title: Novel liposomal gefitinib (L-GEF) formulations.
abstract: BACKGROUND
  Gefitinib is a promising agent for the treatment of non-small cell lung cancer. The purpose of this study was to develop a novel liposomal formulation for gefitinib (L-GEF) to improve its therapeutic index.
  
  
  METHODS
  Several L-GEF formulations were prepared and characterized for their physical chemical properties and cytotoxicity. The pharmacokinetic parameters of the liposomes were determined in mice. The effect of lipid composition, transmembrane pH gradient, and incorporation of hydroxypropyl-β-cyclodextrin (HPβCD) on drug-loading efficiency, liposomal stability, and the rate of drug release were investigated.
  
  
  RESULTS
  The L-GEF formulation composed of hydrogenated soy phosphatidylcholine (HSPC)/cholesterol (Chol)/monomethoxy polyethylene glycol 2000-distearoyl phosphatidyl-ethanolamine (mPEG-DSPE) encapsulating 0.3 M (NH4)2SO4 and 0.1 M HPβCD (L-GEF-HSPC), had a drug-loading efficiency (DLE) of 85.5%. In vitro release studies showed that gefitinib release from L-GEF-HSPC in the presence of human plasma was slow and exhibited non-Fickian kinetics. Pharmacokinetic study in mice after i.v. bolus administration of L-GEF-HSPC showed that the area under the plasma concentration time curve (AUC) for gefitinib was 32.41 μg·h /ml and six times that of free gefitinib. The elimination half life (t(1/2β)) of L-GEF-HSPC was 7.29 h, while that of free gefitinib was 2.26 h.
  
  
  CONCLUSIONS
  It was shown that gefitinib can be efficiently loaded into L-GEF-HSPC composed of HSPC/Chol/mPEG-DSPE (55/40/5 mol/mol) with 0.3 M (NH(4))(2)SO(4) and 0.1 M HPβCD as trapping agents. Compared with the free drug, L-GEF-HSPC had high drug loading, good stability, and long-circulating properties.
authors: State Key Laboratory of Virology, Ministry of Education Key Laboratory of Combinatorial Biosynthesis and Drug Discovery, Wuhan University School of Pharmaceutical Sciences, Wuhan, PR China.
authors: Xiaoju
authors: X
authors: Zhou
authors: Bryant
authors: B
authors: Yung
authors: Yifei
authors: Y
authors: Huang
authors: Hong
authors: H
authors: Li
authors: Xianming
authors: X
authors: Hu
authors: Guangya
authors: G
authors: Xiang
authors: Robert J
authors: RJ
authors: Lee
mesh_terms: D000073738:2-Hydroxypropyl-beta-cyclodextrin; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000737:chemistry* / Q000493:pharmacokinetics; D045744:Cell Line, Tumor; D004355:Drug Stability; D000077156:Gefitinib; D006801:Humans; D008081:Liposomes / Q000737:chemistry*; D008175:Lung Neoplasms / Q000188:drug therapy; D051379:Mice; D008813:Mice, Inbred ICR; D010316:Particle Size; D011799:Quinazolines / Q000008:administration & dosage* / Q000737:chemistry* / Q000493:pharmacokinetics; D047392:beta-Cyclodextrins / Q000737:chemistry
chemical_list: D000970:Antineoplastic Agents; D008081:Liposomes; D011799:Quinazolines; D047392:beta-Cyclodextrins; D000073738:2-Hydroxypropyl-beta-cyclodextrin; D000077156:Gefitinib