Co-administration of darunavir and a new pharmacokinetic booster: Formulation strategies and evaluation in dogs
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- 作者：Elke Van Gyseghem ; Lieven Baert ; Pieter Van Remoortere ; Gerben van ‘ ; t Klooster ; Marie-Claude Rouan ; Jody Voorspoels ; Herman de Kock ; Laurent Schueller ; Jan Rosier ; Liesbeth Grooten ; Guy Van den
- 关键词：TMC114 (darunavir) ; TMC41629 ; Booster ; Pharmacokinetics ; Beads ; Co-formulation ; Dogs ; HIV
- 刊名：European Journal of Pharmaceutical Sciences
- 出版年：2010
- 出版时间：9 October 2010
- 年：2010
- 卷：41
- 期：2
- 页码：193-200
- 全文大小：416 K
文摘
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 (HPβCD) 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.