Patent Application
20230071308
The invention is generally related to dry powder inhalers (DPIs) and, in particular, to DPIs and related apparatuses configured to minimize depositional losses and provide exemplary delivery of aerosolized therapeutics to infants.
The industry is shifting to dry powder medications. There is a need for high dose inhalers. Commercial dry powder inhalers typically require approximately 3 to 4 Liters (L) of air to form an aerosol and empty a device. The best current commercial DPI requires approximately 1600 ml of air for operation. Infants only inhale on the order of 10 ml (˜6 ml/kg) of air with each breath. As a result, current DPIs cannot be used with infants.
According to an aspect of some embodiments, proposed devices operate on positive pressure with as little as 5-6 ml of air and can efficiently empty (emitted doses >80%) and deliver the aerosol to infant lungs (lung delivery efficiency of ˜60% of the loaded dose). Significant features that are specific to infants and differentiate the disclosed technology include: internal flow structure of the air-jet DPI, automatic gas sources, infant-specific interfaces, small diameter nasopharyngeal tubes, sealed nasal prongs, 3D rod array preceding patient interface, nasal CPAP rapid aerosol delivery system, nasal CPAP streamlined interface, multidose storage and delivery unit, and pressure sensing near the infant airways (at the nasal cannula interface).
An exemplary air jet dry powder inhaler (DPI) system for infants includes a gas source configured to deliver in a single actuation up to but not exceeding a full inhalation breath volume for an infant, a patient interface configured to form an airtight seal with one or both of an infant's nostrils, and a fixed position air jet DPI arranged inline between the gas source and the patient interface and configured to introduce an aerosol to gas from the gas source before the gas reaches the patient interface. The air jet DPI system is configured to have airtight communication with lungs of the infant when the patient interface is forming an airtight seal with one or both of the infant's nostrils and all other pulmonary orifices are closed. The air jet DPI system delivers both the aerosol and the full inhalation breath volume for an infant using positive-pressure gas. The full inhalation breath volume delivered may be a maximum of 100 ml or less. The full inhalation breath volume may be a maximum of 10 ml or less. The total air space volume (the dead space) of the air jet DPI system may be 5 ml or less. A total air space volume of the air jet DPI system may be 2 ml or less. The total air space volume may be determined from air jet inlet orifice (capillary) through to the end of the patient interface, so parts would include the aerosolization chamber, outlet capillary, and patient interface. The gas source is configured to deliver full inhalation breath volume for an infant to the patient through the patient interface in one second or less. The system may comprise a bend in flow path downstream of the air jet DPI of 10° to 45°. The system may further include a drying chamber and a one-way valve configured for admitting air from the environment into the air jet DPI system when the gas source volume is expanding.
An exemplary gas source may include one or more hand actuated syringes. The one or more hand actuated syringes may comprise one or more springs. Another exemplary gas source may be a compressed gas source. The gas source may be a bank of gas syringes compressible prior to actuation. The gas syringes may be individually actuatable.
An exemplary patient interface may have a gradually expanding interior over a length of 40-80 mm. The patient interface may include a nasopharyngeal tube.
An exemplary air jet DPI may comprise an elongate aerosolization chamber with a longitudinal axis and one or more inlets and one or more outlets 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 no more than 25%) of the aerosolization chamber.
An exemplary patient interface may include a 3D rod array arranged such that an aerosol jet entering the patient interface must pass through the 3D rod array before exiting the patient interface. The 3D rod array comprises a plurality of rows of rods which extend between opposite walls of a lumen of the patient interface. The exemplary 3D rod array spans less than an entire cross-sectional distance length of the lumen between the at least one inlet and the one or more exit orifices in a direction perpendicular to a long axis of the rods of the 3D rod array. The 3D rod array is spaced 0 to 5 mm (or 1 to 2 mm) away from the at least one inlet orifice along a primary flow axis of the lumen.
An exemplary gas source for an air jet dry powder inhaler (DPI) usable with infants comprises a barrel sized to retain 100 ml or less of gas (the barrel having an exit orifice at one end), a rod, a piston and gasket sealing an end of the barrel opposite the exit orifice and moveable by the rod to change an internal volume of the barrel by driving gas into or out of the exit orifice, a handle piece configured such that the rod, piston, and gasket are moveable a maximum displacement to deliver a predetermined volume of air through the exit orifice using a single squeeze.
An exemplary multidose storage and delivery unit (MDU) for dosing dry powder into an air jet dry powder inhaler (DPI) comprises a main body sized to accommodate 100 mg or less of powder and configured to attach in an airtight manner to an aerosolization chamber of the air jet DPI and a release mechanism for releasing predetermined doses from the main body into the aerosolization chamber of the air jet DPI upon satisfaction of a predetermined condition. The main body may be divided into compartments, each compartment accommodating a separate dose of the powder. The release mechanism is a rotatable retaining disk, and wherein the predetermined condition is a rotation of the retaining disk. Alternatively the release mechanism is a mesh or plate containing one or more small openings sized to limit or prevent passage of powder solely under the force of gravity, and the predetermined condition is a change in air flow or pressure at the one or more small openings.
An exemplary aerosol delivery system for infants may comprise a tubing for transporting a continuous positive airway pressure (CPAP) air supply; nasal prongs sealable with an infant's nostrils; at least one access port along the tubing next to the nasal prongs, the at least one access port comprising a temporarily removable cover and a receiving part, and the at least one access port being sized to allow passage of an aerosol delivery prong into a lumen of the tubing. The receiving part is sized to form an airtight seal with an end of the aerosol delivery prong which puts the delivery prong in fluid communication with at least one of the nasal prongs and the infant's airways.
Another exemplary aerosol delivery system for infants may comprise a tubing for transporting a continuous positive airway pressure (CPAP) air supply and one or more nasal prongs sealable with an infant's nostrils, wherein the one or more nasal prongs are in fluid communication with a lumen of the tubing and a conduit connecting with a single access port independent of the tubing to which an aerosol delivery prong is connectable. The conduit between the access port and the one or more nasal prongs allows the one or more nasal prongs to remain open. The conduit between the access port and the one or more nasal prongs is configured to deliver aerosol to the one or more nasal prongs with no sudden changes in flow direction. The conduit has an S-curve shape. The conduit has a total air volume of 0.5 ml or less.
According to an aspect of some embodiments, CPAP nasal prongs contain partial flow passages and a closable access port leading to the nasal prongs. When the surfactant-aerosol delivery prongs are not inserted, gas flow passes through the partial flow passage opening and into the nasal cannulas as usual. When the surfactant-aerosol delivery prong or prongs are inserted through the closable access port, an airtight flow passage is created between the air-jet DPI and the infants nasal airways while the nasal-CPAP prongs remain in place but the CPAP flow is temporarily bypassed. The temporary passage is used to deliver both aerosol and ventilation breaths to the infant for the period of surfactant-aerosol delivery, which is typically 1 to 5 breaths. Once the surfactant-aerosol is delivered, the delivery ports are removed, the access port is closed and nasal CPAP administration is resumed. Similar interfaces may be used which enable delivery through a nasal mask interface.
The DPI system 100 comprises the following components: a gas source 101, a drying chamber 111, a one-way valve 112, an air-jet DPI 102, and a patient interface 107. To administer an aerosol, gas (e.g., air) moves through these components in the ordered listed, left-to-right in
Operation of an exemplary DPI system 100 may be as follows. The air source is pre-filled and, if applicable, pre-compressed. Powder is loaded, e.g. as a capsule or a dose unit, in the DPI. The system 100 is then effectively sealed from the environment except for the outlet of the patient interface. The patient interface is then positioned with respect to the patient, e.g. prong is inserted in a nostril to achieve an airtight seal. If the patient interface has only a single nasal prong, the user of the system 100 closes the infant's remaining pulmonary openings, namely the other nostril and mouth. The closure is preferably just after exhalation nostril flair from the infant. Immediately after the system 100, in particular the gas source, is actuated. The system 100 delivers a volume of air corresponding with a full inhalation breath in addition to aerosol entrained by the gas. Then the user holds for 5-10 seconds. Next the infant's second nostril (or and/or mouth) is opened for a period of time allowing the infant several normal breaths. Then, the steps of closure of extra nostril (if applicable) and mouth, actuation, and hold are repeated. This cycle may be repeated 3-5 times to deliver the full dose desired. If the patient interface comprises two prongs, the interface may include an exhalation port to be used for ease of opening and closing the infant's free breathing between actuations.
The total air space volume (the dead space) of the air jet DPI system may be 5 ml or less (excluding the volume of the air source, which can be variable). A total air space volume of the air jet DPI system may be 2 ml or less. The total air space volume may be determined from air jet inlet orifice (capillary) through to the end of the patient interface, so pertinent parts would include the aerosolization chamber, outlet capillary, and patient interface.
While the listed components in
Aerosol leaving the DPI 202 enters the patient interface 207 which may include but is not necessarily limited to a nasal cannula. An important aspect of the infant air-jet DPI system 200 is that the nasal interface 207 is configured to form an airtight seal with one or both of the patient infant's nostrils. Airtight communication with the infant's lungs is important such that with a single-prong interface the other nostril is preferably held closed. The infant's mouth is also required to be held closed, either manually or with a chin strap as commonly used during infant respiratory support with nasal interfaces. The cannula of the patient interface 207 may have a gradually expanding interior such that an inlet diameter of e.g. 0.9 mm grows gradually to an outlet diameter of e.g. 3 mm over a length of 40-80 mm. Exemplary patient interfaces 207 include single-prong nasal interfaces as well as dual-prong nasal interfaces. According to the embodiment shown by
Care is taken where separate parts are joined or where the system is intended to be opened by a user to ensure a generally airtight system when administering an aerosol.
The exemplary infant air-jet DPI systems 100 and 200 deliver both the aerosol and a full inhalation breath to the infant in a short amount of time (typically <1 sec for inhalation) and can be used to maintain a short breath hold. The use of positive pressure to deliver the aerosol and inhalation breath better expands the flexible upper airways and may enable deeper than tidal volume inhalation and improved lung penetration of the aerosol. As with manual ventilation with a bag and mask interface, this approach may also help to open closed or obstructed lung regions, further increasing the reach of the inhaled aerosol.
Delivered gas to form the aerosol and support infant respiration depends on infant weight with a typical range of 6-8 ml of gas per kg of infant body weight (i.e., 6-8 ml/kg). For a preterm infant weighting 1600 g, potential delivered gas volumes would range from 10 to 13 ml with a preferred value of approximately 10 ml. For a full-term infant weighting 3550 g, potential delivered gas volumes would range from 21 to 28 ml with a preferred values of approximately 21 ml. In both cases the targeted value was selected as the lower end of the range to prevent lung volutrauma; however, slightly higher values within the range may be preferred by the physician to better open the airways and prevent lung collapse and reopening (cyclic atelectasis), which is also a source of lung injury. Hence, it is important for the administering physician to have precise control over the amount of air delivered to the infant and that this air volume can be adjusted depending on the lung injury and specific case being treated. The lower end of delivered gas volume to extremely preterm infants would be 4-5 ml and the upper end to much older infants suffering acute respiratory distress may be as high as 100 to 200 ml.
For infant air-jet DPI systems such as those of
A volume limiter 311, which may include one or both of a maximum volume limiter knob 312 and a minimum volume limiter knob 313, is arranged to limit the displacement of the hand grip 308 from the body 309 rotationally about the axis of hinge 310. A shaft 318 of the volume limiter passes freely through a hole in a stop 319 of the body 309. The hole in the stop 319 is sized to allow passage of the shaft 318 but not of the limiter knobs 312 and 313. The volume limiter 311 effectively sets maximum and minimum displacements of the rod 302 within the barrel 314. The piston 301 is fixedly connected with the rod 302, and the gasket 303 is fixedly connected with the piston 301, such that all three components 301, 302, 303 move together and are limited together in maximum displacement within the barrel 314 by the volume limiter 311. The knobs 312 and 313 are slidable along the shaft of the volume limiter 311 via a rotational motion exerted by a user to vary the maximum and minimum volumes of air space 304. The barrel may be sized to retain up to 100 ml, or 100 ml or less, of gas to accommodate most infants. Infants are classified as 2 years old and under. For example, given a max infant weight of 15 kg at 2 years*6 ml/kg=90 ml delivery may be desired.
A volume position indicator 315 gives a user a clear readout of the current volume of air space 304 based on the current setting of the maximum volume limiter knob 312. The volume position indicator 315 comprises first indicia 316 which represent respective volume levels, e.g. 0 ml, 10 ml, 20 ml, and 30 ml. The first indicia have fixed positions with respect to the body 309 and barrel 314 housed by the body 309. A second indicium 317 has a fixed position with respect to the handle grip 308 and moves with respect to the first indica 316 whenever the handle grip 308 moves with respect to the body 309. Prior to the application of any external force by a user to handle grip 308, the spring 307 causes maximum displacement of the handle grip 308 with respect to the body 309 as limited by the volume limiter 311, in particular the maximum volume limiter 312. In this configuration, the second indicium 317 will come to rest next to a first indicium 316 which conveys the present volume of air space 304 that will be delivered by the air source 300 through lumen 306 if actuated.
A user actuates the air source 300 by moving the handle grip 308 toward the body 309. This may be achieved through a one-handed squeezing action in which the user has a thumb placed on thumb grip 320 and the remainder of his or her fingers placed on the handle grip 308. It should be noted that air source 300 is depicted in a partially actuated state, as though a user is midway through a full squeeze action. This is apparent from the fact that neither of the knobs 312 and 313 are in contact with the stop 319. In a fully expanded state of the air source 300 in which a user has not applied any rotational force exceeding that of the spring 307, the knob 312 is in contact with the stop 319. In a fully compressed state of the air source 300 in which a user has applied a rotational force exceeding that of the spring 307 and displaced the hand grip 308 a maximum distance toward the body 309, the knob 313 comes into contact with the stop 319. In embodiments that do not include a minimum volume limiter knob 313, the handle grip 308 itself may reach and contact the stop 319.
A volume limiter 411 comprises a maximum volume limiter knob 412 and a threaded shaft 418. The knob 412 is fixed to the end of the shaft 418. The shaft 418 passes through a threaded hole 426 of the body 409. Rotation of the knob 412 by a user displaces the first moving pivot 421 along the axis of the shaft 418 (left or right according to the orientation in
A user actuates the air source 400 by moving the handle grip 408 toward the body 409. This may be achieved through a one-handed squeezing action in which the user has a thumb placed on thumb rest bar 420 and the remainder of his or her fingers placed on the handle grip 408. A minimum volume limiter 413 may be included in some embodiments. The minimum volume limiter 413 has a variable length and extends between the handle grip 408 and the body 409. The minimum volume limiter 413 sets a minimum displacement between the handle grip 408 and body 409 which, in turn, sets the lower limit of volume for air space 404.
In either of the modes depicted by
In some of the above mentioned air sources, a user is required to physically impart energy on the air source to actuate the air source. The user's role may be substituted with one or more small motors which can be activated electronically by a controller such as a computer or microprocessor. In some embodiments pneumatic actuation or electromechanical actuation (e.g., a syringe pump) may be used. In for example pneumatic actuation, a pneumatic actuator replaces the hand and lever mechanism in
The outlet flow passages (right-hand-side of each of
When the infant air-jet DPI is in use, the inlet flow passage is held in the horizontal position with respect to gravity and with the infant lying in the supine position. This orientation forms a bed of un-aerosolized powder on the floor of the aerosolization chamber prior to actuation. The complete internal flow passage of the air-jet DPI is required to curve through an angle of e.g. 10° to 45° for the nasal interface to correctly fit and seal with the infant's nostrils (see, e.g., exemplary bend of 37° in
Briefly, exemplary air-jet DPIs behave as follows. A high velocity jet of air enters the aerosolization chamber, expands creating secondary velocities, and exits through the outlet orifice. The inlet and outlet orifices are typically aligned. The inlet air jet does not impinge on the initial bed of powder. Instead, secondary velocities initially form the aerosol. Typical operating conditions for an infant are 3 to 30 ml of actuation air for infants, but may be as low as 0.3 ml for animals, or higher than 30 ml for larger infants and children (but a unique challenge is good performance with low air volumes). Diameter of inlet flow passage may be 0.3 to 1 mm; preferred for some embodiments is 0.5 to 0.6 mm. Diameter of outlet flow passage: 0.5 to 1.2 mm, or 0.6 to 1.17 mm; preferred for some embodiments is 0.89 mm.
Each compartment 703 is filled with a defined powder mass or deliberately left empty, depending on the amount of dosing desired for a particular patient. The powder mass may be equal among chambers (e.g., 10 mg), or it may vary, e.g., increase with each actuation. Rotation of the dose release selector 704 doses one or more masses of powder 706 to the aerosolization chamber 701 prior to inhaler actuation. Increasing the powder mass with each actuation may be beneficial if initial actuations have very limited air volumes to remain below safe delivery pressures due to non-compliant infant lungs associated with respiratory distress and surfactant dysfunction. As surfactant powder is delivered, the lungs become more compliant allowing for larger air volumes to be safely delivered, which can more efficiently aerosolize larger powder masses. The first compartment to be actuated may be deliberately left empty. This enables an administering clinician to ensure that good fluid communication is established with the patient's lungs prior to delivering the first dose of powder from a subsequent compartment of the MDU 700. For very small infants, only one or two compartments may be loaded delivering 10-30 mg of powder in total. For full term or larger infants, 7 or more chambers may be loaded, delivering 70 mg or more of total powder.
A rotatable retaining disk 705 is positioned at a bottom of the MDU 700 with an opening or openable door sized to match one of the compartments 703. In the case of
Each of the patient interfaces 900, 1000, 1100, and 1200 further comprises a receiver port 901 configured to receive an upstream portion of the air-jet DPI system (e.g., refer back to systems 100 and 200 of
Referring now to
Generally, a 3D rod array 903 may be characterized by a plurality of rows each of which has a plurality of unidirectional rods disposed within a flow passage of an inhaler and spaced apart along a primary direction of air flow in the flow passage. A primary direction of air flow in the flow passage may be described as a longitudinal direction or z-direction of the flow passage. Successive unidirectional rows in a primary direction of air flow may or may not lie on the same line and are preferably staggered. This generally means that the rods of a first row in a first x-y plane of the flow passage and the rods of a second row in a second x-y plane of the flow passage are not in direct alignment with each other in the z-direction. The rows are preferably parallel to one other, and the rods are generally parallel to one another. In a preferred embodiment the rods in the second x-y plane are offset by 1-99% (most preferably 50%) from the rods in the first x-y plane such that air flowing (generally with increased velocity) between two rods of the first row in the first plane impacts on one or more rods (preferably the centers of the rods) of the second row in the second plane. In a preferred embodiment, all the rods of the plurality of rows of a 3D rod array are oriented in a same direction.
The 3D rod arrays 903 and 1103 dissipate the turbulent air-jet leaving the inlet orifice 904 or 1104 from the air-jet DPI. The 3D rod arrays may also deaggregate the powder agglomerates in the aerosol. Dissipation of the air-jet prevents impaction of the aerosol in the patient interface and/or in the infant nostrils. Exemplary 3D rod arrays may be configured to allow aerosol penetration with less than 10% depositional loss of the aerosol by mass. It can be seen in the figures that exemplary 3D rod arrays need not extend wall-to-wall in a direction perpendicular to a long axis of the rods. The percentage of linear distance to the interface side-wall occupied by the rod array may be 5-50%, more preferentially, 10-30%, more preferentially approximately 15%. While more rods can be used, this minimized approach achieves the desired functional advantages while minimizing the cost associated with many rods. The distance from the capillary outlet to the nearest row of rods may be 0 to 5 mm, generally better at 1 to 2 mm, with an exemplary distance being 1.25 mm. Rod arrays may come in different dimensions for different embodiments. For the sake of non-limiting illustration, however, the following are some exemplary dimensional measures. Inlet capillary diameter may be 2.39 mm. Rod diameter may be 0.5 mm. All rods may have the same diameter or, in some cases, some rods may differ in diameter from other rods. Exemplary ranges in terms of capillary diameters are 1.25 mm to 7.5 mm.
The patient interface may comprise a smooth expansion of the sidewalls in the longitudinal direction of the patient interface, from at or near the inlet orifice to the end or past the longitudinal position at which the 3D rod array ends. The widening cross-section of the patient interface in the vicinity of the rods minimizes or avoids depositional loss on the sidewalls. Said differently, expanding the sidewalls in the vicinity of the 3D rod array and in the direction of jet dispersion maintains low deposition in the patient interface.
Patient interfaces may be angled downward (according to the device orientation during use) at an angle of, for example 10-35 degrees, e.g. approx. 30 degrees, to allow the air-jet DPI system to be held level and still tightly seal to the patient nose. The angle of the patient interface with respect to a remainder of the air-jet DPI system may be achieved in the outlet capillary leaving the air-jet DPI component, an arrangement which generally produces no significant loss of powder. Example bends in air path are shown in
This Example provides data for a prototypical system 200 corresponding with
Performance of the air-jet DPI approach was considered in two stages. In a first stage, aerosolization performance of the air-jet DPI through the end of the outlet flow passage (excluding the nasal interface) was evaluated for multiple internal flow pathway designs. To determine expected aerosolization performance for full-term and preterm infant conditions, aerosolization performance was assessed for AAVs of 30 ml and 10 ml, respectively. After evaluation of aerosolization performance, a second stage of assessment was conducted to determine the penetration of the aerosol through an infant NT in vitro model. Best performing devices from the first stage experiments were connected to a gradually expanding nasal interface which was then inserted (˜5 mm) into a single nostril of a full-term infant NT model ending with a tracheal filter. For evaluation with the full-term NT model, air-jet DPIs were actuated with 30 ml of air. Aerosol deposition on the tracheal filter was taken as an approximation of lung delivery. In this Example, aerosol delivery through a preterm NT model was not assessed due to the limited amount of actuation air (10 ml) in comparison to the size of the tracheal filter housing (30 ml). Aerosol delivery with the full-term AAV of 30 ml is likely to penetrate through the filter housing and reach the filter substrate due to an airflow jet effect leaving the trachea.
It is noted that in vitro assessment of lung aerosol delivery frequently includes cyclic respiration of the model subject over an extended period of time. This aspect of the experimental setup is not realistic in evaluation of the air-jet DPI, because the subject's breath is delivered by the positive pressure actuation of the device, much as it would be when using a manual ventilation bag. The device is actuated rapidly, with actuation times <1 sec, and leaving the device in place for a brief period is used to facilitate a breath hold. Furthermore, because the device is operated with a manual syringe filled with air, exhalation into the aerosolization chamber of the device (which could degrade powder performance) does not occur.
The aerosolization chamber had the size zero capsule volume of 0.68 ml; however, the capsule was not included in the prototype as the device was pre-loaded. The inlet and outlet flow passage diameters had values of 0.6 mm and 0.9 mm, respectively.
The six air-jet configurations of
The air-jet DPI designs of
After initial aerosolization experiments, the lead air-jet DPIs were connected to an initial nasal interface design for aerosol delivery testing through the infant NT geometry. The nasal interface consisted of a straight gradually expanding circular cross-section. The design of the nasal interface with a length of 63 mm was based on computational fluid dynamics predictions that indicated a gradual expansion geometry could effectively slow the high-speed jet leaving the DPI with minimal aerosol loss and achieve the target outlet diameter of 4 mm for aerosol delivery to the infant nose. Dimensions of the nasal interface outlet section were based on a Hudson RCI Size No. 4 nasal CPAP cannula (Teleflex Medical, Research Triangle Park, N.C.) for a full-term infant. Resulting nasal interface inner and outer diameters at the outlet tip were 4 and 5.5 mm, respectively. A gradual exterior taper was included at the outlet of the nasal prong to help form an airtight seal with the infant's nostril. During aerosol delivery through the NT model, the single-prong nasal interface was inserted approximately 5 mm into one nostril and the other nostril was held closed.
To test aerosol delivery efficiency to the lungs, administration was considered through a full-term NT airway model beginning at the nostrils and passing through the pharynx, larynx, and ending with a filter (Pulmoguard II, SDI Diagnostics, Easton, Mass.) at the start of the trachea. In this Example, the full-term NT model and delivery conditions were selected for a newborn infant with weight and height of 3550 g and 49.5 cm, respectively. Two methods that produced average age-appropriate depositions were achieved by scaling based on subject height or the DV/As parameter. The DV/As parameter is defined as the airway's volume divided by its surface area. However, since DV/As is not known beyond the two points reported, scaling based on infant height is a reasonable approach. Average age-appropriate height data is readily available from growth charts and can be used for a scaling parameter. A number of studies have shown that subject height can be used as a parameter for scaling airway dimensions. A high-quality NT geometry of a 6-month-old infant that provided nasal airway deposition consistent with mean values was used. Based on infant body length (height) the appropriate geometric scaling factor to reduce this model to that of a new-born infant was 0.73. The resulting full-term newborn NT model employed in this Example had a volume of 3.6 ml and a nasal DV/As of 0.94 mm.
The best characteristic length scale for collapsing impaction data to a single curve was DV/As i.e., the DV/As parameter is a good indicator for predicting age-appropriate nasal deposition. Since the full-term NT model employed in this Example has a DV/As similar to other neonate models of the same age, the scaled NT model used is considerable a reasonable representative of full-term nasal conditions.
In order to provide a smooth and accurate internal airway surface, the middle passage and throat sections of the infant NT model were built using stereo-lithography (SLA) with Accura ClearVue resin through 3D Systems On Demand Manufacturing, resulting in a rigid model. To facilitate nasal interface prong insertion and the formation of an airtight seal, the anterior nose was constructed in flexible Agilus Translucent 30-A material, also using SLA from 3D Systems. During experimental testing, the separate regions were securely connected with a paraffin film lining and a small amount of lubrication on the interface surfaces to ensure an airtight seal.
For each device tested, differences in air-jet design geometry led to different resistances that in turn alter the flow rate during actuation. Actuation was performed by hand after filling the 60 ml syringe (serving as the positive pressure gas source) to the desired AAV (either 10 ml or 30 ml) with room air and connecting to the device with a luer lock adapter. Quantification of the average flow rate for each device was performed using a pressure sensor (SSCDLNN040MBGSAS, Honeywell, Sensing and Control, Golden Valley, Minn.) affixed perpendicular to the outlet flow channel before the nasal interface. Pressure recordings (Sensor Evaluation Kit, Honeywell, Honeywell Sensing and Internet of Things, Fort Mill, S.C.) were taken at 500 samples/second. The pressure profile of the actuation was used to calculate average flow rate based on the fixed AAV and elapsed time. Elapsed time was determined by the number of samples with a pressure reading over a set threshold recoded during actuation, where the threshold was set to double the baseline pressure value.
The tests used 10 mg of AS-EEG powder formulation (manually weighed) and a Next Generation Impactor (NGI; MSP, TSI Incorporated, Shoreview, Minn.) for aerosol particle size analysis. After weighing, the powder mass was poured into the inlet half of the air-jet DPI, which was then assembled and sealed with a twisting motion. To assess the aerosol size distribution, the air-jet DPI (without the nasal interface) was attached to the pre-separator inlet of the NGI using a custom adapter. This adapter positioned the outlet of the air-jet DPI one cm away, perpendicular from the center of the pre-separator inlet with open space allowing for co-flow room air to enter the NGI, which was operated at a flow rate of 45 LPM using a downstream vacuum pump. Room temperature and relative humidity were recorded for every run and found to be between 21-24° C. and 20-40%, respectively. The NGI was positioned 53° off horizontal to allow the device to remain level during use and maintain an inline flow path from the device outlet to the NGI inlet, as it would be during administration to a supine infant. Each stage of the NGI was coated with MOLYKOTE® 316 silicone spray (Dow Corning, Midland, Mich.) to minimize particle bounce and re-entrainment. The NGI flow rate of 45 LPM was chosen to ensure collection of the aerosol, minimize any effects of settling, and provide appropriate stage cutoff diameters for evaluating small aerosol sizes. Before each set of experimental runs, the flow rate was confirmed using a flow sensor (Sensirion SFM3000, Sensirion AG, Stafa, Switzerland) connected to the NGI inlet.
Each device was actuated into the NGI via the 60 ml hand syringe at 30 ml or 10 ml AAV to compare aerosolization at full-term or preterm infant conditions. Three replicate runs for each device at each condition were performed in a randomized order. Analysis metrics included emitted dose (ED) and mass median aerodynamic diameter (MMAD). ED was calculated as the mass of AS in the loaded dose minus the mass of AS remaining in the device divided by the initial loaded mass of AS. Aerosolization calculations were based on the mass of AS recovered in the NGI. MMAD/ED was also used as a general parameter to indicate overall performance (lower values being preferable). Drug masses were determined using HPLC analysis, as described below.
Based on device assessment, the second stage of this Example used the three best performing designs for full-term NT in vitro model testing at an AAV of 30 ml. The experimental setup was the same as for device assessment in terms of device actuation, powder loading, and randomization. However, instead of the device connecting to the NGI adapter, it was connected to the gradually expanding nasal interface which was inserted approximately 5 mm into the left nostril of the infant NT model (the right nostril was manually held closed during actuation). A small amount of lubrication was applied to the exterior of the prong to ensure and airtight seal. All NT model segments were internally coated with silicon spray to minimize particle bounce similar to airway surface liquid. At the end of the NT model, a respiratory filter (Pulmoguard II, SDI Diagnostics, Easton, MA) collected powder passing through the extrathoracic regions and represented the amount of drug delivered to the lung. After aerosol delivery, the nose was held closed and the syringe was not disconnected for 10 seconds to help aid in the capture of all particles. In practice, a breath-hold such as this would help prevent drug loss during expiration as the EEG particles significantly increase in size through hygroscopic growth. Calculations for ED and regional deposition, including the nasal interface and in the NT model and tracheal filter (amount deliver to lung) were expressed as a percentage of the loaded dose of AS.
After actuation and aerosolization, drug masses retained or collected in the air-jet DPI and NGI or nasal interface, NT model, and filter were recovered by dissolving in an appropriate volume of deionized water followed by high performance liquid chromatography (HPLC) analysis. The loaded drug mass was determined through content uniformity analysis of the AS-EEG formulation; where known masses of AS-EEG were dissolved in water and the AS content (μg/mg of formulation) was determined. AS quantification was performed for each deposition site and for the drug mass used to calculate the drug recovery. Drug recovery percentage was expressed as the amount of AS recovered on all deposition sites divided by the loaded AS dose for each experiment.
Based on an airflow rate of 45 LPM, the NGI stage cut-off diameters were determined using the formula specified in United States Pharmacopeia (USP 35) (Chapter 601, Apparatus 5). The MMAD was calculated through linear interpolation between appropriate stages using a plot of cumulative percentage drug mass vs. cut-off diameter.
In preliminary experiments prior to device testing with the NGI and infant NT model, primary particle size of the AS-EEG powder formulation was determined by laser diffraction using the Sympatec HELOS (submicron R1 lens with 20 mm focal length) with RODOS/M disperser at 4 bar, and ASPIROS sample feeder set to 60 mm/sec (Sympatec GmbH, Clausthal-Zellerfeld, Germany). Three consecutive samples were tested on the same day. Testing at the high pressure of 4 bar is intended to show maximum particle dispersion. This primary particle size then serves as a benchmark to evaluate the aerosolization efficiency of the air-jet DPI, which is operated with 1000×-10,000× less pressure.
Statistical analysis for comparing aerosolization performance across all devices and comparison of device performance at different AAVs was performed using JMP Pro 15 (SAS Institute Inc., Cary, N.C.). Comparison of device performance utilized one-way ANOVA followed by post hoc Tukey. Comparison of preterm vs. full-term AAVs for each device were performed with the Students t-test. All statistical tests used a significance limit of P=0.05.
The AS-EEG formulation was characterized as having a mean (SD) geometric diameter of 0.99 (0.0) μm. In order to compare laser diffraction primary particle size to the air-jet DPI performance, the geometric size (measured with laser diffraction) was converted to an aerodynamic diameter using a theoretical solid particle density of 1.393 g/cm3 (based on weighted particle densities of the formulation components).
Time-averaged air flow rates were determined for each device actuated by hand six times, with the mean (SD) results reported in Table 2 for an AAV of 30 ml.
ap < 0.05 significant effect of device design on each of the individual reported parameters (one-way ANOVA).
Aerosolization metrics in terms of ED and MMAD for full-term and preterm AAVs of 30 ml and 10 ml are presented in Tables 2 and 3, respectively. Surprisingly, all devices tested produced an aerosol MMAD below 2 μm at both AAVs. ED values were also relatively high with multiple devices emptying over 85% of the loaded dose. The highest ED values were from designs D5 (94.1%) and D1 (88.1%) actuated with 30 ml of air. Choosing best device performance based only on aerosolization metrics is difficult as increasing ED is often associated with increasing MMAD, which may have a net negative effect on aerosol delivery to the trachea and lungs. A potentially useful metric is MMAD/ED, where lower values are desirable and expected to improve aerosol delivery to the lungs. For both AAVs, the lowest three values of MMAD/ED were provided by designs D5, D6, and D2 (using full-term AAV conditions the MMAD/ED values were 0.0198, 0.0200, and 0.0210, respectively). Examining Table 2 for the 30 ml AAV, it was observed that there were statistically significant differences among the different device designs for each aerosolization performance parameters. For the MMAD/ED metric, D4 design with the highest value MMAD/ED was observed to be significantly different to both designs D5 and D6, with the two lowest MMAD/ED values (post hoc Tukey: P=0.003 and 0.006, respectively).
ap < 0.05 significant effect of device design on each of the individual reported parameters (one-way ANOVA).
To assess overall DPI performance, it is useful to graph MMAD vs. ED, as shown in
ap < 0.05 significant difference between 10 & 30 ml AAV (Student’s t-test)
Best performing devices D2, D5, and D6 were connected to the gradually expanding nasal interface and tested for aerosol delivery through the full-term NT model at an AAV of 30 ml. Deposition fractions in each region of the delivery system and NT model are displayed in
Surprisingly, results showed that depositional losses in different regions tend to provide similar total values leading to a narrow range of 48-53% lung delivery efficiency. Reasons for similar lung delivery efficiencies across the three devices tested can be further explored in
ap < 0.05 significant effect of device design on deposition (one-way ANOVA)
The new infant air-jet DPI prototypes tested in this Example achieved performance metrics of >80% ED, MMAD <1.8 μm, and a lung delivery efficiency of approximately 50% of device loaded dose. In assessing the air-jet DPI designs, two distinct sets of devices were identified based on aerosolization performance. Designs D2, D5, and D6 were found to produce a superior combination of MMAD and ED (based on MMAD/ED and linear best-fit lines) than the remaining three devices. Common design features of the three best performing air-jet designs were a cylindrical and horizontal aerosolization chamber together with a flush or protruding outlet. Designs that also included multiple inlets (D5 and D6) achieved the best aerosolization metrics of approximately >80% ED and MMAD <1.8 m, whereas D2 with a single air inlet did not. Nevertheless, when tested in conjunction with a gradually expanding nasal interface design and infant NT model, all three lead designs achieved approximately 50% drug delivery to the lungs. Furthermore, it is expected that the lung delivery efficiency can be increased beyond 50% by improved regulation of the input flow profile and by inclusion of a 3D rod array in the nasal interface to better dissipate the turbulent jet and further deaggregate the aerosol entering the nose, thereby further reducing the aerosol MMAD and reducing the nasal deposition fraction.
The D5 design appears to perform better than previous devices with an ED of 94% and small aerosol size increase to 1.85 μm. As a result, this Example indicates that air-jet performance was enhanced through the development of an aerosolization chamber with multiple inlets and a flush or protruding outlet.
Despite significant variation in the best performing devices (D2, D5, and D6 with an ED range of 75.6-94.1%), in vitro lung delivery efficiency was consistently around 50% using the full-term NT geometry. As described, the D2 design provided excellent NT penetration with only 8.0% depositional loss, but relatively poor emptying with ED of 75.6% (71.6% when connected to the infant NT model). Increasing the device emptying also increased the MMAD, which led to a significant depositional loss in the NT model. An exemplary device for infant N2L aerosol delivery therefore appears to be one that can achieve an MMAD of 1.6 μm and ED near 95%.
Intended uses of the infant air-jet DPI include the rapid administration of high dose inhaled medications such as aerosolized antibiotics and surfactants. For either of these applications, total doses higher than the 10 mg loaded dose employed in this study will likely be needed. The aerosolization chamber in the current study has a total volume of 0.68 ml, which if approximately half full can accommodate 40-50 mg of powder based on typical EEG powder density. An alternative to accommodate higher total dose loading may be an auto-loading system for the air-jet DPI such that each actuation delivers a 10 mg dose of powder formulation.
As demonstrated in this Example, the infant air-jet DPI is expected to provide a number of advantages for aerosol delivery to infants of all ages. First, device actuations of 10 ml and 30 ml require time periods between 0.2 and 1.0 s. The devices tested performed very similar at both AAVs in terms of aerosolization performance. Therefore, the only reason to implement the higher AAV for the older full-term infant is to provide a full inhalation breath. This air volume can be reduced to accommodate stiff or non-compliant lungs as needed. By operating the delivery system with positive pressure, it is expected that the highly flexible infant upper airways will be expanded, enabling better deep lung penetration of the aerosol. In the current Example an enforced breath hold of 10 s was implemented; however, this length of time is not needed for aerosol retention as EEG aerosols approach their fully hydrated droplet size within approximately 0.5 to 1 s under infant airway conditions. Nevertheless, under resuscitation conditions, infant lung inflation followed by a 10 s breath hold improves lung mechanics and patient outcomes compared with standard rapid ventilation with a bag and mask. With a single-prong design, infant exhalation can be accomplished by releasing the nostril without the nasal interface. For a dual-prong design, an exhalation port is included in the nasal interface close to the patient. Opening of the exhalation port can be automated with a single button on the device that also controls actuation of the air source.
The in vitro NT model employed in the current Example has several differences from in vivo conditions that should be considered. As described previously, the air-jet DPI delivers both the aerosol and a full inhalation breath such that cyclic breathing of the model is not required. However, more realistic airway delivery conditions need to include the downstream resistance and compliance of the lungs. The effect of this resistance and compliance on aerosol generation is expected to be small considering the relatively low ventilation volumes (7-8 ml/kg) that are employed. Furthermore, the airway walls were not warmed and humidified to physiologic conditions. It is known that some size increase of hygroscopic aerosols occurs in the nose. However, this aerosol size increase in the extrathoracic region is small with an associated negligible increase in NT deposition (<5% relative difference) for adult airway conditions. The air-jet DPI forms a closed system with the airways such that subject exhalation into the aerosolization chamber containing the powder is not possible.
Variations in airflow delivery associated with hand-operation of the gas source are observed in
The nasal interface is an important source of potential aerosol loss and also influences loss in the NT model. The single gradual expansion nasal interface used in this study was the result of preliminary design work that improved upon nasal interface losses as high as 40% of the loaded dose. While 10% nasal interface depositional loss is acceptable, it is expected that this deposition can be further reduced, likely through optimization of the inlet flow profile and/or inclusion of a 3D rod array structure in the interface designed to disperse the turbulent jet and further deaggregate the powder.
Finally, this Example considered only one NT model under full-term neonate conditions. Aerosol deposition in the NT region is known to be highly variable and where the tested model falls within this spectrum is currently not known.
In conclusion, this Example tests a prototype air-jet aerosol delivery system to administer high doses of spray-dried powder formulations to infants. The patient interface is a simple gradually expanding flow passage that produced low depositional loss and device actuation times are in a range between 0.2 and 1.0 s. Delivery efficiency of drug to the lungs was approximately 50% of the loaded dose across the three best performing devices. Advantageous design options in the air-jet DPI were identified as a horizontal and cylindrical aerosolization chamber, flush or protruding outlet, and multiple inlets.
Intended applications of exemplary infant air-jet DPIs and DPI systems are the delivery of higher dose inhaled medications where efficacy can be increased with improved lung and deep lung targeting, and where reduced inter- and intra-subject variability is important. Potential candidate medications include inhaled antibiotics, growth hormone, anti-virals, gene therapies for lung diseases, bronchodilators and corticosteroids for asthma management, surfactants, clearance agents, insulin, and anti-inflammatories.
It is to be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to be limiting, since the scope of the present invention will be limited only by the appended claims.
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.
As will be apparent to those of skill in the art 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.
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.
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.
This invention was made with government support under Grant Numbers R01HD087339 and R01HL139673 awarded by the National Institutes of Health. The US government has certain rights in the invention.
| Filing Document | Filing Date | Country | Kind |
|---|---|---|---|
| PCT/US21/14604 | 1/22/2021 | WO |
| Number | Date | Country | |
|---|---|---|---|
| 62964208 | Jan 2020 | US |
