Co-administration of darunavir and a new pharmacokinetic booster: Formulation strategies and evaluation in dogs

被引:5
|
作者
Van Gyseghem, Eike [5 ]
Baert, Lieven [2 ]
Van Remoortere, Pieter [2 ]
van't Klooster, Gerben [4 ]
Rouan, Marie-Claude [4 ]
Voorspoels, Jody [3 ]
de Kock, Herman [1 ]
Schueller, Laurent [2 ]
Rosier, Jan [2 ]
Grooten, Liesbeth [6 ]
Van den Mooter, Guy [5 ]
机构
[1] Tibotec BVBA, Clin Pharmacol, B-2800 Mechelen, Belgium
[2] Tibotec BVBA, Chem Pharm Dev, B-2800 Mechelen, Belgium
[3] Janssen Pharmaceut, Pharmaceut Dev, Beerse, Belgium
[4] Tibotec BVBA, Preclin Dev, B-2800 Mechelen, Belgium
[5] Katholieke Univ Leuven, Lab Farmacotechnol Biofarm, Leuven, Belgium
[6] Johnson & Johnson Pharmaceut Res & Dev, Drug Metab & Pharmacokinet, Beerse, Belgium
关键词
TMC114 (darunavir); TMC41629; Booster; Pharmacokinetics; Beads; Co-formulation; Dogs; HIV; PHARMACEUTICAL APPLICATIONS; SOLID DISPERSIONS; DRUG; STABILIZATION; CYCLODEXTRINS; EXCIPIENTS; STABILITY;
D O I
10.1016/j.ejps.2010.05.017
中图分类号
R9 [药学];
学科分类号
1007 ;
摘要
Various formulations for combination of the anti-HIV protease inhibitor darunavir (DRV) and TMC41629, a pharmacokinetic booster for DRV, were studied. TMC41629 (a BCS-IV compound) was formulated in capsules, as polyethylene glycol 400 (PEG400) solution, binary or ternary self-microemulsifying drug delivery system (SMEDDS), inclusion complex with hydroxypropyl-beta-cyclodextrin (HP beta CD) or polyvinylpyrrolidone-co-vinylacetate 64 (PVP/VA64) extrudate. In addition, tablets were prepared using unmilled or micronized powder and a disintegrant. On co-administration with DRV tablets in dogs, DRV plasma concentration levels were boosted by TMC41629, the PVP/VA64 extrudate achieving the highest DRV levels (2-fold increase). Yet, with extrudate prepared with both compounds, no boosting effect was observed, likely due to transition of DRV from crystalline solvate to amorphous state. Therefore, a co-formulation, combining DRV as crystalline solvate with amorphous TMC41629, was developed. DRV/kappa-carrageenan 80/20% (w/w) beads coated with TMC41629 released at least 80% within 1 h in 0.01 M HCl with 0.5% sodium lauryl sulphate. TMC41629 dissolving faster than DRV. In dogs, the DRV exposure increased 2.7-fold with the TMC41629-coated beads relative to DRV alone, yet remained lower, but less variable, than following co-administration as separate formulations. Coating of TMC41629 on DRV/kappa-carrageenan beads is a suitable technique for co-formulation, whereby TMC41629 can function as a booster of DRV. (C) 2010 Published by Elsevier B.V.
引用
收藏
页码:193 / 200
页数:8
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