WO2007066113A1 - Assessment of fine particle delivery - Google Patents

Assessment of fine particle delivery Download PDF

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Publication number
WO2007066113A1
WO2007066113A1 PCT/GB2006/004572 GB2006004572W WO2007066113A1 WO 2007066113 A1 WO2007066113 A1 WO 2007066113A1 GB 2006004572 W GB2006004572 W GB 2006004572W WO 2007066113 A1 WO2007066113 A1 WO 2007066113A1
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WO
WIPO (PCT)
Prior art keywords
cloud
wavelength
optical
optical response
particles
Prior art date
Application number
PCT/GB2006/004572
Other languages
French (fr)
Inventor
Olga Kusmartseva
Peter Smith
Original Assignee
Loughborough University Enterprises Limited
Simpson, Terry, Anthony
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
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Publication date
Application filed by Loughborough University Enterprises Limited, Simpson, Terry, Anthony filed Critical Loughborough University Enterprises Limited
Priority to EP06820446A priority Critical patent/EP1963826A1/en
Publication of WO2007066113A1 publication Critical patent/WO2007066113A1/en

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Classifications

    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N21/00—Investigating or analysing materials by the use of optical means, i.e. using sub-millimetre waves, infrared, visible or ultraviolet light
    • G01N21/17—Systems in which incident light is modified in accordance with the properties of the material investigated
    • G01N21/47—Scattering, i.e. diffuse reflection
    • G01N21/49—Scattering, i.e. diffuse reflection within a body or fluid
    • G01N21/53—Scattering, i.e. diffuse reflection within a body or fluid within a flowing fluid, e.g. smoke
    • G01N21/534—Scattering, i.e. diffuse reflection within a body or fluid within a flowing fluid, e.g. smoke by measuring transmission alone, i.e. determining opacity
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01F—MEASURING VOLUME, VOLUME FLOW, MASS FLOW OR LIQUID LEVEL; METERING BY VOLUME
    • G01F1/00—Measuring the volume flow or mass flow of fluid or fluent solid material wherein the fluid passes through a meter in a continuous flow
    • G01F1/704—Measuring the volume flow or mass flow of fluid or fluent solid material wherein the fluid passes through a meter in a continuous flow using marked regions or existing inhomogeneities within the fluid stream, e.g. statistically occurring variations in a fluid parameter
    • G01F1/708—Measuring the time taken to traverse a fixed distance
    • G01F1/7086—Measuring the time taken to traverse a fixed distance using optical detecting arrangements
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01F—MEASURING VOLUME, VOLUME FLOW, MASS FLOW OR LIQUID LEVEL; METERING BY VOLUME
    • G01F1/00—Measuring the volume flow or mass flow of fluid or fluent solid material wherein the fluid passes through a meter in a continuous flow
    • G01F1/704—Measuring the volume flow or mass flow of fluid or fluent solid material wherein the fluid passes through a meter in a continuous flow using marked regions or existing inhomogeneities within the fluid stream, e.g. statistically occurring variations in a fluid parameter
    • G01F1/708—Measuring the time taken to traverse a fixed distance
    • G01F1/712—Measuring the time taken to traverse a fixed distance using auto-correlation or cross-correlation detection means

Definitions

  • Embodiments of the present invention relate to the assessment of fine particle delivery, in particular, pulmonary drug delivery.
  • the drug particles that are greater in size than fine particles tend to be absorbed into a user's digestion system, which may cause side effects.
  • the ratio of the fine particle mass to the total dose mass it is referred to as the fine particle fraction and this indicates the efficiency of the delivery to the lung.
  • a method of assessing particle delivery comprising: measuring an optical response of a cloud of particles, which is moving in a first direction, to light of a first wavelength directed along a first axis that is substantially perpendicular to the first direction; determining, using the measured optical response to light of a first wavelength, a measure of the optical density, at the first wavelength, of a first portion of the cloud; measuring an optical response of the cloud of particles, which is moving in the first direction, to light of a second wavelength directed along a second axis that is substantially aligned with the first axis and perpendicular to the first direction; determining, using the measured optical response to light of a second wavelength, a measure of the optical density, at the second wavelength, of the first portion of the cloud ; and using the measures of the optical densities of the first portion of the cloud at the first wavelength and at the second wavelength, to assess the particles in the first portion of the cloud.
  • the method assesses the presence and compositions of particles.
  • a method of assessing the development of a cloud of particles as it moves along a first axis of a conduit comprising: i) for a first location along the conduit,
  • measurement apparatus for assessing particle delivery, comprising:
  • a conduit through which fluid carrying a cloud of particles moves in a first direction during delivery; a first sensor for directing light of a first wavelength along a first axis that is substantially perpendicular to the first direction into the cloud and for measuring a first optical response of the cloud; a second sensor for directing light of a second wavelength along a second axis that is substantially aligned with the first axis and perpendicular to the first direction, into the cloud and for measuring a second optical response of the cloud; a processor for determining, using the first and second optical responses, a measure of the optical density, at the first wavelength, of a first portion of the cloud and a measure of the optical density, at the second wavelength, of the first portion of the cloud and for processing the measures of the optical densities of the first portion of the cloud at the first wavelength and at the second wavelength, to assess the composition of the cloud.
  • a measurement apparatus for assessing particle delivery comprising:
  • a conduit through which fluid carrying a cloud of particles moves during delivery; a plurality of sensors arranged along the conduit each of which is operable to measure an optical response of a cloud of particles as it moves along the conduit; and a processor for identifying at which one of the plurality of sensors, a parameter of the optical responses has a turning point.
  • a method of assessing particle delivery comprising the steps of: measuring an optical response of a cloud of particles, which is moving in a first direction, to light of a first wavelength directed along a first axis that is substantially perpendicular to the first direction; determining, using the measured optical response to light of a first wavelength, a measure of optical density, at the first wavelength, of the cloud; measuring an optical response of the cloud of particles, which is moving in the first direction, to light of a second wavelength directed along a second axis that is substantially aligned with the first axis and perpendicular to the first direction; determining, using the measured optical response to light of a second wavelength, a measure of optical density, at the second wavelength, of the cloud ; and comparing the measures of the optical densities of the cloud at the first wavelength and at the second wavelength.
  • Fig. 1 illustrates an assessment system 10 for the rapid assessment of aerolised particle delivery
  • Fig 2A illustrates a cross-section through the measurement device illustrated in Fig 1 and XA ;
  • Fig 2B illustrates a cross-section through the measurement device illustrated in Fig 1 and XB ; and Fig 3 illustrates optical response for particles of different sizes at different wavelengths.
  • Fig. 1 illustrates an assessment system 10 for the rapid assessment of aerolised particle delivery, for example, in vivo pulmonary drug delivery.
  • the system 10 comprises in axial flow series a delivery device 12 including particles 14 for delivery, a measurement device 20 and a physiological actuator 16.
  • a flow of air F is drawn by the physiological actuator 16 from the delivery device 12, through the measurement device 20.
  • a seal may be required at the interface between the delivery device 12 and the measurement device 20 and a seal may be required between the physiological actuator 16 and the measurement device 20.
  • the air flow F created by the physiological actuator 16 may aerosolises agglomerates in the air flow F and create a cloud 11 of particles or the air flow F may draw an already existing aerosol cloud 11 into the measurement device 20.
  • the size of the particles and the distribution of particles within the cloud change as the cloud moves in the air flow F.
  • Aerosolised particle clouds scatter and absorb radiation according to the cloud composition, particularly the particle concentration and particle size distribution within the cloud.
  • the system 10 is arranged to quantitatively assess the effectiveness of pulmonary drug delivery from measurement profiles that indicate how detected radiation varies as the drug cloud passes between a radiation source and a radiation detector.
  • the drug for pulmonary delivery may be in any formulation including dry or liquid form or formulated as a solution/suspension with a solvent.
  • the delivery device 12 may be a real pulmonary drug delivery device. It could be a currently marketed device or a new design of device intended for the market. Examples of the possible types of suitable pulmonary drug delivery devices include: metered dose inhalers, dry powder inhalers, nebulizers, single breath liquid systems, and metered solution inhalers.
  • the physiological actuator may be provided by a breath in-take of a person or by the operation of a breathing simulator.
  • the measuring device 20 includes a straight optically translucent tube 22 connected between the output of a drug delivery device 12 and a physiological actuator 16.
  • the tube 22 in this example, has a 21 mm internal diameter and a fixed length of 60 mm. In other embodiments the tube 22 may have an internal diameter up to 30mm and a fixed length of between 5 and 200mm.
  • the measuring device also comprises sensors 24 that are exterior to the tube 22, memory buffers 23 connected to the sensors 24, a processor 30 connected to the memory buffers 23, a memory 32 and an output 34.
  • Each sensor 24 includes a radiation source 25 and a radiation detector 26 lying in a plane perpendicular to the longitudinal axis of the tube 22 and the flow direction F as illustrated in Figs 2A and 2B.
  • the sensors 24 operate by obscuration of light and the light source 25 and light detector 26 are positioned diametrically opposite each other.
  • the sensors 24 operates by light scattering and the source and detector are positioned in the same plane but the detector is not positioned in the 'line-of- sight' of the light source so that it detects light at a predetermined scattering angle.
  • a first sensor 24 A i includes a first radiation source 25AI and a first radiation detector 26 A i lying in a first plane P A perpendicular to the longitudinal axis 13 of the tube 22 and the flow direction F.
  • the first plane P A is located at position XA along the longitudinal axis 13 of the tube 22.
  • the first radiation source 25 A1 emits light 27 A i with a wavelength of ⁇ 2 and is positioned at azimuthal angle
  • a second sensor 24 A2 includes a second radiation source 25 A2 and a second radiation detector 26 A2 lying in the first plane P A .
  • the second radiation source 25 A2 emits light 27 A2 with a wavelength of ⁇ 2 and is positioned at azimuthal angle ⁇ 2 .
  • a third sensor 24 A3 includes a third radiation source 25 A3 and a third radiation detector 26 A3 lying in the first plane P A .
  • the third radiation source 25 A3 emits light 27 A3 with a wavelength of K 2 and is positioned at azimuthal angle ⁇ 3 .
  • the first plane P A of sensors is illustrated in plan view in Fig 2A.
  • a fourth sensor 24 B i includes a fourth radiation source 25 B i and a fourth radiation detector 26 B i lying in a second plane PB perpendicular to the longitudinal axis of the tube 22 and the flow direction F.
  • the second plane P B is located at position X B along the longitudinal axis of the tube 22.
  • the fourth radiation source 25 BI emits light 27BI with a wavelength of ⁇ i and is positioned at azimuthal angle ⁇ i so that it is aligned in the flow direction (i.e. paired) with the first radiation source 25 A i ⁇
  • a fifth sensor 24B 2 includes a fifth radiation source 25B2 and a fifth radiation detector 26 B2 lying in the second plane P 6 .
  • the fifth radiation source 25 B2 emits light 27 B2 with a wavelength of K 2 and is positioned at azimuthal angle ⁇ 2 so that it is aligned in the flow direction (i.e. paired) with the second radiation source 25 A2 .
  • a sixth sensor 24 B3 includes a sixth radiation source 25 B3 and a sixth radiation detector 26B 3 lying in the second plane P B .
  • the sixth radiation source 25 B3 emits light 27 B3 with a wavelength of ⁇ 3 and is positioned at azimuthal angle ⁇ 3 so that it is aligned in the flow direction (i.e. paired) with the third radiation source 25 A3 .
  • the second plane P B of sensors is illustrated in plan view in Fig 2B.
  • Each memory buffer 23 records, during a delivery, real-time data from one of the six radiation detectors 26 and the processor 30 transfers the buffered data to memory 32.
  • the real-time data T( ⁇ , x, t) recorded in each buffer are measurement profiles of how the detected radiation varies with time.
  • the processor 30 may start transferring and processing data in response to user input. For example, a button of a user interface of the measurement device 20 could be depressed to start recording. Alternatively, the processor 30 could start automatically in response to a detection of the start of the in- take procedure. For example, a flow detector could be positioned upstream of the sensor 24 A , and the processor 30 could detect when the detected flow rate exceeds a predetermined threshold.
  • the measurement device 20 has been described as a separate add- on component to the drug delivery device 12, in other embodiments the functionality of the measurement device 20 may be integrated into the drug delivery device 12.
  • Figure 3 shows a plot of the light transmittance against the particle diameter at three light wavelengths 450nm, 650nm and 800nm. This Figure illustrates that for each wavelength the optical attenuation is very low for particles less than 0.1 ⁇ m in diameter and also for particles greater than 10 ⁇ m in diameter.
  • a non-variable particle cloud with a large proportion of particles of a diameter less than ⁇ 1 ⁇ m will have a significantly lower transmittance for 450nm than for 650nm and a higher Transmittance for 800nm than for 650nm.
  • the Transmittance for 450nm increases significantly more than that for 650nm and the Transmittance for 650nm increases more than that for 800nm. Consequently the Transmittance for 450nm will no longer be significantly less than for 650nm and the Transmittance for 800nm will not necessarily be higher than for 650nm.
  • Light is obscured according to a standard model of optical density (Beer-Lambert) and the recorded data are a set of six light intensity measurement profiles.
  • /,,(/I 2 ) is the light intensity of each of the radiation sources 25AJ
  • d Al are optical paths of each light-beam produced by the respective radiation sources 25AJ
  • ⁇ are extinction coefficients.
  • Variable p Al represents the particle population on the optical paths d Al .
  • the transmittance for each sensor channel associated with the first plane PA is:
  • I B ( ⁇ ,) is the light intensity of each of the radiation sources 25 B ⁇ .
  • d Bl are optical paths of each light-beam produced by the respective radiation sources 25 B i, and ⁇ are extinction coefficients.
  • Variable p Bl represents the particle population on the optical paths d Bl .
  • t A is the time of measurement at the sensor positioned at x A and t n is the time of measurement, of the same portion of the cloud, at the sensor positioned at ⁇ B i.e.
  • Z 1 (AOOnTnJ) > a would indicate the presence of the fine particles in the cloud at the azimuthal position ⁇ i at time.
  • the parameter a may be set to 1 or to some larger experimentally determined value.
  • the parameter b may be set to 1 or to some smaller experimentally determined value.
  • Fig 1 illustrates the sensors in the first and second planes as being operational at the same but being separated by a distance
  • an alternative embodiment may locate the first and second planes together but interleave the operation of the sensors of the first plane and the sensors of the second plane.
  • Fig.1 illustrates the use of three sensors, however it should be understood that two or more paired sensors may be used.
  • Fig.1 illustrates the use of two planes of paired sensors.
  • three planes of sensors may be used, for example, a third plane P c may be positioned before the first plane PA at a position x c along the longitudinal axis of the tube 22.
  • the third plane Pc is perpendicular to the longitudinal axis of the tube 22 and the flow direction F. It may have three sensors including a seventh sensor 24ci that uses light with a wavelength of ⁇ 3 and is positioned at azimuthal angle ⁇ i so that it is aligned in the flow direction (i.e.
  • an eighth sensor 24c 2 that emits light with a wavelength of ⁇ 2 and is positioned at azimuthal angle Q 2 so that it is aligned in the flow direction (i.e. paired) with the second radiation source 25 A2
  • a ninth sensor 24 C2 that emits light with a wavelength of ⁇ i and is positioned at azimuthal angle ⁇ 3 so that it is aligned in the flow direction (i.e. paired) with the third radiation source 25A 3 .
  • Fig 1 illustrates a single grouping of planes of sensors, it should be understood that two or more groups of planes of sensors may be used. The separation along the longitudinal axis between groups of planes of sensors is much greater than the separation of the planes of sensors within a group.
  • ? 1(/)) is the time of measurement at the sensor of plane P A at positionx-i and t ] ⁇ B) is the time of measurement, of the same portion of the cloud, at the sensor of plane P B at position x-
  • the difference between t-i(B) and t-i(A) is calculated by cross-correlating T A2 ( ⁇ 2 ,x KA) ,t ) and T 112 (A 2 , x KB) ,t ) .
  • T A2 ⁇ 2 ,x KA) ,t
  • T 112 A 2 , x KB
  • t 2 ⁇ A) is the time of measurement at the sensor of plane PA at position X 2
  • t 2 ⁇ B) is the time of measurement, of the same portion of the cloud, at the sensor of plane P B at position X 2 .
  • ⁇ 2 the difference between t 2 (B) and t2(A) is calculated by cross-correlating T 42 (Z 2 , x 2( ⁇ A) , t ) and T B2 (X 2 ,x 2(B) j ) .
  • T 42 (Z 2 , x 2( ⁇ A) , t ) is calculated and constant , it can be used to calculate the cloud flow velocity at X 2 , V 2 .
  • v may be the average of vi and V 2 .
  • the measurements at multiple locations and at multiple colours may facilitate the indicators for the cloud development, e.g. the cloud volume and r- distribution of the particle population in the cloud.
  • ⁇ u (400nmj) > ⁇ would indicate the presence of the fine particles in the cloud at the azimuthal position ⁇ 1 at time.
  • the parameter a may be set to 1 or to some larger experimentally determined value.
  • ⁇ t may also indicate the presence of the fine particles in the cloud at the azimuthal position ⁇ 3 .
  • the parameter b may be set to 1 or to some smaller experimentally determined value.
  • each sensor may calculate the intensity of light sensed at each sensor according to a colorimetric scale at each location.
  • a colorimetric scale At a first location, one may calculate for each sensor, the intensity at that sensor divided by the sum of the intensities at the other sensors at that location.
  • one has three sensors at a location one has three normalised values for the intensities recorded at each sensor. By tracking how these values evolve as one moves from location to location, one can determine important information about the development of the cloud.
  • Sensors can be arranged along the conduit. Each sensor measures the intensity of the light as the cloud passes through.
  • the measurement profile created represents the optical response, at the location of that sensor, of the cloud of particles as it moves along the conduit.
  • Each measurement profile may have a number of associated parameters such as its asymmetry, its height, the area under a fitted curve, etc.
  • the processor can process the plurality of measurement profiles received from the plurality of sensors to extract a parameter for each sensor location and then determine where the turning point of that parameter is located. For example, the amplitude of the measurement profile may increase and then decrease as one moves along the conduit. However, the location where the amplitude is maximum may be where the fine particle dose is maximum. In a further example, the integral under a curve fitted to the measurement profile may increase and then decrease as one moves along the conduit. The location where the integral is maximum may be where the fine particle dose is maximum.
  • the sensors used may be colored or monochrome.
  • Signal processing techniques can be used to generate parametric (e.g. autoregressive moving average) or non-parametric models (e.g. Welch power spectrum estimation) of the evolution of the measurement profiles recorded at different positions along the conduit.
  • a linear model can be created which represents the dispersion of a given profile with respect to another (e.g. a digital filter).
  • the measurement profile can be considered as a superposition of many individual profiles travelling at different speeds.
  • these composite profiles will be displaced with respect to one another and hence the overall profile will be altered.
  • a sufficiently accurate physical model of the evolution process e.g. evaporation of the aerosol propellant in MDIs
  • it will be possible to invert the measurement profile data sets into physical properties of the particle clouds e.g. particle size distribution
  • Optical labels may be used for further discrimination of the cloud characteristics.
  • drug particles might be labelled differently from carrier particles or in the case of multiple drugs delivery each species could be labelled separately.

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Abstract

A method of assessing particle delivery, comprising the steps of : measuring the optical responses of a cloud of particles, which is moving in a first direction, to light of a first and a second wavelengths directed along a first axis that is substantially perpendicular to the first direction; determining, using the measured optical responses to light of the first and second wavelengths, a measure of the optical density, at the first and second wavelengths, of a first portion of the cloud; and using the measures of the optical densities of the first portion of the cloud at the first wavelength and at the second wavelength, to assess the particles in the first portion of the cloud. A method of assessing particle delivery, comprising the steps of : measuring at a plurality of locations along the conduit the optical response of a cloud of particles as it moves in a first direction past the locations; and identifying at which location a parameter of the optical response has a turning point.

Description

TITLE
Assessment of fine particle delivery
FIELD OF THE INVENTION
Embodiments of the present invention relate to the assessment of fine particle delivery, in particular, pulmonary drug delivery.
BACKGROUND TO THE INVENTION The effectiveness of particle delivery in some circumstances, for example pulmonary drug delivery, depends upon the amount of fine particles delivered (the fine particle mass). This represents the amount of drug which is of the correct size (e.g. 0.5 to 1 μm) to reach deep within the lung and have a desirable physiological effect on a user. The drug particles that are greater in size than fine particles tend to be absorbed into a user's digestion system, which may cause side effects. The ratio of the fine particle mass to the total dose mass, it is referred to as the fine particle fraction and this indicates the efficiency of the delivery to the lung. BRIEF DESCRIPTION OF THE INVENTION
It would be desirable to assess the effectiveness of a delivery device at delivering fine particles.
According to an embodiment of the invention there is provided a method of assessing particle delivery, comprising: measuring an optical response of a cloud of particles, which is moving in a first direction, to light of a first wavelength directed along a first axis that is substantially perpendicular to the first direction; determining, using the measured optical response to light of a first wavelength, a measure of the optical density, at the first wavelength, of a first portion of the cloud; measuring an optical response of the cloud of particles, which is moving in the first direction, to light of a second wavelength directed along a second axis that is substantially aligned with the first axis and perpendicular to the first direction; determining, using the measured optical response to light of a second wavelength, a measure of the optical density, at the second wavelength, of the first portion of the cloud ; and using the measures of the optical densities of the first portion of the cloud at the first wavelength and at the second wavelength, to assess the particles in the first portion of the cloud. The method assesses the presence and compositions of particles.
According to an embodiment of the invention there is provided a method of assessing the development of a cloud of particles as it moves along a first axis of a conduit comprising: i) for a first location along the conduit,
repeatedly performing the method of claim 1 for different first portions of the cloud as it moves past the first location to create a first measurement profile; ii) for a second location along the conduit, repeatedly performing the method of claim 1 for different first portions of the cloud as it moves past the second location to create a second measurement profile; iii) using the first and second measurement profiles to assess the development of the cloud of particles.
According to an embodiment of the invention there is provided a
measurement apparatus for assessing particle delivery, comprising:
a conduit through which fluid carrying a cloud of particles moves in a first direction during delivery; a first sensor for directing light of a first wavelength along a first axis that is substantially perpendicular to the first direction into the cloud and for measuring a first optical response of the cloud; a second sensor for directing light of a second wavelength along a second axis that is substantially aligned with the first axis and perpendicular to the first direction, into the cloud and for measuring a second optical response of the cloud; a processor for determining, using the first and second optical responses, a measure of the optical density, at the first wavelength, of a first portion of the cloud and a measure of the optical density, at the second wavelength, of the first portion of the cloud and for processing the measures of the optical densities of the first portion of the cloud at the first wavelength and at the second wavelength, to assess the composition of the cloud. According to an embodiment of the invention there is provided a measurement apparatus for assessing particle delivery, comprising:
a conduit through which fluid carrying a cloud of particles moves during delivery; a plurality of sensors arranged along the conduit each of which is operable to measure an optical response of a cloud of particles as it moves along the conduit; and a processor for identifying at which one of the plurality of sensors, a parameter of the optical responses has a turning point. According to an embodiment of the invention there is provided a method of assessing particle delivery, comprising the steps of: measuring an optical response of a cloud of particles, which is moving in a first direction, to light of a first wavelength directed along a first axis that is substantially perpendicular to the first direction; determining, using the measured optical response to light of a first wavelength, a measure of optical density, at the first wavelength, of the cloud; measuring an optical response of the cloud of particles, which is moving in the first direction, to light of a second wavelength directed along a second axis that is substantially aligned with the first axis and perpendicular to the first direction; determining, using the measured optical response to light of a second wavelength, a measure of optical density, at the second wavelength, of the cloud ; and comparing the measures of the optical densities of the cloud at the first wavelength and at the second wavelength.
BRIEF DESCRIPTION OF THE DRAWINGS
For a better understanding of the present invention reference will now be made by way of example only to the accompanying drawings in which:
Fig. 1 illustrates an assessment system 10 for the rapid assessment of aerolised particle delivery;
Fig 2A illustrates a cross-section through the measurement device illustrated in Fig 1 and XA ;
Fig 2B illustrates a cross-section through the measurement device illustrated in Fig 1 and XB ; and Fig 3 illustrates optical response for particles of different sizes at different wavelengths.
DETAILED DESCRIPTION OF EMBODIMENTS OF THE INVENTION
Fig. 1 illustrates an assessment system 10 for the rapid assessment of aerolised particle delivery, for example, in vivo pulmonary drug delivery. The system 10 comprises in axial flow series a delivery device 12 including particles 14 for delivery, a measurement device 20 and a physiological actuator 16. A flow of air F is drawn by the physiological actuator 16 from the delivery device 12, through the measurement device 20. A seal may be required at the interface between the delivery device 12 and the measurement device 20 and a seal may be required between the physiological actuator 16 and the measurement device 20.
The air flow F created by the physiological actuator 16, may aerosolises agglomerates in the air flow F and create a cloud 11 of particles or the air flow F may draw an already existing aerosol cloud 11 into the measurement device 20. The size of the particles and the distribution of particles within the cloud change as the cloud moves in the air flow F.
Aerosolised particle clouds scatter and absorb radiation according to the cloud composition, particularly the particle concentration and particle size distribution within the cloud. The system 10 is arranged to quantitatively assess the effectiveness of pulmonary drug delivery from measurement profiles that indicate how detected radiation varies as the drug cloud passes between a radiation source and a radiation detector.
The drug for pulmonary delivery may be in any formulation including dry or liquid form or formulated as a solution/suspension with a solvent.
The delivery device 12 may be a real pulmonary drug delivery device. It could be a currently marketed device or a new design of device intended for the market. Examples of the possible types of suitable pulmonary drug delivery devices include: metered dose inhalers, dry powder inhalers, nebulizers, single breath liquid systems, and metered solution inhalers.
The physiological actuator may be provided by a breath in-take of a person or by the operation of a breathing simulator.
The measuring device 20 includes a straight optically translucent tube 22 connected between the output of a drug delivery device 12 and a physiological actuator 16. The tube 22, in this example, has a 21 mm internal diameter and a fixed length of 60 mm. In other embodiments the tube 22 may have an internal diameter up to 30mm and a fixed length of between 5 and 200mm.
The measuring device also comprises sensors 24 that are exterior to the tube 22, memory buffers 23 connected to the sensors 24, a processor 30 connected to the memory buffers 23, a memory 32 and an output 34.
Each sensor 24 includes a radiation source 25 and a radiation detector 26 lying in a plane perpendicular to the longitudinal axis of the tube 22 and the flow direction F as illustrated in Figs 2A and 2B. In this example, the sensors 24 operate by obscuration of light and the light source 25 and light detector 26 are positioned diametrically opposite each other. In other embodiments, the sensors 24 operates by light scattering and the source and detector are positioned in the same plane but the detector is not positioned in the 'line-of- sight' of the light source so that it detects light at a predetermined scattering angle.
A first sensor 24Ai, includes a first radiation source 25AI and a first radiation detector 26Ai lying in a first plane PA perpendicular to the longitudinal axis 13 of the tube 22 and the flow direction F. The first plane PA is located at position XA along the longitudinal axis 13 of the tube 22. The first radiation source 25A1 emits light 27Ai with a wavelength of λ2 and is positioned at azimuthal angle A second sensor 24A2, includes a second radiation source 25A2 and a second radiation detector 26A2 lying in the first plane PA. The second radiation source 25A2 emits light 27A2 with a wavelength of λ2 and is positioned at azimuthal angle θ2.
A third sensor 24A3, includes a third radiation source 25A3 and a third radiation detector 26A3 lying in the first plane PA. The third radiation source 25A3 emits light 27A3 with a wavelength of K2 and is positioned at azimuthal angle θ3.
The first plane PAof sensors is illustrated in plan view in Fig 2A.
A fourth sensor 24Bi, includes a fourth radiation source 25Bi and a fourth radiation detector 26Bi lying in a second plane PB perpendicular to the longitudinal axis of the tube 22 and the flow direction F. The second plane PB is located at position XB along the longitudinal axis of the tube 22. The fourth radiation source 25BI emits light 27BI with a wavelength of λi and is positioned at azimuthal angle θi so that it is aligned in the flow direction (i.e. paired) with the first radiation source 25Ai■
A fifth sensor 24B2, includes a fifth radiation source 25B2 and a fifth radiation detector 26B2 lying in the second plane P6. The fifth radiation source 25B2 emits light 27B2with a wavelength of K2 and is positioned at azimuthal angle θ2 so that it is aligned in the flow direction (i.e. paired) with the second radiation source 25A2.
A sixth sensor 24B3, includes a sixth radiation source 25B3 and a sixth radiation detector 26B3 lying in the second plane PB. The sixth radiation source 25B3 emits light 27B3 with a wavelength of λ3 and is positioned at azimuthal angle θ3 so that it is aligned in the flow direction (i.e. paired) with the third radiation source 25A3.
The second plane PB of sensors is illustrated in plan view in Fig 2B. Each memory buffer 23 records, during a delivery, real-time data from one of the six radiation detectors 26 and the processor 30 transfers the buffered data to memory 32. The real-time data T(λ , x, t) recorded in each buffer are measurement profiles of how the detected radiation varies with time.
The processor 30 may start transferring and processing data in response to user input. For example, a button of a user interface of the measurement device 20 could be depressed to start recording. Alternatively, the processor 30 could start automatically in response to a detection of the start of the in- take procedure. For example, a flow detector could be positioned upstream of the sensor 24A, and the processor 30 could detect when the detected flow rate exceeds a predetermined threshold.
Although the measurement device 20 has been described as a separate add- on component to the drug delivery device 12, in other embodiments the functionality of the measurement device 20 may be integrated into the drug delivery device 12.
Figure 3 shows a plot of the light transmittance against the particle diameter at three light wavelengths 450nm, 650nm and 800nm. This Figure illustrates that for each wavelength the optical attenuation is very low for particles less than 0.1 μm in diameter and also for particles greater than 10μm in diameter.
Between these extremes, as the particle diameter increases the attenuation increases to a maximum at a certain diameter and then decreases. The rate of increase and decrease of attenuation is greater for low wavelengths and the 'certain diameter' is lower for smaller wavelengths. Thus different light wavelengths have slightly different "sensitivity profiles".
A non-variable particle cloud with a large proportion of particles of a diameter less than ~1 μm will have a significantly lower transmittance for 450nm than for 650nm and a higher Transmittance for 800nm than for 650nm.
If the proportion of particles with a diameter less than ~1 μm is reduced, the Transmittance for 450nm increases significantly more than that for 650nm and the Transmittance for 650nm increases more than that for 800nm. Consequently the Transmittance for 450nm will no longer be significantly less than for 650nm and the Transmittance for 800nm will not necessarily be higher than for 650nm.
Consequently measurement of the Transmittance at different wavelengths and subsequent analysis enables features of the cloud to be estimated such as the existence of a significant proportion of fine particles and also its velocity.
Referring back to Figs 1 and 2, there are three sensors in each plane (equally separated in azimuth) and two planes of optical sensors that are separated by a small distance XB - XA■
One plane PA operates at a mono light wavelength (e.g. /L, = 650πm )- The second plane PB operates at three different light wavelengths e.g. A1 = 400nm , A2 = OSOnJn and Λ, = 850«m ).
Light is obscured according to a standard model of optical density (Beer-Lambert) and the recorded data are a set of six light intensity measurement profiles.
For the sensors in the first plane PA
IAi(x,t) = IAW&φ[--dAt(xf t).ε(Λ29pAi(xtt))] where i=1 corresponds to the first sensor, i=2 corresponds to the second sensor and i=3 corresponds to the third sensor. /,,(/I2) is the light intensity of each of the radiation sources 25AJ , dAl are optical paths of each light-beam produced by the respective radiation sources 25AJ, and ε are extinction coefficients. Variable pAl represents the particle population on the optical paths dAl .
The transmittance for each sensor channel associated with the first plane PA is:
TJλ2i,x,t) S χpl-dAl(x,t)ε(λ2,pAi(x,t))]
Figure imgf000011_0001
For the sensors in the first plane PB
IBt(x,t) = IB(λt)exp[-dBi(x,t).ε(λl f pBt(x,t))] where i=1 corresponds to the fourth sensor, i=2 corresponds to the fifth sensor and i=3 corresponds to the sixth sensor. IB(λ,) is the light intensity of each of the radiation sources 25Bι . dBl are optical paths of each light-beam produced by the respective radiation sources 25Bi, and ε are extinction coefficients. Variable pBl represents the particle population on the optical paths dBl .
The transmittance for each sensor channel associated with the second plane
TM9x9t) = 1M'*'^ = Qχp[-dBi(x,t)ε(λi,pBi(x,t))]
7 B
The optical density is the natural logarithm of the transmittance. For each moment (t) there are six independent equations derived from the six channels, and there are at least 12 independent variables. Info, (A2 , x, 0] = -^, (*, 0*fe > ^, (*» 0)
Info, (A1 , x, 0] = -dΛ (x, 0*(Λ > PB1 (*, θ) for i=1 ,2,3.
To solve the optical-density equations in relation to the optical paths and the extinction coefficients we assume that the development of the cloud is slow enough relative to the separation of the first and second planes so that the optical paths at paired sensors and the particle populations on these paths are constant for the same portions of the cloud.
According to this assumption,
a faXX Α>1 "A ) ' ~ a 'bι (X B ^B )
PaXX A ,tA)∞Pbι(XB,tB)
where tA is the time of measurement at the sensor positioned at xA and tn is the time of measurement, of the same portion of the cloud, at the sensor positioned at χB i.e.
1 B ~ t A + τ > where τ = xB - xA I cloud flow velocity, τ is calculated by cross-correlating
Figure imgf000012_0001
and Th2 (A2, xB, t ) . The cloud flow velocity can be calculated from r = xβ - χA I cloud flow velocity, where xB - xA is a known constant.
The ratios of the extinction coefficients at the different wavelengths for the same portions of the cloud are calculated: γ (λ x A -_ g( A . PM (XA » 0) _ MTAl {λ,,xB,t + τ)]
M " λ' ) ε(λ2,pA,(xA,t)) In[T^(Ji2, x A,t)]
Z1(AOOnTnJ) > a would indicate the presence of the fine particles in the cloud at the azimuthal position θi at time. The parameter a may be set to 1 or to some larger experimentally determined value.
The value of γ2(650nm,t) = l is constant if τ is chosen correctly and the assumption on development of the cloud between the first and second planes holds.
If /3(850«w,t) < b , it may also indicate the presence of the fine particles in the cloud at the azimuthal position G3. The parameter b may be set to 1 or to some smaller experimentally determined value.
Thus measuring the optical density at multi-wavelengths for the same (or nearly the same) part of cloud allows elimination of the optical path and the evaluation of the difference between the extinction coefficients ε for different colours. This provides an indicator of the particle size distribution for this particular part of the aerosol cloud.
Although Fig 1 illustrates the sensors in the first and second planes as being operational at the same but being separated by a distance, an alternative embodiment may locate the first and second planes together but interleave the operation of the sensors of the first plane and the sensors of the second plane. For example, the sensors of the first plane may operate at times t= 2n τ , whereas the sensors of the second plane operate at time τ later e.g. t= (2n+1)r . Fig.1 illustrates the use of three sensors, however it should be understood that two or more paired sensors may be used.
Fig.1 illustrates the use of two planes of paired sensors. However three planes of sensors may be used, for example, a third plane Pc may be positioned before the first plane PA at a position xc along the longitudinal axis of the tube 22. The third plane Pc is perpendicular to the longitudinal axis of the tube 22 and the flow direction F. It may have three sensors including a seventh sensor 24ci that uses light with a wavelength of λ3 and is positioned at azimuthal angle θi so that it is aligned in the flow direction (i.e. paired) with the first radiation source 25Ai , an eighth sensor 24c2 that emits light with a wavelength of λ2 and is positioned at azimuthal angle Q2 so that it is aligned in the flow direction (i.e. paired) with the second radiation source 25A2 and a ninth sensor 24C2 that emits light with a wavelength of λi and is positioned at azimuthal angle Θ3 so that it is aligned in the flow direction (i.e. paired) with the third radiation source 25A3 . As before, by using the ratio of the optical densities at plane PB to plane PA at B1 χ^AOOnmj) is calculated and by using the ratio of the optical densities at plane PB to plane PA at Θ3 χ3(850nm,t) is calculated. However, in addition, by using the ratio of the optical densities at plane Pc to plane PA at B1 γλ(%50nm,t) is calculated and by using the ratio of the optical densities at plane Pc to plane PA at G3 χz(400nm,t) \s calculated.
Although Fig 1 illustrates a single grouping of planes of sensors, it should be understood that two or more groups of planes of sensors may be used. The separation along the longitudinal axis between groups of planes of sensors is much greater than the separation of the planes of sensors within a group.
Using the groups of planes of sensors it is possible to perform the analysis described above for a single group of planes for each of the groups of planes. One can then determine how Y varies along the longitudinal axis of the tube and identify where the cloud has the highest proportion of fine particles. For two pairs of rings positioned at x-i and X2, the number of equations is doubled, and equations take the following form: in[ro,(^,χ l,o]= -^,(χ,,0^^OT(^pθ),
Info, (λ, , X1 , 0] = -dhl
Figure imgf000015_0001
Info, (Z2 , x2 , t + Δθ] = -da, (x2 , Off fe , Pa, (x2 » Oi
Info, (4 , X2 , f + ΔO] = -4 (x2 , Off (Λ » Λ, (xi , 0)
According to the assumption, that cloud changes little between the planes at xi
Figure imgf000015_0002
where ?1(/)) is the time of measurement at the sensor of plane PA at positionx-i and t]{B) is the time of measurement, of the same portion of the cloud, at the sensor of plane PB at position x-|. n , the difference between t-i(B) and t-i(A) is calculated by cross-correlating TA2(λ2,xKA),t ) and T112(A2, xKB),t ) . As the distance between x1(A) and Xi(B) is known and constant, it can be used to calculate the cloud flow velocity at xi, V1.
According to the assumption, that cloud changes little between the planes at
X2
Figure imgf000015_0003
Figure imgf000016_0001
PAI \X2(A) ' 1-2(A) ) W P BXX2(B) ^2(B) ) where t2{A) is the time of measurement at the sensor of plane PA at position X2 and t2{B) is the time of measurement, of the same portion of the cloud, at the sensor of plane PB at position X2. τ 2 , the difference between t2(B) and t2(A) is calculated by cross-correlating T42(Z2, x2(^A), t ) and TB2(X2,x2(B)j ) . As the distance between X2(A) and X2(B) is known and constant , it can be used to calculate the cloud flow velocity at X2, V2.
According to the assumption, that cloud changes significantly between Xi and X2, if t2 = t-i + Δt, where Δt = X2 - Xi / v, where xH - xA is a known constant and v is the cloud flow velocity, v may be the average of vi and V2.
The measurements at multiple locations and at multiple colours may facilitate the indicators for the cloud development, e.g. the cloud volume and r- distribution of the particle population in the cloud.
Figure imgf000016_0002
χu(400nmj) > α would indicate the presence of the fine particles in the cloud at the azimuthal position Θ1 at time. The parameter a may be set to 1 or to some larger experimentally determined value.
Compare γu(400nmj) > α and γ]2(400nmJ) > b would give an indicator if the location of the fine particles in the cloud has changed. The value of γ2(650nm,t) = 1 is constant if the assumption on development of the cloud between the first and second planes holds.
If χ3l(850nm,t) < b , \t may also indicate the presence of the fine particles in the cloud at the azimuthal position θ3. The parameter b may be set to 1 or to some smaller experimentally determined value.
Using multiple rings one can follow the cloud development and find an indicator for the optimal distance from the mouthpiece of an inhaler where the cloud has the highest population of the fine particles.
For example, if one spaces rings of sensors along the conduit where each ring corresponds to the second plane PB of sensors illustrated in plan view in Fig 2B, then one may calculate the intensity of light sensed at each sensor according to a colorimetric scale at each location. At a first location, one may calculate for each sensor, the intensity at that sensor divided by the sum of the intensities at the other sensors at that location. Thus if one has three sensors at a location one has three normalised values for the intensities recorded at each sensor. By tracking how these values evolve as one moves from location to location, one can determine important information about the development of the cloud.
Sensors can be arranged along the conduit. Each sensor measures the intensity of the light as the cloud passes through. The measurement profile created represents the optical response, at the location of that sensor, of the cloud of particles as it moves along the conduit. Each measurement profile may have a number of associated parameters such as its asymmetry, its height, the area under a fitted curve, etc. The processor can process the plurality of measurement profiles received from the plurality of sensors to extract a parameter for each sensor location and then determine where the turning point of that parameter is located. For example, the amplitude of the measurement profile may increase and then decrease as one moves along the conduit. However, the location where the amplitude is maximum may be where the fine particle dose is maximum. In a further example, the integral under a curve fitted to the measurement profile may increase and then decrease as one moves along the conduit. The location where the integral is maximum may be where the fine particle dose is maximum. The sensors used may be colored or monochrome.
Signal processing techniques can be used to generate parametric (e.g. autoregressive moving average) or non-parametric models (e.g. Welch power spectrum estimation) of the evolution of the measurement profiles recorded at different positions along the conduit. For example, a linear model can be created which represents the dispersion of a given profile with respect to another (e.g. a digital filter). At any one position in the conduit, the measurement profile can be considered as a superposition of many individual profiles travelling at different speeds. When compared with the measurement profile at another location, these composite profiles will be displaced with respect to one another and hence the overall profile will be altered. With some drug delivery clouds it may be possible to have a sufficiently accurate physical model of the evolution process (e.g. evaporation of the aerosol propellant in MDIs) that it will be possible to invert the measurement profile data sets into physical properties of the particle clouds (e.g. particle size distribution)
Optical labels (absorption, scattering, fluorescent, spectroscopic) may be used for further discrimination of the cloud characteristics. For example drug particles might be labelled differently from carrier particles or in the case of multiple drugs delivery each species could be labelled separately.
Although embodiments of the present invention have been described in the preceding paragraphs with reference to various examples, it should be appreciated that modifications to the examples given can be made without departing from the scope of the invention as claimed. Whilst endeavouring in the foregoing specification to draw attention to those features of the invention believed to be of particular importance it should be understood that the Applicant claims protection in respect of any patentable feature or combination of features hereinbefore referred to and/or shown in the drawings whether or not particular emphasis has been placed thereon.

Claims

Claims
1. A method of assessing particle delivery, comprising the steps of:
a) measuring an optical response of a cloud of particles, which is moving in a first direction, to light of a first wavelength directed along a first axis that is substantially perpendicular to the first direction;
b) determining, using the measured optical response to light of a first wavelength, a measure of the optical density, at the first wavelength, of a first portion of the cloud;
c) measuring an optical response of the cloud of particles, which is moving in the first direction, to light of a second wavelength directed along a second axis that is substantially aligned with the first axis and perpendicular to the first direction;
d) determining, using the measured optical response to light of a second wavelength, a measure of the optical density, at the second wavelength, of the first portion of the cloud ; and
e) using the measures of the optical densities of the first portion of the cloud at the first wavelength and at the second wavelength, to assess the particles in the first portion of the cloud.
2. A method as claimed in claim 1 , wherein measuring the optical response, at the first wavelength, of the cloud occurs at a first position along the first direction and measuring the optical response, at the second wavelength, occurs at a second different position along the first direction, wherein the first and second positions are separated by a distance that is small enough to prevent significant development of the cloud as it moves from the first position to the second position.
3. A method as claimed in claim 1 or 2, wherein the second axis is aligned substantially parallel to the first axis but offset from the first axis along the first direction.
4. A method as claimed in claim 1 , wherein measuring the optical response, at the first wavelength, of the cloud and measuring the optical response, at the second wavelength, occur at the same position along the first direction.
5. A method as claimed in claim 1 or 4, wherein the first and second axes are substantially coincident.
6. A method as claimed in any preceding claim, further comprising: determining a time offset between the passage of the first portion of the cloud past a first position where the optical response, at the first wavelength, of the cloud is measured and a second position where the optical response, at the second wavelength, of the cloud is measured.
7. A method as claimed in claim 6, further comprising:
measuring, at the first position, a first optical response of the cloud of particles, which is moving in a first direction, to light of a third wavelength directed along a third axis that is substantially perpendicular to the first direction;
measuring, at the second position, a second optical response of the cloud of particles, which is moving in the first direction, to light of the third wavelength directed along a fourth axis that is substantially aligned with the third axis and perpendicular to the first direction; and
determining the time offset by cross-correlating the first and second optical responses.
8. A method as claimed in claim 6 or 7, further comprising:
determining the optical density, at the first wavelength, from a first portion of the time varying optical response measured in step a) of claim 1 ;
determining the optical density, at the second wavelength, from a second portion of the time varying optical response measured in step c) of claim 1 that is offset in time from the first portion of the time varying optical response measured in step a) of claim 1 by the determined time offset.
9. A method as claimed in any preceding claim, further comprising: determining the optical density at step d) of claim 1 using a portion of the time varying optical response measured in step c) of claim 1 that is equivalent to a portion of the time varying optical response measured in step a) of claim 1 that is used to determine the optical density at step a) in claim 1.
10. A method as claimed in claim 9, comprising offsetting the time varying optical response measured in step c) of claim 1 relative to the time varying optical response measured in step a) of claim 1 before determining the optical density, at the second wavelength.
11. A method as claimed in any preceding claim, wherein step e) of claim 1 comprises calculating the quotient of the measure of the optical density, at the second wavelength, of the first portion of the cloud and the measure of the optical density, at the second wavelength, of the first portion of the cloud .
12. A method as claimed in any preceding claim, wherein step e) of claim 1 comprises using calibration data that depends upon the optical response for particles of different sizes at different wavelengths.
13. A method of assessing the development of a cloud of particles as it moves along a first axis of a conduit comprising:
i) for a first location along the conduit, repeatedly performing the method of claim 1 for different first portions of the cloud as it moves past the first location to create a first measurement profile;
ii) for a second location along the conduit, repeatedly performing the method of claim 1 for different first portions of the cloud as it moves past the second location to create a second measurement profile;
iii) using the first and second measurement profiles to assess the development of the cloud of particles
14. A method as claimed in claim 13, wherein the distance between the first and second locations along the first direction is large enough to allow significant development of the cloud as it moves from the first location to the second location.
15. A method as claimed in claim 13 or 14, wherein step iii) comprises identifying a location where a parameter characterising an aspect of the measurement profiles is maximum or minimum. .
16. A measurement apparatus for assessing particle delivery, comprising: a conduit through which fluid carrying a cloud of particles moves in a first direction during delivery;
a first sensor for directing light of a first wavelength along a first axis that is substantially perpendicular to the first direction into the cloud and for measuring a first optical response of the cloud;
a second sensor for directing light of a second wavelength along a second axis that is substantially aligned with the first axis and perpendicular to the first direction, into the cloud and for measuring a second optical response of the cloud;
a processor for determining, using the first and second optical responses, a measure of the optical density, at the first wavelength, of a first portion of the cloud and a measure of the optical density, at the second wavelength, of the first portion of the cloud and for processing the measures of the optical densities of the first portion of the cloud at the first wavelength and at the second wavelength, to assess the composition of the cloud.
17. A method of assessing particle delivery, comprising the steps of:
measuring at a plurality of locations along a conduit, the optical response of a cloud of particles, as it moves in a first direction past the locations; and identifying at which one of the plurality of locations, a parameter of the optical responses has a turning point.
18. A method as claimed in claim 17, wherein the parameter is a measure of the peak absorbance for the cloud at that location.
19. A method as claimed in claim 17, wherein the parameter is a measure of the total absorbance for the cloud at that location.
20. A measurement apparatus for assessing particle delivery, comprising: a conduit through which fluid carrying a cloud of particles moves during delivery;
a plurality of sensors arranged along the conduit each of which is operable to measure an optical response of a cloud of particles as it moves along the conduit; and
a processor for identifying at which one of the plurality of sensors, a parameter of the optical responses has a turning point.
21.A method of assessing particle delivery, comprising the steps of:
a. measuring an optical response of a cloud of particles, which is moving in a first direction, to light of a first wavelength directed along a first axis that is substantially perpendicular to the first direction;
b. determining, using the measured optical response to light of a first wavelength, a measure of optical density, at the first wavelength, of the cloud;
c. measuring an optical response of the cloud of particles, which is moving in the first direction, to light of a second wavelength directed along a second axis that is substantially aligned with the first axis and perpendicular to the first direction;
d. determining, using the measured optical response to light of a second wavelength, a measure of optical density, at the second wavelength, of the cloud ; and
e. comparing the measures of the optical densities of the cloud at the first wavelength and at the second wavelength.
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