WO2005102428A1

WO2005102428A1 - Enhanced drug delivery for inhaled aerosols

Info

Publication number: WO2005102428A1
Application number: PCT/CA2005/000616
Authority: WO
Inventors: Warren H. Finlay; Biljana Grgic
Original assignee: The Governors Of The University Of Alberta
Priority date: 2004-04-23
Filing date: 2005-04-22
Publication date: 2005-11-03

Abstract

A combination of a delivery device and a dose adjustment means for delivering an aerosol drug to an individual. The device includes a dosing module (12) for providing an aerosol drug dose, an inhalation air module (14) connected to the dosing module for receiving the aerosol drug dose and mixing air with the aerosol drug dose for providing a delivered dose of the aerosol drug dose, and a mouthpiece (16) connected to the inhalation air module (14) for supplying the delivered dose to the individual. The dose adjustment means allows for the aerosol drug dose to be adjusted for ensuring that a desired amount of the drug dose reaches the lungs of the individual. Adjustement of the dose is based on the morphological characteristics of the individual’s mouth-throat region obtained from magnetic resonance imaging (MRI), computed tomography (CT) or other non-invasive scanning techniques.

Description

ENHANCED DRUG DELIVERY FOR INHALED AEROSOLS

Field of the invention

[0001] The invention relates to a method and device for enhanced drug delivery for inhaled aerosols. More particularly, this invention relates to a method and device with associated means for adjusting the medical dosage of an inhaled aerosol given to an individual based in part on the morphological characteristics of the individual.

Background of the invention

[0002] Aerosol-based drugs consist of an air suspension of solid and/or liquid particles that are commonly used for the therapeutic treatment of lung diseases as well as other diseases. The most frequently used aerosol-based drug delivery systems/devices include pressurized metered dose inhalers (pMDIs) , dry powder inhalers (DPIs) and nebulizers. Optimal particle sizes delivered by these devices are in the range of 1-5 microns in order to achieve optimal clinical benefit since larger particles land in the mouth and are swallowed, while smaller particles tend to be exhaled and much smaller particles are difficult to deliver in sufficient mass.

[0003] MDIs are used to administer bronchodilators, anti-inflammatory agents and steroids. The output of an MDI typically ranges from 20 μg to 5 mg. However, lung deposition of the administered drug is estimated to be approximately 10-50% for most MDIs on average, with the remainder of the drug depositing in the mouth and throat.

[0004] DPIs generate aerosol by passing air through a dose of dry powder medication. The powder medication is either in the form of micronized drug particles or micronized drug particles that are bound to carrier particles which yields agglomerates. Inspiration flow draws the particles and then deagglomerates them into drug particles that target the lung while the carrier particles deposit in the mouth. The magnitude and duration of the patient's inspiratory flow influences aerosol generation from a DPI. DPIs have a high mouth-throat deposition of approximately 50% and low lung deposition of around 20-50%.

[0005] Nebulizers produce mist (aerosol) that is inhaled through a mouthpiece or mask. The lung deposition associated with some nebulizers is approximately 10-40% with mouth-throat deposition around 10-20%, and device deposition and wastage making up the remainder.

[0006] Presently, the doses are prescribed based primarily on the individual's weight and severity of disease. However, the amount of the inhaled aerosol drug that will be deposited in the lungs of a particular individual cannot be predicted with reasonable accuracy because there is large variability in the amount of the aerosol drug that is deposited in the mouth-throat region of different individuals. In fact, it is typical that a relatively small amount of the inhaled drug reaches the targeted region (i.e. the lungs) since a large portion of the inhaled drug deposits in the mouth-throat region where it can create adverse local effects.

[0007] Existing inhalers typically can provide an active pharmaceutical ingredient in a single amount, such as 200 meg or 400 meg for example. A medical practitioner can then prescribe an inhaler that provides a 200 meg amount with enough medication for 100 doses. However, for a 200 meg dose amount, the lungs of one individual may only receive 50% of the dose while the lungs of another individual may only receive 20% of the dose. In actual fact, the amount of drug deposition in the lungs can vary between 10 to 90% amongst different individuals, for example. This is not dangerous for medication that has a wide therapeutic window. However, for aerosol-based drugs with more advanced molecules, for example inhaled insulin, the medical practitioner must be very careful with the prescribed dose because if too much of the medication reaches the lungs then the individual will overdose and possibly suffer severe adverse consequences or even death. Conversely, if not enough of the medication reaches the lungs then, the therapeutic effect is not sufficient and the individual's physical condition will not be improved, or may worsen. Therefore, for aerosol-based drugs with narrow therapeutic windows, it is quite important to be sure of the amount of the drug that is deposited in the lungs of the individual.

[0008] A complex interaction between morphological configuration (i.e the mouth-throat geometry of the individual) , particle size and inhalation flow rate determines the magnitude of the deposition in the mouth and throat. Variation in mouth and throat deposition between different subjects is clearly evident in a number of previous publications, most of which are in vivo studies, since the complexity of characterizing and building realistic geometries often limits the number of subjects explored in in vi tro work. Previous measurements show large intersubject variability in deposition due to different airway geometries and breathing rates. In addition, the morphological dimensions can vary significantly within an individual, giving significant variations in mouth and throat deposition for a given subject .

[0009] Accordingly, it is desirable to prescribe accurate dosages of aerosol-based drugs while taking into account the mouth and throat deposition. Toward this end, it is worthwhile to explore the relevant variables and their effects on mouth-throat deposition and how this relationship can be used to more accurately deliver a sufficient amount of an aerosol-based drug to the lungs of an individual.

Summary of the invention

[0010] The inventors have realized that there is a relationship between the morphology of an individual's mouth-throat region and the amount of an inhaled aerosol drug that is deposited in the individual's mouth-throat region. In particular, there is a complex interaction between the performance of the inhalation device, the interaction of the individual receiving the drug, as well as the mouth and throat morphology (geometry) . The inventors have found that the relationship between mouth- throat morphology and deposition allows for increased accuracy in the prediction of the mouth-throat deposition of an inhaled pharmaceutical aerosol for a particular individual if the volume and path length of the individual's mouth-throat is known. The volume and path length can be obtained from images taken on the individual. The relationship allows for an aerosol-based delivery device, such as an inhaler, to be designed so that it delivers a known amount of an aerosol drug into the individual's lungs based on a predicted amount of the aerosol drug that is deposited in the mouth-throat region. The relationship may also be indicated on a table, or in a computer program, that a medical practitioner refers to when prescribing a dosage of the aerosol drug for the individual. This will allow drugs with narrow therapeutic windows to be used as inhaled aerosols, as well as allowing for much more accurate dosing with all inhaled aerosol drugs. Accordingly, the invention provides a method and use of determining a corrected dose based on morphological data from an individual.

[0011] In one aspect the invention provides a combination of a delivery device and a dose adjustment means for delivering an aerosol drug to an individual. The device comprises a dosing module for providing an aerosol drug dose; an inhalation air module connected to the dosing module for receiving the aerosol drug dose and mixing air with the aerosol drug dose for providing a delivered dose of the aerosol drug dose; and a mouthpiece connected to the inhalation air module for supplying the delivered dose to the individual. The dose adjustment means allows for the aerosol drug dose to be adjusted for ensuring that a desired amount of the drug dose reaches the lungs of the individual.

[0012] In another aspect, the invention provides a method of adjusting the dose of an aerosol drug delivered to the lungs of an individual comprising: a) determining an initial dose of the aerosol drug; b) obtaining values for the geometrical properties of the mouth-throat region of the individual; and, c) adjusting the amount of the initial dose of the aerosol drug for delivering a desired amount of the aerosol drug to the lungs of the individual, the adjustment being done according to the geometrical properties of the mouth-throat region.

[0013] In another aspect, the invention involves the use of a dose adjustment means for adjusting an aerosol drug dose provided by an aerosol drug delivery device, the device comprising: a) a dosing module for providing the aerosol drug dose; b) an inhalation air module connected to the dosing module for receiving the aerosol drug dose and mixing air with the aerosol drug dose for providing a delivered dose of the aerosol drug dose; and c) a mouthpiece connected to the inhalation air module for supplying the delivered dose to the individual,

wherein, the dose adjustment means allows for the aerosol drug dose to be adjusted for ensuring that a desired amount of the drug dose reaches the lungs of the individual.

Brief description of the drawings

[0014] For a better understanding of the invention and to show more clearly how it may be carried into effect, reference will now be made, by way of example only, to the accompanying drawings which show an exemplary embodiment of the invention and in which:

Figure la depicts planar images of exemplary test results for one individual comprising two halves of a mouth-throat model and a filter image;

Figure lb depicts projected outlines of the model shown in Figure la;

Figure 2 is a plot of an inertial parameter dp^Q versus deposition efficiency where dp is the particle diameter in μm and Q is the flow rate in cm³/s;

Figure 3 is a plot of deposition efficiency versus Stokes number;

Figure 4 is a plot of deposition efficiency versus Stokes number based on model mean equivalent diameter ^Dmean ^an<^ ^umean ^ⁿ accordance with the invention;

Figure 5 is a plot of deposition efficiency versus Stokes number with Reynolds number correction;

Figure 6a is a block diagram of an exemplary inhaler that is used in accordance with the invention;

Figure βb is a block diagram of another exemplary embodiment of an inhaler in accordance with the present invention; and

Figure 7 is a diagram of another exemplary embodiment of an inhaler in accordance with the present invention.

Detailed description of the invention

[0015] In the following detailed description, numerous specific details are set forth in order to provide a thorough understanding of the invention. However, it will be understood by those of ordinary skill in the art that the invention may be practiced without these specific details. In other instances, well-known methods, procedures and components have not been described in detail so as not to obscure the invention.

[0016] The inventors have studied regional and total deposition measurements in several realistic mouth and throat geometries. From an experimental reproducibility viewpoint, in vi tro models were used since they have the advantage of known and constant geometric characteristics, allowing for systematic studies on particle size, flow rate and mouthpiece effects. A set of seven geometries that span the range of key dimensions of a larger set of 80 geometries were studied at various combinations of flow rates of 30 and 90 1/min and particle diameters of 3-6.5 μm. Gamma scintigraphy and gravimetry were used to determine deposition in the mouth-throat region.

[0017] In order to obtain physiologically realistic mouth and throat geometries, accurate anatomical models were obtained using the well established noninvasive medical imaging technique of magnetic resonance imaging (MRI) described in detail in McRobbie, D.W., Pritchard, S.E., Quest, R.A., (2003), "Studies of the Human Oropharyngeal Airspaces Using Magnetic Resonance Imaging (MRI) - 1. Validation of a Three-Dimensional MRI Method for Producing Ex Vivo Virtual and Physical Casts of the Oropharyngeal Airways During Inspiration.", Journal of Aerosol Medicine, 16(4), pp. 401-415. The subjects lay in a supine position and data was acquired upon inspiration. A pressure tap was included as part of the mouthpiece to monitor pressure changes during inhalation and trigger scanning at 25% of maximum inspiratory_. pressure drop in the mouthpiece. The total mouth and throat geometry was made up of 120 scans. Spatial resolution was lxlxl.25 mm. The image volume files were converted into 3D volume files and then to the STL file format. CAD designs of models based on the STL geometries were developed using DeskArtes 3Data Expert (DeskArtes, Helsinki, Finland) . The models were constructed as "shells" having a uniform thickness of 6 mm. Inlet and outlet orifices were modeled in the form of straight tubes, with the inlet diameter being the same as the mouthpiece diameter that was used during the in vivo scans. All models were cut approximately along their mid-sagittal plane into halves, allowing planar imaging of each half. Since all models were somewhat asymmetric, the mid-plane was chosen such that each half of the model contained approximately half of the total model volume. Manufacturing of the casts was done using an FDM 8000 rapid prototyper (Stratasys, Eden Prairie, MN) , which used a fused deposition modeling process and produced solid copies of the 3D CAD designs in acrylonitrile-butadiene-styrene (ABS) plastic. The resolution of the manufactured model was 0.127mm. The ABS plastic models were relatively durable and could withstand subsequent testing, drilling and painting.

[0018] A set of seven mouth and throat realistic models obtained from MRI scans were used. The subjects were an even mix of male and female subjects, aged 23-43 and included Caucasian, Asian and African ethnicities. A convex hull statistical analysis was used to ensure this subset maximally covered the multi-dimensional geometric space associated with these dimensions in the larger set (McRobbie et al . , 2003). Thus, the seven models were the most complete possible such subset. Three of the models, designated as S2, S3 and S4, were from three different individuals. The models designated as Sla and Sib, and S5a and S5b were two sets of intrasubject geometric configurations. One additional model designated as an idealized model was built up of regular geometric shapes and represented an average geometry of actual subjects. A full description of the design of the idealized geometry is given in Stapleton, K. W. , Guentsch, E, Hoskinson, M. K. and Finlay, W. H., (2000), "On the Suitability of k-Q Turbulence Modeling for Aerosol Deposition in the Mouth and Throat: A Comparison with Experiment.", Journa l of Aerosol Science, 31, pp. 739-749.

[0019] Monodisperse particles of di-ethylhexyl sebacate (DEHS) oil were generated using a controlled heterogeneous condensation aerosol generator '(CMAG, Model 3475, Topas, Germany) . Particle sizes and monodispersity were monitored using a Mach II Aerosizer (TSI, St. Paul, MN) . Particles were radiolabeled with technetium^99mTc. Flow rates were regulated and measured with a calibrated rotameter (Omega, Stamford, CT) , which was corrected for the actual pressure level in the system. The outlet from the mouth and throat cast was attached directly to Marquest Respirguard filters (#303, Marquest, Boulder, CO) and then to a vacuum pump (GAST MFG Corp., Brenton Harbor, MI) via a flowmeter. After completion of the test, the models were disassembled along their mid-sagittal planes into halves, and together with the filters imaged by a single photon emission gamma camera (Marconi/Prism Axis 2000 Picker, Cleveland, OH) using a low energy high resolution (LEHR) collimator. The resulting images were superimposed with separately drawn contours of regions of interest. Planar projections of the models' physical boundaries and corresponding subregions were obtained from planar images of the models' filled with radioactively-laced water. Image analysis was done using the customized image analysis software MEDisplay 98 (MEDisplay Systems Inc., Edmonton, AB) . Further details on this methodology and image analysis are presented in Grgic B., Finlay W. H. and Heenan A. F., (2004), "Regional Aerosol Deposition and Flow Measurements in an Idealized Mouth and Throat." Journal of Aerosol Science, 35, pp. 21- 32 which is hereby incorporated by reference.

[0020] In order to allow more rapid data acquisition, a gravimetric method was also used for the S4, S5a and S5b models to measure total aerosol deposition, using the same experimental setup. The cast and filters were simply weighed before and after aerosol collection, and collected mass was determined. The two methodologies were crosschecked and good agreement were found, as presented in Grgic et al. (2004) .

[0021] Tests were conducted for particle sizes in the range of 3 to 6.5 microns and flow rates of 30 to 90 1/min. In particular, the following test pairs were used: (3, 30) , (5, 30), (6.5, 30), (3, 90), (5, 90) and (6.5, 90) where the particle size is given first in microns and the flow rate is given second in 1/min.

[0022] Referring now to Figure la, shown therein are planar images of exemplary test results for one individual comprising two halves of the mouth-throat model L and R respectively for the left and right halves of the model and a filter image Fl . Figure lb shows a projected outline P of the model shown in Figure la. At least two filters Fl and F2 were used in-line (filter F2 is not shown) ; a filter image is not shown for the last in-line filter F2 since it contained no activity. The use of two filters Fl and F2 ensures absolute in-line filtering. The dark circle shows the activity in the first downstream filter Fl . The downstream filter shows the amount of aerosol-drug that would have reached the lungs of the individual.

[0023] The mouth-throat model was divided into 4 sub- regions, namely: 1) the oral cavity or mouth (also called the buccal cavity) which extends from the back of the teeth to the uvula; 2) the nasopharynx-epiglottis from the nasopharynx to the tip of epiglottis; 3) the larynx from the tip of the epiglottis to just below the vocal cords and 4) the trachea. These four regions are labeled with corresponding numbers in Figure la . Table 1 shows the major dimensions of the models used, where D is diameter and length is defined as the path-length of the center sagittal line (D_mean is defined below) .

Table 1

[0024] Deposition in each region was determined as a fraction of aerosol entering the mouth. Each test was repeated three times, except for the regional deposition data for the S4, S5a and S5b models, which were obtained using single experiments. Subsequently, the mean and standard deviation were determined for each experimental condition.

[0025] The models Sla and Sib are from the same subject. Sla represents a configuration in which the tongue is pulled back, creating a large oral cavity and obstructing the back of the mouth and oropharynx. Sib represents a configuration in which the tongue is in a forward position with a narrow oral cavity and a large oropharynx and larynx. The magnitude of total deposition for these two models is very similar except for the 5 μm-30 1/min tests. This similarity in total deposition between Sla and Sib is somewhat coincidental since regional deposition and flow field measurements show large differences (see Heenan A.F., Finlay W.H. and Grgic B., (2004), "An Investigation of the Relationship Between the Flow Field and Regional Deposition in the Extrathoracic Airways". Journal of Aerosol Science) . However, for Sla, major deposition occurs at the front of the tongue, while for Sib, it is at the back of the mouth on the soft palate. Further downstream, Sla has some deposition in the larynx caused by epiglottal cross- sectional constriction, while Sib has deposition in the oropharynx caused by the high velocity jet from the mouth.

[0026] Models S5a and S5b, which are from the same subject, had the largest cross-sectional area and large inlet diameter (23 mm) , which together with a gradual curvature at the back of the mouth resulted in lower deposition than the other models. S5b had a geometry that is similar to that of S5a except that S5b has a larger cross-sectional area and larger volume, i.e. a 2 cm longer pharynx, and the tongue is slightly more pulled back. Consequently, deposition was similar, but not identical, with some differences in intensity and location of deposition hot spots. In particular, for S5a the deposition was located primarily just above and below the glottis, which was the narrowest part of its cross-sectional area, while S5b has less intense and more uniformly distributed deposition with the highest deposition occurring on the front of the tongue.

[0027] The model for test subject S3 had a small inlet diameter (14 mm) and a distinctly different morphological configuration from all other models. The tongue position was such that aerosol entering the mouth impinged directly on the tongue, resulting in intense deposition. Significant impaction also occurred on the posterior wall of the mouth (soft palate) . Further downstream, severe geometry narrowing occurred and the uvula was physically connected with the base of the tongue creating a bridge that covered approximately 10% of the total cross-sectional area. This tortuous flow path, together with the severe cross- sectional area constriction in the mouth and oropharynx, resulted in high deposition in those regions. The epiglottal plate was positioned on the anterior wall of the trachea which created a 'wide' opening. This straight and wide flow path in the larynx and trachea resulted in negligible deposition here.

[0028] For the model for test subject S2, aerosol deposited on the back of the mouth and upper pharynx due to a small cross-sectional area in that region. In contrast, the pharynx had a large cross-sectional area with minor flow obstructions, and thus minor deposition. Weak deposition was present in the pharynx due to the epiglottal plate obstruction and in the glottal area due to narrowing within the larynx.

[0029] The model for test subject S4 had a distinctly unique configuration from all other models, in that the model had a wide mouth, very narrow pharynx, and oropharyngeal bending angle close to 90°. The large inlet diameter (23 mm) and large mouth resulted in weak deposition in that region. Very intense deposition started on the back of the mouth (soft palate) just downstream from the first flow obstruction and covered the whole pharyngeal and laryngeal regions up to the glottal opening.

[0030] The results clearly demonstrate that variations in the morphological dimensions of the mouth-throat model for different individuals create quite different deposition intensities and patterns. The oral cavity (mouth) accounts for the most intense deposition for most of the models (Sla, Sib, S3, S2, S5b) , where tongue positioning plays an important role. When the tongue is pulled back, it creates an impinging wall on the front of the mouth for incoming aerosol while at the same time obstructing (squeezing) the oropharynx. This in turn causes major deposition in these spots, as was most pronounced for models Sla and Sib. Regional deposition was highly localized and nearly unaffected, relatively speaking, by changing particle sizes and flow rates for a given model.

[0031] In general, the results show that several factors other than particle size and flow rate affect mouth-throat deposition, including overall morphological dimensions, local flow direction changes and local constriction of the cross-sectional area (which affects the local velocity magnitude) . This finding, together with flow measurements on the Sla and Sib geometries (Heenan et al., 2004) points to inertial impaction as an important deposition mechanism, which confirms previous reports from the literature.

[0032] Referring now to Figure 2, shown therein is a plot of the inertial parameter d p^Q, where (g/cm ³) is the particle density, d_p is the particle diameter in μm and Q is the flow rate in cm³/s, against deposition efficiency. In the tests, particle size dp was changed by changing the settings on the aerosol generator, and Q was varied by changing the valve opening connected to a vacuum pump. Gravimetric data is plotted for test results on models S4, S5a and S5b and gamma scintigraphy data is plotted for the test results on all other models. The semi-empirical curve 6 of Stahlhofen, W., Rudolf, G., James, A. C, (1989), "Intercomparison of Experimental Regional Aerosol Deposition Data.", Journal of Aerosol Medi cine , 2(3), pp. 285:308, is also shown in Figure 2. A similar trend between the Stahlhofen et al . (1989) curve and the test data is evident. The scatter in the test data is due to intersubject variations and different inlet diameter conditions. The idealized model follows the Stahlhofen et al . (1989) curve 6 well possibly because deposition in this model, as in Stahlhofen et al . , is also mostly confined to the larynx. Intrasubject variability (Sla vs. Sib or S5a vs. S5b) is seen to be considerably smaller than intersubject variability.

[0033] The inertial parameter is the traditional independent variable that is used when presenting mouth- throat deposition. However, the inertial parameter does not account for the different geometry and inlet diameter conditions. Instead, a Stokes number can be used, since it takes into account the relevant length and velocity scales. The Stokes number is calculated as: pd²U Stk = !—*— ( 1 ) 18μD

where U is a velocity scale (m/s) , μ is the fluid dynamic viscosity (kg/m»s) and D is a corresponding length scale (m) for the specific geometry or inlet conditions. The velocity scale U is often defined as the mean inhalation flow rate divided by the mouthpiece inlet diameter. The Stokes number is a dimensionless number that indicates how readily a particle will respond to changes in flow direction or flow velocity.

[0034] Inlet diameter certainly has an effect on mouth and throat deposition (Lin, C. T., Breysse, P. N., Beth, L.L., and Swift, D. L. (2001), "Mouthpiece Diameter Affects Deposition Efficiency in Cast Models of the Human Oral Airways.", Journal of Aerosol Medicine, 14(3), pp. 335- 341.), DeHaan and Finlay, 2004, (DeHaan, W. H. Finlay, W. H, (2004), "Predicting Extrathoracic Deposition from Dry Powder Inhalers.", Journal of Aerosol Science, 35(3), pp. 309-331.), especially for mouth deposition (Finlay, W. H., DeHaan, W. H., Grgic, B., Heenan A.F., Matida, E.A., Hoskinson, M. K., Pollard, A. and Lange CF. (2002), "Fluid Mechanics and Particle Deposition in the Oropharynx: the Factors that Really Make a Difference. Proceedings of Respiratory Drug Delivery VIII.", Tuscon, Arizona, pp. 171- 177.) and appears to be a reasonable choice for a length scale D. Using inlet diameter and inlet mean velocity to calculate the Stokes number, deposition efficiency vs. the Stokes number is shown in Figure 3. Plotting the test data vs. the Stokes number collapses the test data much better than the inertial parameter, but there is still significant scattering due to different geometric configuration downstream of the inlet.

[0035] A more accurate approach is to use a geometry specific parameter D in equation 1. In particular, a mean or equivalent diameter D_mean can be used in the Stokes number with the parameter D_mean being calculated simply by dividing cast volume V by the path length L of the central sagittal line of the model to give an area. More specifically, L is the centerline distance from the middle of the mouth entrance to the middle of the tracheal exit downstream of the larynx. The volume V is the airway volume contained between the mouth entrance to the trachea exit downstream of the larynx. Assuming a circular equivalent (mean) cross-sectional area, a mean equivalent diameter (see Table 1) was derived for the models as shown in equation 2:

A corresponding mean velocity scale was calculated from the volume flow rate and the mean cross-sectional area:

The resulting plot is shown in Figure 4 (error bars refer to standard deviations) . When the test data are plotted using the mean effective diameter D_mean and mean effective velocity U_mean in the Stokes number, the scatter among the test data is markedly reduced (i.e. compare Figure 4 to Figure 3) . Rather than using equation 2 to obtain the mean effective diameter, one can take the cross-sectional area at various locations along the airway, e.g. by taking slices with MRI, and then averaging the diameters of circles that have the same area as each cross section of the MRI slices to obtain the mean-effective diameter. The mean effective velocity is then obtained by taking the inhalation flow rate and dividing by the average cross- sectional area associated with the mean effective diameter.

[0036] Previous deposition tests in the idealized geometry (see Grgic et al., 2004) suggested a possible Reynolds number effect on deposition since test data taken at each flow rate followed a distinct curve on the Stokes number versus deposition efficiency plot. The Reynolds number is a dimensionless number that indicates how strong inertial "forces" in fluid are in comparison to viscous forces. Deposition experiments in the idealized geometry with constant Stokes number and varying Reynolds number demonstrated that deposition varies with Reynolds number, due to changes in the flow field with Reynolds number (Heenan A. F., Finlay W. H., Matida, E.A. and Pollard A., (2003) , "Experimental Measurements and Computational Modeling of the Flow in an Idealized Extrathoracic Airway", Experiments in Fl uids , 35, pp. 70-84). For these reasons, an empirical Reynolds number correction was suggested by Grgic et al . (2004), where the Stokes number is multiplied by Reynolds number, Re, to the power of 0.37. With this correction, Grgic et al. (2004) found that deposition data in the idealized geometry collapsed more closely onto a single curve. The same procedure was applied here for the other seven models from Figure 4 using a Reynolds number Re defined below in equation 4 and a Stokes number Stk defined below in equation 5:

The resulting test data is shown in Figure 5 where deposition efficiency is plotted versus a combination of the Stokes number and the Reynolds number. In this case, the test data can be approximated by a least square curve fit function 8 given by equation 6:

?7 = 100 - 100/(11.5(StA - Re⁰'³⁷)¹-⁹¹² + l) (6)

where η is the percent of inhaled aerosol depositing in the mouth-throat region. In general, any sort of equation can be used that provides a reasonable fit to the data shown in Figure 5. Equation 6 is one example of an equation with a good curve fit. Further, it should be noted that the exponent applied to the Reynolds number does not have to be 0.37. In fact, the exponent can be varied as long as there is a good fit to the experimental data. The good collapse of all data onto nearly a single curve indicates that by knowing a patient's mouth and throat mean equivalent diameter D_mean as well as particle size and inhalation flow rate, it is possible to predict deposition when a large diameter (>1.2 cm) straight tube is used as a mouthpiece. The use of equations 2, 4 and 5 to predict mouth-throat deposition requires knowing the volume V and centerline path-length L of the given mouth-throat. When this information is not available, average values of these parameters may be used, for which the average values of V=76.8 cm³ and L=18.8 cm for the seven realistic geometries, given in Table 1, may suffice. In general, based on table 1 and extrapolating, a range for volume V can be 20-150 cm³ while a range for length L can be 18-22 cm, Furthermore, the use of equations 2, 4 and 5 to predict mouth-throat deposition also depend on flow rate and particle size which in turn depend on the particular aerosol delivery device being used. Average flow rate and particle size could be specified for a particular inhaler. In general, for inhaled pharmaceutical aerosols, a range for flow rate is 1-200 1/min and a range for particle size is 0.1 microns to 10 microns.

[0037] Based on the above results, aerosol deposition in mouth-throat replicas is affected by intersubject and, to a lesser extent, by intrasubject geometric configuration. Accordingly, it is beneficial to obtain measurements for a particular individual prior to prescribing a certain dosage of an aerosol-based drug. Nonetheless, average values may be used for the geometrical parameters, as described above, to obtain greater accuracy in lung deposition of the prescribed aerosol-based drug compared to current conventional prescription methods. Deposition locations are very similar for different experimental conditions within a single model. The mouth area seems to be the largest obstacle for inhaled aerosols for most of the models studied. In general, two factors dictate local deposition: rapid changes in flow direction and small local cross- sectional areas (which cause high local flow velocities) . This confirms inertial impaction as the governing mechanism of deposition. Total deposition data collapse into nearly a single curve when plotted against Stokes number based on the mean equivalent diameter and mean equivalent velocity. In addition, when a Reynolds number correction is combined with the Stokes number, the collapse of the data is even better. The empirical function in equation 6 predicts mouth-throat deposition with much reduced intra or intersubject scatter. This function allows better prediction of mouth-throat deposition when inhaling through large diameter mouthpieces .

[0038] In one instance, the invention allows for a conventional aerosol-based drug delivery system, such as an inhaler, to be produced that provides an appropriate dose so that the desired amount of the aerosol drug reaches the lungs of the individual. Referring now to Figure 6a, shown therein is block diagram of an exemplary inhaler 10 (or in more general terms, an aerosol drug delivery device) . The inhaler 10 includes a dosing module 12, an inhalation air module 14, a mouthpiece 16 and a dilution air module 18. The dilution air module 18 is optional and so may not be present in alternative embodiments of the inhaler 10. These components are for a general inhaler. In other embodiments, the inhaler 10 may contain other modules (or leave out or exchange some of these modules) as is well known to those skilled in the art. The loading/dosing module 12 provides a certain dose of an aerosol drug to an individual 20 who uses the inhaler 10. The inhalation air module 14 is responsible for mixing the aerosol drug with the air that is inhaled by the individual 20 when the individual places his/her mouth around the mouthpiece 16 and actuates the inhaler 10. The dilution air module 18 provides an additional volume of air to the individual 20 to ensure that the aerosol drug is suitably diluted and inhaled at an adequate flow rate so that the aerosol drug reaches the lungs of the individual 20 in an appropriate fashion.

[0039] In accordance with the present invention, a medical practitioner prescribes a dosage for the dosing module 12 based on the morphological characteristics of the individual; i.e. the volume and the length of the individual's mouth and throat region. This information is obtained by any suitable imaging method such as, but not limited to CT, X-ray, ultrasound, PET, or gamma scintigraphy. The medical practitioner then refers to a dose adjustment table 22 or alternatively a dose adjustment computer program 24 that can predict mouth-throat deposition according to equation 6 (another implementation can involve using a processor, which can be dedicated or not, that provides this calculation; the processor may be incorporated within an inhaler custom designed in accordance with the invention) . In general, the dose adjustment table 22 and the dose adjustment computer program 24 are referred to as dose adjustment means. The dose adjustment means can include any suitable means that can be used to adjust or tailor the amount of the delivered dose to the particular individual 20 such that the correct or desired amount of medication reaches the lungs of the individual 20.

[0040] One realization of such a table would involve the mouth throat volume and length as input parameters, and would use an average inhalation flow rate and particle size that occurs when a particular inhaler device is used. Accordingly, the table is generated by using the equations specified above, while varying the values for L and V and assuming general or average values for the other parameters. Another realization of such a table, may also include the specific individual's inhalation flow rate on the device as another input into the table. The individual's inhalation flow rate with the inhaler device may be measured using a suitable flow meter or spirometer. When including inhalation flow rate as an input parameter, it is also possible to embed into the tabular data flow rate dependent particle size information for the particular inhaler. Accordingly, there can be a set of tables, with each table being defined for a particular flow rate. It is also possible to include in the table, or generate a set of tables based on, any parameter appearing in the Stokes and Reynolds numbers in equations 4 or 5. Here the word table is used to generally mean any set of tabular data. The computer program 24 can implement these tables. Alternatively, this functionality may be incorporated into the adaptive dosing module of the inhaler 100.

[0041] Based on the prediction information, the medical practitioner then ensures that an adjusted dosage is provided by the dosing module 12. For instance, if it is desired to deliver 40 meg to the lungs of the individual 20 and the table 22 or the program 24 indicates that the individual has 50% deposition in the mouth-throat region, then the medical practitioner can ensure that a dose of 80 meg is provided to the mouthpiece 16 by the dosing module 12 for inspiration by the individual 20. The delivered dose is the dose that the inhaler 10 delivers to the individual 20. Alternatively, the predicted deposition data can be in terms of the loaded dose by adding a suitable conversion factor, as is known by those skilled in the art, between the loaded and the delivered dose. Accordingly, in the embodiment of Figure 6a, the inhaler 10 is loaded with a fixed dose for each inhalation, but the fixed dose comes in different predetermined amounts and each individual 20 is then prescribed the inhaler 10 that is loaded with the appropriate one of the predetermined amounts.

[0042] Referring now to Figure 6b, shown therein is a block diagram of another exemplary embodiment of an inhaler 100 in accordance with the present invention. The inhaler 100 is similar to the inhaler 10 with the exception that the inhaler 100 includes an adaptive dosing module 102. The adaptive dosing module 102 allows the dosage of the aerosol drug delivered to the individual 20 to be tailored to the individual 20 so that the amount of the aerosol drug delivered to the lungs of the individual 20 is the desired dosage. In a similar fashion seen for the inhaler 10, for the inhaler 100, the medical practitioner can set the dose on the inhaler 100 by using mouth-throat geometrical data and equation 6 which can be embodied in a number of ways, including the table 22 and the program 24.

[0043] The adaptive dosing module 102 may be a drug reservoir from which the prescribed dose is loaded each time the patient inhales. The amount of the drug taken from the reservoir every time a dose is delivered is determined by the predictive deposition data obtained in accordance with the invention. A setting on the adaptive dosing module 102 can be adjusted by the medical practitioner, or another suitable person, for this purpose. Alternatively, the adaptive dosing module 102 may be implemented such that it can receive drugs that are prepackaged in a number of different doses such as 50, 100, 200, 400 and 800 meg doses or 50, 100, 150, 200, 300 and 500 meg doses, or some other suitable sequence. Then, when prescribing the correct dosage, the medical practitioner will select the correct dose based on the volume and path length of the mouth- throat region of the individual and the table 22 or the computer program 24.

[0044] There are other ways to tailor the amount of aerosol drug, or the fashion in which the aerosol drug is provided to the individual 20 to ensure that the correct amount of medication reaches the lungs of the individual. For instance, in a further alternative, the adaptive dosing module 102 may have a number of drug reservoirs in which the particle sizes of the different drug reservoirs is varied. Then equations 4 and 5 can be used to select a particle size to achieve a certain deposition in the lungs according to the deposition curve of Figure 5, or alternatively equation 6. The particle size is chosen that results in the right fraction of aerosol-drug getting past the mouth-throat region to deliver a specific dose into the lungs of the individual 20 when the inhaler 100 is loaded with a fixed dose.

[0045] In another alternative, the inhalation flow rate can be varied instead of the particle size. In this case, the inhalation air module 14 is replaced with an adaptive inhalation air module such that, given a certain dose in the inhaler and a certain desired lung dose, the mouth- throat deposition curve in Figure 5 or equivalently equations 3-6 can be used to select an inhalation flow rate that would deliver the right fraction of drug past the mouth-throat region to deliver a specific dose into the lungs of the individual 20.

[0046] In a more general sense, any of the parameters in the Stokes number (see equation 5) or Reynolds number (see equation 6) can be used to ensure that a certain fraction of the aerosol drug makes it past the mouth-throat region and into the lungs of the individual 20. The parameters in the Stokes number that determine drug deposition: particle density, particle size, inhalation flow rate or velocity of particles in the mouth, viscosity of the inhaled gas (usually air), and mouth-throat airway dimensions. The additional parameter in the Reynolds number is gas density.

[0047] The predictive deposition equation assumes an average flow rate and average particle size for the inhaler. However, if more accuracy is desired, then the individual's inhalation flow rate through the inhaler can be measured and used in the predictive deposition equation as well, rather than relying on an average population value for inhalation flow rate. The individual's flow rate can be measured using a fluid flow measurement device that could be separate or could be added on to an inhaler.

[0048] Referring now to Figure 7, another preferred embodiment of the invention will be described. As shown in Figure 7, an inhaler 200 comprises an aerosol generator 201 for generating an aerosol and a liquid reservoir 202 for storing the liquid that is supplied to the aerosol generator 201 for being nebulized when the aerosol generator 201 is operated. Preferably, the aerosol generator 201 comprises a membrane means 201a and an actuator means 201b which is electrically controllable to actuate the membrane means 201a in such a way that the membrane oscillates to produce an aerosol from the liquid supplied to the membrane. The aerosol generated by the aerosol generator 201 is delivered to a mixing chamber 203 to allow air to be mixed with the aerosol so that the air carrying the nebulized liquid, i.e. the aerosol can be inhaled by a patient 210. The mixing chamber 203 comprises inlet openings, but preferably inlet valves 203a, as shown in Figure 7, for providing a passage way for ambient air to enter the mixing chamber 203 and to propagate to a mouthpiece 204 which is provided to facilitate inhalation through the inhaler 200 during an inhalation therapy.

[0049] As shown in Figure 7, the inhaler 200 comprises control means 205 for controlling the operation of the aerosol generator 201 and therefore the generation of the aerosol. Input means 206 are connected to the control means 205 allowing a medical practioner or any other person to enter data describing morphological characteristics of the individual, i.e. the volume and the length of the patient's mouth and throat region. This information is obtained by any suitable method as decribed above. The control means 205 is adapted to perform the calculations which are expressed in the above equations as mentioned before on the basis of the input parameters as well as an average inhalation flow rate and particle size to determine the delivered dose to the patient and to operate the aerosol generator 201 such that the correct or desired amount of medication reaches the lungs of the individual 210.

[0050] In a more preferred embodiment of an inhaler according to the invention the control means 205 are connected to sensor means 207 for detecting the patient's inhalation flow rate. Preferably, the sensor means 207 are provided in the mouthpiece 204 of the inhaler 200 or the vicinity thereof as shown in Figure 7. The measurement results output by the sensor means 207 are supplied to the control means 205 and the control means 205 take the measurement results into account when controlling the operation of the aerosol generator 201. By taking into account the actual flow rate, a higher accuracy regarding the delivered dose can be achieved.

[0051] It should be understood that various modifications can be made to the embodiments described and illustrated herein, without departing from the invention, the scope of which is defined in the appended claims.

SUBSTJTi i

Claims

1. A combination of a delivery device and a dose adjustment means for delivering an aerosol drug to an individual, the device comprising: a) a dosing module for providing an aerosol drug dose; b) an inhalation air module connected to the dosing module for receiving the aerosol drug dose and mixing air with the aerosol drug dose for providing a delivered dose of the aerosol drug dose; and c) a mouthpiece connected to the inhalation air module for supplying the delivered dose to the individual, wherein, the dose adjustment means allows for the aerosol drug dose to be adjusted for ensuring that a desired amount of the drug dose reaches the lungs of the individual.

2. The combination of claim 1, wherein the adjustment means includes deposition prediction data based on a Stokes number that depends on a mean effective diameter of the mouth-throat region of the individual.

3. The combination of claim 2, wherein the deposition prediction data is further based on a Reynolds number that depends on the mean effective diameter of the mouth-throat region of the individual.

4. The combination of claims 2 or 3, wherein the dose adjustment means includes a table based on the deposition prediction data.

5. The combination of claims 2 or 3, wherein the dose adjustment means includes a computer program based on the deposition prediction data.

6. The combination of claims 2 or 3, wherein the dosing module is an adaptive dosing module capable of selecting the desired amount of the drug dose according to the deposition prediction data.

7. The combination of claim 3, wherein the deposition prediction data predicts an amount of mouth-throat deposition of the delivered dose according to η=100-100/(11.5(Stk ^■ Re⁰-³⁷) -⁹¹² +1) or a similar curve fit to deposition data where Stk is the Stokes number and Re is the Reynolds number.

8. The combination of claims 2 or 7, wherein the Stokes number is given by

where p is particle density of the aerosol drug, d_p is particle size of the aerosol drug, μ is fluid dynamic viscosity of the delivered dose, U_mean is a velocity scale and D_mean is a length scale based on the diameter of the mouth-throat airways of the individual.

9. The combination of claims 3 or 7, wherein the Reynolds number is given by

μ where p is particle density of the aerosol drug, μ is fluid dynamic viscosity of the delivered dose, U_mean is a velocity scale and D_mean is a length scale based on the diameter of the mouth-throat airways of the individual.

10. The combination of claims 8 or 9, wherein the length scale is given by

where V is the volume of the mouth-throat region of the individual and L is the length of the mouth-throat region of the individual.

11. The combination of claims 8 or 9, wherein the velocity scale is given by

where V is the volume of the mouth-throat region of the individual, L is the length of the mouth-throat region of the individual and Q is the flow rate of the delivered dose.

12. The combination of claim 1, wherein the delivered dose can be adjusted by varying at least one of: particle density of the aerosol drug dose, particle size of the aerosol drug dose, inhalation flow rate of the delivered drug, viscosity of the delivered dose, gas density of the delivered dose.

13. The combination of claim 1, wherein the device further comprises a dilution air module connected to the mouthpiece for diluting the delivered dose.

14. A method of adjusting the dose of an aerosol drug delivered to the lungs of an individual comprising: a) determining an initial dose of the aerosol drug; b) obtaining values for the geometrical properties of the mouth-throat region of the individual; and c) - adjusting the amount of the initial dose of the aerosol drug for delivering a desired amount of the aerosol drug to the lungs of the individual, the adjustment being done according to the geometrical properties of the mouth-throat region.

15. The method of claim 14, wherein step (c) includes generating deposition prediction data based on a Stokes number that depends on a diameter of the mouth- throat region of the individual.

16. The method of claim 15, wherein step (c) further includes generating the deposition prediction data based on a Reynolds number that depends on the mean effective diameter of the mouth-throat region of the individual .

17. The method of claim 16, wherein the deposition prediction data predicts an amount of mouth-throat deposition of the initial dose of the aerosol drug, the deposition prediction data being defined by η=100-100/(11.5(Stk ^• Reo.37) 1.912 +1) where Stk is the Stokes number and Re is the Reynolds number.

18. The method of claims 15 or 17, wherein the Stokes number is given by St* = .^ 18μE>„ where p is particle density of the aerosol drug, d is particle size of the aerosol drug, μ is fluid dynamic viscosity of the delivered dose, U_mean is a velocity scale and D_mean is a length scale based on the mean effective diameter of the mouth-throat airways of the individual .

19. The method of claim 16 or 17, wherein the Reynolds number is given by n. _ r mean mean μ where p is particle density of the aerosol drug, μ is fluid dynamic viscosity of the delivered dose, U_mean is a velocity scale and D_mean is a length scale based on the diameter of the mouth-throat airways of the individual .

20. The method of claims 18 or 19, wherein the length scale is given by

21. The method of claims 18 or 19, wherein the velocity scale is given by

22. The method of claim 14, wherein the parameters that can be varied include at least one of: particle density of the aerosol drug dose, particle size of the aerosol drug dose, inhalation flow rate of the delivered drug, viscosity of the gas transporting the delivered dose, and density of gas transporting the delivered dose.

23. Use of a dose adjustment means for adjusting an aerosol drug dose provided by an aerosol drug delivery device, the device comprising: a) a dosing module for providing the aerosol drug dose; b) an inhalation air module connected to the dosing module for receiving the aerosol drug dose and mixing air with the aerosol drug dose for providing a delivered dose of the aerosol drug dose; and c) a mouthpiece connected to the inhalation air module for supplying the delivered dose to the individual, wherein, the dose adjustment means allows for the aerosol drug dose to be adjusted for ensuring that a desired amount of the drug dose reaches the lungs of the individual.

24. An inhalation device comprising an aerosol generator for generating an aerosol, a liquid reservoir for storing a liquid for being supplied to said aerosol generator and control means for controlling the operation of said aerosol generator, wherein said control means are connected to input means for entering data describing morphological characteristics of an individual, especially the volume and the length of the individual's mouth-throat region and wherein said control means control the operation of said aerosol generator on the basis of at least the entered data.

25. An inhalation device according to claim 24 wherein said control means are further connected to sensor means for supplying measurement results indicating the individual's inhalation flow rate to said control means .

26. An inhalation device according to claim25 wherein said sensor means are provided in or in the vicinity of a mouthpiece.

27. An inhalation device according to claim 24 or 25 wherein said control means control the operation of said aerosol generator based on a Stokes number that depends on a mean effective diameter of the individual's mouth-throat region.

28. An inhalation device according to claim 27 wherein said control means control the operation of said aerosol generator further based on a Reynolds number that depends on the mean effective diameter of the individual's mouth-throat region.

29. An inhalation device according any one of claims 24 to 27 wherein the deposition prediction data predicts an amount of mouth-throat deposition of the delivered dose according to η=100-100/ (11.5 (Stk • Re⁰-³⁷) ^l-⁹¹² +1) or a similar curve fit to deposition data where Stk is the Stokes number and Re is the Reynolds number.

30. An inhalation device according to claim 27 or 29 wherein the- Stokes number is given by

where p is particle density of the aerosol drug, d_p is particle size of the aerosol drug, μ is fluid dynamic viscosity of the delivered dose, U_mean is a velocity scale and D_mean is a length scale based on the diameter of the mouth-throat airways of the individual .

31. An inhalation device according to claim 28 or 29 wherein the Reynolds number is given by

^■p-a _ ' mean mean μ where p is particle density of the aerosol drug, μ is fluid dynamic viscosity of the delivered dose, U_mean is a velocity scale and D_mean is a length scale based on the diameter of the mouth-throat airways of the individual.

32. An inhalation device according to claim 30 or 31 wherein wherein the length scale is given by

33. An inhalation device according to claim 30 or 31 wherein the velocity scale is given by