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

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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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Authors and Affiliations

  1. Department of Pharmaceutics, Victorian College of Pharmacy, Monash University (Parkville Campus), Parkville, Victoria, 3052, Australia. (e-mail: Chris.Porter@vcp.monash.edu.au)

    Christopher J. H. Porter, Ann Marie Kaukonen, Ben J. Boyd & William N. Charman

  2. Viikki Drug Discovery Technology Center, Division of Pharmaceutical Technology, Faculty of Pharmacy, University of Helsinki, Finland

    Ann Marie Kaukonen

  3. Department of Veterinary Sciences, The University of Melbourne, Werribee, Victoria, 3030, Australia

    Glenn A. Edwards

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  1. Christopher J. H. Porter
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  2. Ann Marie Kaukonen
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  3. Ben J. Boyd
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  4. Glenn A. Edwards
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  5. William N. Charman
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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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