Engineering nanoparticle agglomerates as dry powders for pulmonary drug delivery

Background: Controlled agglomeration of nanoparticles to micrometer-sized composites (i.e. nanoparticle agglomerates) has been suggested as a particle-engineering approach to combine the advantages of nanoparticles with the aerodynamics of microparticles for pulmonary drug delivery. The aim of this thesis was to engineer nanoparticle agglomerates with properties suitable for inhaler formulation, for drugs with different physicochemical properties. Methods: Nanoparticle agglomerates of three model drugs, namely indometacin, ibuprofen and theophylline, were prepared by coupling wet milling and spray drying. In the case of indometacin and ibuprofen, matrix formers (i.e. mannitol and L-leucine) were added to the aqueous nanosuspensions of the drugs prior to spray drying while for theophylline wet milling was carried out in isopropanol in the presence of mannitol. Nanoparticle agglomerates were characterised with respect to their particle size, morphology, solid state, redispersibility and dissolution, while their in-vitro aerosolisation performance was determined using the next generation impactor. A full factorial design and the fast screening impactor were employed in the case of ibuprofen nanoparticle agglomerates while computational modelling was used to investigate interactions between the crystals of theophylline and mannitol. Results: Nanosupensions of indometacin and ibuprofen stabilised with various polymers/surfactants were successfully prepared by wet milling and were further spray dried. Incorporation of matrix formers before spray drying resulted in nanoparticle agglomerates with improved redispersibility (ability to reform nanoparticles upon hydration), dissolution and higher fine particle fractions compared to those without matrix formers. In the case of theophylline, mannitol acted as a co-milling agent facilitating the size reduction of the drug’s needle-like crystals. Increasing the amount of mannitol led to the formation of smaller, more spherical and porous particles with enhanced aerosolisation performance. For each drug, the nanoparticle agglomerates produced retained the crystallinity of the starting materials ensuring the long-term physical stability of the formulations upon storage. Conclusions: Combining wet milling and spray drying can be used as an industrially feasible particle-engineering platform for dry powders for inhalation. By careful selection of formulation and process parameters, this platform can be applied to a range of drugs with different physicochemical properties