Nasal powder formulation employing microenvironmental pH -modifier for rapid absorption of mirtazapine

Abstract

Antidepressant mirtazapine (MRZ) has been drawing attention in the management of delirium. However, oral use of MRZ could have drawbacks in onset of actions and ease of administration by caregivers. This study was the first attempt to develop nasal powder formulation (NP), an easily-administered formulation, of MRZ containing a microenvironmental pH -modifier for rapid dissolution and absorption. Ten mixtures of MRZ and counterions were tested in terms of the supersaturation level and stability to select a favorable pH-modifier. NP of MRZ (NP/MRZ) with the selected counterion was prepared by jet milling and characterized regarding physicochemical properties and pharmacokinetic (PK) behaviors after intranasal administration to rabbits. In phosphate buffer solution (PBS, pH5.6), glutamic acid (Glu) showed 10.7 -fold supersaturation of MRZ, with the value being the highest among the ten counterions tested. The addition of Glu led to no significant change in the photostability or chemical stability of MRZ compared with crystalline MRZ. NP/MRZ with Glu (NP/MRZ-E) consisted of microcrystals of MRZ and Glu attached to lactose carriers, and over 93% of MRZ was emitted from a capsule in Jetlizer^TM. Both NP/MRZ-E and NP/MRZ exhibited enhanced dissolution in PBS compared with crystalline MRZ, and more rapid dissolution was observed for NP/MRZ-E. In rabbits, a crushed MRZ tablet (3mg-MRZ/kg, p.o.) exhibited a time to maximum plasma concentration (T_max) and bioavailability (BA) of 72 min and 10%, respectively. NP/MRZ-E (0.3 mg -MRZ/ kg, i.n.) showed T_max  of <5 min with BA of 93%, and this result might be due to rapid dissolution/permeation in nasal mucosa and avoidance of the hepatic first-pass effect. In conclusion, NP employing a microenvironmental pH -modifier would be a promising dosage form of MRZ to offer rapid nasal absorption.

Keywords

Bioavailability / Dissolution enhancement / Mirtazapine / Microenvironmental pH-modification / Nasal powder formulation

CRediT authorship contribution statement

Kohei Yamada: Writing - original draft, Methodology, Investigation, Data curation, Conceptualization. Tsubasa Kihara: Validation, Investigation. Kaori Shinsato: Conceptualization. Hirofumi Yasui: Writing review & editing, Conceptualization. Michihiro Shino: Conceptualization. Hideyuki Sato: Project administration, Funding acquisition, Conceptualization. Satomi Onoue: Writing - review & editing, Supervision, Project administration, Funding acquisition, Conceptualization.

Data availability statement

The data that support the findings of this study are available from the corresponding author upon reasonable request.

Ethics approval

All procedures in the present study were conducted according to the guidelines approved by the Institutional Animal Care and Ethical Committee of the University of Shizuoka (Approval number: 216500).

Funding information

This work was financially supported in part by JSPS KAKENHI [Grant-in-Aid for Scientific Re-search (C) (No. 24K09917: S. Onoue; and No. 20K07180: H. Sato)] and Shizuoka Cancer Center (Shizuoka, Japan).

Declaration of competing interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Acknowledgements

A special thanks is due to Dr. Ishizeki (Tokico System Solutions Ltd., Kanagawa, Japan) for providing Jetlizer^TM. The authors would like to express our great appreciation to Pion Inc. (Billerica, MA, USA) for lending μ DISS Profiler to us.

Appendix A. Supplementary data

Supplementary data to this article can be found online at https://doi.org/10.1016/j.pscia.2025.100068.

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