WO2007141520A1

WO2007141520A1 - Nicotine inhalation therapies - smoking cessation and other medical uses

Info

Publication number: WO2007141520A1
Application number: PCT/GB2007/002074
Authority: WO
Inventors: John Hywel Davies
Original assignee: Neo-Inhalation Technologies Limited
Priority date: 2006-06-06
Filing date: 2007-06-06
Publication date: 2007-12-13
Also published as: GB0611131D0

Abstract

A breath-activated metered dose inhaler comprises a formulation containing nicotine. Preferably the inhaler comprises an inhalation horn, and also a bluff body positioned between the fluid inlet and the fluid outlet of the inhaler. The inhaler can provide a plume velocity of 5m/sec or less and a fine particle dose of from 40% to 60%. The nicotine-containing formulation preferably also comprises a taste-masking agent and a fluorocarbon propellant.

Description

NICOTINE INHALATION THERAPIES - SMOKING CESSATION AND OTHER MEDICAL USES

This invention relates to nicotine-containing inhalers and their medical uses, and is particularly but not exclusively concerned with nicotine-containing inhalers designed to offer optimal replacement of nicotine as smoking cessation therapy, by the delivery of a controlled, effective dose with minimal incidence of side effects, thereby maximising patient compliance. The nicotine inhalers of the invention offer particularly effective treatment for relapse-prone smokers attempting to remain tobacco abstinent over the long-term.

Nicotine is the main and most potent alkaloid of tobacco and is addictive. Whilst it has been demonstrated to have useful therapeutic properties as an anxiolytic and antidepressant, its current main medical use is as a smoking cessation aid.

The currently available nicotine replacement therapies include various dosage forms such as gums, patches, nasal inhalers and oral vapour inhalers. However, despite the wide spread usage of such aids, most attempts at smoking cessation fail in the long- term with observed relapse rates of as high as 75% or over.

It has been postulated that the major reason for this low success rate is that none of the available therapies truly mimic a cigarette in terms of the rapid puff by puff delivery of an arterial bolus that reaches the brain within seconds. Cigarette smoke produces peak nicotine levels as rapidly as nicotine administered by the intravenous route and it is probably these rapid peak levels that contribute to addiction.

Rapid arterial bolus nicotine delivery can only be achieved by absorption through the lungs and probably the distal regions. It has been demonstrated that cigarette smoke has a mass median aerodynamic diameter (MMAD) of around 0.4 micron and such small particles deposit in the alveoli of the lungs resulting in rapid absorption into the pulmonary circulation.

For these reasons, various investigators have tried in the past, to develop nicotine replacement therapies involving lung deposition of the medicament with a variety of different types of inhalers. For example, WO 97/12639 suggests the use of pressurised aerosols and Burch et al (Am. Rev. Respir. Dis. (1989) 140, 955-957) investigated the use of nebulised inhaler solutions. More recently, Andrus et al (Can. Respir. J. 1999; 6(6); 509-512) suggested the use of pressurised metered dose inhalers (pMDI's) containing nicotine base in a solution with co-solvent (ethanol) and a CFC-free propellant (HFA-134a).

Whilst pMDI's are extremely well recognised forms of delivering medicines into the lung in diseases such as asthma and Chronic Obstructive Pulmonary Disease (COPD), they have well recognised disadvantages which are particularly relevant in the development of an optimised nicotine replacement therapy via the lungs.

It is clear that, for effective nicotine replacement therapy via the lungs, a product must offer reproducible controlled doses of nicotine whilst minimising the well documented side effects of nicotine such as coughing sensation, unpleasant taste, etc. With any medical treatment, it is desirable that a product be efficacious at as low a dose as possible with minimal side effects. In this context, there are two specific disadvantages of pMDI's in relation to the development of an optimised nicotine inhaler product.

The first disadvantage, and probably the more important, is the well documented problem of poor patient co-ordination. In asthma studies, it has been shown that over 50% of patients cannot properly co-ordinate the use of a pMDI without specific training. It is unlikely that smokers will be any better at co-ordinating inhalation than asthma patients who receive considerably more counselling advice and training. Such poor coordination ability would inevitably result in uncontrolled and sub-optimal lung deposition of nicotine and thereby reduce the efficacy of the product.

The second major disadvantage of pMDI's is related to the fast plume velocity of the propelled medicine - a typical velocity is of the order of 30m/second. This results in a rapid impact of the propelled substance in the oropharynx and the incidence of the so-called "Cold Freon" effect. Patients experience a "gagging" effect and do not inhale the medicine properly - this occurs in over 30% of patients treated for asthma with pMDI's.

With a nicotine-containing formulation, it is highly likely that the rapid plume velocity from a conventional pMDI would result in serious problems in terms of patient acceptability because of the known variety of unpleasant side effects with nicotine. It is pertinent to observe that there were very high levels of associated side effects in previous studies such as in the Burch et al (Am. Rev. Respir. Dis ) paper (above) where approximately 50% of the subjects, who were current cigarette smokers, did not complete the short three day study. Over 90% of these subjects experienced cough due to the effects of nicotine in the upper airway. Moreover, about 50% of the patients experienced a burning sensation in the throat. Cough was cited as the limiting side effect of the aerosol.

It is possible that these well documented side effect problems of previous nicotine inhalers are the real reason why no pMDI nicotine replacement therapy has been marketed.

It is therefore clear that any new optimal nicotine replacement therapy should not only be capable of delivering nicotine into the distal parts of the lungs (with a particle size of around 1-2 microns) but should incorporate a delivery device which does not share the well documented disadvantages of the pMDI's.

In the last few years, there have been a number of proposals for breath-actuated MDI aerosols. These devices automatically emit a measured dose of the medication as soon as the user holding the device to his mouth, begins to breathe in. These devices are especially useful in assisting MDI users to co-ordinate the actuation of the device with intake of breath, which is notoriously difficult to achieve satisfactorily, especially for patients with weakened lung function and breathing problems. Breath-actuated inhalers are described in, for example, EP 1073491 A, US 4648393, US 5060643, US5119806, WO 94/19040 and in our WO 2005/007226.

We have now found, in accordance with one aspect of the present invention, that the special requirements for nicotine-replacement therapy are more reliably achieved by using a breath-actuated inhaler. Thus, we have found that, surprisingly, the obtaining of an arterial nicotine bolus quickly reaching the brain and thus mimicking cigarette smoking is more reliably achieved using a breath-actuated device than a conventional MDI aerosol.

In one aspect, therefore, the present invention provides a breath-activated metered dose inhaler which contains a formulation comprising nicotine.

The invention further includes the use of such an inhaler in smoking cessation therapy.

According to a particularly preferred aspect of the invention, the breath-actuated inhaler is as described in our patent application WO 2005/007226. This is described further below and in the accompanying Figures. Such a device includes an outlet to provide uniform sized droplets at relatively low velocity (see also our EP 0308524). Moreover, the particle size is in the range that will mimic that of cigarette smoke. A preferred particle size range is from 1 to 5 μm, particularly from 1-3 μm.

This particular device offers two significant advantages as a nicotine inhaler. Firstly, there is a very real benefit in terms of the low plume velocity and an associated significant reduction in the "Cold Freon" effect. The velocity of the plume is less than 5m/second, most usually around about 2m/second as opposed to about 30m/second with a conventional pMDI.

The low plume velocity is achieved partly by the use of an inhalation horn or spacer. The horn can be any suitable shape, but is preferably as further described below and as illustrated in the Figures. Accordingly, therefore, a preferred feature of the present invention is to employ a breath-activated metered dose inhaler which comprises an inhalation horn. Preferably, the inhalation horn is coupled to the transducer of the inhaler. Preferred features of the horn are described further below.

In particular, it is preferred to employ an inhaler which comprises a bluff body or plug (38) having bluff surface (104) positioned between the fluid inlet (106) and the fluid outlet (124). Further details are given below, with reference to Figures 6 A and 6B. The vortex activity resulting from inclusion of the bluff body results in atomisation of the liquid fraction in the liquid-propellant mixture so that the nicotine contained in the liquid fraction is atomised into a mist substantially containing l-3μm sized droplets. The inclusion of the bluff body contributes to reducing the velocity of the droplets. Preferably, the bluff body is positioned in a flow path between the inlet and the outlet and has an axis contained as a plane perpendicular to the inlet axis plane. The bluff body is preferably a rod. The inhaler suitably comprises a chamber (102) between the inlet and outlet wherein the bluff body (preferably rod-shaped) is positioned within the chamber. Preferably, the chamber comprises a cylindrical chamber wall wherein the rod is positioned concentric with the chamber wall. Secondly, the device results in proven lower levels of oropharyngeal deposition and this results in a lower incidence of nausea with a nicotine-containing product.

A preferred inhaler apparatus comprises for dispensing a first fluid supplied from an external fluid source comprising a transducer adapted for receiving the first fluid from the fluid source, wherein translation of a portion of the fluid source along a first axis releases the first fluid into the transducer. The apparatus will generally have a loading member coupled to the fluid source to impose a biasing force to the fluid source along the first axis.

In all cases, the apparatus has a linkage coupling the transducer and the fluid source, the linkage having a collapsible joint inhibiting translation of the fluid source in the first axis when the collapsible joint is oriented in a first position, and allowing translation of the fluid source in the first axis when the collapsible joint is oriented in a second position. The apparatus further comprises a moveable member coupled to the linkage, the moveable member responsive to an inhalation force exerted on the moveable member, the inhalation force causing the moveable member to shift the collapsible joint from the first position to the second position, thereby allowing translation of a portion of the fluid source in the first axis from a stowed position to a discharge position to discharge the first fluid into the transducer.

In preferred embodiments, the transducer further comprises one or more vents to entrain the first fluid with a second fluid. Additionally, there may be a plug coupled to the transducer. Ideally, the plug is retained in a first chamber of the transducer and has a bluff surface such that the axis of the bluff surface is perpendicular to the first axis.

The apparatus preferably has an inhalation horn coupled to the transducer. The inhalation horn preferably has a second chamber positioned along a second axis, wherein the second chamber is in communication with the first chamber via an outlet positioned at a first end of the second chamber. Suction on the inhalation horn by the user causes an inhalation force on the moveable member. In many embodiments, the second axis is perpendicular to the first axis. Preferably, the second chamber has an internal cross section that increases from the first end to a second end forming an opening in the horn. In some embodiments, the internal cross section of the second chamber is parabolic.

Typically, the moveable member comprises a flap rotatably mounted to the transducer, wherein the flap rotates in response to the inhalation force. The flap is generally configured to rotate from a first orientation retaining the collapsible joint in the first position, to a second orientation allowing the collapsible joint to move to the second position as a result of the force applied in the first axis. Usually the device includes a flap spring coupled to the flap and the transducer to return the flap from the second orientation to the first orientation after the inhalation force has subsided.

In a preferred embodiment, the linkage comprises an upper link and a lower link, the upper link and the lower link rotatably attached to form the collapsible joint, a first end of the lower link rotatably housed in the transducer. A second end of the lower link is coupled to the flap and the mating surfaces of the lower link and the flap are configured so that the lower link contacts the flap to retain the collapsible joint in the first position when the flap is in the first orientation. When the flap is in the second orientation, the lower link is free to advance past the flap to allow the collapsible joint to move to the second position. In a preferred embodiment, a reset spring is coupled to the lower link to return the collapsible joint from the second position to the first position.

In some embodiments, a container holder is configured to receive a first end of the fluid source, wherein the container holder is coupled to the upper link. The container holder further comprises one or more protrusions.

Preferably, a dust cover is pivotably coupled to the transducer. The dust cover covers the horn opening in a first orientation, and allows access to the horn opening in a second orientation. In a preferred embodiment, the dust cover comprises one or more cams that are configured to contact the one or more protrusions on the container holder upon rotation of the dust cover from the second orientation to the first orientation, thereby advancing the container holder and fluid source from the discharge position to the stowed position.

In an alternative embodiment, the moveable member comprises a diaphragm mounted to the transducer, wherein a central portion of the diaphragm moves in response to the inhalation force. In this configuration, the collapsible joint is coupled to the central portion of the diaphragm, so that the inhalation force deflects the central portion of the diaphragm to orient the collapsible joint from the first position to the second position.

The apparatus preferably comprises a dose counter coupled to the fluid source. Ideally, the dose counter is responsive to motion of the fluid source in the first axis to count each dose of fluid released from the fluid source.

In one embodiment, the dose counter further comprises a first wheel having a plurality of teeth along its perimeter, the plurality of teeth positioned to rotationally advance the first wheel in response to movement of the fluid source along the first axis. A second wheel positioned adjacent the first wheel, the second wheel having markings for indicating the number of doses discharged from the fluid source. The first wheel is preferably configured to engage the second wheel such that the second wheel rotates at a scaled movement in relation to the first wheel.

The apparatus may further comprise a sleeve configured to house a portion of the fluid source, wherein the sleeve has a protrusion that contacts the teeth of the first wheel to rotationally advance the first wheel as the fluid source is advanced in the first axis. The loading member may also have a spring coupled to the sleeve, wherein the spring provides a compressive force to the fluid source to bias the fluid source to move in the first axis.

In some embodiments, the apparatus may further have a manual release button. The button is coupled to the collapsible joint to manually shift the collapsible joint from the first position to the second position, thereby releasing the first fluid into the transducer.

An inhaler for use in the present invention for dispensing metered doses of a medicament may comprise a fluid source containing the medicament, wherein the fluid source has a cylindrical container having a nozzle located in line with a discharge axis of the container. The nozzle discharges the medicament when the container is advanced relative to the nozzle from a stowed position to a discharge position along the discharge axis. The inhaler further includes a transducer having a surface configured to engage the nozzle of the fluid source. The inhaler preferably has a loading member coupled to the container, the loading member imposing a biasing force to the container to discharge the container along the first axis. A linkage couples the transducer and the container, wherein the linkage has a collapsible joint inhibiting translation of the container in the first axis when the collapsible joint is oriented in a first position, and allowing translation of the container in the first axis when the collapsible joint is oriented in a second position. The inhaler also has a moveable member coupled to the linkage, the moveable member responsive to an inhalation force, the inhalation force causing the moveable member to shift the collapsible joint from the first position to the second position, thereby allowing translation of the container in the first axis from the stowed position to the discharge position to discharge the fluid into the transducer.

The moveable member comprises a flap rotatably mounted to the transducer, wherein the flap rotates in response to the inhalation force. The flap is configured to rotate from a first orientation retaining the collapsible joint in the first position, to a second orientation allowing the collapsible joint to move to the second position as a result of the force applied in the first axis.

The linkage preferably has an upper link and a lower link, the upper link and the lower link rotatably attached to form the collapsible joint, a first end of the lower link rotatably housed in the transducer. A container holder is configured to receive a first end of the container, wherein the container holder is coupled to the upper link. In some embodiments, the container holder further comprises one or more protrusions. A dust cover is pivotably coupled to the transducer, wherein the dust cover covers a horn opening in a first orientation, and allowing access to the horn opening in a second orientation. The dust cover may also have one or more cams configured to contact the one or more protrusions on the container holder. Upon rotation of the dust cover from the first orientation to the second orientation, the container holder and container are advanced from the discharge position to the stowed position.

In another aspect, a dose counter is coupled to the container, wherein the dose counter is responsive to motion of the container in the first axis to count each dose of fluid discharged from the fluid source. In one embodiment, the dose counter comprises a first wheel having a plurality of teeth along its perimeter, the plurality of teeth positioned to rotationally advance the first wheel in response to movement of the fluid source along the first axis, and a second wheel positioned adjacent the first wheel, the second wheel having markings for indicating the number of doses discharged from the fluid source. Preferably, the first wheel is configured to engage the second wheel such that the second wheel rotates at a scaled movement in relation to the first wheel.

An inhaler for use in the present invention for dispensing metered doses of a medicament preferably comprises a fluid source containing the medicament. The fluid source has a nozzle and a container, wherein the nozzle discharges the medicament when the container is advanced relative to the nozzle from a stowed position to a discharge position along a first axis. The inhaler has a transducer having a surface configured to engage the nozzle of the fluid source and a loading member coupled to the container, the loading member imposing a force to the container to bias the container to discharge along the first axis.

The inhaler further has a means for collapsibly retaining the fluid source from translating along the first axis a means for releasably supporting the collapsible retaining means, wherein the releasable support means releases support of the collapsible retaining means in response to an inhalation force.

In many embodiments, the releasable support means has a first orientation retaining the collapsible retainer means in a first, locked position, and a second orientation allowing the retainer means to collapse to a second unlocked position, and wherein the inhalation force causes the releasable support means to shift from the first orientation to the second orientation, thereby allowing translation of the container in the first axis from the stowed position to the discharge position to discharge the fluid.

In another aspect, the inhaler also includes a means for counting the number of doses of dispensed medicament, wherein the counting means is responsive to the axial motion of the container. Preferably, the counting means is responsive to both the motion of the container from the stowed position to the discharged position, and the motion of the container from the discharged position back to the stowed position.

In many embodiments, the counting means comprises a gear means for translating the axial motion of the container into a corresponding radial motion, and a display means for displaying the number of doses based on the radial motion of the gear means. In preferred embodiments, the display means may be scaled with respect to the gear means to match the total dose count of the fluid source.

An inhaler for use in the present invention for dispensing metered doses of a medicament may comprise a fluid source comprising a cylindrical container having a nozzle located in line with a discharge axis of the container, wherein the nozzle discharges the medicament when the container is advanced relative to the nozzle along the discharge axis. A container sleeve is configured to house a portion of the container, the container sleeve having a protrusion extending outward radially from the container. The inhaler further comprises a first wheel having a plurality of teeth along its perimeter, the plurality of teeth positioned to rotationally advance the first wheel in response to contact from the protrusion on the container sleeve as the container sleeve and container advance in the discharge axis, wherein the rotation motion of the first wheel indicates the number of metered doses dispensed from the fluid source.

In a preferred embodiment, a second wheel is positioned adjacent the first wheel, the second wheel having markings for indicating the number of doses discharged from the fluid source, wherein the first wheel is configured to engage the second wheel such that the second wheel rotates at a scaled movement in relation to the first wheel. The first wheel has a plurality of engagement surfaces for engaging the second wheel, wherein the number of engagement surfaces varies the rate of the movement of the second wheel with respect to the first wheel.

Preferred embodiments of inhalers which may be used in the present invention will now be described with reference to the accompanying drawings, in which:

FIG. IA is an exploded view of an upper portion and dose counter of an embodiment of an inhaler for use in the present invention;

FIG. IB is an exploded view of the lower portion of the embodiment of FIG. IA, including a release mechanism;

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

FIG. 3 A is a cross-sectional view detailing the release mechanism of FIG. IB arranged in a stowed configuration;

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

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

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

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

FIG. 4A is a perspective view of the flap of FIG. IB;

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

FIGS. 5A-B show schematic views of the flap and transducer of the embodiment;

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

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 embodiment in a stowed configuration and a dust cover cut out to show the release mechanism;

FIG. 7B illustrates the device of FIG. 7A with the dust cover rotated away from a 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 a cam of the dust cover driving the release mechanism back to the stowed configuration;

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

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

FIG. 8C illustrates the device of FIG. 8A with the container sleeve in a fully discharged configuration;

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

FIG. 9 is a schematic view of the container sleeve and a biasing spring of the embodiment;

FIG. 10 illustrates a dose counter wheel of the embodiment;

FIGS. 1 IA-C illustrate an embodiment of the display wheel of the embodiment;

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 an inhaler for use in 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 embodiment of FIG. 14;

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

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

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

FIGS. 19A-B illustrate the release mechanism of the embodiment of FIG. 18; and

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

Referring more specifically to the drawings, for illustrative purposes a suitable inhaler for use in the present invention is embodied in the apparatus generally shown in FIG. IA through FIG. 2OB. 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. IA and IB, an inhaler 20 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 medicament 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 or other propellant based medicament readily available in the art. Fluid source 22 generally comprises container 108 holding a mixture of medicament 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. 2 A 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. 2C₅ 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. IB and 3 A through 3E, the breath actuation assembly 100 comprises a 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 surface 72 configured to retain arm 74 of lower link 28 when the flap is in its nominal position shown in FIG. 3 A.

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 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. 3 A, 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. As illustrated in FIG. 3A, the downward force imposed by biasing spring 48 is restrained when joint 66 is held over-center by flap 34.

FIG. 3B illustrates the initiation of the breath actuation mechanism 100 caused by inhalation by a patient through the opening 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 center, 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 flap 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-center 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. 7 A. 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 collapsible linkage independent of the dust cover cams.

The inhaler 20 preferably includes a dose counter for automatically counting the remaining doses left in the container after each discharge of the medicament. 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 l2E.

FIG. 8 A 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. 8 A. 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 advances 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 and 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 208/210 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 medicament.

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.

Figures 18 through 2OB illustrate another alternative embodiment 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. 19 A, 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 2OA and 2OB 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-dispending 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.

The nicotine medicament formulation used in the breath-actuated inhaler of the invention can be a solution or a suspension, in accordance with well known MDI technology. The active can be nicotine base itself, but this has an unpleasant taste so it can be preferable either to include taste-making agents in the formulation or to use a salt or other pharmaceutically equivalent substance. Suitable salts include the sulphate, tartrate, chloride, bi-chloride, bitartrate, picrate, aipicrate, salicylate, picrolonates . and dipicrolonates, for example.

For certain purposes, it can be desirable to administer nicotine together with one or more other active materials. The inhalers of the invention can contain one or more actives in addition to the nicotine, as may be desired. For example, the co-administration of bupropion has been suggested, and this and other actives can be present in the inhalers of the invention.

The propellant will usually be a non-chlorinated fluorocarbon such as HFA- 134a or HFA-227. The formulation may consist of the nicotine medicament suspended in the propellant, optionally with surfactant and/or cosolvent, or the formulation may be in the form of solution. The usual adjuvants may be present as desired.

A preferred formulation is a solution of nicotine base in a co-solvent, with a propellant and a taste-masking excipient such as described in the Example (below). One of the advantages of this and other nicotine formulations delivered by the breath actuated devices in accordance with the invention is the very high levels of lung deposition which can be achieved, with for example fine particle doses of over 40%, especially up to 60% and above, as measured by the well established in vitro testing system, the Andersen Cascade Impactor.

Three products with different concentrations of nicotine have been the subject of dose ranging clinical studies in cigarette smokers to correlate the inhaled doses with plasma nicotine concentrations. The three identified strengths involve a nicotine inhaled dose of 25mcg, 50mcg and lOOmcg per puff. The selected container size was 200 doses per canister of the device but the selected canister size can be selected between 120 and 400 doses. The high levels of lung deposition observed in the in vitro tests allows the selection of an "optimum" dose of nicotine which will be lower than doses recommended in previous studies using nebulising solutions and pMDI's - thereby minimising unwanted side effects also. Thus, the invention provides the very significant advantage of being able to provide an efficacious administration at a lower overall dose than previously with pMDI inhalers. We have found that a dose of around 50mcg per puff or less to be suitable. Preferred doses are about 25mcg to about 50mcg per puff.

The invention provides a nicotine inhaler system for an individual wishing to stop smoking on a long-term basis. The concept is a much better therapeutic option due to its inherent pharmacokinetic performance mimicking real cigarette smoking by delivering small particles of nicotine better to the distal lung region where absorption will be more efficient than current available therapies which do not deliver nicotine via the lung.

Moreover, the delivery devices proposed overcome the major disadvantages of the conventional pMDI's and will enhance controlled and predictable lung deposition, eliminate co-ordination problems and minimise side effects such as coughing and burning sensation. Coughing and the irritant effects of the aerosol on the upper airways were the limiting side effects of the previous aerosols. This reduction in side effects with the associated improvement in patient compliance is an essential pre-requisite for a successful nicotine replacement therapy. In particular, it seems that breath-activation itself may be responsible for a reduction in the perceived side effects of coughing and the burning sensation caused by nicotine. It is thought this may be due to the nicotine formulation being more effectively entrained in the inhaled air, such that a "dilution" effect results that is not obtained with a conventional pMDI.

The inherent simplicity, ease of usage, safety and cost effectiveness of this nicotine inhaler system will offer a real alternative to other cigarette cessation therapies where the relapse rates are known to be extremely high.

Finally, the invention also offers considerable potential in terms of the other therapeutic properties of nicotine outlined above. Consequently, this invention may also be an effective vehicle by which to deliver nicotine in the treatment of neurological disorders where smoking has shown previous benefit, such as Parkinson's disease, Alzheimer's dementia, Tourette's syndrome, sleep apnoea, attention deficit disorders, and for pain release.

Example

The following formulation was prepared in a pMDI plain aluminium canister: nicotine base 20mg ethanol 2% by wt of formulation levomenthol 0.02% by wt of nicotine

HFA- 134a 1Og The formulation provides lOOmcg of nicotine per spray.

When this pMDI was tested, using a breath-actuated inhaler with horn as described in our WO 2005/007226, by the Andersen Cascade Impactor, fine particle doses in the range 40% to 60% were obtained.

Claims

1. A breath-activated metered dose inhaler which contains a formulation comprising nicotine.

2. An inhaler according to claim 1 wherein the plume velocity provided by the inhaler is lower than that provided by a pressured metered dose inhaler.

3. An inhaler according to claim 2 wherein the plume velocity is about 5m/second or less.

4. An inhaler according to claim 2 or 3 wherein the plume velocity is about 2m/second or less.

5. An inhaler according to any preceding claim wherein the fine particle dose delivered by the inhaler, as measured by an Anderson Cascade Impactor, is about 40% or more.

6. An inhaler according to claim 5 wherein the fine particle dose is from 40% to 60%, or is above 60%.

7. An inhaler according to any preceding claim wherein the nicotine dose per puff of the inhaler is up to 50mcg.

8. An inhaler according to any preceding claim wherein the nicotine is in the form of a pharmaceutically-acceptable salt.

9. An inhaler according to any preceding claim wherein the formulation comprises a taste-masking agent.

10. An inhaler according to claim 9 wherein the taste-masking agent is levomenthol.

11. An inhaler according to any preceding claim wherein the composition comprises, in addition to nicotine, one or more further pharmaceutically active compounds.

12. An inhaler according to claim 11 wherein the further active is bupropion.

13. An inhaler according to any preceding claim wherein the composition comprises a solution or suspension of nicotine in a non-chlorinated fluorocarbon propellant, a cosolvent and a taste-masking agent.

14. An inhaler according to claim 13 wherein the composition is a solution comprising nicotine, HFA-134a or HFA-227, ethanol and levomenthol.

15. An inhaler according to any preceding claim wherein the inhaler comprises an inhalation horn.

16. An inhaler according to any preceding claim which further comprises a bluff body positioned between the fluid inlet and the fluid outlet of the inhaler.

17. An inhaler according to any preceding claim for use in therapy.

18. An inhaler according to claim 17 for use in smoking cessation therapy.

19. An inhaler according to claim 17 to 18 for use in treating relapse-prone smokers.

20. Use of an inhaler according to any one of claims 1 to 16 in the manufacture of a medicament for treating smoking addiction.