WO2009013213A2

WO2009013213A2 - Method for charging an aerosol canister with a propellant drug formulation

Info

Publication number: WO2009013213A2
Application number: PCT/EP2008/059359
Authority: WO
Inventors: Patrick Di Giovanni; Yves Marie Jean Luc Quiniou
Original assignee: Glaxo Group Limited
Priority date: 2007-07-20
Filing date: 2008-07-17
Publication date: 2009-01-29
Also published as: WO2009013213A3; GB0714239D0

Abstract

Method There is provided a method of charging an aerosol canister with a propellant drug formulation. The method comprises the steps of: (i) selecting an aerosol canister; (ii) metering a defined quantity of an active drug in dry powder form into said aerosol canister; and (iii) separately introducing a propellant into the aerosol canister.

Description

Method

The present invention relates to a method of charging (e.g. filling) an aerosol canister for use in a drug dispenser that is suitable for use in delivering metered doses of propellant drug formulation and suitably adapted for use with an oral or nasal inhaler.

Drug dispenser devices in the form of inhalers arranged for the metered delivery of aerosol form drug formulation from an aerosol canister thereof are well-known in the prior art, and are commonly referred to as metered dose inhaler (MDI) devices. The drug formulation typically comprises an active drug component; a propellant; and optionally other components such as solvent or surfactant. Metered dispensing of the propellant drug formulation is arranged by means of a metering mechanism, typically a metering valve (e.g. a slide valve), that is provided to the aerosol canister. Typically, the canister is housed within an actuator housing that is arranged to facilitate user actuation of the valve and release of a metered quantity of aerosolized drug formulation, typically through a mouthpiece for inhalation by the user.

Conventional methods of charging the aerosol canister with drug formulation involve the preparation of a pre-mix (e.g. suspension or solution form) of the active drug and propellant, and also optionally other components, which pre-mix is then introduced into the aerosol canister, typically by charging through the valve thereof or by charging an open canister in environmental conditions (temperature and pressure) which maintain the propellant in its liquid state followed by addition of the valve. It is highly desirable that the drug formulation contents of each so-filled aerosol canister are uniform in nature. Such conventional methods of charging therefore require careful analytical monitoring of the homogeneity of the pre-mix, which is typically prepared in a large batch vessel, to ensure that successive introductions of that pre- mix into aerosol canisters on the production line are both homogeneous and of uniform concentration. Applicant recognizes that this need for careful monitoring can add to complexity and cost of the conventional charging method when carried out on an industrial scale. Applicant now proposes an alternative method of charging the aerosol canister that provides for good homogenization and reduces the need for such careful analytical monitoring. Applicant's method involves in a first step, the metering of dry powder form active drug into the canister. Optionally, at this stage other non-propellant components may also be added. The aerosol canister is then separately filled with propellant (e.g. by way of a valve). Thus, Applicant's method does not require the preparation of a drug/propellant pre-mix and hence, avoids the need to monitor the homogeneity of that pre-mix when charging different aerosol canisters on the production line. Complexity and cost are thereby reduced.

The present invention proposes to provide an alternative method of charging an aerosol canister with a drug / propellant formulation.

According to a first aspect of the present invention there is provided a method of charging an aerosol canister according to claim 1 hereof.

There is provided method of charging (e.g. filling) an aerosol canister with a propellant drug formulation. By 'propellant drug formulation' herein it is meant a formulation that comprises both at least one active drug component and a propellant component. Optionally, other components such as one or more solvents, excipients or surfactants may also be comprised within the propellant drug formulation.

The method comprises the first step of selecting an aerosol canister. In embodiments, the aerosol canister adopts a generally cylindrical form and has a longitudinal axis defined by the central axis of the cylinder. The aerosol canister is in embodiments arranged to have a neck at one end. The aerosol canister is typically comprised of metal (e.g. aluminium or stainless steel).

The method comprises a subsequent step of metering a defined quantity of at least one active drug in dry powder form into the aerosol canister, typically through an open mouth thereof. The defined quantity of the at least one active drug in dry powder form is selected according to both the desired active drug dosage and number of doses of active drug to be comprised within the aerosol canister.

It is envisaged that the dry powder form active drug is free from any propellant, thereby contrasting with prior art methods in which a pre-mix of active drug and propellant (e.g. in solution or suspension form) is employed.

Any suitable methods of metering a dry powder are suitable including those making use of powder dosating (e.g. dosimeter) apparatus. One suitable powder dosimeter apparatus is sold under the trade name "Omnidose" by Harro Hόfliger Verpackungsmaschinen GmbH of Helmholtzstraβe 4, 71573 Allmersbach im TaI, Germany. Suitable powder dosimeter apparatus are also described in United States Patent Application No. US2005/023,288, the entire content of which is incorporated herein by reference.

In embodiments, the at least one active drug is in particulate form and has a mean particle size of less than 10 micrometers.

In embodiments, two or more active drug components are metered into the aerosol canister. In embodiments the two or more active drug components are metered into the aerosol canister by means of separate metering steps. In embodiments, a mixture of two or more active drugs is metered into the aerosol canister by means of a single metering step, for example by forming a homogenous blend comprising the various actives and then placing a metered quantity of the blend into the aerosol canister.

In embodiments, the at least one active drug forms part of a mixture with other dry powder components (e.g. one or more excipients) and this mixture is metered into the aerosol canister. In embodiments, the active drug active drug or active drugs is in the form of an agglomerated particle, wherein in embodiments, the co-agglomerant to the drug comprises a pharmaceutically inert material. In embodiments, the active drug or active drugs is in the form of a coated particle, wherein in embodiments, the coating of the drug comprises a pharmaceutically inert material. The method includes the further step of separately introducing a propellant into the aerosol canister. That is to say, the propellant is added separately to and after addition of the at least one active drug in dry powder form. Alternatively, although perhaps less preferably, the at least one active drug in dry powder form could be added after addition of the propellant to the aerosol canister.

The drug-propellant formulation formed by the method of the invention may be a suspension or a solution formulation. In other words, the powder particles of the at least one active drug (drug particles) may be suspended or dissolved in the formulation (which may only additionally contain the propellant or a mixture of the propellant with other components, as detailed herein).

In embodiments, the method additionally includes the step of introducing a valve to the aerosol canister.

In preferred embodiments, the valve is a metering valve, for example a slide valve, which in dispensing use, acts as a discharge mechanism for aerosolized release of the drug propellant formulation to the user. The aerosol canister is generally designed to deliver a predetermined dose of drug upon each actuation by means of the valve, which can be opened either by depressing the valve while the canister is held stationary or by depressing the canister while the valve is held stationary. Typically, the valve is provided with a spring mechanism (or other biasing mechanism) that provides a degree of bias that must be overcome in order to allow discharge of drug from the discharge mechanism. Typically, that spring mechanism also acts as a return mechanism to return the valve to its rest state after firing thereof.

In more detail, the valve typically comprises a valve body having an inlet port through which the drug propellant formulation may enter said valve body, an outlet port through which the drug propellant formulation may exit the valve body and an open/close mechanism by means of which flow through said inlet and outlet ports is controllable.

In embodiments, the valve is a slide valve wherein the open/close mechanism comprises a sealing ring and receivable by the sealing ring a valve stem having a dispensing passage, the valve stem being slidably movable within the ring from a valve-closed to a valve-open position in which the interior of the valve body is in communication with the exterior of the valve body via the dispensing passage.

Typically, the valve is a metering valve. The metering volumes are typically from 10 to 100 μl, such as 25 μl, 50 μl or 63 μl. In embodiments, the valve body defines a metering chamber for metering an amount of propellant drug formulation and an open/close mechanism by means of which the flow through the inlet port to the metering chamber is controllable. Preferably, the valve body has a sampling chamber in communication with the metering chamber via a second inlet port, said inlet port being controllable by means of an open/close mechanism thereby regulating the flow of propellant drug formulation into the metering chamber.

The valve may also comprise a 'free flow aerosol valve' having a chamber and a valve stem extending into the chamber and movable relative to the chamber between dispensing and non-dispensing positions. The valve stem has a configuration and the chamber has an internal configuration such that a metered volume is defined therebetween and such that during movement between its non- dispensing and dispensing positions the valve stem sequentially: (i) allows free flow of aerosol formulation into the chamber, (ii) defines a closed metered volume for propellant drug formulation between the external surface of the valve stem and internal surface of the chamber, and (iii) moves with the closed metered volume within the chamber without decreasing the volume of the closed metered volume until the metered volume communicates with an outlet passage thereby allowing dispensing of the metered volume of propellant drug formulation. In embodiments inner parts of the valve (e.g. those which in dispensing use, will contact the propellant drug formulation) are coated with material (e.g. fluoropolymer material) that reduces the tendency of drug to adhere thereto. As an example, the metering chamber of the metering valve may be so coated, for instance by cold plasma polymerisation. Any movable parts may also have coatings applied thereto, which enhance their desired movement characteristics. Frictional coatings may therefore be applied to enhance frictional contact and lubricants used to reduce frictional contact as necessary.

In embodiments, the method additionally includes the step of fixing the valve to the aerosol canister. Typically, the valve is fixed to (the open mouth end of) the aerosol canister by means of a crimping operation such as to a neck thereof. Such crimping operations are widely known in the art and typically, performed by means of a suitable crimping head.

In embodiments, the step of fixing the valve to the aerosol canister is conducted prior to introducing the propellant into the aerosol canister. In embodiments, the step of separately introducing a propellant into the aerosol canister is by way of a valve, which has been fixed thereto. Typically, the propellant is introduced by engaging the valve stem of the valve with a filling head and introducing (e.g. pumping) the propellant through the valve stem, and hence into the aerosol canister. Such 'valve- filling' techniques are widely known in the art.

In other embodiments, the step of fixing the valve to the aerosol canister is conducted subsequent to introducing the propellant into the aerosol canister. In embodiments, the step of separately introducing a propellant into the aerosol canister is by way of a valve, which has been placed thereon but not fixed thereto. Typically, the propellant is introduced by engaging the valve stem of the valve with a filling head and introducing (e.g. pumping) the propellant through the valve stem, and hence into the aerosol canister. Such 'valve-filling' techniques are widely known in the art. In other embodiments, the step of separately introducing a propellant into the aerosol canister is by way of the open mouth of the canister, wherein such 'open mouth' introduction step is typically carried out at a temperature where the propellant is in its liquid state (the formulation normally comprises a liquefied gas propellant, as known in the art).

In embodiments, the method includes the additional step of purging the canister with propellant. Such purging is typically, carried out to empty (i.e. purge) the aerosol canister of air contained therein. In embodiments, the purging step is carried out either prior to or subsequent to metering the at least one active drug into the aerosol canister. In embodiments, the purging step is carried out either prior to or subsequent to introducing the valve to the aerosol canister. Purging is generally conducted using a purging cannula or purging head for introducing (e.g. injecting) propellant into the aerosol canister.

Optionally, other components may also be added to the aerosol canister such as one or more surfactants in liquid or solid form; one or more solvents; one or more excipients; or other adjuvant components and any mixtures thereof. In embodiments such other components may either be added prior to, at the same time, or subsequent to the metered addition of the powder form active drug to the aerosol canister. In embodiments such other components may either be added prior to, at the same time, or subsequent to the step of introducing the propellant to the aerosol canister. In embodiments, a micro dispenser is used for addition of some or all of the optional other components to the aerosol canister. In embodiments, the other components may be added before or after introducing or fixing the valve to the canister.

It will be appreciated that the method herein is suitable for use on a laboratory scale; on a pilot plant scale or on an industrial scale such as on a production line. Any or all of the method steps herein, may therefore be automated such as to enhance production speeds.

The method herein may provide for good homogeneity of the drug propellant formulation as charged into the aerosol canister. Other benefits achievable include increased production rate, reduced cleaning and batch change time and reduced product quality issues compared to conventional 'pre-mix' based charging methods.

Once charged with propellant drug formulation the aerosol canister with valve herein is suitable for use in a drug dispenser device. In preferred embodiments, the drug dispenser device is an inhaler such as of the well-known "metered dose inhaler"

(MDI) type for example, a hand-held, hand-operable breath-coordinated MDI. In such a MDI, the patient manually actuates the MDI for release of the drug from the drug discharge device while concurrently inhaling at the outlet. Thus inhalation and actuation are coordinated. In embodiments, the drug dispenser device may also be a breath-operated MDI, where the inhalation event itself actuates the MDI so that no patient coordination is required.

The drug dispenser device typically comprises an actuator that defines a housing. The housing may have any suitable form but is in embodiments sized and shaped for ready accommodation by the hand of a patient. In particular, the housing is sized and shaped to enable one-handed operation of the drug dispenser device.

Extending from the housing, there is generally provided an outlet for insertion into a body cavity of a patient. Where the patient body cavity is the mouth of a patient, the outlet is generally shaped to define a mouthpiece. Where the patient body cavity is the nose of a patient, the outlet is generally shaped in nozzle form for receipt by a nostril of the patient. The outlet may be provided with a removeable protective cover such as a mouthpiece cover or nozzle cover.

In embodiments, the valve stem (or discharge channel of other type of metering mechanism on the canister) is received by a cavity or passage provided to a part (e.g. block form) of the housing, which cavity or passage enables communication with the outlet for dispensing of discharged drug propellant formulation to a patient. In preferred embodiments, the valve stem is received within a stem block provided to the housing, which stem block includes a passage which acts such as to channel discharged aerosolized drug from the valve stem to the outlet.

In embodiments, the drug dispenser device is provided with side actuator levers and in particular has the form of any of the drug dispenser devices disclosed in U.S. Provisional Applications Nos. 60/823,139 and 60/823,141 , both filed on 22 August 2006; and U.S. Provisional Application No. 60/894,537 filed on 13 March 2007, all commonly owned, which are incorporated herein by reference in their entirety.

Additional aspects and features of the present invention are set forth in the claims and in the description of exemplary embodiments of the present invention which now follow with reference to the accompanying Figures of drawings. Such exemplary embodiments may or may not be practiced mutually exclusive of each other, whereby each embodiment may incorporate one or more features of one or more of the other embodiments. It should be appreciated that the exemplary embodiments are set forth to illustrate the invention, and that the invention is not limited to these embodiments.

Figure 1 shows a perspective side view of a drug dispenser device of the MDI type that may be provided with an aerosol canister charged with drug propellant formulation according to the method herein;

Figure 2 shows a sectional side view of the neck and valve of an aerosol canister that may be charged with drug propellant formulation according to the method herein;

Figures 3a to 3e show schematic representations of sequential steps in a first method of charging an aerosol canister herein;

Figure 4 shows a schematic representation of a dosimeter as might be used in the step shown at Figure 3c; and Figures 5a to 5d show schematic representations of sequential steps in a second method of charging an aerosol canister herein.

Turning now to the drawings, Figure 1 shows a drug dispenser device 30 that is in the well-known form of a hand-held, hand-operable, breath coordinated metered dose inhaler (MDI). This type of device requires a patient to coordinate their inhalation at a dispensing outlet of the device (in this embodiment, a mouthpiece 32) with manual actuation of the device so that the inhalation is coordinated with release of drug from the device so that drug is entrained by the inhalation airflow to the target location in the respiratory tract (in this case, the lungs) of the patient.

The device 30 comprises an actuator housing 31 of generally upright cylindrical form which is, in this embodiment, formed from plastic. It will be noted that the overall form of the housing is arranged for ease of receipt by a user's hand such that in general terms lower housing part 33 is received by the user's palm or thumb. Mouthpiece 32 may be protected by removeable mouthpiece cover (not shown), and extends from the front of lower housing part 33 and is arranged in use, for insertion into the mouth of a patient for inhalation therethrough.

Provided to the housing 31 , there is a drug discharge device, which takes the form of cylindrical valved aerosol canister 10 of the type commonly known for use in an MDI. Further details of an exemplary aerosol canister 10 and valve 20 thereof may be seen by reference to Figure 2. Within the actuator housing, valve stem 26 of the valve 20 is received within a stem block (not visible) provided to the housing, which stem block includes a passage which acts such as to guide discharged aerosolized drug from the valve stem 26 to the mouthpiece 32.

The aerosol canister 10 has a body made of metal, for instance of stainless steel or, more preferably, of aluminium or an aluminium alloy. The aerosol canister 10 is charged in accord with the method described herein, and contains a propellant drug formulation. The formulation comprises the drug (one or more drug actives) and a fluid propellant, and optionally one or more excipients and/or adjuvants. The drug is in solution or suspension in the formulation. The propellant is typically a CFC-free propellant, suitably a liquified gas propellant, and preferably is a HFA propellant, such as HFA-134a or HFA-227 or a combination thereof. The drug active(s) is typically of the type for use in treatment of a disease or condition, in particular a respiratory disease or condition, such as asthma or chronic obstructive pulmonary disease (COPD). The active(s) may also be for prophylaxis or palliative management of a disease or condition.

The canister 10 may have its inner surface coated with a fluorocarbon polymer, optionally in a blend with a non-fluorocarbon polymer, such as a blend of polytetrafluoroethylene and polyethersulphone (PTFE-PES), as disclosed in US patent Nos. 6,143,277; 6,511 ,653; 6,253,762; 6,532,955; and 6,546,928. This is particularly preferred if the drug is in suspension in the formulation, and especially if the suspension formulation is composed only, or substantially only, of the drug and HFA propellant.

The metering valve 20 fixes to neck 12 of the canister 10 by means of a crimped fixture. Thus, circumferential skirt or ferrule 22 of the valve 20 engages in crimped fashion to the neck 12 of the canister 10. Neck gasket 23 provided at lip 25 of the valve skirt 22 ensures a good seal forms between canister 10 and the valve 20. The metering valve 20 also comprises metering chamber 24; stem gasket 25; stem filling port 27; sampling chamber 28; and return spring 29. This metering valve 20 is of a known type and is described in more detail in PCT Patent Application No. WO 02/092,466, the entire contents of which are incorporated herein by reference.

It will be appreciated that the metering valve type shown at Figure 2 is purely exemplary and that other valve types may be substituted herein. Metering valves are commercially available from manufacturers well known in the aerosol industry, for example, from Valois, France (e.g. DF10, DF30, DF60), Bespak pic, UK (e.g. BK300, BK356) and 3M-Neotechnic Ltd, UK (e.g. Spraymiser™). The metering valve disclosed in US-B-6315173 or US-A-2003/0101993 could be used in place of that shown in Figure 2, those parts of which documents relating to the respective valves disclosed therein are incorporated herein by reference. The metering chamber of the metering valve 20 may be coated with a fluohnated polymer coating, for instance by cold plasma polymerisation, as detailed in US-A-2003/0101993, the entire contents of which are incorporated herein by reference.

It will be appreciated that the mouthpiece 32 in the exemplary embodiment could be configured instead as a nasal nozzle for insertion in a nostril of a human being, so that the propellant drug formulation is deliverable to the nasal cavity of the human being.

Turning now to Figures 3a to 3e, there are shown schematic representations of sequential steps in a first method of charging the aerosol canister 10 with a propellant drug formulation herein.

Figures 3a and 3b show details of an optional pre-step, in which the aerosol canister 10 is purged of air. Thus, at Figure 3a an aerosol canister 10 on a production line 40 is selected. A mask 42 defining a circular port 44 is placed over the canister 10. Purging cannula 46 is then aligned with the circular port 44. At Figure 3b the purging cannula 46 is then inserted through that circular port 44 to allow propellant, in this embodiment an HFA propellant, more particularly HFA 134a, to be injected into the aerosol canister 10. At this stage the aerosol canister 10 is not sealed and thus, air 48 is forced to rush out of the aerosol canister 10, which is thereby purged of that air 48. It will be appreciated that the HFA 134A propellant also vaporises out of the aerosol canister 10 during this purging process. After purging, the cannula 46 is withdrawn.

Figures 3c shows details of the step in which a defined quantity of an active drug 52 in dry powder form is metered into the aerosol canister 10. Thus, dosimeter 50 is now aligned with the circular port 44 and active drug 52 in dry powder form is metered into the aerosol canister 10. The amount of active drug 52 that is so metered is carefully controlled and selected according to the dose strength and number of doses of drug propellant formulation to be prepared. Embodiments involving subsequent metering of a second active drug and/or metering of a mixture 5 of two or more active drugs are envisaged. After metering, the dosimeter 50 and mask 42 are removed.

At Figure 3d the valve 20 is aligned over the open mouth of the aerosol canister 10 for crimping to the neck 12 thereof. Crimping head 60 with crimping arms 62a, 62b is brought about the valve 20 such as to crimp the circular skirt 22 of the valve 20 to0 the neck 12 of the aerosol canister 10. Thus, a seal now exists between the valve 20 and canister 10.

Figure 3e shows the step of introducing the propellant into the aerosol canister 10 by way of the valve 20 thereof. Thus, propellant filling head 70 is aligned with the top of the valve stem 26 of the valve 20. That filling head 70 is then brought down onto the5 valve stem 26 such that propellant can be injected through the metering valve 20 into the aerosol canister 10 to provide the drug propellant formulation therein, as known in the art. In this embodiment, the propellant is an HFA propellant, more particularly HFA 134a.

Preferably, as in this and a later illustrated embodiment, the formulation propellant is o the same as that used for the purging step.

Preferably, as in this and the later illustrated embodiment, the propellant is a liquified gas propellant, as known in the art.

Figure 4 shows a schematic representation of a suitable dosimeter 50 for used in the powder metering step previously described in relation to Figure 3c, or to be5 described in relation to Figure 5a. In this embodiment, the dosimeter 50 is the "Omnidose" of Harro Hόfliger mentioned hereinabove. Active drug in bulk powder form 51 is provided to hopper 53 of the dosimeter, which bulk powder is may be agitated by means of rotary stirrer 54. The dosimeter 50 is provided with a drum 80 having drum sleeve 82, to which on or more dosing bores 84 are provided. The volume of the or each dosing bore 82 corresponds to a defined measure of dry powder. In a first use step, the drum 80 is rotated to a first position (as shown), in which the one or more dosing bores 82 may receive powder 51 feed from the hopper 53. Delivery of that powder 53 occurs under gravity; in response to the action of scraper blade 56; and in response to vacuum pull within the or each dosing bore 82 created as a result of applying negative vacuum by means of vacuum channel 86. A filter membrane 87 separates each dosing bore 82 from the vacuum channel 86, thereby preventing the powder being sucked away. Exhaust channel 88 is also provided.

In a second use step, the drum 80 is rotated 180° to a second 'dosing' position, in which the or each dosing bore 82 faces downwards such that the measured powder contents thereof may be dosated through exit 58 to an aerosol canister 10 (not shown in Figure 4, but see Figure 3c) below. Dosating may simply occur under gravity or in embodiments, positive vacuum may be applied to eject the contents of the or each dosing bore 82 to the aerosol canister 10 positioned below. After dosating, the drum 80 is again rotated 180° to the first position so that bore 82 filling may again occur.

Typically, a line or queue of aerosol canisters 10 is moved one-at-a-time underneath the dosimeter 50 in synchronicity with rotation of the drum 80 whereby each canister 10 receives the metered content of one of the dosing bores 82 before moving on. The canisters may move continuously or step-wise relative to the dosimeter 50.

Turning now to Figures 5a to 5d, where like reference numerals indicate like features with the prior embodiment, there are shown schematic representations of sequential steps in a second method of charging an aerosol canister 110 with a propellant drug formulation herein. In this second method herein, the step of purging the aerosol canister is conducted after metered addition of powdered drug active 152 rather than prior to that drug metering step. Thus, Figure 5a shows details of a step in which a defined quantity of an active drug 152 in dry powder form is metered into the aerosol canister 110. Thus, an aerosol canister 110 on a production line 140 is selected and dosimeter 150 is aligned with the open mouth of the canister 110. Active drug 152 in dry powder form is then metered into the aerosol canister 110. The amount of active drug 152 that is so metered is carefully controlled and selected according to the dose strength and number of doses of drug propellant formulation to be prepared. Embodiments involving subsequent metering of a second active drug and/or metering of a mixture of two or more active drugs are envisaged. After metering, the dosimeter 150 is removed.

Figure 5b show details of a step, in which the aerosol canister 110 is purged of air. Thus, at Figure 5b a valve 120 with circumferential valve skirt 122 and valve stem 126 is placed over the mouth of the aerosol canister 110, but not crimped thereto. Purging head 146 is then aligned with the valve 120 and a propellant, in this embodiment an HFA propellant, more particularly HFA 134a, is injected into the aerosol canister 110. Since at this stage the aerosol canister 110 is not sealed to the valve 120, air 148 is thus forced to rush out of the aerosol canister 110, which is thereby purged of that air 148. It will be appreciated that the HFA 134A propellant also vaporises out of the aerosol canister 110 during this purging process. After purging, the purging head 146 is withdrawn.

At Figure 5c crimping head 160 with crimping arms 162a, 162b is brought over and about the valve 120 such as to crimp the circular skirt 122 of the valve 120 to the neck 112 of the aerosol canister 110. Thus, a seal now exists between the valve 120 and aerosol canister 110.

Figure 5d then shows the step of introducing a propellant, in this embodiment an HFA propellant, more particularly HFA 134a, into the aerosol canister 110 by way of the valve 120 thereof. Thus, propellant filling head 170 is aligned with the top of the valve stem 126 of the valve 120. That filling head 170 is then brought down onto the valve stem 126 such that propellant can be injected therethrough and thus, into the aerosol canister 110 to provide the drug propellant formulation therein.

In the two illustrated embodiments, the aerosol canister 10; 110 is charged with a simple suspension formulation of drug and propellant only. As non-limiting examples, the drug could be fluticasone propionate, salmeterol xinafoate, salbutamol sulphate or a combination of fluticasone propionate and salmeterol xinafoate, in which case the result of the illustrated embodiments would be charging aerosol canisters with the suspension drug-propellant formulations used in the CFC-free MDI products marketed by GlaxoSmithKline as Flixotide™, Serevent™, Ventolin™ and Seretide™ .

In the illustrated embodiments, the aerosol canister 10; 110 may be weighed immediately before and after the dosimeter 50; 150 meters the active drug in powder form thereinto as a check that the correct amount of drug has been dispensed into the aerosol canister 10; 110. Similar check weighing may also be carried out at other stages, e.g. when metering other active drugs or other formulation components into the aerosol canister 10; 110.

One advantage of the illustrated embodiments is that the propellant filling head 70; 170 can be used to fill propellant into aerosol canisters 10;110 containing different active drugs, because it does not come into contact with the active drugs. In the prior art method, a pre-mix of the active drug(s) and propellant was charged into aerosol containers via the filling head 70; 170. Thus, in the prior art method the filling head could not (at least without extensive cleaning) be used with other active drugs to avoid contamination.

It will be appreciated that the method herein is suitable for use on an industrial production line, and thus each step of the first method of Figures 3a/3b; 3c; 3d and 3e or the second method of Figures 5a to 5d may conveniently be carried out at a different 'station' of the production line. The 'stations' may in embodiments, be arranged in linear or circular series with the aerosol canister being moved to each 'station' in turn. Alternatively, each method may be carried out on a lab or pilot plant scale.

Figure 6 is a schematic representation of an industrial implementation of the method of Figures 3a-3e, with like reference numbers indicating like features. In this industrial implementation, the aerosol canisters 210 are fed onto a rotary turntable 250 at station A and then carried by the turntable sequentially to different stations, as will now be described. At station B the aerosol canister 210 is purged, as shown in Figures 3a and 3b. At station C, a metered dose of the active drug(s) is metered into the aerosol canister 210, as described with reference to Figures 3c and 4. At station D a metering valve 220 is placed onto the open end of the aerosol canister 210. The valve 220 is then crimped to the aerosol canister 210 at station E, as shown in Figure 3d. At station F the aerosol canister 210 is filled with the propellant, as shown in Figure 3e. Finally, the charged aerosol canister 210 is removed from the turntable at station G.

The skilled reader will appreciate that the arrangement in Figure 6 could easily be adapted for the method of Figures 5a-d.

The method herein is arranged for the charging of an aerosol canister with a propellant drug formulation, which aerosol canister is suitable for use with a drug dispenser device for administration of drug to a patient. The method has particular, but not exclusive, application in charging an aerosol canister with a suspension formulation. However, the skilled reader will also appreciate the invention has utility in charging an aerosol canister with a solution formulation.

Administration of drug may be indicated for the treatment of mild, moderate or severe acute or chronic symptoms or for prophylactic treatment. It will be appreciated that the precise dose administered will depend on the age and condition of the patient, the particular drug used and the frequency of administration and will ultimately be at the discretion of the attendant physician. Embodiments are envisaged in which combinations of drugs are employed. Appropriate drugs may thus be selected from, for example, analgesics, e.g., codeine, dihydromorphine, ergotamine, fentanyl or morphine; anginal preparations, e.g., diltiazem; antiallergics, e.g., cromoglycate (e.g. as the sodium salt), ketotifen or nedocromil (e.g. as the sodium salt); antiinfectives e.g., cephalosporins, penicillins, streptomycin, sulphonamides, tetracyclines and pentamidine; antihistamines, e.g., methapyhlene; anti- inflammatories, e.g., beclomethasone (e.g. as the dipropionate ester), fluticasone (e.g. as the propionate ester), flunisolide, budesonide, rofleponide, mometasone e.g. as the furoate ester), ciclesonide, triamcinolone (e.g. as the acetonide) or 6α, 9α-difluoro-11 β-hydroxy-16α-methyl-3-oxo-17α-propionyloxy- androsta-1 ,4-diene-17β-carbothioic acid S-(2-oxo-tetrahydro-furan-3-yl) ester; antitussives, e.g., noscapine; bronchodilators, e.g., albuterol (e.g. as free base or sulphate), salmeterol (e.g. as xinafoate), ephedhne, adrenaline, fenoterol (e.g. as hydrobromide), salmefamol, carbuterol, mabuterol, etanterol, naminterol, clenbuterol, flerbuterol, bambuterol, indacaterol, formoterol (e.g. as fumarate), isoprenaline, metaproterenol, phenylephrine, phenylpropanolamine, pirbuterol (e.g. as acetate), reproterol (e.g. as hydrochloride), rimiterol, terbutaline (e.g. as sulphate), isoethahne, tulobuterol or 4-hydroxy-7-[2-[[2-[[3-(2- phenylethoxy)propyl]sulfonyl]ethyl]amino]ethyl-2(3H)-benzothiazolone; adenosine 2a agonists, e.g. 2R,3R,4S,5R)-2-[6-Amino-2-(1 S-hydroxymethyl-2-phenyl-ethylamino)- puhn-9-yl]-5-(2-ethyl-2H-tetrazol-5-yl)-tetrahydro-furan-3,4-diol (e.g. as maleate); α₄ integrin inhibitors e.g. (2S)-3-[4-({[4-(aminocarbonyl)-1 - pipehdinyl]carbonyl}oxy)phenyl]-2-[((2S)-4-methyl-2-{[2-(2-methylphenoxy) acetyl]amino}pentanoyl)amino] propanoic acid (e.g. as free acid or potassium salt), diuretics, e.g., amilohde; anticholinergics, e.g., ipratropium (e.g. as bromide), tiotropium, atropine or oxitropium; hormones, e.g., cortisone, hydrocortisone or prednisolone; xanthines, e.g., aminophylline, choline theophyllinate, lysine theophyllinate or theophylline; therapeutic proteins and peptides, e.g., insulin or glucagon; vaccines, diagnostics, and gene therapies. It will be clear to a person skilled in the art that, where appropriate, the drugs may be used in the form of salts, (e.g., as alkali metal or amine salts or as acid addition salts) or as esters (e.g., lower alkyl esters) or as solvates (e.g., hydrates) to optimise the activity and/or stability of the drug.

The drug formulation may in embodiments, be a mono-therapy (i.e. single active 5 drug containing) product or it may be a combination therapy (i.e. plural active drugs containing) product.

Suitable drugs or drug components of a combination therapy product are typically selected from the group consisting of anti-inflammatory agents (for example a 10 corticosteroid or an NSAID), anticholinergic agents (for example, an M₁, M₂, M₁ZM₂ or M₃ receptor antagonist), other β₂-adrenoreceptor agonists, antiinfective agents (e.g. an antibiotic or an antiviral), and antihistamines. All suitable combinations are envisaged.

15 Suitable anti-inflammatory agents include corticosteroids and NSAIDs. Suitable corticosteroids which may be used in combination with the compounds of the invention are those oral and inhaled corticosteroids and their pro-drugs which have anti-inflammatory activity. Examples include methyl prednisolone, prednisolone, dexamethasone, fluticasone propionate, 6α,9α-difluoro-17α-[(2-furanylcarbonyl)oxy]-

20 11 β-hydroxy-16α-methyl-3-oxo-androsta-1 ,4-diene-17β-carbothioic acid S- fluoromethyl ester, 6α,9α-difluoro-11 β-hydroxy-16α-methyl-3-oxo-17α-propionyloxy- androsta-1 ,4-diene-17β-carbothioic acid S-(2-oxo-tetrahydro-furan-3S-yl) ester, beclomethasone esters (e.g. the 17-propionate ester or the 17,21 -dipropionate ester), budesonide, flunisolide, mometasone esters (e.g. the furoate ester),

25 triamcinolone acetonide, rofleponide, ciclesonide, butixocort propionate, RPR-

106541 , and ST-126. Preferred corticosteroids include fluticasone propionate, 6α,9α-difluoro-11 β-hydroxy-16α-methyl-17α-[(4-methyl-1 ,3-thiazole-5-carbonyl)oxy]- 3-oxo-androsta-1 ,4-diene-17β-carbothioic acid S-fluoromethyl ester, 6α,9α-difluoro- 17α-[(2-furanylcarbonyl)oxy]-11 β-hydroxy-16α-methyl-3-oxo-androsta-1 ,4-diene-17β-

30 carbothioic acid S-fluoromethyl ester, 6α,9α-difluoro-11 β-hydroxy-16α-methyl-3-oxo- 17α-(2,2,3,3-tetrannethycyclopropylcarbonyl)oxy-androsta-1 ,4-diene-17β-carbothioic acid S-cyanomethyl ester, 6α,9α-difluoro-11 β-hydroxy-16α-methyl-17α-(1 - methycyclopropylcarbonyl)oxy-3-oxo-androsta-1 ,4-diene-17β-carbothioic acid S- fluoromethyl ester and 9α, 21 dichloro-11 β, 17α methyl-1 ,4 pregnadiene 3, 20 dione- 17-[2'] furoate (mometasone furoate).

Further corticosteroids are described in WO02/088167, WO02/100879, WO02/12265, WO02/12266, WO05/005451 , WO05/005452, WO06/072599 and WO06/072600.

Non-steroidal compounds having glucocorticoid agonism that may possess selectivity for transrepression over transactivation and that may be useful are disclosed WO03/082827, WO98/54159, WO04/005229, WO04/009017, WO04/018429, WO03/104195, WO03/082787, WO03/082280, WO03/059899, WO03/101932, WO02/02565, WO01/16128, WO00/66590, WO03/086294, WO04/026248, WO03/061651 , WO03/08277, WO06/000401 , WO06/000398 and WO06/015870.

Suitable NSAIDs include sodium cromoglycate, nedocromil sodium, phosphodiesterase (PDE) inhibitors (e.g. theophylline, PDE4 inhibitors or mixed

PDE3/PDE4 inhibitors), leukothene antagonists, inhibitors of leukothene synthesis, iNOS inhibitors, tryptase and elastase inhibitors, beta-2 integrin antagonists and adenosine receptor agonists or antagonists (e.g. adenosine 2a agonists), cytokine antagonists (e.g. chemokine antagonists), inhibitors of cytokine synthesis or 5- lipoxygenase inhibitors. Examples of iNOS inhibitors include those disclosed in WO93/13055, WO98/30537, WO02/50021 , WO95/34534 and WO99/62875. Examples of CCR3 inhibitors include those disclosed in WO02/26722.

Suitable bronchodilators are β₂-adrenoreceptor agonists, including salmeterol (which may be a racemate or a single enantiomer, such as the R-enantiomer), for instance salmeterol xinafoate, salbutamol (which may be a racemate or a single enantiomer, such as the R-enantiomer), for instance salbutamol sulphate or as the free base, formoterol (which may be a racemate or a single diastereomer, such as the R, R- diastereomer), for instance formoterol fumarate or terbutaline and salts thereof. Other suitable β₂-adrenoreceptor agonists are 3-(4-{[6-({(2R)-2-hydroxy-2-[4- hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)hexyl] oxy} butyl) benzenesulfonamide, 3-(3-{[7-({(2R)-2-hydroxy-2-[4-hydroxy-3-hydroxymethyl) phenyl] ethyl}-amino) heptyl] oxy} propyl) benzenesulfonamide, 4-{(1 R)-2-[(6-{2-[(2, 6-dichlorobenzyl) oxy] ethoxy} hexyl) amino]-1 -hydroxyethyl}-2-(hydroxymethyl) phenol, 4-{(1 R)-2-[(6-{4-[3-(cyclopentylsulfonyl)phenyl]butoxy}hexyl)amino]-1 - hydroxyethyl}-2-(hydroxymethyl) phenol, N-[2-hydroxyl-5-[(1 R)-1 -hydroxy-2-[[2-4- [[(2R)-2-hydroxy-2-phenylethyl]amino]phenyl]ethyl]amino]ethyl]phenyl]formamide, and N-2{2-[4-(3-phenyl-4-methoxyphenyl)aminophenyl]ethyl}-2-hydroxy-2-(8- hydroxy-2(1 H)-quinolinon-5-yl)ethylamine, and 5-[(R)-2-(2-{4-[4-(2-amino-2-methyl- propoxy)-phenylamino]-phenyl}-ethylamino)-1 -hydroxy-ethyl]-8-hydroxy-1 H-quinolin- 2-one. Preferably, the β₂-adrenoreceptor agonist is a long acting β₂-adrenoreceptor agonist (LABA), for example a compound which provides effective bronchodilation for about 12 hours or longer.

Other β₂-adrenoreceptor agonists include those described in WO 02/066422, WO

02/070490, WO 02/076933, WO 03/024439, WO 03/072539, WO 03/091204, WO 04/016578, WO 2004/022547, WO 2004/037807, WO 2004/037773, WO 2004/037768, WO 2004/039762, WO 2004/039766, WO01/42193 and WO03/042160.

Preferred phosphodiesterase 4 (PDE4) inhibitors are cis 4-cyano-4-(3- cyclopentyloxy-4-methoxyphenyl)cyclohexan-1 -carboxylic acid, 2-carbomethoxy-4- cyano-4-(3-cyclopropylmethoxy-4-difluoromethoxyphenyl)cyclohexan-1 -one and cis- [4-cyano-4-(3-cyclopropylmethoxy-4-difluoromethoxyphenyl)cyclohexan-1 -ol].

Other suitable drug compounds include: c/s-4-cyano-4-[3-(cyclopentyloxy)-4- methoxyphenyl]cyclohexane-1 -carboxylic acid (also known as cilomalast) disclosed in U.S. patent 5,552,438 and its salts, esters, pro-drugs or physical forms; AWD-12- 281 from elbion (Hofgen, N. et al. 15th EFMC lnt Symp Med Chem (Sept 6-10, Edinburgh) 1998, Abst P.98; CAS reference No. 247584020-9); a 9-benzyladenine derivative nominated NCS-613 (INSERM); D-4418 from Chiroscience and Schering- Plough; a benzodiazepine PDE4 inhibitor identified as CI-1018 (PD-168787) and attributed to Pfizer; a benzodioxole derivative disclosed by Kyowa Hakko in WO99/16766; K-34 from Kyowa Hakko; V-11294A from Napp (Landells, L.J. et al. Eur Resp J [Annu Cong Eur Resp Soc (Sept 19-23, Geneva) 1998] 1998, 12 (Suppl. 28): Abst P2393); roflumilast (CAS reference No 162401 -32-3) and a pthalazinone (WO99/47505, the disclosure of which is hereby incorporated by reference) from Byk-Gulden; Pumafentrine, (-)-p-[(4aR^*,10£>S^*)-9-ethoxy-1 ,2,3,4,4a, 10b-hexahydro- 8-methoxy-2-methylbenzo[c][1 ,6]naphthyhdin-6-yl]-N,N-diisopropylbenzamide which is a mixed PDE3/PDE4 inhibitor which has been prepared and published on by Byk- Gulden, now Altana; arofylline under development by Almirall-Prodesfarma; VM554/UM565 from Vernalis; or T-440 (Tanabe Seiyaku; Fuji, K. et al. J Pharmacol Exp Ther,1998, 284(1 ): 162), and T2585.

Further compounds are disclosed in WO04/024728, WO04/056823 and WO04/103998, all of Glaxo Group Limited.

Suitable anticholinergic agents are those compounds that act as antagonists at the muscarinic receptor, in particular those compounds, which are antagonists of the M₁ or M₃ receptors, dual antagonists of the M₁ZM₃ or M₂/M₃, receptors or pan- antagonists of the M1/M2/M3 receptors. Exemplary compounds include the alkaloids of the belladonna plants as illustrated by the likes of atropine, scopolamine, homatropine, hyoscyamine; these compounds are normally administered as a salt, being tertiary amines.

Other suitable anti-cholinergics are muscarinic antagonists, such as (3-enc/o)-3-(2,2- di-2-thienylethenyl)-8,8-dimethyl-8-azoniabicyclo[3.2.1] octane iodide, (3-enc/o)-3-(2- cyano^^-diphenylethylj-δ.δ-dimethyl-δ-azoniabicyclo [3.2.1] octane bromide, 4- [hydroxy(diphenyl)methyl]-1 -{2-[(phenylmethyl)oxy]ethyl}-1 -azonia bicyclo[2.2.2] octane bromide, (1 R,5S)-3-(2-cyano-2,2-diphenylethyl)-8-methyl-8-{2-

[(phenylmethyl)oxy]ethyl}-8-azoniabicyclo[3.2.1] octane bromide, (ΘΠC/O)-3-(2- methoxy^^-di-thiophen^-yl-ethylJ-δ.δ-dimethyl-δ-azonia-bicyclotS^.iloctane iodide, (enc/o)-3-(2-cyano-2,2-diphenyl-ethyl)-8,8-dimethyl-8-azonia-bicyclo

[3.2.1]octane iodide, (enc/o)-3-(2-carbamoyl-2,2-diphenyl-ethyl)-8,8-dimethyl-8- azonia-bicyclo[3.2.1]octane iodide, (enc/o)-3-(2-cyano-2,2-di-thiophen-2-yl-ethyl)-8,8- dimethyl-8-azonia-bicyclo[3.2.1]octane iodide, and (enc/o)-3-{2,2-diphenyl-3-[(1 - phenyl-methanoyl)-amino]-propyl}-8,8-dimethyl-8-azonia-bicyclo[3.2.1] octane bromide.

Particularly suitable anticholinergics include ipratropium (e.g. as the bromide), sold under the name Atrovent, oxitropium (e.g. as the bromide) and tiotropium (e.g. as the bromide) (CAS-139404-48-1 ). Also of interest are: methantheline (CAS-53-46-3), propantheline bromide (CAS- 50-34-9), anisotropine methyl bromide or Valpin 50 (CAS- 80-50-2), clidinium bromide (Quarzan, CAS-3485-62-9), copyrrolate (Robinul), isopropamide iodide (CAS-71 -81 -8), mepenzolate bromide (U.S. patent 2,918,408), tridihexethyl chloride (Pathilone, CAS-4310-35-4), and hexocyclium methylsulfate (Tral, CAS-115-63-9). See also cyclopentolate hydrochloride (CAS-5870-29-1 ), tropicamide (CAS-1508-75-4), trihexyphenidyl hydrochloride (CAS-144-11 -6), pirenzepine (CAS-29868-97-1 ), telenzepine (CAS-80880-90-9), AF-DX 116, or methoctramine, and the compounds disclosed in WO01/04118. Also of interest are revatropate (for example, as the hydrobromide, CAS 262586-79-8) and LAS-34273 which is disclosed in WO01/04118, darifenacin (CAS 133099-04-4, or CAS 133099- 07-7 for the hydrobromide sold under the name Enablex), oxybutynin (CAS 5633-20-

5, sold under the name Ditropan), terodiline (CAS 15793-40-5), tolterodine (CAS 124937-51 -5, or CAS 124937-52-6 for the tartrate, sold under the name Detrol), otilonium (for example, as the bromide, CAS 26095-59-0, sold under the name Spasmomen), trospium chloride (CAS 10405-02-4) and solifenacin (CAS 242478-37- 1 , or CAS 242478-38-2 for the succinate also known as YM-905 and sold under the name Vesicare). Other anticholinergic agents include compounds disclosed in USSN 60/487,981 and USSN 60/511 ,009.

Suitable antihistamines (also referred to as H_rreceptor antagonists) include any one or more of the numerous antagonists known which inhibit H_rreceptors, and are safe for human use. All are reversible, competitive inhibitors of the interaction of histamine with Hi-receptors. Examples include ethanolamines, ethylenediamines, and alkylamines. In addition, other first generation antihistamines include those which can be characterized as based on piperizine and phenothiazines. Second generation antagonists, which are non-sedating, have a similar structure-activity relationship in that they retain the core ethylene group (the alkylamines) or mimic the tertiary amine group with piperizine or pipehdine.

Examples of H1 antagonists include, without limitation, amelexanox, astemizole, azatadine, azelastine, achvastine, brompheniramine, cetirizine, levocetirizine, efletihzine, chlorpheniramine, clemastine, cyclizine, carebastine, cyproheptadine, carbinoxamine, descarboethoxyloratadine, doxylamine, dimethindene, ebastine, epinastine, efletirizine, fexofenadine, hydroxyzine, ketotifen, loratadine, levocabastine, mizolastine, mequitazine, mianserin, noberastine, meclizine, norastemizole, olopatadine, picumast, pyhlamine, promethazine, terfenadine, tripelennamine, temelastine, trimeprazine and triprolidine, particularly cetirizine, levocetirizine, efletirizine and fexofenadine.

Exemplary H1 antagonists are as follows:

Ethanolamines: carbinoxamine maleate, clemastine fumarate, diphenylhydramine hydrochloride, and dimenhydrinate.

Ethylenediamines: pyrilamine amleate, tripelennamine HCI, and tripelennamine citrate. Alkylamines: chlropheniramine and its salts such as the maleate salt, and achvastine. Piperazines: hydroxyzine HCI, hydroxyzine pamoate, cyclizine HCI, cyclizine lactate, meclizine HCI, and cetirizine HCI.

Piperidines: Astemizole, levocabastine HCI, loratadine or its descarboethoxy analogue, and terfenadine and fexofenadine hydrochloride or another pharmaceutically acceptable salt.

Azelastine hydrochloride is yet another H₁ receptor antagonist which may be used in combination with a PDE4 inhibitor.

The drug, or one of the drugs, may be an H3 antagonist (and/or inverse agonist). Examples of H3 antagonists include, for example, those compounds disclosed in WO2004/035556 and in WO2006/045416.

Other histamine receptor antagonists which may be used include antagonists (and/or inverse agonists) of the H4 receptor, for example, the compounds disclosed in Jablonowski et al., J. Med. Chem. 46:3957-3960 (2003).

Suitably, the drug formulation includes one or more of a β₂-adrenoreceptor agonist, a corticosteroid, a PDE-4 inhibitor and an anti-cholinergic.

Generally, powdered drug particles suitable for delivery to the bronchial or alveolar region of the lung have an aerodynamic diameter of less than 10 micrometers, preferably from 1 -6 micrometers. Other sized particles may be used if delivery to other portions of the respiratory tract is desired, such as the nasal cavity, mouth or throat.

The amount of any particular drug or a pharmaceutically acceptable salt, solvate or physiologically functional derivative thereof which is required to achieve a therapeutic effect will, of course, vary with the particular compound, the route of administration, the subject under treatment, and the particular disorder or disease being treated. The drugs for treatment of respiratory disorders herein may for example, be administered by inhalation at a dose of from O.OOOδmg to 10 mg, preferably O.OOδmg to O.δmg. The dose range for adult humans is generally from 0.0005 mg to 10Omg per day and preferably 0.01 mg to 1.5mg per day.

The propellant drug formulation herein comprises an active drug component; a propellant component; and optionally contains other pharmaceutically acceptable additive components. In embodiments, the propellant drug formulation comprises a suspension or solution of a drug in a propellant. Typically, the propellant is a liquified gas propellant, so that the drug formulation is a liquid formulation. In embodiments, the propellant is a fluorocarbon or hydrogen-containing chlorofluorocarbon propellant.

Suitable propellants include, for example, Ci _4hydrogen-containing chlorofluorocarbons such as CH2CIF, CCIF2CHCIF, CF3CHCIF, CHF2CCIF2, CHCIFCHF2, CF3CH2CI and CCIF2CH3; Ci _4hydrogen-containing fluorocarbons such as CHF2CHF2, CF3CH2F, CHF2CH3 and CF3CHFCF3; and perfluorocarbons such as CF3CF3 and CF3CF2CF3.

Where mixtures of the fluorocarbons or hydrogen-containing chlorofluorocarbons are employed they may be mixtures of the above-identified compounds or mixtures, preferably binary mixtures, with other fluorocarbons or hydrogen-containing chlorofluorocarbons for example CHCIF2, CH2F2 and CF3CH3. Preferably a single fluorocarbon or hydrogen-containing chlorofluorocarbon is employed as the propellant. Particularly preferred as propellants are Ci -4hydrogen-containing fluorocarbons such as 1 ,1 ,1 ,2- tetrafluoroethane (CF3CH2F) and 1 ,1 ,1 ,2,3,3,3- heptafluoro-n-propane (CF3CHFCF3) or mixtures thereof. The drug formulations are preferably substantially free of chlorofluorocarbons such as CCI3F, CCI2F2 and CF3CCI3. Preferably, the propellant is liquefied HFA134a or

HFA-227 or mixtures thereof.

The propellant may additionally contain a volatile adjuvant such as a saturated hydrocarbon for example propane, n-butane, liquefied, pentane and isopentane or a dialkyl ether for example dimethyl ether. In general, up to 50% w/w of the propellant may comprise a volatile hydrocarbon, for example 1 to 30% w/w. However, formulations, which are free or substantially free of volatile adjuvants are preferred. In certain cases, it may be desirable to include appropriate amounts of water, which can be advantageous in modifying the dielectric properties of the propellant.

A polar co-solvent such as C2-6 aliphatic alcohols and polyols e.g. ethanol, isopropanol and propylene glycol, preferably ethanol, may be included in the drug formulation in the desired amount to improve the dispersion of the formulation, either as the only excipient or in addition to other excipients such as surfactants. In embodiments, the drug formulation may contain 0.01 to 5% w/w based on the propellant of a polar co-solvent e.g. ethanol, preferably 0.1 to 5% w/w e.g. about 0.1 to 1 % w/w. In embodiments herein, the solvent is added in sufficient quantities to solubilise part or all of the drug component, such formulations being commonly referred to as 'solution' aerosol drug formulations.

A surfactant may also be employed in the aerosol formulation. Examples of conventional surfactants are disclosed in EP-A-372,777. The amount of surfactant employed is desirable in the range 0.0001 % to 50% weight to weight ratio relative to the drug, in particular, 0.05 to 10% weight to weight ratio.

The aerosol drug formulation desirably contains 0.005-10% w/w, preferably 0.005 to 5% w/w, especially 0.01 to 2% w/w, of drug relative to the total weight of the formulation. In one embodiment, the drug dispenser device is suitable for dispensing aerosolized drug (e.g. for inhalation via the mouth) for the treatment of respiratory disorders such as disorders of the lungs and bronchial tracts including asthma and chronic obstructive pulmonary disorder (COPD). In another embodiment, the drug dispenser device is suitable for dispensing aerosolized drug (e.g. for inhalation via the mouth) for the treatment of a condition requiring treatment by the systemic circulation of drug, for example migraine, diabetes, pain relief e.g. inhaled morphine.

Administration of drug in aerosolized form may be indicated for the treatment of mild, moderate or severe acute or chronic symptoms or for prophylactic or palliative treatment. It will be appreciated that the precise dose administered will depend on the age and condition of the patient, the particular particulate drug used and the frequency of administration and will ultimately be at the discretion of the attendant physician. When combinations of drugs are employed the dose of each component of the combination will in general be that employed for each component when used alone. Typically, administration may be one or more times, for example from 1 to 8 times per day, giving for example 1 , 2, 3 or 4 aerosol puffs each time. Each valve actuation, for example, may deliver 5μg, 50μg, 100μg, 200μg or 250μg of a drug. Typically, each filled canister for use in a metered dose inhaler contains 60, 100, 120 or 200 metered doses or puffs of drug; the dosage of each drug is either known or readily ascertainable by those skilled in the art.

It will be understood that the present invention has been described above by way of example only and that the above description can be modified in many different ways without departing from the scope of the invention as defined by the appended claims.

All publications, patents, and patent applications cited herein, and any US patent family equivalent to any such patent or patent application, are hereby incorporated herein by reference to their entirety to the same extent as if each publication, patent, or patent application was specifically and individually indicated to be incorporated by reference.

It must be noted that, as used in the specification and appended claims, the singular forms "a", "an", "the" and "one" include plural referents unless the content clearly dictates otherwise.

The application of which this description and claims form part may be used as a basis for priority in respect of any subsequent application. The claims of such subsequent application may be directed to any feature or combination of features described therein. They may take the form of product, method or use claims and may include, by way of example and without limitation, one or more of the following claims.

Claims

1. A method of charging an aerosol canister with a propellant drug formulation comprising the steps of:

(i) selecting an aerosol canister;

(ii) metering a defined quantity of at least one active drug in dry powder form into said aerosol canister; and

(iii) separately introducing a propellant into the aerosol canister.

2. A method according to claim 1 , wherein two or more active drugs in dry powder form are metered into the aerosol canister.

3. A method according to claim 2, wherein said two or more active drugs in dry powder form are metered into the aerosol canister by means of separate metering steps.

4. A method according to claim 2, wherein said two or more active drugs in dry powder form are metered into the aerosol canister by means of a single metering step.

5. A method according to any of claims 1 to 4, wherein said metering of the at least one active drug in dry powder form is by means of a powder dosating apparatus.

6. A method according to any of claims 1 to 5, additionally including the step of introducing a valve to the aerosol canister.

7. A method according to claim 6, additionally including the step of fixing said valve to the aerosol canister.

8. A method according to claim 7, wherein the step of fixing said valve to the aerosol canister is conducted prior to introducing the propellant into the aerosol canister.

9. A method according to claim 7, wherein the step of fixing said valve to the 5 aerosol canister is conducted subsequent to introducing the propellant into the aerosol canister.

10. A method according to any of claims 6 to 9, wherein the introducing of the propellant into the aerosol canister is by way of the valve.

11. A method according to claim 10, wherein the introducing of the propellant into 10 the aerosol canister is by means of engaging a valve stem of the valve with a filling head and introducing the propellant through said valve stem.

12. A method according to claim 7 or any other claim when appended thereto, wherein said fixing of the valve to the aerosol canister is by means of a crimping operation.

15 13. A method according to any of claims 6 to 12, wherein said valve is a metering valve.

14. A method according to claim 13, wherein said metering valve is a slide valve.

15. A method according to any of claims 1 to 14, including the additional step of purging the aerosol canister with propellant.

20 16. A method according to claim 15, wherein said purging is carried out prior to metering the at least one active drug in dry powder form into the aerosol canister.

17. A method according to claim 15, wherein said purging is carried out subsequent to metering the at least one active drug in dry powder form into the aerosol canister.

18. A method according any of claims 1 to 17, wherein the at least one active drug is in particulate form and has a mean particle size of less than 10 micrometers.

19. A method according to any of claims 1 to 17, wherein the at least one active drug is in the form of a coated particle.

5 20. A method according to any of claims 1 to 17, wherein the at least one active drug is in the form of an agglomerated particle.

21. A method according to any of claims 1 to 20, wherein the at least one active drug comprises an anti-inflammatory agent.

22. A method according to claim 21 , wherein said anti-inflammatory agent is 10 selected from the group consisting of a corticosteroid, an NSAID, a glucocorticoid compound and mixtures thereof.

23. A method according to any of claims 1 to 20, wherein the at least one active drug comprises a bronchodilator agent.

24. A method according to claim 23, wherein said bronchodilator agent is a β₂- 15 adrenoreceptor agonist.

25. A method according to any of claims 1 to 24, wherein the propellant is a fluorocarbon or hydrogen-containing chlorofluorocarbon propellant.

26. A method according to any of claims 1 to 25, additionally comprising the step of adding at least one other formulation component to the aerosol canister.

20 27. A method according to claim 26, wherein said at least one other formulation component is selected from the group consisting of one or more surfactants; one or more solvents; one or more excipients; and any mixtures thereof.

28. A method according to any of claims 1 to 27, wherein the steps thereof are carried out on an industrial production line.

25

29. An aerosol canister charged with a propellant drug formulation obtained by the method according to any of claims 1 to 28.

30. A drug dispenser device comprising an actuator housing; and provided to said actuator housing an aerosol canister according to claim 29.