Proniosome formulations for pulmonary drug delivery

Abstract

In this study niosomes were generated from proniosomes (Span 60: Cholesterol 1:1) using beclomethasone dipropionate (BDP, 5 mole %) as a model drug. When niosomes were processed via probe sonication, photon correlation spectroscopy study showed that niosomes generated from proniosomes had larger size than conventional niosomes, being 202 nm and 160 nm, respectively. Transmission electron microscopy (TEM) showed that these niosomes were highly aggregated. The zeta potential values of niosomes were negative regardless of the preparation method. However, a highly intense negative charge was detected for niosomes generated from proniosomes (-36 mV) compared to niosomes (-25 mV). The entrapment efficiency (EE) of BDP was higher in proniosomes-driven niosomes compared to conventional niosomes, being 35% and 27%, respectively.
Probe sonicated, niosomes manufactured using the proniosome technology were nebulised using either Pari LC Sprint (air-jet), Aeroneb Pro (actively vibrating-mesh) or Omron Micro Air NEU22 (passively vibrating-mesh) nebulisers. The Pari and Aeroneb Pro nebulisers generated higher aerosol and drug outputs compared with the Omron nebuliser. Whilst drug output was around 80% for the Pari and the Aeroneb Pro, it was around 70% for the Omron. Similarly, droplet size generated from the Omron was larger than that generated from the Pari and the Aeroneb Pro, being 4.86 μm, 3.06 μm and 3.32 μm respectively. Using laser diffraction for aerosol droplet size analysis, the Pari nebuliser generated aerosols with the highest fine particle fraction (FPF) (around 80%) followed by the Aeroneb Pro nebuliser (approximately 70%) and the Omron nebuliser (around 40%). The predicted alveolar deposition was negligible for the Omron and approximately 20% for the Aeroneb Pro and the Pari nebulisers.
Using niosomes generated from proniosomes, the high shear homogeniser (NanoDebee) has produced niosomes having a small size (Zaverage = 236.5 ±13 nm) which was comparable to probe sonicated niosomes (Zaverage =209.2 ±21.4 nm). The zeta potential was also similar, being, respectively -38 and -36 mV. Also similar EE values were found, being 36.4% ±2.8 and 29.65% ±4.04 for the probe sonicated vesicles and the Nano Debee-homogenised vesicles, respectively.
Probe sonicated niosomes generated from proniosomes were freeze-dried. Rehydration of freeze-dried niosomes caused a massive increase of the size (by 13 times) of niosomes, indicating instability of niosomes.
Overall, the study in thesis has demonstrated that niosomes generated from proniosomes were possible to be delivered via medical nebulisers with a high FPF using BDP as a model antiasthmatic drug. A large scale production method was introduced using high shear homogenisation. However, freeze-drying exerted a destabilising effect on niosomes, causing either massive aggregation or fusion of the vesicles.