Department of Pharmacy, Uppsala University, Uppsala Biomedical Center, P.O Box 580, SE-751 23 Uppsala, Sweden.
AstraZeneca R&D, SE-431 50 Gothenburg, Sweden.
J Control Release. 2019 Jun 28;304:90-100. doi: 10.1016/j.jconrel.2019.04.038. Epub 2019 Apr 29.
Lipid-based formulations (LBFs) is a formulation strategy for enabling oral delivery of poorly water-soluble drugs. However, current use of this strategy is limited to a few percent of the marketed products. Reasons for that are linked to the complexity of LBFs, chemical instability of pre-dissolved drug and a limited understanding of the influence of LBF intestinal digestion on drug absorption. The aim of this study was to explore intestinal drug solubilization from a long-chain LBF, and evaluate whether coadministration of LBF is as efficient as a lipid-based drug formulation containing the pre-dissolved model drug carvedilol. Thus, solubility studies of this weak base were performed in simulated intestinal fluid (SIF) and aspirated dog intestinal fluid (DIF). DIF was collected from duodenal stomas after dosing of water and two levels (1 g and 2 g) of LBF. Similarly, the in vitro SIF solubility studies were conducted prior to, and after addition of, undigested or digested LBF. The DIF fluid was further characterized for lipid digestion products (free fatty acids) and bile salts. Subsequently, carvedilol was orally administered to dogs in a lipid-based drug formulation and coadministered with LBF, and drug plasma exposure was assessed. In addition to these studies, in vitro drug absorption from the different formulation approaches were evaluated in a lipolysis-permeation device, and the obtained data was used to evaluate the in vitro in vivo correlation. The results showed elevated concentrations of free fatty acids and bile salts in the DIF when 2 g of LBF was administered, compared to only water. As expected, the SIF and DIF solubility data revealed that carvedilol solubilization increased by the presence of lipids and lipid digestion products. Moreover, coadministration of LBF and drug demonstrated equal plasma exposure to the lipid-based drug formulation. Furthermore, evaluation of in vitro absorption resulted in the same rank order for the LBFs as in the in vivo dog study. In conclusion, this study demonstrated increased intestinal solubilization from a small amount of LBF, caused by lipid digestion products and bile secretion. The outcomes also support the use of coadministration of LBF as a potential dosing regimen in cases where it is beneficial to have the drug in the solid form, e.g. due to chemical instability in the lipid vehicle. Finally, the in vitro lipolysis-permeation used herein established IVIVC for carvedilol in the presence of LBFs.
基于脂质的制剂（LBF）是一种使水溶性差的药物能够口服给药的制剂策略。然而，目前这种策略的应用仅限于市场上产品的少数几种。其原因与 LBF 的复杂性、预溶解药物的化学不稳定性以及对 LBF 肠道消化对药物吸收影响的有限理解有关。本研究旨在探索长链 LBF 的肠道药物增溶作用，并评估 LBF 的联合给药是否与含有预溶解模型药物卡维地洛的基于脂质的药物制剂一样有效。因此，在模拟肠液（SIF）和抽吸狗肠液（DIF）中进行了这种弱碱的溶解度研究。DIF 是在水和两种水平（1 g 和 2 g）LBF 给药后从十二指肠造口收集的。同样，在添加未消化或消化的 LBF 之前和之后进行了体外 SIF 溶解度研究。进一步对 DIF 流体中的脂质消化产物（游离脂肪酸）和胆汁盐进行了表征。随后，将卡维地洛以基于脂质的药物制剂的形式口服给予狗，并评估药物血浆暴露情况。除了这些研究外，还在脂肪酶渗透装置中评估了不同制剂方法的药物吸收情况，并使用获得的数据评估了体外体内相关性。结果表明，与仅给予水相比，当给予 2 g LBF 时，DIF 中的游离脂肪酸和胆汁盐浓度升高。正如预期的那样，SIF 和 DIF 溶解度数据表明，由于脂质和脂质消化产物的存在，卡维地洛的增溶作用增加。此外，LBF 和药物的联合给药与基于脂质的药物制剂具有相同的血浆暴露。此外，体外吸收评估导致 LBF 的相同等级顺序与体内狗研究相同。总之，本研究表明，由于脂质消化产物和胆汁分泌，少量 LBF 可增加肠道增溶作用。研究结果还支持联合使用 LBF 作为潜在的给药方案，例如在脂质载体中的药物化学不稳定时，将药物以固体形式存在有益的情况下。最后，本文中使用的体外脂肪酶渗透法建立了 LBF 存在时卡维地洛的 IVIVC。
