Effervescent Aerosols: A Novel Formulation Technology for Solution and Suspension-type Metered Dose Inhalers

Abstract

Pressurized metered dose inhalers are complex drug delivery systems which have revolutionized the treatment of asthma and chronic obstructive pulmonary disease since the 1950s. Since the early 1990s, solution and suspension metered dose inhalers have been formulated using HFA-134a and HFA-227 as the propellants of choice, along with other excipients such as ethanol and oleic acid. Performance of an inhaler is partially dependent upon the size of particles it generates, which is partially dictated by intra-canister pressure. In this dissertation, a novel method of formulation of inhalers- the "effervescent aerosol technology" has been introduced. A propellant consisting of HFA-134a containing dissolved carbon dioxide has been used to formulate solution and suspension inhalers. We hypothesized that dissolution of carbon dioxide in HFA-134a will lead to higher degree of aerosol particle size reduction upon actuation, caused due to the process of effervescence i.e. escape of dissolved carbon dioxide from HFA -134a droplet. Since this is a novel technology, the initial part of the dissertation tested the hypothesis in a custom-designed pressure vessel capable of holding and spraying solution inhaler formulations. Particle size analysis was done using Malvern Spraytec®, a laser diffractometry instrument. Formulations prepared using a mixture of HFA-134a and carbon dioxide showed significantly lower particle sizes compared to analogous, pressure-controlled formulations. In the later part of the dissertation, a method to transfer the formulation from the pressure vessel to commercially viable canisters has been described. Further laser diffractometry experiments showed that solution and suspension inhalers prepared using effervescent aerosol technology consistently produce particles with significantly lower particle sizes than HFA-134a-only inhalers. Cascade impaction testing showed that inhalers prepared using a mixture of HFA-134a and carbon dioxide cause significantly lower throat deposition and show improvements in other crucial performance parameters, when compared to HFA-134a-only formulations. Additionally, spray characterization studies such as spray force and plume geometry have also been conducted. This thesis demonstrates that using a combination propellant of liquefied HFA-134a and dissolved CO2 to prepare solution and suspension-type metered dose inhalers is a viable formulation strategy to achieve improved inhaled drug delivery.