Clarithromycin nanocrystals in composite dry powder particles for high dose inhalation

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Summary

Pulmonary drug delivery is an established route of administration for local or also systemic therapy. Typically, dry powder inhalers are loaded with an interactive powder consisting of a carrier and a small amount of high potent drugs. By preparing “Trojan” microparticles (microparticles “hiding” many nanoparticles in their shell) structured in a hollow core and a shell out of more than 70 percent drug nanocrystals and a small amount of matrix material, it is possible to use active ingredients with higher therapeutic doses, such as antibiotics. This is especially convenient for pneumonia as with this local administration is possible which avoids the first pass effect of the liver. In this study, Clarithromycin nanocrystals for Trojan particles were prepared by media milling in a stabiliser solution. The influence of different amounts of HPMC as stabiliser was investigated. It was shown, that the lower the stabiliser concentration is the smaller the grinded particles get. However, without HPMC the nanocrystals agglomerate. Through spray drying the nanocrystal suspension, microparticles were prepared and the morphology as well as their geometric diameter were analysed. A minimum HPMC concentration is required for the formation of Trojan particles. By adding further HPMC with a high molecular weight after bead milling the total HPMC concentration can be reduced and it is possible to manufacture Trojan particles with a calculated API load of up to 96 %. The aerodynamic particle size distribution was evaluated for two different batches of microparticles utilising the TwinMax, a novel inhalation device for high dose therapy. First results show that a lower HPMC concentration in the formulation leads to less agglomeration and hence a higher fine particle fraction.

Key Message

We established a method to produce Trojan microparticles with a shell consisting of 88 % Clarithromycin nanocrystals in an HPMC matrix, whose aerodynamic characterisation led to a fine particle fraction of 49.3 %.