Lipid-based formulations of danazol with varying quantities of included surfactant have been examined in vitro and in vivo. Formulations comprising fatty acid ester surfactants were readily hydrolysed during in vitro digestion, although Cremaphor RH40(CrRH) was less effectively hydrolysed than Cremaphor EL(CrEL). Formulations comprising high quantities of digestible surfactant also appeared to less effectively prevent danazol precipitation during in vitro evaluation. These trends were replicated in vivo where danazol bioavailability in beagle dogs was higher after oral administration of self-emulsifying formulations employing 55 (w/w) CrRH when compared with CrEL. The oral bioavailability of danazol after admisnitration of drug formulated in surfactant alone, however, was poor. Studies using predispersed and encapsulated formulations of CrRH subsequently suggested that the low bioavailability of the single surfactant formulations reflected poor dispersion. Mixtures of surfactnats, improved dispersion nd good oral bioavailability of danazol was evident after adminsitration of formulations comprising CrRH and euther Pluronic L121 or Gelucire 44-12, in spite of evidence of danazol precipitation during in vitro digestion of the Gelucire formulation. these data suggest that effective dispersion and resistance to percipitation during both dispersion and digestion are key design paramters for lipid-based formulations comprising high proportions of surfactant.
|Pages (from-to)||995 - 1012|
|Number of pages||18|
|Journal||Journal of Pharmaceutical Sciences|
|Publication status||Published - 2008|