Susceptibility to Lipase-Mediated Digestion Reduces the Oral Bioavailability of Danazol After Administration as a Medium-Chain Lipid-Based Microemulsion Formulation

Abstract

Purpose. To investigate the impact of lipidic formulation type on in vitro dispersion and digestion properties and the relationship to oral bioavailability, using danazol as a model lipophilic poorly water-soluble drug.

Methods. Three lipid-based danazol formulations [a long-chain triglyceride solution (LCT-solution) and self-microemulsifying drug delivery systems (SMEDDS) based on long-chain (C18) lipids (LC-SMEDDS) and medium-chain (C8-C10) lipids (MC-SMEDDS)] were adminis- tered to fasted beagle dogs and compared with a micronized danazol formulation administered postprandially and in the fasted state. In vitro dispersion and particle size data for the two SMEDDS were compared, and the distribution/solubilization patterns of danazol across the various phases produced during in vitro digestion quantified.

Results. The LCT-solution and LC-SMEDDS formulations significantly enhanced the oral bioavailability of danazol when compared to fasted administration of the powder formulation. In contrast, and despite displaying excellent dispersion properties, the MC-SMEDDS resulted in little enhancement in danazol bioavailability. In support of the in vivo findings, in vitro digestion of the medium-chain formulation resulted in significant drug precipitation when compared with the long-chain lipid formulations.

Conclusions. Digestion of microemulsion preconcentrate formulations based on medium-chain lipids may limit in vivo utility when compared with similar formulations based on long chain lipids.

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Correspondence to Christopher J. H. Porter.

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Porter, C.J.H., Kaukonen, A.M., Boyd, B.J. et al. Susceptibility to Lipase-Mediated Digestion Reduces the Oral Bioavailability of Danazol After Administration as a Medium-Chain Lipid-Based Microemulsion Formulation. Pharm Res 21, 1405–1412 (2004). https://doi.org/10.1023/B:PHAM.0000036914.22132.cc

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  • absorption bioavailability
  • dispersion
  • lipid-based drug delivery
  • lipid digestion
  • poorly water-soluble drugs