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

Abstract

Atomization devices and procedures are disclosed that provide enhancements to air-jet and other dry powder inhaler (DPI) technologies to improve and optimize atomization performance and expand dose loading capacity. Exemplary devices include, for example, an atomization chamber having a variable chamber size and an adjustment mechanism configured to adjust the chamber size between actuations. In use, the distance between the air-jet path of the atomization chamber and the top of the powder bed is generally maintained even as the powder is depleted during successive device actuations.

Description

Cross-references to related applications

[0001] This application claims the benefit of U.S. Provisional Patent Application No. 63 / 541,315, filed September 29, 2023, the entire contents of which are incorporated herein by reference. Statement regarding federally funded research or development

[0002] This invention was made with the support of the U.S. government under license number R01 HL139673 granted by the National Institutes of Health (NIH). The U.S. government has certain rights in this invention. Background Technology

[0003] In the field of dry powder inhalers (DPIs), it is often desirable to deliver high powder doses to subjects via multiple device actuations or inhalations following a single powder loading step. Applications requiring high powder doses (such as >5 mg or >10 mg powder mass) include inhaled surfactants, antibiotics, antifungals, antivirals, and nonsteroidal anti-inflammatory drugs.

[0004] Previously developed air-jet DPIs, such as those disclosed in US20200139058A1 and US20230173203A1, achieved a fixed atomization chamber volume. When such a DPI is used with a high powder dose loaded in one step but delivered by multiple actuations, the atomization performance (including aerosol size and emission dose (ED) percentage) tends to change and becomes worse with each successive actuation. Summary of the Invention

[0005] Exemplary medical systems and devices disclosed herein include, but are not limited to, dry powder inhalers (DPIs) and components of DPIs. Generally, exemplary nebulization devices such as DPIs generate the turbulence and particle agglomeration breaking mechanisms required to deagglomerate the powder. Primary powder breaking and nebulization occur in the nebulization chamber and in the outlet capillary that carries the dry powder away from the nebulization chamber. A gas (e.g., air) passes through an inlet airflow passage and forms a high-speed turbulent jet within the nebulization chamber. A secondary velocity formed by the high-speed jet is used to initially fluidize the powder. Additional powder deagglomeration occurs as the fluidized powder enters the high-speed jet region. A small-diameter outlet orifice is used to help form the secondary velocity and allow fully deagglomerated particles to pass through to exit the nebulization chamber. In some, but not necessarily all, embodiments, the secondary mechanism for aerosol breaking may be included downstream of the nebulization chamber to influence the aerosol after it has exited the nebulization chamber.

[0006] Various dry powder formulations and methods of manufacturing thereof are well known in the medical sciences. Typically, any such dry powder formulation can be nebulized by an exemplary device and administered to a patient according to the exemplary methods of this disclosure. As a non-limiting example, excipient-enhanced growth (EEG) particle formulations can be used to reduce the exhalation potential of aerosols and enable targeted drug delivery (see, for example, U.S. Patent No. 10,105,500, issued October 23, 2018, which is incorporated herein by reference). Drugs that can be administered in dry powder formulations include, but are not limited to, inhaled antibiotics, growth hormones, antiviral drugs, gene therapies for lung diseases, bronchodilators and corticosteroids for asthma management, surfactants, scavengers, insulin, and anti-inflammatory drugs. The intended dose of these drugs is typically in the range of 10 mg to 100 mg or higher. The total powder mass to be delivered is partly based on the subject size (e.g., the dose differs for adults, children, and infants).

[0007] According to an exemplary embodiment, the atomization performance of high powder dosage is improved by minimizing the change in distance between the air jet path in the atomization chamber and the top of the powder bed, even as the powder bed decreases with each consecutive actuation.

[0008] Atomization performance (including aerosol size and delivered dose (ED) percentage) is affected by the distances between the air jet path and the top of the powder bed (distance A) and between the air jet path and the bottom of the nebulizer chamber (distance B). If distance A is too small, the aerosol is not sufficiently deagglomerated, and too much powder can be released with each actuation. If distance A is too large, the aerosol release from the device may be too slow, requiring too many actuations to deliver the full dose. In a statically sized nebulizer chamber, distance A will change during continuous actuations from the inhaler as powder is expelled and the powder bed height decreases. For high dose loads, a long / deep chamber is required, but if distance B is too large and the chamber size is not variable, poor evacuation (low ED%) occurs. These competing factors often require trade-offs in performance (e.g., a slightly acceptable small size and a slightly acceptable but low evacuation (ED%)), especially when the powder mass load is >5 mg or >10 mg.

[0009] An exemplary atomizing chamber has variable dimensions. In other words, the chamber size can be adjusted between multiple different sizes. The size can be specified by volume. The size can be specified by one or more dimensions. As a non-limiting example, an atomizing chamber with variable chamber dimensions can be configured such that at least one dimension (e.g., length) can be changed. Changes in dimensions can also result in changes in chamber volume. The variable-size atomizing chamber can be configured to have a predetermined finite set of discrete dimensions. The difference between any two dimensions can be a predetermined discrete amount (e.g., dimensional difference and / or volume difference). Alternatively, the variable-size atomizing chamber can be configured to take any size between a lower and upper limit.

[0010] The exemplary variable-size (i.e., adjustable-size) atomizing chamber is reversible in its dimensional changes. That is, the size of the chamber can be reduced and then increased. When the reduction and increase are equal, the chamber can be returned to its initial conditions. Large and / or small successive changes in size can be made a substantially unlimited number of times.

[0011] An exemplary variable-size (i.e., adjustable-size) atomizing chamber can be easily resized without causing any damage (e.g., by crushing).

[0012] An exemplary variable-size (i.e., adjustable-size) atomizing chamber can be easily resized without compromising or altering the chamber's seal against entry or exit. In other words, resizing does not change the chamber's seal against gas entry by any means other than a clearly provided inlet or outlet.

[0013] An exemplary variable-size (i.e., adjustable-size) atomizing chamber can be easily resized without altering the geometry of its opposite ends. For example, the quarter-end or third-end of the chamber at either end may be geometrically completely unaffected by changes in chamber size. Similarly, in the case of a vertically oriented elongated chamber, an exemplary variable-size (i.e., adjustable-size) atomizing chamber can be easily resized without altering the geometry of its top or bottom. For example, the top quarter-end or third-end and the bottom quarter-end or third-end of the chamber may be geometrically completely unaffected by changes in chamber size.

[0014] The size of the atomization chamber can be reduced by raising the powder support surface (such as the bottom plate of the atomization chamber). Conversely, the size of the atomization chamber can be increased by lowering the powder support surface (such as the bottom plate of the atomization chamber). The bottom plate can be the lower curved surface of the chamber. Typically, the bottom plate is the lowest surface of the chamber relative to gravity orientation. Changes in the position of the bottom plate can be measured relative to the fixed top plate of the chamber and / or relative to the air jet path.

[0015] Typically, changing or adjusting the "size" of an atomizing chamber according to this disclosure requires altering at least one geometric aspect of the chamber, usually at least one dimension characterizing the chamber. The changed dimension could be the distance between the powder support surface on one side and the air jet path, ceiling, inlet (orifice), or outlet (orifice) of the chamber on the other side. If the powder support surface is the bottom plate of the chamber, changing the position of the powder support surface relative to the aforementioned features may cause a change in the length (major axis) dimension of the chamber, and correspondingly, a change in the volume of the chamber. Alternatively, the powder support surface may be disposed above and separated from the bottom plate of the chamber, such as a powder support surface configured as a shelf between the bottom plate and the ceiling of the chamber. In this case, the change in the size of the chamber may not cause a change in the volume of the chamber. The powder support surface can be adjusted relative to the ceiling and / or the bottom plate while the physical distance between the ceiling and the bottom plate of the chamber remains constant.

[0016] When the powder bed is emptied, the variable-size atomization chamber advantageously maintains the desired geometry and aerodynamic characteristics across all available dimensions. In particular, all inner walls defining the chamber maintain a substantially smooth curvature. This smooth curvature is maintained even when the dimensions of the variable-size atomization chamber are changed. This smooth curvature minimizes deposition losses associated with sharp corners and edges.

[0017] An exemplary method of using a dry powder inhaler (DPI) includes at least the following steps: in a single step, loading a large mass of powder into the nebulizer chamber of the DPI, selecting a desired distance (A) between the air jet path of the nebulizer chamber and the top of the powder bed; and maintaining distance A by adjusting the size of the nebulizer chamber (e.g., raising the bottom plate of the chamber) between successive device actuations and / or inhalations while the powder is emptied during successive device actuations and / or inhalations. The final chamber size can then minimize distance B, which improves the total ED%. Methods like these help ensure a more uniform dose (particle size per actuation and dose delivered per actuation) is released with each actuation / inhalation, and an increase in total ED compared to a statically sized nebulizer chamber.

[0018] In many embodiments, the number of actuations occurring between successive adjustments of the chamber size is one. However, in some embodiments, the number of actuations occurring between successive adjustments of the chamber size can be two or more. In some examples, two or more actuations between successive adjustments of 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. Herein, maintaining distance A refers to changing the chamber size to the necessary extent so that the maximum change in distance A between the air jet path of the nebulization chamber and the top of the powder bed remains within predetermined limits.

[0019] Exemplary atomizing chambers and DPIs including such chambers include mechanisms for adjusting the size of the atomizing chamber. For example, a powder support surface (such as the base plate of the atomizing chamber) may be raised using a screw mechanism, a series of tracks, and / or simply by pushing a lower section into the device. This movement can be facilitated manually, mechanically (e.g., by rotating a spring), as part of an actuation process, and / or electromechanically. The adjustment mechanism may include multiple (i.e., two or more) chamber wall segments arranged in a telescopic arrangement, one of which is capable of sliding into and out of an adjacent chamber wall segment. In some embodiments, the adjustment mechanism may include friction-fitting components that maintain their relative arrangement constant in the absence of external force. However, the friction-fitting components may be configured such that a deliberate force applied by the user is sufficient to overcome the friction fit and cause the components to move relative to each other, thereby changing the size of the chamber.

[0020] An exemplary atomizing chamber can be specifically configured as a device that requires multiple actuations to empty. An exemplary atomizing chamber can be configured to require multiple actuations to fully atomize the initial powder mass.

[0021] Exemplary embodiments include one or more inlets and one or more outlets, which are explicitly provided to produce the desired aerodynamic effects for nebulization purposes (e.g., for generating an air jet) and to allow the atomized powder to continue through the device or system for delivery to a patient. For a single inlet, single outlet configuration, the orifices of the inlet and outlet of the nebulization chamber are typically, but not always, aligned with each other on the same axis. The linear air jet path between the orifices does not impinge on the initial powder bed. Secondary velocities within the nebulization chamber form the aerosol from the dry powder bed. Depending on the embodiment, a bypass flow may or may not be included.

[0022] In embodiments where the atomization chamber has multiple air jet axes (e.g., in the case of a chamber with two or more inlets, each inlet corresponding to a corresponding air jet axis), any one of the jet axes can be selected as the optimal value for measuring distance A and keeping that distance A a fixed reference.

[0023] For the purpose of generating a satisfactory air jet within the nebulization chamber, exemplary capillary and orifice diameters are 0.3 mm to 1.17 mm, suitable for lower end flow rates of 2 L / min to 6 L / min or slightly higher (e.g., 10 L / min), such lower end flow rates can be used for DPIs for infants or mixed DPIs 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 a single outlet configuration, a preferred inlet diameter is 0.5 mm to 0.8 mm, and more preferably 0.6 mm; a preferred outlet diameter is 0.6 mm to 1.17 mm, and more preferably 0.89 mm. For lower end flow rates (e.g., 2 L / min to 6 L / min) and multiple inlets and / or multiple outlets, the preferred single inlet / outlet diameter can be repeated, or smaller inlets and / or outlets can be used, potentially such that the sum of the cross-sectional areas is approximately equal to the preferred single inlet and outlet configuration. The diameters of the flow path leading to the inlet orifice (and the inlet orifice diameter) and the diameters of the flow path leading to the outlet orifice (and the outlet orifice diameter), together with the delivered air velocity, control the intensity of the high-speed air jet within the atomization chamber. Larger inlet and outlet diameters are typically used as the flow velocity increases. For intermediate flow velocities in the range of 6 L / min–20 L / min or slightly above 30 L / min (which works well in pediatric DPI), a preferred single inlet diameter is in the range of 0.9 mm–2 mm (typically preferably 1.4 mm), and a preferred single outlet diameter is in the range of 1.8 mm–3.5 mm (typically preferably 2.4 mm). As described, for multiple inlets and outlets in the intermediate flow, the single inlet and outlet diameters can be repeated, or smaller diameters can be used. For high flow rate cases (>20 L / min or >30 L / min) or for passive devices where the flow is actuated by the user's inhalation effort, a preferred inlet range includes 2 mm–3.5 mm and a preferred single outlet range includes 2.5 mm–4 mm. Multiple inlets and outlets are also available for high-flow-rate situations and passive devices. Exemplary actuation flow rates are as low as 100 µL–600 µL for very small test animals (e.g., mice), as low as 1 mL–5 mL or 1 mL–20 mL for medium-sized test animals (e.g., rats and rabbits), as low as 3 mL–100 mL for human infants, as low as 100 mL–2 L or 3 L for human pediatric subjects, and as low as 300 mL–4.5 L for adults. However, if a bypass channel is used, or if an aerosol is injected into the inhaled airflow, the lower-end actuation flow rate volume can be used with any age group or subject. For devices actuated by a positive pressure gas source, typical actuation pressures across the system can range from 1 kPa to 60 kPa or higher, depending on the desired flow rate and device resistance.For passive devices operated by the patient’s inhalation effort, the pressure drop across the system can be 0.5 kPa to 6 kPa or higher.

[0024] An exemplary atomizing chamber in a ready-to-use loaded state is a completely enclosed space except for at least one inlet port and at least one outlet port. The atomizing chamber may have one or more inlet ports. The atomizing chamber may have one or more outlet ports. One or more inlet ports may be the end of a tube (such as a capillary). One or more outlet ports may be the end of a tube (such as a capillary). In some examples (but not necessarily all embodiments), complete enclosure can mean an airtight seal (except for the explicitly intended air inlet / outlet for the aerosol).

[0025] An exemplary nebulizer chamber is elongated in shape and configured to have at least one crossflow air jet with an air jet axis. The air jet is present when the device is physically in use, but the air jet axis is determined by the geometry and arrangement of physical features such as the inlet orifice of the nebulizer chamber, and thus exists regardless of whether 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 nebulizer chamber, forming a vertical nebulizer chamber configuration. For a vertical nebulizer chamber configuration, while the air jet can pass through the nebulizer chamber at any location as long as the jet does not impinge on the powder bed, when oriented for a intended purpose, dose storage and loading are maximized by implementing these structures at the top (preferably the upper ¼) of the air jet DPI. At least one of one or more inlets is typically aligned on a common axis with at least one of one or more outlets, but this is not necessary, especially when using multiple inlets or outlets. For a vertical nebulizer chamber configuration, the air jet axis passes only through the upper longitudinal section of the nebulizer chamber. One or more inlets and one or more outlets are located in the upper longitudinal section of the nebulizer chamber. The upper longitudinal section may extend no more than 50% (or 25%) of the length of the atomizing chamber. The lower longitudinal section of the atomizing chamber is removable and can be reattached to the upper longitudinal section. The lower longitudinal section is opposite to the upper longitudinal section. In contrast to the vertical configuration, if a horizontal configuration is used, where the ends move toward each other with each actuation (e.g., collapse together), resulting in a smaller volume, the air jet can still occur in the upper ¼ or centered along the main axis of the chamber.

[0026] The lower longitudinal section of the nebulizer chamber can be configured to accommodate a small portion of a standard dry powder capsule (e.g., a size 0 capsule containing powder). The lower longitudinal section of the nebulizer chamber can also be configured to contain powder not present in a capsule. The lower longitudinal section of the nebulizer chamber can be opened or is openable to the environment and is configured to receive a powder-containing unit. For example, a portion of a capsule containing powder (e.g., a half-capsule) can be fixed in the DPI nebulizer chamber or inserted into the lower unit. The exemplary nebulizer chamber also allows dry powder to be easily inserted directly into the nebulizer chamber without relying on the containment of powder in a capsule. Regardless of whether the use of the exemplary nebulizer chamber involves the use of a capsule or a portion thereof, the chamber is configured such that the capsule or a portion thereof (if present) does not vibrate or rotate.

[0027] The inlet port may be located on the upper part of the atomization chamber. The inlet port can be opened by removing the cover, allowing a certain amount of powder to be poured in, and then resealed before the device is actuated.

[0028] In one embodiment, the exemplary vertical atomizing chamber has a vertical / vertical orientation (e.g., relative to the air jet path) in its use state. The vertical / vertical orientation of the atomizing chamber can be advantageous for accommodating higher powder qualities and for ease of loading compared to alternatives such as horizontal atomizing chambers. The vertical orientation and loading strategy also enable the use and filling of partial capsule bodies, such as the base ½ or ¾ portion of a size 0 capsule. This is advantageous from a dosage manufacturing and filling perspective because existing capsule-orientation equipment and techniques can be utilized.

[0029] An exemplary nebulization chamber may have one or more inlets pre-formed in or through a wall of the nebulization chamber. An exemplary nebulization chamber may have one or more outlets pre-formed in or through a wall of the nebulization chamber. A pre-formed structure may exist in the device before the dry powder is loaded; for example, the pre-formed structure may be formed by the device manufacturer. Alternatively, an exemplary nebulization chamber may not have pre-formed inlets and / or pre-formed outlets, and / or an exemplary nebulization chamber may have some pre-formed holes, but one or more elements need to be additionally punctured before the dry powder dose is delivered to the patient. One or more inlets and / or one or more outlets may be formed after the dry powder is loaded into the nebulization chamber. As a non-limiting example, one or more inlets and / or one or more outlets may be formed by puncturing one or more walls of the nebulization chamber (and / or objects therein, such as the wall or seal of a capsule or portion of a capsule). Some devices may be configured to include one or more puncturing elements for this purpose. For example, some devices may have one or more capillaries configured for puncture. The inlet flow conduit (which may be a capillary) and / or outlet flow conduit (which may be a capillary) can serve the dual purpose of (i) piercing the wall of the nebulization chamber (and / or objects therein, such as the wall or seal of the capsule or part of the capsule) before the first actuation of the loaded dose and (ii) guiding air / gas into or from the nebulization chamber during actuation.

[0030] Exemplary air sources for supplying air into the nebulization chamber of an exemplary device can be, for example, positive pressure air sources (generating active devices) or negative pressure at the device outlet based on the patient's inhalation effort, and are often referred to as passive devices. The latter (passive devices) applies to dry powder inhalers (DPIs) that rely on an inhaled flow to deliver powder. Active devices actuated using positive pressure air volume external to the patient have a variety of applications, including delivering surfactant aerosols to infants with respiratory distress syndrome or delivering test formulations to small animals. Active devices use an external energy source to form the aerosol. Positive pressure active devices implement an external gas source to nebulize the powder, which can be provided by an air injector, a manually ventilated bag, or a compressed air electromechanical system. Depending on the volume of gas used, these DPIs can be classified as high (≥200 ml) or low (<200 ml) actuated air volume (AAV) devices.

[0031] Positive pressure air source devices can be automated or manual (such as ventilation bags). In either case, the positive pressure air source device actuates the air jet DPI and can also deliver complete inhalation to the patient. As a non-limiting example, an exemplary automated air source may include a pressure regulator, a solenoid valve, and a microprocessor-controlled timer, or a combination of a pressure regulator, a solenoid valve, and a microprocessor-controlled timer. Automated air sources may also include a user-activated switch, such as a button. Button actuation of the device provides a continuous constant pressure application for a defined time period, thereby producing a square wave flow profile. In embodiments employing a manual air source, adults can typically generate a 6 kPa pressure source using one-handed operation of a small ventilation bag. When the injector is actuated by a lever, adults can generate pressures of 10 kPa to 60 kPa. Given the volume of inhalation to be delivered and the flow rate specification, complete delivery typically begins and ends within approximately a few seconds (e.g., 0.1 to 5 seconds), depending in part on resistance. For infants, at a flow rate of 3 LPM (50 ml / s) for an inhalation volume of 10 mL, complete inhalation / delivery takes 0.2 seconds. For children, with an inhalation volume of 750 ml and a flow rate of 15 LPM (250 ml / s), complete inhalation / delivery takes 3 seconds.

[0032] In some embodiments, the atomizing device may alternatively be configured as a passive device that forms an aerosol under negative pressure in response to a user's inhalation through the device.

[0033] Exemplary devices can be tailored for specific patient groups (e.g., adults, children, or infants). Active devices are generally preferred for children and infants due to a higher rate of usage errors compared to adults. Delivering aerosols to the lungs of pediatric patients by using positive pressure to atomize the powder and inflate the lungs avoids dependence on inhalation in children. The advantages of positive pressure devices also include the ability to deliver dry powder aerosols during invasive and non-invasive mechanical ventilation, as well as the ability to administer aerosols and complete inhalation breathing, which is particularly beneficial when administering dry powder aerosols to infants.

[0034] The exemplary device can be configured to provide feedback to the user to help set and change the chamber size. Different visible, audible, and / or tactile indicators can be used to show the correct alignment pattern when raising the base plate during continuous actuation.

[0035] One aspect of some exemplary embodiments is having a single DPI configured to work well with different powders having a range of dispersibility properties. The single DPI has adjustable nebulizer parameters, allowing it to accommodate any range of powders without sacrificing the performance of some powders relative to others. Generally, a smaller distance A is required for powders with low dispersibility. Conversely, a larger distance A is required for highly dispersible powders. A final small distance B is also needed to completely empty the chamber and maximize the emitted dose (ED%). According to some exemplary embodiments, for a given formulation, optimal values ​​for distance A, distance B, actuation mode, and baseplate height elevation are defined for the single DPI device (i.e., it is not necessary to select a specific device from multiple different devices for a given formulation). This approach can be used not only to create single-device models suitable for a variety of patients requiring powders that differ from each other, but also in other situations. For example, this method can be used to determine the optimal static aerosol chamber size, as a final product with a variable atomization chamber size, as a final product that can deliver variable doses without affecting aerosolization performance, and as a universal platform for testing aerosol administration to human subjects and test animals, which can be adapted to work well with different mass loadings and powder characteristics.

[0036] Exemplary applications of the technology disclosed herein include, but are not limited to: delivering dry powder medications to and via the lungs, delivering dry powder medications to the nose and other parts of the respiratory tract, and delivering dry powder therapeutic agents to skin or body areas (internal and external) during surgery.

[0037] An exemplary nebulizer with an adjustable-size nebulization chamber according to this disclosure can be used to determine exemplary dimensions and / or dosage of a nebulizer with a static / fixed chamber size. Static / fixed chamber sizes are acceptable, and simplicity of design is desirable in certain cases, particularly when only a single actuation is needed to nebulize approximately the entire loaded powder mass for a specific treatment of a particular patient. An exemplary method can determine the optimal distance A for a single actuation of a given powder using a variable-size chamber. The variable-size chamber may be loaded with a predetermined amount of dry powder to be delivered and then actuated at a first test value of distance A. The output is monitored. The variable-size chamber is reloaded and actuated at different test values ​​of distance A, and the output is monitored again. This can be repeated at many different test values ​​of distance A. Using data collected from the monitoring steps, a preferred single distance A can be selected from the different tested distances based on the output results. As a more concise statement, an exemplary method for determining the optimal distance A for a given amount of given powder may include the steps of: actuating at different distances, monitoring the output, and selecting a preferred distance from the different distances based on the output results. The method described in this paragraph can also be used to determine / select a specific value for distance A, which will be maintained for embodiments involving a single load mass but involving multiple consecutive actuations (or breaths) to fully atomize the initial load mass.

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

[0039] Typically, the exemplary methods of this disclosure have the benefit of maximizing the size of small aerosols using a single device and ensuring a high ED%. Attached Figure Description

[0040] Figure 1A This is a block diagram of an exemplary medical system for atomizing dry powder.

[0041] Figure 1B This is a block diagram of an exemplary medical device for atomizing a powder bed.

[0042] Figure 1C This is a diagram of the atomizing chamber opened by separating the top and bottom parts.

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

[0044] Figure 2B This is a visual diagram of an atomizing chamber emptied of dry powder through multiple consecutive actuations, wherein the chamber size is adjusted between actuations.

[0045] Figure 3AThis is a cross-sectional view of an exemplary air jet DPI including a variable-size atomizing chamber.

[0046] Figure 3B yes Figure 3A An enlarged cross-sectional view of the air jet DPI adjustment mechanism.

[0047] Figure 4 An exemplary air jet DPI is configured with visual / tactile feedback elements that convey the available size settings and set sizes to the user.

[0048] Figure 5 This is a cross-sectional view of the components of an exemplary DPI and suction nozzle patient interface.

[0049] Figure 6 It is a DPI device (referred to as "D2 device" in this disclosure) that includes a horizontally oriented and statically sized atomizing chamber, the atomization performance of which is described in the example.

[0050] Figure 7 It is a DPI device (referred to as "D3 device" in this disclosure) that includes a vertically oriented and adjustable-size atomizing chamber, the atomization performance of which is described in the example.

[0051] Figures 8A-8D These are the results of the first, second, third, and fourth representative actuations of the D2 device (with a fixed-size atomizing chamber). Top: Intensity and cone angle at approximately half the length of the plume. Middle: Superposition of actuation flow and plume intensity. Bottom: Average particle size distribution (bar graph) and corresponding cumulative volume percentage (curve) over the entire actuation time.

[0052] Figures 9A-9D These are the results of the first, second, third, and fourth representative actuations of the D3 device (which has an adjustable-sized atomizing chamber). Top: Intensity and cone angle at approximately half the length of the plume. Middle: Superposition of actuation flow and plume intensity. Bottom: Average particle size distribution (bar graph) and corresponding cumulative volume percentage (curve) over the entire actuation time.

[0053] Figure 10 This is a graph showing the results of arterial oxygenation in a rabbit model, where the rabbits were treated with dry powder medication nebulized using either a D2 device or a D3 device.

[0054] Figure 11 This is a graph showing the lung compliance results in a rabbit in vivo model, where the rabbits were treated with dry powder medication nebulized using either the D2 device or the D3 device. Detailed Implementation

[0055] Figure 1AAn overview of an exemplary medical system 100 including a medical device 102 configured to atomize dry powder for treating a patient is shown. Consistent with the exemplary embodiments depicted in the following figures, the medical device 102 may be, for example, an air jet dry powder inhaler (DPI). An exemplary DPI may be used for oral aerosol and / or nasal aerosol delivery. Figure 1A The three main sub-components shown are an air source 101, a medical device 102 including a nebulization chamber, and a patient interface 103. Those skilled in the art will understand that, according to the exemplary embodiment, all three of these components are typically related to the treatment of a patient. However, for semantic purposes, the term "DPI system" or simply "system" may be used herein to refer to all three components or any one or a pair of components 101, 102, and 103. The exemplary medical system may also include components not provided by… Figure 1A Other elements are indicated by boxes in the diagram. In the context of many DPI applications, air source 101 is configured as a positive pressure air source. However, in some embodiments, air source 101 may simply be one or more inlets that allow air or other gases to enter system 100 when the patient inhales, thereby creating negative pressure within system 100.

[0056] Figure 1B This is a block diagram of a medical device 102 for nebulizing a powder bed 153b. Device 102 includes a nebulizing chamber 150, the size of which is adjustable between actuations of the medical device and without opening the nebulizing chamber 150. Device 102 also includes an adjustment mechanism 161 configured to adjust the chamber size.

[0057] When referring to the opening or closing of the nebulization chamber in this disclosure, it should be understood that the inlet for allowing air to enter from air source 101 and the outlet for allowing the aerosol to leave the chamber do not make the chamber “open.” For the purposes of this disclosure, the chamber is “closed” even though air or other gases may enter the chamber through one or more inlets (inlet orifices) and even though air, gases, and aerosols may leave the chamber through one or more outlets (outlet orifices). Generally, a closed chamber can be understood as a seal that prevents the entry or exit of air, except for the desired aerodynamic effects for the purpose of generating nebulization (e.g., for generating an air jet) and the inlets and outlets explicitly provided to allow the nebulized powder to continue through the device or system for delivery to the patient.

[0058] The medical device 102 includes at least one inlet port 154 and at least one outlet port 155. An air jet path 153 is aligned with the geometric center line of at least one inlet port 154. The powder support surface 152 is the base plate of the atomization chamber 150. Alternatively, in some embodiments, the powder support surface may be a surface different from the base plate of the chamber 150 and positioned above the base plate of the chamber 150.

[0059] The nebulization chamber 150 is configured to have an air jet path 153 along which an air jet exists during actuation of the medical device to atomize at least a portion of the powder bed 153b. An adjustment mechanism 161 is configured to change the distance between the air jet path 153 and the powder support surface 152 of the nebulization chamber. Due to the fixed geometry between the inlet 154 and the air jet path 154, the adjustment mechanism 161 is also configured to change the vertical distance between at least one inlet orifice 154 and the powder support surface 152 of the nebulization chamber 150.

[0060] It is generally expected that all the inner walls of the atomizing chamber 150 are formed by smooth curvatures of all the various sizes that the atomizing chamber 150 may present. A major exception to this characteristic that may exist in some embodiments is the presence of inlet and outlet orifices and the geometry required by any structure providing such orifices. For example, a capillary may partially protrude into the chamber 150, and the confluence of the capillary and the sidewall of the chamber 150 may or may not have a smooth transition.

[0061] The adjusting mechanism 161 is configured to raise the powder support surface 152 of the atomization chamber 150 (in Figure 1B In an exemplary case, this involves a curved lower / lowest surface of the chamber to reduce its size. The adjustment mechanism includes one or more of a screw mechanism for raising the powder support surface of the atomizing chamber, a series of tracks, and a pushing mechanism. Adjustment of the chamber size can be facilitated by one or more of the following: manually, mechanically, as part of an actuation process, and electromechanically. Figure 1B An option is shown for a controller 162 connected to the regulating mechanism 161 in the case of electromechanical control.

[0062] Figure 1C The chamber 150 is depicted as being opened for the purpose of loading powder mass 153a into the atomization chamber 150. The powder mass 153a forms a powder bed 153b under the influence of gravity.

[0063] The atomizing chamber 150 includes at least a first part 151 and a second part 152 movable relative to the first part 151. The first part 151 includes a first inner surface of the atomizing chamber 150, and the second part 152 includes a second inner surface of the atomizing chamber 150. In other words, the atomizing chamber 150 includes 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 a roof / ceiling / topmost / topmost surface of the atomizing chamber 150. The second part 152 may include a base / bottom / bottommost surface of the atomizing chamber 150. An inlet 154 and an outlet 155 may be pre-existing in the wall of the first part 151. Alternatively, the inlet 154 and the outlet 155 may be generated at a time before use, for example, in a configuration where it is necessary to pierce the initial sealed volume containing the powder mass 153a / powder bed 153b.

[0064] Figure 2A This is a flowchart of a method 200 for atomizing dry powder from a powder bed. Step 201 involves selecting the optimal distance (A) between the air jet path of the atomization chamber and the top of the powder bed. The selection of distance A can be based on the dispersion characteristics of the dry powder to be atomized. For example, if distance A is too small, the aerosol is not sufficiently deagglomerated, and too much powder may be released with each actuation. If distance A is too large, the release of the aerosol from the device may be too slow, or too little powder may be released with each actuation, thus requiring too many actuations to deliver the full dose.

[0065] Step 202 involves loading the powder mass into the nebulizer chamber of the nebulizer in a single step. In the context of a dry powder inhaler (DPI), the single powder mass loading can be relatively large. For example, the powder mass can be >5 mg or >10 mg.

[0066] Step 203 involves actuating the atomizing device to atomize a portion of the loaded powder mass. The atomized portion of the powder mass exits the atomizing device, while the unatomized portion remains in the powder bed within the atomization chamber.

[0067] Step 204 involves adjusting the size of the atomizing chamber before the next actuation. The choice of size will also determine the aerosol characteristics delivered on the next actuation. If the size is too small, too much powder may be released with each actuation. If the size is too large, the release of the aerosol from the device may be too slow, or too little powder may be released with the next actuation. Step 205 involves actuating the atomizing device again. By repeating steps 204 and 205 as needed until the atomizing chamber is empty, the atomizing device is essentially emptied of the initially loaded powder mass. If the atomizing chamber is emptied only with two actuations, steps 204 and 205 do not need to be repeated.

[0068] Figure 2B It corresponds to Figure 2AThe process of visualizing 200. Figure 2B The diagram should be read from left to right and shows a single nebulizer chamber at eight consecutive time points. In this illustrative example, the leftmost description of the nebulizer chamber depicts the loaded and enclosed nebulizer chamber. Distance A is the distance between the air jet path and the top of the powder bed. Distance B is the distance between the air jet path and the powder support surface. In this case, the powder support surface is the bottom of the nebulizer chamber. For illustrative purposes, the dashed lines in the powder bed visually divide the powder bed into four sub-masses. For this example, it is assumed that the initial powder mass is to be delivered after four actuations. For example, this decision could be based on the powder formulation to be nebulized, the total initial load mass, and the patient receiving the powder.

[0069] The description of the second atomization chamber from the left shows the chamber after the first actuation. The first quarter of the initial powder mass has now disappeared, having been atomized and carried out of the atomization chamber by the airflow. The fine dashed line shows the position of the powder bed surface before the first actuation.

[0070] Before the second actuation, the powder support surface (in this case, the bottom plate of the chamber) is raised so that the distance between the air jet path and the top of the powder bed is again distance A. The distance between the air jet path and the powder support surface is then shortened from distance B to distance B'. The second actuation is then performed. The description of the fourth atomization chamber from the left shows the chamber immediately following the completion of the second actuation. Again, dashed lines are drawn to indicate the previous level of the powder bed surface.

[0071] Before the third actuation, the powder support surface is raised again so that the distance between the air jet path and the top of the powder bed is again distance A. The distance between the air jet path and the powder support surface is shortened from distance B' to distance B". Then the third actuation is performed. The description of the sixth atomization chamber from the left shows the chamber immediately following the completion of the third actuation. Again, dashed lines are drawn to indicate the previous level of the powder bed surface.

[0072] Before the fourth actuation, the powder support surface is raised again so that the distance between the air jet path and the top of the powder bed is again distance A. The distance between the air jet path and the powder support surface is shortened from distance B′′ to distance B′′′. Then the fourth actuation is performed. The description of the eighth nebulization chamber from the left shows the chamber immediately following the completion of the fourth actuation. Again, a dashed line is drawn to indicate the previous level of the powder bed surface. At this stage, essentially all the initial load of powder mass has been nebulized and exited the nebulization chamber. In practice, two or more actuations may be used before raising the base plate to expose the next segment of powder. In some cases, two or more actuations before each base plate rise may improve performance, or two or more actuations may be necessary to help maintain subject ventilation during rapid breathing before the base plate rises.

[0073] Summary Figure 2A and Figure 2B The exemplary atomization process illustrated can be described as follows: Continuous device actuation is performed to incrementally atomize the dry powder in the atomization chamber, while maintaining a predetermined distance (A) between the air jet path of the atomization chamber and the top of the powder bed during the evacuation of the dry powder in the continuous device actuation. Figure 2B The illustration of "maintaining" the distance between the air jet path and the powder bed surface does not necessarily mean that this distance will not fluctuate. Rather, "maintaining" the distance between the air jet path and the powder bed surface means that the distance is approximately the same at the moment immediately following the previous actuation, and / or "maintaining" can be used in this disclosure to refer to changing the chamber size to the necessary extent such that the maximum change in distance A between the air jet path of the atomization chamber and the top of the powder bed remains within a predetermined limit. It should be understood that in practice, the powder bed surface is not a perfect geometric plane, but can be characterized as approximately planar. It will be further understood that maintaining the distance may inherently require small, insignificant changes (error range) in a real-world context, and / or removing approximately the same powder volume or mass with each actuation.

[0074] Generally, it is acceptable to adjust the atomizing chamber size between consecutive actuations. This is also true in electromechanically controlled devices with an adjustment mechanism (e.g., see controller 162 mentioned above). Figure 1B (as discussed in the discussion), in some embodiments, the controller 162 can be configured to adjust the chamber size simultaneously with the actuation.

[0075] Figure 3AAn exemplary air jet DPI 300 is depicted, comprising a variable-sized atomizing chamber 301. The DPI 300 includes an inlet port 302 and an outlet port 303 on opposite sides of the chamber 301. An air jet path 304 is located between the inlet 302 and the outlet 303. The air jet path 304 is located at the top of the chamber 301, a short distance below the curved ceiling 305 of the chamber 401. In use, the airflow direction is from right to left, as summarized by the airflow direction arrow 306. In the DPI 300, the inner wall of the atomizing chamber 301 is provided by a first part 307 and a second part 308. The first part 307 includes a first sub-part 307a and a second sub-part 307b. In a fully assembled state suitable for use, the first sub-part 307a and the second sub-part 307b are fixed together such that neither can move relative to the other, thus their common representation is a single part 307. The second part 308 can move relative to the first part 307 to change the size of the atomizing chamber. In the case of the air jet DPI 300, the adjustment mechanism 309 is a screw mechanism, which includes an outer diameter (OD) thread on the sub-part 307b and a corresponding matching inner diameter (ID) thread on the part 308. The part 308 can be manually rotated by the user to rotate clockwise or counterclockwise around the part 307, and in the process, raise or lower the powder support surface 310 relative to the inlet 302, outlet 306, air jet path 304, and ceiling 305 (the latter four features are all geometrically fixed to each other).

[0076] The air jet DPI 300 has a fixed-diameter tube (e.g., a capillary tube made of, for example, a metal such as stainless steel) leading to an inlet port 302 and located away from an outlet port 306. Various other devices or components of the complete medical system can be attached downstream and / or upstream of the adjustable-size nebulizer chamber 301. Figure 3A In the middle, components 311 and 312 are attached downstream. The orifice 313 leads downstream to the patient interface and from there to the patient.

[0077] Figure 3B This is an enlarged cross-sectional view of the adjustment mechanism 309 of the air jet DPI 300. As described above, the adjustment mechanism 309 is a screw mechanism including an OD thread on the sub-part 307b and a corresponding matching inner diameter ID thread on the part 308. Part 308 includes a central shaft 351, the top surface of which is a powder support surface or at least contributes to the powder support surface of the atomization chamber 301 (in this case, a base plate). The shaft 351 is sealed against the inner bore 352 of part 307 via a side O-ring seal 353 to provide airtight operation, even when part 308 of the atomization chamber moves relative to part 307.

[0078] exist Figure 3B In this configuration, the combination of parts 307b and 308 can be configured together to form a dosing container unit having a seal (e.g., a foil seal located above the opening of part 307b). For use, the seal is removed to expose the pre-loaded powder, and the combination of 307b and 308 is attached to part 307a and... Figure 3A The remaining part of the device depicted in the text.

[0079] Figure 4 An air jet DPI 300 is depicted, which is connected downstream to an air source and upstream to a patient interface (specifically, a bi-forked nasal cannula 402) via conduit 401. Size markers 403 are arranged circumferentially around the air chambers within the DPI 300. These size markers (labeled "1", "2", and "3" for illustrative purposes to represent the first, second, and third chamber dimensions, respectively) are fixed in position relative to part 307. Each visual marker 403 also corresponds to a corresponding physical protrusion / flare of material. A second marker 404 is arranged on part 308. In this illustrative example, the second marker is a physical protrusion of solid material. When part 308 is rotated relative to part 307, marker 404 also rotates by an equal measure. The alignment of marker 404 with the corresponding one of markers 403 provides the user with visual feedback that the nebulizer chamber dimensions within the DPI 300 are set to the first, second, or third size, respectively. To use DPI 300 for three actuation delivery sequences, the user can easily set the alignment of mark 400 with mark 403a, actuate the device, move mark 400 (and corresponding part 308) so that mark 400 aligns with mark 403b, actuate the device a second time, move mark 400 (and therefore part 308) so that mark 400 aligns with mark 403c, and actuate the device a third time. Feedback elements (in this case, visual based on the label and tactile based on the protrusion / plate that the user can physically feel for alignment) ensure easy and reliable adjustment of the atomization chamber size between successive actuations.

[0080] Figure 5This is an assembly 500 of an exemplary dry powder inhaler (DPI) 502 and a patient interface 503 (in this case, a mouthpiece). The two parts 502, 503 can be configured to be attachable to and detachable from each other using a twist lock or other attachment mechanism 514. The attachment mechanism 514 may include one or more silicone O-rings 515 to form an airtight seal through which the aerosol cannot escape. Within the DPI 502, an exemplary nebulization chamber 510 includes or is adjacent to an inlet flow passage 511 and an outlet flow passage 512. The inlet flow passage 511 and the outlet flow passage 512 may be constructed with hollow metal capillaries and are often referred to as inlet capillaries and outlet capillaries, regardless of whether the passages are made of metal or another suitable material. The inlet capillaries and outlet capillaries may be oriented along the long / longitudinal axis 513 of the nebulization chamber 510, or at a non-zero angle to the longitudinal axis 513, for example, as shown below. Figure 5 The vertical as shown in the diagram.

[0081] Figure 5 The illustration depicts a secondary mechanism for aerosol fragmentation, which in this example is a three-dimensional (3D) rod array 532. Rod array 532 can be added to provide a secondary mechanism for aerosol fragmentation, further reducing aerosol size while allowing for negligible deposition loss. The rod array also serves to break up the turbulent jet from the nebulizer outlet flow path 512, which enters at an inlet 531 in a downstream lumen, in this case, the lumen of the patient interface 503. The rod array positioned adjacent to inlet 531 reduces downstream aerosol impact and deposition loss along the path to the lungs. The 3D rod array 532 may include some features described by reference to U.S. Patent No. 10,105,500 B2, which is incorporated herein by reference.

[0082] According to some embodiments, exemplary systems, apparatuses, and methods consistent with this disclosure may include one or more features described in the related work of the inventors, namely US 2020 / 0139058A1, US 2023 / 0071308A1, and US 20230173203A1, all of which are incorporated herein by reference. For example, some exemplary embodiments may require DPI devices based on the foregoing publications, which are modified to have an adjustable-sized atomizing chamber consistent with this disclosure. Example

[0083] Example 1: Spray characteristics of a low-volume air jet dry powder inhaler device for delivering synthetic pulmonary surfactant powder formulations

[0084] This example characterizes and compares the spray output of two different low-volume air jet dry powder inhaler devices for delivering excipient-enhanced growth (EEG) synthetic lung surfactant (SLS) powder formulations using a low air volume (approximately 10 mL) and flow rate (approximately 3 L / min).

[0085] Spray-dried SLS-EEG formulations were prepared using a micro-spray dryer (S-300, Büchi Labortechnik AG, Flawil, Switzerland). The formulations used 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. The formulations were atomized using two different positive pressure devices, referred to herein as “D2” and “D3”, respectively, and by… Figure 6 and Figure 7 Illustration.

[0086] like Figure 6 and Figure 7 Both the depicted DPI devices D2 and D3 include an inlet capillary 651 for passing air from a positive pressure source (not depicted), an atomizing chamber 601 or 701, and a long outlet capillary 652 downstream of the respective atomizing chamber. In preliminary tests, the D2 version, with three (0.5 mm diameter) inlets arranged in a triangular pattern, performed better than... Figure 6The single-inlet version depicted in the paper is used here and is therefore used in this comparison. This inlet version is referred to as D2 in the following paper (see Figure 2b therein): “Development of a new dry powder aerosol synthetic lung surfactant product for neonatal respiratory distress syndrome (RDS)”, Momin, MAM et al. (2024), Part 1: In vitro testing and characterization, Pharmaceutical Research 41: 1703-1723. The outlet capillary 652 connects to the diffusion flow conduit 653, which introduces rapid expansion (of the flow conduit's cross-sectional dimensions) and provides a connection port 654 for the pressure monitoring and control (PMC) unit (not depicted). The diffusion flow conduit then connects to the endotracheal tube (ETT) interface 655.

[0087] like Figure 6 As shown, the atomizing chamber 601 of the "D2" DPI device has fixed static dimensions. The chamber 601 is also horizontally oriented, with its long axis parallel to the air jet path between the inlet and outlet. The outlet capillary includes a 2mm overhang extending into the atomizing chamber.

[0088] like Figure 7 As shown, the atomizing chamber 701 of the "D3" DPI device has a variable / adjustable size. The chamber is also vertically oriented, with its long axis perpendicular to the air jet path between the inlet and outlet.

[0089] The D2 device, loaded with 10 mg of powder, was characterized as having a single static reservoir and an 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 inlet and outlet. The static nebulization chamber was pre-determined to perform best in terms of aerosol mass with a 10 mg powder load, while performing poorly with a single 30 mg powder load.

[0090] The D3 device retains an air-jet design; however, it is loaded with 30 mg of powder into a reservoir, which is rotated after each actuation to change the height of the powder bed. Therefore, this variable-chamber device requires only one powder loading step to deliver the target total dose of 30 mg.

[0091] The characteristics of the emitted aerosol spray were compared for each of the four individual actuations from D2 and similarly for each of the four actuations from D3, accompanied by a defined rotation of the reservoir to raise the powder bed after each actuation. The emitted aerosol sprays were characterized using laser diffraction particle size classification (Malvern Spraytec®) and light panel microscopy (Proveris Scientific SprayVIEW®) to determine the particle size distribution and plume geometry of the spray over the time course of each actuation. Data collected included median volume diameter (D50), cone angle and plume width at maximum intensity, and plume front velocity and duration.

[0092] Figures 8A-8D The characteristics of the SLS-EEG formulation emitted from D2 are shown. Figures 8A-8D These correspond to the first, second, third, and fourth actuations in the four consecutive actuations of D2, respectively. Figures 8A-8D Significant variability was revealed in the use of D2 during sequential actuation, where the plume intensity or aerosol concentration decreased and the particle size increased with each actuation as the device emptied. The device, loaded with 10 mg of formulation, was designed to empty rapidly within the first approximately two actuations. Image intensity data revealed that approximately 40% of the dose was emptied in each of the first two actuations and approximately 10% of the dose was emptied in the third and fourth actuations. In all cases, a significant fraction of large particles (taken as >5 µm or >10 µm and shown as histograms in the figures below) is undesirable for pulmonary delivery of the drug aerosol. These particles are known to be lost in the extrathoracic airways and potentially contribute to off-target effects of the therapeutic agent. Improved aerosol depolymerization of the inhaler is needed to convert these large particles into smaller fractions to maximize drug delivery to the lungs.

[0093] Figures 9A-9D The characteristics of the SLS-EEG formulation emitted from D3 are shown. Figures 9A-9DThese correspond to the first, second, third, and fourth actuations in four consecutive actuations of D3, respectively. In contrast to the results for D2, the actuation intensity or aerosol concentration, particle size distribution, and plume geometry were similar for each actuation of the aerosol emitted from the D3 device. The D3 device emitted a substantially consistent mass fraction of the 30 mg loaded dose in each of the four actuations as the reservoir height changed. Importantly, the variable chamber device has significantly reduced the fraction of large particles (e.g., >10 µm) and converted them into small particles suitable for pulmonary delivery of the aerosol.

[0094] Table 1 presents a quantitative summary (N = 3) of the aerosol spray characteristics of the SLS-EEG aerosol emitted from the D2 and D3 inhalers for each actuation, showing the median volume diameter, cone characteristics, and plume front velocity and duration. The multimodal size distribution produced by D2 has median volume diameters of 3.3 µm, 3.7 µm, 4.8 µm, and 14.7 µm for the 1st–4th actuations, respectively. After four actuations, the particle sizes (D50) produced by D3 are 1.5 µm, 1.4 µm, 1.4 µm, and 1.5 µm, respectively, indicating uniform atomization. The consistent dose emission throughout the four actuations results in reproducible aerosol sizes produced by D3, in contrast to D2, where the low dose emission during the 3rd and 4th actuations leads to larger aerosol sizes. The VCU D2 inhaler (Virginia Commonwealth University D2 inhaler) produces a spray plume with a lower cone angle and cone width, and a lower plume front velocity and duration compared to the D3 device (Table 1).

[0095] Table 1 summarizes the aerosol spray characteristics of SLS-EEG aerosol emitted from inhalers D2 and D3 for each actuation, showing cone characteristics, plume front velocity, and duration (N=3 for each actuation).

[0096] Example 2: Cascade Impact Test

[0097] Both D2 and D3 underwent cascade impact testing. D2 was loaded with a nano-SD (spray-dried) SLS-EEG formulation. D3 was loaded with a micro-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.

[0098] The D3 / micro SD combination exhibits significantly higher fine particle fraction (FPF) and fine particle dose (FPD) (<5 µm) compared to the D2 / nano SD formulation. Specifically, the D3 formulation with micro SD SLS-EEG produced the following results: FPF <1 µm: 10.0 ± 0.6%, FPF <5 µm: 87.9 ± 3.3%, and FPD of PL (phospholipids) (<5 µm): 12.4 mg PL per 30 mg loaded formulation. In contrast, the D2 formulation with nano SD SLS-EEG produced the following results: FPF <1 µm: 9.3 ± 0.5%, FPF <5 µm: 27.1 ± 1.5%, and FPD of PL (<5 µm): 3.9 mg PL per 30 mg loaded formulation.

[0099] Example 3: In vivo testing of nano-SD SLS-EEG formulations delivered with D2 and micro-SD SLS-EEG formulations delivered with D3.

[0100] An exemplary application of surfactant powder aerosol products is administration via the nasal-to-lung route in infants. As a test case simulating this, in vivo testing was conducted using an endotracheal tube (ETT) in an intubated rabbit model exhibiting severe RDS caused by surfactant clearance. While this initial system avoided the challenge of delivering the aerosol through the nasal region, delivery of the aerosol to the alveoli via the ETT and upper tracheobronchial (TB) region was not trivial, given that the upper TB airway diameter at the level of the bifurcation B3 ranges from 0.8 mm to 2.3 mm.

[0101] The efficacy of the nano-SD SLS-EEG dry powder formulation was tested using an in vivo rabbit surfactant clearance model previously identified 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 the evaluation of ARCUS® dry powder surfactant aerosol. Rabbits were intubated using ETT and subjected to invasive mechanical ventilation (MV). Surfactants were cleared until the PaO2 / FiO2 values ​​from two arterial blood gas samples (30 minutes apart) were <100 mmHg and dynamic compliance had decreased to ≤50% of the baseline (pre-irrigation) value. Following surfactant removal, animals received either a dry powder nano-SD SLS-EEG formulation (n=5; 60 mg), a clinical dose of liquid surfactant (200 mg / kg of Curesu) (n=4), or a powder-free aerosol delivery process (n=4) as negative sham controls. The formulation was delivered using an infant dry powder aerosol delivery system (iDP-ADS) and a VCU D2 air jet DPI in two 30 mg increments (with consecutive 10 mg and 20 mg loads) at 15-minute intervals. Based on an average rabbit body weight of approximately 1.5 kg, a nominal powder dosage of 60 mg produced approximately 40 mg / kg of powder and 24 mg PL / kg. The iDP-ADS consists of a positive pressure gas source, an air jet DPI, a diffusion flow path conduit, a pressure monitoring and control (PMC) unit, and a subject interface. Further details regarding the iDP-ADS with D2 and in vivo rabbit experiments utilizing D2 can be found in the following publications:

[0102] Momin, MAM et al. (2024) “Development of a novel dry powder aerosol synthetic pulmonary surfactant product for neonatal respiratory distress syndrome (RDS) – Part 1: In vitro testing and characterization”, Drug Research 41: 1703-1723.

[0103] DiBlasi, R. et al. (2024) “Development of a novel dry powder aerosol synthetic pulmonary surfactant product for neonatal respiratory distress syndrome (RDS) – Part 2: In vivo efficacy testing in a rabbit surfactant clearance model”, Drug Research DOI: 10.1007 / s11095-024-03754-7.

[0104] For the aerosol delivery procedure, the powder was loaded into size 0 HPMC (hydroxypropyl methylcellulose) capsules (Qualicaps, Whitsett, NAT, USA) and sealed in blister packs for transport. Just before aerosol delivery, the capsules were opened and the powder loaded into the device. >70% of each loaded dose was delivered to the lungs via five actuations (each 30 mg administered over ≤30 seconds) (with exhalation allowed between actuations). Gas exchange (arterial blood gas (ABG)), ventilation parameters, flow, and pressure data were obtained before and after irrigation (baseline, pre-treatment condition), immediately after surfactant administration, and continuously for 3.5 h at 30-minute intervals after the start of aerosol delivery.

[0105] Animals receiving a 60 mg loaded dose of nano-SD SLS-EEG aerosol (24 mg PL / kg; n=5) recovered PaO2 / FiO2 to approximately 96% of their pre-irrigation values ​​at the end of the 3.5-hour experiment, consistent with a clinical standard first-dose infusion of Curesu fluid at approximately 200 mg PL / kg, while the sham control cases did not recover. Figure 10 For all cases, an oxygenation index (OI) >10 after lavage following surfactant removal indicated significant respiratory distress. As expected, no improvement in OI was observed in the sham control cases during the 3.5-hour observation period, while both the nano-SD SLS-EEG and the Curesu liquid bolus infusion provided OI values ​​below 5 within 90 minutes and close to 1 at 3.5 hours (consistent with healthy lungs). At the 3.5-hour timepoint, neither the liquid infusion nor the sham control showed any improvement in lung compliance (0.63 vs. 0.46 mL / cm H2O, respectively), while the nano-SD SLS-EEG group showed approximately twice the lung compliance, with a mean >1 mL / cm H2O. Figure 11(RDD presentation; compliance). Gross autopsy findings showed high levels of residual surfactant film / foam obstructing the trachea in Culsu, while delivery of the nano-SLS-EEG aerosol formulation showed patent trachea. In a recent ARCUS dry powder aerosol study using a nearly identical lung injury model, the optimal dose of 240 mg / kg (168 mg PL / kg) resulted in a final PaO2 / FiO2 of approximately 300 mmHg, which is 63% of the pre-clearance value, and final compliance did not increase above 0.5 mL / cm H2O (Walther FJ et al.). In contrast, the highly dispersible micron-sized SLS-EEG aerosol achieves improved efficacy at approximately 1 / 10 of the PL dose compared to current clinical standards for other aerosols and animal-derived surfactant liquid infusions.

[0106] The procedure described above was performed in an in vivo rabbit model using a D3 device and a micro SD SLS-EEG aerosol formulation, and... Figure 10 and Figure 11 The results are shown in the comparison with the D2 device and the nano-SD SLS-EEG formulation.

[0107] The arterial oxygenation results were significantly different between devices D2 and D3. Figure 10 For the D2 and nano SD SLS-EEG, 96% of PaO2 was recovered at 3.5 hours, equivalent to Curesu (200 mg / kg) at a dose of 24 mg PL / kg. For the D3 micro SD SLS-EEG, 56% of PaO2 was recovered at 1 minute after the first 30 mg dose (12.5 mg PL / kg), and PaO2 was rapidly and completely recovered within 30–60 minutes at a dose of 25 mg PL / kg. This significant increase in recovery time and performance is attributed to the increased FPF and FPD generated by the D3 device (Example 2). On the other hand, for the same total 60 mg loaded powder mass, the FPD of PL in <5 µm particles produced by the D2 and D3 based on cascade impactor tests was 5.2 mg PL / kg and 16.5 mg PL / kg, respectively, assuming an average rabbit weight of 1.5 kg. The significant increase in FPD associated with the D3 device may increase the amount of PL delivered directly to the intended site of action (i.e., the alveoli deep within the lungs), leading to the observed near-transient response and recovery. These FPD values ​​also... Figure 10 The curves D2 and D3 are shown.

[0108] The compliance results also differed significantly between devices D2 and D3. Figure 11Compared to the sham control, Curesu (liquid drip) did not show a significant increase in compliance. With D2 and nano-SD SLS-EEG, a significant increase in compliance began at 150 minutes (compared to control). With D3 and micro-SD SLS-EEG, compliance increased approximately 1.5-fold at 1 minute after the first 30 mg dose. Compliance doubled at 210 minutes. Increased compliance was observed for both SLS-EEG aerosols at the end of the study. Similar to oxygenation, the near-transient increase in airway compliance was also associated with a much higher (approximately 3-fold) PL dose in the <5µm aerosol size fraction formed with the D3 device. Corresponding FPD values ​​for D2 and D3 were also... Figure 11 The curves are shown near D2 (FPD of PL = 5.2 mg PL / kg) and D3 (FPD of PL = 16.5 mg PL / kg).

[0109] With oxygenation ( Figure 10 ) and adaptability ( Figure 11 Similar to the D3 / micro SD combination, it also shows significant improvements in PaCO2, pH, oxygenation index, ventilation efficiency index, mean airway pressure, peak inspiratory pressure, and respiratory rate.

[0110] It should be noted that, unless the context explicitly states otherwise, as used herein and in the appended claims, the singular forms “a,” “an,” and “the” include plural indicators. It should also be noted that the claims may be drafted to exclude any optional elements. Therefore, this statement is intended to serve as the premise for the use of exclusive terms such as “alone,” “only,” or the use of the restrictive word “negative” in conjunction with the elements of the claims.

[0111] As will be apparent to those skilled in the art upon reading this disclosure, each of the individual embodiments described and illustrated herein has discrete components and features that may be separated from or combined with features of any of the other several embodiments without departing from the scope or spirit of the invention. Any described method may be performed in the order of the described events or in any other logically possible order.

[0112] When providing ranges of values, it should be understood that, unless the context explicitly specifies otherwise, every intermediate value (to one-tenth of the lower limit unit) between the upper and lower limits of the range, as well as any other stated value or intermediate value within the stated range, is encompassed within this invention. The upper and lower limits of these smaller ranges may be independently included within the smaller ranges and also within this invention, subject to any specific exclusions within said ranges. Where a stated range includes one or both of these limits, the range excluding one or both of those included limits is also included in this invention.

[0113] Unless otherwise defined, 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 pertains. While any methods and materials similar to or equivalent to those described herein may also be used in the practice or testing of this invention, representative illustrative methods and materials are described.

[0114] It should be understood that the terminology and interpretations used herein are for the purpose of describing exemplary embodiments only and are not intended to be restrictive, as the scope of the invention will be limited only by the appended claims.

Claims

1. A medical device for atomizing dry powder, comprising: A nebulization chamber, the size of which can be adjusted between actuations of the medical device without opening the nebulization chamber; as well as An adjustment mechanism configured to adjust the chamber size.

2. The medical device according to claim 1, wherein, The atomizing chamber is configured to require multiple actuations to fully atomize the initial powder mass.

3. The medical device according to claim 1, wherein, The nebulization chamber is configured to have an air jet path, during actuation of the medical device, an air jet exists along the air jet path to atomize at least a portion of the dry powder bed, and wherein the adjustment mechanism is configured to change the distance between the air jet path and the powder support surface of the nebulization chamber.

4. The medical device according to claim 3, further comprising at least one inlet port, wherein, The air jet path is aligned with the geometric center line of the at least one inlet orifice.

5. The medical device according to claim 3, wherein, The powder support surface is the bottom plate of the atomization chamber.

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

7. The medical device according to claim 1, wherein, All the inner walls of the atomizing chamber are composed of smooth curvatures of multiple different sizes of the atomizing chamber.

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

9. The medical device according to claim 8, wherein, The adjustment mechanism includes one or more of a screw mechanism for raising the powder support surface of the atomizing chamber, a series of tracks, and a pushing mechanism.

10. The medical device according to claim 1, wherein, The adjustment of the chamber size can be facilitated by one or more of the following: manually, mechanically, as part of the actuation process, and electromechanically.

11. A method for atomizing dry powder from a powder bed using a medical device, the method comprising: Perform continuous device actuation to incrementally atomize the dry powder in the atomization chamber; as well as During continuous device actuation, when the dry powder is emptied, the distance (A) between the air jet path of the atomizing chamber and the top of the powder bed is maintained.

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

13. The method according to claim 12, wherein, The powder support surface is the bottom plate of the atomization chamber.

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

15. The method according to claim 14, wherein, The powder mass loading is greater than 5 mg.

16. The method of claim 11, further comprising: The distance A is selected based on the dispersion characteristics of the dry powder to be atomized.

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