(T1330-10-56) Development of Inhaled Dry Powder Using Electrospinning Method

Purpose: Inhalers are designed to safely and efficiently deliver drug formulations to the pulmonary epithelium, where the drug can then be absorbed into the local tissue or the systemic circulation for therapeutic action. While inhaler include inhalation solutions, pressurized metered-dose inhalers, and dry powder inhalers (DPIs), each with certain advantages for the delivery of drugs, DPIs are the first choice for inhalation drug development. However, some conventional DPI formulation processes require heating, which may damage high molecular weight drugs such as proteins. In this study, we propose the electrospinning method as a novel DPI preparation process that avoids the use of heat.

Methods: The nanofiber mats were composed of polyvinyl alcohol, D(−)-mannitol (Man), and α-chymotrypsin (α-Chy) as the model drug. Dry powders were obtained from electrospinning nanofiber mats by cryomilling. The in vitro aerosol performance metrics of these milled nanofiber mats were evaluated using an eight-stage Andersen cascade impactor. The integrity and function of α-Chy in the milled nanofiber mats were compared to raw enzyme solution (control) and nebulized solution. Finally, we evaluated the safety of dry powders cryomilled from nanofiber mats in vivo by measuring lactate dehydrogenase release from mouse lung tissue into bronchoalveolar lavage fluid.

Results: The cryomilled nanofiber mats without Man were porous to fine particles, and the particle size and α-Chy stability depended on the freezing and milling times. The nanofiber mats milled for 1 and 3 min produced powdered porous particles while maintaining the fiber structure (Fig. 1 (a)). Conversely, milling the nanofiber mat powder for 5 min destroyed its fiber structure. The nanofiber mats containing Man yielded fine particles after a relatively brief milling (less than 0.5 min), formed short and straight aggregated fibers (Fig. 1 (b)). The addition of Man conferred high dispersibility and excellent in vitro aerosol performance to the nanofiber mat powder (Fig. 2). Powders were classified according to the degree of friability, and among these, nanofiber mats containing 15% Man and milled for 0.25 min exhibited the highest aerosol performance. Conversely, milling the nanofiber mat powder for 5 min decreased aerosol performance. Nanofiber mats containing Man milled for less than 0.5 min also exhibited greater α-Chy enzymatic activity than a nebulized α-Chy solution. Furthermore, single inhalation induced no significant lung tissue damage, as evidenced by lactate dehydrogenase activity assays of mouse bronchoalveolar lavage fluid.

Conclusion: This novel method may be suitable for the DPI preparation of various drugs because it avoids the heating step during the DPI preparation process.

References: Molecules 2022, 27, 5158. https://doi.org/10.3390/molecules27165158

Acknowledgements: This work was supported by JSPS KAKENHI [grant numbers 22K15263] and the Uehara Memorial Foundation [grant number 202210032].

Fig. 1. Morphology of electrospun nanofiber mats revealed by scanning electron microscopy.

Fig. 2. Deposition patterns of milled nanofiber mats in an eight-stage Andersen cascade impactor. The loaded mass, flow rate, and inspiration volume were fixed at 2 mg, 28.3 L/min, and 4 L, respectively. Each value represents the mean ± SD of three measurements.