Improving Pulmonary Delivery of Budesonide Suspensions Nebulized with Constant-Output Vibrating Mesh Nebulizers by Using Valved Holding Chamber

Abstract

Background: Vibrating mesh nebulizers (VMNs) are not only used to deliver typical pulmonary drugs but are also a promising platform for novel formulations and therapeutic applications. Typically, these devices operate continuously or on demand and are directly connected to the outflow interface (mouthpiece or mask) without valving systems that could spare the drug during exhalation. This paper examines the possibility of increasing the delivery of inhaled budesonide aerosol by attaching a valved holding chamber (VHC) to selected VMNs. Methods: A laboratory in vitro study was conducted for seven budesonide (BUD) nebulization products (0.25 mg/mL). The rates of aerosol delivery from VMNs alone or VMN + VHC systems were determined gravimetrically for a simulated breathing cycle, while droplet size distributions in mists were measured by laser diffraction. Results: The VMN + VHC systems increased the amount of aerosol available for inhalation and the fraction of fine particles that could penetrate the pulmonary region. Depending on the VMN and BUD product, a relative increase of 30-300% in the total drug delivery (T) and 50-350% in the pulmonary drug availability (P) was obtained. The results are explained by the reduction in aerosol losses during exhalation (the fugitive emission) by the VHC and the simultaneous elimination of the largest droplets due to coalescence and deposition in the chamber. Both VMN and BUD affected the aerosol's properties and discharge mass and thus the actual benefits of the VHC. Conclusions: While the results confirm the superiority of VMN + VHC over VMNs alone in nebulizing BUD suspensions, they also show that it is difficult to predict the effects quantitatively without testing the individual nebulizer-chamber-drug combination.

Keywords: aerosol; budesonide; drug availability; inhalation; nebulization.

Figure 1

Vibrating mesh nebulizers used in the study: (a) Sanity Silent Mesh—SM, (b) Sanity Fast Mesh—FM, (c) Ca-Mi One Pro—OP, and (d) valved holding chamber Turbo Chamber Sanity.

Figure 2

A schematic of the experimental set-up: 1—mesh nebulizer; 2—valved holding chamber (optional); 3—balloon; 4—breathing simulator ASL 5000 XL. The arrows show the bidirectional breathing airflow.

Figure 3

Fine particle fraction of the aerosol that leaves the nebulizers alone (‘No VHC’) and with the holding chamber (‘with VHC’): (a) SM nebulizer; (b) FM nebulizer; (c) OP nebulizer. Statistically significant differences are indicated by an asterisk (p < 0.05).

Figure 4

MMAD of the aerosol that leaves the nebulizers alone (‘No VHC’) and with the holding chamber (‘with VHC’): (a) SM nebulizer; (b) FM nebulizer; (c) OP nebulizer. Statistically significant differences are indicated by an asterisk (p < 0.05).

Figure 5

The relative increase in (a) total availability (T) and (b) pulmonary availability (P) of aerosols administered by SM + VHC. Error bars denote standard deviation (n = 3).

Figure 6

The relative increase in (a) total availability (T) and (b) pulmonary availability (P) of aerosols administered by FM + VHC. Error bars denote standard deviation (n = 3).

Figure 7

The relative increase in (a) total availability (T) and (b) pulmonary availability (P) of aerosols administered by OP + VHC. Error bars denote standard deviation (n = 3).

Figure 8

Arrangement of the air inlets in the outlet tubes of the VMNs (air inlets are indictaed by arrows): (a) three inlets in the SM; (b) single top inlet in the FM; (c) four inlets in the OP elbow.

Figure 9

Comparison of VMN operation during air exhalation by a patient: (a) VMN alone; (b) VMN with VHC. 1—nebulized drug in a VMN head; 2—opening in nebulizer outflow tube; 3—fugitive aerosol; 4—airflow exhaled by a patient; 5—valved holding chamber; 6—unidirectional valve; 7—exhaled air released from the system.