Oscillating jet devices and methods for targeted nasal delivery of aerosols

Abstract

Embodiments provide targeted delivery of powder medications (high and low dose) within the nose and to different nasal regions. Oscillating jet technology provides a unique approach to minimize hotspot formation and the associated irritation associated with high powder mass applications together with improved posterior surface area coverage and improved drug absorption for locally acting or systemically and neurologically targeted medications.

Description

[0001] OSCILLATING JET DEVICES AND METHODS

[0002] FOR TARGETED NASAL DELIVERY OF AEROSOLS

[0003] CROSS-REFERENCE TO RELATED APPLICATIONS

[0004] This application claims the benefit of U.S. Provisional Patent App. No. 63 / 707,377, filed October 15, 2024, the complete contents of which are herein incorporated by reference.

[0005] FIELD OF THE INVENTION

[0006] Embodiments of the invention generally relate to aerosol inhalers and, more particularly, devices and methods especially suited to nasal-targeting of pharmaceutical aerosols past the anterior nose.

[0007] BACKGROUND

[0008] Dry powder pharmaceutical formulations have become increasingly popular for nasally targeted administration. Aerosol devices and products designed to administer nasally targeted dry powder aerosols typically involve a high velocity jet of aerosol and actuation gas with a defined plume angle that enters the nose. Large particle aerosols are used which have typical aerodynamic diameters in the range of 50 pm and above. The combination of the high velocity spray plume and large particles results in straight line deposition of the aerosol along linear trajectory paths. The resulting deposition profile has poor penetration through the anterior nose and nasal valve and produces deposition in highly concentrated areas. High concentrations of aerosol deposition results in poor dissolution and uptake prior to mucociliary clearance and swallowing; poor surface area coverage of the nasal surface; the potential for nasal irritation (in areas of drug hotspot formation) and limited dissolution and absorption of the therapeutic. SUMMARY

[0009] Embodiments provide an aerosol delivery platform for administering nasally targeted dry powder (or liquid spray droplet) aerosol therapeutics that is capable of overcoming many of the current challenges of existing platforms and achieving advantages such as but not limited to the following: i. High efficiency deposition in the posterior nasal regions ii. Targeted delivery within the posterior nasal regions including the upper, middle or lower posterior regions and / or nasopharynx (NP) and nasal sinuses iii. Improved surface-area coverage and / or more uniform dose distribution across the posterior nasal region or within specific regions iv. Reduced formation of hotspots of aerosol deposition v. Use of relatively small and intermediate size aerosols for nasal applications and manually actuated nasal systems (spray pumps and dry powder insufflators) vi. Improved nasal absorption and reduced clearance of the therapeutic vii. Ability to administer high dose powders more efficiently and to both nostrils with one device loading viii. Limited dose delivery of loaded powder with each device actuation and multiple actuations for full dose delivery

[0010] Some exemplary embodiments include delivery of medications (e.g., anti-inflammatory medications; antibiotics, antihistamines, etc.) to treat nasal conditions. Some exemplary embodiments include delivery of medications (e.g., pain medications; drug overdose therapies; anti-seizure medications; migraine medications) through the nose to the body (needle-free with rapid onset). Some exemplary embodiments include delivery of medications (e.g., neurological therapies. Alzheimer’s therapies, antiemitics, anti-convulsants, etc.) through the nose to the brain (bypassing the blood brain barrier). Some exemplary embodiments include delivery of vaccines for respiratory viruses (e.g., influenza, COVID-19, and similar viruses). Some exemplary embodiments include delivery of aerosol medications (e.g., surface-active antibiotics, corticosteroids, regenerative therapies or chemotherapies, etc.) into body cavities. Some exemplary embodiments include delivery of aerosol medications onto the surface of the skin or onto wounds, for example surfactant / antibiotic wound coverings. Some exemplary embodiments include using small or intermediate particle size. Tn particular, exemplary methods use small particles compared with manually operated liquid sprays and conventional dry powder products. The United States Food and Drug Administration (FDA) limits the amount of dose that can enter the lungs, leading many manufacturers to use large particle sizes, since large particle sizes are less likely than small particle sizes to penetrate the airways past the nasal region. Other products typically target large particle aerosols >50 pm to minimize penetration to the lungs. By contrast, exemplary methods of this disclosure use aerosols >3 pm and < 50 pm together with an oscillating jet (and in some embodiments cyclic delivery), thereby targeting deposition in the deeper nasal regions and with improved surface area coverage without unacceptable penetration into the lungs.

[0011] Some exemplary embodiments provide a powder only platform including the advantages of very rapid drug delivery to the nasal region (e.g., 1-10 or more mg / sec) with the use of small particles, e.g., <50 pm, which cannot currently be achieved with any other technology.

[0012] Some embodiments provide a device, system, and method of aerosol delivery for targeting aerosol deposition within the posterior nasal regions.

[0013] Some embodiments include one or more of the following features: (1) multiple cycle (MC) actuation at a defined relatively low frequency (1-5 Hz or possibly higher up to 10 Hz) achieved with hand or automated actuator using a small gas volume (e.g., <1 mL or <2 mL, or 2.5 mL and up to ~4 mL); (2) nasal interface that creates a spatially oscillating jet (OJ) in a primary up and down direction relative to the patient and aligned with the long cross-sectional dimension of the nasal valve; (3) use of a relatively small or intermediate particle size for a nasal spray or dry powder product, e.g., >3 pm and <50 pm or 5-20 pm with a preference for around 10 pm; and (4) integration with an air-jet DPI and air source that enables nasal administration of low and high dose therapeutics under the defined design and delivery parameters, forming the multiple cycle oscillating jet (MC-OJ) nasal platform.

[0014] According to some embodiments, flow is characterized by rapid actuations of -0.017 sec (e.g., 1.7 mL delivered at 6 L / min), or less, followed by -0.3 sec or longer pauses.

[0015] According to some embodiments, an exemplary delivery includes multiple actuations at a specific frequency or narrow frequency range. The multiple actuations are useable to better distribute the high dose masses of powder throughout the nasal region for methods which may require mid-level or high dose masses. For purposes of this disclosure, low dose masses are, for example, <1 up to 5 mg. Mid-level doses are, for example, >5mg up to 10 mg or up to 20 mg. High doses are, for example, >20 mg. High doses may be much greater than 20 mg in some cases, e.g., up to 50 mg, up to 100 mg, or even greater than 100 mg per dose.

[0016] According to some embodiments, an exemplary method involves the use of small particles suited to nasal penetration and delivery.

[0017] According to some embodiments, an exemplary delivery includes successive actuations with partial emission (e.g., <50% of remaining mass on each actuation; or approximately 5 mg / actuation). This approach stands in contrast with delivering a maximum amount of drug with each actuation, or a full mid-level or high mass with a single actuation.

[0018] According to some embodiments, relatively low frequencies (timing of successive actuation cycles) are used for multiple cycle delivery. Between successive actuations are respective pauses which help with low velocity transport. For air sources which require refilling, the pause also serves to give time for the air source to refill or recharge between actuations. The duration of a single actuation is different from the duration of a single pause (i.e., pause period).

[0019] According to some embodiments, a delivery waveform includes rapid actuations each followed by longer pause periods.

[0020] According to some embodiments, an exemplary method has a targeted aerosol size range of >3 pm and <50 pm, or preferentially 5 - 20 pm, or more preferentially 8-15 pm, and even more preferentially ~10 pm.

[0021] According to some embodiments, an exemplary method uses an oscillating jet effect.

[0022] According to some embodiments, an exemplary system includes an air source capable of providing flow of approximately 6 L / min or a range of 3-9 L / min in rapid succession at the specified values of 0.6- 1.9 mL I actuation. The air source may be but is not limited to a multiplecycle manual (MCM) air source.

[0023] According to some embodiments, at least one exemplary flow passage is configured to oscillate an aerosol jet (or air jet) admitted to the flow passage and emit the oscillating jet at its distal end. The flow passage may be referred to in this disclosure as an oscillator. The flow passage may be referred to as a flow modulator (e.g., aerosol flow modulator if the flow contains an aerosol).

[0024] Some exemplary oscillators admit a straight (non-oscillating) jet and emit an oscillating jet. Some exemplary oscillators are configured to achieve this change without any moving parts. That is to say, such oscillators are able to make the jet oscillate by static geometries and components. Oscillation in this disclosure may also be described as whipping back and forth.

[0025] In some embodiments, oscillation of a jet is achieved by flow passage geometries that create an adequate adverse pressure gradient. The jet often primarily oscillates in a single plane.

[0026] According to some embodiments, an exemplary flow modulator or oscillator has an inlet size of -0.89 - 1.2 mm. An exemplary length is - 20 mm, or down to approximately 1 mm and up to approximately 100 mm.

[0027] According to some embodiments, an exemplary flow modulator or oscillator expands in one or more cross-sectional dimensions in the direction of flow (e.g., from the proximal / inlet end to the distal / outlet end). In addition, the height of the flow passage is significantly greater than the width. The height of the oscillator defines the plane of oscillation. The flow passage may have but is not necessarily limited to having a cross-sectional shape of an ellipse or an oval or a slot. These are exemplary cross-sectional shapes but others may be used in alternative embodiments. For instance, another alternative cross-sectional shape is a rectangle.

[0028] The flow modulator or oscillator may be a frustum. The major outlet (total) angle is >5- degrees (e.g., 8-degrees in some embodiments). The minor outlet (total) angle of <5-degrees (e.g., 3.2-degrees in some embodiments). The outlet of the flow modulator or oscillator is for some but not all embodiments an ellipse with dimensions of, for example, 5 mm x 2.5 mm (major axis x minor axis). The corresponding proximal end to such flow modulator or oscillator is for some but not all embodiments an ellipse with dimensions of, for example, 2.5mm x 1.5 mm (major axis x minor axis). This is an exemplary size for an adult subject. However, the proximal end is not an inlet in its entirety. Rather, the proximal end may be a wall with a small orifice in the wall. An exemplary inlet is a circular opening, e.g., from the end of a capillary which opens into the flow modulator in the proximal end of the flow modulator. An exemplary flow modulator oscillator includes a sudden expansion (or step) at the inlet transitioning from a circular cross section which admits a flow jet to an initial non-circular (e.g., elliptical) cross section of the oscillator.

[0029] Exemplary devices may vary in dimensions and operating parameters depending on the intended subject. Embodiments herein may be adjusted to be compatible with infants, children, adolescents, or adults. Generally, younger ages of target subject correspond with smaller nasal interfaces, smaller therapeutic doses, and smaller actuation volumes. Conversely, older ages of target subject correspond with larger nasal interfaces, larger therapeutic doses, and larger actuation volumes.

[0030] For some embodiments, assuming an adult total nasal cavity volume of 15 mL, the target delivered volume to nasal volume ratios are <1:15 or <2:15; and accounting for nasal volumes that are half as large: <1:7.5 and <2:7.5. In children and infants, these delivered gas volume to nasal volume ratios are also applied (e.g., <1:15 to <2:7.5). An exemplary flow rate range is 3-9 L / min, e.g., ~6 L / min.

[0031] For some embodiments, a preferred actuation time range is 0.004 - 0.038 sec. For some embodiments, a preferred actuation time may be 0.038 sec or less. For some embodiments, a preferred actuation time may be 0.075 sec or less. For some embodiments, a preferred actuation time may be 0.1 sec or less. For some embodiments, a preferred actuation time may be 0.2 sec or less.

[0032] Nasal cavity volumes do vary among individual subjects but follow general trends among age populations. For adult nasal volume, in particular a single nasal cavity including the nasopharynx but excluding the sinuses, the volume may be for example 15 - 17 mL. For a child nasal volume, in particular for a single nasal cavity including the nasopharynx but excluding the sinuses, the size can vary considerably depending on ages within the “child” population. Child nasal models have exemplary volumes in the range of 8 mL to 16 mL with age varying from 3 to 9 years, as a non-limiting example.

[0033] An exemplary system with an exemplary dry powder inhaler (DPI) or aerosolization engine (i.e., aerosolizer) may be configured to receive a capsule containing a dry powder. An exemplary system may be loaded with approximate size 5 through 000 capsules (volumes = 0.13-1.37 mL) holding between 3 mg - 1000 mg of powder.

[0034] For some embodiments, a capsule or other dose containment unit is placed inside the airjet DPI and closure of the device pierces the capsule forming a continuous flow pathway. Or, the air-jet DPI is built into the dose containment unit together with the nasal prong that includes the diffuser flow pathway to form the oscillating jet. Other embodiments may have yet other implementations.

[0035] Some embodiments include a nasal interface that seals to the nasal walls on its exterior. Some embodiments include rapid delivery of a therapeutic aerosol through one nostril against which the nasal interface is sealed during a breath-hold or nasal exhalation through the remaining one open nostril.

[0036] In some embodiments, dose delivery is divided among the two nasal cavities with an insertion into one nostril, multiple rapid actuations (e.g., 3), followed by insertion into the other nostril without reloading and multiple rapid actuations (e.g., 3). With each actuation, an approximate consistent amount of dose may be delivered.

[0037] Embodiments of this disclosure yield advantages for both dry powder therapeutic formulations as well as wet (e.g., wet spray; droplet) therapeutic formulations. However, where the option exists for a therapeutic to be delivered as a dry powder, dry powder aerosols are generally preferrable for embodiments of this disclosure over wet aerosols. The advantages of dry powder aerosols over wet aerosols maximize the benefits of exemplary devices and methods of this disclosure.

[0038] Within this disclosure, “air” and “gas” may be used interchangeably unless the context of use plainly says otherwise. In general, both “air” and “gas” refer to the gaseous medium used to entrain and carry aerosol particles. Such “air” and “gas” may be environmental air (conditioned, e.g., humidified or dehumidified, or unconditioned). Conversely, “air” or “gas” may be a deliberate formulation of gases (e.g., with concentrated oxygen relative the oxygen content of environmental air).

[0039] This application incorporates by reference U.S. Patent App. No. 17 / 794,660, filed 07 / 22 / 2022, and titled “DRY POWDER INHALERS AND INTERFACES FOR IMPROVED AEROSOL DELIVERY TO CHILDREN”. This application incorporates by reference U.S. Patent App. No. 17 / 794,875, filed 07 / 22 / 2022, and titled “AIR- JET DRY POWER INHALER FOR RAPID DELIVERY OF PHARMACEUTICAL AEROSOLS TO INFANTS”. This application incorporates by reference U.S. Patent App. No. PCT / US24 / 49285, filed 09 / 30 / 2024, and titled “ADJUSTABLE CHAMBER FOR IMPROVED PERFORMANCE OF A DRY POWDER INHALER WITH HIGH OR VARIABLE DOSE LOADING”. The aforementioned patent applications share inventorship with the present application and detail, e.g., exemplary airjet DPIs usable in connection with technologies of the present application.

[0040] According to an exemplary embodiment, a nasal interface includes a first flow passage configured to form an aerosol jet from air with entrained aerosol particles; a second flow passage downstream of the first flow passage, wherein the second flow passage is configured to spatially oscillate the aerosol jet from the first flow passage; and an outlet through which the oscillating aerosol jet exits the nasal interface. The first flow passage may be a capillary. The second flow passage may have a variable height and a variable width along a longitudinal axis of the second flow passage, with the variable height always exceeding the variable width. The second flow passage may be an elliptical or oval frustum. The first flow passage may be a capillary, and the second flow passage may be an elliptical or oval frustum. The nasal interface may further include a step at the juncture of the first flow passage and the second flow passage.

[0041] According to an exemplary embodiment, an aerosol delivery system may include a gas source; an air-jet DPI; and an exemplary nasal interface according to this disclosure. The gas source may be a hand actuator or automated actuator. The gas source may be a multiple-cycle manual (MCM) air source.

[0042] According to an exemplary embodiment, a method includes creating a spatially oscillating jet of dry powder aerosol or liquid aerosol; the jet oscillates primarily in one geometric plane. According to an exemplary embodiment, a method of administering nasally targeted therapeutic to a subject includes creating a spatially oscillating jet of dry powder aerosol or liquid aerosol; the jet oscillates up and down along the long cross-sectional dimension of the nasal valve of the subject. In such exemplary methods, the aerosol may be a dry powder aerosol. The jet may be formed into an aerosol by forcing air with entrained aerosol particles through a first flow passage. The first flow passage may be a capillary. The jet may be oscillated up and down by emitting the jet from the first flow passage into a second flow passage larger than the first flow passage, and the second flow passage may have a variable height and a variable width along a longitudinal axis of the second flow passage. The variable height may always exceed the variable width. The jet may be oscillated up and down by emitting the jet from the first flow passage into a second flow passage larger than the first flow passage, wherein the second flow passage is an elliptical or oval frustum. An exemplary method may further comprise aerosolizing a dry powder or liquid to form the aerosol prior to forming the aerosol into a jet. The particles of the aerosol may have a mean or median size of >3 pm and <50 pm or 5-20 pm. The aerosol may be emitted from the aerosol system having a mean or median size within the range of 5-15 pm. The aerosol may be emitted from the aerosol system having a mean or median size within the range of 8-15 pm. The aerosol may be emitted from the aerosol system having a mean or median size within the range of 8-12 m. The aerosol may be emitted from the aerosol system having a MMAD of 5-15 pm. The jet may be created using a gas volume <6 mL.

[0043] According to an exemplary embodiment, a method of operating an aerosol device includes forming an aerosol into a jet, the aerosol being a dry powder aerosol or a liquid aerosol; oscillating the jet in a geometric plane; and emitting the oscillating jet from the aerosol device. According to an exemplary embodiment, a method of administering nasally targeted therapeutic to a subject includes forming an aerosol into a jet, the aerosol being a dry powder aerosol or a liquid aerosol; oscillating the jet in a geometric plane; and emitting the oscillating jet into a nasal cavity so that the geometric plane substantially aligns with the long cross-sectional dimension of the nasal valve of the subject. In such exemplary methods, the aerosol may be a dry powder aerosol. The aerosol may be formed into a jet by forcing air with entrained aerosol particles through a first flow passage. The first flow passage may be a capillary. The jet may be oscillated up and down by emitting the jet from the first flow passage into a second flow passage larger than the first flow passage, the second flow passage having a variable height and a variable width along a longitudinal axis of the second flow passage. The variable height may always exceed the variable width. The jet may be oscillated up and down by emitting the jet from the first flow passage into a second flow passage larger than the first flow passage. The second flow passage may be an elliptical or oval frustum. The exemplary method may further include aerosolizing a dry powder or liquid to form the aerosol prior to forming the aerosol into a jet. The particles of the aerosol may have a mean or median size of >3 pm and <50 pm or 5-20 pm. The aerosol may be emitted from the aerosol system having a mean or median size within the range of 5-15 pm. The aerosol may be emitted from the aerosol system having a mean or median size within the range of 8-15 pm. The aerosol may be emitted from the aerosol system having a mean or median size within the range of 8-12 pm. The jet may be formed using a gas volume <6 mL.

[0044] According to an exemplary embodiment, a method of operating an aerosol system includes performing a plurality of aerosol cycles, each aerosol cycle including (i) creating a spatially oscillating jet of aerosol in a single actuation, wherein the jet spatially oscillates, and (ii) pausing for a first duration of time which is different than the time of the single actuation. According to an exemplary embodiment, a method of administering nasally targeted dry powder or liquid aerosol therapeutic to a subject includes performing a plurality of aerosol cycles, each aerosol cycle including (i) creating a spatially oscillating jet of aerosol in a single actuation, wherein the jet oscillates up and down relative to the subject and along the long cross-sectional dimension of the nasal valve, and (ii) pausing for a first duration of time which is different than the time of the single actuation. In such exemplary methods the aerosol cycles may occur at a frequency of 1-5 Hz. Such exemplary methods may further include performing a plurality of clean cycles, each clean cycle comprising (iii) creating a spatially oscillating jet of substantially aerosol-free air in a further single actuation, and (iv) pausing for a second duration of time which is different than the time of the further single actuation. The clean cycles may occur at a frequency of 1-5 Hz. Each actuation may use a gas volume <6 mL. Particles of the aerosol may have a mean or median size of >3 pm and <50 pm or 5-20 pm. The aerosol may be emitted from the aerosol system having a mean or median size within the range of 5-15 pm. The aerosol may be emitted from the aerosol system having a mean or median size within the range of 8-15 pm. The aerosol may be emitted from the aerosol system having a mean or median size within the range of 8-12 pm.

[0045] BRIEF DESCRIPTION OF THE DRAWINGS

[0046] Figure 1 depicts a model of the interior surface of a nasal cavity at the air-to-airway surface liquid (ASL) interface.

[0047] Figures 2A-2D are nasal models from four different adult subjects.

[0048] Figure 3A shows typical droplet or particle (spray plume) trajectory for common nasal spray and dry powder devices.

[0049] Figure 3B shows intersection of the conically oriented straight-line trajectories and nasal interior surface.

[0050] Figure 3C shows the resultant droplet or particle deposition pattern.

[0051] Figure 4 shows percentage delivery of deposited large (>50 pm) spray droplets on the nasal surface for circular spray cones with spray angles ranging from 15 to 55° to the anterior and posterior nasal sections.

[0052] Figures 5A and 5B depict an exemplary flow passage in the process of creating and emitting a spatially oscillating jet (01).

[0053] Figure 5C shows a jet isosurface in a flow passage which is not capable of creating an oscillating jet. Figure 6 is a block diagram of an exemplary system.

[0054] Figure 7A is an exemplary device including internal surfaces (flow pathway) of a nasal interface configured to form an oscillating jet of aerosol.

[0055] Figure 7B shows an enlarged cross-sectional view taken from Figure 7A according to the cross-section arrows labeled “7B”.

[0056] Figure 7C shows an enlarged view taken from Figure 7 A according to the arrows labeled “7C”.

[0057] Figure 7D is a cross-sectional view of the nasal interface taken along the horizontal plane of symmetry through the device of Figure 7A and shows the internal flow pathway of the interface with the primary angle of expansion used to form flow separation and oscillation of the jet along the long axis of the outlet cross-sectional ellipse.

[0058] Figure 7E is a cross-sectional view of the nasal interface taken along the vertical plane of symmetry through the device of Figure 7A and shows the internal flow pathway of the interface with the secondary angle of expansion that is used to form flow separation and oscillation of the jet along the long axis of the outlet cross-sectional ellipse.

[0059] Figure 8 shows an exemplary positioning of a nasal interface inserted into the anterior nasal region so that the primary direction of motion of an oscillating jet of aerosol emitted by the interface moves along the long axis of the nasal valve cross-section.

[0060] Figure 9A is a graph of flow rate (L / min) vs. time for an exemplary multiple cycle (MC) method using an exemplary OJ interface with short actuations followed by longer pauses.

[0061] Figure 9B juxtaposes a single square wave actuation typical of some mechanical actuators with an equivalent quasi sinusoidal or “bell curve” waveform which is more typical of a single actuation from a hand actuated pump.

[0062] Figure 10A is a block diagram of an exemplary system.

[0063] Figure 1 OB is a block diagram of another exemplary system.

[0064] Figure 11 is yet another exemplary system.

[0065] Figure 12 shows an aerosol deposition pattern generated with an exemplary MC-OJ nasal targeting DPI system with computational fluid dynamics (CFD) simulated delivery.

[0066] Figure 13 is a partial view of CFD mesh of the complete model used in some of the Examples including the inserted device and the nasal cavity.

[0067] Figure 14A shows nasal spray droplet deposition on the nasal surface in Example 1. Figure 14B shows nasal spray liquid runoff along the nasal surface and drippage after the deposition in Example 1.

[0068] Figure 15 A shows velocity contour along the device central plane at different time points in the actuation profile in Example 2.

[0069] Figure 15B shows trajectories of 34 pm MMAD powder particles produced by the typical-DPI in Example 2.

[0070] Figure 15C show trajectories of 67 pm MMAD powder particles produced by the typical- DPI in Example 2.

[0071] Figure 16A shows final powder particle deposition location on the nasal surface for the 67 pm MMAD powder in Example 2.

[0072] Figure 16B shows final powder particle deposition location on the nasal surface for the 34 pm MMAD powder in Example 2.

[0073] Figure 16C shows surface drug mass profile for the 67 pm MMAD powder in Example 2.

[0074] Figure 16D shows surface drug mass profile for the 34 pm MMAD powder in Example 2.

[0075] Figure 17 shows alternative aerosol flow modulators considered in Example 3 according to cross-sections taken along a plane of symmetry through the long axis of the flow passages and end views of the outlet openings.

[0076] Figure 18. Velocity fields produced by the MC-OJ expansion unit designs over one powder actuation period (A) Rapid expansion circle. (B) Rapid expansion ellipse. (C) Gradual expansion circle. (D) Gradual expansion ellipse large. (E) Gradual expansion ellipse medium. (F) Gradual expansion ellipse small.

[0077] Figure 19A1 shows 5 pm drug powder particles dispersed from the MC-OJ system using a “rapid expansion circle” aerosol flow modulator over one powder actuation period.

[0078] Figure 19B1 shows 5 pm drag powder particles dispersed from the MC-OJ system using a “rapid expansion ellipse” aerosol flow modulator over one powder actuation period.

[0079] Figure 19C1 shows 5 pm drug powder particles dispersed from the MC-OJ system using a “gradual expansion circle” aerosol flow modulator over one powder actuation period.

[0080] Figure 19D1 shows 5 pm drug powder particles dispersed from the MC-OJ system using a “gradual expansion ellipse large” aerosol flow modulator over one powder actuation period. Figure 19E1 shows 5 m drug powder particles dispersed from the MC-OJ system using a “gradual expansion ellipse medium” aerosol flow modulator over one powder actuation period.

[0081] Figure 19F1 shows 5 pm drug powder particles dispersed from the MC-OJ system using a “gradual expansion ellipse small” aerosol flow modulator over one powder actuation period.

[0082] Figure 19A2 shows 10 pm drug powder particles dispersed from the MC-OJ system using a “rapid expansion circle” aerosol flow modulator over one powder actuation period.

[0083] Figure 19B2 shows 10 pm drug powder particles dispersed from the MC-OJ system using a “rapid expansion ellipse” aerosol flow modulator over one powder actuation period.

[0084] Figure 19C2 shows 10 pm drug powder particles dispersed from the MC-OJ system using a “gradual expansion circle” aerosol flow modulator over one powder actuation period.

[0085] Figure 19D2 shows 10 pm drug powder particles dispersed from the MC-OJ system using a “gradual expansion ellipse large” aerosol flow modulator over one powder actuation period.

[0086] Figure 19E2 shows 10 pm drug powder particles dispersed from the MC-OJ system using a “gradual expansion ellipse medium” aerosol flow modulator over one powder actuation period.

[0087] Figure 19F2 shows 10 pm drug powder particles dispersed from the MC-OJ system using a “gradual expansion ellipse small” aerosol flow modulator over one powder actuation period.

[0088] Figure 19A3 shows 20 pm drug powder particles dispersed from the MC-OJ system using a “rapid expansion circle” aerosol flow modulator over one powder actuation period.

[0089] Figure 19B3 shows 20 pm drug powder particles dispersed from the MC-OJ system using a “rapid expansion ellipse” aerosol flow modulator over one powder actuation period.

[0090] Figure 19C3 shows 20 pm drug powder particles dispersed from the MC-OJ system using a “gradual expansion circle” aerosol flow modulator over one powder actuation period.

[0091] Figure 19D3 shows 20 pm drug powder particles dispersed from the MC-OJ system using a “gradual expansion ellipse large” aerosol flow modulator over one powder actuation period.

[0092] Figure 19E3 shows 20 pm drug powder particles dispersed from the MC-OJ system using a “gradual expansion ellipse medium” aerosol flow modulator over one powder actuation period.

[0093] Figure 19F3 shows 20 pm drug powder particles dispersed from the MC-OJ system using a “gradual expansion ellipse small” aerosol flow modulator over one powder actuation period.

[0094] Figure 20A1 shows 5 pm powder particle final delivery locations from the MC-OJ system using a “rapid expansion circle” aerosol flow modulator over one powder actuation period.

[0095] Figure 20B1 shows 5 pm powder particle final delivery locations from the MC-OJ system using a “rapid expansion ellipse” aerosol flow modulator over one powder actuation period.

[0096] Figure 20C1 shows 5 pm powder particle final delivery locations from the MC-OJ system using a “gradual expansion circle” aerosol flow modulator over one powder actuation period.

[0097] Figure 20D1 shows 5 pm powder particle final delivery locations from the MC-OJ system using a “gradual expansion ellipse large” aerosol flow modulator over one powder actuation period.

[0098] Figure 20E1 shows 5 pm powder particle final delivery locations from the MC-OJ system using a “gradual expansion ellipse medium” aerosol flow modulator over one powder actuation period.

[0099] Figure 20F1 shows 5 pm powder particle final delivery locations from the MC-OJ system using a “gradual expansion ellipse small” aerosol flow modulator over one powder actuation period.

[0100] Figure 20A2 shows 10 pm powder particle final delivery locations from the MC-OJ system using a “rapid expansion circle” aerosol flow modulator over one powder actuation period.

[0101] Figure 20B2 shows 10 pm powder particle final delivery locations from the MC-OJ system using a “rapid expansion ellipse” aerosol flow modulator over one powder actuation period.

[0102] Figure 20C2 shows 10 pm powder particle final delivery locations from the MC-OJ system using a “gradual expansion circle” aerosol flow modulator over one powder actuation period.

[0103] Figure 20D2 shows 10 pm powder particle final delivery locations from the MC-OJ system using a “gradual expansion ellipse large” aerosol flow modulator over one powder actuation period. Figure 20E2 shows 10 pm powder particle final delivery locations from the MC-OJ system using a “gradual expansion ellipse medium” aerosol flow modulator over one powder actuation period.

[0104] Figure 20F2 shows 10 pm powder particle final delivery locations from the MC-OJ system using a “gradual expansion ellipse small” aerosol flow modulator over one powder actuation period.

[0105] Figure 20A3 shows 20 pm powder particle final delivery locations from the MC-OJ system using a “rapid expansion circle” aerosol flow modulator over one powder actuation period.

[0106] Figure 20B3 shows 20 pm powder particle final delivery locations from the MC-OJ system using a “rapid expansion ellipse” aerosol flow modulator over one powder actuation period.

[0107] Figure 20C3 shows 20 pm powder particle final delivery locations from the MC-OJ system using a “gradual expansion circle” aerosol flow modulator over one powder actuation period.

[0108] Figure 20D3 shows 20 pm powder particle final delivery locations from the MC-OJ system using a “gradual expansion ellipse large” aerosol flow modulator over one powder actuation period.

[0109] Figure 20E3 shows 20 pm powder particle final delivery locations from the MC-OJ system using a “gradual expansion ellipse medium” aerosol flow modulator over one powder actuation period.

[0110] Figure 20F3 shows 20 pm powder particle final delivery locations from the MC-OJ system using a “gradual expansion ellipse small” aerosol flow modulator over one powder actuation period.

[0111] Figure 21 is an actuation flow profile from the air-jet MC-OJ DPI system including eight actuation cycles (four powder delivery actuations and four clean gas actuations).

[0112] Figure 22 shows MC-OJ produced velocity field along the sagittal plane at different time points within an actuation cycle (column wise) and over three actuations’ cycles (row wise) with a mechanical actuator with actuation peak flowrate of 4 LPM and actuation volume of 1.7 mL. Figure 23 shows MC-OJ produced velocity field showing random oscillatory jet over the seventh actuation cycle with a mechanical actuator with actuation peak flowrate of 4 LPM and actuation volume of 1.7 mL.

[0113] Figure 24 shows turbulent kinetic energy (TKE) (isosurface TKE= 1 m2 / s2 and contours plotted along coronal planes) at different time points within an actuation cycle (column wise) and over four actuations’ cycles (row wise).

[0114] Figure 25 shows powder particle transport over different timepoints across eight actuation cycles with the MC-OJ DPI system.

[0115] Figure 26 shows powder particle deposition locations at the end of each actuation cycle with the MC-OJ DPI system.

[0116] Figure 27A shows final deposition locations, combining deposition from all the cycles after the multi-cycle actuations with the MC-OJ DPI device in Example 4.

[0117] Figure 27B shows drug mass profiles on the nasal surface for the delivered powder particles in Example 4.

[0118] Figure 28 shows MC-OJ produced velocity field showing random oscillatory jet over the seventh actuation cycle with a mechanical actuator with actuation peak flowrate of 6 LPM and actuation volume of 1.7 mL in Example 5.

[0119] Figure 29A shows final deposition locations, combining deposition from all the cycles after the multi-cycle actuations with the MC-OJ DPI device at 6 LPM in Example 5.

[0120] Figure 29B shows drug mass profiles on the nasal surface for the delivered powder particles in Example 5.

[0121] Figure 30A shows final deposition locations, combining deposition from all the cycles after the multi-cycle actuations with the MC-OJ DPI device with the exhalation flow.

[0122] Figure 30B shows drug mass profiles on the nasal surface for the delivered powder particles with the exhalation flow.

[0123] Figure 31 A shows in-house engineered polydisperse EEG powder size distribution.

[0124] Figure 3 IB shows final deposition locations, combining deposition from all the cycles after the multi-cycle actuations with the MC-OJ DPI system.

[0125] Figure 31C shows drug mass profiles on the nasal surface for the delivered powder particles with the polydisperse powder. Figure 32 shows flowrate profile for single actuation cycle for both a mechanical actuator (producing square wave) or hand actuator (producing bell curve).

[0126] DETAILED DESCRIPTION

[0127] Figure 1 depicts a model 100 of the interior surface of a nasal cavity at the air-to-airway surface liquid (ASL) interface (where aerosol may deposit). The nasal valve divides the anterior portion of the nasal cavity from the posterior components, which include the Upper and Lower Posterior regions and the Nasopharynx (NP). The Lower Posterior region, as shown, is sometimes divided into middle and lower regions. The Upper Posterior region contains the Olfactory region, which is the primary target for nose-to-brain delivery of therapeutics.

[0128] Figure 1 includes a multiple cycle oscillating jet (MC-OJ) interface 101 shown inserted into one nostril and extending partially into the anterior nasal region, where drug deposition is not desirable.

[0129] For maximum therapeutic benefit, it is often desirable to deliver nasally-targeted pharmaceutical aerosols past the anterior nose, where minimal absorption occurs, and to the posterior nasal regions. Within the posterior nasal region, delivery of therapeutics to the upper posterior region is often desirable for potential improved absorption (due to slower clearance) and possible nose-to-brain delivery. The lower and upper posterior regions may be targeted for systemic absorption of a therapeutic or for anti-inflammatory nasal applications, as with inhaleded corticosteroids (ICS). The nasopharynx (NP) is also included within the group of posterior nasal regions and is rich in lymphatic tissue, making it a target for vaccine and immunoregulatory applications.

[0130] Figures 2A-2D show four nasal models from adult subjects denoted Open (Figure 2A), Average (Figure 2B), Constrictedl (Figure 2C). and Contricted2 (Figure 2D) (Jones. N. (2001). The nose and paranasal sinuses physiology and anatomy, Advanced Drug Delivery Reviews 51(1- 3): 5-19; Walenga, R. L., Longest, P. W., Kaviratna, A., and Hindle, M. (2017). Aerosol drug delivery during noninvasive positive pressure ventilation: Effects of intersubject variability and excipient enhanced growth, Journal of Aerosol Medicine and Pulmonary Drug Delivery 30(3): 190-205). Coronal cross-sectional Regions (1 to 4) are depicted for each subject, beginning with the approximate nasal valve region (1), followed by regions showing two and three meatuses (2 and 3, respectively), and ending with the entrance to the nasopharynx (4).

[0131] For an aerosol to reach the posterior nasal regions, it must first pass through the nasal valve, depicted in Figure 2 as slice location 1 for a variety of nasal models. The nasal valve is a constricted region of highest- pres sure loss separating the anterior and posterior nasal regions and also serves as an effective filter to environmental and pharmaceutical aerosols. The nasal valve represents a region of high cross-sectional area constriction and pressure drop, which presents a significant challenge to delivering nasally targeted medications to the posterior nasal regions. The open area of the nasal valve cross section is oriented up and down (i.e„ from head to toe) with respect to the subject. Subjects commonly receive nasal administration of therapeutics when standing or sitting so that “up and down” with respect to the subject generally corresponds with “up and down” with respect to Earth’s gravitational vector.

[0132] Figure 3A shows typical droplet or particle (spray plume) trajectory for common nasal spray and dry powder devices 301 with large-particle aerosols (>50 pm). The devices 301 produce straight-line trajectories forming a conical spray pattern 302. Figure 3B shows intersection of the conically oriented straight-line trajectories and nasal interior surface 303. Figure 3C shows the resultant droplet or particle deposition pattern 304. Intersection of the aerosol spray cone and open (line of sight) nasal geometry produces the final deposition profile.

[0133] Figure 4 shows percentage delivery of deposited large (>50 pm) spray droplets on the nasal surface for circular spray cones with spray angles ranging from 15 to 55° to the anterior and posterior nasal sections. Figure 4 illustrates many of the disadvantages associated with current dry powder nasal devices and larger particle aerosols including: 1) high anterior loss, 2) deposition in very limited areas, or hotspots, possibly leading to localized irritation and cellular disruption or damage, 3) poor coverage of the posterior region limiting treatment area for surface-active products and absorption potential for neurological or systemically targeted therapies, and 4) minimal deposition in the upper posterior and NP regions.

[0134] According to exemplary embodiments, the problems with conventional nasal delivery techniques summarized above are overcome with devices and methods which create and emit spatially oscillating jets of aerosol. When emitted into the nasal geometry in accordance with exemplary embodiments of this disclosure, an oscillating jet (OJ) significantly improves deposition profiles. Figures 5 A and 5B depict an exemplary flow passage 501 (e.g., of an exemplary nasal interface described in greater detail below) in the process of creating and emitting a spatially oscillating jet (OJ). The oscillating jet maintains a high outlet velocity over a wide area while minimizing the amount of required air volume. The Figures 5A and 5B were produced with modeling of an example delivery to a nasal cavity. Iso-surfaces 511 and 522 (regions of constant velocity) for velocity of 12.5 m / s depict jet strength entering the nasal cavity for actuation conditions of 6 L / min over 0.017 sec delivering 1.7 mL gas volumes. Figure 5 A shows the isosurface 511 of the oscillating jet at t = 0.0075 s. Figure 5B shows the iso-surface 522 at t = 0.0125 s. Figure 5B includes the iso-surface 511 in dotted line superimposed with iso-surface 522 to assist in comparing the change in the jet’s orientation over the elapsed time between Figure 5 A and Figure 5B. Further time lapse would show the jet continuing to oscillate between top and bottom of the flow passage 501 until the aerosol delivery actuation is concluded. For comparison, Figure 5C shows an isosurface (again for V=12.5 m / s for actuation conditions of 6 L / min over 0.017 sec delivering 1.7 mL gas volumes) in a flow passage 551 which is not capable of creating an oscillating jet. The isosurface 553 of the illustrated jet does not detach in the flow pathway.

[0135] Figure 6 is a block diagram of an exemplary system 600. The system 600 may alternatively be characterized as a device 600. The system 600 is configured for creating and emitting an oscillating jet of aerosol. An exemplary application of system 600 is administration of nasally targeted dry powder or liquid spray droplet aerosol therapeutic(s) to a subject 699.

[0136] The system 600 comprises a plurality of flow passages. The precise number of flow passages may vary among different embodiments. For exemplary illustration, the system 600 is depicted in Figure 6 with flow passages 601, 602, and 603. The arrows show the direction of flow from one flow passage to the next in succession. Ultimately the flow is emitted through an outlet 620 and may be administered to a subject 699. The subject 699 may be an animal such as but not limited to a human. A human subject may be of any age, e.g., infant, child, adolescent, or adult.

[0137] According to an exemplary embodiment, flow passage 601 may be an aerosolization chamber; flow passage 602 may be a capillary; and flow passage 603 may be an oscillator. The flow passage 603 may be both oscillator and nasal interface; alternatively, a nasal interface apart from the oscillator may be configured downstream of the flow passage 603. Additional flow passages may be arranged before or after the illustrated flow passages. Additional flow passages may be arranged between flow passages 601 and 602. Additional flow passages may be arranged between flow passages 602 and 603.

[0138] Configured as an aerosolization chamber, flow passage 601 is configured to create an aerosol of a dry powder or else an aerosol of liquid spray droplets. For purposes of this disclosure, “aerosol” is used to describe both a dry powder aerosol and a liquid spray aerosol, and “particles” may be used to describe the individual elements of either type of aerosol. An advantage of the air-jet aerosolization engine is that it can be tuned to increase or reduce the rate of powder release per actuation, depending on the desired dose delivery profile of a specific therapeutic.

[0139] Configured as a capillary, flow passage 602 is configured to create an aerosol jet. An exemplary aerosol jet is characterized by a cloud of particles traveling within a fluid flow jet stream. A capillary may be configured, for example, as a constant diameter tube with a diameter no greater than ~3.5 mm and with a length of at least 10 mm, or at least 5 mm.

[0140] Flow passage 603 may be characterized as an aerosol flow regulator or, more particularly, an oscillator. The flow passage 603 is configured to cause the jet emitting from the flow passage 602 to spatially oscillate, in particular, to oscillate up and down. The oscillating jet maintains a high outlet velocity over a wide area while minimizing the amount of required air volume. Use of oscillating jet deposition when administering an aerosol to a subject 699 minimizes hot spot formation (high concentrations) and helps to produce more disperse deposition patterns in the posterior nasal airway with improved surface area coverage. This occurs because the flow passage 603 maintains a high outlet velocity while also releasing (emitting) the aerosol stream along a line that moves up and down approximately along the long axis of the nasal valve crosssection.

[0141] Figure 7A shows an exemplary device 700 to which the description of system 600 is applicable. However, the device 700 includes additional exemplary features beyond those indicated above for system 600. Alike to system 600, the device 700 includes at least three flow passages. These include aerosolization chamber 701, capillary 702, and oscillator 703. Besides these flow passages, the device 700 includes by way of example a further capillary 710 and port 711. As depicted, the device 700 has at least the capillary 702 and oscillator 703 arranged within a nasal interface 715, the distal part of which is sized and shaped to fit snugly into a nostril opening of a subject, with the exterior surface of interface 715 forming a sealed (airtight) ring of contact with the subject’s skin.

[0142] Figures 7B-7E show various alternative views of device 700 or parts thereof. In particular, Figure 7B shows an enlarged cross-section taken from Figure 7A according to the cross-section arrows labeled “7B”. Figure 7C shows an enlarged view taken from Figure 7A according to the arrows labeled “7C”. Figure 7D is a cross-sectional view of the nasal interface taken along the horizontal plane of symmetry through device 700. Figure 7E is a cross-sectional view of the nasal interface taken along the vertical plane of symmetry through device 700.

[0143] From Figures 7A-7E it can be seen that the exemplary flow passage 703 has a variable height and a variable width, wherein the variable height always exceeds the variable width along the longitudinal axis of the flow passage 703. The flow passage 703 expands from one end of the flow passage 703 to the other in the direction of flow, which is the direction toward a subject in a state of use. Figure 7B shows a cross-section of the flow passage 703 at the proximal end where the height 721 and width 722 are at respective minimums. The diameter 723 of flow passage 702 is smaller than dimension 721 and may be smaller than dimension 722. Figure 7C shows the flow passage 703 at the distal end where the height 731 and width 732 are at respective maximums. In this illustrative embodiment, the exemplary flow passage 703 is formed as an elliptical frustum. Alternative embodiments may have other shapes such as but not limited to an oval frustum. A step 704 exists at the juncture of the flow passage 702 and the flow passage 703. The step involves a sudden change in the dimensions of the flow pathway rather than a gradual change. The change involves a sudden increase in cross-sectional dimensions of the flow pathway.

[0144] The transition at step 704 from the circular capillary that is flow passage 702 to the elliptical frustum of flow passage 703 and continued expansion of flow passage 703 along its length contribute to the creation of internal flow separation and a jet that oscillates up and down relative to the subject (and gravity) and along the long cross-sectional dimension of the nasal valve. For an elliptical frustum shaped flow passage 703, some exemplary major to minor diameter elliptical cross section ratios include 1.5, 2, and 4. As seen from Figures 7D and 7E, the flow passage 703 comprises a larger expansion angle 741 (creating, for example, a >5-degree total expansion angle and for some embodiments preferably an ~10-degree expansion angle in the primary elliptical dimension) and a smaller expansion angle 751 creating an ~3-degree total expansion angle. In general, embodiments may have an expansion angle 741 that is >5° and preferably about 8° and an expansion angle 751 that is <5° and preferably about 3.2°.

[0145] The device 700 comprises an outlet 720 through which the oscillating aerosol jet exits the nasal interface. In this exemplary embodiment, the outlet 720 is also the distal end of flow passage 703. In alternative embodiments, one or more other flow passages or flow elements or structural elements might be arranged between flow passage 703 and the outlet 720. In the latter case, any intervening elements do not eliminate the oscillation behavior of the flow. The aerosol flow still has an oscillating waveform when leaving the interface and entering the patient’s airways.

[0146] Figure 8 depicts the device 700 arranged for use with the model 100 (Figure 1) of the interior surface of a nasal cavity at the air-to-airway surface liquid (ASL) interface. The interface 715 is inserted into the anterior nasal region such that the long axis of the interface 715 outlet ellipse is generally aligned with the long axis of the nasal valve cross-section 802. The bold (two sided) arrow 803 indicates the primary direction of the oscillating jet motion, which moves along the long axis of the nasal valve cross-section 802 (open area), enabling improved aerosol delivery to and coverage of the posterior nasal regions. The jet oscillates up and down relative to the subject (and gravity) and along the long cross-sectional dimension of the nasal valve. If the patient were lying on his or her side during administration of the aerosol, the jet oscillation would still be “up and down” relative to the patient (e.g., head to toe) but orthogonal relative to the gravity vector.

[0147] Figure 9A is a graph representing an exemplary process for creating oscillating aerosol jet emissions. When used with a subject, e.g. as illustrated by the arrangement depicted in Figure 8, Figure 9A represents an exemplary process for aerosol delivery. An exemplary process involves a multiple cycle (MC) implementation. An exemplary device 600 / 700 is actuated multiple times in rapid succession. Each cycle has an actuation and a pause. That is to say, a single cycle’s period is the sum of an actuation duration and a pause duration. Despite each cycle being relatively rapid, the pause may be significantly greater in duration than the actuation. The actuation wave pattern in Figure 9A may be described as a square wave. This is typical of some exemplary mechanical actuator air sources. For other air sources, including some hand actuated pumps, each square actuation may have a waveform which is not square. By way of example. Figure 9B juxtaposes a single square wave actuation typical of some mechanical actuators with an equivalent quasi sinusoidal or “bell curve” waveform which is more typical of a single actuation from a hand actuated pump. Reference in this disclosure to flow rates may be understood to refer to peak flow rates in such cases as there is a ramp up and / or ramp down in flow rate according to the specific operation of the gas source.

[0148] According to some exemplary processes, two or more aerosol delivery actuations are performed and either one or no substantially clean gas actuation cycles follow after the aerosol delivery actuations.

[0149] The device 600 / 700 emits a defined mass or percentage of remaining mass of formulation with each actuation, followed by several relatively clean gas actuations at the end (or by no clean gas actuation cycles depending on the embodiment). Figure 9A shows by way of example four aerosol delivery actuations and three clean gas actuations, but the precise quantity of aerosol delivery actuations and the precise quantity of clean gas actuations may vary according to different end use circumstances such as subject characteristics and / or particular formulation being emitted.

[0150] Each aerosol delivery actuation is administered with a limited gas volume that forms an aerosol plume that avoids undesired straight-line plume impingement and straight-line deposition of the aerosol within the nose (the problem described above in connection with Figures 3B and 3C). Each actuation pushes the suspended aerosol deeper into the nasal passages. Moreover, each actuation provides inertia and turbulence for deposition of a fraction of the previously injected and airspace suspended particles within deeper nasal regions. A pause period is implemented to enable continued slow aerosol flow and transport into the deeper nasal regions without deposition; deposition is then fostered by a subsequent rapid actuation, preferably with a waveform shape to maximize system energy and depositional inertia. Such an exemplary MC implementation results in deeper and more diffuse (more disperse; less concentrated) deposition and increased surface area coverage compared with straight line deposition defined by the injection cone intersection with the nasal surface. Figure 10A is an exemplary system 1OOO. The system 1000 comprises by way of example an air source (i.e., gas source) 1001, flow regulator 1002, aerosolizer (i.e., aerosolization engine) 1003, and oscillator 1004. The flow pathway among these elements is portrayed by the arrows in Figure 10A. One of ordinary skill in the art will recognize the identified elements of system 1000 as significant elements but not necessarily the exclusive elements of an exemplary system consistent with this disclosure. Other elements may be added to the elements depicted before, after, or between any of the depicted elements. The air source 1001 (which in this disclosure may be interchangeably referred to as a gas source) may be one or more of a compressed gas source, syringe, automated gas source, hand actuated gas source, and insufflator. The air source 1001 may be configured to limit the total volume of air pushed through the system 1000 per actuation. The per actuation volume may be 0.6- 1.9 mL I actuation, for example. As further non-limiting examples, <6 mL, <5 mL, < 4mL, <3 mL, <2mL, or <1 mL of air may be used per actuation, with the higher values being applicable in some use cases when the subject 699 is an adult. The air source creates a positive pressure which drives flow through the downstream components of the system.

[0151] The flow regulator 1002 is configured to limit the flow rate to a desired value such as a maximum of 6 L / min or a range of 3-9 L / min, for example. The flow regulator 1002 may further include a valve system (e.g., a one way valve) that enables filling (including refilling) the air source 1001 with clean (environmental) gas / air prior to each actuation. In some implementations, the air source 1001 and flow regulator 1002 may be arranged together in a single device 1010.

[0152] Figure 10B is another exemplary system 1050 which is a variation of system 1000. System 1050 is alike to system 1000 by inclusion of the air source 1001 and flow regulator 1002. However, in place of flow passages 1003 and 1004 is device 600 of Figure 6.

[0153] Figure 11 is another exemplary system 1100 consistent with systems 1000 and 1050. The system 1100 comprises such components as a manual multiple cycle (MCM) air source 1101 for rapid device actuation, a one-way valve system and flow restrictor (collectively flow regulator 1102) for refilling the air source with clean air and limiting the device flow rate to a desired value (e.g., 6 L / min), a nasal air-jet aerosolization engine 1103, and MC-OJ patient interface 1104. The aerosolizer 1103 may include a region for dry powder capsule loading or an attachment region for attaching a dose containment unit. The arrow 1111 shows the direction of jet flow oscillation. Figure 12 depicts sample regional drug deposition based on validated CFD simulations (detailed in Examples section below) with the following delivery parameters: five aerosol actuations followed by three clean gas actuations, square actuation waveforms, actuations at 6 L / min with 1.7 mL of gas, 0.3 sec pause between actuations, and 10 pm monodisperse dry particles. The total posterior deposition fraction is >75% (of device emitted dose). The total anterior depositional loss is <5%. The total lung delivery loss is <5%. Figure 12 indicates excellent penetration to the posterior nasal region; low anterior and lung loss of the aerosol; and a well dispersed delivery pattern without hotspot formation and with a primary concentration in the upper posterior region.

[0154] EXAMPLES

[0155] The nasal airway geometry used in the following Examples was selected from an inhouse set of 20 adult healthy nasal geometries that were extracted from computer tomography (CT) scans as part of a larger study to identify a range of representative nasal models based on nasal drug delivery. The representative nasal airway was selected from the nasal models based on medium value of posterior drug delivery among the 20 healthy subjects (Manniello et al., (2021). In vitro evaluation of regional nasal drug delivery using multiple anatomical nasal replicas of adult human subjects and two nasal sprays. International Journal of Pharmaceutics, 593 p.120103.). i.e., the Medium Deposition or M nasal model. The selected model was a 35-year-old healthy male (Hosseini et al., (2020). Use of anatomically-accurate 3-dimensional nasal airway models of adult human subjects in a novel methodology to identify and evaluate the internal nasal valve. Computers in biology and medicine, 123, 103896). The associated nasal surface area and volume values of the nasal model were 34,579 mm2and 61,435 mm3, respectively (Hosseini et al., 2020). The nasal cavity was divided into anterior and posterior regions based on the location of the nasal valve plane. The posterior region was again divided into upper-posterior and lower-posterior regions, covering l / 3rdand 2 / 3rdvolume respectively and nasopharyngeal region, as shown in Figure 1.

[0156] CFD simulations were performed using ANSYS Fluent 2023.R2 or 2024.R2 (ANSYS Inc., Canonsburg, PA, USA). Considering the high Reynolds number values and the large recirculatory flow patterns within the device-interface and near the device outlet / regions in the nasal cavity, computations were performed using a transient incompressible low-Reynolds number (LRN) SST k-co turbulence flow solver (Kolanjiyil et al., (2021 ). Validating CFD Predictions of Nasal Spray Deposition: Inclusion of Cloud Motion Effects for Two Spray Pump Designs. Aerosol Science and Technology, DOI: 10.1080 / 02786826.2021.2011830). The solution was deemed to be converged when all mass and momentum residuals dropped by at least three orders of magnitude and did not change with further iterations. An initial time step size of 1 x ICT4s was used for solving the flow and the powder particles were injected every 5 x 10-4s. The flow solver time step was incrementally increased during the active aerosolization period to 2.5 x 10“4s, while confirming solution convergence. After aerosolization period, flow solver timestep was further incrementally increased to 5 x 10“3s. In-house ANSYS Fluent user-defined functions (UDFs) were used to apply variable time steps for the flow solver. Following the established meshing parameters for nasal drug delivery modeling, nasal geometries were discretized with ~2 million polyhedral surface elements with hexcore per nasal cavity, excluding the nasopharyngeal region, together with near- wall prism elements and a refined mesh in the DPI device interface and nozzle tip vicinity (see Figure 13). Since the primary focus of the study was the powder particle delivery into the nasal cavity, CFD simulations started with flow and powder particles exiting the DPI aerosolization chamber, modeled the transport kinetics through the device outlet, interface and the nasal cavity. Deposition of powder particles in specific nasal regions were quantified as the percentage of the amount of drug reaching the specific region compared to the total injected (initially released aerosol) dose. Specifically,

[0157] _ Amount of drug reaching the region

[0158] % drug delivery to specific nasal region

[0159] Total delivered dose

[0160] The drug mass on the nasal surface was calculated by considering the amount of drug reaching specific nasal surface mesh cell, which are representative of a nasal epithelial cell. By assuming a 10 mg total injected drug dose, the amount of drug was distributed to the emitted powder particles in proportion to their size. A threshold value of 1 ng per surface mesh cell (approximately 0.08 mm2on average) was used as a cutoff value to visualize the drug mass distribution profile on the nasal surface.

[0161] Example 1 - typical nasal spray pump

[0162] This Example evaluates the dose delivery profile (DDP) of a typical nasal spray pump delivering pharmaceutical liquid formulation to the nasal cavity. Figure 3B shows the spray pump inserted into the nasal cavity. Commercially available locally acting glucocorticosteroid nasal sprays, Flonase (active ingredient — fluticasone propionate) and (Glaxo-SmithKline Consumer Healthcare, Warren, NJ), were selected as a representative product for study (Kolanjiyil et al., 2021). Following the recommended nasal spray pump insertion protocol, the spray pump was inserted into the left nasal cavity and aligned with the approximate center of the downstream nasal valve, thereby avoiding direct impaction of spray droplets on the anterior nasal walls. The spray pump insertion depth from the nostril plane was 6 mm, head angle was 60°, and coronal angle was 12°. Further information on the spray pump device, formulation and actuation conditions are reported in a prior publication (See [1] Kolanjiyil et al., 2021; and [2] Kolanjiyil et al. (2022). Importance of spray-wall interaction and post-deposition liquid motion in the transport and delivery of pharmaceutical nasal sprays. Pharmaceutics, 14(5), 956). The spray deposition on the nasal surface was evaluated considering direct impact deposition of spray droplets as well as spray- wall interaction behavior followed by post deposition liquid motion on the nasal surface.

[0163] The typical nasal spray pump produced relatively large droplets - volumetric median diameter - 64 pm - which is a key characteristic of this platform. Two modeling strategies were used to simulate the nasal spray delivery. First, a two-way coupled Euler-Lagrange approach was used to simulate the spray droplet transport and deposition. When the spray droplets impacted the wall, the droplets were assumed to be deposited at the impaction point. As shown in Figure 14A, a majority of the spray droplets travelled along a conical plume pattern and deposited in a small region on the nasal surface where conically oriented straight-line trajectories interacted with the nasal interior surface. Second, the spray- wall interaction and post deposition liquid motion on the nasal surface was modeled, taking into account the volume of deposited liquid, liquid film properties such as thickness and surface interfaces, and driven by the effects of gravity. As shown in Figure 14B, after the initial deposition, a large fraction of the liquid formulation (-60%) dripped out of the posterior nose due to the gravitational force, resulting in drug loss from the posterior region of the nose, which is a common occurrence (Kolanjiyil et al., 2022).

[0164] Example 2 - typical nasal dry powder inhaler (typical DPI)

[0165] This Example evaluates the dose delivery profile (DDP) of a typical nasal dry powder inhaler (DPI; hereafter called ‘typical-DPI’) delivering a pharmaceutical dry powder aerosol to the nasal cavities of an adult subject. The dimensions of the typical nasal DPI were chosen to be representative of currently marketed common nasal DPIs such as the Aptar Unidose (Williams, G. Nasal and sublingual spray delivery devices: Market opportunities and unmet medical needs). The typical-DPI was inserted 14 mm into the nostril and had an insertion angle of 60°, for maximum delivery to the upper posterior region. The internal flow passages of the DPI after the aerosolization chamber were set as the starting point for the CFD simulations. A 2.5 mm circular outlet was assumed as the internal flow passage and a conical nose piece was considered enveloping the internal flow passage.

[0166] Generally, in passive positive pressure DPIs, actuation results in sudden release of compressed air in tandem with breaking the seal or puncturing the powder chamber / capsule. For the typical-DPI case considered in this Example, it was assumed that the actuation resulted in breaking the seal and release of compressed air resulting in aerosolization of the powder.

[0167] In this Example with the typical-DPI, the flow profile applied at the internal flow passage after the aerosolization chamber was a ramp up-ramp down profile with a peak flowrate of 24 LPM reached in 0.005s. The typical-DPI flowrate is based on Aptar Unidose powder delivery system (Baqsimi®, a nasal powder formulation containing 10% glucagon). The total flow time was 0.008s and the actuation volume was 1.7 m . Breathing inhalation / exhalation flow was considered to be zero. Considering the short duration of the actuation and high flowrate with high momentum, the effect of inhalation / exhalation flow is minimal.

[0168] Based on recent literature reported data, typical-DPIs produce particles with mass median aerodynamic diameter (MMAD) of either ~60 pm or ~30 pm. Hence, two powder size distributions were considered for the typical-DPI study - 67 pm with GSD 1.5 and 34 pm with GSD 1.5. See [1] Grosjean et al., (2015). Investigation of Powder Blend Uniformity and Deposition in a Nasal Cast Using a Unit Dose Nasal Device.; [2] Rigaut et al., (2023). What are the key anatomical features for the success of nose-to-brain delivery? A study of powder deposition in 3d-printed nasal casts. Pharmaceutics, 75(12), 2661.; and [3] Williams et al„ (2021). In Vitro and In Vivo Assessment of Regional Nasal Deposition using Scintigraphy from a Nasal Spray and a Nasal Powder. Paper presented at the Respiratory Drug Delivery.

[0169] Actuation of the typical-DPI consisted of a single air pulse with 24 L / min peak flow forming large aerosol particles (MMAD 67 pm or MMAD 34 pm). Figure 15A shows the velocity contour, along the device central plane at different time points in the actuation profile (at Time= 0.005 is the peak flow rate). The typical-DPI produced a high intensity velocity jet with high momentum that collided with the nasal wall along a straight-line conical trajectory. The 34 pm MMAD powder particles produced by the typical-DPI travelled mostly in straight-line trajectories, due to the high inertia, except for the smaller micron particles in the size range of 15 pm, as shown in Figure 15B. When the powder size distribution was large (here 67 pm MMAD) an even greater majority of the powder particles travelled in straight line trajectories following the high momentum flow-jet and impacted on the nasal surface along lines-of-sight. as shown in Figure 15C. This resulted in a highly concentrated hot-spot formation, thereby delivering majority of the drug to a small nasal surface region. Once reaching a quasi-steady state, the flow velocity profile and the powder particle trajectories did not change noticeably over the actuation duration. Table 1 lists the deposition fraction of the delivered drug dose within the nasal regions. Based on the ideal alignment condition, all of the powder particle deposition was in the posterior region, but with a very concentrated deposition pattern.

[0170] Table 1. Percentage values of the delivered drug dose per the nasal regions for the typical-DPI

[0171] Figure 16A shows the final powder particle deposition location on the nasal surface for the 67 pm MMAD powder. Figure 16B shows the final powder particle deposition location on the nasal surface for the 34 pm MMAD powder. For clearly visualizing the dose delivery profile, for 10 mg powder delivered dose per the typical-DPI actuation, a deposited drug mass profile map was created on the nasal surface. For better demarcating the drug received surfaces, a drug mass threshold value of 1 ng mass value per surface mesh cell was chosen for the contour plot. That is if the surface mesh cell has a powder mass of >1 ng, these cells were marked in red and labeled with “1”; while meshes in blue (labeled with “0”) received no drug. Figure 16C shows the surface drug mass profile for the 67 pm MMAD case and Figure 16D for the 34 pm MMAD case. Clearly the powder mass is deposited in a highly localized nasal region, resulting in high concentration drug regions. Only 1% of the total nasal surface area received at least 1 ng of the drug with the 67 pm MMAD powder, while 5% of the total nasal surface area received at least 1 ng of the drug with the 34 pm MMAD powder. Considering that a high concentration drug deposition profile could ultimately lead to poor drug dissolution / uptake, a majority of the drug may be cleared off by the mucociliary clearance process before being absorbed. Furthermore, these hotspots of very high concentration may be irritating or damaging to the underlying nasal tissue, depending on the intended dose delivered and formulation characteristics of the dry powder that is used.

[0172] Example 3 - air-jet dry powder inhaler (air-jet DPI) with aerosol flow modulators

[0173] This Example involves comparison of several flow passage alternatives arranged downstream of aerosol generation via an air-jet DPI. The alternative flow passage alternatives are referred to as aerosol flow modulators and serve to modulate the aerosol stream in one or more ways.

[0174] Materials and Methods

[0175] Inventors of the present technology previously developed a powder-based aerosol generator referred to as the air-jet DPI, which can be operated with a positive pressure gas source for use in targeted nasal drug delivery. See [1] Farkas, D., Hindle, M., & Longest, P. W. (2018a). Application of an inline dry powder inhaler to deliver high dose pharmaceutical aerosols during low flow nasal cannula therapy. International Journal of Pharmaceutics, 546(f-T), 1-9; [2] Farkas, D., Hindle, M., & Longest. P. W. (2018). Development of an inline dry powder inhaler that requires low air volume. Journal of aerosol medicine and pulmonary drug delivery, 31(4), 255-265; and [3] Farkas, D., Hindle, M., & Longest, P. W. (2018b). Efficient Nose-to-Lung Aerosol Delivery with an Inline DPI Requiring Low Actuation Air Volume. Pharmaceutical research, 35(10), 194. Significant components of the air-jet DPI include a small diameter air inlet, aerosolization chamber, and small diameter aerosol outlet. Control of the air-inlet size, number of air inlets, aerosolization chamber size and geometry, and aerosol outlet configuration were previously optimized for efficient powder dispersion and release rate. See [1] Dale Farkas et al., 2018a; [2] D. Farkas et al., 2018; [3] Dale Farkas et al., 2018b; [4] Longest, W., & Farkas, D. (2019). Development of a New Inhaler for High-Efficiency Dispersion of Spray-Dried Powders Using Computational Fluid Dynamics (CFD) Modeling. The A APS journal, 21(2), 25.; and [5] Longest, W., Farkas, D., Bass, K., & Hindle, M. (2019). Use of Computational Fluid Dynamics (CFD) Dispersion Parameters in the Development of a New DPI Actuated with Low Air Volumes. Pharmaceutical research, 36(8), 110.). As a result, the air-jet DPI provides a convenient source of relatively monodisperse powder aerosol in a controlled turbulent jet for high efficiency nasal drug delivery.

[0176] The air-jet DPI is intended to operate over a wide range of flowrates typically ranging from 2 LPM to 12 LPM. The air-jet DPI was re-engineered to work with larger powder particles (consistent with nasal targeting applications) of sizes 5-20 pm and lower actuation volumes ~2 mL. This particular design with lower actuation volume ~2 mL is advantageous for nasal powder delivery, considering that a single nasal cavity including the nasopharynx has a volume of ~ 17 mL, thereby device delivered powder particles will be delivered to a small volumetric region of the nasal cavity during the initial actuation, leading to low momentum impaction deposition / less hotspots, more suspended particles, and partial retention of the aerosol cloud in the nose. These suspended powder particles will be dispersed further into the posterior part of the nasal cavity and driven toward deposition with subsequent small volume actuations. Additionally, subsequent actuated powder particles will be dispersed even further due to existing and newly developed turbulence and recirculation flows within the nasal cavity. For comparing the drug delivery profile, the device was inserted into the nasal cavity following the same insertion parameters as were used with the typical-DPI (described in Example 2 above).

[0177] The outlet of the aerosolization chamber of the air-jet DPI had an internal diameter of 0.89 mm. This outlet continued through a capillary of the same diameter and of suitable length to create and / or maintain an aerosol flow which would emit from the capillary as an aerosol jet (i.e., air jet of aerosol).

[0178] Figure 17 illustrates the alternative aerosol flow modulators considered by this Example according to cross-sections taken along a plane of symmetry through the long axis of the flow passages and end views of the outlet openings. The alternative flow passages for aerosol flow modulation were selected to cause one or more of the following: moderate the high-speed turbulent air-jet coming out of this aerosolization outlet, attenuate the high-speed turbulent airjet, reduce positional losses in the patient interface, maximize powder dispersibility, maximize the internal flow-instability and oscillatory behavior, and maximize aerosol spread and deposited surface area coverage in the nasal cavity.

[0179] The alternative designs mainly focused on connecting the aerosolization chamber outlet extension (internal diameter of 0.89 mm) to the distal end of the nose-piece (hydraulic internal diameter of ~4 mm). The distal end of the nose-piece had an external diameter of ~5.5 mm. Design (a) was a rapid expansion style with circular cross-section, called ‘rapid expansion circle’ below. Design (b) was a rapid expansion style with elliptical cross-section, called ‘rapid expansion ellipse’ below. Designs (c)-(f) focused on a gradual expansion from 0.89 mm to the distal end using a circular cross-section (design (c)) or elliptical cross-sections (designs (d), (e), and (f)). The three elliptical cross-section designs are referred to below as ‘gradual expansion ellipse large’ for design (d), ‘gradual expansion ellipse medium’ for design (e), and ’gradual expansion ellipse small’ for design (f). Figure 17 shows the dimensions relied upon for simulation.

[0180] The alternative aerosol flow modulator designs were inserted into the nasal cavity following the same insertion conditions as that of the Typical nasal DPI reported in Example 2 above.

[0181] For an air source, a mechanical actuator with flow-profile of 4 LPM flow rate and 1.7 mL actuation volume was selected to operate the nasal DPI system. The selection of 1.7 mL followed the idea that a nasal cavity with the naso-pharyngeal air-space has an average volume of 17 mL. The nasal DPI system was configured to emit 1 / 1 Oth of this volume during each actuation so that some powder from the initial actuations would be suspended in the posterior nasal cavity, just passing the anterior region. With subsequent multiple actuations, these powder particles spread throughout the posterior nasal cavity and the naso-pharyngeal air-space, depositing while they progress, all the while avoiding high lung delivery and high impact concentrated hot-spot formation in the nasal cavity. The DPI device nose-piece (nasal interface) was designed to fully occlude the nostrils, avoiding the effect of breathing inhalation / exhalation flow.

[0182] Results

[0183] Velocity Fields. Ligures 18A-18L show the velocity fields produced by the respective aerosol flow modulator designs over one powder actuation period. In all the designs, the velocity field was developed within a few milliseconds. All the designs resulted in expansion of the jet, specifically at the outlet of the expansion unit interface, leading to reduction in jet velocity and spread of the jet. Rapid expansion circle and rapid expansion ellipse had relatively lower peak velocity values compared to the other designs, which was mainly attributed to the larger cross- sectional area. The velocity jet did not shift in position (there was no oscillation) in the rapid expansion designs as shown in Figure 18A and Figure 18B. Similar quasi-steady velocity jet was noticed in the gradual expansion circle, gradual expansion ellipse large and gradual expansion ellipse medium designs (Figures 18C-18E). The gradual expansion ellipse small had an oscillating (shift in location) velocity jet, as shown in Figure 18F. The velocity jet oscillated in the plane of the nasal valve resembling a ‘whiplash stroke’, and the oscillatory jet covered / pushed fluid into a majority of the nasal volumes ranging from the nasal valve to the turbinate regions.

[0184] Powder Particle Dispersion. Three monodisperse powder particle sizes (5 pm, 10 pm and 20 pm) were used to evaluate powder particle dispersion resulting from the different aerosol flow modulator designs. These powder particle sizes are equivalent to monodisperse aerosol sizes of particles with a density of 1 g / cm3or equivalent to monodisperse aerosol sizes based on aerodynamic diameter or geometric diameter. The simulations were performed for a duration of 0.34 s. Figures 19A1-19F1 show dispersion results for the 5 pm powder particles. Figures 19A2- 19F2 show dispersion results for the 10 pm powder particles. Figures 19A3-19F3 show dispersion results for the 20 pm powder particles. The 5 pm and 10 pm powder particles dispersed at the outlet of the interface with most of the modulator designs. The larger powder particles, 20 pm in size, with high inertia, generally followed a straight-line trajectory and impacted on the nasal wall resulting in highly concentrated deposition profile. However, the smaller powder particles, 5 pm and 10 pm, were influenced by the flow from the device and their trajectories followed the velocity jet after some inertial transport, as shown in Figures 19A1-19F1 (for 5 pm particles) and Figures 19A2-19F2 (for the 10 pm particles). In the rapid expansion circle and gradual expansion circle designs, the powder particles had lowest spread / dispersion inside the nasal cavity (Figures 19A1 / 19A2 / 19A3 and 19C1 / 19C2 / 19C3). In the elliptical expansion unit designs, the powder particles had more dispersion inside the nasal cavity, except the gradual expansion large design, which had relatively lowest velocity jet. Gradual expansion medium and small resulted in higher powder dispersion. In the gradual expansion small design, there was significantly higher dispersion of the powder particles inside the nasal cavity, with particles reaching the inner regions of the turbinates and back of the posterior nasal and nasopharyngeal region (Figures 19F1 and 19F2).

[0185] Powder Particle Deposition Distribution. Final powder particle delivery locations are plotted in Figures 20A1-20F1 / 20A2-20F2 / 20A3-20F3 for each of the aerosol flow modulator designs. Figures 20A1-20F1 show final delivery results for the 5 pm powder particles. Figures 20A2-20F2 show dispersion results for the 10 pm powder particles. Figures 20A3-20F3 show dispersion results for the 20 pm powder particles. The deposition location was concentrated for the 20 pm particles in all the expansion unit designs. As seen with the powder particle dispersion plots, the deposition was significantly more dispersed / spread with the gradual expansion small design, as shown in Figures 20F1 and 20F2. With the gradual expansion small design, the 10 pm powder particles deposited in the turbinate regions, while there was increased 5 pm powder deposition in the anterior region, due to the lower stokes number leading to increased powder particle dispersed into the anterior region because of the jet. Table 2 lists the percentage values of powder delivery to specific device and nasal regions for just one cycle of powder actuation. The 5 pm powder particles showed relatively higher deposition in the device interface and anterior nose. The gradual expansion ellipse small design achieved 10-fold increase in 5 pm powder particle delivery to the posterior nose compared to other designs (25% compared to ~2% on average), while keeping the device interface and anterior loss relatively similar to other designs. Similarly, the gradual expansion ellipse small design achieved 2-fold increase in 10 pm powder particle delivery to the posterior nose compared to other designs (49% compared to -24% on average), while keeping the device interface and anterior loss to <4%. Compared to the 5 pm powder particle delivery, there was 2-fold increase in posterior nose delivery and good distributed deposition with 10 pm powder particles, with the gradual expansion ellipse small design. Additionally. 10 pm powder particles achieved more delivery (18% absolute difference) to the upper posterior nasal region compared to the 5 pm powder particles. All the 20 pm powder particle delivered to a small region of the posterior nose.

[0186] Table 2. Percentage values of particle delivery to specific device and nasal regions for just one cycle of device actuation

[0187] Of the six aerosol flow modulator designs tested, the gradual expansion ellipse small

[0188] (design (f) of Figure 17) performed best, exhibiting minimal interface powder deposition and maximum nasal cavity powder spread and deposition. Therefore, this design was selected for use in the further Examples below. Example 4 - Multi-cycle Technology

[0189] This Example establishes the benefits of an exemplary multi-cycle (MC) oscillating jet (OJ) system. The multi-cycle technology comprised of small volume actuations over multiple cycles delivers more particles across the nasal surface while also enhancing the dispersion of the suspended particles, making use of the oscillatory-jet technology.

[0190] Based on the results of Example 3 above, this Example evaluated an MC-OJ system comprising a gradual expansion ellipse small design (design (f) of Figure 17).

[0191] Velocity Fields.

[0192] As shown in Figure 21, four actuations with powder and four empty / blank actuations were tested with a mechanical actuator with actuation peak flowrate of 4 LPM and actuation volume of 1.7 mL.

[0193] Figure 22 shows the resulting velocity field along the sagittal plane at different time points within an actuation cycle (column wise) and over three actuation cycles (Figure 22 row wise). In the first actuation cycle, the oscillatory jet whiplashed across the nasal valve plane with a frequency of -120 Hz. As shown in Figure 22, the oscillatory jet had a random motion over cycles, meaning the jet position was not the same over the same time point across cycles.

[0194] Figure 23 shows the random oscillatory jet over the seventh cycle. The oscillatory whiplash jet frequency increased to -280 Hz from second cycle onwards. This increased oscillatory frequency further ensured that the randomness in jet oscillation over multiple actuation cycles leading to more distribution of suspended powder particles deeper into the nasal cavity. The suspended particles were randomly dispersed across the nasal cavity, leading to enhanced spread and distributed deposition. The random oscillatory jet behavior was instilled by the expansion unit design in addition to the turbulent recirculation inside nasal cavity.

[0195] Overall, the multi-cycle technology provided multiple advantages: ensuring powder particles are suspended without high impaction, filling partial volume of the nasal cavity with each actuation cycle, slowly pushing particle into the inner regions of the nasal cavity and amplifying the oscillatory nature of the jet produced by the jet by two-fold, ensuring random dispersion of the powder particles.

[0196] Turbulent Kinetic Energy (TKE).

[0197] Figure 24 shows the resulting turbulent kinetic energy (TKE) (isosurface TKE= 1 m2 / s2and contours plotted along coronal planes) at different time points within an actuation cycle (column wise) and over four actuation cycles (Figure 24 row wise). As shown in Figure 24, the oscillatory jet led to oscillations in the TKE field. Even after the actuation air source (To + 0.06s), adequate TKE in the posterior turbinate nasal regions and the nasopharyngeal region were noted. These TKE levels drove particle deposition even in regions of reduced flow velocity. Multiple cycles of these TKE levels helped injected aerosols to be transported and deposited deeper within the nose.

[0198] Powder Particle Dispersion.

[0199] Based on the deposition trend from Example 2 above, only 5 pm and 10 pm powder particles were considered in this Example, since a majority of the 20 pm aerosol deposited with high inertial impaction. Based on internal flow measurements using the MC-OJ system, it was noted that each actuation resulted in 0.35s duration, with time for both actuations followed by the reset (air-filling) of the positive pressure gas source. Hence, this Example simulated the same conditions by having an actuation cycle with an actuation duration followed by recoil duration where there was zero air-jet flow from the air-source, though flow in the nasal cavity was replicated because of the recirculating internal flows. Based on internal measurement of the airjet engine, it was noted that, for a 10 mg loaded powder, on average four actuations produced powder aerosols, meaning most of the powder was emptied within four actuations. The four powder actuations were followed with four powder free actuations. After each actuation cycle, the deposited and suspended powder particles were tabulated. An additional advantage of the airjet engine is that it can be tuned in the future to increase or reduce the rate of powder release per actuation, depending on the desired dose delivery profile of a specific therapeutic.

[0200] Figure 25 shows the powder particle transport over different timepoints across eight actuation cycles. Time points were chosen such that the first figure showed the suspended particle locations at the end of the actuation air source of the corresponding actuation cycle and the second figure showed the suspended particle locations at the end of the corresponding actuation cycle. A similar approach was used for visualizing all the cycles, as shown in Figure 25. The particles are colored based on the residence time. At the end of the first actuation air pulse, particles were mainly dispersed in the anterior side of the posterior turbinates. At the end of the first actuation cycle, more powder particles were dispersed in the posterior nasal regions. With the second actuation, more particles were aerosolized and injected into the nasal cavity (grey powder particles at Time = 0.37520). The position of the newly actuated particles in subsequent actuation cycles were different, indicating that they were dispersed well with the multiple actuation cycles. Continuous injection of actuation air and the aerosolized powder particles gently pushed the suspended powder particles to hard-to-reach spaces in the nasal cavity, leading to excellent dispersion throughout the nasal cavity from cycle 3 onwards, as shown in Figure 25.

[0201] Powder Particle Deposition Distribution.

[0202] The powder particle deposition locations at the end of each actuation cycle are plotted in Figure 26. The powder particles are colored based on time from the start of the first cycle device actuation. Cycle 9 denotes the deposition of the remaining suspended particles due to gravitational sedimentation over time without any actuation air. With each actuation cycle, more powder particles deposited deeper into the turbinate and back of the nose. The multi-cycle oscillating-jet technology helped the spread of the suspended particles, increasing the deposition coverage over the nasal surface.

[0203] Figure 27A shows final deposition locations, combining deposition from all the cycles. Table 3 lists the percentage drug deposition in device and nasal regions after the multi-cycle actuations with the MC-OJ DPI device. 10 pm powder particles covered majority of the upper and lower turbinate regions, depositing - 75% of the delivered dose within the posterior nasal region. Of the 75% drug mass, 40% was delivered to the upper posterior region of the nose. Anterior nose loss was - 12%, device loss was minimal and drug mass exiting the nasopharyngeal region was -13%. While the 5 pm powder particles also covered the turbinate nasal regions, only - 46% of the delivered dose deposited in the posterior nasal region. The device and anterior nose loss were -30% and the drug mass exiting the nasopharyngeal region was -24%.

[0204] Table 3. Percentage drug deposition in device and nasal regions after the multi-cycle actuation with the MC-OJ system

[0205] Figure 27B shows drug mass profiles on the nasal surface for the delivered powder particles for a 10 mg delivered dose. For estimating the drug mass surface profile, the deposited 5 pm, 10 pm, and 20 pm powder particles were considered assuming a 25%, 50%, and 25% mass distribution of the 10 mg delivered dose, respectively. The red regions show at least 1 ng of drug delivery, while blue surfaces were below the cutoff. With the multi-cycle oscillatory jet technology, the DPI delivered drug to the nasal cavity covering 65% of the total nasal surface. In comparison, the typical-DPI (with the better performing small aerosol size) only covered 5% of the nasal surface (Example 2). Hence, the MC-OJ device improved the delivery coverage efficiency by 13-fold.

[0206] Example 5. Testing Operational range of the MC-OJ DPI system - Effect of Changes in the Actuation Flowrate

[0207] This Example examines the effect of different actuation flow rates on nasal powder delivery from the MC-OJ system. The MC-OJ DPI system was tested under three different actuation flowrates (2 LPM vs 4 LPM vs 6 LPM) while keeping the actuation volume constant at 1.7 mL. A similar actuation profile to that used above was followed, namely first four powder actuations were performed followed by four powder free actuations. Only 5 pm, and 10 pm powder particles were considered in this Example, since 20 pm was noted to result in higher localized deposition above.

[0208] When the flowrate was 2 LPM, posterior delivery was reduced for both 5 pm and 10 pm powder particles, while device and anterior nose loss increased (Table 4). However, 2 LPM actuation flowrate resulted in -65% nasal surface area coverage, similar to the 4 LPM flow rate. For estimating the drug mass surface profile, the deposited 5 pm, and 10 pm powder particles were considered assuming a 33.3%, and 66.6% mass distribution of the 10 mg in each size bin, respectively.

[0209] When the flowrate was 6 LPM, posterior delivery was increased for both 5 pm and 10 pm powder particles to 56% and 92%, respectively, while device and anterior nose loss were similar to the 4 LPM case (Table 4). The increase in the posterior delivery percentage was mainly attributed to the enhanced oscillatory jet effect, in combination with the multi-cycle technology.

[0210] With the 6 LPM actuation flowrate, in the first actuation cycle, the oscillatory jet whiplashed across the nasal valve plane with a frequency of -175 Hz. The oscillatory whiplash jet frequency increased to -400 Hz from second cycle onwards. Figure 28 shows the random oscillatory jet over the seventh cycle with the 6 LPM actuation flowrate. This increased oscillatory frequency with the 6 LPM actuation flowrate further ensured that the randomness in jet oscillation over multiple actuation cycles leading to more distribution of suspended powder particles deeper into the nasal cavity. Figure 29A shows the deposition locations of the powder particles for 6 LPM actuation flowrate. 6 LPM actuation flowrate resulted in 70% nasal surface area coverage (see Figure 29B).

[0211] Table 4. Percentage values of powder delivery with the MC-OJ DPI system to specific device and nasal regions for different actuation flowrate cases Example 6. Testing Operational range of the MC-OJ DPI system - Effect of Changes in Actuation volume

[0212] This Example examines the effect of different actuation air volumes on nasal powder delivery from the MC-OJ system. The MC-OJ DPI system was tested under three different actuation volumes (0.8 mL, 1.7mL, and 2.5 ml) while keeping the actuation flowrate constant at 4 LPM. Only 5 pm and 10 pm powder particles were considered in this Example, since 20 pm was noted to result in large localized deposition above.

[0213] Table 5 lists the percentage values of powder delivery with the MC-OJ DPI system to specific device and nasal regions for different actuation volume cases. For all the actuation volume cases with 10 pm powder particles, the MC-OJ system consistently delivered -75% mass to the posterior nasal region. The percentage of drug delivered to the posterior region is similar for all the actuation volume cases, especially for the 10 pm powder particles. This indicates that the total amount of drug delivered to the posterior region per DPI actuation could be controlled by specifying the actuation volume of the device without large changes in the regional deposition pattern, i.e., more actuation volume (more actuation duration) could be applied when higher doses are needed per actuation. In addition, experience with air-jet technology indicates that formulation properties and selected device flow passage size can also dramatically impact aerosol release rate per actuation.

[0214] Table 5. Percentage values of powder delivery with the MC-OJ DPI system to specific device and nasal regions for different actuation volume cases

[0215]

[0216] Example 7. Testing Operational range of the MC-OJ DPI device - Effect of subject’s simultaneous exhalation flow considering the complete nasal geometry with two cavities

[0217] In order to further maximize performance of the MC-OJ DPI system and eliminate the potential for lung deposition of the aerosol, the MC-OJ DPI system was tested when the subject was performing a gentle nasal exhalation maneuver at a flowrate of 15 LPM during aerosol administration. As noted above, an exemplary MC-OJ system is intended to form a seal with the aerosol delivery nostril. The nasally exhaled flow rate then exits the other nostril during the period of aerosol administration. For testing, the device was actuated (8 actuations under ~ 2.8s) when the subject was exhaling continuously through the open nostril. An advantage of this maneuver is that it avoids drug powder particles exiting the nasopharynx into the larynx / tracheal regions. This may be preferable for cases in which drug reaching the lung needs to be completely avoided.

[0218] Table 6 lists the percentage values of powder delivery with the MC-OJ DPI system to specific device and nasal regions actuated with 4 LPM actuation flowrate and 1.7 mL actuation, when the subject was exhaling at 15 LPM (gentle exhalation). Only 10 pm powder particles were considered in this Example. Further increase in posterior delivery (93%) was achieved when the device was actuated with the exhalation flow, due to the increased turbulence in the posterior nose created by the interaction between actuation air and exhaling air acting on the suspended particles. 77% of the posterior dose was delivered to the upper posterior region. No powder particles exited the nasopharynx and only a small fraction (<1%) exited the nose into the ambient surrounding with the exhalation flow through the open nostril. Figure 30A shows the deposition locations of the powder particles for the case with exhalation flow. The deposition profile and delivery profile were similar to the 6 LPM actuation flowrate case, covering majority of the posterior nasal surface. Device actuation with exhalation flow resulted in 66% nasal surface area coverage (see Figure 30B).

[0219] Table 6. Percentage values of powder delivery with the MC-OJ DPI device to specific device and nasal regions with the exhalation flow

[0220] Example 8. Testing Operational range of the MC-OJ DPI system - Effect of polydispersity on drug delivery (using in-house engineered powder)

[0221] In order to establish the operational range of the MC-OJ DPI system for changes in powder size distributions, the MC-OJ DPI system was tested with an in-house engineered powder. An aqueous excipient enhanced growth (EEG) model formulation was spray dried using a custom in-house spray-drier to produce a dry powder formulation with a mean aerodynamic size of ~ 10 pm. After formulation production, the powder size distribution as determined with cascade impaction is plotted in Figure 31 A. CFD simulations of aerosol delivery into the nasal model using the MC-OJ system and operating parameters were mechanical actuator profile with actuation flowrate of 4 LPM and actuation volume of 1.7 mF. Delivery percentage is listed in Table 7.

[0222] The MMAD of the powder aerosols was 14.8 pm and GSD =1.4. For simulation testing with the MC-OJ system, only the powder size bins with at least 5% volume fraction were chosen to reduce the computational load. Even though the powder contained particles that are relatively larger than the exact value of 10 pm, higher posterior delivery with good posterior nasal surface coverage was achieved (see Figure 3 IB). Even with this larger powder, the MC-OJ system delivered drug to more than 70% of the total nasal surface (see Figure 31 C), highlighting the high efficiency of the MC-OJ technology.

[0223] Table 7. Percentage values of powder delivery with the MC-OJ DPI device to specific device and nasal regions with the polydisperse powder particles

[0224] Example 9. In vitro prototype testing and CFD comparison

[0225] In vitro experiments were performed using the MC-OJ system with the gradual expansion ellipse medium design. The device and nasal model were 3D printed for testing. The system was actuated using a hand actuator and the device loaded with the in-house engineered powder with an MMAD of 14.8 pm. The hand actuator flow profile is shown in Figure 32. Additional operating conditions of the physical device were peak actuation flowrate of ~5.5 LPM, actuation volume of 1.95 mL and actuation duration of 0.045s.

[0226] Table 8 lists the percentage delivery of the drug to specific nasal regions. The results are reported as the percentage of the total nasal delivery (released from the device). The delivery percentage was similar to the MC-OJ typical delivery rate, except the in vitro testing showed higher delivery to the lower-posterior nasal region, which could be attributed to the minor deviation in the device insertion conditions.

[0227] Table 8. Percentage values of powder delivery with the MC-OJ DPI device to specific device and nasal regions with the polydisperse powder particles after in vitro testing (* denotes combined std of all posterior regions assuming as independent variables)

[0228] In addition, in vitro nasal deposition testing was conducted using three different aerosol sizes (measured at the outlet of the nasal interface) under aerosol delivery conditions of 4 LPM, just under 2 mL air volumes and 10 device actuations. As shown in Table 9, anterior depositional loss was low in all cases (<15%) and aerosol size could be used to target different posterior and nasopharynx regions. Lung filter delivery was lowest with this combination of variables when the aerosol size, based on volumetric aerosol geometric diameter (Dv50) was ~10 um.

[0229] Table 9. 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.

[0230] 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.

[0231] 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.

[0232] 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.

[0233] It is to be understood that the terminology and explanations used herein are for the purpose of describing exemplary embodiments only, and are not intended to be limiting, since the scope of the present invention will be limited only by the appended claims.

Claims

CLAIMSWhat is claimed is:

1. A nasal interface, comprising a first flow passage configured to form an aerosol jet from air with entrained aerosol particles; a second flow passage downstream of the first flow passage, wherein the second flow passage is configured to spatially oscillate the aerosol jet from the first flow passage; and an outlet through which the oscillating aerosol jet exits the nasal interface.

2. The nasal interface of claim 1, wherein the first flow passage is a capillary.

3. The nasal interface of claim 1, wherein the second flow passage has a variable height and a variable width along a longitudinal axis of the second flow passage, wherein the variable height always exceeds the variable width.

4. The nasal interface of claim 1, wherein the second flow passage is an elliptical or oval frustum.

5. The nasal interface of claim 1, wherein the first flow passage is a capillary and the second flow passage is an elliptical or oval frustum.

6. The nasal interface of claim 1, further comprising a step at the juncture of the first flow passage and the second flow passage.

7. An aerosol delivery system, comprising a gas source; an air-j et DPI; and the nasal interface of claim 1.

8. The aerosol delivery system of claim 7, wherein the gas source is a hand actuator or automated actuator.

9. The aerosol delivery system of claim 7, wherein the gas source is a multiple-cycle manual (MCM) air source.

10. A method, comprising creating a spatially oscillating jet of dry powder aerosol or liquid aerosol, wherein the jet oscillates primarily in one geometric plane.

11. The method of claim 10, wherein the aerosol is a dry powder aerosol.

12. The method of claim 10, wherein the jet is formed into an aerosol by forcing air with entrained aerosol particles through a first flow passage.

13. The method of claim 12, wherein the first flow passage is a capillary.

14. The method of claim 12, wherein the jet is oscillated up and down by emitting the jet from the first flow passage into a second flow passage larger than the first flow passage, wherein the second flow passage has a variable height and a variable width along a longitudinal axis of the second flow passage, wherein the variable height always exceeds the variable width.

15. The method of claim 12, wherein the jet is oscillated up and down by emitting the jet from the first flow passage into a second flow passage larger than the first flow passage, wherein the second flow passage is an elliptical or oval frustum.

16. The method of claim 10, further comprising aerosolizing a dry powder or liquid to form the aerosol prior to forming the aerosol into a jet.

17. The method of claim 10, wherein particles of the aerosol have a mean or median size of >3 pm and <50 pm or 5-20 pm.

18. The method of claim 10, wherein the aerosol is emitted from the aerosol system having a mean or median size within the range of 5-15 pm.

19. The method of claim 10, wherein the aerosol is emitted from the aerosol system having a mean or median size within the range of 8-15 pm.

20. The method of claim 10, wherein the aerosol is emitted from the aerosol system having a mean or median size within the range of 8-12 pm.

21. The method of claim 10, wherein the jet is created using a gas volume <6 mb.

22. A method of operating an aerosol device, comprising forming an aerosol into a jet, wherein the aerosol is a dry powder aerosol or a liquid aerosol; oscillating the jet in a geometric plane; and emitting the oscillating jet from the aerosol device.

23. The method of claim 22, wherein the aerosol is a dry powder aerosol.

24. The method of claim 22, wherein the aerosol is formed into a jet by forcing air with entrained aerosol particles through a first flow passage.

25. The method of claim 24, wherein the first flow passage is a capillary.

26. The method of claim 24, wherein the jet is oscillated up and down by emitting the jet from the first flow passage into a second flow passage larger than the first flow passage, wherein the second flow passage has a variable height and a variable width along a longitudinal axis of the second flow passage, wherein the variable height always exceeds the variable width.

27. The method of claim 24, wherein the jet is oscillated up and down by emitting the jet from the first flow passage into a second flow passage larger than the first flow passage, wherein the second flow passage is an elliptical or oval frustum.

28. The method of claim 22, further comprising aerosolizing a dry powder or liquid to form the aerosol prior to forming the aerosol into a jet.

29. The method of claim 22, wherein particles of the aerosol have a mean or median size of >3 pm and <50 pm or 5-20 pm.

30. The method of claim 22, wherein the aerosol is emitted from the aerosol system having a mean or median size within the range of 5-15 pm.

31. The method of claim 22, wherein the aerosol is emitted from the aerosol system having a mean or median size within the range of 8-15 pm.

32. The method of claim 22, wherein the aerosol is emitted from the aerosol system having a mean or median size within the range of 8-12 pm.

33. The method of claim 22, wherein the jet is formed using a gas volume <6 mL.

34. A method of operating an aerosol system, comprising performing a plurality of aerosol cycles, each aerosol cycle comprising (i) creating a spatially oscillating jet of aerosol in a single actuation, wherein the jet spatially oscillates, and (ii) pausing for a first duration of time which is different than the time of the single actuation.

35. The method of claim 34, wherein the aerosol cycles occur at a frequency of 1-5 Hz.

36. The method of claim 34, further comprising performing a plurality of clean cycles, each clean cycle comprising (iii) creating a spatially oscillating jet of substantially aerosol-free air in afurther single actuation, and (iv) pausing for a second duration of time which is different than the time of the further single actuation.

37. The method of claim 36, wherein the aerosol cycles occur at a frequency of 1-5 Hz.

38. The method of claim 37, wherein the clean cycles occur at a frequency of 1-5 Hz.

39. The method of claim 34, wherein each actuation uses a gas volume <6 mL.

40. The method of claim 34, wherein particles of the aerosol have a mean or median size of >3 pm and <50 pm or 5-20 pm.

41. The method of claim 34, wherein the aerosol is emitted from the aerosol system having a mean or median size within the range of 5-15 pm.

42. The method of claim 34, wherein the aerosol is emitted from the aerosol system having a mean or median size within the range of 8-15 pm.

43. The method of claim 34, wherein the aerosol is emitted from the aerosol system having a mean or median size within the range of 8-12 pm.

44. A method of administering nasally targeted therapeutic to a subject, comprising creating a spatially oscillating jet of dry powder aerosol or liquid aerosol, wherein the jet oscillates up and down along the long cross-sectional dimension of the nasal valve of the subject.

45. The method of claim 44, wherein the aerosol is a dry powder aerosol.

46. The method of claim 44, wherein the jet is formed into an aerosol by forcing air with entrained aerosol particles through a first flow passage.

47. The method of claim 46, wherein the first flow passage is a capillary.

48. The method of claim 46, wherein the jet is oscillated up and down by emitting the jet from the first flow passage into a second flow passage larger than the first flow passage, wherein the second flow passage has a variable height and a variable width along a longitudinal axis of the second flow passage, wherein the variable height always exceeds the variable width.

49. The method of claim 46, wherein the jet is oscillated up and down by emitting the jet from the first flow passage into a second flow passage larger than the first flow passage, wherein the second flow passage is an elliptical or oval frustum.

50. The method of claim 44, further comprising aerosolizing a dry powder or liquid to form the aerosol prior to forming the aerosol into a jet.

51. The method of claim 44, wherein particles of the aerosol have a size of >3 pm and <50 pm or 5-20 pm.

52. The method of claim 44, wherein the aerosol is emitted from the aerosol system having a mean or median size within the range of 5-15 pm.

53. The method of claim 44, wherein the aerosol is emitted from the aerosol system having a mean or median size within the range of 8-15 pm.

54. The method of claim 44, wherein the aerosol is emitted from the aerosol system having a mean or median size within the range of 8-12 pm.

55. The method of claim 44, wherein the jet is created using a gas volume <6 mb.

56. A method of administering nasally targeted therapeutic to a subject, comprising forming an aerosol into a jet, wherein the aerosol is a dry powder aerosol or a liquid aerosol; oscillating the jet in a geometric plane; andemitting the oscillating jet into a nasal cavity so that the geometric plane substantially aligns with the long cross-sectional dimension of the nasal valve of the subject.

57. The method of claim 56, wherein the aerosol is a dry powder aerosol.

58. The method of claim 56, wherein the aerosol is formed into a jet by forcing air with entrained aerosol particles through a first flow passage.

59. The method of claim 58, wherein the first flow passage is a capillary.

60. The method of claim 58, wherein the jet is oscillated up and down by emitting the jet from the first flow passage into a second flow passage larger than the first flow passage, wherein the second flow passage has a variable height and a variable width along a longitudinal axis of the second flow passage, wherein the variable height always exceeds the variable width.

61. The method of claim 58, wherein the jet is oscillated up and down by emitting the jet from the first flow passage into a second flow passage larger than the first flow passage, wherein the second flow passage is an elliptical or oval frustum.

62. The method of claim 56, further comprising aerosolizing a dry powder or liquid to form the aerosol prior to forming the aerosol into a jet.

63. The method of claim 56, wherein particles of the aerosol have a mean or median size of >3 pm and <50 pm or 5-20 pm.

64. The method of claim 56, wherein the aerosol is emitted from the aerosol system having a mean or median size within the range of 5-15 pm.

65. The method of claim 56, wherein the aerosol is emitted from the aerosol system having a mean or median size within the range of 8-15 pm.

66. The method of claim 56, wherein the aerosol is emitted from the aerosol system having a mean or median size within the range of 8-12 pm.

67. The method of claim 56, wherein the jet is formed using a gas volume <6 mL.

68. A method of administering nasally targeted dry powder or liquid aerosol therapeutic to a subject, comprising performing a plurality of aerosol cycles, each aerosol cycle comprising (i) creating a spatially oscillating jet of aerosol in a single actuation, wherein the jet oscillates up and down relative to the subject and along the long cross-sectional dimension of the nasal valve, and (ii) pausing for a first duration of time which is different than the time of the single actuation.

69. The method of claim 68, wherein the aerosol cycles occur at a frequency of 1-5 Hz.

70. The method of claim 68, further comprising performing a plurality of clean cycles, each clean cycle comprising (iii) creating a spatially oscillating jet of substantially aerosol-free air in a further single actuation, and (iv) pausing for a second duration of time which is different than the time of the further single actuation.

71. The method of claim 70, wherein the aerosol cycles occur at a frequency of 1-5 Hz.

72. The method of claim 71, wherein the clean cycles occur at a frequency of 1-5 Hz.

73. The method of claim 68, wherein each actuation uses a gas volume <6 mL.

74. The method of claim 68, wherein particles of the aerosol have a mean or median size of >3 pm and <50 pm or 5-20 pm.

75. The method of claim 68, wherein the aerosol is emitted from the aerosol system having a mean or median size within the range of 5-15 pm.

76. The method of claim 68, wherein the aerosol is emitted from the aerosol system having a mean or median size within the range of 8-15 |am.

77. The method of claim 68, wherein the aerosol is emitted from the aerosol system having a mean or median size within the range of 8-12 jam.

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