(M1230-08-54) Design of a Sprayable Powder Formulation Containing Choline-Maleic Acid Ionic Liquid in Porous Silica for Intranasal Delivery

Purpose: Intranasal administration enables direct drug delivery to the brain via the olfactory and trigeminal nerves, and absorption through the nasal mucosa and systemic circulation. It is essential to enhance nasal mucosal permeability and intranasal retention to design nasal formulations for brain delivery. Ionic liquids (ILs) are viscous organic salts composed of cations and anions, known to enhance permeability in topical formulations. Based on their physicochemical properties, we have previously demonstrated that ILs can enhance nasal retention and mucosal permeability, improving brain delivery after intranasal administration. However, due to their high viscosity, ILs are difficult to spray using common nasal devices, a significant challenge for formulation development. Therefore, this study aimed to develop a powder-based nasal formulation incorporating IL into mesoporous silica (MPS), a commonly used absorbent, to improve flowability and enable spraying with nasal devices. We also investigated how the mixing ratio of IL and MPS, processing conditions, and physicochemical properties of MPS affect IL encapsulation efficiency and formulation characteristics.

Methods: Choline-maleic acid IL was synthesized via a metathesis reaction. IL was mixed with several types of MPS with different water and oil absorption properties to prepare IL-loaded MPS powders. The encapsulation behavior of IL into MPS pores was evaluated by monitoring the peak area of IL-derived bands in the IR spectra over time under various mixing temperatures and durations. IL encapsulation was also confirmed by measuring specific surface area using BET analysis and observing particle morphology using SEM. Flow properties of the IL-loaded MPS were evaluated by particle size distribution (sieving method) and angle of repose. Furthermore, IL-loaded MPS powders filled in gelatin capsules were sprayed using a commercial powder nasal delivery device (Jetlizer^®, Tokico System Solutions, Ltd.), and the residual powder in the capsule was measured to assess the spray ability of each formulation.

Results: When IL and MPS (Sylysia^®740, Fuji Silysia Chemical Ltd.) were mixed, a time-dependent decrease in IL-specific IR peak area was observed, indicating gradual IL encapsulation into MPS. Increasing mixing temperatures accelerated this reduction, likely due to reduced IL viscosity at higher temperatures, facilitating pore penetration. When various IL ratios to MPS were tested, the surface area decreased up to an IL ratio of 0.4 compared to MPS alone, and then remained flat at 0.4 or higher. SEM observations showed particle agglomeration at IL ratios above 0.6. These findings suggest that IL can effectively encapsulate within MPS pores without surface leakage when the IL mass ratio to MPS is 0.4. Thus, the optimized preparation condition was determined to be an IL/MPS ratio of 0.4, a mixing temperature of 70°C, and a mixing time of 120 minutes. Flowability assessment based on the angle of repose showed that IL encapsulation did not impair flowability; the flowability was comparable to that of lactose or MPS alone, which are typically used in nasal powder formulations. Furthermore, IL-loaded MPS prepared using other MPS types with higher water/oil absorption (e.g., Sylysia^®350 or Parteck^®SLC500, Merck) showed good encapsulation efficiency and flow properties. Spray ability evaluation using Jetlizer^® revealed low residual powder in capsules for all IL-loaded MPS formulations, indicating favourable spray performance.

Conclusion: These findings demonstrate that IL encapsulation into MPS under optimized conditions can yield sprayable powder formulations suitable for intranasal brain delivery.

Acknowledgements: We sincerely thank Tokico System Solutions, Ltd. for kindly providing the Jetlizer device, which was instrumental in conducting this research.