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

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.

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or continue reading here: Nižić Nodilo, L.; Ugrina, I.; Špoljarić, D.; Amidžić Klarić, D.; Jakobušić Brala, C.; Perkušić, M.; Pepić, I.; Lovrić, J.; Saršon, V.; Safundžić Kučuk, M.; Zadravec, D.; Kalogjera, L.; Hafner, A. A Dry Powder Platform for Nose-to-Brain Delivery of Dexamethasone: Formulation Development and Nasal Deposition Studies. Pharmaceutics 2021, 13, 795. https://doi.org/10.3390/pharmaceutics13060795

Materials
DSP was purchased from Carbosynth Ltd. (Compton, UK). Low methoxy amidated pectin (CF 005, degree of esterification 35%; degree of amidation 15%; further denoted as pectin) was kindly donated by Herbstreith & Fox (Neuenbürg, Germany). Hypromellose (Metolose® SH 4000) was obtained by courtesy of Shin-Etsu Chemical Co., Ltd., Tokyo, Japan. Lactose monohydrate (GranuLac® 200; further denoted as lactose) was obtained from Meggle (Wasserburg am Inn, Germany). Mannitol was purchased from BDH Prolabo (Lutterworth, UK). Simulated Nasal Fluid (SNF) was prepared by dissolving NaCl (150.0 mM; Kemig, Zagreb, Croatia), KCl (40.0 mM; Kemig) and CaCl2 × H2O (5.3 mM; Sigma-Aldrich, Munich, Germany) in distilled water.
For cell biocompatibility and permeability studies in vitro, Hank’s balanced salt solution with 5.3 mM Ca2+ (HBSS-Ca2+; pH 7.4) was prepared by dissolving KCl (5.4 mM), NaHCO3 (4.2 mM), NaCl (136.9 mM), D-glucose monohydrate (5.6 mM) (all purchased from Kemig), KH2PO4 (0.4 mM; Kemika, Zagreb, Croatia), Na2HPO4 × 2H2O (0.3 mM; Fluka Chemie AG, Buchs, Switzerland) and CaCl2 × 2H2O (5.3 mM) (Sigma-Aldrich) in distilled water.

Conclusions
QbD approach enabled rational design of spray-dried DSP-loaded polymeric microspheres. Optimised microspheres/mannitol powder blend showed favourable biopharmaceutical and sprayability properties considering the proposed route of administration. Nasal deposition studies revealed the potential of strategy employed for efficient delivery of DSP to the olfactory region of nasal cavity. The obtained results present a firm base for extending the study to an appropriate in vivo model needed for the final proof-of-concept.