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Mixing Energy as an Adjustment Tool for Aerodynamic Behavior of an Inhaled Product, In Vitro and In Vivo Effects

Thalberg K, Matilainen L, Eriksson P, Husman-Piirainen J, Autio M, Lyberg A, Goransson S, Kirjavainen M, Lahelma S.

Respiratory Drug Delivery 2023. Volume , 2023: 135-140.

Abstract:

This paper describes the development of candidate formulations for fixed dose combination indacaterol maleate (Inda) and glycopyrronium bromide (Glyco) powders in the Easyhaler® inhaler for use in a comparative pharmacokinetic (PK) study. The development aim was to produce formulations with three different in vitro dispersibility profiles for both Inda and Glyco. This ‘rake’ approach allows for quantitation of the candidate formulations relative to the reference product Ultibro® Breezhaler® based on PK data. Formulation development was based on the mixing energy (ME) concept, which has been reported to be a useful tool to control the dispersibility of adhesive mixtures. Three formulations (A, B and C), all having the same composition, but each produced using a different ME, were prepared. Fine particle fraction levels were significantly different for the three formulations, fulfilling the development targets. Inda and Glyco showed similar dispersibility profiles. Formulations for the PK study were manufactured following Good Manufacturing Practice (GMP) guidelines.

In the PK study, there was good discrimination between the three formulations and clear trends were seen between in vitro results and PK parameters. For Inda, formulation B was shown to provide an equivalent lung dose with the reference product. For Glyco, plasma concentrations of the test formulations were at a lower level than that of the reference product. It is believed that further fine tuning of the performance is feasible by adjustment of the mixing energy as well as of particle size for the two active pharmaceutical ingredients (APIs).