Advances in metered dose inhaler technology: formulation development

Abstract

Pressurized metered dose inhalers (MDIs) are a long-standing method to treat diseases of the lung, such as asthma and chronic obstructive pulmonary disease. MDIs rely on the driving force of the propellant, which comprises the bulk of the MDI formulation, to atomize droplets containing drug and excipients, which ideally should deposit in the lungs. During the phase out of chlorofluorocarbon propellants and the introduction of more environmentally friendly hydrofluoroalkane propellants, many improvements were made to the methods of formulating for MDI drug delivery along with a greater understanding of formulation variables on product performance. This review presents a survey of challenges associated with formulating MDIs as solution or suspension products with one or more drugs, while considering the physicochemical properties of various excipients and how the addition of these excipients may impact overall product performance of the MDI. Propellants, volatile and nonvolatile cosolvents, surfactants, polymers, suspension stabilizers, and bulking agents are among the variety of excipients discussed in this review article. Furthermore, other formulation approaches, such as engineered excipient and drug-excipient particles, to deliver multiple drugs from a single MDI are also evaluated.

Fig. 1

Solubility of a variety of solutes in ethanol cosolvent systems in HFA 134a (S ^HFA-EtOH) relative to their solubility in a pure HFA 134a system (S ^HFA) as a function of ethanol concentration. LogP for each solute is represented in parentheses in the legend of the graph. Adapted from Hoye and Myrdal (54)

Fig. 2

The effect of ethanol concentration on the resulting initial droplet MMD for HFA 134a solution MDI with 1% (w/w) drug. Andersen cascade impaction measurements were made using a large volume chamber as the inlet. From Stein and Myrdal (55)

Fig. 3

The effect of ethanol concentration on the solubility of beclomethasone dipropionate (BDP) and the resulting FPF in HFA 134a. The dashed line represents the effective solubility of BDP, which is the net gain in the delivered fine particle mass. Adapted from Gupta et al. (56)

Fig. 4

a The effect of ethanol on the fine particle dose and b the effect of ethanol on FPF for 0.1%, 1%, and 1.5% (w/w) cyclosporine (CSP) formulations in HFA 227. Adapted from Myrdal et al. (57)

Fig. 5

Depiction of the influence of nonvolatile drug concentration (oligolatic acid was used as a drug surrogate) on the residual particle MMAD for a series of HFA 134a solution MDIs. Each data point represents an average of four tests, and the error bar represents the standard deviation. Measurements were made using the USP inlet. From Stein and Myrdal (61)

Fig. 6

The theoretical effect of concentration and MMAD of micronized drug on the residual APSD (MMAD of residual particles) derived from simulations with 50 μL metering chambers, 0.3 mm orifice diameters (OD), 8.5% (w/w) ethanol in HFA 134a. From Stein et al. (108)

Fig. 7

Structures of novel surfactants from Glaxo Group Ltd. Adapted from Looker et al. (126,127)