GB2461752A - Metered dose inhaler with vortex device - Google Patents

Abstract

The present invention relates to metered dose inhalers for the administration of active medicaments/propellants and excipients. The invention provides a pMDI inhaler comprising a pMDI canister 22, a vortex device, an integral horn and a breath-activated mechanism 26, 28, 34 wherein the canister contains a formulation comprising a combination of two or more active ingredients. Proposed active ingredients include beta agonists, inhaled corticosteroids and anticholinergics. The integral horn may have a shape which widens towards the mouthpiece, thus reducing the aerosol flow velocity.

Description

METERED DOSE INHALER

This invention relates to metered dose inhalers for the administration of active medicaments/propellants and excipients from pressurised aerosol cans (pressurised Metered Dose Inhalers) such inhalers are commonly termed, "pMDIs" and, more particularly, to metered dose inhalers for the simultaneous administration of mixtures of active medicaments.

There have been many paper proposals for pMDIs but only two basic designs have actually achieved any extended use. In the first of these, an example of which is the GSK "Evohaler" (herein "EH"), a pMDI can is mounted in a plastic tubular case with a mouthpiece at one end, commonly known as the actuator. The user inserts the mouthpiece into his mouth and, as he inhales, he depresses the distal end of the can, thus releasing a metered dose of active into the inhaled air.

These devices are relatively simple in construction and, hence, relatively inexpensive to manufacture. However, they are not easy to use and patients often need skilled assistance and training to be able to use them reasonably well (see, for example, Giraud et al. Misuse of corticosteroid metered-dose inhaler is associated with decreased asthma stability. Eur Respir J. 2002 Feb,19(2).246-51; and Cochrane MG, Bala MV, Downs et al. inhaled corticosteroids for asthma therapy: patient compliance, devices, and inhalation technique. Chest. 2000 Feb;117(2):542-50). A major problem is for the user to co-ordinate efficiently his breath intake with release of the active.

To try to deal with this problem, it is known to have a spacer device on the mouthpiece so that the released aerosol passes into the spacer from which the patient can inhale it (see, for example, British Guidelines on the management of bronchial asthma. BTS/SJGN July 2007 update; and Expert Panel Report 3 (EPR-3): Guidelines for the Diagnosis and Management of Asthma-Summary Report 2007, The Journal of allergy and clinical immunology 2007 Nov, 120(5 Suppl):S94-138.). The use of a large spacer is generally very effective, but is a nuisance to the user since it is bulky and must be fitted to the pMDI on every occasion for use.

Another approach to assisting with the problem of co-ordination has been to provide breath-actuated inhalers. In these, a patient simply inhales through the mouthpiece of the device and, as inhalation begins, the device automatically releases the drug into the air stream. One example of such a device is "Easi-Breathe" (herein "EB") which may also be used with a small spacer, particularly with Inhaled Corticosteroids.

Both these types of device (ie the EH and the EB) emit the aerosol for inhalation at a flow rate somewhat greater than the normal inhalation flow rate of a patient. A result of this is that the aerosol impacts the back of the patient's throat and some of the medicament, especially larger droplets or particles, will deposit there rather than passing into the lungs. This undesirable effect can be obviated if a large spacer is used with EH, but the small spacer of EB does not slow the gas flow very much. High gas flow emission resulting in some deposition of medicament in the throat is not only uncomfortable for patients but also, in the case of actives such as steroids, can lead to very undesirable side effects, local and systemic.

It has been proposed to slow down the exit flow rate of a pMDI by including a vortex-producing device in the gas flow path (see eg EP 0308524B) together with an integral horn outlet from the vortex device, so that the net result is that any tendency in the aerosol for particle agglomeration is reduced in the vortex, and the final exit flow rate from the horn is very low. In this way, throat deposition can be much reduced due both to the low exit flow rate and to the reduced quantity of larger particles in the inhaled aerosol. In such pMDIs, separate spacers are not required since it has been shown that the same clinical effect is obtained with these pMDIs as when a conventional pMDI is used with a spacer (Menzies et al. An in vitro and in vivo comparison of irthaled steroid delivery via a novel vortex actuator and a conventional valved holding chamber. Ann Allergy Asthma Immunol. 2007:98:471-479).

A further proposal which has been made is to provide a pMDI which, in one unitary device, includes a combination of a vortex device, a horn and breath-actuation means in order to try to combine the advantages individually attributable to the various components. Examples of such proposed inhalers are shown in our WO 2005/007226 and WO 2007/066140, to which reference should be made for further details. These novel pMDI inhalers are known as "SYNCHRO-BREATHE" inhalers (herein "SB").

("SYNCHRO-BREATHE" is a trade mark.) We have now been able to investigate the use of SB inhalers by testing them in a variety of critical conditions and have found them to be, very surprisingly, much more advantageous than the prior known devices, with and without their associated spacers.

For example, Nair et al (British Journal of Clinical Pharmacology, (July 2008, Vol 66, Issue 1, pages 20-26) describe an in.vivo study in mild to moderate asthmatics to compare the respirable dose delivery of hydrofluoralkane fluticasone propionate (HFA-FP) via an optimally prepared Aerochamber Plus spacer (AP), via an SB device, and via a pMDI EH. It was found that the use of the optimally prepared AP and the use of the SB device, when compared to the EH device, both significantly increased respirable dose of HFA-FP. Whilst according to the particular criteria used in this in vivo study, the improvement in respirable dose was numerically greater for the AP then for the SB device, over the EH device, several factors need to be borne in mind in comparing the pMD1/AP combination with the SB. Firstly, considerable effort was made to ensure that the AP spacer was used under optimal conditions (spacer pre-washed and primed to reduce electrostatic charge, as well as using single puffs without inhalation delay), and in practical use patients rarely if ever make these preparations before use of the spacer. Thus, it is very likely that the spacer will operate much less efficiently in ordinary usage than in this study. Secondly, the requirement for the patient to carry round a spacer for occasional use by assembly with their pMDI is a considerable nuisance to the patient (and, in the case of children, to their parents), whereas there is no such problem with an SB device. For these and other reasons, the SB device is highly advantageous not only over a conventional pMDI such as EH, but also over a pMDI/spacer combination such as pMDI/AP spacer. Reference should be made to the Nair et al paper above for further details.

It is well established that there can be significant differences in the in vitro drug delivery characteristics (e.g. Andersen Cascade Impactor test results) between different pMDI's, different spacers and different inhalation drugs. The fact that one particular pMDI device gives good in vitro results with one particular medicament does not mean that the same pMDI will give similarly good in vitro results with another different medicament, nor that the same medicament will necessarily be successful in in vitro tests with a different pMDI. The same is equally true of the use of different pMDI/spacer combinations.

Furthermore, and very importantly, whilst in vitro tests can serve as a guide to likely in vivo test results, they are not a totally reliable guide. Superior in vitro test results do not necessarily mean that better in vivo clinical results will be obtained.

Furthermore, we have found that the excellent in vivo results obtained with FP in SB (as referred to above) were certainly not expected in light of the in vitro results. The in vivo results showed the SB to be far more advantageous than the in vitro results indicated.

It is known to administer a combination of the corticosteroid fluticasone propionate (FP) and the long-acting beta-agonist salmeterol xinafoate (SM) using a conventional pMDI inhaler such as EV. This use of so-called combination inhalers provides the dual benefit of targeting airway inflammation and bronchodilation with a single device, thus potentially encouraging patient compliance. This use of combination inhalers (with or without spacers) results in clinically relevant improvements in symptoms, lung function, and exacerbations, and is superior when compared to doubling the dose of inhaled corticosteroid in asthmatics.

We have now found that, in in vivo tests, the use of an SB device surprisingly results in commensurate increases in the respirable drug delivery of both or all the moieties in a mixture thereof such as FP/SM, for example, compared to a conventional EV pMDI device alone. It is surprising to find that, with the SB device, the respirable dose delivery of both or all the medicaments in a mixture is simultaneously improved.

A significant potential advantage of this is that it enables a clinician to reduce the overall dose of actives administered, thereby increasing the so-called benefit/risk ratio'.

In one aspect, therefore, the invention provides a pMDI inhaler which includes a pMDI canister, a vortex device, an integral horn and a breath-activating mechanism, wherein the canister contains a formulation comprising a combination of two or more active medicaments.

The inhalers of the invention contain a conventional pMIDI canister mounted to release a metered dose of its contents, upon actuation, into a vortex-generating device to generate turbulent vortices in the flowing aerosol. Examples of such devices and their use in pMDI inhalers are given, for example, in EP 0308524A. A very important effect -5-.

of the vortex-formation is to reduce any tendency for larger particles or droplets to form in the aerosol.

The aerosol then passes into one end of an integral horn, the other end of which forms the mouthpiece for the inhaler. The shape of the horn is such as to widen towards the mouthpiece end, thus effectively significantly reducing the flow rate of the aerosol.

At the mouthpiece end, the aerosol will have a low exit flow rate. To this extent, the horn replaces the spacers used with previous devices, and since the horn is an integral part of the inhalers of the invention and of relatively small size, there are significant advantages to the patient in portability and use of the inhaler. There are many suitable shapes and arrangements of horn which may be used. Some are shown, by way of example only, in our WO 2005/007226, WO 2007/066 140 and in Fig. 7 of EP 0308524.

The SB inhaler also includes a breath-actuating mechanism so that release of the metered dose of medicaments occurs in response to initiation of intake of breath through the horn by the user. There are many possible breath-actuation arrangements for pMIDI inlialers: examples of suitable arrangements are shown, for example, in our The advantages of the present invention are obtained with any combination of medicaments to be administered by pMDI. The invention is thus useful, for example, with combination products of an inhaled corticosteroid (ICS) and a long-acting beta-agonist (LABA). Examples of ICS include beclomethasone, budesonide, ciclesonide, fluticasone and mometasone, and examples of LABA include formoterol and salmeterol. A particularly preferred combination is that of fluticasone and salmeterol (FP/SM). Such mixtures are marketed in pMDI canisters by GSK under the trade mark "Seretide". They comprise fiuticasone propionate and salmeterol xinafoate in HFA-134a propellant. The invention is also useful, for example, with combination products of a short-acting beta-agonist (SABA) and an anticholinergic (AC). Examples of SABA include salbutamol, terbutaline and fenoterol, and examples of AC include ipratropium and tiotropium. The invention is also useftil, for example, with triple combination products of, for example, ICS/LABA/AC. Specific examples include fluticasone/salmeterol/tiotropium and budesonide/formoterol/tiotropium.

The SB inhalers of the invention are not only generally very acceptable to patients for the administration of the inhaled mixture of medicaments, but they are also extremely effective in achieving lung deposition. Indeed, tests have shown that lung deposition can be very significantly improved compared with conventional devices.

The achievement of improved lung deposition has a number of advantages. For example, firstly the treatment will generally be more effective the greater the lung deposition. Secondly, greater lung deposition from an administered dose gives the possibility of administering a lower dose whilst still achieving conventional levels of lung deposition. Administration of lower doses in itself is advantageous in minimising side effects, especially with steroids.

Accordingly, in a further aspect, the invention provides the use of the SB inhalers of the invention to administer simultaneously a mixture of medicaments, such as fluticasone and salmeterol, to achieve improved lung deposition per dose of medicament.

In order that the invention may be more fully understood, the following experimental results are given.

Experimental Results An in vitro (Andersen Cascade Impactor) test was carried out, using EV and SB, with pMDI containing a fluticasone 250 tg/salmeterol 25 j.tg combination suspended in HFA propellant. In these tests, the fluticasone moiety showed a fine particle dose of 93.4 ig in EH, and 113.1 ig in SB. The salmeterol moieties were 9.8 jig in EV and 11.0 jig in SB. This represents a 21% improvement in SB over EV for fluticasone and a 12% improvement in SB over EV for salmeterol.

An in vivo deposition study was carried out in healthy volunteers using a randomised double blind, double dummy crossover design. Single doses of placebo or "Seretide" HIFA 250 (total dose ex-valve: fluticasone 2000 mcg/salmeterol 200 mcg) were administered via SB, EH and via a 750 ml plastic spacer "Volumatic" (VM). As there is no absorption of fluticasone from the gut, any absorption detected in the systemic circulation will by definition solely reflect the lung bioavailability, which is in turn determined by the dose delivered to the lungs. The degree of lung bioavailability of fluticasone may be reliably quantified by measuring the amount of adrenal suppression relative to baseline, as measured by the ratio for overnight urinary cortisol/creatinine (OUCC) excretion, ie the lower the ratio of suppression, the greater the lung deposition for a given device. The swallowed fraction of salmeterol contributes to 28-36% of its systemic bloavailability, so its systemic bioavailability depends predominantly, but not entirely, on lung absorption. It is measured as serum potassium. Baseline serum K was collected and was repeated one hour post study drug inhalation to measure the early fall in K (which predominantly reflects lung rather than gut absorption). The results showed that SB resulted in a commensurate increase in the respirable drug delivery of both moieties of FP/SM in combination versus EH alone, and was comparable to the 750 ml large volume plastic Volumatic spacer. In particular, the geometric mean fold suppression ratios for fiuticasone were: IEH 1.51, VM 2.52, SB 2.66, equating to 33.8%, 60.2% and 62.3% suppression, respectively. The falls in K were: EH -0.09, VM -0.27, SB -0.32, equating to 2.2%, 6.8% and 8.06% falls, respectively. There were no significant differences between SB and VM but the differences between SB and EH were significant. Thus, when compared to the EH pMDI, the SB device resulted in 1.75 geometric mean fold greater suppression of OUCC 95% CI and a 0.23 mmol/l greater fall in K 95% CI (equating to a 43% and 6% greater fall in OUCC and K, respectively). Similarly, when compared to EH, pMDI, the geometric mean fold suppression in OUCC with the VM spacer was 1.66 and the arithmetic mean fall in K was 0.18 mmol/l (equating to a 39.9% and 4.7% greater fall in OUCC and K, respectively).

In the above tests, the EH pMDI and the Volumatic spacer were both employed under optimal conditions using the correct techniques which is an unlikely eventuality in real life. Therefore, it is likely that the performance of a new unwashed VM device with multiple puffs and a delayed actuation-inhalation sequence will be less efficient due to effects of static charge, when compared to the optimal used in the above study.

Thus, the observed differences between the pMDI and the Volumatic spacer are probably greater than would be seen in day-to-day clinical practice. In this regard, the SB device is breath-actuated and is not influenced by static as are plastic holding chambers, so that the observed improvements in respirable dose delivery are likely to be at least the same, if not greater, in real life due to inherent problems with pMDI coordination.

Embodiments of SB device suitable for use in the present invention will now be described, by way of example only, with reference to the accompanying drawings, wherein: FIG. IA is an exploded view of the upper portion and dose counter of an embodiment of the present invention FIG. lB is an exploded view of the lower portion of the embodiment of FIG. 1A, including the release mechanism.

FIGS. 2A-C are perspective views of the exterior housing of the embodiment of the inhaler of FIGS. lA-B in a fully assembled configuration.

FIG. 3A is a cross-sectional view detailing the release mechanism of the present invention in a stowed configuration.

FIG. 3B illustrates the device of FIG. 3A with the flap rotated as a result of inhalation forces.

FIG. 3C illustrates the device of FIG. 3A with the collapsible knee in a collapsed configuration and the fluid source discharged.

FIG. 3D illustrates the device of FIG. 3A with the flap returned to the stowed position and the collapsible knee still in a collapsed configuration.

FIG. 3E illustrates the device of FIG. 3A with the release mechanism returned to its stowed configuration.

FIG. 4A is a perspective view of an embodiment of the flap of the present invention.

FIG. 4B illustrates a cross-sectional schematic view the flap of FIG. 3A with the lower linkage retained by the flap in the stored configuration.

FIGS. 5A-B show schematic views of the flap and transducer of the present invention.

FIG. 6A is a perspective view of an embodiment of the transducer of the present invention.

FIG. 6B illustrates a cross-sectional schematic view the transducer of FIG. 6A with the fluid source in a stowed configuration.

FIG. 7A is a cross-sectional view detailing the release mechanism of the present invention in a stowed configuration and the dust cover cut out to show the release mechanism.

FIG. 7B illustrates the device of FIG. 7A with the dust cover rotated away from the horn and the release mechanism in the stowed configuration prior to breath actuation.

FIG. 7C illustrates the device of FIG. 7B with the release mechanism in the discharged configuration after breath actuation.

FIG. 7D illustrates the device of FIG. 7B with the cam of the dust cover driving the release mechanism back to the stowed configuration.

FIG. 8A is a cross-sectional view of the outer cover of the device to illustrate the dose counting mechanism of an embodiment of the present invention in a stowed configuration.

FiG. 8B illustrates the device of FIG. 8A with the container sleeve traveling part way through the discharge of the fluid source.

FIG. 8C illustrates the device of FIG. 8A with the container sleeve at the fully discharged configuration.

FIG. 8D illustrates the device of FIG. 8A with the container sleeve returning to the stowed position.

FIG. 9 is a schematic view of the container sleeve and biasing spring of the present invention.

FIG. 10 illustrates an embodiment of the dose counter wheel of the present invention.

FIGS. 1 lA-C illustrate an embodiment of the display wheel of the present invention.

FIGS. 12A-E are schematic views of the dose counter wheel and display wheel through various counting configurations.

FIG. 13 is a cross-sectional view of an alternative embodiment of the present invention having a release mechanism using a diaphragm.

FIG. 14 is a perspective view of an alternative embodiment of the present invention having a release mechanism above the fluid source.

FIG. 15 is an exploded view of the device of FIG. 14.

FIGS. 16A-D are schematic views of the device of FIG. 14 traveling trough its range of motion from the stowed position, to discharge position, back to the stowed position.

FIG. 17 illustrates the device of FIG. 14 having an electronic dose counter.

FIG. 18 is an alternative embodiment of the present invention with a portion of the outer cover removed to show the release mechanism and a mechanical dose counter with a vertically mounted display wheel.

FIGS. 19A-B illustrate the release mechanism of the device of FIG. 18.

FIGS. 20A-B illustrate the dose counter of the device of FIG. 18.

FIGS. 2 lA-F illustrate a further embodiment of the dose counter through one breath actuation cycle.

FIGS. 22A and B illustrate perspective views of the dose counter of FIGS. 21A-F. FIG. 23 shows a top view of the dose counter of FIGS. 2 lA-F.

FIG. 24 A-D illustrates motion of a breath actuation mechanism using a trip link.

Referring more specifically to the drawings, for illustrative purposes the present invention is embodied in the apparatus generally shown in FIG. 1A through FIG. 24D.

It will be appreciated that the apparatus may vary as to configuration and as to details of the parts, and that the method may vary as to the specific steps and sequence, without departing from the basic concepts as disclosed herein.

Referring first to FIGS. 1A and 1B, an inhaler 20 of the present invention is shown in an exploded view with a breath actuation assembly 100 and a dose counter assembly 130. The breath actuation assembly 100 and the dose counter assembly 130 are housed along with rnedicament fluid source 22 inside front cover 42, back cover 44, and top cap 54, all preferably comprising medical grade plastic or other suitable materials known in the art. Fluid source 22 may comprise a conventional Metered Dose Inhaler (MDI) container comprising a mixture of two or more active medicaments in a propellant. Fluid source 22 generally comprises container 108 holding the mixture of medicaments and propellant, and nozzle 110, which is in line with the discharge axis 86 of the container 108, as shown in FIG. 6B. When the container 108 is advanced relative to the nozzle 110 in the direction of the discharge axis 86 (i.e. the nozzle 110 is pushed into the container 108), the medicament is discharged out the nozzle 110 in the direction of the discharge axis 86.

Turning now to FIGS. 2A through 2C, inhaler 20 is shown in an assembled configuration with dust cover 40 pivotally mounted to cover inhalation horn 58. The dust cover 40 may be rotated away from horn 58 to expose opening 60, as shown in FIG. 2B. A manual release button 62, as shown in FIG. 2C, may also be incorporated into the back cover 44. Top cap 54 has an opening 56 to give visual access to display wheel 52.

Referring also to FIGS. lB and 3A through 3E, the breath actuation assembly comprises a housing or transducer 32 that rotatably houses lower link 28 at pivot 78. Lower link 28 is connected to upper link 26 at collapsible joint 66. Reference may also be made to FIGS. 5A-6B, wherein the transducer is illustrated in greater detail.

Container holder 24 is shaped to receive the nozzle end of container 108 such that the nozzle 110 passes through to contact surface 112 of the transducer 32. Container holder 24 also has a pair of guides 122 having slots 90 sized to house a pair of bosses 92 as shown in FIG 7A at the upper end of upper link 26.

As shown in FIGS. 3A through 4B, flap 34 is rotatably mounted to the transducer 32 via peg 98, which extends across the top surface of flap 34, and holes 114 in the sidewalls of transducer 32. The bottom and side extremities of flap 34 are sized to fit within the internal surface of transducer 32 to form gap 76. The flap 34 has an upper restraining surface 72 configured to retain arm 74 of lower link 28 when the flap is in its nominal position shown in FIG. 4B.

As illustrated in FIGS. 6A and 6B, the transducer 32 is configured to receive nozzle 110 of fluid source 22 at surface 112. The transducer also comprises an inlet 106 that spans from surface 112 to a first chamber 102. The inlet 106 is configured to be in line with the nozzle 110 and discharge axis 86 such that medicament discharged from the fluid source 22 is received through the inlet 106 and downstream into first chamber 102.

The transducer 32 is also configured to receive plug 38 having bluff surface 104.

Fluid entering chamber 102 through inlet 106 is dispersed and redirected by plug 38 and into outlet 124 that terminates downstream at section 68 of second chamber 64. The fluid dispersion characteristics of transducer 32 can be seen in greater detail with reference to U.S. Patent 4,972,830 and EP308524B, which are expressly incorporated by reference herein.

The fluid source 22 is biased to discharge along axis 86 by compressing a loading member, such as biasing spring 48, between the top cap 54 and container sleeve 46, which is adapted to receive the other end of the container 108 opposite the nozzle 110. Biasing spring 48 preloads the container 108 to move in the direction of surface 112 of transducer 32 along the discharge axis 86.

In the stowed configuration shown in FIG. 3A, the fluid source container 108 is retained from translating along axis 86 by a collapsible linkage comprising upper link 26 and lower link 28. Upper link 26 and lower link 28 are rotatably coupled at a collapsible knee-type joint 66. The upper end of upper link 26 has a pair of bosses 92 that are retained by a pair of guides 122 in the container holder 24 having slots 90. The guides are generally in-line, or at least parallel with the discharge axis 86, and allow motion of the bosses 92 (see FIG. 7A) of the upper link to slideably translate upward and downward in the discharge axis 86, as well as allow the boss to rotate as necessary.

The lower link 28 has one end fixed to the transducer 32 at pivot 78. As illustrated in FIG. 3A, the boss 92 of the upper link 26 and pivot 78 of the lower link are essentially in-line with discharge axis 86, i.e. they form a loading path that is parallel to, or aligned with the discharge axis 86. Because collapsible joint 66 is off-centre, i.e. positioned away from the loading path formed by the boss 92 of the upper link 26 and pivot 78, the downward force imposed by biasing spring 48 on the container 108 in the stowed position predisposes the knee joint 66 to collapse. Such collapse is restrained in the stowed position by imposition of arm 74 of lower link 28 on flap 34.

FIG. 3B illustrates the initiation of the breath actuation mechanism 100 caused by inhalation by a patient through theopening 60 of horn 58. As shown in FIGS. 3B-3C and 4A, an outward airflow 80 is created in the second chamber 64, which pulls through a plurality of slots 70 in the transducer. Suction of air through slots 70 creates a small pressure differential 82 across the inner surface of flap 34, causing the flap to rotate about peg 98 and into the cavity of the transducer 32, as illustrated in FIGS. 3A and 3B.

The gap 76 between the flap 34 and the transducer 32 provides enough clearance to allow the flap to rotate into the cavity of the transducer, while also being small enough to allow a pressure differential with minimal suction on the horn. As the flap 34 rotates, arm 74 of the lower link 28 is no longer retained by the upper surface 72 of the flap, and the arm 74 clears the flap 34 through recess 88 as the lower link 28 is allowed to rotate about pivot 78.

With rotation of the lower link 28 as shown in FIG. 3C, the collapsible joint 66 moves over centre, allowing the container holder 24 and container 108 to translate downward along axis 86, forcing a portion of the nozzle 110 into the container 108 to stimulate discharge of the medicament from the container 108. The medicament travels through the first chamber 102 and into the second chamber 64 where it is entrained with air flowing through slots 70, as described in further detail in U.S. Patent 4,972,830, previously incorporated by reference. In the embodiment shown, the second chamber 64 has an internal cross section that is shaped like a parabola. The entrained medicament flows through the second chamber 64 and out of the opening 60 of horn 58 to be inhaled by the patient. Therefore, the release of the metered dose of medicament is timed to be inhaled by the patient at an optimal moment during the inhalation phase of the patient's breath cycle.

After the inhalation of the dose by the patient, the tiap is returned to its nominal position shown in FIG. 3D by a return force exerted by flap spring 36. Flap spring 36 is a metallic rod or wire assembled between retention arms 96 of the transducer 32 and flange 94 on the flap 34. Rotation of the flap bends the spring to create a return force to return the flap 94 to its nominal position after the inhalation forces have subsided.

The upper and lower links 26, 28, container holder 24, and container 108 remain in the collapsed discharge position as seen in FIG. 3D due to the force imposed by the biasing spring 48. The return of the dust cover 40 (described in greater detail with reference to FIGS. 7A-7E below) to cover the horn 58 manually forces the container holder 24 and container 108 to return to the stowed position under compression from biasing spring 48. Return torsion spring 30 is mounted on lower link 28 to engage the transducer 32 such that a torsional force is exerted on the collapsible linkage to return to the locked configuration. The collapsible joint 66 is thus retained from collapsing once the dust cover 40 is again opened.

Turning to FIGS. 7A-7E, the operation of the dust cover 40 will now be described. In the present embodiment, the dust cover 40 not only serves as a shield to cover horn entrance 60, but it also serves to reset the container to the stowed position after discharge of the medicament. FIG. 7A illustrates inhaler 20 in a stowed configuration with the dust cover 40 shielding the entrance 60 to horn 58. The dust cover 40 is pivotably connected to the transducer 32 such that it can be rotated out of place to allow access to the horn opening 60. In alternative embodiments, the dust cover may be pivotably connected to either the front or back covers 42, 44. The dust cover 40 has two cams 120, which are configured to engage the bottom surface of guides 122 of container holder 24 through its entire range of motion along axis 86. When the dust cover 40 is rotated about pivot 118 (shown in FIG. 7B), the cams disengage guides 122.

The container holder 24 and container 108 remain in the stowed position from the over-centre orientation of the collapsible linkage.

FIG. 7C illustrates the breath actuation assembly 100 in the collapsed configuration with the container holder 24 and container 108 in the discharge position.

The breath actuation assembly 100 is biased to remain in this configuration due to the compressive force of the biasing spring 48. When the dust cover is rotated back toward the horn opening 60, as shown in FIG. 7D, the cams 120 engage the bottom surface of guide 122, pushing the container holder 24 and container 108 upward along axis 86.

When the dust cover 40 is in its final stowed position covering the horn entrance 60, the cams 120 have pushed the container holder 24 to the stowed position, as shown in FIG. 7A. In this configuration, the return spring 30 has reset the breath actuation assembly 100 to the locked position, and movement of the container 108 will be retained by the dust cover cams independent of the collapsible linkage.

The inhaler 20 preferably includes a dose counter for automatically counting the remaining doses left in the container after each discharge of the rnedicament. The inhaler may be configured with a dose counter having a number of different configurations, including mechanical or electrical counters. The operation of a preferred embodiment utilizing a mechanical dose counter assembly 130 will be described with respect to FIGS. 8A to 12E.

FIG. 8A illustrates inhaler 20 with dose counter assembly 130 configured above the container sleeve 46. The container sleeve 46 is sized to receive the non-dispensing end of the container 108. The container sleeve preferably has one or more tabs 132 having a boss 136 configured to engage the teeth of first wheel 50 disposed just above the container sleeve 46. The embodiment shown in FIG. 9 has two tabs 132 and bosses 136. However, it will be appreciated that any number of tabs and bosses may be employed.

Referring back to FIG. 8A, first wheel 50 is a gear rotatably mounted in a horizontal orientation to top cap 54. Wheel 50 has a plurality of lower teeth 140 and upper teeth 138 disposed along the outer perimeter of wheel 50.

In a preferred embodiment, display wheel 52 is also rotatably mounted to top cap 54 in a horizontal orientation between first wheel 50 and the top cap. Display wheel 52 has an opening 154 to allow clearance for column 142 of first wheel 50 that is vertically disposed to mount to top cap 54. Display wheel 52 has markings 150 to indicate the number of doses left in the container 108 based on the position of the display wheel 52.

As seen in FIG. 2A and 2B, the markings 150 that are showing through opening 56 in top cap 54 indicate the number of remaining doses.

FIGS. 8A-8D illustrate the interaction between the container sleeve 46 and the first wheel 50 upon discharge of the fluid source 22. When the container 108 is in the stowed position, boss 136 lines up on the perimeter of wheel 50 between two of the upper teeth 138. As the container 108 and container sleeve 46 moves downward along the discharge axis as a result of the breath actuation mechanism, boss 136 contacts the upper incline of one of the lower teeth 140, as shown in FIG. 8B. The boss 136 continues its translation along axis 86, forcing the first wheel 50 to turn clockwise (looking down from the top) until the container 108 reaches the discharge position, as shown in FIG. 8C. When the dust cover 40 is closed to return the container 108 to the stowed position, boss 136 translates upward until contacting the lower incline of upper tooth 138, as shown in FIG. 8D. The boss 136 continues its upward translation, forcing the wheel 50 to further turn clockwise until the container 108 reaches the stowed position, shown in FIG. 8A. When another dose is dispensed, the cycle repeats.

The lower wheel 50 may be configured to vary the number of doses required to turn the lower wheel 360 degrees by varying the number of teeth. In the above embodiment, a 40-tooth index was used. However, this number may be varied depending on the number of doses included in the container.

FIGS. 12A-12C illustrate the interaction between the display wheel 52 and the lower wheel 50. As shown in Figure 10 and in hidden line in FIGS 12A-12C, the lower wheel 50 has a drive peg 144 disposed on the upper surface of the lower wheel. Display wheel 52 has a plurality of semi-circular receiving pegs 152 disposed on the lower surface of the display wheel. As first wheel rotates about column mount 142, drive peg 144 engages a first of the receiving pegs 152 and causes the display wheel 52 to rotate about mount 156 a specified distance along mark 150, the specified distance indicating the range of doses left (e.g. "full 200 to 160") (see FIG, 12A). At a portion of first wheel's rotation, the drive peg 144 slips past the first of the receiving pegs 152 (see FIG. 12B) and continues to complete one full rotation (40 doses) until contacting the second of the receiving pegs 152 (FIG. 12C). The cycle repeats itself until all the receiving pegs 152 are driven such that the "empty" indicator is displayed at window 56 when the specified number of doses has been dispensed.

The effect of the gearing as shown in FIGS. 12A-C is to scale the motion of the display wheel 52 with respect to the first wheel 50. To change the scale of the motion, one or more additional driving pegs 144 may be disposed on the upper surface of the first wheel 50. For example, a second driving peg (not shown) may be disposed 180 degrees from the first such that the display wheel would advance twice as fast relative to the first wheel for a container having 100 total doses.

FIG. 13 illustrates an alternative embodiment showing an inhaler having a breath actuated release mechanism 200 using a diaphragm 202 rather than the flap 34 shown in FIGS. 1-7E. The diaphragm 202 is configured to mount to transducer 204 and be sized so that a portion of the diaphragm deflects in response to inhalation forces from the patient. Release mechanism 200 further includes a catch 204 coupled to the diaphragm and the lower link 208 to retain the collapsible linkage comprised of the lower link 208 arid the upper link 210.

During use, inhalation forces from the patient deflect the portion of the diaphragm in communication with catch 204. Motion of the catch 204 allows lower link 208 to rotate past the catch, thereby allowing the 208/2 10 linkage to collapse and discharge fluid source 22.

FIGS. 14-17 illustrate another alternative embodiment of inhaler 300 having a load lever 302 and a breath actuated release mechanism 350 on top of fluid source 22.

By placing the release mechanism above the MDI container, the mechanism can be applied to any MDI actuator with minimal mold modification. Inhaler 300 has a lower portion 304 housing fluid source 22 and a transducer (not shown) for dispersing the medicament. Middle body 308 interfaces with lower portion 304 and slideably houses plunger 318 to selectively advance fluid source 22 downward to discharge the medic ament.

Plunger 318 is retained from moving relative to middle body 308 by a collapsible linkage comprising lower link 320 and upper link 322. Plunger 308 is also configured to receive biasing spring 312 at its up extremity. The biasing spring 312 is shaped to receive spring cap 310 which may be depressed to compress spring 312 against plunger 318 in a downward discharge direction, as shown in FIG. 16A. To depress spring cap 310, load lever 302 is rotatably attached to top shell 306 such that rotation of load lever 302 to a vertical orientation forces the spring cap 310 down to bias the plunger to discharge fluid source 22.

Motion of the collapsible link 320, and linkage 320/322, is restrained by flap 316. Flap 16 is pivotably mounted such that inhalation forces cause it to rotate as illustrated in FIG. 16B, thereby allowing the lower link 320 to rotate downward such that linkage 320/322 collapses. The biasing force from spring 312 forces the plunger downward as illustrated in FIG. 16C. The load lever 302 is then reset to the first position, allowing the fluid source 22 to translate back to the stowed position illustrated in FIG. 16D.

FIG. 17 illustrates an embodiment of the inhaler 300 incorporating an electronic dose counter 324. In such a configuration, flap 316 is coupled to trigger 326, which depresses a sensor in dose counter 324 each time the flap is tripped to dispense a dose of medicament. Dose counter 324 generally comprises a printed circuit board (PCB) and other electronic components such as an LCD to digitally display the dose count.

Alternatively, a mechanical dose counter may instead be incorporated into inhaler 300 in much the same way as the inhaler disclosed in FIGS. 9-12, or FIGS. 21A-23.

Figures 18 through 20B illustrate another alternative embodiment of the present invention with inhaler 400 having a mechanical dose counter 420 that has a vertically mounted display wheel 422. Inhaler 400 has a load lever 402 that manually biases the fluid source 22 discharge upon downward motion.

As illustrated in FIG. 19A, fluid source 22 is retained from discharging by collapsible joint 416, which is formed by the junction of upper link 406 and lower link 408. Lower link is coupled to horizontally oriented flap 410. Inhalation forces on horn 404 cause air flow through port 412 into negative pressure chamber 414 such that a negative pressure is exerted on flap 410 to force flap 410 to rotate downward, as shown in FIG. 19B. With collapsible joint 416 away from the locked position, the fluid source is free to translate downward and discharge the medicament.

Figures 20A and 20B illustrate an alternative embodiment of using a dose counter 420 with a vertically oriented display wheel 422. Container sleeve 426, adapted to receive the non-dispensing end of container 22, has a plurality of protrusions 434.

When the container cycles downward upon discharge, translation of the container sleeve 426 causes protrusions 434 to strike the teeth 432 of gear 424, forcing the gear 424 to rotate clockwise. The clockwise rotation of gear 424 engages vertically oriented sprocket 430 of display wheel 422, causing the display wheel 422 to turn. Sprocket 430 may be configured to engage gear 424 at specified intervals to vary the rate of rotation of the display wheel 422 with respect to the rate of rotation of the gear 424.

Referring to FIG. 2 lA-F, another preferred embodiment is shown as dose counter mechanism 450. The mechanism 450 comprises a canister sleeve 46 which is rotationally constrained, but able to move axially with an MDI canister, and a rotatable top link 452. The top link 452 is coupled to gear column 468 such that gear column 468 rotates incrementally with rotation of the top link. In FIG. 21A, the mechanism 450 is in ready state (prior to breath actuation) with the canister sleeve 46 in the upward-most position in its travel. The canister sleeve 46 has a plurality of teeth 456 that are shaped to mate with and lock with the teeth 454 of the top link 452. In other words, both teeth 456 and 454 have opposing angled surfaces that prevent rotation of the top link 452 with respect to the canister sleeve 46 when engaged. When MDI canister 22 (shown in FIG. 1B) is actuated, the canister sleeve 46 and top link 452 move downward.

A compression load is generated on the top link. 452 from count spring 462, which is disposed between the display wheel 464 and top link 452. The count spring keeps the top link 452 and canister sleeve 46 together, ensuring engagement of the teeth 456, 454. Any other suitable resilient biasing means such as a compressible rubber element could also be used. The top link has a plurality of radial protrusions, or keys 460 around its periphery which are positioned and sized to mate with the columnar tines 458 of cap bottom 466. Cap bottom 466 may be bonded to or integral with top cap 470 (shown in FIG. 22) or a cover piece, such that the tines 458 remain fixed during motion of the canister and the top link 452. As the canister sleeve 46 and the top link move down the opposing inclined surfaces of the key 460 and cap bottom 466 engage, causing the top link 452 to separate from the canister sleeve 46 and allowing the teeth 456, 454 to partially disengage and slide past each other. The top link 452 therefore becomes able to rotate relative to the canister sleeve 46. The opposing angled surfaces of the key 460 and the tines 458 can now slide past one another, causing the top link to rotate 4.5° as seen in FIG 21B.

Referring now to FIG. 21C, the canister sleeve 46 continues to travel downward without further rotation, as the keys 460 of the top link push in between the columnar tines 458 of the cap bottom 466. When the canister sleeve 46 has bottomed out, as shown in FIG. 21D, it will then rebound and then start moving up towards its original ready state positioning, pushing the top link 452 up with it. At this stage the points of the teeth 454 of the top link have passed beyond the points of the teeth 456 of the canister sleeve 46. Further rotation of the top link 452 is prevented by the engagement of the key 460 and the tines 458. As the canister sleeve 46 moves up further, the key 460 clears the tines 458 of the cap bottom 466 as shown in FIG. 2lE. The teeth 456 of the canister sleeve 46 then fully re-engage the teeth 454 of the top link 452, causing the top link 452 to rotate another 4.5° clockwise, as shown in FIG.21F. This completes the full cycle of MDI canister actuation and the indexing mechanism has rotated a total of 9°. The indexing mechanism top link 452 has advanced 1/40th of a full revolution per actuation.

Referring now to FIG. 22A, the dose counter mechanism 450 is mounted on top of the breath actuation assembly 100 (see FIG. 1B). Top cap 470 surrounds canister sleeve 46, shown in FIG. 22B with a section of the top cap 470 removed for clarity. The top cap has a window 472 for showing the dose count as provided by the display wheel 464. Display wheel 464 has a display label 474 showing remaining dose counts from 0 to 200 in ten dose increments (e.g. markings of 200, 190, 180, etc).

FIG. 23 illustrates a top portion of the top cap 470 cut out and display label 474 removed to show planetary gear mechanism 478. The display wheel 464 is rotationally coupled to gear column 468 via three intermediary gears 476. The three intermediary gears 476 of the planetary gear mechanism 478 are driven by the rotation of centre gear column 468. The teeth of the three intermediary gears 476 mate with the internal geared surface of the top cap 470 such that the display wheel 464 rotates clockwise. When the centre gear column 468 rotates 90 due to motion of the indexing mechanism, the planetary gear will rotate the display wheel 1/10 of a graduation. The label is set to a resolution of 10 shots per indication, however may be altered to reflect different increments. After 200 actuations, the label will have advanced total of 260° -going from "200" to "0" or "Empty".

The planetary gear mechanism 478 has the effect of scaling down the rotational motion of the top link 452 and gear column so that the display wheel may rotate through actuations in less than one full rotation. For smaller dose counts (e.g. 120 or 60 count canisters), the display wheel may simply be positioned so that the correct count is initially viewed through window 472. Alternatively, a different tooth count for the planetary gear mechanism 478 may be implemented along with changing the display label 474 to accommodate different total dose counts.

Referring to FIG 24A-D, the breath actuation mechanism 500 is another preferred embodiment that incorporates a trip link 502 to increase the operational range of previously described breath actuation mechanism 100 shown in FIGS. 3A through 4E.

FIG. 24 illustrates the breath actuation mechanism is ready (non actuated, and loaded) stated. Instead of interfacing directly with flap 34, lower link 504 interfaces indirectly with flap 34 via trip link 502. The upper link 506 and lower link 504 retain motion of the fluid source 22 and load F from biasing spring via locking knee joint 66.

Knee joint 66 is located off-centre from load F in discharge axis 86 (i.e. the discharge axis 86 passes through pivot 78 and the boss of 516 of upper link 506 through FIGS. 24A-D), thus the downward force imposed by biasing spring 48 on the container 108 in the ready position predisposes the knee joint 66 to collapse.

The upper link 506 and lower link 504 are restrained from rotating or collapsing because the lower link 504 is locked from rotation from a catch, or trip edge 510 in trip link 502. Trip link 502 is locked from rotating because of impingement of upper surfaces (contact surface) 512 of the trip link 502 with a restraining surface, or circular cutout 514, in flap 508.

Referring now to FIG. 24B, when flap 508 rotates due to force created by patent inhalation (vacuum), upper edge 512 if the trip link clears the cutout 514, allowing the trip link 502 to rotate clockwise. Trip edge 510 corresponding rotates to release the contacting surface of the lower link 504.

With lower link 504 now unrestrained, as shown in FIG. 24C, knee joint 66 collapses and shifts to the left. Because of constraints on the top edges of upper link 506 with container holder 24, the upper link can only travel in line with the force load path F, and trip link 502 further rotates clockwise, causing lower link 504 to further rotate counter-clockwise.

Referring now to FIG. 24D, the mechanism further collapses as lower link 504 continues to rotate counter-clockwise on joint 78, 26 travels down allowing MDI canister 22 to travel downward causing the valve stem to activate.

After activation, the canister travels upwards such that the knee joint moves back towards its stowed orientation with lower link rotating clockwise towards trip link 502.

The trip link 502 is able to catch lower link 504 in trip edge 510 for retention of the knee joint 66 until subsequent breath actuation of flap 508.

The addition of trip link 502 over previously described embodiments expands the operational margin of the lower 504 with the flap 508, improving overlap on trip edges to ease manufacturing tolerances while maintaining breath actuation sensitivity.

In particular, the addition of the trip link 502 expands the operational margin of the lower link 504 with the flap 508 in that, when in the ready state, the inhaler is less prone to accidental actuation as a result of a sudden movement or vibration of the inhaler which causes an unintended rotation of the flap 508. With reference to FIG. 24A, it will be seen that the amount of overlap between the cutout surface 514 and the meeting upper edge 512 is sufficient for the flap 508 be able to rotate a considerable distance without the trip link 502 being released so as to allow the knee joint 66 to collapse. Since the mating surfaces 514, 512 have a cylindrical shape with a concentric curvature, the area of contact between the flap 508 and trip link 502 remains comparatively large until just before the trip link 502 is released. This also contributes to rendering it more difficult to accidentally actuate the inhaler.

Furthermore, after actuation, the canister travels upward and the lower link 504 engages the trip link 502. An end 520 of the lower link 504 engages a portion 522 of the trip link 502 and pushes the trip link 502 so as to rotate said link 502 in an anti-clockwise direction (FIG. 24D). As the trip link 502 so rotates, the flap 508 may be cammed along a surface 524 of the trip link 502. The surface 524 is configured relative to the rotational axis of the trip link 502 so as to engage with the flap 508 in such a way that rotation of the trip link 502 is not prevented by the engagement therewith of the flap 508. The arrangement of the trip link surface 524 may be such said surface is cylindrical with a centre of curvature coincident with the rotational axis of the trip link 502. In this way, as the trip link 502 rotates in an anti-clockwise direction (as viewed in FIG. 24), the engagement between the flap 508 and trip link surface 524 is such that the flap 508 is not itself rotated. However, the surface 524 may be arranged so that, as the trip link 502 rotates in an anti-clockwise direction, the surface 524 allows a camming of the flap 508 back towards a ready state position. It will be understood therefore that the surface 524 facilitates a return of the linkage and flap 508 back to the ready state position and ensures a movement of the linkage back to this position is not prevented by the flap 508. In the arrangement shown in FIG.24, the surface 524 is arranged on the trip link 502 adjacent the upper edge 512.

As the lower link 504 pushes the trip link 502 in the anti-clockwise direction, the end 520 of the lower link 504 cams into a groove 526 partly defined by trip edge 510.

Although the description above contains many details, these should not be construed as limiting the scope of the invention but as merely providing illustrations of some of the presently preferred embodiments of this invention.

Claims (17)

1. CLAIMS1. A pMDI inhaler comprising a pMDI canister, a vortex devices, an integral horn and a breath-activated mechanism, wherein the canister contains a formulation comprising a combination of two or more active medicaments.
2. 2. An inhaler according to claim 1, wherein the formulation comprises a combination of an inhaled corticosteroid (ICS) and a long-acting beta-agonist (LABA).
3. 3. An inhaler according to claims 2, wherein the ICS comprises one or more of beclomethasone, budesonide, ciclesonide, fluticasone and mometasone.
4. 4. An inhaler according to claim 2 or 3, wherein the LABA comprises one or more of formoterol and salmeterol.
5. 5. An inhaler according to claim 1, wherein the formulation comprises a combination of fluticasone and salmeterol.
6. 6. An inhaler according to claim 1, wherein the formulation comprises a combination of fLuticasone propionate and salmeterol xinafoate in HFA-134a propellant.
7. An inhaler according to claim 1, wherein the formulation comprises a combination of a short-acting beta-agonist (SABA) and an anticholinergic (AC). * * * *..
8. 8. An inhaler according to claim 7, wherein the SABA comprises one or more of salbutamol, terbutaline and fenoterol.

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9. 9. An inhaler according to claim 7 or 8, wherein the AC comprises one of more of ipratropium and tiotropium.
10. 10. An inhaler according to claim 1, wherein the formulation comprises a combination of three active medicaments.
11. 11. An inhaler according to claim 10, wherein the three active medicaments are inhaled corticosteroid (ICS), long-acting beta-agonist (LABA) and anticholinergic (AC).
12. 12. An inhaler according to claim 11, wherein the three active medicaments are fluticasone/salmeterol/tiotropium or budesonide/formoterol/tiotropium.
13. 13. An inhaler according to any of the preceding claims, wherein the pMDI canister is mounted to release a metered dose of its contents, upon actuation, into the vortex device, which generates turbulent vortices in a flowing aerosol.
14. 14. An inhaler according to any of the preceding claims, wherein the integral horn is arranged so that aerosol flow from the pMDI canister passes into one end of the integral horn, the other end of which forms a mouthpiece for the inhaler.
15. 15. An inhaler according to claim 14, wherein the shape of the horn is such as to widen towards the mouthpiece end, thus reducing the aerosol flow velocity.
16. 16. An inhaler according to any of the preceding claims, wherein the breath-actuated :mechani5m operates so that release of a metered dose of medicaments occurs in response to initiation of intake of breath through the horn by a user. 4s * * * S..
17. 17. A method of simultaneously administering a mixture of medicaments, the method comprising the steps of providing a pMDI canister with said mixture; providing * an inhaler according to any of the preceding claims wherein the pMDI canister of said * S. .S L * inhaler is said canister provided with said mixture; and inhaling through said inhaler so as to activate the breath-activated mechanism and thereby administer said mixture.