Research Article
Pharmaceutics, Drug Delivery and Pharmaceutical Technology
Effect of Spacers on the Bipolar Electrostatic Charge Properties of Metered Dose Inhaler Aerosols—A Case Study With Tilade®

https://doi.org/10.1016/j.xphs.2017.02.014Get rights and content

Abstract

Aerosols emitted from metered dose inhalers (MDIs) are generally electrically charged and bipolar in nature. Although a spacer can effectively dampen the charge magnitude of aerosols, the electrostatic interactions between the positively and negatively charged particles and the spacer have not yet been characterized separately. The Bipolar Charge Analyzer (BOLAR) was employed to investigate interactions between the spacer and the charged aerosols. Three individual actuations of Tilade® MDI were introduced without a spacer and through an antistatic AeroChamber Plus® Z Stat®, an uncoated and a detergent-coated AeroChamber Plus® spacer into the BOLAR at 60 L/min. Charge and mass profiles were determined. The surface potential of spacers followed the order of uncoated > detergent-coated > antistatic spacer. The spacers had minimal impact on the positively charged particles but the charge magnitude of the negatively charged particles was in the opposite order as the spacer surface potential. The charge-to-mass ratio of particles had little alteration for all measurements. Negatively charged particles had a higher tendency to deposit on the spacer walls, possibly due to their higher abundance in the confined spacer volume. The bipolar data may prove useful for designing better MDIs and spacers and modelling lung deposition of charged aerosol particles.

Introduction

Metered dose inhalers (MDIs) have been widely used for the treatment of asthma and chronic obstructive pulmonary disease (COPD) since its invention in 1956.1 Yet, improper use of the inhaler device remains one of the major causes for poor management of these chronic diseases.2 Failure to coordinate actuation with inhalation, too short a breath-hold, high inspiratory flow, and stopping inspiration when the MDI spray hits the throat are the common errors.3 Spacer devices have then been implemented to overcome these problems, especially actuation-inhalation coordination. A spacer device serves as a reservoir to retain MDI aerosols to allow the reduction of the momentum and size of the droplets upon propellant evaporation. Hence, patients can inhale the aerosols through a 1-way valve of the spacer at their own pace. Aerosol drug particles actuated into a spacer can deposit on the spacer walls by inertial impaction (large, fast-moving particles), gravitational sedimentation (smaller particles), and electrostatic attraction between the drug particles and the walls.2 Therefore, the use of a spacer device has showed to reduce drug deposition in the mouth and throat regions.4

To achieve good portability and durability, most spacers are made of lightweight plastic materials, such as polycarbonate and polypropylene.5, 6 Due to the nonconducting nature of plastic spacers, electrostatic charge inevitably accumulates on the surface of these devices upon packaging and handling. As reported in previous studies,7, 8, 9, 10 aerosols emitted from MDIs are electrically charged and generally bipolar in nature. Since charged aerosols are confined inside the spacer, they may experience mutual repulsion because their space charge causing them to move toward the walls.6, 11 As a result, the electrostatic interactions between the emitted aerosol particles and charged spacer wall are inevitable and may affect the drug delivery. Indeed, the negative impact of the spacer charges on MDI aerosol drug output was well reported.12, 13, 14 Coating spacers with ionic detergent has been shown to be an effective and economic method for reducing the spacer wall charges and improve drug delivery.12, 14, 15 Due to the recent advancement in material sciences, spacers made of nonmetallic, antistatic materials to improve drug delivery efficiency have become widely available.16

The electrostatic interactions between the spacer walls and MDI aerosols were first characterized by Kwok et al.17 using a modified 13-stage electrical low pressure impactor (ELPI). They showed that the charge magnitudes of the aerosols discharged from 4 commercially available MDIs were significantly dampened with the use of a spacer. Although both positive and negative charged particles are present in the same-size fraction,7, 9 the ELPI measures only the net charge,18 masking the influences on particles of individual polarities. The capability of the Bipolar Charge Analyzer (BOLAR) in simultaneously characterizing bipolar electrostatic charge profiles and measuring the size distribution of MDIs was demonstrated in our previous work.9 In the present study, we extend the applicability of BOLAR to study the influence of 3 spacers: (1) AeroChamber Plus® Z Stat® which is made of an antistatic material, (2) AeroChamber Plus® which is made of a nonconducting plastic (polycarbonate), and (3) detergent-coated AeroChamber Plus® on the bipolar electrostatic characteristics and the deposition of drug emitted from Tilade® MDI. The influences of the spacers on positively and negatively charged particles emitted from MDI are first assessed. Collected information would be relevant for the design and use of spacer with MDI.

Section snippets

Metered Dose Inhaler and Spacers

Tilade® (Aventis Pharma, Guildford, UK) is a suspension MDI containing 2 mg of nedocromil sodium and povidone, macrogol 600 as excipients, with HFA-227ea as the propellant. As reported in our previous study, a valid charge measurement does not guarantee a valid mass measurement using the BOLAR. Also, the sensitivity of the mass assay dropped significantly as the amount of active pharmaceutical ingredient decreases. Therefore, Tilade® was chosen as the model inhaler for the present study to

Surface Potential of Spacers

The surface potential inside the spacers was measured before and after actuating the Tilade® MDI for the charge measurement using BOLAR. Figure 2 shows the representative profiles at the 2 measurement locations (5 cm and 10 cm from the inhaler end) of the antistatic, uncoated, and detergent-coated spacers. The magnitude and polarity of the surface potential were found to be nonuniformly distributed inside the spacers. The surface potential profiles of the uncoated and detergent-coated

Discussion

The influences of spacers on the positively and negatively charged particles present in the MDI aerosols were first examined separately using the BOLAR. From the surface potential profiles within the spacers (Fig. 2), the spacers were negligibly (AeroChamber Plus® Z Stat®), slightly (detergent-coated AeroChamber Plus®), or highly (uncoated AeroChamber Plus®) charged, where the positively and negatively charged areas nonuniformly distributed within the spacer. Therefore, it was difficult to

Conclusion

The BOLAR was successfully employed to investigate the influence of commercially available spacers on the charged Tilade® MDI aerosols which are bipolar in nature. Interestingly, the influence of the charged spacer on the charged particles was polarity dependent—the charge magnitude of the positively charged particles remained relatively similar but the charge level of negatively charged particles decreased as the surface potential inside the spacer became higher. Despite there are changes in

Acknowledgments

This study was supported by an Australian Research Council Discovery Project (DP160102577). Sharon Leung is a research fellow supported by the University of Sydney.

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