Oral saquinavir mesylate solid dispersions: In vitro dissolution, Caco-2 cell model permeability and in vivo absorption studies

• SQVM was released faster from the PEG-based SDs than from those with Gelucire at pH 1.2.
• SQVM was released slower from the PEG-based SDs than from those with Gelucire at pH 6.8.
• Gelucire and PVP K30 reduced the efflux ratio to a level similar to that of verapamil.
• Amphiphilic carriers displayed higher oral bioavailability of SQVM in dogs than PEG.

The aim of this study was to investigate the effects of solid dispersions (SDs) containing a mixture of PVP K30 and different carriers (PEG 4000 or Gelucire® 44/14) on in vitro dissolution and intestinal permeability of saquinavir mesylate (SQVM), and to evaluate their impact on the oral bioavailability of SQVM in a dog model by comparing with Svir® (commercial formulation). Although hydrophilic carriers such as PEG may provide advantages in terms of drug release, their limited solubilization capacity led to precipitation of drug and therefore to a reduced and variable oral bioavailability, as observed for SQVM from this carrier. On the other hand, self-emulsifying systems composed of Gelucire® 44/14 or oleic acid/Castor oil mixture (Svir®) were more effective at improving oral bioavailability of SQVM (approximately 5-fold higher than PEG-based formulations), probably due to the improved solubility of SQVM in GI tract, reduced particle size and inhibitory effects on P-gp (a 2.3-fold reduction of efflux ratio). The selection of carriers and other excipients which display a solubilizing effect and inhibitory effect on P-gp seems to be key factors for increasing the oral bioavailability of SQVM. Gelucire might be considered as a promising carrier for the development of a SQVM commercial formulation.

Effects of amphiphilic and hydrophilic carriers on dissolution, permeability and oral bioavailability of a poorly soluble drug were investigated. Hydrophilic systems presented low solubilization capacity, leading to drug precipitation and limited bioavailability. On the other hand, amphiphilic systems increased drug solubilization in GIT, reducing drug precipitation in pH intestinal and inhibited efflux on P-gp, which would explain the higher bioavailability.Figure optionsDownload as PowerPoint slide