Abstract
Obstructive sleep apnea (OSA) is a common sleep disorder characterized by the upper airway collapse, leading to interrupted breathing and reduced oxygen levels during sleep. This condition often results in chronic inflammation and is associated with various long-term health problems. To address OSA-related inflammation, an FDA-approved drug, Doxycycline, was formulated in this study as a dry powder inhaler due to its favorable anti-inflammatory properties that was tested in subsequent cellular and animal studies of OSA. This comprehensive and systematic study aimed to develop inhalable excipient-free spray-dried (SD) one-component drug powders of Doxycycline. Advanced organic solution spray-drying in closed mode, with three different feed pump rates (10%, 50%, and 100%), was used to design and produce Doxycycline microparticles in the solid state successfully. The SD Doxycycline formulations comprised hollow, spherical, dimpled particles (<2 μm). The solid-state characterization of SD formulations confirmed the amorphous nature of Doxycycline after spray drying with a glass transition temperature between 82.73 °C and 89.29 °C. However, compared to the raw drug, residual water content was higher in the SD formulation, ranging from 6.4 ± 0.02% w/w in SD Doxycycline at the low feed pump rate to 6.79 ± 0.06% w/w in SD Doxycycline at the high feed pump rate. SD formulations showed good aerosolization behavior with a Respirable Fraction (RF) of >60% with NeoHaler inhaler device (63.19 ± 7.59 to 68.53 ± 3.73%) while HandiHaler showed lower RF (39.61± 0.57 to 53.90 ± 8.03%). The fine particle fraction (FPF) was higher in the NeoHaler group (24.91 ± 1.17 to 36.72 ± 2.01%) compared to HandiHaler (19.61 ± 5.41 to 33.76 ± 5.21%). This could be explained by the difference in median aerodynamic diameter (8.21 ± 2.68 to 4.69± 1.27 μm) in the NeoHaler group compared to (3.07 ± 0.36 to 3.67 ± 0.59 μm) HandiHaler group. Furthermore, in vitro cell viability as a function of lung cell type and drug dose showed 10 µM of Doxycycline as a safe concentration for the A549, H358, H441, and Calu-3 epithelial-like immortal human cell lines. Inhalable dry powder formulation of Doxycycline could offer new treatment options for patients suffering from sleep apnea.