A simple approach to predict the stability of phospholipid vesicles to nebulization without performing aerosolization studies

Abstract

Membrane extrusion was investigated for predicting the stability of soya phosphatidylcholine liposomes and surfactosomes (Tween 80-enriched liposomes) to nebulization. Formulations were prepared with or without cholesterol, and salbutamol sulfate (SBS) or beclometasone dipropionate (BDP) were incorporated as model hydrophilic or hydrophobic drugs respectively. Formulations were extruded through 5, 2, 1 and 0.4 μm polycarbonate membrane filters to study the influence of membrane pore size on drug retention by the vesicles. Surfactosomes were found to be very leaky to SBS, such that even without extrusion greater than 50% of the originally entrapped drug was lost; these losses were minimized by the inclusion of cholesterol. The smaller the membrane pore size, the greater the leakage of SBS; hence only around 10% were retained in cholesterol-free surfactosomes extruded through 0.4 μm filters. To study the influence of vesicle size on SBS retained entrapment, an excessive extrusion protocol was proposed (51 extrusion cycles through 1 μm filters) to compare the stability of freshly prepared vesicles (i.e. unextruded; median size approx. 4.5-6.5 μm) with those previously extruded through 1 μm pores. Cholesterol was essential for minimizing losses from liposomes, whilst for surfactosomes size reduction prior to extrusion was the only way to minimize SBS losses which reached up to 93.40% of the originally entrapped drug when no cholesterol was included. When extrusion was applied to BDP-loaded vesicles, greater proportions of the drug were retained in the vesicles compared to SBS. Even with extrusion through 0.4 μm, BDP retention was around 50-60% with little effect of formulation. Excessive extrusion showed BDP retention using small liposomes (1 μm) to be as high as 71-87%, compared to 50-66% for freshly prepared vesicles. The findings, based on extrusion, were compared to studies of vesicle stability to nebulization, published by a range of investigators. It was concluded that extrusion is a valid method for predicting the stability of liposomes to nebulization.

Proliposome tablets manufactured using a slurry-driven lipid-enriched powders: Development, characterization and stability evaluation

“…Furthermore, no significant difference (p˃0.05) was also found with respect to un-entrapped BDP (i.e. free BDP crystal sedimented and dissolved BDP in aqueous media, post centrifugation) (Khan et al, 2015, Subramanian et al, 2016, Khan et al, 2017. Upon comparison, no significant difference was found for the un-entrapped BDP for sorbitol-based proliposome tablets in both 1:10 and 1:15 lipid to carrier ratios (46.18 ± 7.29% and 42.58 ± 8.77%).…”

Development of Injectable PEGylated Liposome Encapsulating Disulfiram for Colorectal Cancer Treatment

“…Proliposomes represent an economical approach to scale-up liposome production and resolve the instability problems associated with conventional thin-film-made liposomes. These advantages are attributed to the predominance of the ethanolic phase in proliposomes instead of water, avoiding phospholipid hydrolysis and offering self-antimicrobial preservation [22,23].…”

Proliposome powder or tablets for generating inhalable liposomes using a medical nebulizer

“…TEM images of liposome generated from, (g) sorbitol-based proliposome powder 1:10 w/w and, (h) sorbitol-based proliposome tablets 1:10 w/w ratio. These images are typical of three such different experiments to the presence of large liposomes or liposome aggregates (Clay et al 1983;Elhissi et al 2006Elhissi et al , 2012Khan et al 2016). The total mass of the formulation delivered from the nebulizer (i.e.…”

“…1998;Godet et al 2017). Moreover, the pulmonary system offers a large surface area (82-100 m 2 ), facilitating fast drug absorption to the systemic circulation (Khan et al 2013(Khan et al , 2016. However, deep lung deposition, associated with better treatment outcomes, is challenging.…”

“…Liposomes have been investigated for around five decades as drug carriers in pulmonary inhalation. This is due to their ability to entrap hydrophilic and hydrophobic drugs (Rojanarat et al 2012;Kontturi et al 2019;Subramanian et al 2016;Bnyan et al 2020) and localize drug action in the lung for prolonged periods (Elhissi. 2017).…”