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.

Inhaler Characteristics in Asthma

“…29 Not all HFA pMDIs are the same as they can be formulated with the drug insoluble in the formulation (suspension pMDI) or completely dissolved in the formulation (solution pMDI). 30 Solution pMDIs contain a more homogeneous formulation, which does not require shaking prior to use, and deliver aerosols of smaller particle sizes. 19 However, in order to achieve solubility of the drug, a cosolvent such as ethanol must be added to the formulation.…”

Devices for Dry Powder Drug Delivery to the Lung

“…Although this was a milestone for the therapy of pulmonary diseases, concerns arose in 1974 when the contribution of chlorofluorocarbon (CFC) propellants to the depletion of the ozone layer was hypothesized (2). As requested by the Montreal Protocol in 1987, CFCs eventually were substituted in 1995 by more Benvironmental friendly^hydrofluoroalkane (HFA) gases, which were shown not to disturb the oxygen/ ozone equilibrium in the upper stratosphere (3)(4)(5)(6). It has since been realized that HFA gases are up to 2000-fold more potent than carbon dioxide as greenhouse gases, even so they are estimated to contribute less than 0.1% to global greenhouse gas emission (7,8).…”

The Formation of Aerosol Particles from Solution-Based Pressurized Metered Dose Inhalers and Implications of Incomplete Droplet Drying: Theoretical and Experimental Comparison

“…The use of pressurized metered dose inhalers (pMDIs) to deliver medicaments is now commonplace and both suspension-and solution-based formulations exist for the treatment of respiratory diseases including asthma and chronic obstructive pulmonary disease (Rogueda et al 2012;Myrdal et al 2014). In general, the final aerosol particle size distribution of a suspension-based system will primarily be governed by the properties of the suspended particles; including primary particle size, suspension density, ability to resuspend, and accurately meter the drug during use (Myrdal et al 2014). In comparison, the aerosol particle size distribution of a solution-based pMDI will be primarily dependent on the nonvolatile component (NVC) and the vapor pressure of the formulation (Myrdal et al 2014;Zhu et al, accepted).…”

“…In general, the final aerosol particle size distribution of a suspension-based system will primarily be governed by the properties of the suspended particles; including primary particle size, suspension density, ability to resuspend, and accurately meter the drug during use (Myrdal et al 2014). In comparison, the aerosol particle size distribution of a solution-based pMDI will be primarily dependent on the nonvolatile component (NVC) and the vapor pressure of the formulation (Myrdal et al 2014;Zhu et al, accepted). This governs the initial droplet diameter distribution and based on the mass of nonvolatiles in solution, the density of the residual particles and thus the final MMAD (Lewis et al 2004;Stein and Myrdal 2004;Lewis 2013).…”