title: A dry powder formulation of liposome-encapsulated recombinant secretory leukocyte protease inhibitor (rSLPI) for inhalation: preparation and characterisation.
abstract: Inhaled recombinant secretory leukocyte protease inhibitor (rSLPI) has shown potential for the treatment of inflammatory lung conditions. Rapid inactivation of rSLPI by cathepsin L (Cat L) and rapid clearance from the lungs has limited clinical efficacy to date. Previous studies by us have shown that encapsulation of rSLPI within1,2-dioleoyl-sn-glycero-3-[phospho-L-serine]/cholesterol (DOPS/Chol) liposomes protects rSLPI against Cat L inactivation in vitro. Liquid DOPS-rSLPI preparations were found to be unstable upon long-term storage and nebulisation. The aim of this study was therefore to develop a method of manufacture for preparing DOPS-rSLPI liposomes as a dry powder for inhalation. DOPS-rSLPI dry powders were lyophilised and subsequently micronised with a novel micronisation aid. The effects of formulation and processing on rSLPI stability, activity, and uniformity of content within the powders were characterised. Using D-mannitol as the micronisation aid, dry powder particles in the inhalable size range (<5 μm) were prepared. By optimising process parameters, up to 54% of rSLPI was recovered after micronisation, of which there was no significant loss in anti-neutrophil elastase activity and no detectable evidence of protein degradation. Aerosolisation was achieved using a dry powder inhaler, and mass median aerodynamic diameter (MMAD) was evaluated after collection in a cascade impactor. Aerosolisation of the DOPS-rSLPI dry powder yielded 38% emitted dose, with 2.44 μm MMAD. When challenged with Cat L post-aerosolisation, DOPS-rSLPI dry powder was significantly better at retaining a protective function against Cat L-induced rSLPI inactivation compared to the aqueous DOPS-rSLPI liposome dispersion and was also more stable under storage.
authors.affiliation: School of Pharmacy, Royal College of Surgeons in Ireland, York House, York Street, Dublin 2, Ireland.
authors.forename: Aileen
authors.initials: A
authors.lastname: Gibbons
authors.forename: Noel G
authors.initials: NG
authors.lastname: McElvaney
authors.forename: Sally-Ann
authors.initials: SA
authors.lastname: Cryan
mesh_terms: D000280:Administration, Inhalation; D000336:Aerosols / Q000138:chemical synthesis*; D002214:Capsules / Q000138:chemical synthesis*; D003890:Desiccation; D004058:Diffusion; D004355:Drug Stability; D006801:Humans; D008081:Liposomes / Q000138:chemical synthesis*; D011208:Powders; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000138:chemical synthesis; D053481:Secretory Leukocyte Peptidase Inhibitor / Q000008:administration & dosage* / Q000737:chemistry* / Q000235:genetics
chemical_list: D000336:Aerosols; D002214:Capsules; D008081:Liposomes; D011208:Powders; D011994:Recombinant Proteins; D053481:Secretory Leukocyte Peptidase Inhibitor