Air-jet dry power inhaler for rapid delivery of pharmaceutical aerosols to infants

Abstract

Proposed devices operate on positive pressure with as little as 5-6 ml of air and can efficiently empty (emitted doses >80%) and deliver the aerosol to infant lungs (lung delivery efficiency of ~60% of the loaded dose). Significant features include internal flow structure of the air-jet DPI, automatic gas sources, infant-specific interfaces, small diameter nasopharyngeal tubes, sealed nasal prongs, 3D rod array preceding patient interface, nasal CPAP rapid aerosol delivery system, nasal CPAP streamlined interface, multidose storage and delivery unit, and pressure sensing near the infant airways (at the nasal cannula interface).

Description

ap<0.05 significant effect of device design on deposition (one-way ANOVA). Discussion The new infant air-jet DPI prototypes tested in this Example achieved performance metrics of >80% ED, MMAD <1.8 pm, and a lung delivery efficiency of approximately 50% of device loaded dose. In assessing the air-jet DPI designs, two distinct sets of devices were identified based on aerosolization performance. Designs D2, D5, and D6 were found to produce a superior combination of MMAD and ED (based on MMAD / ED and linear best-fit lines) than the remaining three devices. Common design features of the three best performing air-jet designs were a cylindrical and horizontal aerosolization chamber together with a flush or protruding outlet. Designs that also included multiple inlets (D5 and D6) achieved the best aerosolization metrics of approximately >80% ED and MMAD < 1.8pm, whereas D2 with a single air inlet did not. Nevertheless, when tested in conjunction with a gradually expanding nasal interface design and infant NT model, all three lead designs achieved approximately 50% drug delivery to the lungs. Furthermore, it is expected that the lung delivery efficiency can be increased beyond 50% by improved regulation of the input flow profile and by inclusion of a 3D rod array in the nasal interface to better dissipate the turbulent jet and further deaggregate the aerosol entering the nose, thereby further reducing the aerosol MMAD and reducing the nasal deposition fraction. The D5 design appears to perform better than previous devices with an ED of 94% and small aerosol size increase to 1.85 pm. As a result, this Example indicates that air-jet performance was enhanced through the development of an aerosolization chamber with multiple inlets and a flush or protruding outlet. Despite significant variation in the best performing devices (D2, D5, and D6 with an ED range of 75.6-94.1%), in vitro lung delivery efficiency was consistently around 50% using the full-term NT geometry. As described, the D2 design provided excellent NT penetration with only 8.0% depositional loss, but relatively poor emptying with ED of 75.6% (71.6% when connected to the infant NT model). Increasing the device emptying also increased the MMAD, which led to a significant depositional loss in the NT model. An exemplary device for infant N2L aerosol delivery therefore appears to be one that can achieve an MMAD of 1.6 pm and ED near 95%. Intended uses of the infant air-jet DPI include the rapid administration of high dose inhaled medications such as aerosolized antibiotics and surfactants. For either of these applications, total doses higher than the 10 mg loaded dose employed in this study will likely be needed. The aerosolization chamber in the current study has a total volume of 0.68 ml, which if approximately half full can accommodate 40-50 mg of powder based on typical EEG powder density. An alternative to accommodate higher total dose loading may be an auto-loading system for the air-jet DPI such that each actuation delivers a 10 mg dose of powder formulation. Figures 7A, 7B, 8A, and 8B and their corresponding descriptions above show and describe some exemplary auto-loading systems. As demonstrated in this Example, the infant air-jet DPI is expected to provide a number of advantages for aerosol delivery to infants of all ages. First, device actuations of 10 ml and 30 ml require time periods between 0.2 and 1.0 s. The devices tested performed very similar at both AAVs in terms of aerosolization performance. Therefore, the only reason to implement the higher AAV for the older full-term infant is to provide a full inhalation breath. This air volume can be reduced to accommodate stiff or non-compliant lungs as needed. By operating the delivery system with positive pressure, it is expected that the highly flexible infant upper airways will be expanded, enabling better deep lung penetration of the aerosol. In the current Example an enforced breath hold of 10 s was implemented; however, this length of time is not needed for aerosol retention as EEG aerosols approach their fully hydrated droplet size within approximately 0.5 to 1 s under infant airway conditions. Nevertheless, under resuscitation conditions, infant lung inflation followed by a 10 s breath hold improves lung mechanics and patient outcomes compared with standard rapid ventilation with a bag and mask. With a singleprong design, infant exhalation can be accomplished by releasing the nostril without the nasal interface. For a dual-prong design, an exhalation port is included in the nasal interface close to the patient. Opening of the exhalation port can be automated with a single button on the device that also controls actuation of the air source. The in vitro NT model employed in the current Example has several differences from in vivo conditions that should be considered. As described previously, the air-jet DPI delivers both the aerosol and a full inhalation breath such that cyclic breathing of the model is not required. However, more realistic airway delivery conditions need to include the downstream resistance and compliance of the lungs. The effect of this resistance and compliance on aerosol generation is expected to be small considering the relatively low ventilation volumes (7-8 ml / kg) that are employed. Furthermore, the airway walls were not warmed and humidified to physiologic conditions. It is known that some size increase of hygroscopic aerosols occurs in the nose. However, this aerosol size increase in the extrathoracic region is small with an associated negligible increase in NT deposition (<5% relative difference) for adult airway conditions. The air-jet DPI forms a closed system with the airways such that subject exhalation into the aerosolization chamber containing the powder is not possible. Variations in airflow delivery associated with hand-operation of the gas source are observed in Figure 16. Despite these variations, performance of the air-jet DPI was relatively consistent with acceptable standard deviation values. The nasal interface is an important source of potential aerosol loss and also influences loss in the NT model. The single gradual expansion nasal interface used in this study was the result of preliminary design work that improved upon nasal interface losses as high as 40% of the loaded dose. While 10% nasal interface depositional loss is acceptable, it is expected that this deposition can be further reduced, likely through optimization of the inlet flow profile and / or inclusion of a 3D rod array structure in the interface designed to disperse the turbulent jet and further deaggregate the powder. Finally, this Example considered only one NT model under full-term neonate conditions. Aerosol deposition in the NT region is known to be highly variable and where the tested model falls within this spectrum is currently not known. In conclusion, this Example tests a prototype air-jet aerosol delivery system to administer high doses of spray-dried powder formulations to infants. The patient interface is a simple gradually expanding flow passage that produced low depositional loss and device actuation times are in a range between 0.2 and 1.0 s. Delivery efficiency of drug to the lungs was approximately 50% of the loaded dose across the three best performing devices. Advantageous design options in the air-jet DPI were identified as a horizontal and cylindrical aerosolization chamber, flush or protruding outlet, and multiple inlets. Intended applications of exemplary infant air-jet DPIs and DPI systems are the delivery of higher dose inhaled medications where efficacy can be increased with improved lung and deep lung targeting, and where reduced inter- and intra-subject variability is important. Potential candidate medications include inhaled antibiotics, growth hormone, anti-virals, gene therapies for lung diseases, bronchodilators and corticosteroids for asthma management, surfactants, clearance agents, insulin, and anti-inflammatories. 2021209916   10 Aug 2026 It is to be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to be limiting, since the scope of the present invention will be limited only by the appended claims. It is noted that, as used herein and in the appended claims, the singular forms "a", "an", 5 and "the" include plural referents unless the context clearly dictates otherwise. It is further noted that the claims may be drafted to exclude any optional element. As such, this statement is intended to serve as antecedent basis for use of such exclusive terminology as "solely," "only" and the like in connection with the recitation of claim elements, or use of a "negative" limitation. As will be apparent to those of skill in the art upon reading this disclosure, each of the 0 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. 15          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, 20 subject to any specifically excluded limit in the stated range. Where the stated range includes one or both of the limits, ranges excluding either or both of those included limits are also included in the invention. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention 25 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. Any reference in this specification to prior art or matter which is said to be known is not to be taken as an acknowledgement or admission that such prior art or matter forms part of the 30 common general knowledge in the field of invention to which this specification relates. 2021209916   10 Aug 2026 Throughout this specification, unless the context requires otherwise, the word “comprise” and any variations thereof, such as “comprises” or “comprising”, are to be interpreted in a nonexhaustive sense.

Claims

1. An air jet dry powder inhaler (DPI) system for infants, comprising:a positive pressure gas source comprising a volume limiter, wherein the volume limiter is adjustable to allow precise control over an amount of a gas volume to be delivered to an infant;a patient interface configured to form an airtight seal with one or both of an infant’s nostrils; andan air jet DPI arranged inline between the gas source and the patient interface and configured to introduce dry powder particles to the gas volume from the gas source to form an aerosol before the gas reaches the patient interface,wherein the air jet DPI comprises an aerosolization chamber and one or more inlets configured so that an inlet air jet entering the aerosolization chamber does not impinge on an initial bed of powder.

2. The DPI system of claim 1, wherein the volume limiter is adjustable so that the gas volume to be delivered is a maximum of 100 ml or less, and / or wherein a total air space volume of the air jet DPI system excluding a volume of the gas source is 5 ml or less.

3. The DPI system of claim 1 or 2, wherein the gas source is configured to deliver the gas volume to be delivered in one second or less.

4. The DPI system of any one of claims 1 to 3, wherein the gas source comprises one or more hand-actuated syringes.

5. The DPI system of any one of claims 1 to 3, wherein the gas source is a compressed gas source, wherein the gas source is a bank of gas syringes compressible prior to actuation, wherein the gas syringes are individually actuatable to separately release predetermined volumes of compressed gas to a single outlet of the gas source.

6. The DPI system of any one of claims 1 to 5, wherein a cannula of the patient interface has a gradually expanding interior over a length of 40-80 mm.2021209916   10 Aug 20267. The DPI system of any one of claims 1 to 5, wherein the patient interface comprises a nasopharyngeal tube.

8. The DPI system of any one of claims 1 to 7, further comprising a bend in flow path downstream of the air jet DPI of 10° to 45°.

9. The air jet DPI system of any one of claims 1 to 8, further comprising:a drying chamber; anda one-way valve configured for admitting air from the environment into the air jet DPI system when the gas source volume is expanding.

10. The DPI system of any one of claims 1 to 9, wherein the air jet DPI comprises: an elongate aerosolization chamber with a longitudinal axis, andone or more inlets and one or more outlets all positioned at an upper longitudinal segment of the aerosolization chamber,wherein the upper longitudinal segment extends no more than 50% of a length of the aerosolization chamber.

11. The DPI system of any one of claims 1 to 10, wherein the patient interface comprises a 3D rod array arranged such that an aerosol jet entering the patient interface must pass through the 3D rod array before exiting the patient interface.

12. The DPI system of any one of claims 1 to 11, wherein the positive pressure gas source further comprises:a barrel sized to retain 100 ml or less of gas, the barrel having an exit orifice at one end;a rod;a piston and gasket sealing an end of the barrel opposite the exit orifice and moveable by the rod to change an internal volume of the barrel by driving gas into or out of the exit orifice;a body that houses the rod and the piston;a handle grip;2021209916   10 Aug 2026a hinge; anda spring arranged to urge the handle grip away from the body about the hinge,wherein the handle grip is configured such that the rod, piston, and gasket are moveable a maximum displacement to deliver a predetermined volume of air through the exit orifice using a single squeeze that moves the handle grip toward the body.

13. The DPI system of any one of claims 1 to 12, further comprising a multidose storage and delivery unit (MDU) for dosing dry powder into the air jet DPI, the MDU comprising:a main body sized to accommodate 100 mg or less of powder and configured to attach in an airtight manner to an aerosolization chamber of the air jet DPI, wherein the main body is not subdivided into compartments; anda release mechanism for releasing predetermined doses from the main body into the aerosolization chamber of the air jet DPI upon satisfaction of a predetermined condition.

14. The DPI system of any one of claims 1 to 13, wherein the volume limiter is adjustable to set the gas volume to be delivered to be 6-8 ml of gas per kg of infant body weight.

15. The DPI system of any one of claims 1 to 14, wherein the patient interface comprises a pressure port and a pressure sensor connected to the pressure port and configured to monitor pressures to which the infant lungs are exposed.

16. The DPI system of claim 15, further comprising a pressure-limiting valve or pop-off valve that opens if the pressure sensed by the pressure sensor exceeds a specified safe amount.

17. The DPI system of claim 10, wherein the positive pressure gas source further comprises a timer relay set to run air out of one or more of the outlets depending on the gas volume to be delivered.

18. A method of using an air jet dry powder inhaler (DPI) system for infants, comprising:adjusting a volume limiter on a gas source to an amount of a gas volume to be delivered to an infant depending on infant weight;2021209916   10 Aug 2026forming, by a patient interface, an airtight seal with one or both nostrils of the infant;introducing, by an air jet DPI arranged inline between the gas source and the patient interface, dry powder particles to the gas volume from the gas source to form an aerosol before the gas reaches the patient interface; anddelivering in a single actuation of the gas source the aerosol that includes the gas volume to be delivered to the infant using positive pressure;wherein the air jet DPI system is configured to have airtight communication with lungs of the infant when the patient interface is forming an airtight seal with one or both of the infant’s nostrils and all other pulmonary orifices are closed.

19. The method of claim 18, wherein the aerosol and gas volume to be delivered are delivered at a delivery flow rate of 1.2 to 5 LPM.

20. The method of claim 18 or 19, further comprising limiting delivery pressure received by the infant, measured at the patient interface, to 15 to 40 cm H2O to best prevent lung damage.

21. The method of any one of claims 18 to 20, wherein the gas volume to be delivered is delivered in one second or less.

22. The method of any one of claims 18 to 21, further comprising repeating a cycle of the forming, introducing, and delivering steps multiple times to deliver the full dose desired, wherein the infant’s second nostril and / or mouth is opened between cycles.

23. The method of any one of claims 18 to 21, further comprising repeating a cycle of the forming, introducing, and delivering steps multiple times to deliver the full dose desired, wherein the infant exhales through an exhalation port located on the patient interface.

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