Lipid digestion as a trigger for supersaturation: Evaluation of the impact of supersaturation stabilization on the in vitro and in vivo performance of self-emulsifying drug delivery systems

Mette U. Anby, Hywel D. Williams, Michelle McIntosh, Hassan Benameur, Glenn Edwards, Colin W. Pouton, Christopher J.H. Porter

Research output: Contribution to journalArticle

100 Citations (Scopus)

Abstract

The generation of supersaturation in the gastrointestinal (GI) tract is an increasingly popular means of promoting oral absorption for poorly water-soluble drugs. The current study examined the impact of changes to the quantities of medium-chain (MC) lipid (Captex 300:Capmul MCM), surfactant (Cremophor EL) and cosolvent (EtOH), and the addition of polymeric precipitation inhibitors (PPI), on supersaturation during the dispersion and digestion of MC self-emulsifying drug delivery systems (SEDDS) containing danazol. The data suggest that digestion acts as a "trigger" for enhanced supersaturation and that solubilization/precipitation behavior is correlated with the degree of supersaturation on dispersion (S(M)(DISP)) or digestion (S(M)(DIGEST)). The ability of the formulation to maintain solubilization in vitro decreased as the S(M) of the formulation increased. PPI significantly increased supersaturation stabilization and precipitation was inhibited where S(M)(DISP) < 3.5 and S(M)(DIGEST) < 4. In the presence of polymer, some degree of supersaturation was maintained up to S(M)(DIGEST) ~ 8. Differentiation in the ability of SEDDS to maintain drug solubilization stems from the ability to stabilize supersaturation and for MC SEDDS, utilization of lower drug loads, higher surfactant levels (balanced against increases in S(M)(DISP)), lower cosolvent and the addition of PPI enhanced formulation performance. In vivo studies confirmed the ability of PPI to promote drug exposure at moderate drug loads (40% of saturated solubility in the formulation). At higher drug loads (80% saturation) and in lipid-free SEDDS, this effect was lost, suggesting that the ability of PPIs to stabilize supersaturation in vitro may, under some circumstances, overestimate utility in vivo.
Original languageEnglish
Pages (from-to)2063-2079
Number of pages17
JournalMolecular Pharmaceutics
Volume9
Issue number7
DOIs
Publication statusPublished - Jul 2012

Fingerprint Dive into the research topics of 'Lipid digestion as a trigger for supersaturation: Evaluation of the impact of supersaturation stabilization on the in vitro and in vivo performance of self-emulsifying drug delivery systems'. Together they form a unique fingerprint.

  • Cite this