In the field of nasal drug delivery, nose-to-brain delivery is among the most fascinating applications, directly targeting the central nervous system, bypassing the blood brain barrier. Its benefits include dose lowering and direct brain distribution of potent drugs, ultimately reducing systemic side effects. Recently, nasal administration of insulin showed promising results in clinical trials for the treatment of Alzheimer’s disease. Nanomedicines could further contribute to making nose-to-brain delivery a reality. While not disregarding the need for devices enabling a formulation deposition in the nose’s upper part, surface modification of nanomedicines appears the key strategy to optimize drug delivery from the nasal cavity to the brain. In this review, nanomedicine delivery based on particle engineering exploiting surface electrostatic charges, mucoadhesive polymers, or chemical moieties targeting the nasal epithelium will be discussed and critically evaluated in relation to nose-to-brain delivery.

Background: European and United States Pharmacopoeia compendial procedures for assessing the in vitro emitted dose and aerodynamic size distribution of a dry powder inhaler require that 4.0 L of air at a pressure drop of 4 kPa be drawn through the inhaler. However, the product performance should be investigated using conditions more representative of what is achievable by the patient population. This work compares the delivered dose and the drug deposition profile at different flow rates (30, 40, 60, and 90 L/min) of Foster NEXThaler ^® (beclomethasone dipropionate/formoterol fumarate), Seretide ^® Diskus ^® (fluticasone propionate/salmeterol xinafoate), and Symbicort ^® Turbohaler ^® (budesonide/formoterol fumarate). Methods: The delivered dose uniformity was tested using a dose unit sampling apparatus (DUSA) at inhalation volumes either 2.0 or 4.0 L and flow rates 30, 40, 60, or 90 L/min. The aerodynamic assessment was carried out using a Next Generation Impactor by discharging each inhaler at 30, 40, 60, or 90 L/min for a time sufficient to obtain an air volume of 4 L. Results: Foster ^® NEXThaler ^® and Seretide ^® Diskus ^® showed a consistent dose delivery for both the drugs included in the formulation, independently of the applied flow rate. Contrary, Symbicort ^® Turbohaler ^® showed a high decrease of the emitted dose for both budesonide and formoterol fumarate when the device was operated at airflow rate lower that 60 L/min. The aerosolizing performance of NEXThaler ^® and Diskus ^® was unaffected by the flow rate applied. Turbohaler ^® proved to be the inhaler most sensitive to changes in flow rate in terms of fine particle fraction (FPF) for both components. Among the combinations tested, Foster NEXThaler ^® was the only one capable to deliver around 50% of extra-fine particles relative to delivered dose. Conclusions: NEXThaler ^® and Diskus ^® were substantially unaffected by flow rate through the inhaler in terms of both delivered dose and fine particle mass.