is a schematic cross-sectional view of a metered-dose inhaler (MDI). The cross-sectional view is taken along a central symmetry plane of the metered-dose inhaler. Elements or features which correspond in construction and/or function to elements or features of the metered-dose inhaler of figure 3 are indicated by the same reference numerals.

The metered dose inhaler comprises an actuator 41 and a canister 2. A valve stem block 14 is disposed in the actuator housing. The orifices formed in the valve stem block 14 taper in the downstream direction of the aerosol flow. The angle 33 between the longitudinal axis of the mouthpiece portion 12 and the longitudinal axis 18 of the orifice is greater than 90 °, said longitudinal axis 18 corresponding to the longitudinal axis of the canister 2 when the canister 2 is inserted into the actuator 41.

In the actuator 41, one or more air inlets 20 are formed in the housing of the actuator housing. An air inlet 20 is formed near the base of the actuator.

FIG. 5 is a schematic cross-sectional view of a metered-dose inhaler (MDI). The cross-sectional view is taken along a central symmetry plane of the metered-dose inhaler. Elements or features which correspond in construction and/or function to elements or features of the metered-dose inhaler 1 of figures 1 and 2 are indicated by the same reference numerals.

The metered-dose inhaler comprises an actuator 51 and a canister 2. A valve stem block 14 is disposed in the actuator housing. A cylindrical orifice 16 is formed in the valve stem block 14. The interface portion 13 of the actuator housing is arranged at an angle of about 90 deg. relative to the canister receiving portion 12.

A plurality of air inlets 20 are formed in the rear wall of the actuator 51. At least two of the air inlets 20 are spaced apart along the longitudinal axis of the canister receiving portion 12. An air inlet 20 is formed near the base of the actuator so that the air inlet 20 is visible from the interface opening. In other words, the air inlet 20 is arranged in direct communication with the interface opening, so that no solid part of the actuator is interposed between the air inlet 20 and the interface opening.

Various other configurations of air inlets may be implemented in actuators according to other embodiments. For example, one or more air inlets may be formed in the actuator base, in addition to or in lieu of the air inlet(s) being provided in the rear wall of the actuator. One or more air inlets provided in the actuator base may be positioned so as to face the valve stem block.

In the metered-dose inhaler actuator according to the embodiment explained above, the orifice formed in the valve stem block is arranged such that its longitudinal axis is aligned with the longitudinal axis of the valve stem receptacle. An air inlet is provided in the housing of the actuator housing through which air is drawn into the actuator during inhalation. The resulting airflow may carry a large portion of the respirable particles or droplets of the aerosolized formulation. A large portion of the non-respirable particles or droplets of the aerosolized formulation may impinge on the inner surface of the actuator. The fraction of non-respirable particles or droplets in the aerosol cloud may be reduced prior to dispensing the aerosol cloud via the interface opening.

Fig. 6 is a graph illustrating delivered dose. For the sake of distinction, fig. 6 shows: a respirable dose (fine particle dose) that is the number of particles delivered with an aerodynamic diameter less than or equal to 5 μm upon actuation of the inhaler; and a non-respirable dose that is the number of particles delivered with an aerodynamic diameter greater than 5 μm upon actuation of the inhaler, the actuator containing a solution formulation of Beclomethasone Dipropionate (BDP) (50 μ g/50 μ L) and 8% w/w ethanol and up to 100% w/w of a hydrofluoroalkane 134a (1, 1, 1, 2-tetrafluoroethane) propellant.

The delivered dose and respirable dose were evaluated separately by an Andersen multistage impactor fitted with a USP throat (apparatus 1, USP-USP 34-NF 29). Drug deposition in each stage was determined by UPLC/MS (ultra high performance liquid chromatography-mass spectrometry).

The delivered breathable dose and the delivered non-breathable dose are shown at 52 for an actuator in which the outlet of the orifice formed in the valve stem block is located 22mm above the base of the actuator, the distance being measured along the longitudinal axis of the container receiving portion. As shown for the configuration of fig. 1 and 2, three air inlets are provided in the actuator rear wall. The inlet port has a circular cross-section and a diameter of 3mm, respectively, resulting in a total cross-sectional area of the inlet port of 21.2mm²。

The data represented at 53 and 54 are obtained for an actuator that does not include an air inlet in the housing of the actuator housing at a location spaced from the canister receiving opening and the interface opening. Data, indicated at 53, is obtained for an actuator in which the outlet of the aperture formed in the valve stem block is located 22mm above the base of the actuator, the distance being measured along the longitudinal axis of the container receiving portion. Data, represented at 54, is obtained for an actuator in which the outlet of the orifice formed in the valve stem block is located 42mm above the base of the actuator, the distance being measured along the longitudinal axis of the container receiving portion.

In each of the actuators that have been used to obtain the data 52-54, the valve stem block is arranged spaced from the actuator base, and the longitudinal axis of the orifice formed in the valve stem block is aligned with the longitudinal axis of the valve stem receptacle. As shown in fig. 13, a cylindrical inner expansion chamber is formed between the valve stem receiving portion and the cylindrical orifice. The orifice size is the same for the three actuators for which data 52-54 has been obtained.

As can be appreciated from the data 52, 53 and 54 in fig. 6, an actuator configuration in which the longitudinal axis of the orifice is aligned with the longitudinal axis of the valve stem receptacle has the effect that only a small fraction of non-respirable particles are entrained in the aerosol cloud output via the interface orifice. Non-breathable particles are more likely to impact the inner surface of the actuator housing when the longitudinal axis of the orifice is aligned with the longitudinal axis of the valve stem receptacle than in designs in which the longitudinal axis of the orifice is aligned with the interface axis.

As can be seen from a comparison of data 52 and data 53 in fig. 6, providing an air inlet in the housing of the actuator housing allows for an increase in the respirable dose (data indicated at 52 for actuators having an air inlet) compared to the case where no air inlet is provided in the housing of the actuator housing (data indicated at 53 for actuators without an air inlet).

As can be seen from a comparison of data 52 and data 54 in fig. 6, providing an air inlet in the housing of the actuator allows the breathable dose (data represented at 52) to match that obtainable by an actuator having a larger orifice-actuator base distance but no air inlet (data represented at 54). The provision of the air inlet opening(s) in the housing of the actuator housing allows for an actuator design in which the outer dimensions of the actuator substantially correspond to one of the conventional actuators for a desired respirable dose.

Fig. 7 illustrates that an actuator according to various embodiments may be provided with outer dimensions corresponding to the outer dimensions of a conventional actuator 61 (shown on the left). By way of example, the actuator design 41 of fig. 4 is shown in fig. 7 (shown on the right), but actuator dimensions similar or equal to conventional actuator dimensions may be obtained for an actuator according to any of the embodiments described with reference to fig. 1 to 5.

As already explained with reference to fig. 6, the provision of one or more air inlets in the actuator housing at a location spaced from the canister receiving opening and the mouthpiece opening has the effect that a desired respirable dose can be obtained with the aperture formed in the valve stem block at a smaller distance 42 from the actuator base than an actuator without an air inlet formed in its housing.

Distance 42 represents a reference height distance 42. The reference height distance is defined as the distance between the plane of the face of the member in which the orifice outlet is located and the actuator base, said distance being measured along the rear wall of the actuator and parallel to the longitudinal axis of the orifice.

The actuator 41 of the embodiment may thus be configured to have external dimensions corresponding to conventional actuators and indicated at 61 in fig. 7.

A metered-dose inhaler according to embodiments, in which the canister 2 is received in the container receiving portion of the actuator, may be configured such that it has similar or identical external dimensions as a conventional metered-dose inhaler assembled from the actuator 61 and canister 62. For this purpose, a tank 2 with a reduced volume can be used. For example, a canister 2 having a capacity of 10mL to 14mL may be used in combination with the actuator according to the embodiment.

Figure 8 is a graph showing the respirable dose (fine particle dose) (i.e. the number of particles delivered having an aerodynamic diameter of less than or equal to 5 μm) and the non-respirable dose obtained from a solution formulation of Beclomethasone Dipropionate (BDP) (100 μ g/50 μ L) and 12% w/w ethanol and up to 100% w/w hydrofluoroalkane 134a (1, 1, 1, 2-tetrafluoroethane) propellant.

Data 63, 64 and 65 have been obtained using an actuator in which the valve stem block is arranged at a distance from the actuator base and the longitudinal axis of the orifice formed in the valve stem block is aligned with the longitudinal axis of the valve stem receptacle. As shown in fig. 13, a cylindrical inner expansion chamber is formed between the valve stem receiving portion and the cylindrical orifice. The orifice size is the same for the three actuators for which data 63, 64 and 65 have been obtained.

Data 63 is obtained for an actuator that does not have an air inlet in the housing of the actuator housing at a location spaced from the container receiving opening and the interface opening. The actuator has an interface arranged at an angle of more than 90 ° and in particular about 98 ° with respect to the longitudinal axis of the valve stem receptacle.

Data 64 is obtained for an actuator that does not have an air inlet in the housing of the actuator housing at a location spaced from the receptacle-receiving opening and the interface opening. The actuator has an interface wherein the angle relative to the longitudinal axis of the stem receiver increases to greater than 110 °.

Data 65 is obtained for an actuator having three circular air inlets formed in the housing of the actuator housing. Each inlet was circular with a diameter of 3 mm. An air inlet is disposed in the actuator base. The actuator has an interface arranged at an angle of more than 90 ° and in particular about 98 ° with respect to the longitudinal axis of the valve stem receptacle. Data 65 is obtained for an actuator having a housing substantially similar to the actuator of fig. 4, with the air inlet positioned slightly more towards the interface opening.

Data 66 has been obtained for a conventional actuator as shown in fig. 40. Conventional actuators have a valve stem block disposed on an actuator base. An orifice formed in the valve stem block has a longitudinal axis directed toward the interface opening. The orifice diameter of the conventional actuator is the same as the orifice diameter of the actuator for which data 63, 64 and 65 have been obtained.

As can be seen from data 63 to 66, the actuator configuration with the longitudinal axis of the orifice aligned with the longitudinal axis of the valve stem receptacle (data 63, 64 and 65) has the effect that the fraction of non-respirable particles carried in the aerosol cloud output via the interface orifice can be reduced compared to the conventional design (data 66). When the longitudinal axis of the orifice is aligned with the longitudinal axis of the valve stem receptacle, the non-respirable particles are more likely to strike the inner surface of the actuator housing so that a majority of the non-respirable particles can be removed from the aerosol cloud before the aerosol cloud exits the interface opening.

As can be seen from a comparison of data 65 and data 63, providing an air inlet in an actuator in which the longitudinal axis of the mouthpiece portion is arranged at an angle of greater than 90 ° relative to the longitudinal axis of the valve stem receptacle surprisingly increases the delivered dose of breathable particles.

As can be seen from a comparison of data 65 and data 66, the arrangement of providing an air inlet port in the actuator housing and arranging the longitudinal axis of the interface portion at an angle greater than 90 ° relative to the longitudinal axis of the valve stem receptacle significantly reduces the non-breathable dose as compared to conventional actuators and facilitates matching the breathable dose with that of conventional actuators.

The actuators of the different embodiments allow for various shapes of concavities to be formed in the valve stem block 14. The actuator of the different embodiments allows for a variety of orifice shapes to be defined without requiring the valve stem block 14 to be separately formed and inserted into the housing of the actuator. Although an exemplary valve stem receptacle and orifice geometry is shown in fig. 1-5, a variety of different orifice, expansion chamber, and valve stem receptacle designs may be implemented for any of the actuator geometries described herein.

Fig. 9 to 14 show a cross-sectional view of a central portion of the valve stem block 14, in which the valve stem 3 is received in the valve stem receiving portion 15. The various geometries of the concave surfaces explained with reference to fig. 9-13 may be implemented in the valve stem block of any of the actuators described herein.

FIG. 9 illustrates a cross-sectional view 71 of the valve stem block 14 of an actuator according to one embodiment. The valve stem block 14 defines a cylindrical valve stem receiving portion 15. The valve stem block 14 also defines a cylindrical orifice 16 for aerosolizing the formulation dispensed by the valve stem 3. The orifice 16 may be formed as a rotationally symmetrical orifice, i.e., formed with a cylindrical shape having a circular base.

FIG. 10A illustrates a cross-sectional view 72 of the valve stem block 14 of an actuator according to one embodiment. The valve stem block 14 defines a cylindrical valve stem receiving portion 15. An orifice having a conical portion 73 and a cylindrical portion 74 is formed in the valve stem block 14. The tapered portion 73 may serve as an abutment for the valve stem 3. The tapered portion 73 may have a frustoconical shape. The cylindrical portion 73 may be formed as a rotationally symmetrical portion, i.e., formed with a cylindrical shape having a circular base.

In the valve stem block 14 of fig. 10A, the portion 73 tapers in the downstream direction of the aerosol flow, i.e., toward the face of the valve stem block 14 opposite the valve stem receptacle 15. This tapered geometry can be easily achieved when the actuator is produced using conventional molding or other manufacturing techniques.

FIG. 10B illustrates a cross-sectional view of the valve stem block 14 of the actuator according to one embodiment. The valve stem block 14 defines a cylindrical valve stem receiving portion 15. An orifice is formed in the valve stem block 14, the orifice having a conical portion 73 corresponding to that of fig. 10A, but without a terminal cylindrical portion at the interface with the interface.

FIG. 11A illustrates a cross-sectional view 75 of the valve stem block 14 of an actuator according to one embodiment. The valve stem block 14 defines a cylindrical valve stem receiving portion 15. An orifice having a conical portion 76 and a cylindrical portion 77 is formed in the valve stem block 14. The tapered portion 77 may have a frustoconical shape. The cylindrical portion 77 may be formed as a rotationally symmetrical portion, i.e., formed with a cylindrical shape having a circular base.

In the valve stem block 14 of fig. 11A, the maximum diameter of the tapered portion 76 matches the inner diameter of the valve stem 3, i.e., the tapered surface defining the tapered portion 76 is adjusted to the inner edge of the hollow valve stem 3. A step may be formed at the top edge of the tapered portion 76 to serve as an abutment for the valve stem 3. This configuration may prevent drug from being deposited within the orifice formed in the valve stem block 14. This configuration may also reduce the formation of vortices when dispensing aerosol formulations containing high concentrations of polar compounds (such as water or ethanol) from the valve stem 3.

FIG. 11B illustrates a cross-sectional view of the valve stem block 14 of the actuator according to one embodiment. The valve stem block 14 defines a cylindrical valve stem receiving portion 15. An orifice is formed in the valve stem block 14 having a conical portion 76 corresponding to the conical portion of fig. 11A, but without a terminal cylindrical portion at the interface with the interface.

FIG. 12 illustrates a cross-sectional view 78 of the valve stem block 14 of an actuator according to one embodiment. The valve stem block 14 defines a cylindrical valve stem receiving portion 15. An orifice having a conical portion 79 and a cylindrical portion 80 is formed in the valve stem block 14. The tapered portion 79 may have a truncated conical shape. The cylindrical portion 80 may be formed as a rotationally symmetrical portion, i.e., formed with a cylindrical shape having a circular base.

In the valve stem block 14 of fig. 12, the maximum diameter of the tapered portion 79 matches the outer diameter of the valve stem 3, i.e., the tapered surface defining the tapered portion 79 is adjusted to the outer edge of the hollow valve stem 3.

FIG. 13 illustrates a cross-sectional view 81 of the stem block 14 of an actuator according to an embodiment. The valve stem block 14 defines a cylindrical valve stem receiving portion 15. An expansion chamber or sump 82 is formed in the valve stem block 14. The expansion chamber 82 may have a cylindrical shape. The volume of the expansion chamber 82 may be less than the typical volume of an inner expansion chamber formed in a conventional actuator in which a nozzle block is disposed on the actuator base. The expansion chamber 82 has a smooth tapered portion 83. The tapered portion 83 may have a truncated conical shape. A cylindrical orifice 84 may be formed in the valve stem block. The cylindrical orifice 84 may be formed as a rotationally symmetric orifice, i.e., formed with a cylinder shape having a circular base.

FIG. 14 illustrates a cross-sectional view 85 of the stem block 14 of the actuator according to one embodiment. The valve stem block 14 defines a cylindrical valve stem receiving portion 15. An expansion chamber or sump 86 is formed in the valve stem block 14. The expansion chamber 86 may have a cylindrical shape. The expansion chamber 86 has a lower side 87 that extends transverse to the side walls of the expansion chamber 86. A cylindrical orifice 88 may be formed in the valve stem block. The cylindrical orifice 88 may be formed as a rotationally symmetric orifice, i.e., formed with a cylinder shape having a circular base.

Various modifications may be made to the valve stem block configuration. For example, according to yet another embodiment, the aperture may have an elliptical cross-section. That is, the aperture may not be rotationally symmetric.

The various configurations of the valve stem block configurations illustrated in fig. 9-14 include portions that taper in the downstream direction of the aerosol flow, i.e., toward the face of the valve stem block disposed opposite the valve stem receptacle 15. This tapered geometry can be easily achieved when the actuator is produced using conventional molding or other manufacturing techniques. For example, a pin that tapers toward the base of the actuator may be used when molding the actuator to define a tapered surface. The pins may be removed from the molded actuator in a direction away from the actuator base.

The tapered orifice geometries illustrated in fig. 10-13 may be used to improve atomization, particularly for aerosol formulations containing high concentrations of polar compounds, which may be one or more polar co-solvents such as alcohol (ethanol), water, or ethylene glycol. Such formulations may allow for higher drug loadings when compared to solutions of many conventional pressurized metered dose inhalers. The art requires increasing the fraction of drug that can be delivered as respirable particles or droplets formed from formulations containing high concentrations of polar compounds. The use of a tapered orifice geometry may also increase the rate at which the aerosol is aerosolized, resulting in a spray pattern with a smaller cone angle.

When an orifice that tapers in the downstream direction of aerosol flow is defined in the valve stem block, more efficient atomization can be achieved, at least for certain formulations. The use of conical orifices allows for smaller sized droplets to be generated than those formed using non-conical orifices.

The use of a valve stem block with a conical orifice whose longitudinal axis is aligned with the longitudinal axis of the valve stem receptacle in the actuator housing in which the air inlet is located, as described with reference to fig. 1-8, may help to increase the fraction of respirable particles or droplets, at least for certain types of formulations, such as formulations with higher concentrations of polar low-volatility compounds. The air flow provided through the actuator base through the air inlet formed in the housing of the actuator can carry a large number of atomized droplets. Since non-respirable particles or droplets tend to impinge on the actuator base, the proportion of non-respirable particles or droplets that are not entrained in the airflow can be reduced. Thereby increasing the ratio of smaller droplets while preventing larger droplets from striking the throat of the patient.

As can be seen from fig. 10 to 13, a tapered orifice design may be implemented in the actuators of the various embodiments. The cross-sectional area of the orifice may be decreasing depending on the position along the longitudinal axis of the orifice, although it need not decrease steadily. The ratio of the orifice diameter at the face of the valve stem block opposite the receptacle 15 to the maximum orifice diameter may be less than 1: 10. The ratio of the orifice diameter to the maximum orifice diameter at the face of the valve stem block opposite the receptacle 15 may be greater than 1: 30.

Although the air inlets may be located in the rear wall of the actuator, at least one of the air inlets or all of the air inlets may also be located at the actuator base. The actuator base may be defined by a boundary of the mouthpiece portion which is arranged opposite the canister receiving portion, i.e. a lower side of the mouthpiece portion may define the actuator base.

Fig. 15 is a schematic cross-sectional view of a metered-dose inhaler according to another embodiment. The metered dose inhaler has an actuator 91 and a canister 2, the canister 2 being insertable into a canister receiving portion of the actuator 91. The actuator 91 has a configuration substantially similar to that of one of the actuators of fig. 1 to 5 and 7. The valve stem block 94 extends across the cross-section of the canister receiving portion. The valve stem block 94 may be configured to block the passage of air radially outward of an aperture provided in the valve stem block 94. The valve stem block 94 and the orifice formed in said valve stem block 94 are arranged such that the longitudinal axis of the orifice is aligned with the longitudinal axis of the canister receiving portion of the actuator 91.

One or more air inlets 20 are formed in the housing of the actuator 91. An air inlet(s) 20 is formed in the actuator base 92. The actuator base 92 is defined by an interface portion. The actuator base 92 is defined by the lower side of the interface portion when the actuator 91 is held in an operating position in which the longitudinal axis of the canister receiving portion extends in a vertical direction and the canister is inserted or insertable into the upper end opening of the actuator.

In the actuator 91, at least one air inlet 20 is arranged such that said air inlet 20 is spaced apart from the rear wall 94 of the actuator 91.

The air inlet port(s) 20 may be positioned in the actuator base 92 such that they are arranged towards the rear wall 94 with respect to a virtual intersection 93 between the longitudinal axis of the aperture and the actuator base 92. The air inlet(s) 20 may be positioned in the actuator base 92 such that said air inlet 20 is arranged towards the rear wall 94 with respect to the impact point of the plume dispensed upon actuation of the canister 2. In other words, a distance 95 of the air inlet to the mouthpiece opening measured along a line parallel to the longitudinal axis of the mouthpiece may be greater than a distance 96 from the point 93 to the mouthpiece opening also measured along a line parallel to the longitudinal axis of the mouthpiece.

This configuration of the air inlet or inlets being located on the actuator base creates an air flow that is directed almost opposite to the direction of the plume in the vicinity of the air inlet(s). This may improve aerosol performance.

Positioning the air inlet within the rear of the actuator as illustrated in fig. 1 or 2 creates an air flow that is substantially perpendicular to the direction of the plume. For the air inlet positioned in the actuator base, the interaction between the plume and the air flow may be increased in the sense that the air flow influences the particle trajectories more strongly when the air inlet is provided in the actuator base. This may result in reduced actuator deposits.

The position of the air inlet opening(s) on the actuator base may be further set according to the transverse dimension of the impact area of the plume impacting on the actuator base. This is illustrated in fig. 16.

Fig. 16 is a schematic plan view of the actuator base 92. At one longitudinal end, the actuator base 92 defines an edge of the interface opening 99. Two air inlets 20 are positioned on the actuator base 92. The air inlets 20 are mutually offset in a direction transverse to the longitudinal direction of the mouthpiece portion. The distance 98 between the centers of the air inlets 20 may be set according to the size of the impact area 97 where the plume impinges on the actuator base 92. Distance 98 may be set such that air inlet 20 is disposed toward the edge of impact region 97. Distance 98 may be set according to a reference height.

An additional air inlet(s) may be provided. For example, one additional air inlet may be positioned in the actuator base such that the three air inlets form a triangular arrangement or a linear arrangement.

The positions of the air inlet(s) on the actuator base may be set individually according to the reference distance.

Different effects can be obtained using the metered dose inhaler actuator, metered dose inhaler and method of embodiments. For example, upon actuation of the canister, a plume may be ejected along the common axis 16, 24 depicted in fig. 1. Most or almost all of the non-respirable dose can be removed from the aerosol by internal impaction within the actuator, resulting in a high fraction, perhaps 90% or more, of fine particles (particles with a size ≦ 5 μm). This may reduce oropharyngeal drug deposition and associated gastrointestinal adverse effects.

By way of further example, despite the reduced fraction of non-respirable particles compared to conventional actuator designs, the aerosol performance in a metered-dose inhaler having an actuator according to an embodiment for each formulation is comparable to that of a conventional actuator, regardless of the non-volatile content (% w/w). This applies to both suspension and solution formulations. This suggests that the chosen design can be used successfully for different formulations.

Although embodiments of a metered-dose inhaler actuator have been described in detail with reference to the accompanying drawings, various modifications may be implemented in other embodiments. For example, although an arrangement in which the longitudinal axis of the orifice is aligned with the longitudinal axis of the valve stem receptacle allows a conical orifice geometry to be achieved, the orifice does not have to be provided with a conical shape. The geometry of the orifice may be selected according to the formulation to be dispensed.

By way of further example, the actuator of any of the various embodiments may be configured to act as an actuator for a breath-actuated inhaler (BAI). The actuator may include additional components to automatically trigger the release of a dose of aerosol when the patient inhales with his/her lips in contact with the mouthpiece. The metered-dose inhaler according to various embodiments may be a breath-actuated inhaler.

Although embodiments of a metered-dose inhaler actuator having an exemplary number, shape, size and arrangement of air vents have been explained in the context of illustrative embodiments, other numbers, shapes, sizes and arrangements of air vents may be implemented in actuators according to other embodiments.

Metered dose inhaler actuators and metered dose inhalers can be used for a variety of aerosol formulations. For example, although the actuator of some embodiments may be used to dispense formulations containing high concentrations of polar, low-volatility compounds (such as water, ethanol, or glycols), the actuator is not limited to this particular field of application.

Although embodiments have been described in which the conical orifice is formed in a stem block of an actuator having an air inlet in its housing at a location spaced from the canister receiving opening and the mouthpiece opening, other actuators may also implement the conical orifice. For example, an orifice that tapers in the downstream direction of aerosol flow may be formed in a valve stem block that is incorporated into the housing of an actuator that is devoid of an air inlet port in its housing at a location spaced from the canister receiving opening and the mouthpiece opening.

By way of further example, metered-dose inhalers according to various embodiments will be described in more detail with reference to examples.

Examples of the invention

Screening pressurized metered dose inhalers according to embodiments

For rapid screening of the different actuators according to the embodiments, which have an in-line configuration (orifice axis aligned with the longitudinal axis of the canister receiving portion), the delivered dose, fine particle fraction (%) and respirable dose (particles ≦ 5 μm) were determined at a flow rate of 28.3(± 5%) L/min using a rapid screening andersen (fsa) impactor (from Copley).

The FSA was equipped with two stages and filters of ≦ 5 μm and ≦ 1 μm. After a single injection into the assembled FSA, the mouthpiece and USP throat were flushed to determine Beclomethasone Dipropionate (BDP) deposition. The collection plate and filter were removed from the FSA to determine BDP deposition at each stage. The FSA is then reassembled with the clean collection plate, throat and mouthpiece. A second injection of FSA was performed and sample collection was repeated. After three actuations have been collected, the actuator and canister are disassembled and the average actuator deposition for four injections is determined. Samples were collected in a 15:85 aqueous methanol solution and analyzed by UPLC.

The FSA was used as a screening tool for rapid evaluation of in-line actuators for improved delivery dose, fine particle fraction, and fine particle dose (< 5 μm) relative to controls. The control experiment was performed using the FSA method described above using a conventional actuator with an orifice diameter of 0.22mm, or using a conventional actuator with an orifice diameter of 0.30 mm.

Using Andersen multistage impinger (ACI) USP apparatus 1 with inlet, USP34-NF29 at 28.3 (+ -5%) L/min^-1The prototype of the actuator of the example was further evaluated to determine the difference in particle size distribution compared to the control.

The determined aerosol characteristics include: mass Median Aerodynamic Diameter (MMAD), i.e., the diameter on which the mass aerodynamic diameter of the ejected particle is evenly distributed centered; a Fine Particle Dose (FPD) corresponding to particles having a diameter of 5 μm or less; fine Particle Fraction (FPF), which is the percentage between respirable dose and delivered dose; and the ultrafine particle dose and the ultrafine particle fraction, which correspond to particles having a diameter of 1 μm or less, respectively, collected in the ACI.

Actuator prototype design

The prototype of the actuator of the embodiment used in the test comprised a stem block having an aperture with a longitudinal axis aligned with the longitudinal axis of the canister receiving portion of the actuator (hereinafter also referred to as "in-line actuator," in-line configuration ", etc.). The stem block is formed of aluminum. The lower and upper actuator parts of a conventional pressurized metered-dose inhaler are assembled into a valve stem block.

The orifice design of the bar block used in the experiment mainly corresponds to the orifice design of fig. 13. The diameter of the orifice 84 is measured using stereo microscopy to give an accurate diameter of 0.26mm for a length of about 0.6 mm. The expansion chamber 82 is 7.02mm in length and 2.10mm in diameter.

In a prototype of the actuator of the embodiment, the angle between the longitudinal axis of the mouthpiece portion and the longitudinal axis of the canister receiving portion was 107 °. The control actuator, i.e. the conventional or standard actuator used for comparison, has the same angle between the two longitudinal axes.

Formulation of

The following Beclomethasone Dipropionate (BDP) formulation was used to test different device designs. These formulations provide different atomization characteristics in terms of particle size distribution and evaporation rate. Each formulation was packaged in a standard 19ml aluminum can fitted with a conventional 50 μ L valve.

Table 1: formulation ingredients Using HFA134a (13.6g loading)

EF ═ ultrafine formulation (formulation without low volatility component);

LVC ═ low volatility component formulations (formulations that include glycerol as the low volatility component);

HE ═ high ethanol content formulations (with twice the ethanol concentration compared to that of EF or LVC);

low or high NVC ═ formulations with low or high nonvolatile content (i.e., formulations with lower or higher concentrations of active ingredient).

Structure of air inlet

Prototypes of actuators according to embodiments are designed with different numbers, positions and sizes of air inlets (i.e., different vent designs) and with different reference heights. The effect of the baseline height, vent design and total cross-sectional area of the air inlet on actuator performance was determined for each test formulation.

The main design of the air intake used (vent design I, II, III, IV) is shown in fig. 17.

Design I, shown at 121, has a single air inlet in the actuator base or rear wall. The diameter of the air inlet was 3.0 mm. The area of the air inlet is 7mm²。

Design II, shown at 122, has two air inlets in the actuator base or back wall. The diameter of each inlet was 3.0 mm. The total area of the air inlet is 14mm²。

Design III, shown at 123, has three air inlets in the actuator base or back wall. The air inlets are arranged in a straight line. The diameter of each air inlet was 3.0 mm. The total area of the air inlet is 21mm²。

Design IV, shown at 124, has three air inlets in the actuator base or back wall. The air inlets are arranged in a straight line. The diameter of each inlet was 4.25 mm. The total area of the air inlet is 43mm²。

Other prototypes of actuators according to yet another embodiment were fabricated for study. The construction of such an actuator is described in the results and discussion of the relevant sections.

Different configurations of the air inlet were evaluated.

Actuators according to various embodiments are rapidly screened to evaluate the performance of different configurations of air inlets for different distances of the orifice from the actuator base.

(a) Reference height

The reference height is defined as the distance from the actuator base to the valve stem block (see distance 27 in fig. 1 and distance 42 in fig. 7, which are measured as the distance from the housing base to the lower side of the member in which the orifice is formed along the rear outer boundary of the housing, respectively; i.e. the reference height may be defined as the distance of the lower end of the rear wall of the actuator from the plane in which the outlet of the orifice is provided.

Three reference heights representing an upper limit, a lower limit and a midpoint were chosen: 12mm, 32mm and 52mm to identify which of the various configurations of air intakes exhibit the best performance (also referred to herein as "best design", it being understood that best refers to the various different configurations of air intakes being tested and need not represent the overall optimum). For each reference height, the actuator with that reference height is evaluated for each vent design and location. Additional work was performed using a reference height of 22 mm.

(b) Air inlet configuration and total cross-sectional area

An air inlet opening in the lower part of the actuator has been shown to improve the aerosol performance of a metered-dose inhaler using an actuator according to embodiments. To establish the effect of air inlet arrangement (vent design) and total cross-sectional area on aerosol performance of the formulation, a primary use corresponds to 7mm²、14mm²、21mm²Or 43mm²Four different designs I-IV of total cross-sectional area (see fig. 17). The vent design is illustrated in fig. 17. Actuator prototypes with multiple vent designs were fabricated for three different datum heights of 12mm, 32mm and 52 mm.

(c) Position of air inlet

Two positions were explored for vent design. The air inlet is located on the lower portion of the actuator base or the actuator rear portion of the actuator.

For an air inlet design provided with multiple air inlets, a fixed distance of 5mm between the center points of the air inlets is typically used.

Fig. 18A shows the air inlet in the actuator base 92. The air inlet is typically located at a distance 126 of 10mm from the rear wall. The distance 125 between the centers of the air inlets is 5 mm. The air inlet is positioned parallel to the interface opening. The position of the air inlet is not changed unless otherwise specified.

Fig. 18B shows the air inlet in the actuator rear wall 94. The rear wall 94 is a wall extending substantially parallel to the longitudinal axis of the canister receiving portion at the side facing away from the interface portion. The air inlet is generally positioned a distance 127 of 10mm from the actuator base. However, for an actuator with a reference height of 12mm, the distance 127 is only 5mm for the case where the design I (one air inlet) and the air inlet are provided in the rear wall. The distance 125 between the centers of the air inlets is 5 mm. The air inlet is positioned parallel to the top of the actuator, i.e. the canister receiving opening. The position of the air inlet is not changed unless otherwise specified. Measurements were made for actuators having different reference heights 128 (i.e., different distances between the outlet of the orifice and the actuator base).

(d) Resistance of the device

The device resistance or pressure drop is directly related to the pressure differential across the device, which is created when flow passes through the in-line actuator. The device resistance is also related to the air flow velocity at the air inlet. As shown in FIG. 19, a sample collection tube with pressure taps (apparatus B; delivered dose uniformity-USP 34-NF29) was used to measure the pressure drop through the in-line prototype.

The apparatus 130 shown in fig. 19 includes: sample collection tube 131, filter 132, two-way solenoid valve 133, vacuum pump 134, timer 135, flow control valve 136, interface adapter 137, inlet 138. P1, P2, P3 represent pressure measurement points.

The actuator of an embodiment is placed at the inlet 138 of the device 130 using a molding interface. Air was drawn through the sample collection tube 131 using the vacuum pump 134 and the flow rate was adjusted to 28.3 (+ -5%) L/min using the bidirectional solenoid valve 133^-1. A differential pressure gauge was attached to the pressure tap P1 and the pressure drop across the device was measured in kPa using a different gauge (digital glow tube).

Performance for different configurations of air intakes of different reference heights

Each of the four vent designs I-IV (see fig. 17) at baseline heights of 12mm, 32mm and 52mm was tested using the BDP (100/50) formulation (table 1), i.e., using the EF, LVC, HE formulations. The air inlet is located on the base or rear wall of the lower actuator portion. Studies were conducted to determine the relationship between actuator design and performance.

(a) Air inlet in actuator base

Fig. 20A-20C show aerosol performance of BDP (100 μ g/50 μ L) ultrafine, low volatile component and high ethanol content formulations using an actuator of the embodiment with air inlet(s) located in the base of the actuator. The aerosol performance of the BDP (100/50) formulation (EF; LVC; HE) with different actuator designs is given in FIG. 20A (for ultra-fine formulation EF), FIG. 20B (for low volatility component formulation LVC) and FIG. 20C (for high ethanol content formulation HE). For the data shown in fig. 20A-20C, the actuator had an air inlet located on the base of the actuator. The different vent designs I-IV shown in fig. 17 were used on actuators with reference heights of 12mm, 32mm and 52mm, respectively.

The use of the actuators of the examples reduced the non-respirable dose (> 5 μm) compared to the control for all designs and formulations. The control was a conventional actuator having an orifice diameter of 0.22mm for which the longitudinal axis of the orifice was not aligned with the longitudinal axis of the canister receiving portion.

With a baseline height of 12mm, the absence of air inlets greatly reduced the delivered dose and the respirable dose compared to the control. Increasing the base height to 52mm improved the dose characteristics but failed to match the respirable dose (< 5 μm) obtained from the control when no air inlet was provided.

When an air inlet is added to the design, and is located in the actuator base, the respirable dose is increased at each base height condition. The effect of vent design and total cross-sectional area is most pronounced at lower reference heights. For example. The introduction of one air inlet at a 12mm base height (design I) resulted in a five-fold increase in respirable dose achieved with the BDP (100/50) ultra-fine formulation when compared to the case where no air inlet was used. The effect is diminished to a lesser extent for other formulations, the relative increase for the ultra fine (EF) formulation is greater than for the high ethanol formulation (HE), and the effect is more pronounced for the high ethanol formulation (HE) than for the low volatility component formulation (LVC). This is probably due to the difference in droplet size caused by the increased concentration of glycerol or ethanol contained in the droplet at the 12mm reference height.

The use of vent design I results in a respirable dose equivalent to 81.8% and 77.5% of conventional actuators for ultra-fine (EF) and High Ethanol (HE) formulations, respectively. However, only 46.6% of the respirable dose of the conventional actuator was achieved when the LVC formulation was dispensed. With a reference height of 12mm, an increase in the total cross-sectional area of the inlet port(s) results in a corresponding decrease in the respirable dose. Although this trend was observed for all formulations, the effect was reduced for both LVC formulations and high ethanol formulations.

As the base height increased to 32mm, the respirable dose increased between design I and design II, and then decreased as the total cross-sectional area of the air inlet(s) increased (design III and design IV). This trend is the same in all three formulations. This effect is modified by increasing the base height to 32mm, which determines a reduction in performance associated with an increase in cross-sectional area at a base height of 12 mm. At this height, performance improves between vent design I and vent design II. Of the different vent designs evaluated, the design with two air inlets in the base (design II) achieved the maximum respirable dose.

The effect of the configuration of the air inlet and/or cross-sectional area is reduced when the reference height is extended to 52 mm. There is little or no difference between vent design I, II, and III. However, a slight decrease in performance was observed for the ultra-fine (EF) formulation when design IV was used. This may be due to the increase in diameter of the air inlet from 3.0mm to 4.25mm and the subsequent effect this may have on the airflow within the prototype.

The prototype design that performed best for each formulation at a 32mm datum height was a configuration with two air inlets in the base (design II in fig. 17). The aerosol characteristics of each formulation compared to a conventional metered dose inhaler (orifice diameter 0.22mm) as a control are given in table 2. The respirable doses achieved when using this in-line prototype were 95.3%, 89.7% and 122.1% of the respirable doses observed when using a conventional metered dose inhaler, for the ultra-fine (EF), Low Volatile Content (LVC) and High Ethanol (HE) formulations, respectively.

Table 2: the aerosol properties of the formulations were tested using an actuator according to the example ("in-line") with vent design II (see fig. 17) and a reference height of 32mm BDP (100/50) compared to a conventional metered-dose inhaler (number of measurements: n-3; mean ± standard deviation)

Using the actuator of an embodiment, the fraction of non-respirable particles can be reduced. With the use of an air inlet, the respirable dose may substantially match that of a conventional actuator.

(b) Air inlet in the rear wall of the actuator

Fig. 21A-21C show aerosol performance of ultra-fine (EF), Low Volatile Component (LVC) and High Ethanol (HE) content formulations of BDP (100 μ g/50 μ L) using an embodiment of the actuator having the air inlet(s) located in the rear wall of the actuator. The aerosol performance of the BDP (100/50) formulation (EF; LVC; HE) with different actuator designs is given in FIG. 21A (for ultra-fine formulation EF), FIG. 21B (for low volatility component formulation LVC) and FIG. 21C (for high ethanol content formulation HE). For the data shown in fig. 21A-21C, the actuator had an air inlet located on the rear wall of the actuator. The different vent designs I-IV shown in fig. 17 were implemented for actuators with reference heights of 12mm, 32mm and 52mm, respectively.

As can be seen from fig. 21A to 21C, the effect on the respirable dose resulting from the introduction of the air inlet in the rear portion is different from that observed when using an air inlet in the base portion. For example, even at low reference heights, changing the vent design and total cross-sectional area has minimal effect on the respirable dose.

With a 12mm base height, a slight downward trend of the respirable dose with increasing total cross-sectional area was observed for the EF (ultra fine) formulation. The overall difference in mean respirable dose achieved between vent design I and vent design IV was 5.8 μ g. In contrast, for the air intake located in the base, the difference between the vent design I and the vent design IV was 23 μ g.

For all other formulations, the respirable doses achieved between designs are roughly within one standard deviation. The introduction of the air inlet into the rear of the actuator improves performance compared to a prototype without the air inlet, despite minor differences in design.

High Ethanol (HE) formulation doses achieve respirable doses approaching those of conventional metered dose inhaler actuators, despite the minimal impact on performance by vent design. For both ultra-fine (EF) and Low Volatile Component (LVC) formulations, the respirable dose was less than half the respirable dose of the corresponding conventional actuator (control), but a significant reduction in the non-respirable dose was still observed. This observed difference in formulation properties was due to the reduced HFA content of 73.8% w/w (for low volatility formulations) compared to 86.8% w/w and 85.5% w/w in the EV and LVC formulations, respectively.

When the reference height is increased to 32mm, the actuator does not achieve a significant increase in the respirable dose. In some cases, most notably in the case of high ethanol formulations, the dose was reduced. Also at a reference height of 52mm, no overall increase was observed. At 52mm, the actuator performance was similar with or without the air inlet.

(c) Summary of the results

Generally, an air inlet in the base of the actuator has a greater effect on the respirable dose obtained from an actuator according to some embodiments than an air inlet in the rear wall of the actuator.

The effect on the respirable dose obtained when using an air inlet located in the base of the actuator varies according to the reference height. This effect may be related to the design pattern or total cross-sectional area of the air inlet.

The reference-height dependent effect of vent design is related to the evolution of the plume from the measured reference height. This effect is not greatly affected by the type of formulation.

The amount of respirable dose produced by the air scoop located in the back wall is less affected by the vent design, total cross-sectional area, or reference height. The performance of an in-line configured actuator with a rear air intake is formulation dependent when compared to a conventional actuator. For High Ethanol (HE) content formulations, a respirable dose matching that of a conventional metered dose inhaler is obtained.

Other examples illustrating the relationship between vent design and performance

(a) Device resistance and air flow rate at the air inlet

To illustrate the effect of vent design on airflow resistance in connection with an actuator having an in-line configuration, the pressure drop (kPa) across a metered-dose inhaler was measured.

Fig. 22A shows the variation in pressure drop across the metered-dose inhaler for different vent designs I-IV with air vents located in the base of the actuator. Fig. 22B shows the variation of the pressure drop across the metered-dose inhaler for different vent designs I-IV with the air inlet located in the rear of the actuator.

Neither the reference height (12mmvs.52mm) nor the air inlet position (base vs. rear) had a significant effect on the device resistance. High resistance was observed in the case where a single 3.0mm inlet port (vent design I in fig. 17) was used, but was greatly reduced when a 3.0mm second inlet port (vent design II in fig. 17) was introduced. The addition of a third air inlet (vent design III in fig. 17) and increasing the opening diameter (vent design IV in fig. 17) resulted in an additional and smaller reduction in device resistance.

The average air flow rate for each vent design can also be calculated as:

wherein v is the mean air flow velocity (m/s); q is the volume flow (L/min); a is the cross-sectional area (mm) of the air inlet²) And n is the number of inlets. The calculated values are given in table 3. The average air flow rate is inversely proportional to the total cross-sectional area. Therefore, as the number of air inlets having a diameter of 3.0mm increases (vent design I-III shown in FIG. 17), the desired average air flow rate decreases. An additional reduction occurs when the diameter of the air intake increases from 3.0mm to 4.25mm (vent design III to vent design IV illustrated in fig. 17).

Table 3: average air flow rate at air inlet calculated at volume flow of 28.3L/min

(b) Actuator with a reference height of 12mm and with a vent design I (see FIG. 17) with air inlet in the base of the actuator

To determine whether the pressure drop across the actuator is related to the observed reduction in respirable dose when using a vent design located in the base at a 12mm base height, a series of actuators each having a base height of 12mm were prepared. A single base vent is formed in the actuator base. The diameter of the base inlet is in the range between 3.0mm and 4.5mm at 0.5mm intervals.

The pressure drop associated with these devices having a single gas inlet is in the range between-4 kPa and-1 kPa. The effect on respirable dose of the reduced pressure drop obtained with the BDP (100/50) ultra fine (EF) formulation when using an actuator dispense with a reference height of 12mm and with a single air inlet located in the base of the actuator is given in fig. 23.

Fig. 23 shows the aerosol performance of BDP (100/50) ultra fine (EF) formulations as a function of air inlet diameter given a 12mm base height. Two measurements were made for each inlet diameter.

The pressure drop decreases as the diameter of the base inlet increases. However, there is no overall effect on the respirable dose.

The total cross-sectional area of the individual air inlets in the base is 16mm, with a diameter of 4.5mm for the inlets². Compare this to 7mm for vent design I (single base intake) in FIG. 17²And 14mm for vent design II (two base inlets) in fig. 17²Are compared.

Fig. 24 shows the particle characteristics of the BDP (100/50) ultrafine (EF) formulation when measured by FSA. The dose characteristics were obtained using vent designs I and II at a reference height of 12mm and compared to an actuator provided with a single air inlet in the base, the diameter of which was 4.5 mm. The number of measurements for each actuator configuration is n-3.

The reduction in fine particle dose and ultrafine particle dose between vent design I with one inlet (see fig. 17) and vent design II with two inlets (see fig. 17) is evident. However, if the reason for this reduction is due to a reduction in the device resistance (4 kPa to 1kPa) or an increase in the total cross-sectional area (from 7 mm) associated with different configurations²To 14mm²) When using a single air inlet of 4.5mm diameter located in the base of the actuator (1 kPa and 16 mm)²) It is expected that a similar reduction will also occur. This effect cannot be attributed to the total cross-sectional area or device resistance because there is little difference in dose characteristics between a single 3.0mm base inlet (vent design I) and a single 4.5mm base inlet.

(c) The actuator has a reference height of 32mm and has different vent designs, with the air inlet located in the base of the actuator

For reference heights of 12mm, 32mm and 52mm among vent designs I-IV, the maximum respirable dose was achieved for all three formulations (see fig. 20A-20C) with an actuator having a reference height of 32mm with two air inlets formed in the actuator base with a diameter of 3.0mm (vent design II in fig. 17). While increasing the total cross-sectional area and reducing the device resistance, increasing the diameter of a single air inlet at a base height of 12mm has less of an effect on the respirable dose.

To confirm this, the diameter of the air inlet of the vent design with two air inlets in the actuator base was varied between 2.0mm and 3.5mm at 0.5mm intervals.

Fig. 25 shows aerosol performance of BDP (100/50) ultra fine (EF) formulations in response to an increase in air inlet diameter at a base height of 32 mm. A total number of measurements n-3 were made for each actuator configuration.

Interestingly, the respirable dose increased as the inlet diameter increased to 3.0mm, after which the performance dropped (fig. 25). These observations suggest that the optimum diameter is 3.0mm among the different diameters tested. The calculated average air flow rate through the actuator having this configuration was 33.4m/s (table 3).

To investigate whether this value of the average air flow rate represents an optimal flow rate, a series of prototypes each having a reference height of 32mm were designed to match the flow rate and total cross-sectional area based on the vent design. The configuration of an air inlet port manufactured using an air inlet port having a diameter of 2.5mm is illustrated in fig. 26.

Design V, shown at 135, has three air inlets in the base of the actuator. The air inlets are arranged in a straight line. The diameter of each air inlet was 2.5 mm.

Design VI shown at 136 and design VII shown at 137 each have a triangular arrangement of air inlets. The position of the two air inlets indicated at 134 in fig. 26 is the same as the air inlet position in vent design II in fig. 17 for both triangular arrangements, although the diameter of 2.5mm is smaller compared to the diameter of 3.0 mm. Design VI defines a "rear" triangle pointing towards the rear of the actuator, while design VII defines a "front" triangle pointing towards the interface opening of the actuator.

All of the inlets in designs V, VI and VII were 2.5mm in diameter, respectively. The vent design is different in terms of the relative arrangement of the air inlets. The actual total cross-sectional area of the actuator is 14.7mm²And the calculated average air flow rate at the air inlet was 32.0m/s, which is comparable to the value of vent design II (table 3).

The air intake configuration of fig. 26 was used to determine the aerosol performance of BDP (100/50) ultra fine (EF) formulations to assess whether the calculated average air flow rate and total cross-sectional area resulted in an "optimal" respirable dose obtained through dual air intakes.

Fig. 27A shows aerosol performance in response to BDP (100/50) ultra-fine (EF) formulations using 2.5mm diameter air inlets and a design with three air inlets (design V-VII in fig. 26) compared to a dual air inlet design (design II in fig. 17, air inlet diameter of 3.0mm) at a base height of 32 mm. A total of 3 measurements were performed. Data show mean ± standard deviation.

The respirable dose obtained from the configuration with three air inlets was lower than that obtained from the configuration with two air inlets (design II in fig. 17). However, there is a slight difference between actuators having three air inlets. The "rear" triangle configuration (design VI) performs better than the straight line design (design V) and the front triangle design (design VII).

Figure 27B shows aerosol performance when the design with three inlet ports is compared to the design with two inlet ports of the same diameter (i.e., the design with two inlet ports of 2.5mm diameter). In fig. 27B, aerosol performance of BDP (100/50) ultrafine formulations is shown at a baseline height of 32mm in response to a design using an air inlet with a diameter of 2.5 mm. A total of 3 measurements were performed. Data show mean ± standard deviation.

Interestingly, the design with two inlets having an inlet diameter of 2.5mm and the three rear triangle design with an inlet diameter of 2.5mm (design VI in fig. 26) were nearly identical when the performance achieved with the design with three inlets was compared to the performance obtained with the design with two inlets having the same vent diameter. Moreover, the efficiency of the front triangle design (design VII in fig. 26) decreases only slightly. This teaches that the positioning and sizing of the inlet ports, indicated at 134 in fig. 26, contributes most to the respirable dose obtained, with the third inlet port causing the least effect.

A straight line design with three inlet ports (design V in fig. 26) can deliver the lowest respirable dose because the position of the inlet ports does not match the design with two inlet ports at all (see data in fig. 27B).

To determine the significance of the location of the two inlets for a configuration with two inlets, another prototype was made in which the spacing between the inlets was increased. A different configuration is shown in fig. 28. The configuration II shown at 122 and the configuration V shown at 135 have already been explained with reference to fig. 17 and 26.

Design VIII, shown at 138, has two air inlets in the base of the actuator. The diameter of each air inlet was 3 mm. The distance between the centers of the air inlets in design VIII was 10mm, i.e., twice the distance of design II.

The positions of the air inlets in design VIII, which are spaced 10mm apart from each other with respect to the center, match the positions of the outer air inlets used in vent design III or vent design V (three straight vents, see fig. 17 and 26).

Fig. 29 shows the aerosol performance of the BDP (100/50) ultrafine (EF) formulation when vent design II (two base inlets 3.0mm in diameter and 5mm apart) was used and when vent design VIII (two base inlets 3.0mm in diameter and 10mm apart) was used.

By increasing the distance between the two air inlets, the performance has been significantly reduced, with an overall reduction in respirable dose of 37% (from 44 to 28 μ g). Furthermore, the reduction in respirable dose is primarily due to a reduction in fine particle dose (1-5 μm) rather than a reduction in ultra fine particle dose (< 1 μm).

(d) Vent design showing best performance for actuators with reference heights of 12mm, 22mm and 32mm

For all formulations, vent design I (single inlet in the base, i.e., single base inlet) and vent design II (two inlets in the base, i.e., two base inlets) produced the maximum respirable dose at base heights of 12mm and 32mm, respectively (fig. 20A-20C).

Other studies have shown that the location of the air inlet has a significant effect on the respirable dose. The effect of the location may be related to the spread of the plume over a distance. For example, the characteristics of the plume in terms of droplet size, particle velocity and expansion are different in the case where the reference height is 12mm than in the case where the reference height is 32 mm. Thus, a single air inlet can make a major contribution in producing a high respirable dose at a base height of 12mm, since it is concentrated in a specific area of the plume. When this area changes with distance, a design with two air inlets in the base can make a major contribution in producing a high respirable dose, with a base height of 32 mm.

To determine which arrangement and configuration of air inlets produced a high respirable dose for an in-line actuator having a reference height of 22mm, two prototype in-line actuators having a reference height of 22mm were fabricated. Both actuators have vent designs I and II shown in fig. 17. The aerosol performance of the BDP (100/50) ultra fine (EF) formulation with a base height of 22mm and using vent design I and vent design II was compared to the performance of the actuators with base heights of 12mm and 32mm in fig. 30.

Fig. 30 shows aerosol performance (expressed as mean ± standard deviation for 3 measurements) of BDP (100/50) ultra fine (EF) formulations using actuators with vent design I (single inlet) and vent design II (two inlets) at 12mm, 22mm and 32mm baseline heights. The performance was compared to that of a conventional actuator having an orifice of 0.22mm in diameter (n-3; ±. standard deviation).

For a base height of 22mm, the respirable dose was greater when vent design II was used compared to when vent design I was used.

The performance difference between the actuator with the reference height of 22mm and the actuator with the reference height of 32mm when vent design II was used was 5.2 μ g (table 4). The most significant reason for this difference is due to the reduced proportion of fine particle doses ≦ 5 μm and >1 μm, while the ultrafine dose ≦ 1 μm remains within one standard deviation. Conversely, the difference in respirable dose between an actuator with a reference height of 12mm and an actuator with a reference height of 22mm is minimal. However, the proportion of ultra-fine particles is increased compared to fine particles which contribute to the respirable dose. All respirable doses obtained from the inline prototype were within ± 25% of the respirable dose of a conventional metered-dose inhaler. The number and fraction of non-respirable particles is significantly reduced compared to conventional metered dose inhalers.

Table 4: dose characteristics of BDP (100/50) ultrafine (EF) formulation using vent design I at 12mm base height and vent design II at 22mm and 32mm base height. The results were compared with a conventional metered dose inhaler (number of measurements: n ═ 3; mean. + -. standard deviation)

(d) Summary of the invention

Increasing and decreasing the diameter of the individual air inlets (arranged as shown for vent design I in fig. 1) does not affect the respirable dose obtained in the in-line design of the embodiment for the measured diameter at the 12mm base height condition.

Increasing and decreasing the diameter of the air inlet in a two-vent design has an effect on the respirable dose at a 32mm base height. Of the different diameters tested, a diameter of 3.0mm gave the best performance.

The performance obtained when using a configuration with two air inlets each having a diameter of 3.0mm and located in the base is independent of the cross-sectional area or the calculated average air flow rate, but is highly dependent on positioning.

The air flow rate also plays a role in generating the observed respirable dose, but is not as critical as the location of the air inlet(s).

Between 12mm and 32mm, the configuration of the air inlets that yields the best performance between the different tested configurations changed from the configuration with one air inlet to the configuration with two air inlets.

The spread of the plume causes the expansion to increase with increasing distance until a maximum is reached. During this expansion, the droplet size and velocity change. The spray pattern within such an actuator may give rise to the observed effects.

Actuator having at least one air inlet opening in the base of the actuator and at least one air inlet opening in the rear wall

To investigate the effect of the combined vent design, two additional prototypes of actuators according to the embodiments were fabricated. The reference height of the actuator is 32 mm.

The actuator is provided with an air inlet configuration or vent design having an air inlet in the base of the actuator and an air inlet in the rear wall. More specifically, the following vent designs were used:

design IX combines two air inlets in the base of the actuator (located as shown in fig. 17 for vent design II) with a diameter of 3.0mm with one air inlet in the rear wall of the actuator. The diameter of the air inlet in the rear wall is 3.0 mm. The center of the air inlet in the rear wall is positioned 10mm from the actuator base.

Design X combines two air inlets in the base of the actuator (located as shown in fig. 17 for vent design II) with a diameter of 3.0mm with one air inlet in the rear wall of the actuator. The diameter of the air inlet in the rear wall is 3.0 mm. The center of the air inlet in the rear wall is positioned 20mm from the actuator base.

Fig. 31 shows the performance of the BDP (100/50) ultrafine (EF) formulation with combined base and rear vent designs IX and X for a base height of 32mm (mean data ± standard deviation obtained for 3 measurements where n ═ n). The results were compared to base vent designs II and III (see fig. 17) (mean data ± standard deviation obtained for 3 measurements where n is 32mm) with a baseline height of 32 mm.

Vent designs in which the rear air inlet is located closer to the orifice (i.e., at a height of 20mm from the actuator base) produce a larger respirable dose when compared to each other. When the performance of these combined vent prototypes was compared to that of the original vent design III (where the total number of air inlets was equal), the respirable dose was slightly increased, which could be attributed to the location of the third air inlet. However, the differences were small and not compared to the performance obtained using vent design II.

Study of ACI

According to an optimization study with respect to air inlet configurations, configurations with a base height of between 12mm and 32mm can produce a respirable dose that is within ± 25% of the respirable dose of a conventional metered-dose inhaler. This section will focus on confirming the results obtained using FSA with ACI according to the method outlined above.

(a) ACI study for actuators with reference heights of 12mm, 22mm and 32mm

The performance of the actuator configurations showing the best performance at 12mm, 22mm and 32mm base heights (12mm base height for design I and 22mm and 32mm base height for design II) for the three test formulations when measured using the Andersen multistage impactor is given in FIGS. 32-34. The air inlets are respectively provided in the actuator base.

Fig. 32 shows data for a BDP (100/50) ultra-fine (EF) formulation, obtained using an actuator with a reference height of 12mm and using vent design I, according to an embodiment, an actuator with a reference height of 22mm and using vent design II, according to an embodiment, and an actuator with a reference height of 32mm and using vent design II. Data obtained by taking two measurements (n-2) for each of the actuators is shown.

Fig. 33 shows data for a BDP (100/50) Low Volatile Component (LVC) formulation, obtained using an actuator of example base height 12mm and using vent design I, an actuator of example base height 22mm and using vent design II, and an actuator of example base height 32mm and using vent design II. Data obtained by taking two measurements (n-2) for each of the actuators is shown.

Fig. 34 shows data for a BDP (100/50) High Ethanol (HE) content formulation, obtained using an actuator of example with a base height of 12mm and using vent design I, an actuator of example with a base height of 22mm and using vent design II, and an actuator of example with a base height of 32mm and using vent design II. Data obtained by taking two measurements (n-2) for each of the actuators is shown.

The dose profile for each formulation is given in tables 5-7. For comparison, control data for a conventional actuator with an orifice diameter of 0.22mm and a conventional actuator with an orifice diameter of 0.30mm have been included.

The aerosol performance determined by ACI shows that the fine particle dose (< 5 μm) achieved at a 12mm base height using a single inlet port design (vent design I in FIG. 17) is lower than the results obtained from an actuator with base heights of 22mm and 32mm and having two inlet ports (vent design II). The difference between the FSA and ACI data may be due to the difference between the void volumes of the two impactors combined with the use of a single vent design, which provides higher airflow resistance. For the ultra-fine formulation, the difference between the conventional actuator with an orifice diameter of 0.22mm and the actuator with the example base height of 12mm was the largest, thus achieving only 69.4% of the respirable dose of the conventional actuator (table 5). This corresponds to 72.3% of the respirable dose achieved by a conventional actuator with an orifice diameter of 0.22mm in the case of a High Ethanol (HE) formulation, and 77.7% of the respirable dose achieved by a conventional actuator with an orifice diameter of 0.22mm in the case of a low volatile component (LVE) formulation.

For actuators with reference heights of 22mm and 32mm, the fine particle dose achieved is in the range of ± 25% of the fine particle dose of a conventional actuator with an orifice diameter of 0.22 mm.

Data have been obtained for the performance of BDP (100/50) ultra fine (EF) formulations and Low Volatile Component (LVC) formulations in a conventional actuator having an actuator orifice diameter of 0.30mm (tables 5 and 6). In both examples, the actuator of the embodiment with in-line configuration outperformed the conventional actuator with orifice diameter of 0.30mm in fine particle dose especially at reference heights of 22mm and 32 mm. At a reference height of 12mm, the data are similar, although the Mass Median Aerodynamic Diameter (MMAD) achieved using the in-line actuator of the example is still lower than that obtained by the conventional actuator.

Table 5: dose characteristics of BDP (100/50) ultra fine (EF) formulations using actuators according to embodiments at three base heights (n-2 measurements). Including the aerosol performance of a conventional actuator with an orifice diameter of 0.20mm (mean; n-3 ± standard deviation) and a conventional actuator with an orifice diameter of 0.30mm (mean obtained for n-2 measurements).

For the actuator of the example, the orifice diameter of the prototype actuator was 0.26mm, exactly midway between the 0.22mm and 0.30mm nozzle orifice diameters of the conventional actuator. Thus, the performance of the prototype is related to the orifice diameter.

Fig. 35 shows the undersized cumulative mass of the BDP (100/50) ultra-fine (EF) formulation when using an embodiment of an actuator with a reference height of 12mm and with vent design I and an embodiment of an actuator with a reference height of 22mm and with vent design II and an embodiment of an actuator with a reference height of 32mm and with vent design II. For comparison, data obtained with a conventional actuator with an orifice diameter of 0.22mm are also shown (n-the average of 3 measurements).

Interestingly, the increase in the baseline height of the in-line actuator caused the MMAD of the formulation to shift upward and gradually approach the MMAD of the conventional actuator with an orifice diameter of 0.22 mm. Thus, the particle size distribution of the resulting formulation can be varied by selecting an appropriate optimized base height.

The MMAD (table 5) and the oversize cumulative mass (%) approach a conventional actuator with an orifice diameter of 0.22mm as the base height increases. The magnitude of MMAD shift in the Low Volatile Component (LVC) formulation was greatest (table 6), with an increase of 0.9 μm in MMAD as the baseline height increased from 12mm to 32 mm. For the High Ethanol (HE) content formulation, 0.5 μm was added and for the ultra fine (EF) formulation, 0.4 μm was added. This difference is related to the non-volatile content (NVC) within each formulation. The inclusion of propylene glycol in the Low Volatile Component (LVC) formulation increased NVC from 0.175% w/w to 1.475% w/w compared to the ultra-fine (EF) formulation and the High Ethanol (HE) content formulation. The effect on upper particle size is therefore greater for the calculated MMAD value. Therefore, removing large particle size caused by the actuator has a greater impact on MMAD.

Table 6: the dose profile of BDP (100/50) with a Low Volatility Component (LVC) formulation using an actuator according to the example was used at three base heights (n-2 measurements). Aerosol performance of a conventional actuator comprising an orifice diameter of 0.20mm (mean ± standard deviation for n-3 measurements) and a conventional actuator comprising an orifice diameter of 0.30mm (mean of 3 measurements).

Table 7: the dose profile of BDP (100/50) High Ethanol (HE) content of the actuator according to the example was used at three base heights (n ═ 2 measurements). Aerosol performance of a conventional actuator including an orifice diameter of 0.20mm (n-3 measurements, mean ± standard deviation).

(b) Effect of non-volatile content

To determine the effect of increasing non-volatile content on actuator performance compared to a conventional actuator, additional tests were performed on a prototype of an actuator having a reference height of 32mm and having vent design II (fig. 17) according to an embodiment. Ideally, the performance of an in-line actuator with an appropriately selected reference height and/or vent design, or an in-line actuator that is optimal in terms of reference height and vent design, is only weakly or not substantially affected by formulation differences. As shown above, increasing the non-volatile content (NVC) in the formulation (e.g., formulation with Low Volatile Content (LVC) compared to the ultra-fine formulation (EF) and high ethanol content formulation (HE)) enhanced the effect on the MMAD shift upward with increasing baseline height.

The effect of increasing the non-volatile content was evaluated for an actuator according to the embodiment with a reference height of 32mm and with vent design II (fig. 17). Additional BDP formulations "high NVC" and "low NVC" were prepared as specified in table 1. The formulation is packaged as set out above. The Low Volatile Component (LVC) formulation and the ultra-fine (EF) formulation were used for comparison, giving an overall range of NVC from 0.01% w/w to 1.475% w/w (Table 8). The delivery characteristics of each formulation were tested in an actuator with a reference height of 32mm and a conventional actuator with an orifice diameter of 0.22mm according to an embodiment. The results and comparison are given in table 8.

Table 8: comparison of dose and particle size distribution between BDP formulations comprising a range of non-volatile contents with 13% w/w ethanol (average of 2 measurements for BDP (6/50) and BDP (250/50; average of 3 measurements for BDP (250/50) and BDP (100/50)).

With an increased non-volatile content, the match between the fine particle dose (< 5 μm) obtained using an in-line actuator with a base height of 32mm and the fine particle dose (< 5 μm) obtained with a conventional actuator with an orifice diameter of 0.22mm is improved. Although the value of MMAD between formulations decreased slightly as the non-volatile content increased, the difference was smaller. This demonstrates that an in-line design optimized at a 32mm datum height can achieve the same particle size distribution as a 0.22mm conventional actuator.

(c) Ethanol-containing suspension formulation

To evaluate the effectiveness of the actuators of the embodiments having an in-line configuration with a suspension formulation, a formulation comprising salbutamol sulfate (a), (b), and (c) was selectedIVAX).

One metered dose contains salbutamol sulphate equivalent to 100 micrograms of salbutamol;

excipient:

anhydrous ethanol

Noflumamine (propellant HFA-134a)

The formulation was contained in a pressurized aluminum container with a dosing valve.

Is provided withThe conventional actuator of (a) is a breath-actuated device. To evaluate the performance of the product, a conventional actuator was turned on and manually actuated, thereby serving as a control. For the actuator of the embodiment, fromThe canister with the device removed was placed in a prototype of an actuator of an embodiment having a reference height of 32mm and having two air inlets (vent design II in fig. 17) formed in the base of the actuator to evaluate performance. The size of the aperture used on the control device was 0.24mm when measured using optical stereo microscopy (NikonSM 2800). This is directly analogous to the orifice diameter of an in-line actuator according to an embodiment having an orifice diameter of 0.26 mm. Thus, any differences between the aerosol properties of the formulations are less likely to be caused by the orifice diameter.

Figure 36 shows the aerosol performance (particle size distribution) of suspended salbutamol sulphate (100 μ g/25 μ L) (100 μ g salbutamol; 117.01 μ g salbutamol sulphate) using a prototype of an in-line actuator having a reference height of 32mm and having vent design II and a control device. Two measurements were performed for each device (n-2).

Figure 37 shows the undersized cumulative mass of salbutamol sulphate (100/25) using an in-line actuator with a reference height of 32mm and a control device. The data obtained in two measurements (n-2) are shown for each device.

Table 9 shows the dose characteristics.

A comparison between the prototype of the control device and the in-line actuator shows similar deposition curves up to stage 5. Above this, the control device delivers a slightly higher dose (see also the very high deposition into the throat).

Table 9: dose characteristics of salbutamol sulphate (100/25) (actual dose: 117.01 μ g salbutamol sulphate) using an in-line actuator with a reference height of 32mm and a control device (n ═ 2 measurements)

The percentage difference between the average fine particle dose obtained from the actuator of the example and the average fine particle dose obtained from the control device was 81.5%. This difference corresponds to the results found for the ultra-fine (EF) formulation (table 8 above). According to the accumulation of undersize, there was an MMAD offset between the in-line actuator and the control device (fig. 37) that was slightly greater than the offset observed for the solution formulation for the in-line actuator with a baseline height of 32 mm. This may be due to small differences between the properties of the suspension and solution formulations.

Flow dependency

For the actuators of the embodiments, operation relies on the respiration of the patient to generate a flow of gas through the in-line actuator. Experimental data for a flow of 28.3 (+ -5%) L/min have been obtained in accordance with standard test requirements for metered dose inhaler systems. However, because the airflow within the device determines the respirable dose, it is desirable to assess how performance depends on inspiratory flow. Particle size analysis using FSA and ACI impactors relies on careful calibration at a single flow rate, making the two impactors unsuitable for use at different flow rates. Thus, flow dependence was assessed by examining the difference in delivered dose obtained using a sample collection tube on the order of 10L/min over a flow range of 10L/min to 50L/min. Because the actuator according to embodiments produces a high fine particle fraction due to the removal of larger particles by the device design, the measurement of the delivered dose will accurately reflect performance.

Tests were conducted on a prototype of the actuator of an embodiment having a reference height of 32mm and two air inlets in the base (vent design II in fig. 17).

The delivered dose obtained under a range of flow rates is given in fig. 38 and the resulting actuator deposition is shown in fig. 39. Fig. 38 shows the delivered dose of a prototype delivery BDP (100/50) ultra-fine (EF) formulation using an actuator according to an embodiment with a reference height of 32mm (data representing mean ± standard deviation obtained in n-4 measurements). Fig. 39 shows the average of actuator deposition for BDP (100/50) ultra fine (EF) formulations in response to a range of volumetric flow rates. The data represent the average of 5 injections for a prototype of an actuator according to an embodiment having a reference height of 32mm and having vent design II (fig. 17).

When the flow rate was increased to 30L/min, the device performance was significantly dependent on the flow rate. However, after increasing to 30L/min, the increase in performance did not continue and the response reached equilibrium. The dose may be lost when the patient does not reach a flow of about 30L/min, but using a higher flow does not result in a higher dose.

Claims

1. A metered dose inhaler actuator comprising:

a housing having an interface portion (13) and a canister receiving portion (12) configured to receive a canister (2), the housing extending from an opening (21) for receiving the canister (2) to an interface opening (22);

a member (14) disposed within the housing and defining: a valve stem receiving portion (15) configured to receive a valve stem (3) of the canister (2); an aperture (16; 73, 74; 76, 77; 79, 80; 84; 88) formed in the member (14), the aperture (16; 73, 74; 76, 77; 79, 80; 84; 88) being in fluid communication with the valve stem receiving portion (15) and extending to a face (19) of the member (14) opposite the valve stem receiving portion (15);

the longitudinal axis (18) of the orifice (16; 73, 74; 76, 77; 79, 80; 84; 88) is aligned with the longitudinal axis (17) of the valve stem receiving portion (15);

a longitudinal axis (25) of the interface portion (13) is arranged at an angle relative to the longitudinal axis (18) of the aperture (16; 73, 74; 76, 77; 79, 80; 84; 88); and is

At least one air inlet (20) is provided in the housing of the housing, spaced from the opening (21) for receiving the canister (2) and the interface opening (22), the at least one air inlet (20) being in fluid communication with the interface opening (22).

2. The actuator of claim 1,

the at least one air inlet (20) is provided in a portion of the outer shell of the housing extending from the member (14) towards the interface opening (22).

3. The actuator according to claim 1 or 2,

the housing comprises a wall oriented at an angle relative to the longitudinal axis (25) of the mouthpiece portion (13), an air inlet (20) of the at least one air inlet (20) being provided in the wall.

4. The actuator of claim 1,

an air inlet (20) of the at least one air inlet (20) is positioned on a line of sight (29) through the interface opening (22) and aligned with the longitudinal axis (25) of the interface portion (13).

5. The actuator of claim 4,

each of the at least one air inlet (20) is positioned on the line of sight (29) through the interface opening (22) and aligned with the longitudinal axis (25) of the interface portion (13), respectively.

6. The actuator of claim 1,

the component (14) and the air inlet opening (20) are configured such that all air output via the interface opening (22) during use of the actuator (11; 31; 41; 51; 91) is drawn into the interior of the housing through the at least one air inlet opening (20).

7. The actuator of claim 1,

the member (14) extends across a cross-sectional area of the canister receiving portion (12).

8. The actuator of claim 7,

the member (14) is configured to prevent gas from passing through the member (14) radially outward of the apertures (16; 73, 74; 76, 77; 79, 80; 84; 88).

9. The actuator of claim 1,

the orifice (73, 74; 76, 77; 79, 80) has at least one tapered portion (73; 76; 79) towards the face (19) of the member (14) opposite the valve stem receiving portion (15).

10. The actuator of claim 9,

the conical portion (79) of the orifice (79, 80) has a maximum diameter corresponding to the outer diameter of the valve stem (3).

11. The actuator of claim 9,

the tapered portion (76) of the orifice (76, 77) has a maximum diameter corresponding to the inner diameter of the valve stem (3).

12. The actuator of claim 1,

an expansion chamber (82, 83; 86, 87) is formed in the member (14), the expansion chamber (82, 83; 86, 87) being in fluid communication with the aperture (84; 88) and the valve stem receptacle (15) and having a longitudinal axis aligned with the longitudinal axis (17) of the valve stem receptacle (15).

13. The actuator as set forth in claim 1,

the longitudinal axis (18) of the aperture (16; 73, 74; 76, 77; 79, 80; 84) is arranged at an angle (28) of more than 90 DEG relative to the longitudinal axis (25) of the interface portion (13).

14. A metered-dose inhaler comprising:

an actuator (11; 31; 41; 51; 91) according to any one of claims 1 to 13, and

a canister (2) provided with a metering valve (32) comprising a valve stem (3) to be fitted into the valve stem receptacle (15) formed in the member (14) of the actuator (11; 31; 41; 51), the canister (2) containing an aerosol formulation.

15. Use of an actuator (11; 31; 41; 51; 91) according to any one of claims 1 to 13 for dispensing an aerosol formulation from a canister (2) without interaction with the human or animal body.