HK1182034B

HK1182034B - Metered-dose inhaler and method of using the same

Info

Publication number: HK1182034B
Application number: HK13109299.4A
Authority: HK
Inventors: G．布拉姆比拉; D．A．刘易斯; R.约翰森; D．豪利特
Original assignee: 奇斯药制品公司
Priority date: 2010-09-06
Filing date: 2011-09-05
Publication date: 2018-04-13

Description

Metered dose inhaler and method of using the same

Technical Field

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

Background

Among the devices that can be used to deliver medicaments to the lungs, Metered Dose Inhalers (MDIs) are widely used. MDIs are aerosol delivery systems designed to deliver a medicament that can be formulated with a solvent, such as a compressed, low boiling point liquid gas propellant. MDIs are designed to meter a predetermined amount of a medicament that is completely dissolved (in solution) or suspended in a formulation and dispense the dose as an inhalable aerosol cloud or plume.

A conventional MDI includes an actuator and a barrel. When the MDI is ready for use, the cartridge is received in the actuator. The cartridge contains a formulation in which the medicament is in solution or suspension with a low boiling point propellant. The cartridge may be provided with a metering valve having a hollow valve stem for measuring discrete doses of a medicament formulation. When the cartridge is pressed into the actuator, a predetermined dose of the medicament formulation is delivered from the cartridge. A dose of medicament formulation is aerosolized at a nozzle orifice, which may be arranged in an actuator. The dose of medicament is delivered from the MDI as an inhalable cloud or plume.

Conventional MDI designs may impose limitations on the active ingredients or formulations that can be delivered or on the delivery characteristics that can be achieved. For the sake of illustration, conventional MDI cannot achieve the desired particle size distribution or fine particle dose with any solvent, e.g. a solvent that allows a high loading with active ingredient. Vice versa, when using special propellant/solvent systems, it can be difficult to obtain the desired particle size distribution or fine particle dose. While the delivery characteristics may in some cases be affected by a properly designed nozzle orifice, this does not always allow the desired delivery characteristics to be obtained. In addition, conventional MDI designs impose limitations on co-administration of active ingredients or other excipients. For purposes of illustration, physical or chemical incompatibilities may not allow different excipients or active ingredients to be formulated in an aerosol formulation that is held in a container for an extended period of time.

WO92/16249 discloses an inhaler device capable of accommodating a plurality of removable medicament cartridges and may also have an extendable and retractable nozzle, a spacer device, a cover and a wide variety of cap designs to ensure proper use and application of medicament. The inhaler apparatus is configured to sequentially deliver medicament from a plurality of cartridges.

WO02/072183A1 describes a double cartridge inhaler. The inhaler has a cartridge selection mechanism that allows selection of one of the two cartridges from which the formulation will be dispensed upon actuation of the inhaler.

US5,002,048 describes an inhalation device utilising two or more aerosol containers. The housing has two receptacles to receive separate aerosol containers. The apparatus is configured such that one of the aerosol containers is actuated by the patient for delivering a dose of the medicament in order to deliver different formulations in a sequential manner. The inhalation device prevents formulation mixing.

WO03/061744A1 and WO2004/011070A1 each relate to an apparatus comprising: a first medicament container containing a plurality of co-formulated compatible medicament components; a first release for releasing the contents of the first medicament container for delivery; at least one or more medicament containers, each of said medicament containers containing at least one co-formulated incompatible medicament component; and at least one other release means for releasing the contents of each at least one other medicament container for delivery.

Although the inhaler described in WO02/072183a1 or in US5,002,048, for example, allows one of a number of different formulations to be selectively delivered, there is also a need in the art for a metered dose inhaler that provides enhanced versatility in controlling delivery characteristics such as particle size distribution. There is also a need in the art for a metered dose inhaler that reduces the limitations imposed on formulators by conventional MDI designs.

In view of the above, there is also a need in the art for a metered dose inhaler and method that addresses some of the above needs.

Disclosure of Invention

These and other needs are addressed by a metered dose inhaler according to claim 1 and a method of using the metered dose inhaler according to claim 15. The dependent claims define embodiments.

The present invention relates to a metered dose inhaler system having at least two formulation reservoirs, each metered by a different valve system delivering the formulation through a single orifice or separate orifices.

According to one aspect, a metered dose inhaler is provided. The metered dose inhaler includes at least one vessel and an actuator for receiving the at least one vessel. The at least one vessel includes a first reservoir containing a first formulation and a second reservoir, different from the first reservoir, containing a second formulation. The metered dose inhaler is configured to be actuatable when the at least one vessel is received by the actuator. The metered-dose inhaler is configured to simultaneously deliver at least a first metered dose of a first formulation from the first reservoir and a second metered dose of a second formulation from the second reservoir upon actuation of the metered-dose inhaler in a state in which the at least one vessel is received in the container.

The metered dose inhaler according to this aspect allows for simultaneous delivery of the formulation from separate reservoirs. A metered dose inhaler having this configuration allows the delivery characteristics of one of the formulations to be adjusted by mixing with another of the formulations. The first and second formulations, or the active agent or other excipient contained therein, which when formulated together with the first and second formulations would enhance stability issues, may be co-administered using a metered dose inhaler.

The metered dose inhaler of this aspect need not be fully assembled. For the sake of illustration, the metered dose inhaler may be provided in the form of a kit comprising an actuator and at least one vessel, in a state in which the at least one vessel has not been fully assembled with the actuator. The patient may insert at least one vessel into the actuator. In still other embodiments, the metered dose inhaler may be assembled with at least one vessel received in the actuator.

At least one of the first formulation and the second formulation may include an active ingredient. The first formulation and the second formulation may be a solution formulation or a suspension formulation, respectively. The first and second formulations may be different from each other.

Both the first reservoir and the second reservoir may be pressurized.

The metered dose inhaler may comprise a first metering system for metering a first metered dose and a second metering system for metering a second metered dose. The first and second metering systems may be different. The first metering system may include a first metering valve. The second metering system may include a second metering valve.

The first metering system may meter between 1 μ l per dose and 100 μ l per dose. The second metering system may meter between 1 μ l per dose and 100 μ l per dose.

The first metering system may be configured to provide a first metered dose independent of the actuation duration. The second metering system may be configured to provide a second metered dose independent of the actuation duration. Thus, upon repeated actuations of the metered dose inhaler, a consistent first dose and a consistent second dose may be delivered.

The metered dose inhaler may comprise an actuation device configured to effect simultaneous actuation of the first and second metering systems upon actuation of the metered dose inhaler when the at least one vessel is received by the actuator. The actuation means may have various configurations and may be integrally formed with other components of the metered dose inhaler. For purposes of illustration, the actuation means may comprise a combined valve stem of the first and second valves. The actuation device may further comprise a rigid coupling between the first stem of the first valve and the second stem of the second valve. The actuation arrangement may further comprise a mechanical arrangement configured to effect joint movement of the separate vessels defining the first and second reservoirs.

The actuator may be configured such that when the at least one vessel is received by the actuator, the first and second metered doses are mixed prior to delivery through the mouthpiece opening of the actuator upon actuation of the metered dose inhaler. Thus, the particle size distribution or fine particle dose can be adjusted prior to delivery of the formulation to the patient.

The actuator may comprise a nozzle orifice for aerosolizing the first and second metered doses upon actuation of the metered-dose inhaler. This allows the first and second formulations to be mixed prior to formulation atomization.

The at least one vessel may have a valve stem for supplying a first metered dose from a first reservoir and a second metered dose from a second reservoir. The actuator may have a seat for receiving the valve stem, the nozzle orifice being in communication with the seat for receiving the valve stem. This configuration allows the first and second metered doses to mix in the valve stem. The seat and the nozzle orifice may be defined by an actuator block disposed within a housing of the actuator.

The at least one vessel may have a first valve stem for supplying a first metered dose and a second valve stem for supplying a second metered dose. The actuator may have a first seat for receiving the first valve stem and a second seat for receiving the second valve stem, the nozzle orifice being in fluid communication with both the first seat and the second seat. This arrangement allows the first and second metered doses to be mixed prior to aerosolization when the first and second metered doses are supplied by separate valve stems. The first and second seats and the nozzle orifice may be defined by an actuator block disposed within a housing of the actuator.

The actuator may comprise a first passage for supplying a first metered dose to the nozzle orifice and a second passage for supplying a second metered dose to the nozzle orifice. The first path may be linear. The second path may be linear.

The actuator may have a receiving portion for receiving the vessel, the receiving portion having a longitudinal axis. The first passage may be disposed at an angle relative to the longitudinal axis. An angle between a longitudinal axis of the first passage and a longitudinal axis of the receiving portion is a first orifice angle. The second passageway may be disposed at an angle relative to the longitudinal axis. The angle between the longitudinal axis of the second passage and the longitudinal axis of the receiving portion is a second orifice angle. The first and second orifice angles may each be included in an interval of 0 ° to 90 °, in particular in an interval of from 15 ° to 60 °, in particular in an interval of 20 ° to 60 °. The first and second orifice angles may be the same. An actuator having this configuration assists in delivering the first and second metered doses simultaneously.

The at least one vessel may have a first valve stem for supplying a first metered dose and a second valve stem for supplying a second metered dose. The actuator may define a first nozzle orifice, a second nozzle orifice separate from the first nozzle orifice, a first seat for receiving the first valve stem, and a second seat for receiving the second valve stem. The first nozzle orifice may be in fluid communication with the first seat and the second nozzle orifice may be in fluid communication with the second seat. This configuration allows the first and second metered doses to be aerosolized through separate first and second nozzle orifices. The aerosolized doses may interact. The first and second seats and the first and second nozzle orifices may be defined by an actuator block disposed within a housing of the actuator. The actuator block may be configured such that the first nozzle orifice is not in communication with the second seat and the second nozzle orifice is not in communication with the first seat.

The first nozzle orifice and the second nozzle orifice may be arranged such that a longitudinal axis of the first nozzle orifice and a longitudinal axis of the second nozzle orifice are arranged at an angle with respect to each other. The angle between the longitudinal axis of the first nozzle orifice and the longitudinal axis of the second nozzle orifice is an impingement angle. The impingement angle may be comprised in a range from 0 ° to 180 °, in particular in a range from 10 ° to 110 °, in particular in a range from 15 ° to 60 °, which ranges comprise the range boundaries, respectively. This configuration allows the plume of one of the recipes to be directed toward the plume of another recipe.

The at least one vessel may comprise a vessel having a first compartment and a second compartment. The first compartment may define a first reservoir and the second compartment may define a second reservoir. The first and second reservoirs are integrated into one vessel, which enhances user comfort when the metered dose inhaler is assembled. The vessel may have the same outer dimensions as the outer dimensions of the cartridge used in conventional metered dose inhalers.

The second compartment may be formed by a container arranged in the interior of the vessel. The container may be a cartridge having an outer dimension smaller than an inner dimension of the vessel.

A vessel having a first compartment and a second compartment may be provided with a single valve stem through which a first metered dose of a first formulation and a second metered dose of a second formulation are delivered. This configuration allows the first and second metered doses to mix within the valve stem.

A vessel having a first compartment and a second compartment may be provided with a first valve stem for supplying a first metered dose and a second valve stem for supplying a second metered dose. The first and second valve stems may be coaxially aligned. The first and second valve stems may be rigidly joined together. This configuration allows the first and second metered doses to be aerosolized through separate valve stem orifices. The aerosolized doses may interact with each other after nebulization.

The at least one vessel may include a first vessel defining a first reservoir and a second vessel defined a second reservoir formed separately from the first vessel. The first vessel may be formed as a first cartridge and the second vessel may be formed as a second cartridge. Each cartridge may be provided with a different metering system.

At least one of the first and second formulations may be selected such that the particle size distribution after atomization of at least the other of the first and second formulations is adjusted by mixing the first and second metered doses. Selecting one of the formulations such that the particle size distribution of the other formulation is tailored adds flexibility to the formulator.

At least one of the first and second formulations may be selected such that the fine particle dose of at least the other of the first and second formulations after aerosolization is adjusted by mixing the first and second metered doses.

At least one of the first and second formulations may include a medicament, solvent, propellant or other excipient that will be compatible with the other of the first and second formulations when formulated in the same container. Alternatively or additionally, at least one of the first and second formulations may include a medicament, solvent, propellant or other excipient that will be incompatible with the material of the cartridge, the cartridge interior coating, the valve of the cartridge or the valve coating that contains the other of the first and second formulations. Incompatibility can result from chemical or physical incompatibility that can result in unsatisfactory chemical or physical stability. Each of the first and second reservoirs may have separate formulation solubilizers and/or stabilizers and/or packaging (can, can coating, valve material or coating) that would not be compatible in the same formulation.

The at least one vessel may include a third reservoir containing a third formulation. The metered-dose inhaler may be configured to simultaneously deliver a first metered dose of the first formulation, a second metered dose of the second formulation, and a second metered dose of the third formulation from the third reservoir when the at least one vessel is received by the actuator. This allows three active agents to be delivered simultaneously.

According to another aspect, there is provided a method of delivering a first formulation and a second formulation using the metered dose inhaler of any aspect or embodiment described herein.

According to yet another aspect, a vessel for use in a metered dose inhaler is provided. The vessel has a first compartment containing a first formulation and a second compartment containing a second formulation. The vessel has a first metering system for metering a first dose of a first formulation and a second metering system for metering a second dose of a second formulation. The vessel has a hollow valve stem configured to simultaneously deliver a first dose of a first formulation and a second dose of a second formulation.

The capsule of this aspect may be used in conjunction with a metered dose inhaler actuator to effect simultaneous delivery of a first dose of a first formulation and a second dose of a second formulation through one nozzle orifice or through separate nozzle orifices. The first and second formulations may be mixed in the valve stem or at the nozzle orifice.

According to yet another aspect, a metered dose inhaler actuator is provided. The actuator includes an actuator block defining a first seat for receiving the first valve stem and a second seat for receiving the second valve stem. The actuator block also defines at least one nozzle orifice. The actuator block includes a passage communicating the first seat with a nozzle orifice of the at least one nozzle orifice and a passage communicating the second seat with a nozzle orifice of the at least one nozzle orifice.

The actuator of this aspect allows for delivery of the first and second formulations from separate vessels.

In the actuator, one nozzle orifice may be in fluid communication with both the first seat and the second seat.

In the actuator, the actuator block may define both the first nozzle orifice and the second nozzle orifice. The longitudinal axis of the first nozzle orifice may be arranged at an angle relative to the longitudinal axis of the second nozzle orifice. The impingement angle may be defined as an angle between a longitudinal axis of the first nozzle orifice and a longitudinal axis of the second nozzle orifice. The impingement angle can be selected from the range from 0 ° to 180 °, in particular from 10 ° to 110 °, in particular from 15 ° to 60 °, which ranges each include a range boundary.

Various effects and advantages are obtained by the apparatus and method of the embodiments. To illustrate, in embodiments, a multi-reservoir system incorporating a formulation before or after the outlet orifice provides the ability to focus attention on solubility and stability during formulation. The Particle Size Distribution (PSD) and efficacy of the formulation can be adjusted and/or enhanced by aerosolization with a second formulation, or optionally a third formulation, and the like. In embodiments, a multi-reservoir system incorporating the formulation before or after the outlet orifice allows incompatible excipients to be mixed upon aerosolization. In an embodiment, a multi-reservoir system incorporating formulations before or after the outlet orifice allows consistency between the PSDs of the mixed formulations to be controlled by designing and selecting the mixing process (valve/canister/actuator). This allows the PSDs to be designed to match each other, range between two (or more) initial recipes, or remain separate. According to various embodiments, the same or different metered volumes may be used for different formulations. Various nozzle positions may be used in embodiments that may be accurately selected to achieve a desired nozzle positioning.

Drawings

Fig. 1 is a schematic cross-sectional view of a metered dose inhaler according to an embodiment;

FIG. 2 is a schematic cross-sectional view of a metered dose inhaler according to another embodiment;

figure 3 is a schematic cross-sectional view of a two-compartment vessel of a metered dose inhaler according to an embodiment in an unactuated state;

figure 4 is a schematic cross-sectional view of the vessel of figure 3 in an actuated state;

figure 5 is a schematic cross-sectional view of a two-compartment vessel of a metered dose inhaler according to another embodiment in an unactuated state;

figure 6 is a schematic cross-sectional view of the vessel of figure 5 in an actuated state;

figure 7 is a cross-sectional view of a two-compartment vessel of a metered dose inhaler according to an embodiment in an unactuated state;

FIG. 8 shows a sealing arrangement for the inner container of the vessel of FIG. 7;

fig. 9 is a partial cross-sectional view of the two-compartment vessel of fig. 7 in an unactuated state (left) and an actuated state (right);

figures 10 to 13 illustrate a valve stem and nozzle orifice arrangement of a metered dose inhaler according to an embodiment;

fig. 14A is a schematic cross-sectional view of a metered dose inhaler, according to an embodiment;

figure 14B shows an exploded view and a plan view of a metered dose inhaler according to an embodiment;

figure 14C shows a cross-sectional view of the guide member of the metered dose inhaler of figure 14B;

FIG. 15A is a schematic cross-sectional view of a metered dose inhaler according to another embodiment;

FIG. 15B is a cross-sectional view through an actuator having a plurality of nozzle orifices;

figure 16A shows an arrangement of containers in a metered dose inhaler according to an embodiment;

fig. 16B shows a metered dose inhaler according to an embodiment;

FIG. 17A shows a cross-sectional view through a nozzle block with a single orifice, and FIG. 17B shows a cross-sectional view through a nozzle block with two separate orifices;

FIG. 18 is a graph showing delivery characteristics for two formulations having different particle size distributions simultaneously delivered through a nozzle orifice having a diameter of 0.22 mm;

fig. 19 is a graph showing delivery characteristics for formoterol and placebo formulations having different particle size distributions delivered simultaneously through a nozzle orifice having a diameter of 0.22 mm;

fig. 20 is a graph showing delivery characteristics for delivering a formoterol formulation and an incompatible budesonide formulation simultaneously through a nozzle orifice having a diameter of 0.22 mm;

FIG. 21 is a graph showing delivery characteristics for the simultaneous delivery of a Beclomethasone Dipropionate (BDP) (50 μ g/25 μ L) formulation and a budesonide (50 μ g/100 μ L) formulation with low volatility components through a nozzle orifice having a diameter of 0.22 mm;

FIG. 22 is a graph showing delivery characteristics for simultaneous delivery of a BDP (50 μ g/50 μ L) formulation and a budesonide (50 μ g/50 μ L) formulation with low volatility components through a nozzle orifice having a diameter of 0.22 mm;

FIG. 23 is a graph showing delivery characteristics for simultaneous delivery of a BDP (50 μ g/100 μ L) formulation and a budesonide (50 μ g/25 μ L) formulation with low volatility components through a nozzle orifice having a diameter of 0.22 mm;

FIG. 24 is a graph showing delivery characteristics for a BDP (50 μ g/25 μ L) formulation and a budesonide (50 μ g/25 μ L) formulation, both having low volatility components, delivered simultaneously through separate nozzle orifices having a diameter of 0.22 mm;

FIG. 25 is a graph showing delivery characteristics for simultaneous delivery of a BDP (50 μ g/25 μ L) formulation and a budesonide (50 μ g/25 μ L) formulation with low volatility components through separate nozzle orifices having a diameter of 0.22 mm;

FIG. 26 is a side view image of first and second plumes delivered simultaneously through separate nozzle orifices;

FIG. 27 shows images showing plume cross-sections at various distances from the nozzle orifice;

FIG. 28 is a graph showing delivery characteristics for simultaneous delivery of a BDP (50 μ g/25 μ L) formulation and a budesonide (50 μ g/25 μ L) formulation through a nozzle orifice having a diameter of 0.30 mm;

FIG. 29 is a graph showing Anderson Cascade Impactor (ACI) drug deposits for BDP (100 μ g/25 μ l), 26% w/w ethanol formulation, and HFA134a formulation delivered through a single nozzle orifice having a diameter of 0.30 mm;

FIG. 30 is a graph showing delivery characteristics for simultaneous delivery of a BDP (50 μ g/25 μ L) formulation and a budesonide (50 μ g/100 μ L) formulation through a nozzle orifice having a diameter of 0.30 mm;

FIG. 31 is a graph showing delivery characteristics for simultaneous delivery of a BDP (50 μ g/100 μ L) formulation and a budesonide (50 μ g/25 μ L) formulation through a nozzle orifice having a diameter of 0.30 mm;

fig. 32 is a graph showing Anderson Cascade Impactor (ACI) drug deposits for delivery of BDP and budesonide formulations through a dual orifice configuration;

FIG. 33 is a chart showing delivery characteristics for delivering two formulations simultaneously for a configuration through a single nozzle orifice and through a dual orifice;

fig. 34 is a graph showing the delivery characteristics of a BDP formulation when delivered simultaneously with a salbutamol sulfate formulation through a dual orifice configuration;

fig. 35 is a graph showing the delivery characteristics of a salbutamol sulfate formulation when delivered simultaneously with a BDP formulation through a dual orifice configuration;

fig. 36 is a graph showing the delivery characteristics of a BDP formulation and a salbutamol sulfate formulation when delivered simultaneously by a single orifice configuration;

FIG. 37 is a chart showing delivery characteristics when a combination product is simultaneously delivered with another formulation through a single orifice configuration;

fig. 38 is a chart showing delivery characteristics for a system having dual reservoirs with a single orifice actuator (as shown in fig. 14B), one reservoir containing the BDP/formoterol combination formulation and the other reservoir containing the glycopyrronium bromide formulation; and

fig. 39 is a chart showing delivery characteristics for a system having a three-reservoir with a single orifice actuator (as shown in fig. 17B), a first reservoir containing a BDP/formoterol combination formulation, a second reservoir containing a glycopyrrolate formulation, and a third reservoir containing a budesonide formulation.

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 specifically stated otherwise.

According to an exemplary embodiment, a Metered Dose Inhaler (MDI) is provided that is configured as a pressurized MDI (pmdi). The MDI includes an actuator and at least one vessel. The at least one vessel includes a first reservoir and a second reservoir different from the first reservoir. When the at least one vessel is assembled with the actuator, the MDI is configured to simultaneously deliver at least a first metered dose of a first formulation from the first reservoir and a second metered dose of a second formulation from the second reservoir, as will be described in more detail below.

At least one of the first formulation and the second formulation may include at least one active ingredient in a propellant/solvent system and, optionally, further include an excipient. According to an exemplary embodiment, both the first formulation and the second formulation comprise at least one active ingredient, respectively. According to an exemplary embodiment, at least one of the first formulation and the second formulation may not include an active ingredient.

An MDI according to an embodiment allows two or more aerosol components to mix to form a common aerosol. Fine mixing can be performed before or after the orifice to create a new aerosol that can be customized using MDI hardware including an actuator and one or more formulations.

Both the first formulation and the second formulation may be pressurized. Thus, any of a variety of propellants may be utilized. For purposes of illustration and not limitation, propellants known in the art that may be used in the first and/or second reservoirs of an MDI in accordance with the embodiments include tetrafluoroethane (HFC 134 a), tetrafluoroethane (P-134 a), heptafluoropropane (P-227), combinations thereof, or any other suitable propellant. Those skilled in the art will appreciate that such suitable propellants are readily available. For purposes of illustration and not limitation, other examples of propellants are illustrated in Lippincott Williams & Wilkins, version 21 (2005), page 1012 and below, "Remington: the Science and Practice of pharmacy.

The first reservoir containing the first formulation may be formed of a rigid material, in particular a metallic material. The first reservoir may be an aluminum, aluminum alloy or stainless steel cartridge. Similarly, the second reservoir containing the second formulation may be formed of a rigid material, in particular a metallic material. The second reservoir may be an aluminum, aluminum alloy or stainless steel cartridge. An outer boundary of the first reservoir and an outer boundary of the second reservoir may be formed separately so as to allow the first reservoir and the second reservoir to be non-deformed as doses are repeatedly dispensed from the first reservoir and the second reservoir. The cartridge defining the first reservoir and the cartridge defining the second reservoir may be separate from each other or may be combined in one vessel, as will be explained in more detail below. The cartridge defining the first reservoir and/or the cartridge defining the second reservoir may have its inner surface partially or wholly made of anodized aluminum or lined with an inert coating material. If one of the cartridges is disposed inside the other cartridge, the one cartridge may have an anodized aluminum outer surface or may have an inert coating on its outer surface.

The first reservoir may be provided with a first metering valve and the second reservoir may be provided with a second metering valve. The first/second metering valve may be configured to deliver a measured amount of the first/second formulation. The first/second metering valve may be configured such that the delivered dose is reproducible. The first/second metering valve may be configured for inverted use or for upright use. When configured for upright use, the respective metering valve may be provided with a dip tube. The dip tube may be sized as a capillary dip tube. The first and second metering valves may have a configuration that is based on the configuration of conventional metering valves used in conventional pmdis. In particular, the first/second metering valve may comprise a first/second metering chamber. The dimensions of the first/second metering chamber may be varied according to the respective application in order to deliver the desired first and second doses in use. The first/second valves may include a metering gasket and a stem gasket, respectively. In the first position, which may be a rest position of the first/second valve, the valve stem gasket will form a seal that prevents the flow of formulation between the first/second metering chamber and the valve stem, and the metering gasket may allow the flow of formulation between the first/second metering chamber and the first/second reservoir. In the second position, which may be an actuated position of the first/second valve, the valve stem gasket will allow the flow of formulation from the first/second metering chamber to the valve stem. The metering gasket, in turn, may form a seal that inhibits the flow of formulation between the first/second metering chamber and the first/second reservoir, while the first/second valve is actuated. In this way, consistent amounts of the first and second formulations may be delivered.

According to embodiments, the MDI may be configured such that the first and second metering valves are actuated simultaneously upon actuation of the MDI. This may be achieved in various ways, as will be explained in more detail with reference to the drawings. For the sake of illustration, the first and second metering valves may be coupled to each other, thereby enabling simultaneous actuation of the first and second metering valves.

Fig. 1 is a schematic cross-sectional view of a metered dose inhaler 1 according to an embodiment. The cross-sectional view is taken along a central symmetry plane of the MDI.

The MDI1 includes an actuator 2 having a cartridge receiving portion 3 and a mouthpiece portion 4. The aerosolized formulation is delivered through the mouthpiece opening 5 in use of the MDI 1. An air inlet opening 6 is formed in the outer housing of the actuator 2 to allow air 9 to be drawn into the actuator housing by the breathing action of the patient. Within the actuator housing an actuator block 7 is arranged, said actuator block 7 acting as a nozzle block having a valve stem seat for receiving a valve stem 15. A nozzle orifice or orifices 8 are formed in the actuator block 7 for atomizing the formulation upon actuation of the MDI 1.

The MDI1 also includes a vessel 10. When the MDI1 is ready for use, the vessel 10 is received by the actuator 2 and the valve stem of the vessel 10 is received in a seat formed in the actuator block 7. The interior of the hollow valve stem communicates with the nozzle orifice in this state. In a state in which the vessel 10 is not yet received in the actuator 2, the MDI1 may be provided to the patient. The patient may then prepare the dose delivery by inserting the vessel 10 into the actuator 2. The capsule 10 may be removably received in the actuator 2, allowing the actuator 2 to be cleaned after dose delivery.

The vessel 10 has a first reservoir 11 containing a first formulation and a second reservoir 12 containing a second formulation. At least one of the first formulation and the second formulation may contain an active ingredient. In an embodiment, both the first and second formulations contain an active ingredient. In still other embodiments, at least one of the first formulation and the second formulation does not contain an active ingredient. The first and second formulations may be different from each other. The formulation containing at least one active ingredient may be an aerosol suspension formulation or an aerosol solution formulation. The formulation may include at least one active ingredient in a propellant/solvent system, and may optionally contain other excipients.

The vessel 10 has an outer barrel defining an outer housing of a first reservoir 11 and an inner barrel defining a second reservoir 12. The inner cylinder is completely encapsulated by the outer cylinder. The inner and outer cylinders are formed of a rigid material. When the MDI1 is repeatedly actuated, the inner and outer barrels do not change their shape.

The MDI1 has a first metering valve 13 and a second metering valve 14. The first and second metering valves may have different valve stems or may share a single valve stem. The metering valves 13 and 14 may be integrated into the vessel 10. The valve stem 15 protrudes from the vessel 10 and may be received in a valve stem seat formed in the actuator block 7.

The first metering valve 13 meters a first dose of the first formulation that is delivered upon actuation of the MDI 1. The second metering valve 14 meters a second dose of the second formulation that is delivered upon actuation of the MDI 1. The metering valves 13 and 14 are discontinuous valves, said metering valves 13 and 14 providing a predetermined amount of the respective formulation, respectively. The metering valves 13 and 14 are configured to reproducibly deliver predetermined first and second doses. The first dose of the first formulation and the second dose of the second formulation may be of the same size or may be of different sizes depending on the volume of the respective metering chamber.

The MDI1 is configured such that the first metered dose and the second metered dose are delivered simultaneously so that the first and second doses can interact in the actuator housing. The MDI1 may be configured such that the first metered dose and the second metered dose are mixed prior to aerosolization. The MDI1 may be configured such that the first and second metered doses are mixed at the nozzle orifice 8. For purposes of illustration, the vessel 10 may be configured such that the first and second metered doses are mixed in the valve stem 15 and fed to the nozzle orifice 8 upon actuation of the MDI 1. The vessel 10 and the actuator 2 may also be configured such that the first and second metered doses are separately fed to the nozzle orifice 8 and mixed in the nozzle orifice 8 prior to aerosolization. Alternatively, the MDI1 may be configured such that the first and second metered doses interact after delivery through separate nozzle orifices.

The MDI1 may include an actuation device configured to ensure that the first and second metered doses are delivered simultaneously. The actuating means may be integrally formed with other components of the MDI, for example with the first and second valves. For the sake of illustration, the simultaneous delivery of the first and second metered doses may be achieved by suitably configuring the first and second metering valves so that they are actuated simultaneously. The first and second metering valves may be configured such that upon actuation of the MDI1 fluid communication is established with the hollow interior of the valve stem 15 so as to cause both the first and second metered doses to be delivered from the first and second reservoirs, respectively, through the valve stem 15.

In use of the MDI1, the patient may actuate, for example, by pressing the container 10 into the actuator 2. Other actuation mechanisms may be utilized. A first metered dose of the first formulation and a second metered dose of the second formulation are delivered through the nozzle orifice 8. The first and second metered doses may be mixed prior to aerosolization, for example in the valve stem 15 or in the nozzle orifice 8. The inhalable particles in the spray cloud are entrained in the air flow 9. The mixed dose of the first and second formulations is delivered through the mouthpiece opening 5 of the MDI 1.

By appropriately selecting the formulations, the particle size distribution of at least one of the first formulation and the second formulation may be influenced by mixing with the other of the first formulation and the second formulation. This enhances control over the delivery characteristics.

MDI1 may allow a formulator to focus on the solubility and stability of the first and second formulations during formulation. The particle size distribution can be affected by atomizing the first and second formulations together. The particle size distribution of at least one of the first and second formulations may be controlled by mixing with the other of the first and second formulations at the time of delivery.

The MDI1 also allows incompatible excipients to be stored in separate reservoirs and mixed in the actuator prior to delivery to the patient.

The particle size distribution of the first and second formulations may be controlled via a mixing process. Control of the particle size distribution may be achieved by appropriate selection of the first and second doses, the configuration of one or more nozzle orifices in the actuator, and/or the actuator geometry. For purposes of illustration, in embodiments, the particle size distributions of the first and second formulations may be designed to match each other. The particle size distributions of the first and second formulations may be designed to be in a range between a particle size distribution that would result from aerosolizing the first formulation by a single actuator and a particle size distribution that would result from aerosolizing the second formulation by a single actuator.

While the MDI1 of FIG. 1 has a design in which the longitudinal axis of the nozzle orifice 8 is aligned with the longitudinal axis of the valve stem 15, other numbers and arrangements of nozzle orifices may be implemented in further embodiments. For illustration, the nozzle orifice may be arranged such that its longitudinal axis is arranged at an angle of, for example, 90 ° or more than 90 ° relative to the longitudinal axis of the valve stem 15 when the vessel 10 is received in the actuator 2. A plurality of separate nozzle orifices may be provided. The longitudinal axes of the plurality of nozzle orifices may be parallel, or may be arranged at an angle relative to each other.

FIG. 2 is a schematic cross-sectional view of an MDI21 according to another embodiment. The cross-sectional view is taken along a central symmetry plane of the MDI. Elements or features that correspond in their configuration and/or function to elements or features of the MDI1 of fig. 1 are indicated with the same reference numerals.

The MDI21 has a two-compartment vessel 10 and an actuator 22. The actuator 22 has an actuator block 26, in which actuator block 26 the valve stem 15 is received when the vessel 10 is inserted into the actuator 22. The first metered dose of the first formulation and the second metered dose of the second formulation are fed to the nozzle orifice 28 via the internal chamber 27 upon actuation of the MDI 21. The first metered dose and the second metered dose are mixed and aerosolized. The atomized blended formulation is delivered as a spray cloud 29. In the actuator 22, the nozzle orifice 28 that mixes the first and second formulations is arranged at an angle relative to the longitudinal axis of the valve stem 15 when the vessel 10 is received in the actuator 22.

In MDI1 and MDI21, the first formulation and the second formulation may be mixed and delivered through a nozzle orifice. The outer barrel forming the outer housing of the vessel 10 may be of the same size as the barrels used in conventional MDIs. This allows actuators of conventional size and/or design to be used in association with a dual compartment vessel.

The dual-compartment vessel and valve assembly for use in the MDIs 1, 21 according to embodiments may have various configurations. For purposes of illustration, the first and second metering valves may, in certain embodiments, share a single valve stem. In still other embodiments, the first metering valve may have a first valve stem through which a first metered dose is supplied to the nozzle orifice, and the second metering valve may have a second valve stem through which a second metered dose is supplied to the nozzle orifice. The first and second valve stems may be rigidly coupled.

The configuration of the dual-compartment vessel and valve assembly for an MDI according to an embodiment will be explained in more detail with reference to fig. 3 to 9.

Fig. 3 is a schematic cross-sectional view of the two-compartment vessel 30 and valve assembly in an unactuated, rest state. Fig. 4 is a schematic cross-sectional view of the two-compartment vessel 30 and valve assembly in the actuated state.

The vessel 30 has an outer cylinder 31 and an inner cylinder 32. The inner tube 32 separates a first formulation accommodated in a space defined between the outer tube 31 and the inner tube 32 from a second formulation accommodated in the interior of the inner tube 32. The outer cylinder 31 and the inner cylinder 32 are formed to be rigid, respectively. A first pressurized aerosol formulation is contained in the space defined between the outer barrel 31 and the inner barrel 32. A second pressurized aerosol formulation is contained in the second cartridge 32.

The first and second metering valves are integrally formed with the vessel 30. A first metering valve, schematically indicated at 34, defines a first metering chamber 33. A second metering valve, schematically indicated at 36, defines a second metering chamber 35. A first valve stem 41 and a second valve stem 44 are provided. The first valve stem 41 and the second valve stem 44 are disposed in a coaxial arrangement. The first valve stem 41 and the second valve stem 44 are attached to each other so that they are axially fixed, i.e., so that the first valve stem 41 and the second valve stem 44 are forced to be jointly displaced in the axial direction. First and second valve stems 41, 44 may be rigidly coupled to one another. The combination of first valve stem 41 and second valve stem 44 may be considered to form a joint valve stem having a split configuration in which different formulations move in different portions of the joint valve stem.

First valve stem 41 includes one or more recessed portions 42 or other recesses. The recessed portion 42 is arranged such that when the valve is in an unactuated state, the space inside the first barrel 31 and outside the first metering valve 34 is in fluid communication with the first metering chamber 33. An unactuated, rest state is shown in fig. 3, into which the valve stem 41 is biased by a biasing member, such as a spring 38. The recessed portion 42, which may be formed as a slot, allows the first formulation to flow between the first reservoir and the first chamber 33 via a metering gasket member 47 provided in the first metering valve 34. The first formulation is allowed to flow into/out of the chamber until the point of actuation. The recessed portion 42 is further arranged such that fluid communication between the first reservoir and the first metering chamber 33 is blocked when the first valve is actuated by displacement of the first valve stem 41. Upon actuation, the first metering chamber 33 is isolated from the first reservoir by a metering gasket. The actuated state, which is achieved by a relative displacement of the first valve stem 41, is shown in fig. 4.

First valve stem 41 also includes one or more openings 43. The opening 43 is arranged such that the first metering chamber 33 is not in fluid communication with the interior of the first valve stem 41 when the valve is in the unactuated state, as shown in figure 3. In the unactuated state, a seal may be formed that prevents the first formulation from moving from the first metering chamber 33 into the interior of the first valve stem 41. Accordingly, a valve stem gasket member 48 may be provided in the first metering valve 34. The opening 43 is also arranged such that the first metering chamber 33 is in fluid communication with the interior of the first valve stem 41 when the valve is in an actuated state, as shown in fig. 4. Upon actuation, the first formulation moves from the chamber 33 into the valve stem 41 via the opening 43.

The second valve stem 44 has a similar configuration. The second valve stem 44 includes one or more recessed portions 45 or recesses formed therein. The recessed portion 45 is arranged such that when the valve is in an unactuated state, the interior space of the second cylinder 32 is in fluid communication with the second metering chamber 35. The recessed portion 45, which may be formed as a slot, allows the second formulation to flow between the second reservoir and the second metering chamber 35 via a metering gasket member 47 provided in the second metering valve 36. The second formulation is allowed to flow into/out of the chamber until the point of actuation. The recessed portion 45 is further arranged such that fluid communication between the second reservoir and the second metering chamber 35 is blocked when the second valve is actuated by displacement of the second valve stem 44. Upon actuation, the second metering chamber 35 is isolated from the second reservoir by a metering gasket. The actuated state, which is achieved by the relative displacement of second valve stem 44, is shown in fig. 4.

The second valve stem 44 also includes one or more openings 46. The opening 46 is arranged such that the second metering chamber 35 is not in fluid communication with the interior of the second valve stem 44 when the valve is in the unactuated state, as shown in fig. 3. In the unactuated state, a seal may be formed that prevents the second formulation from moving from the second metering chamber 35 into the interior of the second valve stem 44. Accordingly, a valve stem gasket member 48 may be provided in the second metering valve 36. The opening 46 is also arranged such that when the valve is in the actuated state, the second metering chamber 35 is in fluid communication with the interior of the second valve stem 44, as shown in fig. 4. Upon actuation, the second formulation moves from the second metering chamber 35 into the valve stem 44 via the opening 46.

The first and second valves are configured such that upon actuation of the valves, the first metered dose and the second metered dose are delivered simultaneously. Thus, the recessed portions 42 and 45, the openings 43 and 46 and the shim members 46 and 47 may be arranged such that in parallel the first metering chamber 33 may be filled with the first formulation and the second metering chamber 35 may be filled with the second formulation when the valve is not actuated. The recessed portions 42 and 45, the openings 43 and 46, and the spacer members 46 and 47 may also be arranged such that upon valve actuation, when fluid communication is established between the second metering chamber 35 and the interior of the second valve stem 44, fluid communication may be established between the first metering chamber 33 and the interior of the first valve stem 41 simultaneously. The recessed portions 42 and 45, the openings 43 and 46 and the spacer members 46 and 47 may also be arranged such that upon actuation of the valve, fluid communication between the first reservoir and the first chamber 33 and between the second reservoir and the second chamber 35 may be interrupted simultaneously.

In the vessel 30 and valve assembly, a biasing member such as a spring 38 is provided on the outside of the outer barrel 31. The actuator seat 37 holds the external spring 38 in place against the valve collar 39. The biasing member may be configured to bias the first valve into a rest position in which the first metering chamber 33 is not in fluid communication with the hollow interior of the valve stem, i.e. in which the seal isolates the first metering chamber 33 from the hollow interior of the valve stem. The biasing member may be configured to bias the second valve into a rest position in which the second metering chamber 35 is not in fluid communication with the hollow interior of the valve stem, i.e., in which the seal isolates the second metering chamber 35 from the hollow interior of the valve stem.

It will be appreciated that a biasing member 38 may be located on the exterior of the outer barrel 31, the biasing member 38 biasing the valve stem and thereby the first and/or second valves into the rest position. In contrast, conventional cartridges for MDIs typically employ a biasing member disposed within the interior of the cartridge. The arrangement with the biasing member positioned outside the cartridge, which may be implemented in the various embodiments described herein, has the effect that the first and second formulations will not be in contact with the biasing member 38. By locating the biasing member 38 outside the outer barrel 31, the potential risk of contamination by metal ions that could lead to formulation instability can be reduced.

Fig. 5 is a schematic cross-sectional view of the two-compartment vessel 50 and valve assembly in an unactuated state. Fig. 6 is a schematic cross-sectional view of the two-compartment vessel 50 and valve assembly in the actuated state. Elements or features corresponding in their configuration and/or function to elements or features of the vessel and valve assembly of figures 3 and 4 are indicated with the same reference numerals.

The vessel 50 has a first cylinder 31, a second cylinder 32 and first and second metering chambers 33, 35 as described with reference to figures 3 and 4 respectively. The valve assembly has a single valve stem 51. A biasing member 38, such as a spring, biases the valve stem 51 into the unactuated position shown in fig. 5. It will be appreciated that the biasing member 38 may be positioned outside of the outer barrel 31, as shown in fig. 5.

The valve stem 51 is configured such that a first formulation can flow between the first reservoir and the first chamber 33 and a second formulation can flow between the second reservoir and the second chamber 35 when the valve is not actuated. The valve stem 51 is configured such that the seal or gasket inhibits the flow of the first formulation from the first chamber 33 into the valve stem 51 and inhibits the flow of the second formulation from the second chamber 35 into the valve stem 51 when the valve is not actuated. The valve stem 51 is also configured such that the first chamber 33 is isolated from the first reservoir and the second chamber 35 is isolated from the second reservoir when the valve is actuated. The actuated state is shown in fig. 6. The valve stem 51 is configured such that the first formulation moves from the first chamber 33 into the valve stem 51 and the second formulation moves from the second chamber 35 into the valve stem 51 when the valve is actuated by axial displacement of the valve stem 51.

The valve stem 51 has one or more first recesses 52, said first recesses 52 allowing the first formulation to flow freely between the first reservoir and the first metering chamber 33 in the rest state shown in fig. 5, past the metering gasket member 47 provided in the first valve 34. The valve stem 51 has one or more second recesses 53, said second recesses 53 allowing the second formulation to flow freely between the second reservoir and the second metering chamber 35 in the rest state shown in fig. 5, past the metering gasket member 47 provided in the second valve 36. The first 52 and second 53 recesses are arranged such that upon actuation the first chamber 33 is isolated from the first reservoir and the second chamber 35 is isolated from the second reservoir due to axial displacement of the valve stem 51, as shown in figure 6.

The valve stem 51 has one or more first openings 54, said first openings 54 being arranged such that in the rest state shown in fig. 5, a seal is formed which prevents the first formulation from moving from the first metering chamber 33 to the interior of the valve stem 51. Accordingly, a stem gasket member 48 may be provided in the first valve 34. The at least one first opening 54 is arranged to allow the first formulation to move from the first chamber 33 to the interior of the valve stem 51 in the actuated state as shown in fig. 6. The valve stem 51 has one or more second openings 55, said second openings 55 being arranged such that in the rest state shown in fig. 5a seal is formed preventing the second formulation from moving from the second chamber 35 to the interior of the valve stem 51. Accordingly, a stem gasket member 48 may be provided in the second valve 36. The at least one second opening 55 is arranged to allow the second formulation to move from the second chamber 35 to the interior of the valve stem 51 in the actuated state.

When the first metering valve and the second metering valve have a common valve stem as schematically shown in fig. 5 and 6, the valve stem 51 having a simple configuration can be formed.

Additionally, the first metering valve and the second metering valve have a common valve stem in which a first metered dose of a first formulation and a second metered dose of a second formulation may be mixed. Mixing before atomization can be achieved.

The two-compartment vessels and associated valve assemblies described with reference to fig. 3-6 may be used to deliver a first formulation and a second formulation simultaneously. The formulations may be mixed prior to aerosolization, such as in a two-compartment vessel 50 (fig. 5 and 6) having a common valve stem, or mixed after aerosolization. The post-nebulisation mixing may for example be achieved using a two-compartment vessel having a first valve stem and a second valve stem which may be combined as shown in figures 3 and 4.

Various embodiments of the two-compartment vessel and associated valve assembly described with reference to figures 3 to 6 may be implemented. For the sake of illustration, embodiments of single-stem vessels will be explained in more detail with reference to fig. 7 to 9.

Fig. 7 shows a dual compartment vessel 10 and associated valve assembly which may be used as the vessel 10 of the MDI of fig. 1 and 2. Elements or features corresponding in their configuration and/or function to elements or features of the vessel and valve assembly of figures 3 to 6 are indicated with the same reference numerals.

The vessel 10 has an outer cylinder 31 and an inner cylinder 32. The outer cylinder 31 and the inner cylinder 32 may be formed to be rigid. A first reservoir 61 is defined in the interior of the outer barrel 31 and the exterior of the inner barrel 32. A second reservoir 62 is formed in the interior of the inner cartridge 32. The first reservoir 61 contains a first formulation and the second reservoir 62 contains a second formulation. The first and second formulations may be different from each other.

For purposes of illustration and not limitation, the inner barrel 32 may be formed from a13 mm diameter can. The outer barrel 31 may be formed from a standard 22mm diameter can. A13 mm diameter can for the inner barrel 32 can fit into a 22mm can for the outer barrel.

The design of the combined valve stem allows for another method for pressure filling of a propellant, such as an HFA propellant or other propellant. A plug 63 can be used to seal the base of the inner barrel 32. The plug 63 can be disposed at the center of the base of the inner barrel 32. As seen more clearly in fig. 8, the plug 63 has engagement means for engaging the base of the inner barrel 32. The engagement means is configured as a recess that receives an edge of the base defining an opening through which the plug 63 is inserted, as shown in the right-hand view in fig. 8.

Mating engagement means may be provided in the interior of the outer barrel 31 and on the exterior of the inner barrel 32. For the sake of illustration, an engaging protrusion 64 may be provided in the interior of the outer cylinder 31. The engagement projection engages with the structured outer surface of the inner barrel 32.

A first valve is provided for metering a first dose of a first formulation from the first reservoir and a second valve is provided for metering a second dose of a second formulation from the second reservoir. The first and second valves have a stem 67, which stem 67 is common to both the first and second valves. The valve stem 67 is biased towards the rest position by a biasing means such as a spring 66. The biasing means may be arranged outside the outer barrel 31.

The first and second valves may have a standard valve design. The metering of the first and second doses may be performed using a mechanism substantially corresponding to that described with reference to figures 5 and 6. In particular, the first and second valves may each comprise a metering chamber. The first and second valves may be provided with a metering gasket and a valve stem gasket, respectively. The first and second valves may each be configured such that in an unactuated, rest state, the metering chamber is in fluid communication with the respective reservoir, while fluid communication between the metering chamber and the interior of the valve stem 67 is blocked. In the actuated state of the first or second valve, the associated metering chamber may be isolated from the respective reservoir, respectively, and the metering chamber may be in fluid communication with the hollow interior of the valve stem 67.

The valve assembly may include a first metering chamber 68 defined by a first valve. In the rest position as shown in fig. 7, the first formulation may flow between the first reservoir and the first metering chamber 68. At this point, the gasket may prevent flow between the first metering chamber 68 and the interior of the valve stem 67. When the valve stem 67 is axially displaced for actuating the valve, the first metering chamber 68 is isolated from the first reservoir and the first formulation is allowed to move from the first metering chamber 68 to the internal cavity of the valve stem 67.

The valve assembly may include a second metering chamber 69 defined by a second valve. In the rest position as shown in fig. 7, the second formulation may flow between the second reservoir and the second metering chamber 69. At this point, the gasket may prevent flow between the second metering chamber 69 and the interior of the valve stem 67. When the valve stem 67 is axially displaced for actuating the valve, the second metering chamber 69 is isolated from the second reservoir and the second formulation is allowed to move from the second metering chamber 69 to the internal cavity of the valve stem 67.

The valve stem 67 common to the first and second valves ensures that the first metered dose of the first formulation and the second metered dose of the second formulation are delivered simultaneously upon actuation of the MDI. The metered doses of the first and second formulations may then be mixed in the valve stem and/or at the nozzle orifice.

Fig. 9 shows a partial cross-sectional view of the vessel 10 with the associated valve assembly in a rest state (left) and an actuated state (right).

In the rest position, the recess 71 in the valve stem 67, which may be formed as a slot, allows the first formulation to flow from the first reservoir into the first metering chamber 68. Similarly, a depression 73 in the valve stem 67, which may be formed as a slot, allows the second formulation to flow from the second reservoir into the second metering chamber 69.

In the actuated state shown in the right side view in fig. 9, the valve stem 67 is axially displaced against the biasing force of the spring 66. The formation of the first seal 72 isolates the first metering chamber 68 from the first reservoir. The formation of the second seal 74 isolates the second metering chamber 69 from the second reservoir. In the actuated state, at least one first opening 75 in the valve stem 67 allows a first dose of the first formulation to move into the valve stem 67. At least one second opening 76 in the valve stem 67 allows a second dose of the second formulation to move into the valve stem 67.

In MDIs comprising a dual compartment vessel which may be formed by an outer barrel fully enclosing an inner barrel, the mixing of the first and second formulations may be carried out within a valve stem as described with reference to figures 5 to 9, or at an actuator block defining an actuator seat for the valve stem as described with reference to figures 3 and 4. The actuator is of conventional design and a nozzle orifice defined in the actuator block may be used when mixing is performed in the valve stem or at the nozzle orifice.

According to an embodiment, the actuator may be provided with an actuator block having one or more nozzle orifices. The number and arrangement of nozzle orifices may be selected according to the desired actuator characteristics. Actuators defining multiple nozzle orifices may be used in applications where post-atomization mixing is desired. Thus, the nozzle orifice may be configured such that the spray clouds of the first and second formulations collide with each other upon actuation of the MDI.

Referring to fig. 10 to 13, the configuration of the actuator block defining one or more nozzle orifices will be explained. An actuator for receiving a dual compartment vessel, such as the actuator 2 of the MDI1 described with reference to figure 1 or the actuator 22 of the MDI21 described with reference to figure 2, may define any of the nozzle configurations schematically illustrated in figures 10 to 13. Still other nozzle configurations may be implemented in still other embodiments.

For better understanding, end portions of the outer valve stem 78 and the inner valve stem 79 are also shown. The outer and inner valve stems are coaxially aligned and may be rigidly joined to each other as described with reference to fig. 3 and 4.

Fig. 10 shows a cross-sectional view of the actuator block 81. The actuator block 81 defines an actuator seat in which the outer and inner valve stems are received when the vessel is received by the actuator. The actuator block 81 defines an aperture 82. The orifice 82 is in fluid communication with the actuator seat. The orifice 82 may have a cylindrical shape. Other orifice shapes may be used. When the outer and inner valve stems are received in the actuator seat, the orifice 82 is in fluid communication with both the hollow interior of the inner valve stem 79 supplying the second formulation and the hollow space supplying the first formulation, which is encapsulated by the inner surface of the outer valve stem 78 and the outer surface of the inner valve stem 79.

The internal valve stem 79 containing the second formulation from the second reservoir encounters the external valve stem 78 containing the first formulation from the first reservoir at the actuator block 81. The formulations from the separate reservoirs are mixed at the actuator block and the mixed formulation is atomized through the single orifice 82.

Fig. 11-13 illustrate other actuator block designs in which a first formulation is atomized at a first orifice and a second formulation is atomized at a second orifice different from the first orifice. When the MDI is actuated, a first formulation from the first reservoir moves through one of the inner and outer valve stems and is atomized at the first orifice, and a second formulation from the second reservoir moves through the other of the inner and outer valve stems and is atomized at the second orifice.

Fig. 11 shows a cross-sectional view of the actuator block 83. The actuator block 83 defines a socket in which the outer valve stem and the inner valve stem are received when a vessel containing a medicament is received by the actuator. The actuator block 83 defines two apertures 84 and 85. The first orifice 84 may be in fluid communication with a portion of the actuator seat that receives the outer valve stem 78. The second orifice 85 may be in fluid communication with a central portion of the actuator seat that receives the inner valve stem 79. The orifices 84 and 85 may each have a cylindrical shape. One or both of the apertures 84 and 85 may also be provided with shapes other than cylindrical. The first and second apertures 84, 85 are spaced from one another. The longitudinal axes of the apertures 84 and 85 are parallel. The longitudinal axes of the apertures 84 and 85 are aligned with the longitudinal axis of the actuator seat.

When the outer and inner valve stems are received in the actuator seat, the first orifice 84 is in fluid communication with a hollow space supplying the first formulation, which is enclosed by the inner surface of the outer valve stem 78 and the outer surface of the inner valve stem 79. The second orifice 85 is in fluid communication with the hollow interior of the internal valve stem 79 supplying the second formulation. When the MDI is actuated, the first formulation moves through the outer valve stem 78 and atomizes at the first orifice 84. The second formulation moves through the internal valve stem 79 and is atomized at the second orifice 85.

The configuration of the nozzle block as shown in fig. 11 allows the first and second formulations to interact after atomization at orifices 84 and 85, respectively. The particle size distribution and/or fine particle dose of one formulation may even be affected by mixing after atomization with another formulation.

When at least two apertures are defined by the actuator block, the longitudinal axes of the apertures may be arranged at an angle relative to each other, i.e. the apertures may be arranged such that the apertures are non-parallel. The first and second apertures may be arranged to form a cross-flow aperture path in which formulation from one of the first and second reservoirs is atomized at one of the apertures, producing a spray pattern that results in flow interaction with a plume produced by atomization of formulation from the other reservoir at the other aperture. Thereby, a modification of the combined plume geometry, the direction of the combined plume, or a modification of the final atomized product may be achieved.

In particular embodiments, the orifice spacing and impingement angle may be set to produce an aerosol plume crossover distance of 2.5cm to 10cm from the actuator. In particular, the impingement angle between the orifices may be set to have a value comprised in the range from 15 ° to 60 °.

Fig. 12 shows a cross-sectional view of an actuator block 85 having an orifice design in which the longitudinal axes of the orifices are arranged at an angle relative to each other.

The actuator block 86 defines an actuator seat in which the outer and inner valve stems are received when a vessel containing a medicament is received by the actuator. The actuator block 86 defines two apertures 87 and 88. The first orifice 87 may be in fluid communication with a portion of the actuator seat that receives the outer valve stem 78. The second orifice 88 may be in fluid communication with a central portion of the actuator seat that receives the inner valve stem 79. The orifices 87 and 88 may each have a cylindrical shape. One or both of the apertures 87 and 88 may also be provided with a shape other than cylindrical. The first and second apertures 87, 88 are spaced from one another. The longitudinal axes of the apertures 87 and 88 are arranged at an angle relative to each other. The longitudinal axis of one of the apertures 87 and 88 may be aligned with the longitudinal axis of the actuator seat.

When the outer and inner valve stems are received in the actuator seat, the first orifice 87 is in fluid communication with a hollow space supplying the first formulation, which is surrounded by the inner surface of the outer valve stem 78 and the outer surface of the inner valve stem 79. The second orifice 88 is in fluid communication with the hollow interior of the internal valve stem 79 supplying the second formulation. Upon actuation, the first formulation moves through the outer valve stem 78, through the first orifice 87, and is atomized at the first orifice 87. The second formulation moves through the internal valve stem 79, passes through the second orifice 88, and is atomized at the second orifice 88. The orientation of the first apertures 87 creates a cross-flow, so the plume of the first formulation atomized at the first apertures 87 has an average velocity with a velocity component directed transversely relative to the longitudinal axis of the actuator seat. In other words, the configuration of the first orifice 87 directs the atomized first formulation toward the atomized second formulation, thereby allowing the first and second formulations to interact with each other within the actuator housing.

Cross-flow of atomized formulation can be achieved using a variety of different orifice configurations. For purposes of illustration, in other embodiments, a first orifice for atomizing a first formulation may have a longitudinal axis aligned with the longitudinal axis of the actuator seat, while a longitudinal axis of a second orifice for atomizing a second formulation is disposed at an angle relative to the longitudinal axis of the actuator seat. In other embodiments, both the longitudinal axis of the first orifice for atomizing the first formulation and the longitudinal axis of the second orifice for atomizing the second formulation may be disposed at an angle relative to the longitudinal axis of the actuator seat.

The plurality of nozzle orifices may also be formed such that a longitudinal axis of the nozzle orifices is disposed at an angle of about 90 ° relative to a longitudinal axis of the actuator seat.

Fig. 13 shows a cross-sectional view of an actuator block 89 having an orifice design in which the longitudinal axis of the orifice is disposed at an angle of about 90 ° relative to the longitudinal axis of the actuator seat. The actuator block 89 defines two nozzle orifices 84 and 85. The first orifice 84 may be in fluid communication with a portion of the actuator seat that receives the outer valve stem 78. The second orifice 85 may be in fluid communication with a central portion of the actuator seat that receives the inner valve stem 79. The orifices 84 and 85 may each have a cylindrical shape. One or both of the apertures 84 and 85 may also be provided with shapes other than cylindrical. The first and second apertures 84, 85 are spaced from one another. The longitudinal axes of the apertures 84 and 85 are parallel. The longitudinal axes of the apertures 84 and 85 are disposed at about 90 deg. relative to the longitudinal axis of the actuator seat.

When the outer and inner valve stems are received in the actuator seat, the first orifice 84 is in fluid communication with a hollow space supplying the first formulation, which is surrounded by the inner surface of the outer valve stem 78 and the outer surface of the inner valve stem 79. The second orifice 85 is in fluid communication with the hollow interior of the internal valve stem 79 supplying the second formulation. Upon actuation, the first formulation moves through the outer valve stem 78 and atomizes at the first orifice 84. The second formulation moves through the internal valve stem 79 and is atomized at the second orifice 85.

Actuators having nozzle blocks defining one orifice for atomizing a plurality of different formulations as shown in fig. 10 or a plurality of orifices for atomizing a plurality of different formulations as shown in fig. 11-13 may be utilized in actuators of MDIs according to various embodiments. The particle size distribution of one formulation can be affected by mixing with another formulation before or after atomization. A variety of possible nozzle orifice designs provide additional versatility in adjusting the MDI to achieve a desired particle size distribution or fine particle dose.

In the embodiments described with reference to fig. 1-13, a dual-compartment vessel may be used that defines both a first reservoir containing a first formulation and a second reservoir containing a second formulation. Alternatively or additionally, a plurality of separate vessels may be used, as will be explained in more detail with reference to fig. 14 to 16.

FIG. 14A is a schematic cross-sectional view of an MDI91 according to an embodiment.

The MDI91 includes an actuator 92 and at least a first vessel 101 and a second vessel 102. The first vessel 101 and the second vessel 102 are at least partially received within the actuator housing. The actuator 92, the first vessel 101 and the second vessel 102 may be configured such that the first and second vessels 101, 102 are not removable from the actuator 92 and/or cannot be reinserted into the actuator 92 after removal from the actuator.

The actuator 92 comprises means 93 for facilitating simultaneous actuation of a first metering valve 104 associated with the first vessel 101 and a second metering valve 107 associated with the second vessel 102. The apparatus 93 may be designed according to any of various configurations. For the sake of illustration, if the valves 104, 107 are actuated by further pressing the first and second vessels 101, 102 into the actuator 92 to effect relative displacement between the vessels and their associated valve stems, the device 93 may be configured as a member, such as an actuation plate, that distributes pressure across the vessels 101 and 102, ensuring that the first vessel 101 and the second vessel 102 will be pressed jointly. Suitable guides may be provided for the panel to ensure that the panel travels along a predetermined path in a predetermined orientation upon actuation of the MDI 91.

The actuator 92 also includes an actuator block 94 formed in the actuator housing. The actuator block 94 defines a first actuator seat for a first valve stem 105 associated with the first vessel 101 and a second actuator seat for a second valve stem 108 associated with the second vessel 102. A nozzle orifice 95 is formed in the actuator block 94. The nozzle orifice 95 is in fluid communication with both a first actuator seat for the first valve stem 105 and a second actuator seat for the second valve stem 108. A channel may lead from the first seat to nozzle orifice 95 and yet another channel may lead from the second seat to nozzle orifice 95.

The first vessel 101 contains a first formulation 103. The second vessel 102 contains a second formulation 106. The first and second vessels may be pressurized separately. At least one of the first and second formulations 103, 106 may contain an active agent. In an embodiment, both the first and second formulations contain an active ingredient. In still other embodiments, at least one of the first formulation and the second formulation does not contain an active ingredient. The first and second formulations may be different from each other. The formulation containing at least one active ingredient may be an aerosol suspension formulation or an aerosol solution formulation. The formulation may include at least one active ingredient in a propellant/solvent system, and may optionally contain other excipients.

The first vessel 101 is provided with a first metering valve 104. The first metering valve 104 is configured to meter a predetermined and consistent first dose of the first formulation 103 upon actuation. The second vessel 102 is provided with a second metering valve 107. The second metering valve 107 is configured to meter a predetermined and consistent second dose of the second formulation 106 upon actuation. The first metering valve 104 and the second metering valve 107 are distinct and independently operated. Conventional valve designs may be used. For the sake of illustration, a valve design similar to the valve design described with reference to the first and second metering valves of fig. 3 to 9 may be used for the first valve 104 and the second valve 107, respectively. The first formulation of the first dose and the second formulation of the second dose may be the same size or different sizes.

Upon actuation of the MDI91, the device 93 allows the first vessel 101 and the second vessel 102 to be jointly pressed. The first metered dose of the first formulation and the second metered dose of the second formulation are delivered upon actuation. The first formulation moves to the orifice 95 through a valve stem 105 associated with the first vessel 101 and through a passageway defined in the actuator block 94. The second formulation moves to the orifice 95 through a valve stem 108 associated with the second vessel 102 and through a passageway defined in the actuator block 94. As the expanding formulations meet at the orifice 95, the first and second formulations mix prior to atomization.

While the actuator block 94 of the actuator 92 has the orifice 95 arranged such that the longitudinal axis of the orifice 95 is disposed at an angle of about 90 ° relative to the longitudinal axis of the actuator block seat receiving the valve stem, in other embodiments, the actuator block 94 may be configured such that the longitudinal axis of the one orifice 95 formed in the actuator block for atomizing the first and second formulations is disposed substantially parallel to the longitudinal axis of the actuator block seat receiving the valve stem.

FIG. 14B shows an exploded view of the MDI131 according to an embodiment. Also shown in fig. 14B are a front view 141 and a side view 142 of the MDI in an assembled state. Elements or features that correspond in their configuration and/or function to elements or features of the MDI91 of fig. 14A are indicated with the same reference numerals.

The MDI131 includes an actuator and at least a first vessel 101 and a second vessel 102. The first vessel 101 and the second vessel 102 are at least partially received within the actuator housing.

The actuator of the actuator MDI131 includes a body 132, a cap 133, and a mouthpiece 135. An actuator block 134 is formed on the mouthpiece 135. Mouthpiece 135 may be a conventional actuator mouthpiece. The mouthpiece 135 and the actuator body 132 may be provided with cooperating engagement means that couple the actuator body 132 and the mouthpiece 135 to each other in the operational state of the MDI 131. The engagement means of the actuator body 132 may be configured for engagement with a conventional actuator mouthpiece. This allows the mouthpiece to be selectively used with either the MDI of the embodiment or with the conventional actuator.

In the assembled state of the MDI131, the first vessel 101 and the second vessel 102 are at least partially received in the actuator body 132. The lid 133 is slidably supported on the actuator body 132 so as to displace the first vessel 101 and the second vessel 102 when the lid 133 is displaced relative to the actuator body 132. Movement of the cap 133 relative to the actuator body 132 may be guided by cooperating guides provided on the cap 133 and actuator body 132.

A support member 136, a guide member 138, and an O-ring 137 are disposed in the actuator body 132. The support member 136 may extend across the interior of the actuator body 132. The support member 136 has a through hole for allowing the valve stem 105, 108 of the vessel 101, 102 to pass through the support member 136. The through-hole may extend parallel to the longitudinal axis of the actuator body 132.

The guide member 138 has a socket for receiving the ends of the valve stems 105, 108. The guide member 138 defines a passageway for receiving a first metered dose of a first formulation in the first vessel 101. The guide member 138 defines another passageway for receiving a second metered dose of a second formulation in the second vessel 102. When the actuator is assembled, the outlet aperture of the guide member 138 is in fluid communication with the actuator block 134.

An O-ring 137 is disposed in the receptacle of the guide member 138. The valve stems 105, 108 of the vessels 101, 102 are held in place and prevented from leaking using O-rings 137.

As best seen in side view 142, actuator body 132 has vent 139. A vent 139 may be formed in the base of the actuator body 132. In operation, a flow path for air is created by the actuator.

Upon actuation of the MDI131, the caps 133 fitted on all the vessels 101, 102 cause the vessels 101, 102 to be pressed together. The first metered dose of the first formulation and the second metered dose of the second formulation are delivered upon actuation. The first formulation moves through a valve stem 105 associated with the first vessel 101 and through a passageway defined in the guide member 138 to an outlet orifice. The second formulation moves through the valve stem 108 associated with the second vessel 102 and through a passageway defined in the guide member 138 to the outlet orifice. As the formulations meet at the interconnection point of the path in the guide member 138, the first and second formulations mix prior to aerosolization.

Fig. 14C shows a cross-sectional view of the guide member 138. The guide member 138 may be contained by the actuator block. In the guide member 138, a passageway 144 is formed for guiding the first formulation dispensed from the first vessel. Another passageway 145 is formed for directing a second formulation dispensed from a second vessel. The first passageway 144 may be straight. The second passageway 145 may be straight. The first and second passages may be arranged at an orifice angle relative to the longitudinal axis of the actuator body 132. That is, a longitudinal axis 146 of the first passage 144 may enclose an angle 148 with an axis 147 parallel to the longitudinal axis of both vessels 101, 102. The angle 148 is also referred to as an orifice angle. The orifice angle 148 defines the orientation of the passage in the guide member 138 relative to the axis 147.

In a single orifice actuator, such as the one described with reference to fig. 14A, 14B and 14C, each formulation path connecting the valve stem outlet and the outlet orifice 95 of the respective container is preferably linear and arranged in the interconnection point at an orifice angle comprised within an interval from 15 ° to 60 ° with respect to an axis parallel to the longitudinal axis of the container. The orifice angle 148 may be comprised in the range of 0 ° to 90 °, in particular in the range of 15 ° to 60 °, in particular in the range of 20 ° to 60 °. The orifice angle may be in particular 20 ° or 30 °.

While an actuator having an actuator block defining one nozzle orifice may be used, in still other embodiments, multiple nozzle orifices may be formed in the actuator block.

FIG. 15A is a schematic cross-sectional view of an MDI96 according to another embodiment. Elements or features that correspond in their configuration and/or function to elements or features of the MDI91 of fig. 14A are indicated with the same reference numerals.

The MDI96 includes an actuator 92 and at least a first vessel 101 and a second vessel 102. The first vessel 101 contains a first formulation and the second vessel 102 contains a second formulation.

The actuator 92 has an actuator block 97. The actuator block 97 defines a first actuator seat for a first valve stem 105 associated with the first vessel 101 and a second actuator seat for a second valve stem 108 associated with the second vessel 102. Two nozzle orifices 98 and 99 are formed in the actuator block 97. The first nozzle orifice 98 is in fluid communication with a first actuator seat for a first valve stem 105. The second nozzle orifice 99 is in fluid communication with a second actuator seat for a second valve stem 108. A channel may be formed in the actuator block 97 for connecting the actuator seat with the associated nozzle orifice.

Upon actuation of the MDI96, the device 93 allows the first vessel 101 and the second vessel 102 to be jointly pressed for simultaneous delivery of the first and second formulations. The first metered dose of the first formulation and the second metered dose of the second formulation are delivered upon actuation. The first formulation moves to the first aperture 98 through a valve stem 105 associated with the first vessel 101 and through a passageway defined in the actuator block 97. The second formulation moves through a valve stem 108 associated with the second vessel 102 and through a passageway defined in the actuator block 97 to the second aperture 99. The first formulation and the second formulation are mixed after atomization.

The first and second apertures 98, 99 may be configured to have any of a variety of geometries. For illustration, as shown in fig. 15A, the first and second apertures 98 and 99 may be arranged to extend parallel to each other. The longitudinal axes of the first and second apertures 98, 99 may be disposed at an angle of about 90 ° relative to the longitudinal axis of the actuator seat that receives the valve stem.

In still other embodiments, the longitudinal axes of the first and second orifices 98, 99 may be arranged substantially parallel to the longitudinal axis of the actuator seat receiving the valve stem, similar to the nozzle orifice configuration shown in fig. 11.

In still other embodiments, the first and second orifices 98, 99 may be disposed such that their longitudinal axes are disposed at an angle relative to each other, similar to the nozzle orifice configuration shown in fig. 12. Thereby, a cross-flow situation may be established in which the average velocity of one of the first and second formulations after atomization has a component directed towards the atomization cloud of the other of the first and second formulations.

Further, for any of the various orientations of the first and second apertures 98, 99, the distance between the first and second apertures 98, 99 may be selected according to a desired interaction point between the plumes of the first and second formulations. Additionally or alternatively, the relative orientation between the first and second apertures 98, 99 may be selected according to a desired interaction point between the plumes of the first and second formulations.

Fig. 15B shows a cross-sectional view taken in a plane in which the longitudinal axis of the first aperture 98 and the longitudinal axis of the second aperture 99 lie. Impingement angle 149 may be defined as the angle between the longitudinal axis of first aperture 98 and the longitudinal axis of second aperture 99.

The impingement angle may be selected from the range of 0 ° to 180 °, in particular from the range of 10 ° to 110 °, in particular from the range of 15 ° to 60 °. For purposes of illustration, the impingement angle may be 15 °, 60 °, or 90 °.

Due to the separate orifices and various parameters including orifice distance and orientation, which may be used to affect post-atomization plume interactions, post-atomization mixing may be used to adjust at least one of the fine dose, fine fraction, and particle size distribution in the formulation. The orifice separation distance may be defined as the distance between the center of the outlet opening of the first nozzle orifice and the center of the outlet opening of the second nozzle orifice.

While an MDI with two separate vessels is shown, for example, in fig. 14A, 14B and 15A, in further embodiments a greater number of vessels may be employed. To allow the vessel to be received in the actuator housing without requiring a significant increase in the size of the actuator, the separate vessel may be formed from a cartridge having a size smaller than that of a conventional MDI system. For the sake of illustration, the separate vessels used may each have a diameter of less than 22 mm.

Fig. 16A shows a possible arrangement 110 of three cartridges in plan view. Each of the three cartridges had a diameter of 13 mm. In contrast, a conventional cartridge having a diameter of 22mm is shown in plan view at 109. The cross-sectional area occupied by three 13mm cartridges is only slightly larger than the cross-sectional area occupied by a single 22mm cartridge.

FIG. 16B illustrates an MDI151 according to an embodiment. The MDI151 utilizes three cartridges. FIG. 16B shows a perspective view of the MDI, partially cut away. FIG. 16B also shows a side view 164, a front view 165 and a top view 166 of the MDI 151.

The MDI151 is generally similar in construction and operation to the MDI131 of fig. 14B. Elements or components that correspond in their configuration and/or function to elements or features of the MDI91 of fig. 14A or elements or features of the MDI131 of fig. 14B are indicated with the same reference numerals.

The MDI151 includes an actuator and at least a first vessel 101, a second vessel 102, and a third vessel 167. The first, second and third vessels 101, 102 and 167 are at least partially received within the actuator housing. Each of these vessels will have a dedicated metering valve system.

The actuator of the MDI151 includes an actuator body 152, a cap 153 and a mouthpiece 155. The actuator block 154 is formed on a mouthpiece 155. The mouthpiece 155 and the actuator body 152 may be provided with cooperating engagement means that couple the actuator body 152 and the mouthpiece 155 to each other in the operational state of the MDI 151.

In the assembled state of the MDI151, the first, second and third vessels 101, 102, 167 are at least partially received in the actuator body 152. The cover 153 is slidably supported on the actuator body 152 such that the first vessel 101, the second vessel 102 and the third vessel 167 are displaced when the cover 153 is displaced relative to the actuator body 152. The cover 153 covers all the vessels and causes the vessels to be pressed together. The movement of the cover 153 relative to the actuator body 152 may be guided by cooperating guides provided on the cover 153 and the actuator body 152.

A support member 156, a guide member 158, and an O-ring are disposed in the actuator body 152. These members may have a configuration and arrangement corresponding to the members of the MDI131 of fig. 14B. The guide member 158 may have a socket for receiving the ends of the valve stems of the three vessels. The guide member 158 defines a first passageway for receiving a first metered dose of the first formulation in the first vessel 101. The guide member 158 defines a second passageway for receiving a second metered dose of a second formulation in the second vessel 102. The guide member 158 defines a third passageway for receiving a second metered dose of a third formulation in a third vessel 167. When the actuator is assembled, the outlet aperture of the guide member 158 is in fluid communication with the actuator block 154.

The first, second and third paths may be straight. The first, second and third passages may each be arranged such that their longitudinal axes are arranged in the interconnection point with respect to an axis parallel to the longitudinal axis of the container at an orifice angle comprised in an interval from 0 ° to 90 °, said orifice angle 148 being in particular in an interval from 15 ° to 60 °, in particular in an interval from 20 ° to 60 °. The orifice angle may be in particular 20 ° or 30 °.

The valve stems of vessels 101, 102, 167 are held in place and prevented from leaking using O-rings.

At 166, a top view of MDI151 with cover 153 removed is shown. The vessels 101, 102, 167 are arranged in a side-by-side relationship. Support ribs 168 may be formed on the actuator body 152 to support the vessels 101, 102, 167.

Upon actuation of the MDI151, the caps 153 fitted on all the vessels 101, 102, 167 cause the vessels 101, 102, 167 to be pressed together. The formulation dispensed from the vessel flows through a passageway formed in the guide member 158, as indicated at 161. A vent hole formed in the base of the actuator body 152 allows an air flow 152 to be established in the actuator. Air enters the actuator at its base.

According to an embodiment, an MDI is provided having a first reservoir of a first formulation and a second reservoir of a second formulation. The MDI allows a first metered dose of a first formulation and a second metered dose of a second formulation to be delivered when the at least one vessel is received by the actuator. The two formulations may be metered by different valving to ensure consistent first and second doses are delivered.

In the MDI of the example, both the first dose of the first formulation and the second dose of the second formulation may be aerosolized through the same orifice, or the first formulation may be aerosolized through a first orifice and the second formulation may be aerosolized through a second orifice separate from the first orifice.

The first and second formulations may be mixed prior to atomization or after atomization.

Various effects can be obtained by means of the MDI according to the embodiment.

When two formulations are delivered, the particle size distribution of each of the formulations can be affected by the presence of the other formulation.

When a formulation containing an active ingredient in solution or suspension in a propellant is delivered with another formulation containing a low volatility ingredient such as ethylene glycol and in particular glycerol, the particle size distribution of the formulation containing the active ingredient may change due to the presence of a second formulation (placebo formulation) containing a low volatility ingredient (e.g. glycerol). The efficacy of the aerosol formulation in terms of particle size distribution can be improved by co-aerosolization with the presence of a second formulation, e.g., a placebo formulation.

When two formulations are delivered, the particle size distribution can be affected by the volume of the two formulations delivered. By using different combinations of the first and second metered volumes, the total median aerodynamic diameter (mass median aerodynamic diameter) can be varied in particular.

Incompatible formulations, such as formulations having physical or chemical incompatibility, may be mixed at a nozzle orifice. Incompatible formulations may be stored in separate reservoirs until delivery. This can be particularly advantageous when simultaneous administration of the combined active ingredients is desired or required, the active ingredients, solvents, propellants or other excipients being incompatible from a chemical or physical (from suspension and solution formulations) standpoint.

The ability to influence the particle size distribution and efficacy of the first formulation by mixing the first formulation with the second formulation before or after atomization provides additional flexibility for formulations that can be administered using an MDI. For purposes of illustration, the first or second formulation may be selected in view of the desired solubility, stability, or drug loading capability. The resultant particle size distribution and/or fine particle dose of the aerosolized cloud delivered by the MDI may be matched to a desired particle size distribution and/or fine particle dose by mixing with another formulation. The consistency between the particle size distributions of the two mixed recipes can be controlled by appropriately selecting the mixing process of the recipes.

According to an embodiment, at least one of the first and second formulations may be selected such that the particle size distribution after atomization of at least the other of the first and second formulations is adjusted by mixing the first and second formulations.

According to an embodiment, at least one of the first and second formulations may be selected such that the fine particle dose of at least the other of the first and second formulations is adjusted by mixing the first and second formulations. The fine particle dose of the other of the first and second formulations, which is affected by the mixing, is determined relative to a threshold diameter, which may be selected for the respective application.

The MDI of the example may include three reservoirs. The first reservoir may contain a first formulation, the second reservoir may contain a second formulation, and the third reservoir may contain a third formulation. Three reservoirs may be formed in separate cartridges, or at least two of the reservoirs may be formed as compartments of one vessel. Upon actuation of the assembled MDI, metered doses of the first, second and third formulations may be administered. These MDIs can be used in "triple therapy" in which three active agents are delivered. An embodiment of an MDI having three separate cartridges defining three reservoirs has been explained with reference to fig. 16B.

For further explanation, the following examples are provided.

Examples of the invention

The following examples are provided to further illustrate the effect of two formulations mixing before atomization (examples 1 to 6, 11 to 13, 15, 17, 18), for example at a nozzle orifice, or by letting two formulations interact with each other after atomization (examples 7 to 10, 14, 15, 16).

Data has been obtained for a metered dose inhaler in which a first formulation is contained in a first cartridge and a second formulation is contained in a second cartridge. The data obtained when the first and second formulations are mixed is also referred to in the illustration of the example as a "two-pot" or "MDI" configuration. Comparative data for delivering a formulation from a cartridge has been obtained. This data is also referred to in the illustration of the examples as a "single pot" or "standard MDI" configuration.

Actuator

It will be given that data is obtained from three different actuators that allow two formulations to be delivered simultaneously from separate reservoirs.

The data obtained for the "dual MDI" or "dual can" configurations in examples 1 to 6 were obtained using two different types of actuators. A schematic cross-sectional view through the actuator block 111 of the actuator is shown in fig. 17A. The actuator block defines two actuator seats 112 and 113 for receiving the valve stems of the first and second cartridges, respectively. An aperture 114 is formed extending in a direction perpendicular to the longitudinal axis of the actuator seats 112 and 113. The actuator block 111 has been arranged in an actuator housing identical to that of the actuator used for performing the comparison measurements in the "single pot" or "standard MDI" configuration. In one of the actuators for a dual MDI (referred to as a "0.22 mm actuator orifice"), the nozzle orifice 114 has a diameter of 0.22 mm. In the other of the actuators for the dual MDI (referred to as the "0.30 mm actuator orifice"), the nozzle orifice 114 has a diameter of 0.30 mm. The length of the orifices is respectively equal to the orifice length in a conventional actuator for comparative measurements in a single reservoir configuration.

The data obtained for the "dual MDI" or "dual can" configurations in examples 7-10 was obtained using one type of actuator. A schematic cross-sectional view through the actuator block 121 of the actuator is shown in fig. 17B. The actuator block defines two actuator seats for receiving the valve stems of the first and second cartridges, respectively. Two apertures 122 and 123 are formed extending in a direction perpendicular to the longitudinal axis of the actuator seat. The actuator block 111 has been arranged in an actuator housing identical to that of the actuator used for performing the comparison measurements in the "single pot" or "standard MDI" configuration. In the actuator for the "dual MDI" measurement, the nozzle orifices 122 and 123 each have a diameter of 0.22 mm.

In addition, a test rig has been developed to help evaluate the drug delivery performance of various dual reservoir orifice configurations that provide good control over a range of variables used in the experiment as compared to the original prototype (fig. 17A and 17B). When the test stand is in use, actuation of the canisters is remotely controlled and both canisters can be in an inverted position (unlike the prototype of fig. 17A and 17B, in which one canister is inverted and one canister is upright). The developed test rig allows to accurately control the timing of the actuation (simultaneously or with a delay between the reservoirs) and the positioning of the two or three canisters with respect to the expansion chamber/orifice. Configurations that examine the effects of single orifice delivery and dual orifice delivery can be achieved with available micron control of the separation distance between the two spray orifices and various impingement angles. The single orifice configuration utilized an orifice angle of 30 °. The dual orifice configuration allows for the study of multiple separation distances and impingement angles. The data in examples 11 to 18 were obtained using a test stand.

The data obtained for the "dual" reservoir configuration in examples 11 to 13 was obtained using a test rig. The nozzle orifice has a diameter of 0.30 mm. The path is linear. That is, the recipe path connecting the valve stem outlet and the outlet orifice of each vessel is linear (compare, fig. 14B or 14C). The passageway is aligned at an angle of 20 deg. (orifice angle) with respect to an axis parallel to the longitudinal axis of the container.

The data obtained for the "dual" reservoir configuration in example 14a was obtained using a test rig with different orifice separation distances and different orifice orientations. Two orifices are used. In example 14b, the test rig was adapted for use in a dual orifice configuration with an orifice diameter of 0.25mm, a separation distance of 6mm, and an impingement angle of 60 °.

The data obtained for the "dual" reservoir configuration with a single orifice in example 15 was obtained using a test rig with a single orifice configuration (orifice diameter of 0.30mm, orifice angle of 30 °). The data obtained for the "dual" reservoir configuration with dual orifices in example 15 was obtained using a test rig with a dual orifice configuration (orifice diameter of 0.25mm, impingement angle of 60 °, separation distance of 6.0 mm).

The data obtained for the "dual" reservoir configuration with dual orifices in example 16 was obtained using a test rig with a dual orifice configuration (orifice diameters of 0.30mm and 0.25mm, impingement angle of 15 °, separation distance of 6.0mm or 10 mm).

The data obtained for the "dual" reservoir configuration with single orifice in example 17 was obtained using a test rig with a dual-reservoir single orifice configuration having an orifice angle of 30 ° and a nozzle orifice diameter of 0.30 mm.

The data obtained for the "dual" reservoir configuration with single orifice in example 18 was obtained using a test rig with a dual-reservoir single orifice configuration having an orifice angle of 30 ° and a nozzle orifice diameter of 0.30 mm.

The data in example 19 was obtained using the system of fig. 14B, which has two valve-can assemblies and an actuator with one nozzle orifice.

The data in example 20 was obtained using the system of fig. 16B, which has three valve-can assemblies and an actuator with one nozzle orifice.

Comparative data for the "standard MDI" or "single pot" configurations in examples 1 to 6 were obtained using a standard actuator having an orifice diameter of the nozzle orifice of 0.22mm or 0.30mm, respectively, and an orifice length equal to that of the actuator used for the dual MDI measurement.

Comparative data for the "standard MDI" or "single canister" configurations in examples 7 to 10 were obtained by inserting only one canister into the actuator for the two-canister measurement.

Comparative data for the "single" reservoir configurations in examples 11-13 were obtained using a conventional actuator for a single reservoir single orifice system, with the orifice diameter of the nozzle orifice being 0.30 mm.

Comparative data for the conventional MDI configuration with a single reservoir in example 14 was obtained using a conventional actuator with an orifice diameter of the nozzle orifice of 0.22 mm.

Comparative data for the conventional MDI configuration with a single reservoir in example 15 was obtained using a conventional actuator with an orifice diameter of the nozzle orifice of 0.22 mm.

Comparative data for examples 16 and 17 were obtained using a conventional actuator with one nozzle orifice of 0.30mm diameter (for the BDP formulation) and a conventional actuator with one nozzle orifice of 0.50mm diameter (for the salbutamol sulphate formulation).

Comparative data for example 18 was obtained using a conventional actuator having one nozzle orifice with a diameter of 0.30 mm.

Method of producing a composite material

The actuator designs used in some examples, such as examples 1-10 (fig. 17A and 17B), require one canister in an inverted position (conventional valve) and one canister in an upright position. Thus, a modified metering valve provided with a dip tube is used with a canister in an upright position. For the actuator design of fig. 14B (such as used in example 11), no such modification is required and a conventional valve without a dip tube is used.

Measurements are performed to quantify the drug delivery characteristics of the MDI delivering the first and second formulations from separate reservoirs. Data has been acquired for various different first and second recipes.

The spray characteristics of the system were evaluated by means of an anderson cascade impactor (Andersen cascademapactor) equipped with a USP throat (apparatus 1, USP 33). The particle size distribution of the sprays produced by the standard pMDI and by the pMDI according to the examples of the invention was evaluated by an Anderson's Cascade Impactor (ACI) fitted with a USP throat (section <601 >; apparatus 1; USP 33). The apparatus was used at a flow rate of 28.3 liters/min. The multistage impactor is set up according to the manufacturer's instructions. The cartridge uses a standard actuator to discharge waste twice to prime the metering valve prior to analysis. The cartridge is then fitted to the pMDI actuator system and ejected with primary waste. The pMDI actuator system is then attached to the USP throat using a mouthpiece adapter. ACI was sprayed once at a flow rate of 28.3 liters/minute and left for a period of 60 seconds. This was repeated twice. The weights before and after injection were recorded. After the final dose has been expelled, at 85: 15 ethanol: the water flushes each stage of the actuator system, mouthpiece, USP throat and from the cascade impactor. The solution was analyzed for drug deposition by using a UPLC/MS (ultra performance liquid chromatography/mass spectrometry) system.

By ACI, the following parameters of the particles ejected from pressurized MDI can be determined:

i) the total median aerodynamic diameter (MMAD) is the diameter around which the total aerodynamic diameter of the ejected particles is evenly distributed;

ii) the delivered dose was calculated by dividing the accumulated deposits in ACI by the number of actuations per experiment;

iii) the inhalable dose (fine particle dose = FPD) is obtained by dividing the deposit from grade 3 (S3) of the filter (AF) of ACI, corresponding to particles with a diameter ≦ 5 μm, by the number of actuations per experiment;

iv) respirable fraction (also known as fine particle fraction, FPF), which is the percentage between respirable dose and delivered dose.

For example 8, plume duration was measured using an online PC microphone in conjunction with audacityl 1.2.6 software.

Example 1

Formulations 1 and 2 were mixed and ejected through a single actuator orifice having a diameter of 0.22mm or 0.30 mm. The formula is as follows:

formulation 1 (beclometasone dipropionate (BDP) formulation with low volatility component, 25 μ l dose per spray):

BDP50 μ g/25 μ l, 13% w/w ethanol, 1.3% w/w glycerol, HFA134a to 100%

Formulation 2 (beclomethasone dipropionate formulation with low volatility component, 25 μ l dose per spray):

same as in formulation 1.

For containing: comparative data ("standard MDI") were obtained for BDP100 μ g/50 μ l, 13% ethanol, 1.3% glycerol, HFA134a to 100% standard actuator and single can.

Table 1 shows the delivered dose, Fine Particle Dose (FPD). ltoreq.5 μm, Fine Particle Fraction (FPF), total median aerodynamic diameter (MMAD) and the number of repetitions performed (n) for the respective experiments.

Table 1: delivery from dual MDI for a single formulation delivered from two chambers through a single orifice as compared to conventional MDI delivery

The resulting performance and particle size distribution for the dual MDI delivered dose from a separate canister is similar to that of a conventional MDI delivering 100 μ g/50ul (i.e. the sum of formulations 1 and 2).

This example shows that if formulations 1 and 2 are the same, the drug delivery characteristics obtained with the dual MDI are similar to those of a standard MDI.

Example 2

Formulations 3 and 4 were mixed and ejected through a single 0.22mm actuator orifice. The formula is as follows:

formulation 3 (formoterol formulation, 25 μ l dose per spray):

formoterol fumarate 6. mu.g/25. mu.l, 12% w/w ethanol, 0.0474% w/w HCI (1M), HFA134a to 100%

Formulation 4 (BDP formulation with low volatile components, 25 μ Ι dose per spray):

BDP100 ug/25 ul, 12% w/w ethanol, 1.3% w/w glycerol, HFA134a to 100%

Comparative data were obtained by firing a dose of either the BDP formulation or the formoterol formulation through a standard actuator having an orifice diameter of 0.22 mm. Formulation in single pot configuration: 100 μ g/50 μ l of BDP, 13% ethanol, 1.3% glycerol, HFA134a to 100%; or: formoterol fumarate 6 μ g/50 μ l, 12% EtOH, 0.024% HCI (1M), HFA134a to 100%.

The drug delivery characteristics from the dual MDI system are shown in table 2 and figure 18. The particle size distribution of each formulation is affected by the presence of another formulation. The data obtained for the dual MDI system are shown in fig. 18 as circles and diamonds, respectively. The comparison data are shown by squares and triangles, respectively.

This example shows that the particle size distribution of one formulation can be changed by the presence of a second formulation.

Table 2: dual MDI delivery for two formulations with different particle size distributions

Example 3

Formulations 3 and 5 were mixed and ejected through a single 0.22mm actuator orifice. These formulations are:

formulation 3 (formoterol formulation, 25 μ l dose per spray):

Formulation 5 (placebo formulation with low volatile components, 25 μ Ι dose per spray):

13% w/w ethanol, 1.3% w/w glycerol, HFA134a to 100%

Comparative data were obtained by firing a formoterol formulation through a standard actuator having an orifice diameter of 0.22 mm. Formulation in single pot configuration: formoterol fumarate 6 μ g/50 μ l, 12% EtOH, 0.024% HCI (1M), HFA134a to 100%.

The drug delivery characteristics from the dual MDI system are shown in table 3 and figure 19. The particle size distribution of the formoterol formulation (indicated by the diamond in the comparative data in figure 19) was influenced by the presence of the placebo formulation. The data obtained for blend formulations 3 and 5 are shown by diamonds in fig. 19.

This example demonstrates that the particle size distribution of one formulation can be altered by the presence of another placebo formulation containing glycerol as the low volatile ingredient.

Table 3: dual MDI delivery of formoterol formulations and placebo with different particle size distributions

Example 4

Formulations 6 and 7 were mixed and ejected through a single 0.22mm actuator orifice. The two formulations are:

formulation 6 (high ethanol content BDP formulation, 25 μ l dose per spray):

BDP100 ug/25 ul, 26% w/w ethanol, 1.3% w/w glycerol, HFA134a to 100%

Formulation 7 (100% HFA134a, 25 μ l dose per ejection):

100% w/w HFA134a delivered through a 25 μ l valve

Comparative data were obtained by firing BDP formulations through a standard actuator with an orifice diameter of 0.22 mm. Formulation in single pot configuration: BDP100 ug/25 ul, 26% w/w ethanol, 1.3% w/w glycerol, HFA134a to 100%.

The drug delivery characteristics from the standard MDI and the drug delivery characteristics from the dual MDI system are shown in table 4. The efficacy of the high ethanol (26% w/w) formulation was improved when the high ethanol (26% w/w) formulation was mixed with HFA134a prior to atomization through the nozzle. Due to the mixing of HFA134a before the nozzle, the FPD increased from 27 μ g to 41 μ g and the FPF increased from 27% to 48%.

This example demonstrates that the efficacy of a high ethanol content formulation can be improved by the presence of another placebo formulation.

Table 4: standard MDI and Dual MDI delivery for high ethanol (26% w/w) BDP100 μ g formulations

Example 5

Formulations 8 and 3 were mixed and ejected through a single 0.22mm actuator orifice. The two formulations are:

formulation 8 (high dose budesonide formulation, 63 μ l dose per spray):

budesonide 400. mu.g/63. mu.l, 15% w/w ethanol, 2% w/w water, 0.002% w/w phosphoric acid (15M), 0.2% w/w glycerol, HFA134a to 100%

Formulation 3 (formoterol formulation, 25 μ l dose per spray):

Formulation 8 and formulation 3 are examples of incompatible formulations. The stability of the formulation depends on the type of container and the excipients in the formulation. The dual MDI system provides the opportunity to use a different container type (or container coating) for each formulation. Additionally, formulation stabilizers or solubilizers may be necessary in one formulation, but these are incompatible with a second formulation. This example combines two incompatible formulations and shows that better drug delivery can be achieved by mixing the formulations at the nozzle.

The drug delivery characteristics from the dual MDI system are shown in table 5 and figure 20 (comparative data indicated by triangles). The particle size distribution of the formoterol formulation is significantly affected by the presence of the budesonide formulation. The MMAD of the formoterol formulation is close to that of budesonide.

This example shows that two incompatible formulations can be mixed at the actuator nozzle orifice.

Table 5: dual MDI delivery of formoterol formulations and high dose budesonide formulations with different particle size distributions

Example 6

The BDP solution formulation and the budesonide solution formulation with low volatility component were mixed and ejected through a single 0.22mm actuator orifice, respectively. Measurements were performed on different metered volumes of BDP formulations and on different metered volumes of budesonide formulations. This example shows that the particle size distribution can be influenced by controlling the metered volume of the different solutions.

The BDP solution formulations were selected from the following formulations 9 to 11, respectively, and the budesonide formulations having low volatility compounds were selected from the following formulations 12 to 14, respectively:

formulation 9 (BDP solution formulation, 50 μ g/25 μ L dose per spray):

0.18% w/w BDP, 15% w/w ethanol, HFA134a to 100%

Formulation 10 (BDP solution formulation, 50 μ g/50 μ L dose per spray):

0.09% w/w BDP, 15% w/w ethanol, HFA134a to 100%

Formulation 11 (BDP solution formulation, 50 μ g/100 μ L dose per spray):

0.04% w/w BDP, 15% w/w ethanol, HFA134a to 100%

Formulation 12 (budesonide solution formulation with low volatility component, 50 μ g/25 μ L dose per spray):

0.18% w/w budesonide, 15% w/w ethanol, 1.3% w/w glycerol, 0.002% w/w phosphoric acid (15M), HFA134a to 100%

Formulation 13 (budesonide solution formulation with low volatility component, 50 μ g/50 μ L dose per spray):

0.09% w/w budesonide, 15% w/w ethanol, 1.3% w/w glycerol, 0.002% w/w phosphoric acid (15M), HFA134a to 100%

Formulation 14 (budesonide solution formulation with low volatility component, 50 μ g/100 μ L dose per spray):

0.04% w/w budesonide, 15% w/w ethanol, 1.3% w/w glycerol, 0.002% w/w phosphoric acid (15M), HFA134a to 100%

Comparative data were obtained by shooting formulations 9 to 14 in a single pot configuration using an actuator with a nozzle orifice of 0.22 mm.

Drug delivery characteristics from the single canister configuration are shown in table 6. The MMAD of the BDP formulation (50 μ g) and budesonide formulation (50 μ g) was not significantly affected by the metered volume when ejected using a 0.22mm actuator (table 6) in a single pot configuration. Values of 1.1 μm to 1.2 μm and 3.0 μm to 3.1 μm for BDP and budesonide MMAD, respectively, were consistently obtained.

Table 7 and fig. 21 to 23 show the drug delivery characteristics from the dual MDI system (comparative data are indicated by open symbols and dual MDI data are indicated by filled symbols). In contrast to the single tank configuration, the MMAD can be specifically changed when different combinations of metered volumes are used in the dual tank configuration (table 7). The larger volume of the budesonide formulation relative to the BDP formulation resulted in a shift in MMAD of BDP (2.6 μm) towards the MMAD of budesonide (2.7 μm) (fig. 21). Two formulations of equal volume result in a shift of the MMAD towards the center of the two original values; values of 1.9 μm and 2.4 μm were obtained for BDP and budesonide MMAD, respectively (fig. 22). The larger volume of BDP formulation relative to budesonide formulation, including low volatile components, resulted in a shift in MMAD of budesonide (2.1 μm) towards MMAD of BDP (1.8 μm) (fig. 23). However, this shift is mediated by the presence of a low volatility component (glycerol) in the budesonide formulation.

This example illustrates the ability of an MDI to simultaneously deliver a first formulation and a second formulation to modify the particle size distribution. In particular, this example shows that the particle size distribution of the formulation can be adjusted by adjusting the metering volume. This allows the particle size distribution to be adjusted via the metering volume.

Table 6: aerosol characterization of BDP and budesonide (50 μ g dose) at different metered volumes using a 0.22mm actuator

Table 7: aerosol characterization of dual-can BDP and budesonide using different combinations of metered volumes

Example 7

Formulations 15 and 16 were mixed and ejected by a dual orifice actuator as shown at 121 in fig. 17B. The two formulations used were:

formulation 15 (budesonide formulation with low volatility component, 25 μ l dose per spray):

0.18% w/w budesonide (50. mu.g/25. mu.l), 13% w/w ethanol, 1.3% w/w glycerol, HFA134a to 100%

Formulation 16 (BDP formulation with low volatile components, 25 μ Ι dose per spray):

0.18% w/w BDP (50. mu.g/25. mu.l), 13% w/w ethanol, 1.3% w/w glycerol, HFA134a to 100%

For each measurement, a dual orifice actuator was used, with the formulation 15 being fired in an inverted position and the formulation 16 being fired in an upright position.

Table 8 and fig. 24 show the drug delivery characteristics and accumulated screen underflow for each formulation ejected from the dual orifice actuator simultaneously (indicated by the solid symbols in fig. 24, "dual canister") or separately (indicated by the open symbols in fig. 24, "single canister"). The upright orientation of the BDP formulation reduces the dose delivered due to the BDP formulation remaining on the valve stem, valve and actuator. When the formulations are actuated simultaneously, the delivered dose is improved by reducing the interaction between plumes of deposits on the actuators. The particle size distribution of the simultaneously actuated formulations is comparable to the particle size distribution of the formulations produced by the independent actuations. This shows that two similar formulations atomized at the same time can produce the same particle size distribution as if actuated independently.

This example shows that similar particle size distributions can be obtained when two nearly identical formulations are actuated simultaneously, as compared to actuation alone. This example also demonstrates that the formulation undergoes post-atomization mixing after simultaneous actuation from two very close orifices.

Table 8: aerosol features of budesonide and BDP actuated separately or simultaneously by dual orifice actuator

Example 8

The formulation combinations 17 a-18 a and 17B-18B are ejected by a dual orifice actuator as shown at 121 in fig. 17B. The plume duration for simultaneous actuation of two 25 μ L valves and two 63 μ L valves was measured compared to the plume duration for each dual canister. This example demonstrates that the metered volume can be doubled without increasing the plume duration. The two formula combinations are:

25 μ L of the formulation combination:

formulation 17 a: 0.18% w/w budesonide; 13% w/w ethanol; 1.3% w/w glycerol; HFA134a to 100%; and

formulation 18 a: 0.18% w/w BDP; 13% ethanol; HFA134 a-100%

63 μ l of the formulation combination:

formulation 17 b: 0.07% w/w budesonide; 13% w/w ethanol; 1.3% w/w glycerol; HFA134a to 100%; and

formulation 18 b: 0.07% w/w BDP; 13% w/w ethanol; HFA134a to 100%; and is

The plume duration measurements are summarized in table 9. The Standard Deviation (SD) and the Relative Standard Deviation (RSD) are also given in table 9. The plume duration of the combined formulation is compared to the plume duration of each canister.

This example demonstrates that using a dual can configuration, the metered volume can be doubled without increasing the plume duration when the formulation is ejected through two nozzle orifices.

Table 9: plume duration for individual and twin tanks

Example 9

Formulations 17a and 18a of the previous example 8 were emitted by a dual orifice actuator and their aerosol characteristics were compared to the aerosol characteristics of each formulation emitted separately. This example demonstrates that the formulation undergoes post-atomization mixing after simultaneous actuation from two very close orifices. The two formulations used were:

formulation 17a (budesonide formulation with low volatility component, 25 μ l dose per spray):

Formulation 18a (BDP formulation, 25 μ Ι dose per spray):

0.18% w/w BDP (50. mu.g/25. mu.l), 13% w/w ethanol, HFA134a to 100%

For each comparative measurement, the formulation 17a (budesonide) was fired in an inverted position and the formulation 18a (bdp) was fired in an upright position using a dual orifice actuator.

Table 10 and fig. 25 show aerosol characteristics of budesonide (50 μ g/25 μ L) and BDP (50 μ g/25 μ L) actuated either individually (indicated by open symbols in fig. 25, "single canister") or simultaneously (indicated by solid symbols in fig. 25, "double canister") using a dual orifice actuator. The upright orientation of the BDP delivered from the single canister formulation reduces the dose delivered due to the BDP remaining on the valve stem, valve and actuator. When the formulations are actuated simultaneously, the delivered dose is improved due to reduced interaction between the deposited plumes on the actuators. In addition, the MMAD of BDP increases (from 0.9 μm to 1.5 μm) and budesonide decreases (from 3.0 μm to 2.4 μm). This can be attributed to post-atomization mixing of the formulation, resulting in a change in the measured particle size distribution.

This example illustrates the post-atomization mixing of the formulation. This example also shows that the particle size distribution can be adjusted after atomization, which indicates that particle formation occurs after the orifice.

Table 10: aerosol features of budesonide and BDP actuated either individually ("single canister") or simultaneously ("dual canister") by dual orifice actuators

Example 10

After simultaneously actuating both valve systems, the plume produced using the dual orifice actuator is visible using high speed imaging.

Fig. 26 shows a side view of the plume. Fig. 27 shows a cross-sectional view taken at positions 7mm (shown at 131 in fig. 27), 14mm (shown at 132 in fig. 27) and 28mm (shown at 133 in fig. 27) from the orifice.

The images shown in fig. 26 and 27 demonstrate that the plume interacts after the two formulations are actuated simultaneously. The captured image confirms that the two individual plumes combine and that the plume geometry after collision changes, as is more apparent comparing image 131 and image 132.

The angle and distance between the nozzle orifices will determine the collision point and the type of mixing that occurs after atomization.

Example 11

This example also demonstrates that the PSD of a first formulation is adjusted by simultaneously delivering a second formulation.

Using the actuator of fig. 14B, BDP formulation 9 and budesonide formulation 12 were delivered through an orifice of 0.30mm diameter (see example 6).

To obtain comparative data ("single", meaning single reservoir), the same formulations (formulations 10 and 13 of example 6) packaged in a 50 μ Ι valve were used to match the total volume of the double dose and were delivered by a conventional MDI system with an actuator having an orifice diameter of 0.30 mm.

Experiments performed using the actuator of fig. 17A show that delivery of two different formulations through a single orifice results in their PSDs becoming more similar (see example 6). One effect of the system according to fig. 14B, in which each formulation path connecting the valve stem outlet and the outlet orifice 95 of each container is linear and aligned in the point of interconnection at an angle of 20 ° with respect to an axis parallel to the longitudinal axis of the container, is that it is easier to achieve an overall synchronization of the actuation of the two canisters, allowing the two formulations to be mixed simultaneously.

The drug delivery characteristics for the two-canister single orifice MDI system are shown in table 11 and figure 28. This data was obtained using a test rig in a configuration with a single orifice. The data points connected by the dashed lines in fig. 28 indicate that for both formulations, dual delivery results in nearly identical particle size distributions, with the MMAD of BDP moving from 1.3 μm (data obtained for conventional MDI) to 2.8 μm, and the MMAD of budesonide moving from 3.2 μm to 2.9 μm. This confirms that a high degree of synchronicity of actuation is desirable for simultaneous mixing.

The MMAD of BDP formulation 9 showed a greater change than budesonide formulation 12. This can be attributed to the effect of glycerol (low volatility component) on the BDP particles during the mixing process starting before the orifice.

In addition to the shift in MMAD, the fines fraction (% FPF) can be compared (see table 11) which falls between the fines fractions obtained for two single MDIs (27% and 35%).

Table 11: aerosol features for dual can delivery of BDP and budesonide formulations for dual can single orifice MDI

Example 12

This example demonstrates that HFA can be used to increase atomization of high ethanol formulations.

Formulations 19 and 20 were ejected through a system with two reservoirs and a single orifice, similar to the configuration shown in fig. 14B. The dose volumes were 25. mu.l each. This data was compared to data obtained from delivery of formulation 19 (high ethanol formulation) by a conventional single reservoir actuator with an orifice diameter of 0.30 mm.

Formulation 19 (high ethanol formulation): BDP (100. mu.g/25. mu.l), 26% w/w ethanol

The formula 20 is as follows: HFA134a

The delivery characteristics for the dual reservoir single orifice MDI system are shown in table 12 and fig. 29. Fig. 29 shows drug deposition measured with ACI. In fig. 29, the hollow bars indicate ACI drug deposits for a dual reservoir single orifice actuator. The solid bars indicate the comparison data obtained with a conventional actuator having only one reservoir.

Mixing the high-ethanol formulation with the HFA increases atomization of the high-ethanol formulation. With the addition of HFA (see table 12), MMAD decreased from 3.7 μm to 2.8 μm, indicating increased particle breakage. The FPD also increased from 18.1 mug measured for the conventional MDI data to 36.3 mug measured for the dual can single orifice MDI and the suction port deposits decreased.

Table 12: aerosol characteristics for dual can delivery of high ethanol formulations for dual can single to orifice MDI

Example 13

BDP formulation 9 and budesonide formulation 12 (see example 6, but the dose volume per shot is 25 μ Ι or 100 μ Ι) were ejected simultaneously through a 0.30mm diameter orifice using a configuration with a single orifice as schematically shown with an actuator according to fig. 14B. The dose volumes are set to be different, one of the dose volumes being 25 μ l and the other of the dose volumes being 100 μ l.

Fig. 30 and 31 show the results obtained from delivering unequal volumes of BDP formulation 9 and budesonide formulation 12. In both cases, both canisters were activated simultaneously, meaning that the duration of the 25 μ Ι dose was contained within the longer duration of the 100 μ Ι dose.

Comparative measurements (indicated by "BDP" and "Bud" in fig. 30 and 31) were performed using a conventional single reservoir MDI, the nozzle orifice diameter being 0.30 mm.

Formulations containing glycerol (low volatility ingredient) had a greater effect on the PSD of BDP formulations (no low volatility ingredient). For BDP formulations using a dose volume of 25 μ Ι, the MMAD of BDP moved from 1.2 μ η ι (data obtained for conventional MDI) to 3.1 μ η ι when delivered with 100 μ Ι of budesonide formulation (figure 30). The MMAD of the budesonide formulation only shifted slightly from 3.5 μm to 3.2 μm. The results are similar to those of fig. 28, where two formulations of equal volume were delivered simultaneously in fig. 28. However, the difference is that the effect of the glycerol-containing formulation was increased compared to BDP, which shifted the MMAD of both formulations further towards that of the budesonide data generated for the traditional MDI control (compare figures 30 and 31).

Two formulations of equal dose volume resulted in similar MMAD of 2.8 μm and 2.9 μm (see table 11 above).

Example 14a

This example demonstrates that the impingement angle and the orifice separation distance of the plumes delivered through two orifices affects atomization and plume mixing.

BDP formulation 9 and budesonide formulation 12 were delivered through a test rig in a configuration with two orifices (see example 6). I.e. a dual reservoir dual orifice configuration is used. This is done for various actuators having different orifice separation distances and impingement angles.

To obtain comparative data ("one pot"), the same formulation was used. The formulation was delivered through a conventional actuator with an orifice of 0.22mm diameter. A conventional single reservoir MDI has a 50 mul valve. The comparative data gave an MMAD of 1.3 μm for the BDP formulation and 3.1 μm for the budesonide formulation for comparison.

The drug delivery characteristics obtained with the aid of the test rig for the dual reservoir dual orifice MDI system are shown in table 13. The orifice diameter is also allowed to vary. Table 14 and fig. 32 show the drug delivery characteristics for the dual-reservoir dual-orifice MDI system compared to the comparative data obtained for the single-reservoir single-orifice MDI system.

Table 13: effect of separation distance and impingement Angle on MMAD

Table 13 demonstrates that orifice distance and impingement angle affect drug delivery characteristics. The desired characteristics can be obtained by setting the orifice distance and impingement angle.

As shown by table 13, at an impingement angle of 60 °, the MMAD becomes more similar as the separation distance decreases, indicating that mixing does occur after the orifice.

At an impingement angle of only 15 °, even at small separation distances, the mixing becomes less effective. This smaller impingement angle of 15 ° means that the plumes exit from the orifice for further impingement. Thus, the plume has more time to atomize and spread before impinging and mixing.

As the separation distance decreases, the actuator deposit also decreases: at a collision of 15 ° and a separation of 6.0mm, the actuator deposit was comparable to that of a standard actuator (6.1 μ g for BDP and 5.9 μ g for budesonide). However, as the separation distance changes, there is a reverse relationship between the actuator and the suction port deposits.

Example 14b

To assess how effective the dual orifice delivery is due to mixing of the plume after the orifice by releasing both formulations simultaneously, or whether it is due in part or in whole to other factors such as impingement on one side of the mouthpiece and inhalation port, a single dose of budesonide (50 μ g/25 μ l) was delivered by a test rig in a dual orifice dispensing system using only a single canister.

Fig. 32 and table 14 show that for single canister delivery, the actuator deposit is approximately doubled compared to dual delivery with two canisters, since the second plume has no opposing force directing the flow toward the mouthpiece opening.

However, actuation of the single canister by this system also reduced the intake port and deposits on stages 0, 1, 2 and 3, effectively reducing the MMAD from 2.9 μm (from dual delivery data with ultra-fine formulation) to 2.3 μm. The FPD was almost identical (see Table 14, 15.4. mu.g and 15.6. mu.g).

Table 14: dual reservoir dual orifice: single canister delivery to dual canister delivery

Example 15

This example demonstrates how the PSD of one formulation can be affected by delivering a second formulation simultaneously when using a dual orifice and single orifice configuration.

For the single orifice configuration, formulations 9 and 12 (see example 6) were ejected through the test rig in the single orifice configuration, which corresponds to a single orifice actuator having a nozzle orifice diameter of 0.30 mm. For the dual orifice configuration, formulations 9 and 12 (see example 6) were ejected through the test rig in the dual orifice configuration, which corresponds to a dual orifice actuator with a nozzle orifice diameter of 0.25mm, an impingement angle of 60 °, and a nozzle separation distance of 6.0 mm.

Comparative data were obtained by firing BDP and budesonide formulations separately through a conventional actuator of a single reservoir MDI system. The nozzle orifice diameter was 0.22 mm.

The delivery feature is shown in fig. 33. Data obtained with a single nozzle orifice for a dual reservoir MDI is indicated by "single orifice". The data obtained with a dual orifice configuration for a dual reservoir MDI is indicated by "dual orifice". The comparison data is indicated by "pMDI, 0.22 mm".

Delivery through a single orifice with a diameter of 0.30mm resulted in the MMAD of the two different formulations becoming nearly identical (2.8 μm for BDP formulation 9 and 2.9 μm for budesonide formulation 12).

The same degree of mixing does not occur through the dual orifice. The MMAD for the BDP ultra-fine formulation shifted from 1.3 μm (data obtained for conventional MDI) to 2.3 μm, and the MMAD for the budesonide formulation shifted from 3.1 μm (data obtained for conventional MDI) to 2.9 μm. This trend is similar to that seen for single orifice delivery: the MMAD of the BDP ultra-fine formulation was further moved towards the MMAD of the budesonide formulation. This demonstrates that glycerol can be used to significantly modulate particle size.

Comparison shows that although no mixing occurs after the orifice, in order to produce the same PSD, or a very similar PSD, from two different formulations, an actuator design should be chosen that starts mixing right in the groove.

An advantage of the dual orifice system is that the PSD and MMAD can be optimized to any desired combination by suitably selecting a combination of the following three variables: orifice diameter, impingement angle, and separation distance. It is not always necessary to set each of the three parameters appropriately, but it is sufficient that one or both of the indicated parameters can be adjusted to obtain the desired PSD and MMAD. For purposes of illustration, three variables may be set to minimize the effect of one plume on another in order to keep the PSD different.

Example 16

In this example, the formulations are delivered simultaneously from the dual reservoirs through the dual orifices (fig. 34 and 35). The two formulations used were:

formulation commercially available from Clenil Modulite 21: BDP (250. mu.g/actuation), ethanol, glycerol, HFA134a

Commercial formulation 22 of Ventolin Evohaler: salbutamol sulphate (100. mu.g/actuation), HFA134a

Formulation 21 is a solution formulation and formulation 22 is a suspension formulation.

For delivery in a dual reservoir dual orifice configuration, the test rig is used with a dual orifice configuration. The configuration of the dual-reservoir dual orifice corresponds to the configuration shown for the actuator generally as shown in fig. 17B. Measurements for two different orifice distances (6 mm and 10 mm) were performed. An impingement angle of 15 deg. is chosen to reduce plume interaction. The orifice used to deliver formulation 21 (Clenil) had a diameter of 0.30 mm. The orifice used to deliver the formulation 22 (Ventolin) had a diameter of 0.50 mm. The comparison data was obtained by firing the corresponding formulations 21 and 22 by a conventional actuator, which is an MDI actuator having a reservoir and an orifice. For formulation 21, the actuator had a nozzle orifice diameter of 0.30 mm. For formulation 22, the actuator had a nozzle orifice diameter of 0.50 mm.

Fig. 34 shows the drug delivery characteristics for formulation 21 when formulation 21 (Clenil) is delivered with formulation 22, with two different orifice separation distances of 10mm and 6mm, respectively. Fig. 35 shows the drug delivery characteristics for formulation 22 when formulation 22 (Ventolin) is delivered with formulation 21 with two different orifice separation distances of 10mm and 6mm, respectively.

When two formulations were delivered simultaneously, the PSDs of the two formulations, particularly the PSD of formulation 21 (Clenil), closely matched the comparative data obtained using a single-reservoir single orifice actuator. The FPD of the Clenil formulation decreased with decreasing separation distance (from 41.3 pg at an orifice pitch of 10.0mm to 37.6 pg at an orifice pitch of 6.0 mm; comparative data: 55.6 pg). As the separation distance increases, the actuator and suction port deposits increase. Similar results were observed for Ventolin: the FPD was reduced from 16.8. mu.g at an aperture pitch of 10.0mm to 15.9. mu.g at an aperture pitch of 6.0mm (comparative data: 35.9. mu.g).

At both separation distances, the MMAD decreased from 3.4 μm for the comparative data (single reservoir single orifice) to 3.3 μm for the dual delivery, with no significant change in MMAD. The slight reduction can be explained by the effect of Ventolin on the additional HFA added to the plume, which would promote atomization.

Example 17

In this example, two formulations 21 and 22 are delivered simultaneously from dual reservoirs through a single orifice (see example 16). The nozzle orifice diameter was 0.30 mm.

Comparative data was obtained in the same manner as described with reference to example 16. That is, using an MDI with a conventional single reservoir single orifice configuration, the orifice diameters were 0.30mm (formulation 21) and 0.50mm (formulation 22), respectively.

Fig. 36 and table 15 show delivery characteristics. As shown in fig. 36, the mixing of the two formulations resulted in a shift in MMAD from that of the traditional MDI, which was similar to the effect of mixing the two solution formulations.

The MMAD of formulation 21 (Clenil Modulite) decreased from 3.4 μm to 3.0 μm (table 15) due to the increased atomization produced by the HFA delivered by formulation 22 (Ventolin). The FPD also increased from 56 μ g to 86 μ g. This is similar to the effect seen in example 12, where HFA was used to facilitate the atomization of high ethanol solutions. The MMAD of the Ventolin formulation increased from 2.9 μm to 3.3 μm because the glycerol in the Clenil formulation increased the size of the particles produced.

Table 15: dual reservoir single orifice delivery of formula 21 (Clenil Module) and formula 22 (Ventolin)

Example 18

In this example, a test stand in a dual reservoir single orifice configuration is used to co-administer a combination product (a commercial Fostair, a formulation containing a steroid (BDP) and a β 2 agonist with glycopyrrolate (formoterol) that acts on a muscarinic receptor) simultaneously with Glycopyrrolate (GP), a receptor antagonist of muscarinic. Different glycopyrronium bromide formulations have been used. The same configuration as in example 17 was used, having an orifice diameter of 0.30 mm.

Combination (commercial Fostair): BDP/FF (100/6 μ g/min), ethanol, HCI (1M), HFA134a

Formula 23: glycopyrrolate (25. mu.g/actuation), 12% w/w ethanol, HFA134a

Formula 24: glycopyrrolate (25. mu.g/actuation), 12% w/w ethanol, 0.144% w/w glycerol

Formulation 25: glycopyrrolate (25 μ g/actuation), 12% w/w ethanol, 0.144% w/w isopropyl myristate (IPM)

For the combined products, comparative data for the combined products were obtained by shooting a dose of the combined product using a conventional commercial single reservoir single orifice actuator having an orifice diameter of 0.30 mm.

Fig. 37 illustrates the delivery characteristics when the combination product is ejected through a single nozzle orifice with one of the formulations 23 to 25. The FPD of BDP and the FPD of formoterol were comparable under control when delivered with super-optimal glycopyrrolate by the actuator of a dual-reservoir single-orifice system. The addition of the non-volatile additive to the glycopyrronium bromide formulation resulted in a slight increase in the MMAD of BDP and the MMAD of formoterol.

The problem with formulations is that it is often difficult to find two actives that are suitable for the same carrier. However, as shown by examples 16-18 and other examples, and as described in detail herein, using the dual-reservoir dual-orifice concept, two such medicaments can be delivered simultaneously. It is also possible to match two separate formulations, such as Clenil Modulite and Ventolin, in performance, resulting in a dual therapy.

Example 19

Two formulations were made using a 16mm valve-can assembly and delivered by the dual reservoir prototype system of fig. 14B:

BDP/formoterol (100. mu.g/6. mu.g/25. mu.l), 12% w/w ethanol, 0.024% w/w HCI (1M), HFA134a to 100% w/w and

glycopyrrolate (12.5. mu.g/25. mu.l), 12% w/w ethanol, 0.019% w/w HCI (1M), HFA134a to 100% w/w.

Fig. 38 illustrates a delivery feature. Fig. 38 shows that the particle size distribution of the formulations was the same as observed when using a test stand with a single orifice piece.

MMAD for all three drugs, which is 1.3 μm, is recorded in table 16. This value was comparable to the data collected using a test rig having a dual reservoir single orifice (0.30 mm) configuration as recorded in example 18 (fig. 37) for the same formulation. However, the FPF for the formulation delivered by the prototype of fig. 14B was larger (44% compared to 30-32%) due to the reduced throat deposits.

Table 16: dual reservoir single orifice prototype

Example 20

For the system shown in fig. 16B with three reservoirs, similar results to those obtained in example 19 were seen in fig. 39. The same BDP/formoterol formulation as used in example 19 was contained in the first container of the system. The same glycopyrronium bromide formulation as used in example 19 was contained in the second container of the system. A third formulation is contained in a third container, the third formulation consisting of:

budesonide (50. mu.g/25. mu.l), 12% w/w ethanol, HFA134a to 100% w/w.

Fig. 39 illustrates a delivery feature.

In Table 17, the MMAD is similar, but not identical, the MMAD is in the range from 1.2 μm to 1.5 μm. However, due to the fact that three valve springs can increase the force required to depress the canister in the triple prototype, there will be minor differences in the actuation timing of the cartridge which can affect the mixing process of the emitted aerosol cloud.

Table 17: three reservoir single orifice prototype

Claims

1. A metered dose inhaler, comprising:

at least one vessel comprising a first reservoir containing a first formulation and a second reservoir different from the first reservoir containing a second formulation, and

an actuator for receiving the at least one vessel, the actuator having an actuator block,

the metered-dose inhaler configured to be actuatable when the at least one vessel is received by the actuator and configured to simultaneously deliver at least a first metered dose of the first formulation from the first reservoir and a second metered dose of the second formulation from the second reservoir when the metered-dose inhaler is actuated, wherein the first formulation is a first pressurized aerosol formulation and the second formulation is a second pressurized aerosol formulation,

it is characterized in that

The actuator includes a guide member defining a passage for at least a first metered dose and a passage for a second metered dose, and an outlet orifice of the guide member is in fluid communication with the actuator block, at least one of the first and second formulations being selected such that a particle size distribution of at least the other of the first and second formulations is adjusted by mixing the first and second metered doses, wherein:

a single nozzle orifice is formed in the actuator block, and the first and second metered doses are mixed prior to aerosolization at the nozzle orifice.

2. The metered-dose inhaler of claim 1, comprising

A first metering system for metering said first metered dose and a second metering system for metering said second metered dose, and

actuation means for effecting simultaneous actuation of the first and second metering systems upon actuation of the metered dose inhaler when the at least one vessel is received by the actuator.

3. The metered-dose inhaler of claim 1,

the nozzle orifice is for aerosolizing both the first metered dose and the second metered dose upon actuation of the metered dose inhaler.

4. The metered-dose inhaler of claim 3,

the at least one vessel having a valve stem for supplying the first metered dose from the first reservoir and the second metered dose from the second reservoir,

the actuator has a seat for the valve stem, the nozzle orifice being in communication with the seat for the valve stem.

5. The metered-dose inhaler of claim 3,

the at least one vessel having a first valve stem for supplying the first metered dose and a second valve stem for supplying the second metered dose,

the actuator has a first seat for receiving the first valve stem and a second seat for receiving the second valve stem, the nozzle orifice being in communication with both the first seat and the second seat.

6. The metered-dose inhaler of claim 1,

the at least one vessel includes a vessel having a first compartment defining the first reservoir and a second compartment defining the second reservoir.

7. The metered-dose inhaler of claim 6,

the second compartment is formed by a cartridge arranged in the interior of the vessel.

8. The metered-dose inhaler of claim 1,

the at least one vessel includes a first vessel defining the first reservoir and a second vessel defined the second reservoir formed separately from the first vessel.

9. The metered-dose inhaler of claim 1,

at least one of the first and second formulations is selected such that the fine particle dose after atomization of at least the other of the first and second formulations is adjusted by mixing the first and second metered doses.

10. The metered-dose inhaler of claim 1,

the at least one vessel includes a third reservoir containing a third formulation,

the metered-dose inhaler is configured to simultaneously deliver the first metered dose of the first formulation, the second metered dose of the second formulation, and a second metered dose of the third formulation from the third reservoir when the at least one vessel is received by the actuator.