title: Enhancement of cellular uptake, transport and oral absorption of protease inhibitor saquinavir by nanocrystal formulation.
abstract: OBJECTIVE
  Saquinavir (SQV) is the first protease inhibitor for the treatment of HIV infection, but with poor solubility. The aim of this study was to prepare a colloidal nanocrystal suspension for improving the oral absorption of SQV.
  
  
  METHODS
  SQV nanocrystals were prepared using anti-solvent precipitation-high pressure homogenization method. The nanocrystals were characterized by a Zetasizer and transmission electron microscopy (TEM). Their dissolution, cellular uptake and transport across the human colorectal adenocarcinoma cell line (Caco-2) monolayer were investigated. Bioimaging of ex vivo intestinal sections of rats was conducted with confocal laser scanning microscopy. Pharmacokinetic analysis was performed in rats administered nanocrystal SQV suspension (50 mg/kg, ig), and the plasma SQV concentrations were measured with HPLC.
  
  
  RESULTS
  The SQV nanocrystals were approximately 200 nm in diameter, with a uniform size distribution. The nanocrystals had a rod-like shape under TEM. The dissolution, cellular uptake, and transport across a Caco-2 monolayer of the nanocrystal formulation were significantly improved compared to those of the coarse crystals. The ex vivo intestinal section study revealed that the fluorescently labeled nanocrystals were located in the lamina propria and the epithelium of the duodenum and jejunum. Pharmacokinetic study showed that the maximal plasma concentration (Cmax) was 2.16-fold of that for coarse crystalline SQV suspension, whereas the area under the curve (AUC) of nanocrystal SQV suspension was 1.95-fold of that for coarse crystalline SQV suspension.
  
  
  CONCLUSIONS
  The nanocrystal drug delivery system significantly improves the oral absorption of saquinavir.
authors.affiliation: School of Pharmacy, Chongqing Medical University, Chongqing 400016, China.
authors.forename: Yuan
authors.initials: Y
authors.lastname: He
authors.affiliation: Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
authors.forename: Deng-ning
authors.initials: DN
authors.lastname: Xia
authors.affiliation: School of Pharmacy, Chongqing Medical University, Chongqing 400016, China.|Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
authors.forename: Qiu-xia
authors.initials: QX
authors.lastname: Li
authors.affiliation: Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.|Department of Pharmacy, College of Clinical Medicine, Nanchang University, Nanchang 330047, China.
authors.forename: Jin-song
authors.initials: JS
authors.lastname: Tao
authors.affiliation: Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
authors.forename: Yong
authors.initials: Y
authors.lastname: Gan
authors.affiliation: School of Pharmacy, Chongqing Medical University, Chongqing 400016, China.
authors.forename: Chi
authors.initials: C
authors.lastname: Wang
mesh_terms: D000284:Administration, Oral; D000818:Animals; D018938:Caco-2 Cells; D003460:Crystallization / Q000379:methods; D017320:HIV Protease Inhibitors / Q000008:administration & dosage / Q000097:blood / Q000737:chemistry / Q000493:pharmacokinetics*; D006801:Humans; D007408:Intestinal Absorption; D007413:Intestinal Mucosa / Q000378:metabolism; D008297:Male; D053758:Nanoparticles / Q000008:administration & dosage / Q000737:chemistry; D051381:Rats; D017207:Rats, Sprague-Dawley; D019258:Saquinavir / Q000008:administration & dosage / Q000097:blood / Q000737:chemistry / Q000493:pharmacokinetics*; D012995:Solubility
chemical_list: D017320:HIV Protease Inhibitors; D019258:Saquinavir