Devices for Improved Delivery of Nebulized Pharmaceutical Aerosols to the Lungs

Abstract

Nebulizers have a number of advantages for the delivery of inhaled pharmaceutical aerosols, including the use of aqueous formulations and the ability to deliver process-sensitive proteins, peptides, and biological medications. A frequent disadvantage of nebulized aerosols is poor lung delivery efficiency, which wastes valuable medications, increases delivery times, and may increase side effects of the medication. A focus of previous development efforts and previous nebulizer reviews, has been an improvement of the underlying nebulization technology controlling the breakup of a liquid into droplets. However, for a given nebulization technology, a wide range of secondary devices and strategies can be implemented to significantly improve lung delivery efficiency of the aerosol. This review focuses on secondary devices and technologies that can be implemented to improve the lung delivery efficiency of nebulized aerosols and potentially target the region of drug delivery within the lungs. These secondary devices may (1) modify the aerosol size distribution, (2) synchronize aerosol delivery with inhalation, (3) reduce system depositional losses at connection points, (4) improve the patient interface, or (5) guide patient inhalation. The development of these devices and technologies is also discussed, which often includes the use of computational fluid dynamic simulations, three-dimensional printing and rapid prototype device and airway model construction, realistic in vitro experiments, and in vivo analysis. Of the devices reviewed, the implementation of streamlined components may be the most direct and lowest cost approach to enhance aerosol delivery efficiency within nonambulatory nebulizer systems. For applications involving high-dose medications or precise dose administration, the inclusion of active devices to control aerosol size, guide inhalation, and synchronize delivery with inhalation hold considerable promise.

Keywords: inhalers; nebulizers; pharmaceutical aerosol devices; respiratory drug delivery.

FIG. 1.

(a) Large-volume mixer/heater design illustrating a reservoir mixing region to hold the aerosol during periods of exhalation with minimum depositional loss and a narrow channel heating region to evaporate liquid from the aerosol droplets producing a humidified gas stream with submicrometer particles. (b) CFD simulations of mixer/heater operation at an airflow rate of 30 LPM demonstrating aerosol evaporation to submicrometer size and low device depositional loss (<5% of nebulized dose). CFD, computational fluid dynamics; LPM, liters per minute. Portions redrawn from Golshahi et al.⁽⁷⁶⁾ with permission of Taylor and Francis.

FIG. 2.

Drug deposition fractions from in vitro experiments of nose-to-lung nebulized aerosol delivery for a conventional mesh nebulizer (control) compared with ECG delivery with a divided nasal cannula. The ECG delivery cases implemented the same mesh nebulizer combined with a mixer/heater device to produce submicrometer aerosol size. In all cases, the model drug was AS. For ECG delivery, hygroscopic excipients of MN or NaCl were also considered. AS, albuterol sulfate; ECG, enhanced condensational growth; MN, mannitol; NaCl, sodium chloride. From Golshahi et al.⁽⁷¹⁾ with permission of Springer Nature.

FIG. 3.

CFD simulation results of nose-to-lung aerosol delivery during HFNC therapy employing a conventional mesh nebulized aerosol (control) and ECG aerosol generated with a mixer/heater device. In all cases, a mesh nebulizer delivered an AS formulation: (a) Control-AS deposition, (b) ECG-AS:NaCl deposition, (c) Control-AS trajectories, (d) ECG-AS:NaCl trajectories. The ECG approach implemented a mixer/heater to form a submicrometer aerosol and included a hygroscopic excipient (NaCl). The initial submicrometer aerosol size of the ECG aerosol reduces nasal cavity depositional loss by an order of magnitude (a vs. b). Interestingly, the size of the control aerosol decreases due to impaction of larger droplets whereas the size of the ECG-AS:NaCl aerosol increases due to hygroscopic growth (c vs. d). HFNC, high-flow nasal cannula. From Golshahi et al.⁽⁷¹⁾ with permission of Springer Nature.

FIG. 4.

Different forms of synchronized aerosol delivery during a breathing waveform as described by Denyer et al.⁽⁸²⁾ Light gray indicates aerosol that is generated during inhalation and ideally reaches the lungs. Darker gray indicates the proportion of aerosol that is generated during exhalation and has little chance of reaching the lungs. Both the flow rate and delivery duration of the delivered aerosol varies with synchronization method.

FIG. 5.

Comparison of conventional (left column) and streamlined (right column) designs⁽⁶⁹⁾: (a, b) nebulizer T-connectors; (c, d) Y-connectors for invasive ventilation; (e, f) nasal cannula for high-flow nasal cannula (HFNC) therapy; (g, h) Y-connectors for low-flow oxygen therapy; (i, j) nasal cannula for low-flow oxygen therapy.

FIG. 6.

CFD simulations of Y-connector performance when connected to an ETT during invasive mechanical ventilation. Compared with the conventional system (a), the streamlined design (b) significantly reduces turbulent viscosity ratio, which is a measure of turbulence intensity and correlates with aerosol particle deposition. Due to reduced turbulence and continually curving surfaces, high depositional drug loss in the conventional Y-connector (c) is reduced in the streamlined design (d). ETT, endotracheal tube. Redrawn from Longest et al.⁽⁹⁰⁾ with permission of American Association for Respiratory Care.

FIG. 7.

CFD-based comparison of particle trajectories through (a) conventional and (b) streamlined HFNC. The streamlined cannula is observed to have improved particle transmission and reduced exit velocity. Reproduced from Longest et al.⁽⁸⁹⁾ with permission of Springer Nature.

FIG. 8.

(a) CFD simulation results of velocity in two planes during aerosol formation from the CAG. Significant flow recirculation in the region of the mouthpiece forms an effective diameter (d_eff) that reduces the area available for aerosol transmission. (b) The effective mouthpiece diameter (d_eff) correlates with mouthpiece deposition fraction and can be used as a quantitative design parameter for improving the CAG aerosol depositional loss, as verified with concurrent in vitro experiments. CAG, capillary aerosol generator. Reproduced from Hindle and Longest⁽⁶⁰⁾ with permission of Mary Ann Liebert, Inc.

FIG. 9.

Aerosol induction charger developed to produce highly charged droplets from a conventional mesh nebulizer. Droplet charge has been suggested as a potential strategy to target aerosol deposition within the lungs. Reproduced from Golshahi et al.⁽¹¹⁵⁾ with permission of Springer Nature.

FIG. 10.

SUPRAER^™ system designed to produce high concentrations of respirable aerosols from viscous liquid formulations. Reproduced from Yeates and Heng⁽¹²⁰⁾ with permission from Respiratory Drug Delivery 2016, Virginia Commonwealth University and RDD Online.

FIG. 11.

Small-volume mixer/heater system containing separate humidity and drug nebulizers. Submicrometer aerosols are generated using a combined heating and nebulizer control unit that is capable of breath synchronized delivery.

FIG. 12.

CFD analysis of ECG aerosol delivery via oral inhalation including (a) design of a dual flow mouthpiece for administering aerosol and humidity streams, and (b) simulated hygroscopic growth of a submicrometer ECG aerosol following oral inhalation. Particle size distributions were determined at the exit of the MT and at respiratory generation G5. (c) Particle trajectories contoured based on increasing aerosol diameter with RH contours indicating the formation of supersaturated conditions during ECG delivery. For a variety of ECG delivery conditions, both in vitro experiments and CFD simulations predicted <3% MT depositional loss of the ECG aerosol⁽⁷³⁾ with an aerosol MMAD of 3.4 μm entering the lung lobes. MMAD, mass median aerodynamic diameter; MT, mouth/throat; RH, relative humidity. Redrawn from Hindle and Longest⁽⁷³⁾ with permission of Springer Nature.