Adjustable chamber for improved performance of a dry powder inhaler with high or variable dose loading

Abstract

Aerosolization devices and procedures are disclosed which provide enhancement to air-jet and other dry powder inhaler (DPI) technologies to improve and optimize aerosolization performance and expand dose loading capabilities. An exemplary device includes, for example, an aerosolization chamber which has a variable chamber size and an adjustment mechanism configured to adjust the chamber size between actuations. In use, a distance between an air-jet pathway of the aerosolization chamber and a top of the powder bed is substantially maintained even as the powder is emptied over the successive device actuations.

Description

[0001] ADJUSTABLE CHAMBER FOR IMPROVED PERFORMANCE OF A DRY POWDER INHALER WITH HIGH OR VARIABLE DOSE LOADING

[0002] CROSS-REFERENCE TO RELATED APPLICATIONS

[0003] This application claims the benefit of U.S. Provisional Patent App. No. 63 / 541,315, filed September 29, 2023, the complete contents of which are herein incorporated by reference.

[0004] STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT

[0005] This invention was made with U.S. government support under grant number R01 HL139673 awarded by the National Institutes of Health (NIH). The U.S. government has certain rights in the invention.

[0006] BACKGROUND

[0007] In the field of dry powder inhalers (DPIs), it is often desirable to deliver a high powder dose to a subject over multiple device actuations or inhalations after a single powder loading step. Applications requiring high powder doses (such as >5 mg or >10 mg of powder mass) include inhaled surfactants, antibiotics, antifungals, antivirals, and non-steroidal antiinflammatories.

[0008] Previously developed air-jet DPIs such as disclosed in US20200139058A1 and US20230173203A1 implement a fixed aerosolization chamber volume. When such DPIs are used with a high powder dose loaded in one step but delivered in multiple actuations, aerosolization performance (including aerosol size and emitted dose (ED) percentage) tends to change and become poorer with each successive actuation. SUMMARY

[0009] Exemplary medical systems and devices of this disclosure include but are not limited to dry powder inhalers (DPIs) and components of DPIs. In general, exemplary aerosolization devices such as DPIs generate the turbulence and particle aggregate break-up mechanisms that are needed to deaggregate a powder. Primary powder breakup and aerosolization occurs in the aerosolization chamber and outlet capillary bearing the dry powder away from the aerosolization chamber. Gas (e.g., air) passes through the inlet airflow passage and forms a high-speed turbulent jet within the aerosolization chamber. Secondary flow velocities formed by the highspeed jet are used to initially fluidize the powder. As the fluidized powder enters the high speed jet region, additional powder deaggregation occurs. The small diameter outlet orifice serves to both help form the secondary velocities and allow passage of sufficiently deaggregated particles out of the aerosolization chamber. In some but not necessarily all embodiments, secondary mechanisms of aerosol breakup may be included downstream of the aerosolization chamber to affect the aerosol after the aerosol has exited the aerosolization chamber.

[0010] Various dry powder formulations and methods for making the same are generally known in the medical sciences. In general, any such dry powder formulations may be aerosolized by exemplary devices and administered to patients according to exemplary methods in accordance with this disclosure. As a non-limiting example, an excipient enhanced growth (EEG) particle formulation may be used to reduce the potential for exhalation of the aerosol and to enable targeted drug delivery (see, e.g., U.S. Patent No. 10,105,500, issued October 23, 2018, incorporated herein by reference). Medications which may be administered in a dry powder formulation include but are not limited to inhaled antibiotics, growth hormone, anti-virals, gene therapies for lung diseases, bronchodilators and corticosteroids for asthma management, surfactants, clearance agents, insulin, and anti-inflammatories. Expected doses of these medications are often in the range of 10-100 mg or more. Total powder mass desirable to deliver is partly based on subject sizes (e.g., dosing varies for adults, children, and infants).

[0011] According to an aspect of exemplary embodiments, aerosolization performance for high powder doses is improved by minimizing the change in distance between an air-jet pathway in an aerosolization chamber and the top of the powder bed even as the powder bed diminishes with each successive actuation. Aerosolization performance (including aerosol size and emitted dose (ED) percentage) is impacted by the distance between the air-jet pathway and top of the powder bed (distance A) and distance between the air-jet pathway and bottom of the aerosolization chamber (distance B). If distance A is too small, then the aerosol is not sufficiently deaggregated and too much powder may be released with each actuation. If distance A is too large, then aerosol release from the device may be too slow, requiring too many actuations to deliver a full dose. In a static size aerosolization chamber, distance A will change during successive actuations from the inhaler as powder is emitted and the powder bed height is reduced. For high dose loadings, a long / deep chamber is needed, but if distance B is too large and the chamber size is not variable, then poor emptying (low ED%) occurs. These competing factors often require a compromise in performance (e.g., marginally acceptable small size and marginally acceptable but low emptying (ED%)), especially when powder mass loadings are >5 mg or >10 mg.

[0012] An exemplary aerosolization chamber has a variable size. In other words, the chamber size is adjustable among a plurality of different sizes. Size may specified by volume. Size may be specified by one or more dimensions. As a non-limiting example, an aerosolization chamber with a variable chamber size may be configured such that at least one dimension (e.g., the length) may be changed. A change in dimension may also result in a change in volume of the chamber. A variable size aerosolization chamber may be configured to have a predetermined finite set of discrete sizes. The difference between any two sizes may be a predetermined discrete amount (e.g., dimensional difference and / or volume difference). Alternatively, a variable size aerosolization chamber may be configured to assume any size between a lower limit and an upper limit.

[0013] An exemplary variable size (i.e., adjustable size) aerosolization chamber is reversible in size change. That is to say, the chamber may be reduced in size then enlarged in size. The reduction and enlargement, when equal in magnitude, may restore the chamber to its starting condition. Successive changes in sizes larger and / or smaller may be made a substantially unlimited number of times.

[0014] An exemplary variable size (i.e., adjustable size) aerosolization chamber is susceptible to a change in size without incurring any damage, e.g., by crushing.

[0015] An exemplary variable size (i.e., adjustable size) aerosolization chamber is susceptible to a change in size without disrupting or changing the extent to which the chamber is sealed from ingress or egress. That is to say, the change in size does not change any extent to which the chamber is scaled against ingress of gas by any means other than expressly provided inlets or egress of gas or aerosol by any means other than expressly provided outlets.

[0016] An exemplary variable size (i.e., adjustable size) aerosolization chamber is susceptible to a change in size without changing the geometries of the opposite ends of the chamber. For instance, the end quarter or third of the chamber at either end may be entirely unaffected geometrically by a change in chamber size. An exemplary variable size (i.e., adjustable size) aerosolization chamber is susceptible to a change in size without changing the geometries of the top or bottom of the chamber in the case of a vertically oriented elongate chamber. For instance, the top quarter or third and the bottom quarter or third of the chamber may be entirely unaffected geometrically by a change in chamber size.

[0017] A size of an aerosolization chamber may be reduced by raising a powder support surface such as a floor of the aerosolization chamber. Conversely, the size of the aerosolization chamber may be increased by lowering a powder support surface such as a floor of the aerosolization chamber. The floor may be a lower curved surface of the chamber. In general the floor is the lowest surface of the chamber with respect to the orientation of gravity. A change in floor position may be measured relative to a fixed roof of the chamber and / or relative to an air-jet pathway.

[0018] In general, changing or adjusting a “size” of an aerosolization chamber according to this disclosure entails changing at least one geometric aspect of the chamber, typically at least one dimension characterizing the chamber. The dimension changed may be the distance between a powder support surface on the one hand and, on the other hand, an air-jet pathway, ceiling, inlet (orifice), or outlet (orifice) of the chamber. If the powder support surface is the floor of the chamber, changing the position of the powder support surface relative to the aforementioned features may entail changing the size of the length (the long axis) of the chamber, and correspondingly changing the volume of the chamber. Alternatively, a powder support surface may be provided above and separate from a floor of a chamber, such as a powder support surface configured as a shelf which lies between the floor and ceiling of the chamber. In such a case as this, a change in size of the chamber may not entail a change in volume of the chamber. The powder support surface may be adjusted relative to the ceiling and / or the floor while the physical distance between the ceiling and floor of the chamber remains constant. A variable size aerosolization chamber advantageously maintains desirable geometries and aerodynamic features at all available sizes as the powder bed empties. In particular, all inner walls defining the chamber maintain substantially smooth curvatures. When changing the size of a variable size aerosolization chamber smooth curvatures for all of the chamber walls are maintained. The smooth curvatures minimize depositional losses associated with sharp comers and sharp edges.

[0019] An exemplary method of using a dry powder inhaler (DPI) includes at least the following steps: loading in a single step a large powder mass into an aerosolization chamber of the DPI, selecting a desired distance (A) between an air-jet pathway of the aerosolization chamber and top of the powder bed; and maintaining the distance A as the powder is emptied over successive device actuations and / or inhalations by adjusting a size of the aerosolization chamber (e.g., raising a floor of the chamber) between successive device actuations and / or inhalations. The final chamber size can then minimize distance B, which improves the total ED%. Methods such as this help to ensure that a more uniform dose (particle size per actuation and dose delivered per actuation) is released with each actuation / inhalation and that that total ED is increased compared with a static size aerosolization chamber.

[0020] In many embodiments, the number of actuations which come between successive adjustments in chamber size is one. However, in some embodiments, the number of actuations which come between successive adjustments in chamber size may number two or more. In some instances, two or more actuations between successive adjustments in the powder support surface may improve performance, or two or more actuations may be required to help maintain subject ventilation during rapid breathing before the powder support surface is raised. In this context, maintaining distance A refers to changing the chamber size to the extent necessary so the maximum variation of distance A between an air-jet pathway of the aerosolization chamber and top of the powder bed remains under a predetermined limit.

[0021] Exemplary aerosolization chambers and DPIs which include such chambers include a mechanism for adjusting the aerosolization chamber size. For instance, the powder support surface such as the floor of the aerosolization chamber may be raised using a screw mechanism, using a series of tracks, and / or by simply pushing a lower section higher into the device. This motion can be facilitated by hand, mechanically (e.g., rotational spring), as part of the actuation process, and / or electromechanically. An adjustment mechanism may comprise multiple (i.e., two or more) chamber walls segments which are arranged in a telescoping arrangement, with one chamber wall segment able to slide into and out of a neighboring chamber wall segment. In some embodiments, the adjustment mechanism may include friction fit components which hold their relative arrangement constant in an absence of external forces. However, the friction fit components may be configured so that deliberate force applied by a user is sufficient to overcome the friction fit and cause the components to move relative one another, thereby changing the size the of the chamber.

[0022] An exemplary aerosolization chamber may be specifically configured to be a multi- actuation-to-empty device. An exemplary aerosolization chamber may be configured to require multiple actuations to fully aerosolize an initial powder mass.

[0023] Exemplary embodiments include one or more inlet(s) and one or more outlet(s) expressly provided for creating desired aerodynamic effects for the purpose of aerosolization (e.g., for creating an air jet) and for passing aerosolized powder onward through the device or system for delivery to the patient. For single inlet, single outlet configurations, orifices of the inlet and outlet to an aerosolization chamber are typically but not always necessarily aligned on the same axis as one another. The linear air jet pathway between the orifices does not impinge on the initial bed of powder. Secondary velocities in the aerosolization chamber form the aerosol from the dry powder bed. A bypass flow may or may not be included depending on the embodiment.

[0024] In embodiments in which an aerosolization chamber has multiple air jet axes (e.g., as in the case of a chamber with two or more inlets each corresponding with a respective air jet axis) any one of the jet axes is selectable as the fixed reference for measuring the optimal value of distance A and maintaining that distance A.

[0025] For purposes of producing a satisfactory air jet within an aerosolization chamber, exemplary capillary and orifice diameters are 0.3 to 1.17 mm, for lower end flow rates of 2 L / min - 6 L / min or marginally higher (e.g., 10 L / min), as may be used in a DPI for infants or for a hybrid DPI including bypass flow, which can be used for any subject age range or inhalation condition. For lower end flow rates with a single inlet and single outlet configuration, preferred inlet diameters arc 0.5-0.8 mm with an additional preference for 0.6 mm; preferred outlet diameters are 0.6-1.17 mm, with an additional preference for 0.89 mm. For lower end flow rates (e.g., 2-6 L / min) and multiple inlets and / or multiple outlets, the preferred single inlet / outlet diameters may be repeated, or smaller inlets and / or outlets may be used, potentially such that the sum of the cross-sectional areas is approximately equal to the preferred single inlet and outlet cases. The diameters of the flow passagc(s) to the inlet orificc(s) (and inlet orifice diameter) and the diameters of the flow passage(s) to the outlet orifice(s) (and outlet orifice diameter) together with the delivered air flow rate control the strength of the high-speed jet of air within the aerosolization chamber. As flow rate is increased, typically larger inlet and outlet diameters are used. For intermediate flow rates in the range of 6-20 L / min, or marginally higher to 30 L / min, which may work well in a pediatric DPI, preferred single inlets are in a range of 0.9 - 2 mm (1.4 mm often preferred) and preferred single outlet are in a range of 1.8 - 3.5 mm (2.4 mm often preferred). As described, for multiple inlets and outlets at intermediate flows, the single inlet and outlet diameters may be repeated, or smaller diameters may be used. For high flow rate cases (>20 L / min or >30 L / min) or for passive devices in which the user drives the flow through inspiratory effort, preferred inlet ranges include 2 - 3.5 mm and preferred single outlet ranges include 2.5 - 4 mm. Multiple inlets and outlets may also be employed for high flow rate cases and for passive devices. Exemplary actuation flow volumes are as low as 100 - 600 pL for very small test animals (e.g., mice), 1-5 or 1-20 mL for intermediate size test animals (e.g., rats and rabbits), 3-100 mL for human infants, 100 mL to 2 L or 3 L for human pediatric subjects, and 300 mL - 4.5 L for adults. However, if bypass channels are employed, or if the aerosol is injected into an inhalation gas stream, then the lower end actuation flow volumes may be used with any age group or subject. For devices actuated by a positive pressure gas source typical actuation pressures across system may range from 1 - 60 kPa, or higher, depending on desired flow rate and device resistance. For passive devices operated by a patient’s inhalation effort, pressure drops across system may be 0.5 to 6 kPa or higher.

[0026] An exemplary aerosolization chamber in a loaded state ready for immediate use is a fully enclosed space but for at least one inlet orifice and at least one outlet orifice. An aerosolization chamber may have one inlet orifice or a plurality of inlet orifices. An aerosolization chamber may have one outlet orifice or a plurality of outlet orifices. One or more inlet orifices may be an end of a tube such as a capillary. One or more outlet orifices may be an end of a tube such as a capillary. Fully enclosed may mean hermetically sealed (except for expressly intended inlets for air / outlets for aerosol) in some instances but not necessarily all embodiments.

[0027] An exemplary aerosolization chamber is elongate in shape and configured to have at least one cross flow air jet with an air jet axis. The air jet exists when the device is physically in use, but the air jet axis is determined from the geometries and arrangement of physical features (such as the inlet orifice to the acrosolization chamber) and therefore exists whether or not the device is in use. According to aspects of some exemplary air jet DPIs, the air jet axis is perpendicular to the longitudinal axis of the acrosolization chamber, creating a vertical aerosolization chamber configuration. For a vertical aerosolization chamber configuration, while an air jet can cross the aerosolization chamber at any location provided the jet does not impinge on the powder bed, dose storage and loading are maximized by implementing these structures at the top (preferably upper *4) of the air-jet DPI when in the orientation of intended use. At least one of the one or more inlets is often aligned on a common axis with at least one of the one or more outlets, but this is not required especially when multiple inlets or outlets are used. For a vertical aerosolization chamber configuration, the air jet axis passes only through an upper longitudinal segment of the aerosolization chamber. The one or more inlets and the one or more outlets are all positioned at an upper longitudinal segment of the aerosolization chamber. The upper longitudinal segment may extend no more than 50% of a length (or 25% of the length) of the aerosolization chamber. A lower longitudinal segment of the aerosolization chamber is removable and reattachable to the upper longitudinal segment. The lower longitudinal segment is opposite the upper longitudinal segment. As opposed to a vertical configuration, if a horizontal configuration is employed, in which the ends move one toward the other (e.g., collapse together) creating a smaller volume with each actuation, then the air jet may still be in the upper *4 or may occur centrally along the primary axis of the chamber.

[0028] A lower longitudinal segment of an aerosolization chamber may be configured to accommodate a fractional part of a standardized dry powder capsule, e.g., a Size 0 capsule, containing powder. The lower longitudinal segment of the aerosolization chamber may be configured to contain powder that is not in a capsule. The lower longitudinal segment of the aerosolization chamber may be open or openable to an environment and configured to receive a containment unit holding a powder. For instance, a partial capsule (e.g. half capsule) containing a powder may be secured in the DPI aerosolization chamber or inserted into a lower unit. An exemplary aerosolization chamber also permits dry powder to be inserted directly into the aerosolization chamber with ease and without reliance upon the powder’s containment in a capsule. Whether or not use of an exemplary aerosolization chamber involves use of a capsule or a part thereof, the chamber is configured so that the capsule or part thereof, if present, does not oscillate or spin.

[0029] An access port may exist on the top half of the aerosolization chamber that may be opened, by removing a cover, allowing a dose of powder to be poured in, and then resealed prior to device actuation.

[0030] In one embodiment, an exemplary vertical aerosolization chamber has a perpendicular / vertical orientation (e.g., relative to the air jet pathway) in a state of use. A perpendicular / vertical orientation of the aerosolization chamber may be advantageous for accommodating higher powder masses and ease of loading compared to alternatives such as a horizontal aerosolization chamber. The vertical orientation and loading strategies also enable the use and filling of partial capsule bodies, e.g., base I / 2 or % components of a Size 0 capsule. This is advantageous from a dose manufacturing and filling perspective in that existing capsule- oriented equipment and technology can be utilized.

[0031] An exemplary aerosolization chamber may have one or more inlets which are preformed in or passing through the walls of the aerosolization chamber. An exemplary aerosolization chamber may have one or more outlets which are preformed in or passing through the walls of the aerosolization chamber. Preformed structures may exist in the device prior to the device being loaded with dry powder, e.g., they are formed by the manufacturer of the device. Alternatively, an exemplary aerosolization chamber may have no preformed inlets and / or preformed outlets, and / or an exemplary aerosolization chamber may have some preformed orifices but require additional piercing of one or more elements prior to delivery of a dry powder dose to a patient. One or more inlets and / or one or more outlets may be formed after a dry powder is loaded in the aerosolization chamber. As a non-limiting example, one or more inlets and / or one or more outlets may be formed by piercing a wall or walls of the aerosolization chamber (and / or object therein, such as a wall or seal of a loaded capsule or partial capsule). Some devices may be configured to include one or mor piercing elements for this purpose. For example, some devices may have one or more capillaries configured for piercing. An inlet flow conduit (which may be capillary) and / or outlet flow conduit (which may be a capillary) may serve the dual purposes of (i) piercing a wall of an aerosolization chamber (and / or object therein, such as a wall or seal of a loaded capsule or partial capsule) before the first actuation of a loaded dose and (ii) conducting air / gas to or from the aerosolization chamber during actuations. Exemplary air sources for supplying air which enters an aerosolization chamber of an exemplary device may be, for example, a positive pressure air source (creating an active device) or based on a patient’s inhalation effort, creating a negative pressure at the device outlet, and often referred to as a passive device. The latter (passive device) case is applicable for dry powder inhalers (DPI) that rely on inspiratory flow to deliver the powder. Active devices that employ actuation with positive pressure air volumes external to the patient have a number of applications including the delivery of surfactant aerosols to infants with respiratory distress syndrome or test formulations to small animals. Active devices use an energy source external to the user to form the aerosol. Positive-pressure active devices implement an external gas source to aerosolize the powder, which can be supplied by an air-syringe, manual ventilation bag, or compressed air electromechanical system. Depending on the volume of gas used, these DPIs can be classified as high (>200 ml) or low (<200 ml) actuation air-volume (AAV) devices.

[0032] A positive pressure air-source device may be an automated air source or a manual air source such as a ventilation bag. In either case the positive pressure air source device actuates the air-jet DPI and may also provide a full inhalation to the patient. As one non-limiting example, an exemplary automated air source may comprise or consist of a pressure regulator, solenoid valve, and microprocessor controlled timer. The automated air source may further comprise a user activated switch such as a push button. Push button actuation of the device provides constant pressure application for a defined time period, resulting in a square waveform flow profile. In embodiments employing a manual air source, an adult can generally generate a 6 kPa pressure source with one hand operation of a small ventilation bag. When operating a lever- actuated syringe, an adult can generation 10-60 kPa of pressure. Given the inhalation volume to be delivered and flow rate specifications, a complete delivery generally occurs start to finish in a matter of seconds, e.g. 0.1 to 5 seconds, depending in some part on resistance. For an infant, with an inhalation volume of 10 mL at a flow rate of 3 LPM (50 ml / s), a full inhalation / delivery requires 0.2 seconds. For a child, with an inhalation volume of 750 ml and a flow rate of 15 LPM (250 ml / s), a full inhalation / delivery takes 3 seconds.

[0033] In some embodiments, an aerosolization device may instead be configured as a passive device which forms an aerosol under negative pressure in response to a user’s inhalation through the device. Exemplary devices may be tailored to particular patient groups, for example, adults, children, or infants. In general, active devices arc preferred for children and infants owing to higher rates of usage error compared to adults. Delivering aerosol to the lungs of pediatric patients by using positive pressure to aerosolize the powder and inflate the lungs avoids reliance on the child’s inspiration. Advantages of positive-pressure devices further include the ability to deliver dry powder aerosol during invasive and non-invasive mechanical ventilation and the ability to administer both the aerosol and a full inhalation breath, which can be especially beneficial in administering dry powder aerosol to infants.

[0034] Exemplary devices may be configured to provide feedback to user to assist setting and changing of chamber size. Different visible, audible, and / or tactile indicators may be used to show the correct alignment pattern while raising the floor over successive actuations.

[0035] An aspect of some exemplary embodiments is to have a single DPI configured to work well with different powders with a range of dispersive characteristics. A single DPI has tunable aerosolization chamber parameters so that it can accommodate any of a range of powders without sacrificing performance for some powders over others. As a general matter, for powders with low dispersive properties, a smaller distance A is needed. Conversely, a larger distance A is needed for highly dispersible powders. To fully empty the chamber and maximize the emitted dose (ED%), a final small distance B is also needed. According to some exemplary embodiments, for a given formulation, optimal values of distance A, distance B and a pattern of actuations and floor height raises are defined for a single DPI device (which is to say, without a need for selecting a particular device from among multiple different devices depending on the given formulation). This approach is useful not only for manufacturing a single model of device useable for a variety of patients who need different powders from one another, but for other contexts as well. For instance, this approach may be applied for determining an optimal static aerosol chamber size, as an end product with variable aerosolization chamber size, as an end product that can deliver variables doses without impacting aerosolization performance, and as a general platform for test aerosol administration to human subjects and to test animals that can be tuned to work well with different mass loadings and powder characteristics.

[0036] Exemplary applications for technology of this disclosure include, but are not limited to: delivery of dry powder medications to and via the lungs, delivery of dry powder medications to the nose and other parts of the respiratory tract, and delivery of dry powder therapeutics to the skin or to regions of the body (internal and external) during surgery.

[0037] An exemplary aerosolization device with an adjustable size aerosolization chamber according to this disclosure may be employed to determine exemplary sizing and / or dosing of a static / fixed chamber size aerosolization device. A static / fixed chamber size is acceptable, and the simplicity of design desirable, in certain contexts, in particular, when a particular treatment for a particular patient merits using only a single actuation to aerosolize substantially all of the loaded powder mass. An exemplary method may determine an optimal distance A for a single actuation of a given powder using a variable size chamber. The variable size chamber may be loaded with the pharmaceutically predetermined amount of dry powder to be delivered, then actuated at a first test value of distance A. The output is monitored. The variable size chamber is reloaded, actuated at the different test value of distance A, and the output monitored again. This may be repeated at many different test values of distance A. With the collected data from the monitoring step, a preferred single distance A may be selected from among the different distances tested based on the output results. As a more succinct statement, an exemplary method of determining an optimal distance A for a given powder of a given quantity may comprise the steps of: actuating at different distances, monitoring the output, and selecting a preferred distance from among the different distances based on the output results. The methods described in this paragraph may also be used to determine / select the particular value of distance A which is to be maintained for embodiments that involve a single loading mass but multiple successive actuations (or breaths) to fully aerosolize the initial loading mass.

[0038] Some exemplary methods according to this disclosure are designed to maintain a substantially constant dose / actuation without additional metering elements (or at least without the need for additional metering elements).

[0039] In general, exemplary methods of this disclosure have the benefit of maximizing small aerosol size and ensuring high ED% with a single device.

[0040] BRIEF DESCRIPTION OF THE DRAWINGS

[0041] Figure 1A is a block diagram of an exemplary medical system for aerosolizing a dry powder. Figure IB is a block diagram of an exemplary medical device for aerosolizing a powder bed.

[0042] Figure 1C is a diagram of an aerosolization chamber opened by separation of top and bottom parts.

[0043] Figure 2A is a flowchart of an exemplary method for aerosolizing a dry powder from a powder bed.

[0044] Figure 2B is a visual diagram of an aerosolization chamber emptied of dry powder by multiple successive actuations with adjustments in chamber size between actuations.

[0045] Figure 3A is a cross-sectional view of exemplary air-jet DPI which includes a variable size aerosolization chamber.

[0046] Figure 3B is an enlarged sectional view of the adjustment mechanism of the air-jet DPI of Figure 3 A.

[0047] Figure 4 is an exemplary air-jet DPI configured with visual / tactile feedback elements conveying the available size settings and set size to a user.

[0048] Figure 5 is a cross-sectional view of an assembly of an exemplary DPI and mouthpiece patient interface.

[0049] Figure 6 is a DPI device (called the “D2” device in this disclosure) containing a horizontally oriented and static size aerosolization chamber the aerosolization performance of which is described in Examples.

[0050] Figure 7 is a DPI device (called the “D3” device in this disclosure) containing a vertically oriented and adjustable size aerosolization chamber the aerosolization performance of which is described in Examples.

[0051] Figure 8A-8D are, respectively, results of first, second, third, and fourth representative actuations of the D2 device (which had a fixed size aerosolization chamber). Top: intensity and cone angles at the approximate half-length of the plume. Middle: Overlay of actuation flow and plume intensity. Bottom: particle size distribution (bars) and corresponding cumulative volume percentage (curved line) averaged over the actuation time course.

[0052] Figures 9A-9D are, respectively, results of first, second, third, and fourth representative actuations of the D3 device (which had an adjustable size aerosolization chamber). Top: intensity and cone angles at the approximate half-length of the plume. Middle: Overlay of actuation flow and plume intensity. Bottom: particle size distribution (bars) and corresponding cumulative volume percentage (curved line) averaged over the actuation time course.

[0053] Figure 10 is a graph of arterial oxygenation results for an in vivo rabbit model in which rabbits were treated with dry powder medicaments aerosolized with the D2 device or aerosolized with the D3 device.

[0054] Figure 11 is a graph of lung compliance results for an in vivo rabbit model in which rabbits were treated with dry powder medicaments aerosolized with the D2 device or aerosolized with the D3 device.

[0055] DETAILED DESCRIPTION

[0056] Figure 1A shows an overview of an exemplary medical system 100 including a medical device 102 configured for aerosolizing a dry powder for treatment of a patient. Consistent with exemplary embodiments depicted in subsequent figures, the medical device 102 may be, for example, an air-jet dry powder inhaler (DPI). Exemplary DPIs may be used for oral and / or nasal aerosol administration. Three main subparts illustrated in Figure 1A are an air source 101, the medical device 102 which includes an aerosolization chamber, and a patient interface 103. It will be understood to those of ordinary skill in the art that all three of these elements are typically involved in a patient’s treatment according to exemplary embodiments. As a semantic matter, however, the term “DPI system” or simply “system” may be used herein to refer to all three elements collectively or any one or pair of the elements 101, 102, and 103. An exemplary medical system may also include further elements not represented by the blocks in Figure 1A. In the context of many DPI applications, the air source 101 is configured as a positive pressure air source. In some embodiments, however, the air source 101 may simply be one or more inlets which admit air or other gas to the system 100 when the patient inhales, creating a negative pressure within system 100.

[0057] Figure IB is a block diagram of a medical device 102 for aerosolizing a powder bed 153b. The device 102 includes an aerosolization chamber 150 adjustable in size between actuations of the medical device and without opening the aerosolization chamber 150. The device 102 further includes an adjustment mechanism 161 configured to adjust the chamber size. When speaking of an aerosolization chamber being open or closed in this disclosure, it should be understood that inlct(s) for admitting air from air source 101 and outlct(s) for permitting aerosol to exit the chamber do not render the chamber “open”. The chamber is “closed” for purposes of this disclosure even if air or other gases are admissible to the chamber via one or more inlets (inlet orifices) and even if air, gases, and aerosol are permitted to exit the chamber via one or more outlets (outlet orifices). In general, a closed chamber may be understood to be sealed against the entry or exit of air but for the inlet(s) and outlet(s) expressly provided for creating desired aerodynamic effects for the purpose of aerosolization (e.g., for creating an air jet) and for passing aerosolized powder onward through the device or system for delivery to the patient.

[0058] The medical device 102 includes at least one inlet orifice 154 and at least one outlet orifice 155. The air-jet pathway 153 aligns with a geometric centerline of the at least one inlet orifice 154. The powder support surface 152 is a floor of the aerosolization chamber 150. Alternatively, in some embodiments, the powder support surface may be a surface distinct from and positioned above the floor of the chamber 150.

[0059] The aerosolization chamber 150 is configured to have an air-jet pathway 153 along which an air jet exists during actuation of the medical device to aerosolize at least a fraction of the powder bed 153b. The adjustment mechanism 161 is configured to change a distance between the air-jet pathway 153 and a powder support surface 152 of the aerosolization chamber. Because of the fixed geometric relationship between the inlet 154 and air-jet pathway 154, it is also the case that the adjustment mechanism 161 is configured to change a vertical distance between the at least one inlet orifice 154 and the powder support surface 152 of the aerosolization chamber 150.

[0060] It is generally desirable for all inner walls of the aerosolization chamber 150 to consist of smooth curvatures at all the multiple different sizes the aerosolization chamber 150 may assume. The main exception to this trait which may exist in some embodiments is the geometries required for the presence of the inlet and outlet orifices and any structures providing such orifices. For instance, capillary tubes may project partly into the chamber 150 and the meeting junctions of capillary tube and sidewalls of the chamber 150 may or may not have smooth transitions.

[0061] The adjustment mechanism 161 is configured to raise the powder support surface 152 (the curved lower / lowest surface of the chamber in the exemplary case of Figure IB) of the aerosolization chamber 150 to reduce the chamber size. The adjustment mechanism comprises one or more of a screw mechanism, a series of tracks, and a push to move mechanism for raising the powder support surface of the aerosolization chamber. Adjustment of chamber size may be facilitated by one or more of: by hand (of a user), mechanically, as part of the actuation process, and electromechanically. Figure IB shows the option of a controller 162 connected to the adjustment mechanism 161 in the case of electromechanical control.

[0062] Figure 1C depicts the chamber 150 opened for purposes of loading a powder mass 153a into the aerosolization chamber 150. The powder mass 153a forms powder bed 153b under the influence of gravity.

[0063] The aerosolization chamber 150 comprises at least a first part 151 and second part 152 moveable with respect to the first part 151. The first pail 151 comprises a first inner surface of the aerosolization chamber 150, and the second part 152 comprises a second inner surface of the aerosolization chamber 150. Stated differently, the aerosolization chamber 150 comprises a first inner surface belonging to the first part 151 and a second inner surface belonging to the second part 152. The first part 151 may include the roof / ceiling / uppermost / topmost surface of the aerosolization chamber 150. The second part 152 may include the floor / bottom / bottommost surface of the aerosolization chamber 150. The inlet 154 and outlet 155 may preexist in the walls of the first part 151. Alternatively, the inlet 154 and outlet 155 may be created moments before use, e.g., in a configuration which calls for puncturing an initially sealed volume containing the powder mass 153a / powder bed 153b.

[0064] Figure 2A is a flowchart of a method 200 for aerosolizing a dry powder from a powder bed. Step 201 is selecting an optimal distance (A) between an air-jet pathway of the aerosolization chamber and top of the powder bed. The selection of distance A may be made based on dispersion characteristics of the dry powder to be aerosolized, for instance, if distance A is too small, then the aerosol is not sufficiently deaggregated and too much powder may be released with each actuation. If distance A is too large, then aerosol release from the device may be too slow or too little powder may be released with each actuation, requiring too many actuations to deliver a full dose.

[0065] Step 202 is loading in a single step a powder mass into an aerosolization chamber of the aerosolization device. The single powder mass loading may be relatively large within the context of dry powder inhalers (DPIs). For instance, the powder mass may be >5 mg or >10 mg. Step 203 is actuating the aerosolization device to aerosolize a fraction of the loaded powder mass. The aerosolized fraction of the powder mass exits the aerosolization device and an un-aerosolized fraction remains in a powder bed in the aerosolization chamber.

[0066] Step 204 is adjusting a size of the aerosolization chamber prior to the next actuation. The choice of size will also determine the aerosol properties of the aerosol delivered with the next actuation. If the size is too small too much powder may be released with each actuation. If the size is too large, then aerosol release from the device may be too slow or too little powder may be released with next actuation. Step 205 is actuating the aerosolization device again. The aerosolization device is substantially emptied of the initially loaded powder mass by repeating steps 204 and 205 as necessary until the aerosolization chamber is empty. If the aerosolization chamber is emptied with simply two actuations, steps 204 and 205 needn’t be repeated.

[0067] Figure 2B is a visual diagram corresponding to process 200 of Figure 2A. The diagram of Figure 2B should be read from left to right and shows a single aerosolization chamber at eight successive points in time. In this illustrative example, the far left depiction of the aerosolization chamber depicts a loaded and closed aerosolization chamber. Distance A is the distance between the air-jet pathway and top of the powder bed. Distance B is the distance between the air-jet pathway and the powder support surface. In this case, the powder support surface is the bottom of the aerosolization chamber. For explanatory purposes, dashed lines in the powder bed visually divide the powder bed into four submasses. It is assumed for this example that it is desirable to deliver the initial powder mass over four actuations. This determination may be made based on the powder formulation to be aerosolized, the total initial loaded mass, and the patient receiving the powder, for example.

[0068] The second from the left depiction of the aerosolization chamber shows the chamber after the first actuation. The first quarter of the initial powder mass is now gone, having been aerosolized and carried out of the aerosolization chamber by air flow. A thin dashed line shows where the powder bed surface was prior to the first actuation.

[0069] Before proceeding to a second actuation, the powder support surface (the floor of the chamber in this case) is raised so that the distance between the air-jet pathway and top of the powder bed is again distance A. The distance between the air-jet pathway and the powder support surface has shortened from distance B to distance B'. The second actuation is then performed. The fourth depiction from the left of the aerosolization chamber shows the chamber immediately after the second actuation is complete. Once again, a dashed line is depicted to show the former level of powder bed surface.

[0070] Before proceeding to the third actuation, the powder support surface is again raised so that the distance between the air-jet pathway and top of the powder bed is again distance A. The distance between the air-jet pathway and the powder support surface has shortened from distance B' to distance B". The third actuation is then performed. The sixth depiction from the left of the aerosolization chamber shows the chamber immediately after the third actuation is complete. Once again, a dashed line is depicted to show the former level of powder bed surface.

[0071] Before proceeding to the fourth actuation, the powder support surface is again raised so that the distance between the air-jet pathway and top of the powder bed is again distance A. The distance between the air-jet pathway and the powder support surface has shortened from distance B" to distance B"'. The fourth actuation is then performed. The eighth depiction from the left of the aerosolization chamber shows the chamber immediately after the fourth actuation is complete. Once again, a dashed line is depicted to show the former level of powder bed surface. At this stage substantially all of the initial loaded powder mass has been aerosolized and exited the aerosolization chamber. In practice, two or more actuations may be used before raising the floor to expose the next segment of powder. In some instances, two or more actuations before each floor raise may improve performance, or two or more actuations may be required to help maintain subject ventilation during rapid breathing before the floor is raised.

[0072] In summary of Figures 2A and 2B, the illustrated exemplary aerosolization process may be described as follows. Successive device actuations are performed to incrementally aerosolize the dry powder in the aerosolization chamber while maintaining a predetermined distance (A) between an air-jet pathway of the aerosolization chamber and top of the powder bed as the dry powder is emptied over the successive device actuations. As Figure 2B illustrates, “maintaining” the distance between the air-jet pathway and the powder bed surface does not necessarily mean such distance does not fluctuate. Rather, “maintaining” the distance between the air-jet pathway and the powder bed surface refers to the distance being substantially the same at the moments immediately preceding actuations, and / or “maintaining” may be used in this disclosure to refer to changing the chamber size to the extent necessary so the maximum variation of distance A between an air-jet pathway of the aerosolization chamber and top of the powder bed remains under a predetermined limit. It will be understood that in practice a powder bed surface is not a perfect geometric plane but may be characterized as substantially planar. It will be further understood that maintaining a distance may inherently entail small insignificant variations (margins of error) in a real world context, and / or removing an approximate same powder volume or mass with each actuation.

[0073] In general, it is acceptable for the adjustment of the aerosolization chamber size to be performed between successive actuations. In a device which has electromechanical control of the adjustment mechanism (e.g., see discussion of Figures IB above involving controller 162), the controller 162 may be configured to adjust chamber size concurrently with actuations in some implementations.

[0074] Figure 3A depicts an exemplary air-jet DPI 300 which includes a variable size aerosolization chamber 301. The DPI 300 includes an inlet orifice 302 and outlet orifice 303 on opposite sides of the chamber 301. An air-jet pathway 304 lies between the inlet 302 and outlet 303. The air-jet pathway 304 is at the top end of the chamber 301, a short distance below the curved ceiling 305 of the chamber 401. In a state of use airflow direction is from figure right to 1'igure left, as summarized by airflow directional arrow 306. In DPI 300 the inner walls of the aerosolization chamber 301 are supplied by a first part 307 and a second part 308. The first part 307 includes a first subpart 307a and second subpart 307b. In a fully assembled state in which the DPI is suitable for use, the first subpart 307a and second subpart 307b are secured together so that neither is moveable relative the other, thus their collective characterization as a single pail 307. The second part 308 is moveable relative the first part 307 in order to change the size of the aerosolization chamber. In the case of air-jet DPI 300, the adjustment mechanism 309 is a screw mechanism that includes outer diameter (OD) threads on subpart 307b and corresponding mating inner diameter (ID) threads on part 308. The part 308 is rotatable by hand (of a user) to cause the part 308 to rotate clockwise or counterclockwise about the part 307 and, in the process, raise or lower the powder support surface 310 relative to the inlet 302, outlet 306, air-jet pathway 304, and ceiling 305 (these latter four features all having geometrically fixed relationships to one another).

[0075] The air-jet DPI 300 has fixed diameter tubes (e.g., capillaries made of for example metal such as stainless steel) leading to inlet orifice 302 and away from outlet orifice 306. Various further devices or components of a complete medical system may be attached downstream and / or upstream of the adjustable size aerosolization chamber 301. In Figure 3A components 311 and 311 are attached downstream. Orifice 313 leads downstream to a patient interface and from there to the patient.

[0076] Figure 3B is an enlarged sectional view of the adjustment mechanism 309 of the air-jet DPI 300. As stated above, the adjustment mechanism 309 is a screw mechanism that includes OD threads on subpart 307b and corresponding mating inner diameter ID threads on part 308. Part 308 includes a center shaft 351 the top surface of which is the powder support surface or at least contributes to the powder support surface (in this case the floor) of the aerosolization chamber 301. The shaft 351 seals against an inner bore 352 of part 307 via a side O-ring seal 353 to provide air-tight operation even while the part 308 of the aerosolization chamber moves relative the part 307.

[0077] In Figure 3B, the combination of parts 307b and 308 may be configured together to form a dose containment unit with a seal, e.g. a foil seal, located over the opening of part 307b. For use, the seal is removed exposing the preloaded powder, and the combination of 307b and 308 is attached to part 307a and the remainder of the device depicted in Figure 3 A.

[0078] Figure 4 depicts air-jet DPI 300 connected downstream to an air source via tubing 401 and upstream to a patient interface, in particular a two-prong nasal cannula 402. Sizing indicia 403 are arrayed circumferentially around the air chamber within the DPI 300. The sizing indicia, which for illustrative purposes are here labeled “1,” “2,” and “3,” to indicate a first chamber size, second chamber size, and third chamber size, respectively, have fixed positions relative to pail 307. Each visual indicium 403 also corresponds with a respective physical projection / tab of material. A second indicium 404 is arranged on the part 308. In this illustrative example the second indicium is a physical projection of solid material. When part 308 is rotated relative to part 307, indicium 404 also rotates in equal measure. Alignment of the indicium 404 with respective ones of the indicia 403 provides visual feedback to a user that the size of the aerosolization chamber within the DPI 300 is set to the first size, second size, or third size, respectively. To use the DPI 300 for a three actuation delivery sequence, the user may conveniently set the indicium 400 to align with the indicium 403a, actuate the device, move the indicium 400 (and correspondingly part 308) so that indicium 400 aligns with indicium 403b, actuate the device a second time, move the indicium 400 (and thus part 308) so that indicium 400 aligns with indicium 403c, and actuate the device a third time. The feedback elements, which in this case are visual according to the labels as well as tactile according to the projections / tabs which the user’s fingers may physically feel as being aligned or not, ensure easy and reliable adjustment of the acrosolization chamber size between successive actuations.

[0079] Figure 5 is an assembly 500 of an exemplary dry powder inhaler (DPI) 502 and patient interface 503, in this case a mouthpiece. The two parts 502 and 503 may be configured to be attachable to and separable from one another with a twist-lock or other attachment mechanism 514. The attachment mechanism 514 may include one or more silicone O-rings 515 to form a tight seal through which aerosol may not escape. Within the DPI 502 an exemplary acrosolization chamber 510 comprises or else adjoins an inlet orifice flow passage 511 and an outlet orifice flow passage 512. The inlet and outlet orifice flow passages 511 and 512 may be constructed with hollow metal capillaries and are often referred to as inlet and outlet capillaries, whether or not the passages are made of metal or another suitable material. The inlet and outlet capillaries may be oriented along the long / longitudinal axis 513 of the acrosolization chamber 510 or at a non-zero angle with the longitudinal axis 513, e.g., perpendicular as illustrated in Figure 5.

[0080] Figure 5 is illustrative of the use of a secondary mechanism of aerosol breakup, in this instance, a three-dimensional (3D) rod array 532. The rod array 532 may be added to provide a secondary mechanism of aerosol breakup, further reducing the aerosol size with negligible depositional loss. The rod array also functions to break apart a turbulent jet from the acrosolization chamber outlet flow passage 512 admitted at inlet 531 of the downstream lumen, in this case, the lumen of patient interface 503. The rod array positioned adjacent to the inlet 531 reduces downstream aerosol impaction and depositional loss on the way to the lungs. The 3D rod array 532 may comprise some features described by U.S. Patent No. 10,105,500 B2 which is incorporated herein by reference.

[0081] According to some embodiments, exemplary systems, devices, and methods consistent with this disclosure may include one or more features described in related work by the inventors, namely US2020 / 0139058A1, US 2023 / 0071308 Al, and US20230173203A1, all of which are herein incorporated by reference. For instance, some exemplary embodiments may entail DPI devices in accordance with the foregoing publications modified to have adjustable size acrosolization chambers consistent with this disclosure. EXAMPLES

[0082] Example 1. Spray Characterization of Low Volume Air- Jet Dry Powder Inhaler Devices for the Delivery of a Synthetic Lung Surfactant Powder Formulation

[0083] This Example characterizes and compares the spray output of two different low volume air-jet dry powder inhaler devices for the delivery of an excipient enhanced growth (EEG) synthetic lung surfactant (SLS) powder formulation using low air volumes (~ 10 mL) and flow rates (~ 3 L / min).

[0084] A spray dried SLS-EEG formulation was produced using a Mini Spray Dryer (S-300, Biichi Labortechnik AG, Flawil, Switzerland). The formulation employed is described in: Comparison of In Vitro Aerosol Performance and Powder Characteristics of a Synthetic Lung Surfactant Powder Aerosol Formulation Produced using Two Spray Drying Methods, Hall F, Momin M, Farkas DR, Longest P, Hindle M, Respiratory Drug Delivery 2024: 536-539. The formulation was aerosolized using two different positive pressure devices, referred to respectively in this disclosure as “D2” and “D3” and illustrated by Figures 6 and 7.

[0085] As depicted by Figures 6 and 7, both DPI devices D2 and D3 included an inlet capillary 651 for passing air from a positive pressure source (not depicted), an aerosolization chamber 601 or 701, and a long outlet capillary 652 downstream of the respective aerosolization chamber. In preliminary testing, a version of D2 that contained three (0.5 mm diameter) inlets (arranged in a triangular pattern) performed better than the single inlet version depicted in Figure 6, and was therefore used in this comparison. This inlet version is referenced as D2 in the following paper (see Fig. 2b therein): Momin, M. A. M., et al. (2024). "Development of a new dry powder aerosol synthetic lung surfactant product for neonatal respiratory distress syndrome (RDS) - Part I: In vitro testing and characterization." Pharmaceutical Research 41: 1703-1723. The outlet capillary 652 connected to a diffusional flow conduit 653 which introduced rapid expansion (of flow conduit cross-sectional dimension) and provided a connection port 654 for a pressure monitoring control (PMC) unit (not depicted). The diffusional flow conduit then connected to an endotracheal tube (ETT) interface 655.

[0086] As shown in Figure 6, the aerosolization chamber 601 of the “D2” DPI device had a fixed, static size. The chamber 601 was also oriented horizontally, with the long axis of the chamber parallel with the air jet pathway between the inlet to the outlet. The outlet capillary included a 2mm overhang into the aerosolization chamber. As shown in Figure 7, the aerosolization chamber 701 of the “D3” DPT device had a variablc / adjustablc size. The chamber was also oriental vertically, with the long axis of the chamber perpendicular with the air jet pathway between inlet and outlet.

[0087] The D2 device was loaded with 10 mg of powder and is characterized as having a single, static reservoir together with the air-jet design (Pangeni R, Hassan AA, Farkas D, Sudarjat H, Longest PW, Hindle M, Xu Q: New air-jet dry powder insufflator for high-efficiency aerosol delivery to rats. Molecular Pharmaceutics 2023, 20: 2207-2216) with small diameter inlets and outlets. It was predetermined that the static aerosolization chamber performed best with 10 mg powder loadings in terms of aerosol quality and did not perform well when loaded with 30 mg of powder all at once.

[0088] The D3 device maintains the air-jet design, however it is loaded with 30 mg of powder into a reservoir that is turned to alter the height of the powder bed after each actuation. As a result, the variable chamber device required only one powder loading step to administer a targeted total dose of 30 mg.

[0089] The emitted aerosol spray characteristics were compared for each of the individual four actuations from D2 and similarly, four actuations from D3, which were accompanied by a defined rotation of the reservoir to elevate the powder bed after each actuation. Emitted aerosol sprays were characterized using laser diffraction particle sizing (Malvern Spraytec®) and light sheet microscopy (Proveris Scientific Spray VIEW®) to determine particle size distributions and plume geometry of the sprays over the time course of each actuation. Data collected include median volume diameter (D50), cone angle and plume width at the maximum intensity, and plume front velocity and duration.

[0090] Figures 8A-8D show the characteristics of the SLS-EEG formulation emitted from D2. Figures 8A-8D correspond, respectively, with the first, second, third, and fourth actuations of four successive actuations of D2. Figures 8A-8D reveal that using D2, there was significant variability in the sequential actuations where plume intensity or aerosol concentration decreases and particle sizes increase with each actuation as the device empties. The design criteria for this device that was loaded with 10 mg of formulation was to empty rapidly within the first ~ 2 actuations. Image intensity data revealed ~ 40% of the dose was emitted in each of the first two actuations and ~ 10% emitted on the third and fourth actuations. In all cases, the significant fraction of large particles, taken as >5pm or >10pm and shown in the lower panels as histograms, are not desirable for lung delivery of pharmaceutical aerosols. It is well known that these particles will be lost in the cxtrathoracic airways and potentially contribute to off target effects of the therapeutic. Improved aerosol deaggregation by the inhaler is needed to convert these large particles to a smaller size fraction to maximize drug that is deliverable to the lungs.

[0091] Figures 9A-9D show the characteristics of the SLS-EEG formulation emitted from D3. Figures 9A-9D correspond, respectively, with the first, second, third, and fourth actuations of four successive actuations of D3. In contrast to the D2 results, the actuation intensities or aerosol concentrations, particle size distribution, and plume geometries were similar for each actuation for the aerosol emitted from the D3 device. The D3 device emitted a substantially consistent mass fraction of the 30 mg loaded dose over each of the four actuations as the reservoir chamber height was altered. Importantly, the variable chamber device has greatly reduced the fraction of large particles (e.g., >10pm) and converted them to small particles that can be used for lung delivery of the aerosol.

[0092] Table 1 presents a quantitative summary (N = 3) of the aerosol spray characteristics per actuation for the SLS-EEG aerosol emitted from the D2 and D3 inhalers showing median volume diameter, cone properties and plume front velocity and duration. The multi-modal size distribution produced by D2 had median volume diameters of 3.3, 3.7, 4.8 and 14.7 pm for actuations 1-4, respectively. Particle sizes (D50) produced in the D3 were 1.5, 1.4, 1.4 and 1.5 pm, respectively over the four actuations, demonstrating uniform aerosolization. Consistent dose emission over the four actuations results in reproducible aerosol sizes generated by D3, in contrast to D2 where dose emission is low for actuations 3 and 4, resulting in large aerosol sizes. The VCU D2 inhaler generated a spray plume with a lower cone angle and cone width, and the plume front velocity and duration was lower compared to the D3 device (Table 1).

[0093] Table 1. Summary of aerosol spray characteristics per actuation for the SLS-EEG aerosol emitted from the D2 and D3 inhalers showing cone properties, plume front velocity and duration (N = 3 for each actuation).

[0094] Example 2. Cascade Impaction Testing

[0095] Both D2 and D3 were subjected to cascade impaction testing. The D2 was loaded with Nano SD SLS-EEG formulation. The D3 was loaded with the Mini SD SLS-EEG formulation. These formulations are described in: Comparison of In Vitro Aerosol Performance and Powder Characteristics of a Synthetic Lung Surfactant Powder Aerosol Formulation Produced using Two Spray Drying Methods, Hall F, Momin M, Farkas DR, Longest P, Hindle M, Respiratory Drug Delivery 2024: 536-539.

[0096] The D3 / Mini SD combination had a significantly higher fine particle fraction (FPF) and fine particle dose (FPD) < 5pm compared to the D2 / Nano SD formulation. Specifically, the D3 with Mini SD SLS-EEG formulation yielded the following results: FPF < 1 pm: 10.0+0.6%, FPF < 5 pm: 87.9±3.3%, and FPD (< 5 pm) of PL: 12.4 mg PL / 30 mg of loaded formulation. By contrast, the D2 with Nano SD SLS-EEG formulation yielded the following results: FPF < 1 pm: 9.3+0.5%, FPF < 5 pm: 27.1+1.5%, and FPD (< 5 pm) of PL: 3.9 mg PL / 30 mg of loaded formulation.

[0097] Example 3. In Vivo Testing of the Nano SD SLS-EEG Formulation Delivered with D2 and the Mini SD SLS-EEG Formulation Delivered with D3

[0098] An exemplary application of surfactant powder aerosol product is administration through the nose-to-lung route in infants. As a test case modeling this scenario, in vivo testing was conducted using an endotracheal tube (ETT) in an intubated rabbit model with severe RDS induced by surfactant washout. While this initial system avoids the challenge of getting aerosol past the nasal region, aerosol delivery through the ETT and upper tracheobronchial (TB) region to reach the alveoli was not trivial because upper TB airway diameters at the level of bifurcation B3 are in the range of 0.8-2.3 mm.

[0099] The efficacy of the Nano SD SLS-EEG dry powder formulation was tested using a nearly identical in vivo rabbit surfactant washout model as previously considered by Walther et al. (Walther FJ et al.: Efficacy, dose-response, and aerosol delivery of dry powder synthetic lung surfactant treatment in surfactant-deficient rabbits and premature lambs. Respiratory Research 2022, 23(1): 1-16.) for their evaluation of ARCUS® dry powder surfactant aerosol. Rabbits were intubated with an ETT and placed on invasive mechanical ventilation (MV). Surfactant wash out was conducted until PaC / FiCh values from two arterial blood gas samples (30 mins apart) were < 100 mmHg and dynamic compliance had decreased to < 50% of the baseline (prelavage) value. Following surfactant washout, animals received either dry powder Nano SD SLS- EEG formulation (n = 5; 60 mg), a clinical dose of instilled liquid surfactant (Curosurf at 200 mg / kg) (n = 4), or the aerosol delivery process without powder (n = 4) as a negative sham control. The formulation was delivered in two 30 mg increments (with successive 10 and 20 mg loadings) separated by a 15-minute period using the infant dry powder aerosol delivery system (iDP-ADS) and VCU D2 air-jet DPI. The nominal powder formulation dose of 60 mg resulted in approximately 40 mg / kg of powder formulation and 24 mg PL / kg, based on an average rabbit weight of ~ 1.5 kg. The iDP-ADS consisted of a positive pressure gas source, air-jet DPI, diffusional flow pathway conduit, pressure monitoring control (PMC) unit, and subject interface. Additional details related to the iDP-ADS with D2 and the rabbit in vivo experiments with D2 can be found in the following publications:

[0100] Momin, M. A. M., et al. (2024). "Development of a new dry powder aerosol synthetic lung surfactant product for neonatal respiratory distress syndrome (RDS) - Part I: In vitro testing and characterization." Pharmaceutical Research 41: 1703-1723.

[0101] DiBlasi, R., et al. (2024). "Development of a new dry powder aerosol synthetic lung surfactant product for neonatal respiratory distress syndrome (RDS) - Part 2: In vivo efficacy testing in a rabbit surfactant washout model." Pharmaceutical Research DOI: 10.1007 / s 11095-024-03754-7. For the aerosol delivery procedure, the powder was loaded into size 0 HPMC capsules (Qualicaps, Whitsett, NC) and sealed in blister packs for shipping. Just prior to aerosol delivery, the capsules were opened and the powder was loaded into the device. Aerosol delivery was > 70% of each loaded dose to the lungs with five actuations (requiring < 30 sec for each 30 mg administration) while allowing exhalation between each actuation. Gas exchange (arterial blood gas (ABG)), ventilation parameters, flow and pressure data were obtained pre-lavage, post-lavage (baseline, pre-treatment condition), directly following surfactant and at 30-minute intervals for 3.5 h after the start of aerosol delivery.

[0102] Animals that received the 60 mg loaded dose of the Nano SD SLS-EEG aerosol (24 mg PL / kg; n = 5) had mean PaO2 / FiO2 recovery to approximately 96% of pre-lavage values at the end of the 3.5-hour experiment, consistent with instilled Curosurf liquid at a clinical standard first dose of approximately 200 mg PL / kg, while the sham control cases did not recover (Figure 10). The post-lavage oxygenation index (OI) following surfactant washout was > 10 for all cases, indicating significant respiratory distress. As expected, OI improvement was not observed for the sham control cases over the 3.5-hour observation period, whereas both Nano SD SLS-EEG and Curosurf liquid bolus instillation provided OI values below five within 90 minutes and values near one at 3.5 hours (consistent with healthy lungs). At the 3.5-hour time point, liquid instillation and sham groups did not demonstrate improvements in lung compliance (0.63 vs. 0.46 mL / cm H2O, respectively) whereas the Nano SD SLS-EEG group had approximately doubled lung compliance with an average value > 1 mL / cm H2O (Figure 11 ; RDD Presentation; Compliance). Macroscopic necropsy findings showed high residual of surfactant films / foam obstructing the trachea with Curosurf whereas delivery of the Nano SD SLS-EEG aerosol formulation showed a patent trachea. For the recent ARCUS dry powder aerosol study with a nearly identical lung injury model, best case doses of 240 mg / kg (168 mg PL / kg) resulted in a final PaOz / FiCF of ~ 300 mmHg, which was 63% of pre-washout values, and final compliance did not rise above 0.5 mL / cm H2O (Walther FJ et al.). In contrast, the highly dispersible micrometer- sized SLS-EEG aerosol achieved improved efficacy at ~ 1 / 10 the PL dose compared with other aerosols and the current clinical standard of animal-derived surfactant liquid instillation. A comparable procedure to the preceding description was conducted for In Vivo rabbit model using the D3 device and Mini SD SLS-EEG aerosol formulation, and results arc shown in comparison to the D2 device and Nano SD SLS-EEG formulation in Figures 10 and 11.

[0103] Arterial oxygenation results differed significantly between the D2 and D3 devices (Figure

[0104] 10). With D2 and Nano SD SLS-EEG, there was 96% recovery of PaCL at 3.5 hr, equivalent to Curosurf (200 mg / kg) at 24 mg PL / kg dose. With D3 Mini SD SLS-EEG, there was 56% of PaO2 recovered at 1 min after first 30 mg dose (12.5 mg PL / kg), rapid and complete recovery of PaOi within 30-60 mins at 25 mg PL / kg dose. This massive increase in recovery time and performance is attributed to the increased FPF and FPD generated by the D3 device (Example 2). Viewed another way, for the same total 60 mg loaded powder masses, the FPDs of PL in particles <5p m generated by D2 and D3, based on cascade impactor testing, were 5.2 mg PL / kg and 16.5 mg PL I kg assuming an average rabbit weight of 1.5 kg. The large increase in FPD associated with the D3 device likely increased the amount of PL delivered directly to the intended site of action, namely the alveoli deep within the lungs, leading to the nearly instantaneous response and recovery that were observed. These FPD values are also shown in Figure 10 for the D2 and D3 curves.

[0105] Compliance results differed significantly between the D2 and D3 devices, too (Figure

[0106] 11). Curosurf (Liquid instillation) showed no significant increase in compliance compared to Sham control. With D2 and Nano SD SLS-EEG, there was significant increase in compliance (vs. controls) beginning at 150 mins. With D3 and Mini SD SLS-EEG, compliance increased by ~ 1.5-fold at 1 min after first 30 mg dose. Compliance doubled at 210 mins. There was increasing compliance at the end of the study for both SLS-EEG aerosols. As with oxygenation, the near instantaneous increase in airway compliance was also associated with the much higher (~3-fold) PL dose in the aerosol size fraction that was <5pm and formed with the D3 device. The respective D2 and D3 FPD values are also shown in Figure 11 near the D2 (FPD of PL = 5.2 mg PL / kg) and D3 (FPD of PL = 16.5 mg PL / kg) curves.

[0107] As with the oxygenation (Figure 10) and compliance (Figure 11), the D3 / Mini SD combination also had significant improvements in PaCCh, pH, oxygenation index, ventilation efficiency index, mean airway pressure, peak inspiratory pressure, and respiratory rate. It is noted that, as used herein and in the appended claims, the singular forms “a”, “an”, and “the” include plural referents unless the context clearly dictates otherwise. It is further noted that the claims may be drafted to exclude any optional element. As such, this statement is intended to serve as antecedent basis for use of such exclusive terminology as “solely”, “only”, and the like in connection with the recitation of claim elements, or use of a “negative” limitation.

[0108] As will be apparent to those of skill in the ail upon reading this disclosure, each of the individual embodiments described and illustrated herein has discrete components and features which may be separated from or combined with the features of any of the other several embodiments without departing from the scope or spirit of the present invention. Any recited method can be carried out in the order of events recited or in any other order which is logically possible.

[0109] Where a range of values is provided, it is understood that each intervening value, to the tenth of the unit of the lower limit unless the context clearly dictates otherwise, between the upper and lower limit of that range and any other stated or intervening value in that stated range, is encompassed within the invention. The upper and lower limits of these smaller ranges may independently be included in the smaller ranges and are also encompassed within the invention, subject to any specifically excluded limit in the stated range. Where the stated range includes one or both of the limits, ranges excluding either or both of those included limits are also included in the invention.

[0110] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Although any methods and materials similar or equivalent to those described herein can also be used in the practice or testing of the present invention, representative illustrative methods and materials are described.

[0111] It is to be understood that the terminology and explanations used herein are for the purpose of describing exemplary embodiments only, and are not intended to be limiting, since the scope of the present invention will be limited only by the appended claims.

Claims

CLAIMSWhat is claimed is:

1. A medical device for aerosolizing a dry powder, comprising an aerosolization chamber adjustable in size between actuations of the medical device and without opening the aerosolization chamber; and an adjustment mechanism configured to adjust the chamber size.

2. The medical device of claim 1, wherein the aerosolization chamber is configured to require multiple actuations to fully aerosolize an initial powder mass.

3. The medical device of claim 1, wherein the aerosolization chamber is configured to have an air-jet pathway along which an air jet exists during actuation of the medical device to aerosolize at least a fraction of the dry powder bed, and wherein the adjustment mechanism is configured to change a distance between the air-jet pathway and a powder support surface of the aerosolization chamber.

4. The medical device of claim 3, further comprising at least one inlet orifice, wherein the air-jet pathway aligns with a geometric centerline of the at least one inlet orifice.

5. The medical device of claim 3, wherein the powder support surface is a floor of the aerosolization chamber.

6. The medical device of claim 1, further comprising at least one inlet orifice, wherein the adjustment mechanism is configured to change a vertical distance between the at least one inlet orifice and a powder support surface of the aerosolization chamber.

7. The medical device of claim 1, wherein all inner walls of the aerosolization chamber consist of smooth curvatures at multiple different sizes of the aerosolization chamber.

8. The medical device of claim 1 , wherein the adjustment mechanism is configured to raise a powder support surface of the acrosolization chamber to reduce the chamber size.

9. The medical device of claim 8, wherein the adjustment mechanism comprises one or more of a screw mechanism, a series of tracks, and a push to move mechanism for raising the powder support surface of the acrosolization chamber.

10. The medical device of claim 1, wherein adjustment of chamber size is facilitated by one or more of: by hand, mechanically, as part of the actuation process, and electromechanically.

11. A method of aerosolizing a dry powder from a powder bed with a medical device, the method comprising performing successive device actuations to incrementally aerosolize the dry powder in an acrosolization chamber; and maintaining a distance (A) between an air-jet pathway of the acrosolization chamber and top of the powder bed as the dry powder is emptied over the successive device actuations.

12. The method of claim 11, wherein the distance A is maintained by raising a powder support surface of the acrosolization chamber between successive device actuations.

13. The method of claim 12, wherein the powder support surface is a floor of the acrosolization chamber.

14. The method of claim 11, further comprising loading in a single step all the dry powder required for a single medical treatment into the acrosolization chamber.

15. The method of claim 14, wherein the powder mass loading is >5 mg.

16. The method of claim 11, further comprising selecting the distance A based on dispersion characteristics of the dry powder to be aerosolized.

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