Pulmonary delivery of therapeutic peptides via dry powder inhalation: effects of micronisation and manufacturing.

Pulmonary drug delivery is increasingly appreciated as a route of administration for systemically acting proteins and peptides. A respirable particle size of the drug is a key requirement, but the fragile nature of many proteins may be a limitation for the application of conventional production processes. The aim of this study was to examine the effect of different micronisation processes on the degradation and aerodynamic properties of the GnRH-antagonist cetrorelix in order to enable its application by a dry powder inhaler (Novolizer). A modified pearl mill was used for milling in fluid propellant. Furthermore, a spray drying procedure was established using a novel process of atomisation and drying. Adhesive mixtures of lactose and 5-20% of micronised cetrorelix-acetate were prepared. Analysis by laser light scattering, HPLC, Karl Fischer, cascade impactor and scanning electron microscopy were performed to characterise the manufactured powders. Both micronisation procedures succeeded in producing small range particle size distributions, suitable for deep lung deposition (D50 = 1.6 microm for milling and 3.3 microm for spray drying). The pearl milled cetrorelix showed promising results when delivered by the Novolizer: a reproducible and highly efficient dispersion of the drug was achieved (around 60% of aerosolised drug < 5 microm). The spray dried drug was not suitable when processed as adhesive mixture. Copyright 2004 Elsevier B.V.