Formulations generated from ethanol-based proliposomes for delivery via medical nebulizers

Abstract

Multilamellar and oligolamellar liposomes were produced from ethanol-based soya phosphatidylcholine proliposome formulations by addition of isotonic sodium chloride or sucrose solutions. The resultant liposomes entrapped up to 62% of available salbutamol sulfate compared with only 1.23% entrapped by conventionally prepared liposomes. Formulations were aerosolized using an air-jet nebulizer (Pari LC Plus) or a vibrating-mesh nebulizer (Aeroneb Pro small mesh, Aeroneb Pro large mesh, or Omron NE U22). All vibrating-mesh nebulizers produced aerosol droplets having larger volume median diameter (VMD) and narrower size distribution than the air-jet nebulizer. The choice of liposome dispersion medium had little effect on the performance of the Pari nebulizer. However, for the Aeroneb Pro small mesh and Omron NE U22, the use of sucrose solution tended to increase droplet VMD, and reduce aerosol mass and phospholipid outputs from the nebulizers. For the Aeroneb Pro large mesh, sucrose solution increased the VMD of nebulized droplets, increased phospholipid output and produced no effect on aerosol mass output. The Omron NE U22 nebulizer produced the highest mass output (approx. 100%) regardless of formulation, and the delivery rates were much higher for the NaCl-dispersed liposomes compared with sucrose-dispersed formulation. Nebulization produced considerable loss of entrapped drug from liposomes and this was accompanied by vesicle size reduction. Drug loss tended to be less for the vibrating-mesh nebulizers than the jet nebulizer. The large aperture size mesh (8 m) Aeroneb Pro nebulizer increased the proportion of entrapped drug delivered to the lower stage of a twin impinger. This study has demonstrated that liposomes generated from proliposome formulations can be aerosolized in small droplets using air-jet or vibrating-mesh nebulizers. In contrast to the jet nebulizer, the performance of the vibrating-mesh nebulizers was greatly dependent on formulation. The high phospholipid output produced by the nebulizers employed suggests that both airjet and vibrating-mesh nebulization may provide the potential of delivering liposome-entrapped or solubilized hydrophobic drugs to the airways.

An Ethanol-Based Proliposome Technology for Enhanced Delivery and Improved “Respirability” of Antiasthma Aerosols Generated Using a Micropump Vibrating-Mesh Nebulizer

“…This quantity of ethanol was found to be appropriate to dissolve the lipids (Elhissi et al, 2006). Salbutamol sulphate in NaCl (0.9%) solution (5 mg/ 100 µl) was added and formulation was mixed for 1 min to generate a "milky" dispersion of liposomes.…”

“…The preparation was further diluted with 4.9 ml drug-free solution of NaCl (0.9%). This formulation was prepared by following the procedure conducted in our previous publications, and found to yield an entrapment efficiency exceeding 60% for this drug (Elhissi et al, 2006;. Surface tension measurements of liposome formulations and conventional salbutamol sulphate solution were performed using a Kibron Delta-8 multichannel microtensiometer (Kibron, Finland).…”

“…For instance, ethanol-based proliposomes are concentrated ethanolic solutions of phospholipid which generate liposomes by addition of aqueous phase and shaking (Perrett et al, 1991). The suitability of ethanol-based proliposomes to generate inhalable liposomes via nebulizers has been demonstrated (Elhissi et al, 2006;Elhissi et al, 20011).…”

“…Whilst traditional ultrasonic nebulizers are generally unsuitable for delivery of liposomes (Elhissi and Taylor, 2005), air-jet nebulizers are superior in delivery of "respirable" liposome aerosols (Farr et al, 1985;Waldrep et al, 1993;Waldrep et al, 1994;Saari et al, 1998;Saari et al, 1999;Albasarah et al, 2010). However, the shearing occurring within air-jet nebulizers may damage the liposome bilayers, resulting in considerable losses of entrapped hydrophilic materials (Taylor et al, 1990;Elhissi et al, 2007 (Dhand, 2002; are suitable for liposome delivery (Elhissi and Taylor, 2005;Li et al, 2008;Gaspar et al, 2010;Elhissi et al, 2012) and may cause less losses of the entrapped drug during aerosolization when compared to air-jet nebulizers (Elhissi et al, 2006;Elhissi et al, 2007;Kleemann et al, 2007). An example of vibrating-mesh nebulizers is the Aeroneb Pro device ( Fig.1) which employs a perforated plate that is connected to a vibrational element, causing a "micropump" action which extrudes the medical fluid and generates the aerosol (Dhand, 2002;Ghazanfari et al, 2007).…”

“…Using liposomes generated from ethanol-based proliposomes, the entrapment efficiency of this drug in liposomes may exceed 60% (Elhissi et al, 2006;. In this study, the aerosol properties of salbutamol sulphate liposomes generated from proliposomes were compared to aerosols generated from a conventional drug solution using the micropump Aeroneb Pro vibrating-mesh nebulizer.…”