title: Solid lipid particles for oral delivery of peptide and protein drugs I--elucidating the release mechanism of lysozyme during lipolysis.
abstract: The mechanism of protein release from solid lipid particles was investigated by a new lipolysis model in a biorelevant medium containing both bile salts and phospholipids. Lysozyme, a model protein, was formulated into solid lipid particles using four different types of lipids, two triglycerides with different chain-length of fatty acyl groups i.e. trimyristin (TG14) and tristearin (TG18), and two lipid blends dominated by diglycerides and monoglycerides, respectively. The release of lysozyme from the solid lipid particles and the lipid hydrolysis process were assessed in the lipolysis model, while the change in particle surface during the lipolysis process was evaluated using scanning electron microscopy. The lysozyme release profiles from TG14 and TG18 as well as diglyceride particles correlated well with the release of free fatty acids from the lipid particles during the lipolysis and therefore exhibited a lipase-mediated degradation-based release mechanism. The release of lysozyme from monoglyceride particles was independent on lipase degradation due to the instability of the lipid matrix in the lipolysis medium. In conclusion, the established lipolysis model is successfully used to elucidate the drug release mechanism from solid lipid particles and can potentially be used in rational selection of lipid excipients for oral delivery of peptide/protein drugs.
authors.affiliation: Department of Pharmacy, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark. Electronic address: philip.christophersen@sund.ku.dk.
authors.forename: P C
authors.initials: PC
authors.lastname: Christophersen
authors.forename: L
authors.initials: L
authors.lastname: Zhang
authors.forename: M
authors.initials: M
authors.lastname: Yang
authors.forename: H Mørck
authors.initials: HM
authors.lastname: Nielsen
authors.forename: A
authors.initials: A
authors.lastname: Müllertz
authors.forename: H
authors.initials: H
authors.lastname: Mu
mesh_terms: D000284:Administration, Oral; D001647:Bile Acids and Salts / Q000378:metabolism; D016503:Drug Delivery Systems; D005079:Excipients / Q000737:chemistry*; D005230:Fatty Acids, Nonesterified / Q000378:metabolism; D008049:Lipase / Q000378:metabolism; D008055:Lipids / Q000737:chemistry*; D008066:Lipolysis; D008855:Microscopy, Electron, Scanning; D008954:Models, Biological; D009113:Muramidase / Q000008:administration & dosage* / Q000378:metabolism; D010455:Peptides / Q000008:administration & dosage; D010743:Phospholipids / Q000378:metabolism; D011506:Proteins / Q000008:administration & dosage
chemical_list: D001647:Bile Acids and Salts; D005079:Excipients; D005230:Fatty Acids, Nonesterified; D008055:Lipids; D010455:Peptides; D010743:Phospholipids; D011506:Proteins; D008049:Lipase; D009113:Muramidase
keywords: DL; EE; FA; FDA; FFA; Food and Drug Administration; GDS; GIT; GMS; HPLC; HPTLC; Lipase; Lipid hydrolysis; Lipid-based drug delivery system; Oral drug delivery; PVA; Protein-loaded microparticle; RT; SEM; SLM; Solid lipid particle; TFA; TG; TG14; TG16; TG18; drug loading; entrapment efficiency; fatty acid; free fatty acid; gastrointestinal tract; glycerol distearate type 1; glycerol monostearate 40–55 type 1; high-performance liquid chromatography; high-performance thin-layer chromatography; polyvinyl alcohol; room temperature; scanning electron microscopy; solid lipid microparticles; trifluoroacetic acid; triglyceride; trimyristin; tripalmitin; tristearin