WO2014106727A1

WO2014106727A1 - Inhaler and formulation

Info

Publication number: WO2014106727A1
Application number: PCT/GB2013/050001
Authority: WO
Inventors: Karen Lisa WESTERN
Original assignee: Vectura Limited
Priority date: 2013-01-03
Filing date: 2013-01-03
Publication date: 2014-07-10

Abstract

A dry powder formulation suitable for delivery by inhalation comprising an antifungal agent and a force control agent.

Description

Inhaler and Formulation Description

The present invention relates to delivery of an antifungal agent by an inhalation device for oral or nasal delivery of a medicament in powdered form, to an inhaler device comprising an antifungal agent, antifungal agent formulations for inhalation and uses of those formulations in inhaled delivery devices. In particular aspects of the invention, the antifungal agent is an azole antifungal agent.

Oral or nasal delivery of a medicament using an inhalation device is a particularly attractive method of drug administration as these devices are relatively easy for a patient to use discreetly and in public. As well as delivering medicament to treat local diseases of the airway and other respiratory problems, they have more recently also been used to deliver drugs to the bloodstream via the lungs thereby avoiding the need for hypodermic inj ections.

It is common for dry powder formulations to be pre-packaged in individual doses, usually in the form of capsules or blisters each of which contain a single dose of the powder that has been accurately and consistently measured. A blister is generally cold formed from a ductile foil laminate or a plastics material and includes a puncturable or peelable lid which is heat-sealed around the periphery of the blister during manufacture and after introduction of the dose into the blister. A foil blister is preferred over a polymer blister or gelatine capsule as each dose is protected from the ingress of water and penetration of gases such as oxygen in addition to being shielded from light and UV radiation all of which can have a detrimental effect on the delivery characteristics of the inhaler if a dose becomes exposed to them. Therefore, a blister offers excellent environmental protection to each individual drug dose.

It is known to provide an inhaler that is capable of holding a number of doses to enable it to be used repeatedly over a period of time without the requirement to open and/or insert a blister into the device each time it is used. Such a device is known from the earlier international application which has been published as WO 2005/037353 A1.

However, it is also desirable to provide a simple, low-cost unit-dose device that receives only one blister at a time. Once the dose contained in a blister has been inhaled, the blister is removed from the device and discarded by the patient. A fresh blister is then inserted into the device for a subsequent dose. This avoids the need for a strip indexing mechanism and so greatly simplifies the construction and operation of the device as well as reducing its overall dimensions. A re-usable, unit-dose, passive dry powder inhaler for the delivery of medicinal products is known. The dose is pre-metered and contained in a foil blister to ensure the highest possible degree of protection for the drug together with reproducible dosing. The individual blister may be provided with a tab to enable a user to grasp it easily without damaging the dose containing cavity or blister bowl and to facilitate its insertion into the device and its subsequent removal therefrom after inhalation. Actuation of the device causes a piercing element to breach or rupture an inserted blister bowl so that when the patient inhales through the mouthpiece of the device, air is drawn through the blister to entrain the dose contained therein which is then carried out of the blister through the device and via the patient's airway down into the lungs.

Azole antifungal agents are known as actives for inhalation, see WO90/011754A1.

The listing or discussion of an apparently prior-published document in this specification should not necessarily be taken as an acknowledgement that the document is part of the state of the art or is common general knowledge.

Statements of invention

The present invention relates to:

An inhaler comprising a dry powder formulation according to the invention

An inhaler comprising a housing having a mouthpiece through which a user may inhale a dose of medicament and a blister support member having a slot to receive a dose containing blister, the housing and the blister support member being pivotable relative to each other between a first position for insertion of a blister into said slot and, a second, pierced position, in which a blister piercing element carried by the housing pierces an inserted blister so that when a user inhales on the mouthpiece, the dose is entrained in an airflow and flows out of the blister through the mouthpiece and into the user's airway, the inhaler comprising a blister comprising an antifungal agent, such as a formulation of the invention.

A kit comprising an inhaler and a blister, the blister suitable for use in the inhaler and the blister comprising a formulation of the invention. A method of treatment of a fungal infection or disease resulting therefrom, the method comprising delivery to an individual in need thereof an effective amount of a formulation of the invention, wherein the delivery is by inhalation using an inhaler.

A bl ister or other unit dosage form comprisi ng a formul ation of the invention .

A method for the preparation of an antifungal agent for delivery by inhalation, the method comprising subjecting the antifungal agent to compression and shearing forces in the presence of a force control agent.

In a preferred embodiment of all the above aspects of the invention, the antifungal or active agent is an azole antifungal agent.

Detailed description

The i nvention rel ates to formulations of antifungal agents, to devices com prisi ng antifungal agents for i nhal ation del ivery, and to methods of treatment usi ng said formul ations and devices.

Formulations of the invention may be used in conjunction with an inhalation device such as a metered dose inhaler, a dry powder inhaler or a nebulizer. For example, an inhaler may comprise microparticles or a powder according to the invention. The inhaler may be a metered dose inhaler, a dry powder inhaler (e.g unit dose i nhal ers, i ncl udi ng breath actuated dry powder i nhalers, for exampl e Monohaler and Dinki haler) or a nebulizer. In one embodiment, the inhaler is a dry powder inhaler, such as defined herein.

Dry powder inhaler devices (DPIs) are well known in the art and there are a variety of different types. The dry powder inhaler devices suitable for use in the present invention include "single dose" devices, for example the Rotahaler®, the Spinhaler® and the Diskhaler® in which individual doses of the powder composition are introduced into the device in, for example, single dose capsules or blisters, and also multiple dose devices, for example the Turbohaler® in which, on actuation of the inhaler, one dose of the powder is removed from a reservoir of the powder material contained in the device.

Dry powder inhalers can be "passive" devices in which the patient's breath is the only source of gas which provides a motive force in the device. Examples of "passive" dry powder inhaler devices include the Rotahaler® and Diskhaler® (GlaxoSmithKline), Handihaler® (Boehringer Ingelheim), Eclipse® (Aventis), AIR inhaler (Alkermes), Cyclohaler (Plastiape), Concept 1 also known as Breezhaler (Trade Mark) as disclosed in WO 2005/1 13042 (Novartis), Flowcaps (Hovione), Turbospin (PH&T), Monohaler (Pfizer), Spinhaler (Aventis), Gyrohaler® (Vectura Delivery Devices Limited), E-Flex, Microdrug, and the Turbohaler (Astra-Draco) and Novolizer® (trade mark) (Viatris GmbH). Alternatively, "active" devices may be used, in which a source of compressed gas or alternative energy source is used. Examples of suitable active devices include Aspirair® (Vectura) and the active inhaler device produced by Nektar Therapeutics Exubera® inhalation device, which is described in U.S. Patent No. 6,257,233.

With regard to doses for multi dose dry powder inhalers, the inhalers can be configured to provide any suitable number of doses, typically between about 30 - 120 doses and more typically between about 30-60 doses. The inhalers can deliver one drug or a combination of drugs, according to formulations of the invention. In some embodiments the inhalers can provide between about 30-60 doses of two different drugs (in the same or different unit amounts), for a total of between about 60-120 individual unit doses, respectively. The inhaler can provide between a 30 day to a 60 day (or even greater) supply of medicine. In some embodiments the inhalers can be configured to hold about 60 doses of the same drug or drug combination according to formulations of the invention, in the same or different unit amounts, which can be a 30 day supply (for a twice per day dosing) or a 60 day supply for single daily treatments.

Particularly preferred "active" dry powder inhalers are described in more detail in WO 01/00262, WO 02/07805, WO 02/89880 and WO 02/89881 , the contents of which are hereby incorporated by reference. It should be appreciated, however, that the compositions of the present invention can be administered with either passive or active inhaler devices. Capsule-based passive inhalers are particularly useful due to their larger unit dose volume (compared to current blister devices), which facilitates higher lung doses per actuation.

However, it is also known for powders to be held in a reservoir in a dispensing device, such as the Novolizer (Viatris) or Clickhaler® (Innovata Biomed). In such a case, a predetermined amount of powder is measured out and then dispensed by the device.

Actuation of the dispensing device refers to the process during which a dose of the dry powder formulation is removed from its rest position in the inhaler (be it in a blister or capsule or other container). The actuation may be caused by the user of the device inhaling in the case of a passive device, or by firing an active device. The actuation of a dispensing device occurs after the powder has been loaded ready for use within the device.

One example of an inhalation device, or inhaler, for use in the invention is a pressurized metered dose inhaler; a device which produces the aerosol clouds for inhalation from solutions and/or suspensions of respiratory drugs in chlorofluorocarbon (CFC) and/or hydrofluoroalkane (HFA) solutions. The metered dose inhaler can be a soft mist inhaler (SMI), in which the aerosol cloud containing a respiratory drug can be generated by passing a solution containing the respiratory drug through a nozzle or series of nozzles. The aerosol generation can be achieved in SMI, for example, by mechanical, electromechanical or thermomechanical process. Examples of suitable soft mist inhalers include the Respimat® Inhaler (Boehringer Ingelheim GmbH), the AERx® Inhaler (Aradigm Corp.), the Mystic™ Inhaler (Ventaira Pharmaceuticals, Inc) and the Aira™ Inhaler (Chrysalis Technologies Incorporated).

In one aspect the invention relates to use of a preferred inhaler for delivery, as described below. Such an inhaler comprises a housing having a mouthpiece through which a user may inhale a dose of medicament and a blister support member having a slot to receive a dose containing blister, the housing and the blister support member being pivotable relative to each other between a first position for insertion of a blister into said slot and, a second, pierced position, in which a blister piercing element carried by the housing pierces an inserted blister so that when a user inhales on the mouthpiece, the dose is entrained in an airflow and flows out of the blister through the mouthpiece and into the user's airway.

The invention thus relates to such a device comprising an antifungal agent, and to delivery of an antifungal agent using such a device. Preferably the device is used to deliver an azole antifungal agent, most preferably in a formulation as described herein, although other suitable azole antifungal agent formulations may also be utilised in such a preferred device.

Although the present invention refers to embodiments in which the device is intended to be loaded with a blister immediately prior to use, other 'pre-loadable' device

embodiments are also described. By 'preloadable' is meant a device which is designed so that a blister may be inserted into the device which is then maintained in a pre-punctured state ready for use at a later time so that the patient has immediate access to a dose whenever required and does not have to load the device with a blister immediately prior to inhalation. With many existing devices, it is difficult or impossible to pre-load them without inadvertent piercing of the blister occurring during transport and prior to actual inhalation of the dose, usually because the device must be primed or opened in some way to enable the blister to be inserted, movement back into its original state then causing the blister to be pierced. However, in a primed state the device is relatively unstable and premature piercing can easily occur by accident. Furthermore, if the blister is provided with a tab to enable a user to grasp it more easily, the tab may protrude from the device when the blister bowl is in a piercing-ready position which also makes it harder to carry comfortably and may also preclude the attachment of a cap or cover over the device when it is not being used because the blister tab is in the way.

To ensure that a powdered medicament is delivered with an accurately controlled range of particle sizes in order that they are absorbed effectively in the lung, it is necessary to deagglomerate the particles as they flow through the device prior to entry into the patient's airway. To achieve this, co-owned and co-pending the European patent application no.08100886.4 describes an inhaler which includes an aerosolising device having a generally cylindrical chamber and inlet and outlet ports at opposite ends of the chamber for the flow of drug laden air through the chamber, entering axially at the inlet port and exiting at the outlet port. The inhaler also has tangential bypass air inlets for the flow of clean, non-drug laden air into the chamber which forms a cyclone in the chamber that interacts with the drug laden air flowing between the inlet and outlet ports. As the bypass air forms a cyclone within the device the drug laden air flow is caused to rotate and follow at least a part helical path towards the outlet port due to the effect of the cyclone upon it. This interaction of the vortex formed from the bypass air spinning around chamber on the drug laden air flowing into the chamber in an axial direction results in an improvement in the performance of the inhaler as the drug laden air is accelerated as it flows through the chamber and experiences increased shear forces and differential velocities which further deagglomerate the particles and improve the fine particle fraction of the emitted dose.

Although not essential to the unit-dose inhalation device of the present invention, the concepts described in the earlier application referred to above may also be applied to any embodiment of unit-dose inhaler of the present application to provide the associated advantages of increased deagglomeration and fine particle fraction of the delivered dose in a unit-dose inhaler. A generalised embodiment of the device disclosed in

EP08100886.4 is described in more detail below, with reference to Figures 1 A and 1 B of the accompanying drawings, prior to describing specific embodiments of a unit dose inhaler according to the present invention and which incorporate a bypass air cyclone of the type described in this previous application.

When used herein, "Device XX", or variants of this wording, refers to a device that falls within the generalised and specific embodiments of WO 2010/086285 and as disclosed herein.

According to the present invention, there is provided an inhaler comprising a housing having a mouthpiece through which a user may inhale a dose of medicament and a blister support member having a slot to receive a dose containing blister, the housing and the blister support member being pivotable relative to each other between a first position for insertion of a blister into said slot and, a second, pierced position, in which a blister piercing element carried by the housing pierces an inserted blister so that when a user inhales on the mouthpiece, the dose is entrained in an airflow and flows out of the blister through the mouthpiece and into the user's airway.

In one embodiment, the blister support member is pivotally mounted within, and extends from, the housing to enable a user to pivot the blister support member relative to the housi ng i nto said second, pi erced position so that a blister i nserted i nto the slot and supported by the bl ister support mem ber is pierced by said bl ister pierci ng element.

The blister support member may include a lever portion that extends into a cut-out section formed in a wall of the housing. The lever portion may fill only a portion of the cut-out section such that the housing and the lever portion together define a recess therebetween.

Preferably, the slot is located such that a blister tab of a blister received in the blister support member protrudes from said slot into said recess. In particular, the slot may be configured such that a blister tab extending into said recess is spaced from the housing and from the blister support member when the blister support member is in its first position.

Advantageously, the blister support member and the housing is configured such that, when the blister support member is rotated into its second, pierced position, a blister tab protruding from the aperture into the recess lies substantially against the housing and/or is in a less accessible or clearly visible position than when the blister support member is in its first position. As the blister tab is less accessible and/or visible, it less likely that the user will attempt to remove or pull the blister out of the device when the blister support member is in its pierced position.

In one embodiment, the housing has opposite end walls and the cut-away section is formed in one of said end walls, the lever portion extending into said cut-away section being shaped so as to partially resemble the non-cut-away section of said opposite end wall.

Preferably, the housing has a lower end remote from the mouthpiece, said lower end comprising a laterally protruding shoulder to support a protective cap located over the housing. Ideally, the lever portion also includes a shoulder that forms an extension of the shoulder on the housing when the lever portion is in its first position, such that a cap is supported by both the shoulder on the housing and the shoulder extension on the lever portion.

In a preferred embodiment, the protective cap extends over the recess formed by said cut-away section of the housing and said lever portion without interfering with a blister tab of a blister received in the housing and extending into said recess.

The lever portion may be configured such that, if a cap is placed over the housing with the blister support member in its second, pierced position, the cap contacts the shoulder on the lever portion so that further movement of the cap onto the housing causes the cap to rotate the lever portion back into its first position.

In a preferred embodiment, arcuate guide surfaces are formed on the housing, the lever portion having a cooperating guide member that slides along the guide surfaces to guide movement of the lever portion between its first and second positions. The blister support member may include a resilient arm having a tongue at its free end that is biased against the inner surface of the housing, the housing having detents positioned such that said tongue locates in respective detents when said blister support member is in its first and second positions.

The inhaler may have a base member that closes a lower end of the housing remote from the mouthpiece, said base member having a wall to support the housing upright on a flat surface.

In one embodiment, the lever portion has an underside that forms a continuation of said wall of the base member when said lever portion is in its non-pierced position such that, when the inhaler is placed upright on a flat surface, the inhaler is supported by said wall and the underside of the lever portion.

The blister support member may contact the base member in its first position and prevent the blister support member from rotating beyond said first position in a direction away from its second position.

In one embodiment, the base member comprises a resilient arm that extends upwardly within the housing from the wall of the base member, the free end of said arm having a tongue that engages in an opening in the housing to attach the base to the housing.

Preferably, the tongue protrudes through the opening beyond the outer surface of the housing to contact a cap located over the housing.

Accordi ng to another preferred embodiment, the housi ng is pivotable by a user relative to the bl ister support member between said first and second positions.

I n any embodiment of inhaler accordi ng to the present i nvention, the bl ister support member may com prise a seat to support a blister that has been i nserted through the slot i n its first position .

The housi ng of the i nhal ers accordi ng to the i nvention may also com prise a substantial ly cyli ndrical chamber having an i nl et at one end for the flow of drug laden ai r into the chamber from a pi erced bl ister and an outlet at its opposite end for the flow of drug laden air out of the mouthpi ece and i nto a patient's ai rway.

Preferably, the cham ber has a longitudi nal axis that extends between the i nlet and the outlet. The substantial ly cylindrical chamber may have at least one bypass ai r i nlet for the flow of clean ai r i nto the cyclone chamber to interact with the drug laden ai r flowi ng between the inl et and the outlet. The bypass air inlet(s) may meet the chamber at a tangent so that a cyclonic air flow is generated from clean air that interacts with the drug laden air flow.

In a preferred embodiment, the chamber and bypass air inlets comprise an insert located within the housing.

Preferably, the housing comprises a pair of spaced side walls with the insert being located between the side walls, the side walls extending laterally beyond the ends of the bypass air inlets.

In one embodiment, the housing has a home or storage position in which the housing is located in a lowered position against the blister support member and the blister piercing element is in a position in which a blister located in the blister support member is pierced by the piercing elements. The housing may then also have a primed position in which it is pivoted relative to the blister support member out of its home or storage position into a raised position in which the housing is angled relative to the blister support member and in which the blister piercing element is moved out of a blister pierced position to enable a blister to be inserted into the blister support member through said slot and subsequently removed therefrom. The home or storage position may be stable. The primed position may be unstable.

In one embodiment, the longitudinal axis of the chamber is substantially at right-angles to the direction of insertion of a blister into the blister support member, when the blister support member is in its home or storage position.

A cap may be positionable over the housing and the blister support member only when the housing is in its home or storage position.

In another embodiment, the housing has a home or storage position in which the housing is raised relative to the blister support member and the direction of insertion of a blister into the slot is angled relative to the longitudinal axis of the chamber. The housing may then have a pierced position in which it is pivoted out of its home or storage position into a lowered angled position against the blister support member in which the blister piercing elements assume a blister pierced position to pierce a blister inserted into the blister support member at an angle through the slot.

In this embodiment, the longitudinal axis of the chamber is substantially at right-angles to the direction of insertion of a blister into the blister support member, when the housing is in its lowered blister pierced position. In some preferred embodiments, the blister support member is configured so as to support a blister such that the plane of a blister surrounding the blister bowl lies at an acute angle relative to the longitudinal axis of the chamber when the housing is in its home position prior to pivotal movement of the housing to lower it onto the blister support member to pierce said blister.

Preferably, the longitudinal axis of the chamber lies substantially at right-angles to the plane of a lid of a blister after the housing has been pivoted out of its home position into its lowered position to pierce said blister.

In preferred embodiments, the blister support member has a lower supporting surface to stand the blister support member, together with the housing, upright on a level surface when not in use and the longitudinal axis of the chamber may lie substantially at right- angles to the plane of the lower supporting surface when the housing is in a first position prior to pivotal movement of the housing relative to the blister support member to pierce said blister.

Preferably, the blister seat comprises a blister support surface to support the periphery of a blister surrounding a blister bowl. Ideally, the blister support surface is located below a surrounding wall such that the edges of a blister located on the support surface are supported between the support surface and the surrounding wall. In one embodiment, the blister support surface has a generally U-shaped cut out to receive a blister bowl and an arcuately shaped cantilever arm extends into the cut out from the base of the U-shape. The cantilever can have an enlarged head with a blister bowl engaging lip, the cantilever arm resiliently deforming to allow a blister bowl to ride over the head and locate within the arcuately shaped cantilever arm to retain the blister within the device.

In some embodiments, the blister support member has a tab receiving recess formed in a side wall of the blister support member to receive a folded blister tab of a pre-loaded blister.

In one embodiment, wherein the blister support member has convex shaped support surfaces that cooperate with corresponding concave shaped support surfaces on the housing when the housing is rotated relative to the blister support member.

In preferred embodiments, the slot is formed in a depression in the blister support member so that a blister tab extending from the slot does not protrude beyond the walls of the device.

The inhalation device according to the embodiments of the invention may comprise a cap positionable such that it substantially covers the housing and the blister support member after a blister has been inserted into the slot and whilst the housing is in its first position, the cap being positionable without interfering with a blister tab extending from said slot.

In some embodiments, an opening is preferably formed between the housing and the blister support member to enable a user to see the blister piercing element and a blister inserted into the slot in the blister support member.

An inhalation device according to the embodiments of the invention may also comprise a dose containing blister having a tab such that, when the blister is inserted into the slot, the tab protrudes from the slot and facilitates the removal of the blister from the slot after inhalation.

In some embodiments, the tab is foldable relative to the remaining portion of the blister received in the slot such that the tab lies substantially flush against the base when the blister is received in the slot. The base may comprise a recess to locate a folded tab therein.

Preferably, the base and the cap are configured so that the cap extends over and covers the folded tab.

According to the invention, there is also provided a method of preloading an inhalation device ready for later use, said device comprising a blister support member having a slot, a housing having a mouthpiece and a cap that covers the housing and the blister support member when the device is not in use, the blister support member and the housing being pivotable relative to each other, after removal of the cap, between a first position for insertion of a blister into said slot and, a second, pierced position, in which a blister piercing element carried by the housing pierces an inserted blister, the method including the step of removing the cap, inserting a dose containing blister into the slot when the mouthpiece is in its first position and subsequently replacing the cap such that the cap substantially covers the housing and the blister support member whilst the mouthpiece remains in its storage position and with the dose containing blister received in the slot.

In one embodiment, the blister has a tab, the tab protruding from the slot when the blister is inserted therein to facilitate the removal of the blister from the slot after inhalation, and the method includes the step of folding the tab relative to the remaining portion of the blister received in the slot such that it lies substantially flush against the base. The base may include a recess to receive the blister tab of a blister received in said slot and the method may include the step of folding the tab into the recess in the base prior to placing the cover over the housing and the blister support member. According to another aspect of the invention, there is provided a blister piercing element for a dry powder inhalation device comprising a metal plate having a plurality of peripheral blister piercing blades bent out of the plane of the plate along fold lines to form drug flow openings through the plate, wherein each blade points away from each of the other peripheral piercing blades and the fold lines of each peripheral piercing blade lies substantially at 90 degrees to the fold line of each of the remaining peripheral piercing blades.

In one embodiment, there are four peripheral piercing blades.

The blister piercing element may also comprise a central piercing blade surrounded by the peripheral piercing blades. The central piercing blade may be bent out of the plane of the plate along a fold line.

Ideally, the fold line of the central piercing blade extends at an angle relative to the fold lines of each of the four peripheral piercing blades. In one embodiment the fold line of the central piercing blade is angled at 45 degrees to the fold lines of each of the four peripheral piercing blades.

In one embodiment of blister piercing element, arms depend outwardly from the plane of the plate at an angle and tabs extend from the ends of the arms in a plane parallel to the plane of the plate, the tabs having holes therein to facilitate the attachment of the piercing element to an inhalation device.

The invention also provides an inhalation device comprising a base having a slot for insertion of a single blister containing a dose of medicament to be inhaled into the base, and a mouthpiece pivotally mounted to the base and carrying a blister piercing element operable to pierce a blister received in said slot when the mouthpiece is pivoted relative to the base so that, when a user inhales on the mouthpiece, the dose is entrained in an airflow and flows out of the blister through the mouthpiece and into the user's airway.

In addition to aspects of the invention relating to devices for delivery of antifungal agents, the present invention also relates in one aspect to certain antifungal agent formulations.

Suitable antifungal agents for delivery from a device as described herein or for antifungal agent formulations according to the invention, include polyene antifungals such as natamycin, rimocidin, filipin, nystatin, amphotericin B, candicin and hamycin; allylamines such as terbinafine, amorolfine, naftifine, butenafine; echinocandins such as

anidulafungin, caspofungin, micafungin; cicloprox olamine; tolnaftate; undecylenic acid and salts thereof; haloprogin; allicin; imidazoles, triazoles and thiazoles such as those listed below, and combinations thereof. In one aspect, the invention relates to azole antifungal agent formulations.

The invention also relates to a blister or other unit dosage form comprising an antifungal agent formulation as described herein suitable for insertion into an inhaler. The invention also relates to the combination of an inhaler, suitably as described herein, and a blister, the blister comprising an antifungal agent formulation for use in the inhaler. In one aspect the blister may be provided with the inhaler as a separate component, for example in the form of a kit. The blister may also be already inserted into the inhaler.

The inhaler may also comprise an antifungal agent formulation as described herein in unit doses other than in blister form, or comprise a powder, a proportion of which is delivered.

Preferred azol e antifungal agents i ncl ude imidazoles such as clotrimazole, econazole ketoconazole, miconazole nitrate, bifonazole, butoconazole, fenticonazole, isoconazole, oxiconazole, sertaconazole, sulconazole, tioconazole; triazoles such as fluconazole, itraconazole, isavuconazole, ravuconazole, saperconazole, terconazole, voriconazole and posaconazole; thiazoles such as abafungin; and combinations thereof In one aspect the azole antifungal agent is itraconazole

Itraconazole is a preferred azole antifungal agent. It may also be referred to as or (+)-cis-4-[4- [4-[4-[[2-(2,4-dichlorophenyl)-2-(1 H-1 ,2,4-triazol-1 -yl-methyl)-1 ,3-dioxolan-4-yl]methoxy]phenyl]-1 - piperazinyl]phenyl]-2,4-dihydro-2- (1 -methylpropyl)-3H-1 ,2,4-triazol-3-one or as ((2R,4S)-re/-1 - (butan-2-yl)-4-{4-[4-(4-{[(2R,4S)-2-(2,4-dichlorophenyl)-2-(1 H-1 ,2,4-triazol-1 -ylmethyl)-1 ,3- dioxolan- 4-yl]methoxy}phenyl)piperazin-1 -yl]phenyl}-4,5-dihydro-1 H-1 ,2,4-triazol-5-one). It is a triazole antifungal compound with a piperazine portion. See generally Merck Index Reg. No. 5262 (12^th ed. 1996). Itraconazole is disclosed in U.S. Pat. No. 4,267,179 and may be produced in accordance with known techniques such as, for example, described in U.S. Pat. No. 4,916,134

Reference to azoles/azole antifungal agents herein is to be interpreted broadly and comprises the free base form and the pharmaceutically acceptable addition salts. The acid addition forms may be obtained by reaction of the base form with an appropriate acid. Appropriate acids comprise, for example, inorganic acids such as hydrohalic acids, e.g., hydrochloric or hydrobromic acid; sulfuric acid; nitric acid; phosphoric acid and the like; or strong organic acids such as, for example, methanesulphonic, ethanesulphonic, benzenesulphonic, 4- methylbenzenesulphonic, cyclohexanesulfamic, and like acids.

In one aspect the antifungal agent, preferably the azole antifungal agent, is provided in combination with an additive which is a force control agent [FCA]. A FCA, as used herein, is generally an agent whose presence on the surface of a particle can modify (and generally reduce) the adhesive and cohesive surface forces experienced by that particle, in the presence of other particles, thereby exhibiting anti-adherent and/or anti-friction properties.

FCAs usually consist of physiologically acceptable material, although such material may not always reach the lung. The FCA may be an amino acid, peptide or polypeptides having a molecular weight of between 0.25 and 1000 kDa and derivatives thereof.

The FCA may comprise or consist of one of any of the following amino acids: leucine, isoleucine, lysine, valine, methionine and phenylalanine. The FCA may be a salt or a derivative of an amino acid, for example aspartame or acesulfame K. In one aspect, the FCA consists substantially of an amino acid, more preferably of leucine, advantageously L-leucine. The D- and DL-forms may also be used. The FCA may comprise Aerocine®, amino acid particles as disclosed in the earlier patent application published as WO 00/3381 1 .

Alternatively, the FCA may comprise a phospholipid or a derivative thereof. Lecithin has been found to be a good material for the FCA.

The FCA may comprise or consist of dipolar ions, which may be zwitterions. It is also

advantageous for the FCA to comprise or consist of a spreading agent, to assist with the dispersal of the composition in the lungs. Suitable spreading agents include surfactants such as known lung surfactants (e.g. ALEC®) which comprise phospholipids, for example, mixtures of dipalmitoyi phosphatidylcholine (DPPC) and phosphatidylglycerol (PG). Other suitable surfactants include, for example, lecithin, dipalmitoyi phosphatidylethanolamine (DPPE) and dipalmitoyi phosphatidylinositol (DPPI).

FCAs are described in more detail in Begat et al "The Influence of Force Control Agents on the Cohesive-Adhesive Balance in Dry Powder Inhaler Formulations ", KONA No.23 (2005)

In one aspect the FCA may be a metal stearate, or a derivative thereof, for example, sodium stearyl fumarate or sodium stearyl lactylate. In one aspect the antifungal agent is combined with a metal stearate, for example, zinc stearate or distearate, magnesium stearate, calcium stearate, sodium stearate or lithium stearate. Preferably, the FCA comprises magnesium stearate, for example vegetable magnesium stearate, or any form of commercially available metal stearate, which may be of vegetable or animal origin and may also contain other fatty acid components such as palmitates or oleates. Metal stearates such as magnesium stearate, may be used in any suitable concentration such as a concentration of 0.1 to 20% or, particularly, 0.5 to 20% w/w of any formulation, suitably 1 to 10% w/w, suitably 1 -9% w/w, 2-8% w/w, in particular 2 to 5% w/w , in particular 2 to 3% w/w.

In one aspect the metal stearate coats particles of antifungal agent, either completely or in part. Other FCAs suitable for use in combination with antifungal agents of the invention include aspartame, sorbitol, cellulose acetate, starch and poloxamers. These FCAs may be used in any suitable concentration, such as a concentration of up to 20% by weight of the formulation, such as 0.1 to 15% by weight, 0.5 to 10% by weight or, particularly, 1 -9% by weight, 2-8% by weight, 2-5% by weight, in particular 2 to 3% w/w or any other suitable concentration in between.

In one aspect the FCA is lactose. Suitably, lactose is used in an amount of up to 20 % w/w of the formulation, suitably 2-20% w/w, 2-18% w/w of the formulation, 2- 8% w/w, 2-5% w/w, in particular 2 to 3% w/w or any other suitable concentration in between.

In one aspect the FCA is suitable for use in size reduction techniques, such as micronisation, such as jet milling.

In one aspect the FCA is suitable for use in processes which apply compression and shearing forces, such as those described herein. Such FCAs include metal stearates, leucine, valine and lecithin.

The formulation comprising an antifungal agent, preferably the azole antifungal agent, and a FCA may also comprise an additional additive.

In a further embodiment of the present invention there is provided a composition, preferably a pharmaceutical composition, comprising an antifungal agent and FCA and an additional additive material, which additive may be a carrier and/ or flavouring or taste-masking agent or other pharmaceutically acceptable excipient.

The additive may include or consist of one or more surface active materials. A surface active material may be a substance capable reducing the surface tension of a liquid in which it is dissolved. Surface active materials may in particular be materials that are surface active in the solid state, which may be water soluble or water dispersible, for example lecithin, in particular soya lecithin, or substantially water insoluble, for example solid state fatty acids such as oleic acid, lauric acid, palmitic acid, stearic acid, erucic acid, behenic acid, or derivatives (such as esters and salts) thereof such as glyceryl behenate. Specific examples of such materials are phosphatidylcholines, phosphatidylethanolamines, phosphatidylglycerols and other examples of natural and synthetic lung surfactants; lauric acid and its salts, for example, sodium lauryl sulphate, magnesium lauryl sulphate; triglycerides such as Dynsan 1 18 and Cutina HR; and sugar esters in general. Alternatively, the additive may be cholesterol.

Other possible additive materials include sodium benzoate, hydrogenated oils which are solid at room temperature, talc, titanium dioxide, aluminium dioxide, silicon dioxide and starch. Also useful as additives are film-forming agents, fatty acids and their derivatives, as well as lipids and lipid-like materials. In one aspect additive particles are composed of lactose. The additive particles may be lactose fines, such as lactose powders with a mean particle size of less than 50 microns. The additive lactose may be added a various stages of the formulation assembly or the additive lactose may be formed as a result of processing of a larger lactose carrier particle. Said processing produces smaller lactose particles that may adhere to the larger carrier particles or combine with different components of the composition. Suitably, lactose is used in an amount of up to 20 % w/w of the formulation, suitably 2-20% w/w, 2-18% w/w of the formulation, 2-8 w/w, 2-5% w/w, or any other suitable concentration in between.

Carrier particles may be of any acceptable inert excipient material or combination of materials. For example, carrier particles frequently used in the prior art may be composed of one or more materials selected from sugar alcohols, polyols and crystalline sugars. Other suitable carriers include inorganic salts such as sodium chloride and calcium carbonate, organic salts such as sodium lactate and other organic compounds such as polysaccharides and oligosaccharides. Advantageously, the carrier particles comprise a polyol. In particular, the carrier particles may be particles of crystalline sugar, for example mannitol, dextrose or lactose. Preferably, the carrier particles are composed of lactose. Suitable examples of such excipient include, SV010

(Respitose), SV003, ML006 or particularly, LactoHale 300 (Friesland Foods Domo), LactoHale 200 (Friesland Foods Domo), LactoHale 1 00 (Friesland Foods Domo), PrismaLac 40 (Meggle), InhaLac 70 (Meggle).

Where an additive which is a taste masking agent is used, then such additives may be provided in a form and size such that they are deposited in the mouth and not the lung. Such additives are, in one aspect, not micronized or subjected to compression or shearing forces as described herein.

The ratio in which the carrier particles (if present) and antifungal agent and FCA are mixed will depend on the type of inhaler device used, the type of active particle used and the required dose. The carrier particles may be present in an amount of at least 50%, more preferably 70%, advantageously 90% and most preferably 95% based on the combined weight of the antifungal agent and/or additives and the carrier particles. In other embodiments, the carrier particles constitute a lesser proportion of the total formulation, such that they may be present in an amount of not more than 50% w/w, or 30% w/w, or 20% w/w, or 1 0% w/w, or 5% w/w, based on the combined weight of the active ingredient and/or additives and the carrier particles.

Other additives suitable for use in combination with antifungal agent formulations of the invention include aspartame, sorbitol, cellulose acetate, starch and poloxamers,

Metal stearates, poloxamers and starch may be used when the antifungal agent is subjected to compression and shearing forces using, for example, a mechanofusion (also known as mechanochemical bonding) process (MCB), whereas leucine, cellulose acetate, aspartame and sorbitol are less preferred for use.

Preferred formulations include:

an azole antifungal agent such as itraconazole in combination with a metal stearate, an azole antifungal agent such as itraconazole in combination with a metal stearate and lactose,

an azole antifungal agent such as itraconazole in combination with a metal stearate and aspartame,

an azole antifungal agent such as itraconazole in combination with a metal stearate and cellulose acetate,

an azole antifungal agent such as itraconazole in combination with a metal stearate and sorbitol.

In a preferred embodiment of the above formulations, the formulation comprises 90 - 95% w/w of the azole antifungal agent, 2-3% w/w of a first FCA such as a metal stearate and 2-3% w/w of a second FCA such as lactose or particularly aspartame, cellulose acetate or sorbitol.

In a broad aspect the formulation of the invention is prepared by micronisation of the antifungal agent in combination with a FCA, or micronisation of the antifungal agent followed by admixture with a FCA, or mixing of a premicronised antifungal agent with a FCA. The first option is preferred. In one aspect the micronisation is carried out by jet milling.

In a further aspect the combination of micronized antifungal agent, preferably the azole antifungal agent, and FCA is then subjected to a compressive and shearing force, for example using a mechanofusion process as described herein, also referred to herein as the MCB process. The antifungal agent formulations of the invention are preferably prepared using such processes.

Where a FCA and an additional additive are used in the formulation of the invention then in one aspect the antifungal agent of the invention may be mixed with a first component (FCA or additive), subjected to compression and shearing forces, before mixture with the second component (FCA or additive) as disclosed herein. For example, an azole antifungal agent may be combined with magnesium stearate and then subjected to compression and shearing forces before combination with a taste masking agent.

In another aspect the antifungal agent component and first and second additives may be mixed all together and then subjected to compression and shearing forces.

The antifungal agent, which constitutes the active ingredient, may be micronised prior to compression and shearing. Micronisation may be by any suitable method. Micronization is the process of reducing the average diameter of a solid material's particles, for example by milling or grinding. In one aspect a micronised active is an active ingredient that has been subjected to a mechanical process which applies sufficient force to the active ingredient that the process is capable of breaking coarse particles down to fine particles of mass median aerodynamic diameter of not more than 50 μηι mass median aerodynamic diameter (MMAD) as discussed below.

In one aspect micronisation of the antifungal agent may be achieved using one or a combination of the following methods: ball milling, jet milling, jet blending, high-pressure homogenisation, or any other milling method.

Jet milling is preferred.

Ball milling is a milling method used in many of the prior art co-milling processes. Centrifugal and planetary ball milling may also be used.

Jet mills are capable of reducing solids to particle sizes in the low-micron to submicron range. The grinding energy is created by gas streams from horizontal grinding air nozzles. Particles in the fluidised bed created by the gas streams are accelerated towards the centre of the mill, colliding within. The gas streams and the particles carried in them create a violent turbulence and, as the particles collide with one another, they are pulverized.

High pressure homogenisers involve a fluid containing the particles being forced through a valve at high pressure, producing conditions of high shear and turbulence. Suitable homogenisers include EmulsiFlex high pressure homogenisers which are capable of pressures up to 4000 bar, Niro Soavi high pressure homogenisers (capable of pressures up to 2000 bar) and Microfluidics Microfluidisers (maximum pressure 2750 bar).

Alternatively micronised antifungal agent may be produced by using a high energy media mill or an agitator bead mill, for example, the Netzsch high energy media mill, or the DYNO-mill (Willy A. Bachofen AG, Switzerland).

Data provided herein show that itraconazole jet milled with various FCAs provides improved delivered dose and fine particle dose in comparison to the itraconazole delivered with FCA.

The antifungal agent of the invention is preferably prepared by subjecting the antifungal agent to a compressive and shearing force, suitably in the presence of a suitable FCA. Suitably the FCA is a metal stearate as described above, such as magnesium stearate. Suitably the antifungal agent is an azole antifungal agent such as itraconazole.

The antifungal agent is preferably micronized prior to processing in this manner or may alternatively be micronized during the compressive and shearing processes as described below. In one aspect an antifungal agent and additive such as a force control agent are located in a vessel and the force is exerted on the antifungal agent between the wall of the vessel and the face of an inner element within the vessel which rotates within the vessel. In one aspect rotation of the inner element results in a compression and shearing force being applied to the antifungal agent in the space between the wall and the face of the inner element.

In one aspect a compressive and shearing force is applied in a gap of predetermined width, suitably between the wall of the vessel and an inner element.

In one aspect the compressive and shearing force is achieved by subjecting the antifungal agent and any additive such as a FCA to mechanofusion (also known as mechanochemical bonding), Cyclomix or Hybridiser methods processes, as described below. In one preferred aspect the compressive and shearing force is achieved by use of mechanofusion technique as described herein.

In one aspect the antifungal agent is in the form of particles prior to processing.

The following processes, which are not limiting, are suitable to provide a compressive and shearing force.

Mechanofusion has previously been described as a dry process designed to mechanically fuse a first material onto a second material. It should be noted that the use of the terms "mechanofusion" and "mechanofused" are supposed to be interpreted as a reference to a particular type of milling process, but not a milling process performed in a particular apparatus. The compressive milling processes work according to a different principle to other milling techniques (Comminution techniques), relying on a particular interaction between an inner element and a vessel wall , and they are based on providing energy by a controlled and substantial compressive force.

The antifungal agent and any additive, such as a FCA, may be fed into the vessel of a mechanofusion apparatus (such as a Mechano-Fusion system (Hosokawa Micron Ltd)) or the Nobilta (Hosokawa Micron Ltd) or Nanocular (Hosokawa Micron Ltd) apparatus, where they are subject to a centrifugal force and pressed against the vessel inner wall. In the present invention the antifungal agent and additive are compressed between the fixed clearance of the drum wall and a curved inner element with high relative speed between drum and element. The inner wall and the curved element together form a gap or nip in which the particles are pressed together. As a result, the ingredients experience very high shear forces and very strong compressive stresses as they are trapped between the inner drum wall and the inner element (which has a greater curvature than the inner drum wall). The particles are pressed against each other with enough energy to locally increase the temperature and soften, break, distort, flatten and thereby reduce the amount of amorphous/disordered material in the sample. Either the outer vessel or the inner element may rotate to provide the relative movement. In an alternate embodiment the outer vessel and the inner element may rotate with respect to each other.

The gap between the outer vessel and the inner element surfaces is relatively small, and is typically less than 10 mm and is preferably less than 5 mm, more preferably less than 3 mm, more preferably less than 2 mm, preferably less than 1 mm or preferably less than 0.5 mm. This gap is fixed, and consequently leads to a better control of the compressive energy than is provided in some other forms of mill such as ball and media mills. Alternatively, a sequential use of rotors with smaller gaps throughout the blending process may be used. Such an approach lends itself to providing control over initial powder processing permitting gentler forces before using rotors with smaller gaps to impart a milling process of greater intensity.

Another compressive milling process that may be used in the present invention is the Cyclomix method. The Cyclomix comprises a stationary conical vessel with a fast rotating shaft with paddles which move close to the wall. Due to the high rotational speed of the paddles, the ingredients are propelled towards the wall, and as a result experience very high shear forces and compressive stresses between wall and paddle. Such effects are similar to those in

Mechanofusion as described above and may be sufficient to increase the temperature and soften, to break, distort, and flatten the ingredient particles.

The device used is preferably capable of exerting a force of greater than 1 N. It will be appreciated by the skilled person, that pressure force that is exerted upon the ingredients will be affected by multiple factors including the force imparted by the rotor on the powder when compressed against the drum wall, the volume of powder within the processing chamber, weight of the powder, density of the powder and the inherent cohesiveness of the powder components which dictate the resistance to flow. In addition to these, the speed, temperature, humidity, amount of powder and type of machine can be varied independently to achieve a suitable form of an active according to the present invention.

In another aspect the compressive and shearing forces may be carried out by the Hybridiser® [Nara Machinery Co., Ltd] Method. The antifungal agent and additive are fed into the Hybridiser and subjected to ultra-high speed impact, compression and shear as they are impacted by blades on a high speed rotor inside a stator vessel, and is re-circulated within the vessel. Typical speeds of rotation are in the range of 5,000 to 20,000rpm.

The above processes suitably apply a high enough degree of force to separate individual particles of antifungal agent and to break up tightly bound agglomerates of the active ingredient.

In general, no impaction of milling media surfaces is present so that wear and consequently contamination are minimised. The speed of rotation may vary between the ranges of 200 to 1 0,000 rpm through out processing. Typical processing capacity is between 4000 - 5000 rpm, which equates to 80% engine capacity. It is, however, preferable to introduce powder into the processing chambers at slower speeds. Introduction of powder at slower speeds prevents clogging because it is easier to process an already moving powder. A scraper may also be present to break up any caked material building up on the vessel surface. This is particularly advantageous when using fine cohesive starting materials.

The local temperature may be controlled by use of a heating/cooling jacked built into the drum vessel walls.

The ingredients may be re-circulated through the vessel.

Suitably these compression milling processes produce little or no size reduction of the active ingredient, especially where they are already in a micronised form (suitably <10 μηι MMAD). One physical change which may be observed is a plastic deformation of the particles to a rounder shape.

In one aspect the use of compressive and shearing forces enables coating of the antifungal agent by the metal stearate. In embodiments thereof, the coating may be complete or incomplete.

In one aspect the antifungal agent is combined with a metal stearates and/or poloxamers and/or starch when subjected to processes comprising compression and shearing forces, such as a mechanofusion process.

The mass median aerodynamic diameter (MMAD) of particles comprising the antifungal agent generated using the method of this invention is preferably not more than 10 μηη, and

advantageously it is not more than 5 μηη, more preferably not more than 3 μηη and most preferably not more than 1 pm.

The median geometric diameter of particles can be measured using a laser diffraction instrument (for example Helos KF, manufactured by Sympatec, Clausthal-Zellerfeld, Germany) as described in Example 1 or using optical techniques (for example using a Morphologi G3 Particle Image Analyser, manufactured by Malvern Instruments Limited, Malvern, UK). Other instruments for measuring geometric particle diameter are well known in the art. The diameter of particles in a sample will range depending upon factors such as particle composition and methods of synthesis. The distribution of size of particles in a sample can be selected to permit optimal deposition to targeted sites within the respiratory tract. For laser diffraction particle sizing systems, the terms "X50" as used herein refers to the median diameter (μηη) as measured on a volume basis, i.e. 50% by volume of the particles are smaller than this diameter and 50% are larger. The term "X90" refers to the median diameter (μηη) measured on a volume basis wherein 90% of the particles are smaller than this diameter and 10% are larger. The term "X1 0" refers to the median diameter (μηη) measured on a volume basis wherein 10% of the particles are smaller than this diameter and 90% are larger. Laser diffraction measuring systems include, as an example, Sympatec HELOS system or Malvern Mastersizer 2000.

For optical particle sizing systems, the terms "D50" as used herein refers to the median diameter (μηη) as measured on a number basis by a laser diffraction particle sizing system, i.e. 50% by number of the particles are smaller than this diameter and 50% are larger. The term "D90" refers to the median diameter (μηη) measured on a number basis wherein 90% of the particles are smaller than this diameter and 1 0% are larger. The term "D1 0" refers to the median diameter (μηη) measured on a number basis wherein 10% of the particles are smaller than this diameter and 90% are larger. Optical measuring systems include, as an example, Malvern Morphologi G3 Particle Image Analyser.

In one embodiment of the invention, a reference to "median diameter" or "median geometric diameter" in any embodiment herein is a reference to the X50 or D50.

The term "mass median aerodynamic diameter" or "MMAD" is defined as the median of the distribution of mass with respect to aerodynamic diameter. The median aerodynamic diameter and the geometric standard deviation are used to describe the particle size distribution of an aerosol, based on the mass and size of the particles. The median (50%) particle size is obtained from a linear regression analysis of the cumulative distribution data. According to such a description, fifty percent of the particles by mass will be smaller than the median aerodynamic diameter, and fifty percent of the particles will be larger than the median aerodynamic diameter.

The metered dose (MD) of a dry powder formulation is the total mass of active agent present in the metered form presented by the inhaler device in question.

The emitted dose (ED) is the total mass of the active agent emitted from the device following actuation. It does not include the material left on the internal or external surfaces of the device, or in the metering system including, for example, the capsule or blister. The ED is measured by collecting the total emitted mass from the device in an apparatus frequently identified as a dose uniformity sampling apparatus (DUSA), and recovering this by a validated quantitative wet chemical assay (a gravimetric method is possible, but this is less precise).

The fine particle dose (also referred to hereinafter as FPM or FPD) is the total mass of active agent which is emitted from the device following actuation which is present in an aerodynamic particle size smaller than a defined limit. This limit is generally taken to be 5μηι if not expressly stated to be an alternative limit, such as 3μηι, 2μηι or 1 μηι, etc. The FPD is measured using an impactor or impinger, such as a twin stage impinger (TSI), multistage impinger (MSI), Andersen Cascade Impactor (ACI) or a Next Generation Impactor (NGI). Each impactor or impinger has a pre-determined aerodynamic particle size collection cut points for each stage. The FPD value is obtained by interpretation of the stage-by-stage active agent recovery quantified by a validated quantitative wet chemical assay (a gravimetric method is possible, but this is less precise) where either a simple stage cut is used to determine FPD or a more complex mathematical interpolation of the stage-by-stage deposition is used.

The fine particle fraction (FPF) is normally defined as the FPD divided by the ED and expressed as a percentage. Herein, the FPF of ED is referred to as FPF(ED) and is calculated as FPF(ED) = (FPD/ED) x 100%.

The fine particle fraction (FPF) may also be defined as the FPD divided by the MD and expressed as a percentage. Herein, the FPF of MD is referred to as FPF(MD), and is calculated as FPF(MD) = (FPD/MD) x 100%.

A common technique or apparatus for measuring the mass median aerodynamic diameter (MMAD) of a powder for inhalation is the Andersen Cascade Impactor (ACI). The aerodynamic particle size distribution and/or MMAD of the powder may also be determined using a Next Generation Impactor (NGI).

The particles comprising antifungal agents generated using the method of this invention or in the formulation or inhaler according to the typically have a mass median aerodynamic diameter (MMAD) of equal to or less than about 10 pm, such as from about 0.1 to 10 pm.

In one embodiment, the MMAD is from about 1 pm to about 5 or 6 pm. In another embodiment of the invention, the MMAD is from about 1 pm to about 3 pm. In a further embodiment, the MMAD is from about 2, 3 or 4 pm to about 5 or 6 pm such as from 2 to 4 or 2 to 3 pm.

Experimentally, aerodynamic diameter can be determined by employing a gravitational settling method, whereby the time for an ensemble of particles to settle a certain distance is used to infer directly the aerodynamic diameter of the particles. An indirect method for measuring the mass median aerodynamic diameter (MMAD) is the Andersen Cascade Impactor (ACI). The particle size may also be determined using a Next Generation Impactor (NGI).

The particles may be for localized delivery to selected regions of the respiratory tract such as the deep lung or upper or central airways. Particles having an MMAD ranging from about 3 to about 5 pm are preferred for delivery to the central and upper airways. Particles having an MMAD ranging from about 1 to about 3 pm are preferred for delivery to the deep lung. In one embodiment, microparticles administered to the respiratory tract travel through the upper airways (oropharynx and larynx), the lower airways which include the trachea followed by bifurcations into the bronchi and bronchioli and through the terminal bronchioli which in turn divide into respiratory bronchioli leading then to the ultimate respiratory zone, the alveoli or the deep lung. The microparticles may impact at any stage.

Accordingly, advantageously at least 90% by weight of particles comprising the antifungal agent have a diameter of not more than 10 μηη MMAD, advantageously not more than 5 μηη, preferably not more than 3 pm and more preferably not more than 1 pm. In one aspect at least 90% by weight of particles comprising the azole antifungal agent have a mass median aerodynamic diameter in the range of 10 to 2 pm, preferably in the range of 5 to 1 pm, advantageously in the range of 3 to 0.5 pm, and especially advantageously in the range of 2 to 0.05 pm.

Particles comprising the antifungal agent may be of a suitable size for inhalation to the desired part of the lung, for example, having an MMAD in the range of 3 to 0.1 pm for absorption in the deep lung, 5 to 0.5 pm for absorption in the respiratory bronchioles, 10 to 2 pm for delivery to the higher respiratory system and 2 to 0.05 pm for delivery to the alveoli.

Additionally, the antifungal agent particles discussed above may be formulated with excipient particles that have a median geometric diameter in the range of 5 to 250 pm, preferably 10 to 100 pm, advantageously 20 to 75 pm, and especially advantageously 40 to 50 pm. The geometric diameter of the particles will not normally be higher than 350 pm.

In one embodiment of the present invention, there is provided an antifungal agent obtainable or obtained using any of the methods described in the specification, suitably in the form of a powder such as a dry powder, the latter suitably containing less than 10 %, more preferably less than 7% or most preferably less that 5% (w/w) water or other fluid or solvent.

In a further embodiment, the formulation may be placed into a suitable container following its manufacture. For example, the formulation may be placed into blisters following its manufacture or the formulation may be placed into an amber jar and optionally sealed in a foil pouch (or similar moisture exclusion method) until the formulation is required to be placed into blisters. The formulation is generally placed into a container within 1 hour or within 24, 36, 48, 72 or 100 hours of its manufacture. In the period from manufacture to being placed within a container it may be exposed to ambient conditions (e.g. 18-24^<€, 40-60%RH).

Depending on the disorder, and the patient, to be treated, as well as the route of administration, the formulations disclosed herein may be administered at varying therapeutically effective doses to a patient in need thereof. However, the dose administered to a mammal, particularly a human, in the context of the present invention should be sufficient to effect a therapeutic response in the mammal over a reasonable timeframe. One skilled in the art will recognize that the selection of the exact dose and composition and the most appropriate delivery regimen will also be influenced by inter alia the pharmacological properties of the formulation, the nature and severity of the condition being treated, and the physical condition and mental acuity of the recipient, as well as the potency of the specific compound, the age, condition, body weight, sex and response of the patient to be treated, and the stage/severity of the disease.

Administration may be regular (e.g. as per a dosing schedule) or irregular (e.g. on an as-needed basis). The dosage may also be determined by the timing and frequency of administration. In the case of oral or parenteral administration the dosage can vary from about 0.0001 mg to about 1000 mg per day of an active agent disclosed herein (e.g. an antifungal agent, such as itraconazole).

In any event, the medical practitioner, or other skilled person, will be able to determine routinely the actual dosage, which will be most suitable for an individual patient. The above-mentioned dosages are exemplary of the average case; there can, of course, be individual instances where higher or lower dosage ranges are merited, and such are within the scope of this invention.

The invention provides for an inhaler as disclosed herein for use in delivery of an antifungal agent, in particular an azol e antifungal agent such as itraconazole, to an individual in need thereof.

In one aspect the invention relates to the use of an inhaler as described herein for the delivery of an antifungal agent, in particular an azole antifungal agent such as itraconazole, for the treatment of fungal infections, or diseases that may arise from fungal infections, such as fungal - induced inflammation of mucosal tissue as well as asthma including uncontrolled asthma with underlying fungal sensitisation. Underlying fungal sensitization is considered interchangeable with underlying fungal sensitivity for the purposes of this invention. Other indications for which formulations and devices of the invention may be used include moderate-to-severe persistent asthmatic patients who have a positive skin prick test and/or in vitro reactivity to a fungal allergen and whose symptoms are inadequately controlled with inhaled corticosteroids (ICS), moderate-to- severe persistent asthmatic patients who have a positive skin prick test and controlled with inhaled corticosteroids (ICS), Allergic Broncho-Pulmonary Aspergillosis or fungal infections associated with transplants.

In vitro reactivity to a fungal allergen may be measured by radioallergosorbent test (RAST) and in vivo methods include skin testing. RAST is a radioimmunoassay test to detect specific IgE antibodies responsible for hypersensitivity: the allergen is bound to insoluble material and the patient's serum is reacted with this conjugate; if the serum contains antibody to the allergen, it will be complexed to the allergen. Radio labeled anti-human IgE antibody is added where it reacts with the bound IgE. The amount of radioactivity is proportional to the serum IgE (Stedman's Medical Dictionary 28th Edition. Copyright 2006) and is well known to persons working in this field.

In one aspect, RASTV ImmunoCAP assay values and IgE levels are used to assess whether a patient is identified as "suitable" for therapy with a formulation, such as an azole antifungal formulation according to the invention. Thus further aspects of the invention include treatment of only patients in need of antifungal medication, however determined or assessed, and also kits comprising diagnostic means to identify individuals in need of treatment in combination with devices or formulations for treatment as described herein.

The invention also relates to an antifungal agent for use in treatment of a fungal infection or disease resulting therefrom, such as uncontrolled asthma with underlying fungal sensitisation, wherein the antifungal agent is delivered by inhalation using an inhaler comprisi ng a housi ng having a mouthpi ece throug h which a user may inhale a dose of medicament and a bl ister support member having a slot to receive a dose contai ni ng bl ister, the housi ng and the blister support member being pivotable relative to each other between a first position for i nsertion of a bl ister i nto said slot and, a second, pi erced position, i n wh ich a bl ister piercing el ement carried by the housi ng pierces an i nserted bl ister so that when a user i nhales on the mouthpi ece, the dose is entrai ned in an ai rflow and flows out of the blister through the mouthpi ece and i nto the user's airway.

The invention further relates to a method of treatment of a fungal infection or disease resulting therefrom, such as asthma including uncontrolled asthma with underlying fungal sensitisation, the method comprising delivery to an individual in need thereof an effective amount of an antifungal agent, wherein the delivery is by inhalation using an inhaler com prisi ng a housi ng having a mouthpi ece throug h wh ich a user may inhal e a dose of medicament and a blister support member having a slot to receive a dose contai ning blister, the housing and the bl ister support member bei ng pivotable relative to each other between a first position for i nsertion of a bl ister i nto said slot and, a second, pi erced position, i n which a blister piercing el ement carried by the housi ng pierces an i nserted bl ister so that when a user i nhales on the mouthpi ece, the dose is entrai ned in an ai rflow and flows out of the bl ister through the mouthpi ece and i nto the user's ai rway.

The i nvention further relates to an antifungal agent form ulation as disclosed herei n for treatment of a fungal infection or disease resulting therefrom, such as uncontrolled asthma with underlying fungal sensitisation. Antifungal agent formulations of the invention are suitably delivered by inhalation, and may be delivered by any suitable inhaler device, with the devices as described in the present invention preferred. The invention further relates to use of an antifungal agent formulation of the invention in the manufacture of a medicament for treatment of a fungal infection or disease resulting therefrom, such as uncontrolled asthma with underlying fungal sensitisation.

Embodiments of the present invention will now be described, by way of example only, and with reference to Figures 2A to 24 of the accompanying drawings, in which:

FIGURE 1 A is a cross-sectional side view of a portion of a generalised inhalation device having a bypass air cyclone, as described and illustrated in the Applicant's earlier copending application referred to above;

FIGURE 1 B is a cross-section along the line X-X of the device shown in Figure 1 ;

FIGURE 2A is a perspective view of a first embodiment of unit-dose inhalation device of the present invention with the housing in a storage or home position on the blister support member and with a cap in place over the housing and blister support member;

FIGURE 2B is a perspective view of the device shown in Figure 2A but with the cap removed and the housing pivoted out of its home or storage position into its primed position ready for insertion of a blister to be pierced;

FIGURE 2C is the same view as Figure 2B but following insertion of a blister to be pierced through the slot in the side of the blister support member;

FIGURE 2D is a perspective view of the device shown in Figures 2A and 2B after the housing has been pivoted back into its home position from its primed position shown in Figure 2B to pierce an inserted blister;

FIGURE 3A is a side sectional view of the device shown in Figure 2A;

FIGURE 3B is an inside perspective view of the housing with bypass air cyclone shown in

Figure 3A, with the cyclone chamber closure plate removed;

FIGURE 4A is a side view of the housing used in the embodiment of Figures 2 and 3; FIGURE 4B is a perspective view of the housing shown in Figure 4A;

FIGURE 5A is a perspective view of the bypass air cyclone chamber insert which is received in the housing shown in Figure 4;

FIGURE 5B is a bottom plan view of the bypass air cyclone chamber insert shown in Figure 5A;

FIGURE 6A is a perspective view of the blister support member of the inhalation device shown in Figures 2 and 3A;

FIGURE 6B is a top plan view of the blister support member shown in Figure 6A;

FIGURE 6C is a side view of the blister support member shown in Figures 6A and 6B; FIGURE 6D shows a simplified side-sectional view through a portion of the blister support member, to illustrate how a blister is held in position between the blister support surface and the surrounding wall;

FIGURE 7A is a side view of a second pre-loadable embodiment of inhalation device according to the present invention, with the housing in its home or storage position; FIGURE 7B is a front view of the second embodiment of inhalation device shown in Figure 7A;

FIGURE 7C is a rear view of the second embodiment of inhalation device shown in Figure 7A and 7B;

FIGURE 8A is the side view of the inhalation device shown in Figure 7A with the housing in its pierced position;

FIGURE 8B is the front view of the inhalation device shown in Figure 7B with the housing in its pierced position;

FIGURE 8C is the rear view of the inhalation device shown in Figure 7C with the housing in its pierced position;

FIGURE 9A is a side view of a third embodiment of inhalation device according to the present invention, with the housing in its home or storage position;

FIGURE 9B is a front view of the third embodiment of inhalation device shown in Figure

9A;

FIGURE 9C is a rear view of the third embodiment of preloadable inhalation device shown in Figures 7A and 7B;

FIGURE 10A is the side view of the inhalation device shown in Figure 9A with the housing in its pierced position;

FIGURE 10B is the front view of the inhalation device shown in Figure 9B with the housing in its pierced position;

FIGURE 10C is the rear view of the inhalation device shown in Figure 9C with the housing in its pierced position;

FIGURE 11 is a perspective view of a fourth embodiment of a unit-dose inhalation device of the present invention with the housing in its first storage or home position and with a cap in place over the housing and the blister support member;

FIGURE 12 is a side view of the inhalation device shown in Figure 11 with the cap removed and showing a blister about to be inserted into the device;

FIGURE 13 is a perspective view of the inhalation device shown in Figures 11 and 12 with a blister inserted therein;

FIGURE 14 is a cross-sectional view of the inhalation device of Figures 11 to 13 with a blister inserted therein;

FIGURE 15 is a perspective view of the inhalation device of Figures 11 to 14 with the blister support member rotated into its pierced position;

FIGURE 16 is a bottom perspective view of the inhalation device of Figures 11 to 16, with the blister support member and base removed;

FIGURE 17 is a bottom perspective view of the blister support member forming part of the inhalation device of Figures 11 to 16;

FIGURE 18 is a bottom perspective view of the housing forming part of the inhalation device of Figures 11 to 17;

FIGURE 19 is a bottom perspective view of the cap shown in Figure 11 ; FIGURE 20A is a perspective view of a blister piercing member for use with any embodiment of the inhalation device of the invention;

FIGURE 20B is a top plan view of the blister piercing member shown in Figure 20A; and FIGURE 20C is a side view of the blister piercing member shown in Figures 20A and 20B. Figures 21 - 24 demonstrate the effects of different treatments and additives/FCAs on aerosol performance. In Figure 24 the first bar for each formulation represents the delivered dose, the middle bar represents <3μηι FPM and the third bar represents <5μηι FPM.

Referring now to Figure 1A, there is shown a portion of an inhalation device 1, as described and illustrated in the Applicant's own earlier co-pending application, and in which the bypass air flow is used to assist in the deagglomeration of the drug dose. With reference to Figure 1A, the device has a housing 2, having a mouthpiece 2a, defining an internal chamber 3 having a chamber wall 4, a drug laden air inlet port 5, an outlet port 6 and bypass air inlets 7. A cross-sectional view taken along the line X-X in Figure 1 A is also shown in Figure 1B.

The device 1 includes a cyclone chamber closure plate 8 extending across a lower end of the mouthpiece 2 that closes the chamber 3. The drug laden air inlet port 5 is formed in, and extends through, the cyclone closure plate 8 and is coaxial with the longitudinal axis (A-A in Figure 1A) of the chamber 3.

Although the closure plate 8 can be formed integrally with the housing 2, it is preferably formed as a separate component that is attached to the housing 2 or to the end of the chamber 3 during assembly.

As shown in Figure 1B, the bypass or clean, non-drug laden air inlets 7 are preferably tangentially oriented arcuately shaped channels formed in the sides of the housing 2 and the closure plate 8 forms the lowermost wall and encloses the lower end of the chamber 3 (apart from the drug laden air inlet port 5), but also forms the lower surface of the channels 7 so that the channels 7 are open only at each of their ends. Although two channels 7 are shown in Figures 1A and 1B, it will be appreciated that one channel 7 is also sufficient to produce the desired cyclonic effect.

As the bypass air inlets 7 are arranged tangentially, or so as to direct the bypass air in a substantially tangential direction into the chamber 3, the clean air flowing through these inlets 7 into the chamber 3 is forced to spin around the chamber 3 so as to form a cyclone or vortex (as indicated by arrow "B" in Figure 1 A).

The outlet port 6 may be in the form of a mesh extending across the end of the chamber 3 through which the entrained drug may flow out of the chamber 3 into the patient's airway. Preferably, the mouthpiece 2a incorporates a flow diffuser 9 that extends beyond the outlet port 6 and has a cross-sectional area that gradually increases towards the top edge 10 of the mouthpiece 2a. The wall 11 of the diffuser 9 is curved in shape.

A piercing device 12 is disposed beneath the chamber 3 on the opposite side of the closure plate 8 and may extend from and/or be connected to the closure plate 8. The piercing device 12 comprises a piercing head 13 having piercing elements 14, 15 depending therefrom. The blister piercing elements 14, 15 are configured to puncture the lid 16b of a blister bowl 16a so that, when a patient inhales through the mouthpiece 2, clean air enters the blister bowl 16a through the air inlet flow passages formed by blister piercing elements 14 (in the direction of arrow "C" in Figure 1 A) and entrains the dose contained in the blister bowl 16a. The drug laden air then flows out of the blister 16a through a central drug laden air outlet passage 17 (in the direction of arrow "D"). The drug laden air outlet passage 17 is connected to the drug laden air inlet port 5 of the chamber 3 so that it flows in an axial direction into the chamber 3 (in the direction indicated by arrow "E"). At the same time, clean bypass air enters the chamber 3 through the tangential bypass air inlets 7 and spins around the chamber 3 (in the direction of arrow "B") forming a vortex or cyclone.

Turning now to Figures 2A to 2D, there is shown a first embodiment of a unit-dose dry powder inhaler 19 according to the present invention which generally comprises a blister support member 20, a housing 21 , having a mouthpiece 21a, pivotally attached to the base and a cap 22 (which may be transparent, as shown in Figure 2A) that extends over the housing 21 and the blister support member 20. In Figure 2A, the device is shown in its storage state in which the housing 21 is in its 'home' or storage position and in which the cap 22 covers the housing 21 and blister support member 20 to protect it and to prevent ingress of dirt into the mouthpiece 21a and those parts of the mouthpiece 21a which are inserted into the patient's mouth during inhalation. In this state, with the housing 21 against the blister support member 20, the device is in a stable condition because the housing 21 can only pivot away from the blister support member 20 into an unstable primed position by rotating the housing 21 away from the blister support member 20.

Figure 2B shows the device 19 in its primed state after the cap 22 has been removed and the housing 21 has been pivoted out of its home position (in the direction of arrow "P" about axis "A" in Figure 2B) ready for insertion of a blister to be punctured through a slot 23 in the side wall of the blister support member 20.lt will be appreciated that, in this state, the device is in a relatively unstable condition because it is easy for the housing 21 to be pushed back into its home position in which the housing 21 is against the blister support member when, for example, the device is being carried in a pocket or bag.

Therefore, the device described with reference to this embodiment is not intended to be carried in this state but is designed so that a user inserts a blister into the device at the time a dose is to be inhaled, i.e. immediately prior to piercing.

Figure 2C shows the device as shown in Figure 2B after a blister has been inserted through the slot 23 in the side of the device 19 and in which a tab 16d, extending from the blister, is visible protruding from the side of the device 19. The tab facilitates the insertion of the blister into the device, and its removal therefrom, as it enables a user to grasp the blister between their fingers placed on either side of the blister tab, without contacting or damaging the blister bowl containing the medicament dose.

Figure 2D shows the device 19 after the housing 21 has been rotated back into its home position in the direction of arrow P' from its position shown in Figure 2B following insertion of a blister through the slot 23. In this position, the blister has been pierced and the device is ready for a patient to inhale through the mouthpiece 21a.

It will be appreciated that, in this first embodiment, it is only possible to put the cap 22 over the housing 21 and blister support member 20 when the housing 21 is in it home position and no blister is located in the device, as shown in Figure 2A, because the protruding blister tab would interfere with the cap 22 when the cap is passed over the blister support member 22.

Figure 3A shows a vertical cross-section through the device 19 shown in Figure 2A, and in which a cyclone chamber 24, similar to that described with reference to Figures 1A and 1 B, is disposed within the housing 21. The cyclone chamber 24 takes the form of an insert 25, as shown more clearly in Figures 5A and 5B, which is received within and mounted to the housing 21. The outlet end 26 of the cyclone, which may be in the form of a mesh, has a shoulder 26a that engages with a lower edge of a curved diffuser 27 integrally formed with the mouthpiece 21a and the insert 25 is retained in position by a cyclone closure plate 28 that extends across the inlet end of the chamber 24 and has an aperture 29 therein for the flow of drug laden air into the chamber 24 from a blister during inhalation. The closure plate 28 extends over the insert 25 and closes the lower open end of the cyclone chamber 24, apart from the inlet 29, and forms the bottom wall of the bypass air flow inlets 30.

The closure plate 28 includes a pair of hollow cylindrical posts 31 upstanding therefrom alongside and outside of the chamber 24 which mate against corresponding posts 32 formed in the housing 21 (see Figure 3A and 3B). Screws (not shown) may be inserted into the posts 31 so that they threadingly engage with the corresponding posts 32 in the housing 21, thereby securely attaching the closure plate 28 to the housing 21 and sandwiching the cyclone chamber insert 25 therebetween. However, it will be appreciated that the insert 25 may be mounted within the housing 21 using any appropriate fastening method. Similarly, the closure plate 28 may be coupled to the insert 25 or housing 21 using any known methods of attachment. Ridges 33 (see Figure 3B and 4A) are formed on opposite sides of the internal surface of the housing 21 to help steady the cyclone chamber insert 25 and position it centrally within the housing 21. The ridges 33 also act as keying features to ensure correct orientational assembly of the closure plate 28 and piercing element 34 (see below) relative to the housing 21.

A blister piercing element 34 (see Figure 3A) having downwardly directed blades 35 is mounted on the closure plate 28 below the aperture 29, i.e. on the opposite side of the closure plate 28 to the chamber 24. As is apparent from Figure 3A, when the housing 21 is in its home position, the blades 35 extend downwardly into a space which would be occupied by the lid of a blister (not shown) received in the blister support member 20 so that, when a blister is inserted through the slot 23 and the housing 21 is returned to its home position from its primed position shown in Figure 2B, the blades 35 puncture the lid so that the dose will be entrained in the airflow during subsequent inhalation through the mouthpiece 21 a.

As shown most clearly in Figures 4A and 4B, the housing 21 (Figure 3B) generally has an inverted U-shape with the mouthpiece 21a at the curved end of the 'U' and with the legs of the 'U' surrounding a central portion of the blister support member 20. The cyclone chamber insert 25 is positioned within the housing 21 between facing sidewalls 21a, 21b. The bypass air inlets 30 of the cyclone chamber 24 are configured so that they open into end regions of the housing 21 between the sidewalls 21 a, 21 b. As the side walls 21 a, 21 b extend laterally beyond the end of the bypass air inlets 30, the bypass air inlets 30 will not be blocked by a person's fingers holding the device, as their fingers are spaced away from the bypass air inlet openings by the protruding side walls 21a, 21b.

As can most clearly be seen from Figure 5A and 5B, the insert 25 is provided with arcuate shaped flanges 30a at the end of the bypass air inlets 30 that extend between the side walls 21a, 21b.

The housing 21 (Figure 3B) is pivotally attached to the blister support member 20 at one lower end (at a remote end of one leg of the 'U') and includes a hub 35a that extends laterally between the side walls 21a, 21b. The housing 21 pivots about the longitudinal axis "A-A" of the hub 35 between its home and primed positions. The hub 35a is generally rectangular in cross-section so that its height Ή' is greater than its width 'W, as shown in Figure 4A. The blister support member 20 includes a part cylindrical recess 36 (see Figure 6C) that has an opening or mouth 37 extending along its length. The height of the opening 37 is equal to or only slightly greater than the width 'W of the hub 35a so that the hub 35a can only be inserted into, or removed from, the recess 36 through the opening when the housing 21 is rotated into a position relative to the blister support member 20 in which the width W of the hub 35a is in alignment with the height of the opening 37 so that the hub 35a will clear the mouth of the opening 37. It will be appreciated that once the hub 35a has been inserted through the opening 37 and into the recess 36 and the housing 21 rotated relative to the base 20, it is not possible for the hub 35a to be removed from the recess 36 until the housing 21 has been rotated back into the same orientation.

The opposite end of the housing 21 remote from the hub 35a (the remote end of the other leg of the 'U') includes a resilient catch 38 which may either be formed integrally with the housing 21 or as a separate component that is attached to the housing 21 during assembly. The catch 38 has a hooked end 39 that engages with a cooperating surface 40 on the base 20 to limit rotation of the housing 21 relative to the blister support member 20 to a small angle (such as that shown in Figure 2B) sufficient only to allow the piercing blades 35 to move by a sufficient distance to allow a blister to be inserted through the slot 23 into the blister support member 20 without fouling the blades 35 of the piercing element 34.

The cooperating surface 40 may include an initial ramp surface section 41 to provide a small degree of initial resistance to pivotal movement of the housing 21 relative to the blister support member 20 and so that the catch 38 resiliency deforms slightly as it rides over the ramp surface section 41 to enable pivotal movement of the housing 21 from its initial home position, an intermediate surface section 42 in which the deformation of the catch 38 generally remains constant during further pivotal movement of the housing 21 but which offers some degree of friction so that the housing 21 will not drop back under its own weight if released when only partially pivoted out of its home position, and an end ramp surface section 43 that terminates in a stop 44 against which the hook 39 engages when the housing 21 has pivoted its fullest extent into its open position ready for insertion of a blister. The end ramp surface section 43 ensures that at least some of the deformation of the catch 38 is released prior to the hook 39 reaching the stop 44. This ensures that the housing 21 will remain in its primed position and will not drop back into its home position too easily prior to being rotated by the patient.

The slot 23 is in the form of a narrow slit 23a with an enlarged blister bowl-shaped central opening 23b. The blister lid and planar region surrounding the blister bowl 16a is received in the slit 23a and the blister bowl 16a passes through the central opening 23b into the device. The blister support member 20 includes a blister support surface 45 on which the planar region of the blister surrounding the blister bowl 16a sits and a surrounding wall 46. As can be most clearly seen from Figure 6D, which shows a simplified, partial side- sectional view through a portion of the blister support member 20 with a blister held in position between the blister support surface 45 and the surrounding wall 46, the support surface 45 is positioned slightly below the surrounding wall 46 and its width, extending at right-angles to the direction of insertion of a blister into the blister support member 20, is slightly less than the width of a blister so that the edges 16c of a blister 16 overhang the side edges 45a of the blister support surface 45. The surrounding wall 46 terminates above and spaced from the side edges 45a of the support surface 45 so that the surrounding wall 46 extends over the edges of a blister thereby effectively forming a slot along either side between the blister support surface 45 and the surrounding wall 46 to receive the blister edges. The blister edges 16c are therefore held between the support surface 45 and the surrounding wall 46 to provide maximum support to the blister edges 16c surrounding the blister bowl 16a. The distance between the support surface 45 and the surrounding wall 46 of the blister support member 20 can be selected so that the blister edge is an interference fit between the support surface 45 and the surrounding wall 46 (although the distances between the support surface 45 and the blister and between the blister and the surrounding wall 46 are shown greatly exaggerated in Figure 6D for clarity). It will also be appreciated that the surrounding wall 46 may partially overhang the support surface 45 and/or that the width of the support surface 45 may equal to or greater than the width of the blister in alternative embodiments.

The support surface 45 has a generally U-shaped open region 45b in plan view (see Figure 6B) with a resiliently deformable cantilever arm 47 extending from the base of the 'U' towards the slot 23. In a vertical cross-section taken along the length of the cantilever arm 47, the cantilever arm 47 is generally curved in shape so as to correspond to the shape of a blister bowl 16a. The free end of the cantilever arm 47 is integrally formed with an enlarged head or tab 48 with a downwardly curved forwardly facing lip 49. The lip 49 makes initial contact with the surface of the blister bowl 16a during insertion of a blister into the slot 23b. Once initial contact has been made, further insertion causes the cantilever arm 47 to be deflected downwardly as the bowl 16a rides over the tab 48. Once the blister is fully inserted, the tab 48 has ridden back up along the opposite side of the blister bowl back towards its original position. The blister bowl 16a is thereby held or cradled snugly in position within the arcuate shape of the cantilever arm 47 ready for piercing. A stop 48a may be formed on the support surface 45 which engages with the rearmost edge of the blister to prevent over-insertion of the blister into the slot 23. As can be seen from Figure 6D, the upper surface of the tab 48 is also arcuate in shape in a direction extending at right angles to the direction of insertion of a blister so that it conforms as closely as possible to the curved shape of the blister bowl 16a.

The blister support member 20 has a flat lower supporting surface 67 to enable the blister support member 20 to be stood upright on a table with the housing 21 upstanding from the blister support member 20. This ensures that the housing 21 need not come into contact with the surface on which the device is placed. When the housing 21 is in its home position, the longitudinal axis A-A of the chamber 24 extends substantially at right- angles to the plane of the flat lower supporting surface 67. A second embodiment of inhalation device according to the present invention will now be described with reference to Figures 7 A to 8C. In this embodiment, the home or storage position is also the position in which a blister is inserted into the device, i.e. the housing 60 does not need to be pivoted into a primed position to move the piercing blades out of the way to facilitate insertion of the blister. On the contrary, the housing 60 in this embodiment is only pivoted out of its home or storage position relative to the blister support member 61 after a blister has been inserted so as to pierce the blister. Once the dose has been inhaled, the housing 60 is then pivoted back into its home position to lift the piercing blades 62 out of the blister and enable the used blister to be removed from the device and a fresh one inserted ready for subsequent use. The housing 60 is relatively stable in its home position and more stable than the inhaler of the first embodiment of the invention in its primed position because the walls of the housing 60 and blister support member 61 are in alignment and the device is maintained generally upright, whereas in the first embodiment the housing is canted over at an angle away from the blister support member.

This embodiment has the advantage that the device can be pre-loaded ready for later use such as when the patient needs to take a dose in a hurry and does not have time to load the device or is incapable of loading the device at the moment a dose needs to be taken due to, for example, symptoms related to their illness. It also means that the user does not have to carry a dose separate to the inhaler.

It will be appreciated that a problem with the previous embodiment is that to maintain it in a preloaded state, the housing 21 must be kept in its primed, relatively unstable, position in which it has been pivoted away from the blister support member 20, as shown in Figure 2B and in which the piercing blades 35 are kept out of the inserted blister. This is problematic because not only is it impossible to place the cap 22 on the device when the housing 21 is in its primed position, but it is also difficult to prevent the housing 21 from inadvertently rotating back into its home position when, for example, it is being carried in a pocket or handbag, thereby prematurely puncturing a preloaded blister.

In the present embodiment, the slot 63 is angled relative to the longitudinal axis of the piercing member and/or cyclone chamber within the housing 60 when the housing 60 is in its home position so that rather than inserting the blister laterally through the slot 63 in the side wall of the blister support member 61 after pivoting the housing 60 out of its home position, the blister is inserted at an angle thereto relative to the longitudinal axis A-A of the chamber and of the piercing member 62, in the direction of arrow 'X' as shown in Figure 7A, and at a downwardly directed angle in the orientation of the device as shown in the drawings. Because the blister is inserted at an angle relative to the longitudinal axis of the chamber within the housing 60, it does not foul the piercing blades 62 during insertion and the housing 60 can be maintained in an upright and aligned positon relative to the blister support member in its home position.

As can be seen from Figure 7A, the housing 60, incorporating the mouthpiece 60a, is pivotally mounted to the blister support member 61 along one long side of the device for rotation about axis 'A' and so that the housing 60 will pivot in the direction of arrow 'FT from the upright position shown in Figures 7A to 7C into the downwardly angled position shown in Figures 8A to 8C to pierce an inserted blister.

The blister support member 61 has an upper peripheral wall 65 that is angled away from the horizontal at the same angle as the slot 63 for insertion of the blister. The housing 60 also has a lower peripheral wall 64 that is horizontal when the housing 60 is in its home position and which extends at an acute angle relative to the upper peripheral wall 64 of the blister support member 61. When the housing 60 is pivoted relative to the blister support member 61, the upper peripheral wall 65 of the blister support member 61 and the lower peripheral wall 64 of the housing 60 meet and lie flush against each other. In this position the longitudinal axis A-A of the cyclone chamber is now substantially at right angles to the plane of the blister lid and the part of the blister that surrounds the blister bowl and the piercing elements are inserted through the plane of the blister lid into the blister bowl. An inner skirt 66 depends from the housing 60 within the confines of the lower peripheral wall 64 and which is received within the blister support member 61 when the housing 60 is rotated into its pierced position, as shown in Figures 8A to 8C.

As with the first embodiment, the blister support member 61 of the device has a lower supporting surface 67 to enable the device to be stood upright on a table or level surface.

As mentioned above, the blister may have tab 16d to facilitate its insertion into and removal from the device. If the device is preloaded ready for use, it is possible to fold part of the tab protruding from the device so that it lies flush against the side wall of the blister support member 61. As shown in Figure 7B, the side wall of the blister support member 61 may include a recess 68 to receive the folded tab 16d and the edge of the recess may have a lip 69 behind which the tab can be pushed to retain it in position against the side wall of the blister support member 61 until the blister needs to be removed.

An opening 70 is formed in the skirt 66 between the housing 60 and the blister support member 61 so that a patient can see into the device and visibly check to determine whether a blister is located therein and also whether it has already been pierced or not, as well as see the piercing elements 62 to check for damage or dirt.

A third embodiment of inhalation device will now be described with reference to Figures 9A to 10C. This embodiment is similar to the second embodiment and so like features will not be described again in detail. In this embodiment, the blister is again inserted at an angle to the horizontal or to the longitudinal axis of the cyclone chamber in its home or storage position but the slot 80 is in a shorter side wall of the device rather than in a longer front or rear wall, although the housing 85, incorporating the mouthpiece 85a, is still pivotal ly mounted to the blister support member 82 along an axis extending along a long side of the device.

Furthermore, the slot 80 is recessed within a bowl or hemispherically shaped depression 81 formed in the blister support member 82 so that the tab 16d of a blister does not protrude beyond the side walls of the device when a blister is inserted into the device. Therefore, it is not necessary to fold the blister tab 16d to move it out of the way in this embodiment. The bowl or depression 81 is of a size and configuration to enable a patient to insert a thumb and index finger therein on either side of a blister tab 16d so as to grasp the tab 16d and withdraw the blister from the device.

In the third embodiment, the blister support member 82 of the device is provided with upwardly facing convex shaped supporting walls 83 which mate with correspondingly shaped downwardly facing concave surfaces 84 formed on the housing 85. As the housing 85 is pivoted (in the direction of arrow 'R' from its home position shown in Figures 9A to 9C into its pierced position shown in Figures 10A to 10C) after insertion of a blister, the concave surfaces 84 of the housing 85 ride over the convex shaped supporting walls 83, thereby guiding movement of the housing 85 and ensuring that it is fully supported throughout its full range of movement.

As with the previous embodiment, the housing 85 has a skirt 86 that is received within the blister support member 82 and slides within it during pivotal movement of the housing 85. The skirt 86 has an aperture 87 to enable a user to see the piercing element 88 and also to enable them to ascertain whether a blister located in the device has already been pierced or not.

A fourth embodiment will now be described with reference to Figures 11 to 19 of the accompanying drawings. In this embodiment, the housing and the base are fixed relative to each other and the blister is received in a blister support member that has a lever portion extending from within the housing and which is pivotal ly mounted with respect to the housing and the base. An advantage of this embodiment over the previous embodiments is that the housing, together with the bypass cyclone, remains stationary and only the blister support element, together with the blister mounted thereto, is rotated to pierce the blister. The housing contains and mounts a bypass cyclone and blister piercing element, as previously described with reference to the previous embodiments and Figures 1 A and 1 B. Referring to the drawings, Figure 11 shows a perspective view of an inhalation device 100 according to the fourth embodiment having a housing 101 including a mouthpiece 101a, a base part 102 (see Figure 14) immovably attached to the housing 101 and a pivotally mounted blister support member 103 which is received within the housing 101 and held in place by the base 102. The blister support member 103 has a lever portion 103a that protrudes from a cut-out 101a formed in the wall of the housing 101. A cap 104 (shown as being transparent in Figure 11 ) extends over the housing 101 and locates on a shoulder 105 having a first part 105a formed at the lowermost edge of the housing 101 and a second part 105b formed at the lowermost edge of the portion 103a of the lever portion 103a that protrudes from the housing 101. The cap 104 thereby substantially covers the whole of the device, apart from the shoulder 105.

Figures 11 and 12 show the device with the lever portion 103a in its home or storage position in which the device is ready to receive a blister 16 by inserting it into the device through a slot 106 formed in the blister support member 103, in the angled direction of arrow shown in Figure 12. Figure 13 shows the device once a blister 16 has been fully inserted therein but prior to piercing. It will be noted that the blister support member 103 and the housing 101 together define a roughly hemispherically shaped recess 'FT in the side of the device and the tab 16d of the blister extends into this recess when the blister 16 is fully inserted into the device 100. This enables the cap 104 to be located over the device 100 so as to locate against shoulder 105 even when a blister 16 is received within it, with the blister tab extending into said recess without interference from the cap 104. As can be seen from the cross-sectional view of Figure 14, the blister tab 16d does not extend beyond the outer surface of the housing 101 or lever portion 103a and so does not come into contact with the cap 104. Therefore, the device 100 can be made-ready for later use (i.e. pre-loaded) by removing the cap 104, inserting a blister 16 into the device and by replacing the cap 104. It will be noted that the device remains in a stable position even when a blister has been inserted therein and it does not need to be primed i.e. moved into an unstable position to allow a blister to be inserted.

Figure 14 shows a cross-sectional view through the device with a blister 16 inserted therein and from which it can be seen that the blister bowl 16a is positioned below the blister piercing elements 35. To pierce the blister 16, the blister support member 103 is rotated by rotating the lever portion 103a in the direction of arrow ' and into the position shown in Figure 15. This can be achieved by placing a thumb on the underside 103b of the lever element 103 and a finger on a reaction surface 107 formed on the housing 101 on the opposite side of the recess R. By squeezing the thumb and finger together, the blister support member 103 rotates into the position shown in Figure 15 together with the blister 16. When the position shown in Figure 15 is reached, the blister tab 16d is located towards the top of the cut-out in the mouthpiece 101 and directly beneath the reaction surface 107. As the tab 16d is made relatively inaccessible in this position, a user is less inclined to attempt to pull on it so as to try and remove the blister 16 from the device whilst the blister support member 103 is in its pierced position.

The blister support member 103 has a support structure for the blister and blister bowl which is similar to that described with reference to the previous embodiments (with reference to Figures 6A to 6D) and so a description of it will not be repeated again here. However, in this embodiment, the blister support member 103 has a pair of spaced parallel legs 108 extending from the blister seat and an axle 109 extending between the legs 108 having protruding portions 109a extending from opposite sides thereof. The protruding portions 109a locate in openings formed in a corresponding pair of legs 110 depending from the cyclone element closure plate 111 (see Figure 14) so as to define an axis 'A' about which the blister support member 103 can rotate between its first, stable or home position and its, second, pierced position.

The blister support member 103 is also provided with a pair of resilient arms 112 depending from each side. Each arm 112 has a tongue 113 at its free end. A pair of spaced detents 114 are also formed on opposite sides on the inner wall of the housing 101 (see Figure 18) and positioned so that, when the blister support member 103 is in its home position, the tongue 113 of each arm 112 is received in one detent 114 and, when the blister support member 103 is in its pierced position, the tongue 113 is received in the other detent 114, the arm 112 resiliently deforming when the blister support member 103 is pivoted so that the tongue 113 is lifted out of one detent 114 and drops into the other detent 114 when the pierced position has been reached. The cooperation between the tongue 113 and the detents maintains the blister support member 103 in either its home or pierced position and ensures that the blister support member 103 will only rotate when sufficient force is applied to it in order to overcome the resilience of the arms 112 and lift the tongues 113 out of their detents 114. As the tongues 113 slide against the inner wall of the housing 101 between detents 114, this creates friction which prevents the blister support member 103 from falling under its own weight back into its home position, if it were to be released prior to reaching the pierced position.

As can be seen most clearly from Figures 13 and 17, the housing 101 has an arcuate guide surface 115 and the blister support member 103 has a corresponding guide member 116 that slideably cooperates with the guide surface 115 so as to guide pivotal movement of the blister support member 103 relative to the housing 101.

The base 102 may removably clip onto the housing 101. In particular, the base 102 is provided with a pair of resilient uprights 117 on each side, each upright having a head portion 118 that locates in an elongate aperture 119 in the housing 101. One of the head portions 118a protrudes through the aperture 119 so as to be slightly raised above the outer surface of the housing 101 and functions so as to hold the cap 104 in position over the device. This means that the cap 104 need not be a friction fit with the outer surface of the housing 101. It also ensures that, when a user removes the cap 104 from the device, pressure is applied only to the head 118a of the resilient upright 117 protruding through the housing 101 so as to deform that upright 117 and not the housing 101 itself. As shown in Figure 19, the cap 104 also has a detent 120 formed in its inner surface to receive the head portion 118a when the cap 104 is positioned on the device 100.

It will be appreciated that the cap 104 cannot be located over the device 100 when the blister support member 103 is in its pierced position. If an attempt is made to locate the cap 104 over the device 100 whilst the blister support member 103 is in its pierced position, the cap 104 will push against the blister support member 103 and cause it to rotate back into its home position as the cap 104 slides onto the device 100.

A preferred blister piercing member 34 for use with any inhalation device, including those of the present invention, is shown in Figures 20A to 20C and will now be described in more detail. The piercing member 34 is stamped from a flat plate 50 to form piercing blades 35 that depend downwardly out of the plane of the plate 50. Mounting arms 51 also extend laterally from the edges of the plate 50 at an angle to the plane of the plate 50. Tabs 52 extend from the free ends of the arms 51 in a plane parallel to the plane of the plate 50 and holes 53 are formed in the tabs 52 to facilitate connection of the piercing member 34 to the closure plate 28 during assembly so that the plate 50 is spaced from the surface of the cyclone chamber insert closure plate 28. As is apparent from Figures 20A and 20B, the piercing member 34 has four clean air inlet flow openings 54 spaced equidistantly and symmetrically around a central drug laden air outlet opening 55 so that clean air enters the blister bowl 16a through the air inlet flow openings 54 and entrains the dose contained in the blister bowl 16. The drug laden air then flows out of the blister bowl 16a through the central drug laden air outlet opening 55. The drug laden air outlet opening 55 is connected to the drug laden air inlet port 29 of the chamber 24 so that the drug laden air flows in an axial direction into the chamber 24. The peripheral clean air inlet flow openings 54 are isolated from the central drug laden air outlet opening 55 when the piercing member 34 has been mounted to the closure plate 28 so that all the drug laden air flows through the drug laden air outlet opening 55 and via the drug laden air inlet port 29 into the chamber 24.

It will be appreciated from Figures 20A and 20B, that the blades 35 of the peripheral drug flow inlet openings 54 are all the same size and shape and are formed by bending them out of the plane of the plate along edges or fold lines 56 that connect the blades to the plate 50. Each blade 35 is folded out of the plane of the plate 50 by the same angle of approximately 45 degrees. The fold lines 56 of opposite, non-adjacent blades 35 are parallel to each other whereas the fold lines of adjacent blades 35 are arranged at an angle of 90 degrees to each other so that they are oriented symmetrically. The blade 35a forming the central drug laden air outlet openi ng 55 also depends from the plane of the plate 50 along a fold li ne 57. Fold li ne 57 preferably extends at 45 degrees to each of the fold li nes 56 of the drug flow i nlet openi ngs 54. The drug flow outlet openi ng 55 and its correspondi ng bl ade 35a may be larger than each of the drug flow i nlet openi ngs 54 and thei r correspondi ng bl ades 35.

Although the device accordi ng to the embodiments of Figu res 7A to 1 9 are intended to be preloadabl e, as expl ai ned above, it is also envisaged that it could be used i n the sam e way as the first embodiment of Figures 2A to 6D and i n which a bl ister is i nserted into the device immedi ately prior to use.

Although not shown i n the embodiments of Figures 7A to 1 0C, it wi ll be appreciated that the device may be provided with a cap, as with the first embodiment. The cap may be placed over the mouthpi ece and base of the device i rrespective of whether a bl ister has been inserted i nto the device ready for piercing at a later time.

As mentioned herein a further aspect of the invention, there is disclosed a particulate formulation comprising an active agent and magnesium stearate, wherein the formulation exhibits a consistent blister evacuation and/or FPD over a period of at least 1 month from filling the blister.

In embodiments the particulate formulation may use the devices hereinbefore disclosed and/or use any of the carriers, FCAs and active ingredients disclosed herein.

In a specific embodiment, the particulate formulation in blisters is prepared by use of a fill to weight machine (e.g. the 3P innovation fill2weight machine - 3P Innovation Ltd, Welton Road, Warwick, Warwickshire, CV34 5PZ, UK). In a further embodiment, the consistent blister evacuation and/or FPD is exhibited for at least 2, 3, 4, 5, 6, 7, 8, 9, 10, 1 1 or 12 months, up to a maximum of 4 years (e.g. a maximum of 3 years or, particularly, 2 years) from filling the blister.

In a further embodiment, the formulation may be placed into a suitable container following its manufacture. For example, the formulation may be placed into blisters following its manufacture using a fill to weight machine or the formulation may be placed into an amber jar and optionally sealed in a foil pouch (or similar moisture exclusion method) until the formulation is required to be placed into blisters using said fill to weight machine. The formulation is generally placed into a container within 1 hour or within 24, 36, 48, 72 or 100 hours of its manufacture. In the period from manufacture to being placed within a container it may be exposed to ambient conditions (e.g. 18-24^<€, 40-60%RH).

There is also provided further aspects of the invention:

(a) a method of making the particulate formulation comprising an active agent and

magnesium stearate, wherein the formulation exhibits a consistent blister evacuation and/or FPD over a period of at least 1 month from filling the blister, wherein the formulation is placed into a blister using a fill to weight machine (e.g. 3Pi fill2weight machine);

(b) a blister comprising a particulate formulation comprising an active agent and magnesium stearate, wherein the formulation exhibits a consistent blister evacuation and/or FPD over a period of at least 1 month from filling the blister;

(c) a device (e.g. device XX) comprising a particulate formulation comprising an active agent and magnesium stearate, wherein the formulation exhibits a consistent blister evacuation and/or FPD over a period of at least 1 month from filling the blister; and

(d) a particulate formulation comprising an active agent and magnesium stearate, wherein the formulation exhibits a consistent blister evacuation and/or FPD over a period of at least 1 month from filling the blister obtainable by placing said formulation into a blister using a fill to weight machine (e.g. 3Pi fill2weight machine).

Embodiments of (a) to (d) may utilise the embodiments described for the particulate formulation disclosed herein. Further embodiments of (a) to (d) may also use the devices hereinbefore disclosed and/or use any of the carriers, FCAs and active ingredients disclosed herein .

"Consistency" as used in relation to the particulate formulation aspect and aspects (a) to (d) is as defined hereinbefore.

The aspects of the invention described herein (e.g. the above-mentioned compounds, combinations, methods and uses) may have the advantage that, in the treatment of the conditions described herein, they may be more convenient for the physician and/or patient than, be more efficacious than, be less toxic than, have better selectivity over, have a broader range of activity than, be more potent than, produce fewer side effects than, or may have other useful pharmacological properties over, similar compounds, combinations, methods (treatments) or uses known in the prior art for use in the treatment of those conditions or otherwise.

It will be appreciated that the foregoi ng description is given by way of exam ple only and that modifications may be made to the support assem bly of the present i nvention without departi ng from the scope of the appended clai ms.

Examples

Itraconazole was used as an active in the following examples.

1 Manufacturing Processes - Laboratory Scale

Scale

As used herein, the AS50 is typically used to produce batches of approx. 30g, although larger batches have been produced of up to 3kg. As used herein, the Mini kit is typically used to produce final batch sizes of ~30g but larger batches have been produced by combining portions (approximately 18g-100g).

Jet milling control

100% itraconazole (ITZ) was jet milled (JM) using the AS50 (Spiral jet mill manufactured by Hosokawa Alpine) at venturi pressure 5 and grind pressure 3 bar at a feed rate of 2g/min.

Jet milling active + FCA

Jet milling of ITZ was carried out in the presence of a force control agent such as 2% or 5% magnesium stearate (MgSt) or other excipient as disclosed in the result herein.

Using magnesium stearate by way of example, itraconazole and magnesium stearate were sandwiched together in glass jar and mixed by Turbula for 10 mins at 30 rpm. The mixture was jet milled using the AS50 at venturi pressure 5 and grind pressure 3 bar, at a feed rate of 2g/min.

Magnesium stearate was used at 2 or 5% by weight of the formulation (the remainder being itraconazole).

Compression and shearing

Where mechanofusion (MCB) was used, typically components were blended and jet milled as above prior to MCB processing.

The MCB Machine was the Hosokawa Micron AMS Mini Kit. (The Nobilta 300, another Hosokawa MCB machine which is a larger scale MCB machine is an alternative).

The MCB Gap size was selected as between 0.5mm - 3mm.

A typical MCB process was performed as follows:

The material to be processed is added (for example over a period of 2 minutes) with the apparatus rotating at a low speed (e.g. 5% of the maximum possible processing speed).

Then the material is processed at a higher speed (e.g. 20% of the maximum possible processing speed), for a period of time (e.g. 5 minutes).

Finally, the material is processed at high speed (e.g. 80% of the maximum possible processing speed), for a period of time (e.g. 10 minutes).

The corresponding rpm and calculated tip speeds for the process, are as follows: Material loading Stage = e.g. 5% speed for 2 min = 320rpm = 1 .3 meters per second (m/s) Pre-mix Stage = e.g. 20% speed for 5 min = Pre-mix = 1275rpm = 5.2 m/s

MCB Processing Stage = e.g. 80% speed for 10 min = 51 OOrpm = 20.8 m/s

Alternatively, where mechanofusion (MCB) was used to further process the powder, the

Hosokawa Micron AMS mini kit was used with a gap setting of 0.5-3mm. The processing speed was set to 20% for 5 mins to pre-mix before being gradually increased to 80% and held. The total processing time was 15 mins.

Alternatively (additional additives):

Where a further additive is used, then generally ITZ and the FCA were mixed by Turbula and jet milled and then mixed by MCB processing as described above. A second additive may be then mixed to the resulting formulation by Turbula. For example ITZ, magnesium stearate and sorbitol formulations and ITZ, magnesium stearate and aspartame formulations may be prepared in this way. Particularly when the second additive has a larger particle size than the ITZ:MgSt components, the second additive is Turbula mixed at a speed between 30-90rpm to the jet milled/MCB ITZ/MgSt.

Alternatively:

ITZ and FCA and a second additive were all mixed by Turbula, jet milled and then mixed by MCB processing as described above. ITZ, magnesium stearate and cellulose acetate formulations may be prepared in this way.

The ITZ:MgSt may be loosely attached to the second additive so it separates from itraconazole during aerosolisation. This could allow the second additive (with a larger particle size D50-15- 60μηι) to deposit in a different region of the lung or oral-pharyngeal route such as the mouth and throat, this would be beneficial if the second additive has taste masking properties.

As a further alternative, a second excipient (typically Respitose SV003, Respitose SV010, Respitose ML006, sorbitol, aspartame and cellulose acetate) may be added to the active powder and tumble mixed for 10mins at 30-44rpm.

Results are illustrated in the tables below (XX Device indicates the preferred device according to the invention):

Table 1 indicates properties of tested additives/excipients

Table 2 demonstrates properties of Jet milled and MCB Formulations (Itraconazole [ITZ] and MgSt)

Table 3 demonstrates properties of jet milled formulations with different additives Table 4 demonstrates alternative excipients to magnesium stearate for use in MCB Table 5 demonstrates properties of formulations with two excipients.

Table 6 shows the 1 month stability data for XX Device blisters stored at 40^qC/75RH (in most instances the FPM performance increases after storage).

Tables 7 and 8 shows up to twelve months stability data for bulk jet-milled formulations of ITZ and magnesium stearate stored in amber glass jars sealed in a foil pouches for the indicated time under either 25 ^<€/60%RH or 40°C/75%RH. The test blisters were hand-filled and rested for approximately 24 hours before testing in order to minimise electrostatic effects (under ambient conditions of between 1 8-24 40-60%RH). All tests in these tables were conducted using a monohaler device.

Table 9 shows stability data for bulk formulations with two excipients, where the ITZ and the first excipient (magnesium stearate) are blended by turbula mixing, jet-milled and then subjected to mechanofusion. A second excipient (as indicated) is then added to the mechanofused formulation and mixed by turbula blending. The bulk formulations and test blisters were prepared and stored in the same manner as those described for Tables 7 and 8. All tests were conducted using the XX device.

Table 10 shows stability data for blisters filled with ITZ formulations containing one or two excipients (as shown in table). The formulations were prepared in line with the methods described in Tables 7 to 9 and were subsequently hand filled into blisters for the XX Device.

Unless otherwise stated, all data were generated using the preferred device of the invention as disclosed in the Figures herein.

Table 1

Table 2

%RSD in the tables refers to the relative standard deviation

• Adding 2%MgSt improves SW (blister evacuation), Delivered Dose, FPM.

• Without MgSt the formulation cannot undergo the MCB process.

• MCB with 2%MgSt improves consistency of performance. Table 3

Tabl e 4

Alternative Excipients to Magnesium Stearate (MCB)

Table 5

MCB Formulations with two excipients in XX Device(95:2.5:2.5%w/w ITZ:MgSt:excipient or 80:2.5:17.5%w/w ITZ:M St:excipient where stated)

FSI= (Fast Screen Impactor) an alternative impactor to the NGI that only characterises the FPM at <5μηι

SV010 and ML006 are grades of lactose.

All 1 mm gap Table 6

SV010 and ML006 are grades of lactose. All 1mm gap

Tabl e 7

Bul k stability trial of ITZ:MgSt (98:2) formul ation usi ng Monohaler Device

Manufacture process: Lab scale manufacture ITZ:MgSt turbula mixed (30rpm, 10 mins). Then Jet mill (AS50, 2g/min feed, 5 bar venturi, 3 bar grind) Hand filled blisters

Tabl e 8

Bul k stability trial of ITZ:MgSt (98:2) formul ation usi ng Monohaler Device

Table 9

Bulk Stability trial of ITZ blends containing a second excipient using XX Device

Manufacturing process: Lab scale manufacture ITZ:MgSt turbula mixed, co-jet milled (2g/min feed, 5 bar venturi, 3 bar grind), then MCB processed. Second excipient then added and all turbula mixed. Hand filled blisters

Table 10 - Stability data for blisters filled with ITZ formulations containing one or two excipients, used with Device XX.

Manufacturing process: Lab scale manufacture ITZ:MgSt (or ITZ:ZnSt) turbula mixed, co-jet milled (2g/min feed, 5 bar venturi, 3 bar grind), then MCB processed. Second excipient (if present) then added and all turbula mixed. Hand filled blisters.

2 Manufacturing Processes - Pilot Scale

As will be appreciated, the processes outlined in respect of Example 1 may be adapted for use on a larger scale. As indicated below, scale up of the process may result in an inproved formulation.

Scale

Equipment - AS100 jet mill and Nobilta 300 for MCB are considered to be pilot scale (scale up). This equiptment has been used to produce final batch sizes of up to approx. 2.5kg.

Jetmilling active and FCA

ITZ was tumble mixed with force control agent (MgSt) at 44rpm for 1 0 minutes. The resulting powder was then jet milled using the AS100 at a feed rate of 22g/min, 5 bar Venturi Pressure and

3 bar Grind Pressure.

Compression and shearing

Mechanofusion (MCB) was used to further process the powder. The Nobilta 300 was used with a gap setting of 2-4mm. The processing speed was gradually increased to between 668-1343rpm and held. The total processing time was between 7-10 mins

Combination with lactose (Respitose SV003)

The lactose was added to the active powder and tumble mixed for 1 0mins at 44rpm.

Table 1 1 shows stability data for bulk formulations with two excipients, where the ITZ and the first excipient (magnesium stearate) are blended by turbula mixing, jet-milled and then subjected to mechanofusion. A second excipient (SV003 lactose) is then added to the mechanofused formulation and mixed by turbula blending (to generate a ratio of 95:2.5:2.1 (ITZ:MgSt:Lactose (SV003), respectively)). The bulk formulations and test blisters were prepared and stored in the same manner as those described for Tables 7 and 8, except that a fill to weight machine was used to fill the blisters. All tests were conducted using the XX device.

Table 12 shows stability data for bulk formulations with two excipients, where the ITZ and the first excipient (magnesium stearate) are blended by turbula mixing, jet-milled and then subjected to mechanofusion. A second excipient (SV003 lactose) is then added to the mechanofused formulation and mixed by turbula blending (to generate a ratio of 95:2.1 :2.5 (ITZ:MgSt:Lactose (SV003), respectively)). The bulk formulations and test blisters were prepared and stored in the same manner as those described for Tables 7 and 8 unless otherwise indicated (unpouched means that the amber jar was not sealed in a foil pouch). All tests were conducted using the XX device.

Table 1 1

Manufacturing process: Pilot scale manufacture: ITZ:MgSt turbula mixed (44rpm, 10 mins). AS100 Jet milled (22g/min feed, 5 bar venturi, 3 bar grind). MCB (Nobilta - gradually increased to 668rpm and held. Total time 7mins. Approx gap 2-4mm). Lactose added, turbula mixed (44rpm, 10 mins). Blisters filled using 3Pi fill to weight equipment.

Table 12

Manufacturing process: Pilot scale manufacture of ITZ:MgSt turbula mixed (44rpm, 10 mins). AS100 Jet milled (22g/min feed, 5 bar venturi, 3 bar grind). MCB (Nobilta - gradually increased to 1343rpm and held. Total time 10mins. Approx gap 2-4mm). Lactose added, turbula mixed (44rpm, 10 mins) Hand filled blisters

3 Filling Machines

A filling trial using Harro Hofliger table top filler, 3P innovation fill2weight™ and the 3P

LabDosator (3P innovation), assess filling reproducibility, evacuation and FPM, as set out in Table 13. Blisters were tested using XX Device. The table top filler was too variable, so is not included below. The above mentioned devices may be obtained from the companies mentioned and were unmodified.

Table 13

Rll to Weight blisters (3P innovation fill2weight machine)

Formulation Manufacture Method Rll Mean FPD (mg) weight %evacuation (n=3) (mg) (n=10) (%RSD)

(%RSD)

ITZMgS 95:5 Turbula mix ITZMgS 10 24.73 92.9 (2.3) 5.69 (10.3) OZ100629KOC mins @30rpm

co-jet mill, AS50, 2g/min,

5bar venturi/3bar grind

MCBat 80%

ITZMgS: lactose Turbula mix ITZMgS 10 25.06 93.1 (1.6) 5.59 (2) S^01095:2.5:2.5 mins @30rpm

OZ100630KCB co-jet mill, AS50, 2g/min,

ITZMgS :lactose 5bar venturi/3bar grind 24.92 92.7 (2.8) 4.24 (11.2) S 01080:2.5:17.5 MCBat 80%

OZ100630KOC Addition second excipient

ITZMgS :lactose via turbula mix, 10mins 24.95 92.1 (1.6) 4.6 (58.1 ) ML00680:2.5:17.5 @90rpm

OZ100630KCD

ITZMgS :S)rbitol 24.99 92 (2.3) ND

95:2.5:2.5

CIZ100603KCA

ITZMgS :Aspartame 24.75 94 (1.3) 6.6 (1.1)

95:2.5:2.5

QZ100705RPB

The 3Pi fill2weight machine was the best filling method as it gave the best aerosol performance and also appears to help to break up agglomerates in the formulation. It is also noted that the formulations prepared using the 3Pi fill2weight device appear to have superior FPD properties, even over extended storage (see, for example, the results set out in Table 1 1 ).

Claims

1 A dry powder formulation suitable for delivery by inhalation comprising an

antifungal agent and a force control agent.

2 A dry powder formulation according to claim 1 wherein said antifungal agent is an azole antifungal agent, preferably selected from imidazoles and triazoles.

3 An inhaler comprising a dry powder formulation according to claim 1 or claim 2.

4 An inhaler according to claim 2 wherein the formulation is comprised within a blister.

5 A kit comprising an inhaler and a blister, the blister suitable for use in the inhaler and comprising an antifungal agent according to claim 2.

6 An inhaler according to claim 3 for use in prevention or treatment of fungal infections, or diseases that may arise from fungal infections or spores, the prevention or treatment comprising delivery of an effective amount of an antifungal agent to an individual in need thereof.

7 A formulation according to claim 1 or claim 2, for use in treatment of a fungal infection or disease resulting therefrom, wherein the antifungal agent is delivered by inhalation using an inhaler.

8 A method of prevention or treatment of a fungal infection or disease resulting therefrom, the method comprising delivery to an individual in need thereof an effective amount of a formulation according to claim 1 or claim 2, wherein the delivery is by inhalation using an inhaler.

9 A blister comprising a formulation according to claim 1 or claim 2.

10 A method for the preparation of an antifungal agent for delivery by inhalation, the method comprising subjecting the antifungal agent to compression and shearing force in the presence of a force control agent.

11 A method according to claim 10, wherein the antifungal agent is in a micronized form prior to compression and shearing.

12 An inhaler according to any of claims 3-6, wherein the inhaler comprises a housing having a mouthpiece through which a user may inhale a dose of medicament and a blister support member having a slot to receive a dose containing blister, the housing and the blister support member being pivotable relative to each other between a first position for insertion of a blister into said slot and, a second, pierced position, in which a blister piercing element carried by the housing pierces an inserted blister so that when a user inhales on the mouthpiece, the dose is entrained in an airflow and flows out of the blister through the mouthpiece and into the user's airway.

13 A inhaler, formulation, kit, use, method, or blister according to any preceding claim wherein the antifungal agent is itraconazole.

14 A inhaler, formulation, kit, use, method, or blister according to any preceding claim wherein the force control agent comprises a metal stearate.

15 An inhaler, kit, use, method, formulation or blister according to any preceding claim wherein the antifungal agent is combined with an additional force control agent.

16 A inhaler, kit, use, method, formulation or blister according to any preceding claim wherein the antifungal agent is itraconazole wholly or partially coated with magnesium stearate.

17 A inhaler, kit, use, method, formulation or blister according to any preceding claim wherein the antifungal agent is for prevention or treatment of asthma, such as uncontrolled asthma with underlying fungal sensitisation.

18 An inhaler comprising a housing having a mouthpiece through which a user may inhale a dose of medicament and a blister support member having a slot to receive a dose containing blister, the housing and the blister support member being pivotable relative to each other between a first position for insertion of a blister into said slot and, a second, pierced position, in which a blister piercing element carried by the housing pierces an inserted blister so that when a user inhales on the mouthpiece, the dose is entrained in an airflow and flows out of the blister through the mouthpiece and into the user's airway, the inhaler comprising a blister, the blister comprising an antifungal agent.

19 An inhaler according to claim 20, wherein the antifungal agent is an azole antifungal agent, preferably selected from an imidazoles and triazoles.