School of Pharmacy, University College Cork, College Road, T12 YN60 Cork, Ireland.
Drug Product Development, Janssen Research and Development, Johnson & Johnson, Turnhoutseweg 30, 2340 Beerse, Belgium.
Mol Pharm. 2021 Jun 7;18(6):2174-2188. doi: 10.1021/acs.molpharmaceut.0c00645. Epub 2021 Apr 23.
The concept of using precipitation inhibitors (PIs) to sustain supersaturation is well established for amorphous formulations but less in the case of lipid-based formulations (LBF). This study applied a systematic -- approach to assess the merits of incorporating PIs in supersaturated LBFs (sLBF) using the model drug venetoclax. sLBFs containing hydroxypropyl methylcellulose (HPMC), hydroxypropyl methylcellulose acetate succinate (HPMCAS), polyvinylpyrrolidone (PVP), PVP--vinyl acetate (PVP/VA), Pluronic F108, and Eudragit EPO were assessed calculating a drug-excipient mixing enthalpy, using a PI solvent shift test, and finally, bioavailability was assessed in landrace pigs. The estimation of pure interaction enthalpies of the drug and the excipient was deemed useful in determining the most promising PIs for venetoclax. The sLBF alone (i.e., no PI present) displayed a high initial drug concentration in the aqueous phase during screening. sLBF with Pluronic F108 displayed the highest venetoclax concentration in the aqueous phase and sLBF with Eudragit EPO the lowest. , the sLBF alone showed the highest bioavailability of 26.3 ± 14.2%. Interestingly, a trend toward a decreasing bioavailability was observed for sLBF containing PIs, with PVP/VA being significantly lower compared to sLBF alone. In conclusion, the ability of a sLBF to generate supersaturated concentrations of venetoclax was translated into increased absorption . While and PI screening suggested benefits in terms of prolonged supersaturation, the addition of a PI did not increase bioavailability. The findings of this study are of particular relevance to pre-clinical drug development, where the high exposure of venetoclax was achieved using a sLBF approach, and despite the perceived risk of drug precipitation from a sLBF, including a PI may not be merited in all cases.
利用沉淀抑制剂 (PIs) 维持过饱和度的概念在无定形制剂中得到了很好的验证，但在脂质制剂 (LBF) 中则较少。本研究应用系统方法，使用模型药物维奈托克评估在过饱和脂质制剂 (sLBF) 中加入 PIs 的优点。评估了含有羟丙基甲基纤维素 (HPMC)、羟丙基甲基纤维素醋酸琥珀酸酯 (HPMCAS)、聚乙烯吡咯烷酮 (PVP)、PVP-醋酸乙烯酯 (PVP/VA)、泊洛沙姆 F108 和 Eudragit EPO 的 sLBF，通过计算药物-赋形剂混合焓、使用 PI 溶剂移位测试，最后在长白猪中评估生物利用度。药物和赋形剂的纯相互作用焓的估计被认为有助于确定维奈托克最有前途的 PIs。单独的 sLBF（即，没有 PI 存在）在筛选过程中显示出在水相中有很高的初始药物浓度。含有泊洛沙姆 F108 的 sLBF 在水相中有最高的维奈托克浓度，而含有 Eudragit EPO 的 sLBF 则最低。单独的 sLBF 显示出 26.3±14.2%的最高生物利用度。有趣的是，对于含有 PI 的 sLBF，观察到生物利用度呈下降趋势，与单独的 sLBF 相比，PVP/VA 显著降低。结论是，sLBF 产生维奈托克过饱和浓度的能力转化为吸收增加。虽然 PI 筛选在延长过饱和度方面显示出益处，但加入 PI 并不能提高生物利用度。这项研究的结果对于临床前药物开发具有特别重要的意义，在这种开发中，使用 sLBF 方法实现了维奈托克的高暴露，尽管从 sLBF 中存在药物沉淀的风险，但在所有情况下都可能不需要包括 PI。
