Patent Description:
Standard tests exist for inhalers, for example to determine the delivered dose or particle size distribution from an inhaler during use. The test process involves simulating a patient inhalation through an inhaler and a collector, typically either a sampling apparatus (in the case of delivered dose) or a cascade impactor (in the case of particle size determination) using a constant flow vacuum pump and a flow controller.

Two known cascade impactors are the Next Generation Impactor (NGI) and Andersen Cascade Impactor (ACI) supplied by Copley Scientific. In both cases, sample/medicament laden air flow passes sequentially through a number of distinct stages of the Impactor. Each stage retains a defined range of particle sizes on a collection plate or cup for further analysis, and the stages are configured and arranged to separate particles, on the basis of particle inertia, into a series of progressively smaller size bands or fractions in the respirable range. The separation broadly corresponds to the particles' likely deposition sites in the respiratory tract. Further details of the operation of the NGI and ACI are available from https://www. copleyscientific. com/en/inhaler-testingl.

A feature of the ACI is that stages are replaceable so that the most appropriate combination of stages (for example stages suitable for generally larger or smaller particle sizes) can be provided for any particular inhaler under test. A further benefit of this adaptable configuration is that stages can be removed entirely so that the impactor can focus on just a subset of the total range of particle sizes.

Abbreviated Impactor Measurement (AIM) is a process where, once the full Aerodynamic Particle Size Distribution (APSD) profile of the product has been established in development using a full-resolution cascade impactor, product batch release testing and quality control applications are possible using simpler but highly sensitive metrics, solely to determine if the product is fit for purpose. Products suitable for AIM include the Fast Screening Impactor (FSI) and Fast Screening Anderson (FSA), both supplied by Copley Scientific. These can be considered essentially simplified or 'abbreviated' versions of the NGI and ACI respectively, comprising fewer stages, and can be used with the same vacuum pump and flow controller as previously described.

The operation of the vacuum pump and flow controller can be adjusted to set a desired pressure drop and duration for the simulated inhalation event, as required for a particular inhaler design. The pressure drop profile ideally takes the form of a square wave, but resistance and dead volume within the overall system results in deviation from the ideal. Variations in the dead volume and resistance change the amount of deviation from the ideal square wave profile, typically by altering the rise-time, and potentially the amount of medicament released, which reduces the reliability and consistency of the testing process.

The present invention serves to overcome or mitigate this problem and improve the consistency and reliability of the testing process.

<CIT> describes an inhaler for the inhalation of powder medication. The inhaler has a body and at least one reservoir containing powder medication, the body having an air inlet and an outlet for the transmission to a patient of air entering the body through the air inlet and powder medication. The outlet has a total cross-sectional area for flow which is more than <NUM>% of the total cross-sectional area of the air inlet. An airflow adaptor and a method for modifying airflow through the outlet port of a deagglomerator in a breath-actuated dry powder inhaler are also described.

According to a first aspect of the invention there is provided a volume and resistance compensator device (VRC) as defined in the appended claim <NUM>. Further optional features are recited in the associated dependent claims.

Different types and designs of collector for use in testing a single inhaler device can have quite different volumes and flow resistances. For example, the more stages are present in a cascade impactor, the greater the 'dead' volume and flow resistance. This means that the flow characteristics (e.g. resistance and rise-time for a simulated inhalation) between a full impactor and an 'abbreviated' impactor can be quite different. The differences can reduce the consistency and reliability of the overall testing process.

For example, the internal volume of the FSI (<NUM>) is substantially less than that of the NGI (<NUM>). This volume difference alters the pressure drop profile for a given device, thereby changing the characteristics of the pressure wave which passes through the device and impactor during testing. The flow resistance of the FSI is also considerably lower than that of the NGI, further changing the characteristics of a test. Providing a means to compensate for differences in flow resistance and/or volume help to ensure that an inhaler experiences the same flow characteristics throughout a testing process, regardless of whether a full or 'abbreviated' impactor is used, and remove or minimise variability in inhaler testing.

For a 'passive' dry powder inhaler (DPI) in particular, the activation, dose emission and subsequent dispersion and aerosolisation of a formulation is largely governed by the characteristics of the inhalation event, particularly the rise-time. Any difference in rise-time can result in a significant difference in the aerosolisation and distribution of a medicament, even for a set duration and overall pressure drop, so failing to provide the same flow conditions in a series of tests risks fundamentally changing the performance of the inhaler under test.

The VRC as claimed comprises a variable volume chamber with an inlet and an outlet, at least one of the inlet and outlet being adjustable to vary the resistance to gas flow through the chamber.

The maximum volume of the variable volume chamber may be <NUM>.

The variable volume chamber comprises a cylinder and a piston movable, via a shaft, within the cylinder. The piston may seal with one of more interior walls of the chamber to provide a sealed working volume below the piston.

The shaft may comprise a graduated scale to allow a user to monitor the positions of the piston from outside the VRC. A clamp may be provided for selectively fixing the position of the piston within the cylinder as required.

At least one of the inlet and outlet of the VRC is configured to receive a removable choke plate to reduce the diameter of the flow path through the inlet and/or outlet. The VRC may be provided with two or more choke plates, each choke plate comprising a through hole of a set diameter. A variety of choke plates may be provided. The diameter of the through hole each choke plates is one of <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM> and <NUM>. More than one choke plate of each diameter may be provided. When used without choke plates the VRC may provide negligible flow resistance, or may provide a fixed/known low flow resistance that can be increased by inserting one or more choke plates.

The volume of the chamber in the VRC may be adjusted independently of the resistance to gas flow through the chamber.

The invention also provides inhaler testing apparatus comprising a collector for connection to an inhaler device, a vacuum pump for generating a gas flow through the collector, a flow controller for controlling the duration of the pressure drop experienced by the collector, and a VRC according to any preceding claim, wherein the volume and resistance compensator device is arranged between the collector and the vacuum pump.

The collector may comprise a sampling apparatus or a cascade impactor. The testing apparatus may further comprise a passive dry powder inhaler connected to the collector.

The invention also provides a method of testing inhalers, performed using the testing apparatus previously described, comprising:.

Step A of the method may comprise a first step A1 in which the flow resistance is measured and a second step A2 in which the rise-time is measured. Step B may comprise a first step B1 in which the flow resistance is measured and a second step B2 in which the rise-time is measured.

The method may further comprise the subsequent step of:
D. Testing an inhaler device using the second collector and volume and resistance compensator device as adjusted in step C to acquire data to supplement or complement data acquired from a test of the same inhaler using the first collector.

Practicable embodiments of the invention are described in further detail below with reference to the accompanying drawings, of which:.

<FIG> shows a volume and resistance compensator (VRC) <NUM> for use in inhaler testing. The VRC <NUM> comprises a generally cylindrical chamber <NUM> defining an internal volume with first and second pneumatic connectors <NUM>,<NUM> providing an inlet and outlet respectively. A piston (not shown) is attached to a shaft <NUM> with a handle <NUM>, and is adjustable vertically to alter the working volume of the chamber <NUM>. A graduated scale <NUM>, indicative of the working chamber volume, is provided on the shaft <NUM>. A two-part clamp <NUM> is provided to selectively fix the position of the shaft <NUM>, and thus the piston. A screw <NUM> is provided to loosen or tighten the clamp <NUM> as required.

A cross section of the VRC <NUM>, including a section of the shaft <NUM> and the piston <NUM>, is shown in <FIG>. The position of the piston <NUM> is adjustable within the chamber <NUM> to provide an adjustable working volume <NUM> defined below the piston <NUM>. As shown in <FIG> the piston <NUM> has been moved into the chamber <NUM> by a distance <NUM> to reduce the working volume <NUM> of the chamber from <NUM> to approximately <NUM>. The first and second pneumatic connectors <NUM>,<NUM> shown in <FIG> have been removed from the inlet <NUM> and outlet <NUM> of the chamber <NUM>.

Further detail of the outlet <NUM> is shown in <FIG> (the inlet <NUM> has a similar design). The outlet <NUM> comprises an internally threaded portion <NUM> allowing attachment of the second pneumatic connector <NUM> to the outlet <NUM>, and an outlet aperture <NUM> from the working volume <NUM> of the chamber <NUM>. A recess <NUM> is provided between the outlet aperture <NUM> and the threaded portion <NUM> for receiving a choke plate <NUM> as shown in <FIG>.

A front view of a choke plate <NUM> is shown in <FIG>, with a side view shown in <FIG>. The choke plate comprises a thin disk of brass with a central through hole <NUM> having a smaller diameter than the outlet aperture <NUM> of the chamber <NUM>. For example, the outlet aperture <NUM> may have a diameter of <NUM>, while the hole <NUM> in the choke plate <NUM> may have a diameter of <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM> or <NUM>. In use, the choke plate <NUM> is received in the recess <NUM> in the outlet <NUM> (or inlet <NUM>) and is retained in place by a pneumatic connector <NUM>,<NUM> screwed into the threaded portion <NUM>.

The smaller diameter through hole <NUM> of the or each choke plate <NUM> compared to the outlet aperture <NUM> (or inlet aperture) increases the flow resistance through the chamber <NUM>. It will be understood that several different flow resistances could be achieved by selecting just a single choke plate <NUM>, or by using two choke plates <NUM> with through holes <NUM> of the same or different diameters in combination.

The tuning of the VRC <NUM> for a particular testing configuration is an empirical process, essentially performed in two parts. First, the VRC <NUM> is configured to compensate for the flow resistance of an 'abbreviated' impactor. An example of a testing setup to achieve this is illustrated schematically in <FIG>.

<FIG> shows an arrangement of components <NUM>, namely an NGI <NUM> connected in series with a filter <NUM>, a flow meter <NUM>, a flow controller <NUM> and a vacuum pump <NUM>. The arrangement <NUM> allows the flow resistance of a full impactor, such as an NGI <NUM> to be determined by measuring the pressure drop over the NGI <NUM> at component <NUM>. <FIG> shows a similar arrangement of components <NUM> but with an FSI <NUM> and VRC <NUM> in place of the NGI <NUM> from <FIG>. As in the previous example, the flow resistance of the FSI <NUM> and VRC is determined by measuring the pressure at component <NUM>. By inserting one or more appropriate choke plates <NUM> in the inlet <NUM> and/or outlet <NUM> of the VRC <NUM> (see <FIG>), the flow resistance through the FSI <NUM> and VRC <NUM> can be tuned so that it matches the previously measured flow resistance of the NGI <NUM>.

<FIG> is a bar chart <NUM> showing examples of the compensation in flow resistance. The left-hand side of the chart <NUM> shows a first bar <NUM> illustrates the flow resistance of the NGI <NUM> measured in <FIG>. In contrast, the second bar <NUM> shows the lower flow resistance measured for an FSI <NUM> without any compensation. The third bar <NUM> shows the measured flow resistance for a combination of the FSI <NUM> with the VRC <NUM> configured with choke plates <NUM> having <NUM> and <NUM> through holes. The heights of the first bar <NUM> and third bars <NUM> match, indicating that this combination of choke plates <NUM> in the VRC <NUM> compensates for the lower flow resistance of an FSI <NUM> compared to an NGI <NUM>.

The right-hand side of the chart <NUM> shows a fourth bar <NUM>, fifth bar <NUM> and sixth bar <NUM> illustrating a similar comparison for an ACI and an FSA. In this instance, the difference in resistance between the ACI and FSA is shown in the contrast between the fourth bar <NUM> and fifth bar <NUM>. The compensation illustrated in the increased height of the sixth bar <NUM> is provided by a pair of choke plates <NUM> having <NUM> through holes in the VRC <NUM>.

It will be understood that the use of choke plates <NUM> each having a through hole of a fixed diameter helps to ensure that, once set, the flow resistance provided by the VRC <NUM> is not inadvertently changed. Providing a variable aperture at the inlet <NUM> and/or outlet <NUM>, for example in the form of a needle valve or similar, could provide faster and simpler adjustment, but with increased risk of variation once set.

Once the VRC <NUM> has been properly configured to compensate for a reduction in flow resistance, the second step of the setup involves measuring the difference in rise time, and adjusting the volume of the VRC <NUM> to compensate. The apparatus for this stage is schematically shown in <FIG>.

<FIG> shows an arrangement of components <NUM>, largely similar to that shown in <FIG>, including an NGI <NUM>, flow meter <NUM>, flow controller <NUM> and vacuum pump <NUM>. In addition, a personal computer <NUM> is provided and an inhaler device <NUM> is connected to an inlet of the NGI <NUM>. The arrangement <NUM> of <FIG> allows the inhalation profile, and specifically the rise-time, to be monitored for a set pressure drop through the inhaler <NUM> and NGI <NUM>. The flow meter <NUM> is used in place of the inhaler to ensure that the correct flow conditions are set for the test prior to the rise time being measured with the inhaler attached as shown in <FIG>.

In the arrangement <NUM> of <FIG>, the NGI <NUM> has been replaced by an FSI <NUM> and a VRC <NUM>. The VRC <NUM> has already been configured to compensate for the change in flow resistance as described above. The handle <NUM> of the VRC <NUM> can be used to adjust the piston position and thus the working volume within the VRC <NUM> until the rise-time resulting from the combination of the FSI <NUM> and VRC <NUM> matches that determined for the NGI <NUM>. The shaft <NUM> can then be locked in place using the clamp <NUM> (see <FIG>) to fix the working volume of the VRC <NUM> at the required level.

<FIG> shows an example graph <NUM> of pressure against time illustrating the compensation described above for a Turbohaler (RTM) inhaler device <NUM>. The plotted data <NUM>,<NUM>,<NUM> show, respectively, the pressure profile where an NGI <NUM> is used in isolation, the profile for an FSI 52in isolation, and the profile for an FSI <NUM> and VRC <NUM> in series. It can be seen that the data plots <NUM>,<NUM> are almost coincident, showing that the shorter rise time for the FSI <NUM>, indicated by the steeper initial gradient of the line <NUM>, has been slowed by the addition and adjustment of the VRC <NUM> until it matches that determined for the NGI <NUM> under the same conditions. The VRC <NUM> in the example has been adjusted to provide a working volume of <NUM>, having previously been configured to compensate for the different flow resistance as described with reference to the left-hand side of chart <NUM> in <FIG>. As noted above, the difference between the internal volume of the FSI <NUM> and the NGI <NUM> is over <NUM>, so it can be seen that there is more to matching the rise time than simply adding volume equal to the known difference between two impactors. The volume required in the VRC <NUM> is less than the difference in volume between the full impactor and abbreviated impactor.

The graph <NUM> in <FIG> shows similar data plots <NUM>,<NUM>,<NUM> for, respectively, an ACI, an FSA, and an FSA in series with an appropriately adjusted VRC <NUM>. In this example, the VRC <NUM> has been adjusted to provide a smaller working volume of <NUM>, having previously been configured to compensate for the different flow resistance as described with reference to the right-hand side of chart <NUM>.

The VRC <NUM> is effective in matching both the flow resistance and rise-time of a full impactor with an abbreviated impactor. It allows independent adjustment of flow resistance and volume, to compensate for differences between a wide range of different test setups. Each of the resistance and volume can be reliably set, once adjusted for a particular cascade impactor, but the VRC <NUM> remains adjustable for subsequent use with different cascade impactors.

While the invention is described above with specific reference to particle size determination, it should be appreciated that the described volume and resistance compensator (VRC) would be equally suitable for compensating for differences in resistance and volume experienced in different testing setups, for example with different sampling apparatus for delivered dose testing or for other collectors within a similar overall setup.

Claim 1:
A volume and resistance compensator device (<NUM>) for use in inhaler testing, the device comprising a variable volume chamber (<NUM>) with an inlet (<NUM>) and an outlet (<NUM>), at least one of the inlet (<NUM>) and outlet (<NUM>) being adjustable to vary the resistance to gas flow through the chamber (<NUM>), characterised in that the variable volume chamber (<NUM>) comprises a cylinder and a piston (<NUM>) movable, via a shaft (<NUM>), within the cylinder, and wherein at least one of the inlet (<NUM>) and outlet (<NUM>) is configured to receive a removable choke plate (<NUM>) to reduce the diameter of the flow path through the inlet (<NUM>) and/or outlet (<NUM>), and further comprising one or more choke plates (<NUM>), the or each choke plate (<NUM>) comprising a through hole (<NUM>) of a set diameter.