A Dry Powder Platform for Nose-to-Brain Delivery of Dexamethasone: Formulation Development and Nasal Deposition Studies

Abstract

Nasal route of administration offers a unique opportunity of brain targeted drug delivery via olfactory and trigeminal pathway, providing effective CNS concentrations at lower doses and lower risk for adverse reactions compared to systemic drug administration. Therefore, it has been recently proposed as a route of choice for glucocorticoids to control neuroinflammation processes in patients with severe Covid-19. However, appropriate delivery systems tailored to enhance their efficacy yet need to emerge. In this work we present the development of sprayable brain targeting powder delivery platform of dexamethasone sodium phosphate (DSP). DSP-loaded microspheres, optimised employing Quality-by-Design approach, were blended with soluble inert carriers (mannitol or lactose monohydrate). Powder blends were characterized in terms of homogeneity, flow properties, sprayability, in vitro biocompatibility, permeability and mucoadhesion. Nasal deposition studies were performed using 3D printed nasal cavity model. Mannitol provided better powder blend flow properties compared to lactose. Microspheres blended with mannitol retained or enlarged their mucoadhesive properties and enhanced DSP permeability across epithelial model barrier. DSP dose fraction deposited in the olfactory region reached 17.0% revealing the potential of developed powder platform for targeted olfactory delivery. The observed impact of nasal cavity asymmetry highlighted the importance of individual approach when aiming olfactory region.

Keywords: 3D nasal cavity model; dexamethasone sodium phosphate; hypromellose; in vitro nasal deposition; mannitol; nose-to-brain delivery; pectin; spray-dried microspheres.

Figure 1

Prediction of yield in relation to hypromellose concentration (HPMC), inlet air temperature (T_inlet) and feed flow rate (FFR). Values in brackets refer to 95% confidence interval.

Figure 2

Interaction profiler illustrates the interaction effect between inlet air temperature (T_inlet) and feed flow rate (FFR).

Figure 3

Prediction of moisture content (MC) in relation to hypromellose (HPMC) and DSP concentrations. Values in brackets refer to 95% confidence interval.

Figure 4

In vitro release profile of DSP from DSP-MS microspheres (circle) compared to dissolution of pure DSP powder (square). Graph insert: DSP in vitro release profile from DSP-MS microspheres blended with inert carrier (DSP-MS/Mannitol 1:9, w/w; reversed triangle) compared to dissolution of DSP from corresponding DSP/inert carrier blend (DSP + Mannitol; triangle). Q represents cumulative percentage of DSP released at time t. Data are expressed as the mean ± SD (n = 3).

Figure 5

SEM micrographs of DSP-MS (A), DSP-MS/lactose blend (B) and DSP-MS/mannitol blend (C) with DSP-MS to inert carrier ratio 1:9, w/w.

Figure 6

Correlation between dose percentage retained within the capsule and Hausner ratio (left; Pearson’s coefficient of 0.9517) and between spray cone angle and Hausner ratio (right; Pearson’s coefficient of 0.9511) established based on statistical analysis of data for DSP-MS, mannitol, lactose and DSP-MS blends with mannitol or lactose at weight ratios of 1:19 and 1:9.

Figure 7

Spray cone of DSP-MS/Mannitol 1:9 upon aerosolisation with Miat^® insufflator.

Figure 8

Work of adhesion (W_ad; left) and maximum detachment force (F; right) of DSP-MS microspheres, inert carriers (mannitol and lactose) and pure drug powder compared to control (filter paper). Graph insert: Work of adhesion (W_ad; left) and maximum detachment force (F; right) for DSP-MS/inert carrier blends at ratios 1:9 and 1:19 (w/w). For all graphs, bars coloured in blue represent measured values W_ad (left) and F (right) for 5 mg of each tested powder. Shaded bars represent theoretical values for W_ad (left) and F (right) calculated based on weight ratios and individual parameter values of powder blend constituents presented in the main graph. Data are expressed as the mean ± SD (n = 3).

Figure 9

Viability of cells (MTT test) in Calu-3 cell monolayers used in permeability studies of DSP from DSP-MS suspensions and DSP solutions with and without mannitol. Corresponding DB solutions were also included in the study (see Table 3). Concentration of DSP, DB and mannitol (where applicable) in the test samples was equal to 0.9 mg mL⁻¹, 0.075 mg mL⁻¹ and 54.5 mg mL⁻¹, respectively. Data are expressed as mean ± SD (n = 3). DSP * (p < 0.05); DB * (p < 0.05).

Figure 10

Schematic presentation of a 3D-printed nasal cavity model (A) and nasal geometry measurements including length of a nasal cavity (92.11 mm; (B) and smallest vertical cross-sectional areas (left: 98.36 mm²/right 141.32 mm²; (C).

Figure 11

Nasal deposition of DSP-MS/Mannitol 1:9 in olfactory region (superior turbinate with a small portion of the middle turbinate (■) and corresponding segment of the nasal septum (■)) and the rest of turbinates innervated by trigeminal nerve (■) at various administration parameters in left and right half of 3D printed nasal cavity model (left and right bar, respectively). Administration parameters include angle of administration from horizontal plane (AA) and inspiratory airflow (IAF). All values are mean ± SD, n = 3.