Elucidating the Mechanism of the Effects of Co-jet-milled L-leucine on the Dispersibility of Levodopa Dry Powder for Inhalation
Julia M.E. Berends1, Henderik W. Frijlink1, Floris Grasmeijer1,2
1Department of Pharmaceutical Technology and Biopharmacy, University of Groningen, Antonius Deusinglaan 1, Groningen, the Netherlands
2PureIMS B.V., Ceintuurbaan Noord 152, Roden, the Netherlands
Summary
Introduction – A common approach to enhance the dispersion of highly dosed dry powders for inhalation is to add force control agents, such as L-leucine. In co-spray-dried formulations, L-leucine enhances the dispersion by the formation of a shell surrounding the particles. However, the mechanism whereby L-leucine exerts its dispersion-enhancing effects in co-jet-milled formulations is unknown. This study aims to gain insight into this mechanism.
Methods – Pure levodopa and L-leucine were micronized to an inhalable size range using a jet mill. Furthermore, levodopa was co-jet-milled with L-leucine in contents of 0.5%, 2%, and 10%. Inhaler dispersion measurements were performed to analyse the performance of the formulations regarding dispersion efficiency and inhaler retention. Furthermore, the morphology of the formulations was assessed.
Results and discussion – Co-jet-milling of only 0.5% L-leucine led to a marked increase in dispersibility and a reduction in inhaler retention compared to pure jet-milled levodopa. The particles of the co-jet-milled formulations exhibited a less smooth surface and appeared to be more edgy than particles of pure jet-milled levodopa. Furthermore, the primary particle size distribution of the co-jet-milled formulations was smaller than that of pure jet-milled levodopa. Additionally, the pure jet-milled L-leucine exhibited poor dispersion properties, including high inhaler retention. These results suggest that the mechanism behind the increased dispersibility arises from an interacting effect between L-leucine and levodopa during co-jet-milling.
Conclusion – Co-jet-milled L-leucine enhances the powder emission and dispersion of levodopa dry powder for inhalation. The underlying mechanism could possibly be attributed to an increased surface roughness of the co-jet-milled formulations, but other interacting effects may play a role as well.
Key Message
The existing hypothesis that L-leucine exerts its dispersion enhancing and inhaler retention reducing effects by an increased surface rugosity appears likely based on SEM imaging, but further experiments are necessary to verify this hypothesis and to test other explanations.