Department of Pharmacy, Faculty of Health and Medical Sciences, University of Copenhagen, 2100 Copenhagen, Denmark.
Faculty of Pharmaceutical Sciences, University of British Columbia, Vancouver, BC V6T 1Z3, Canada; Department of Physics and Astronomy, University of British Columbia, Vancouver, BC V6T 1Z1, Canada.
J Control Release. 2020 Jan 10;317:375-384. doi: 10.1016/j.jconrel.2019.11.024. Epub 2019 Nov 23.
Using lipid-based drug delivery systems (LbDDS) is an efficient strategy to enhance the low oral bioavailability of poorly water-soluble drugs. Here the oral absorption of fenofibrate (FF) from LbDDS in rats was investigated in pharmacokinetic, in vitro lipolysis, and SPECT/CT in vivo imaging studies. The investigated formulations were soybean oil solution (SBO), a mixture of soybean oil and monoacyl phosphatidylcholine (MAPC) (SBO-MAPC), self-nanoemulsifying drug delivery systems with and without MAPC (SNEDDS-MAPC and SNEDDS, respectively), and an aqueous suspension (SUSP) as a reference. Oral bioavailability of the LbDDS ranged from 27 to 35%. A two-step in vitro lipolysis model simulating rat gastro-intestinal digestion provided in vitro FF solubilisation data to understand oral absorption. During the in vitro lipolysis, most FF was undissolved for SUSP and distributed into the poorly dispersed oil phase for SBO. For the SNEDDS without MAPC, practically all FF solubilised into the aqueous phase during the dispersion and digestion. Adding MAPC to SBO enhanced the dispersion of the oil phase into the digestion media while adding MAPC to SNEDDS resulted in a distribution of 29% of FF into the oil phase at the beginning of in vitro lipolysis. FF distribution into both oil and aqueous phases explained the higher and prolonged oral absorption of LbDDS containing MAPC. To elucidate the relatively low bioavailability of all formulations, FF and triolein were labeled with I and I, respectively, to study the biodistribution of drug and lipid excipients in a dual isotope SPECT/CT in vivo imaging study. The concentration of radiolabeled drug as a function of time in the heart correlated to the plasma curves. A significant amount of radiolabeled drug and lipids (i.e., 28-59% and 24-60% of radiolabeled drug and lipids, respectively) was observed in the stomach at 24 h post administration, which can be linked to the low bioavailability of the formulations. The current study for the first time combined in vitro lipolysis and dual isotope in vivo imaging to find the root cause of different fenofibrate absorption profiles from LbDDS and an aqueous suspension.
利用基于脂质的药物递送系统（LbDDS）是提高疏水性差的药物口服生物利用度的有效策略。在这里，通过药代动力学、体外脂肪分解和 SPECT/CT 体内成像研究，研究了贝特类药物非诺贝特（FF）在大鼠体内从 LbDDS 的口服吸收情况。研究的制剂包括大豆油溶液（SBO）、大豆油和单酰基磷脂酰胆碱（MAPC）的混合物（SBO-MAPC）、具有和不具有 MAPC 的自微乳给药系统（SNEDDS-MAPC 和 SNEDDS）以及水混悬剂（SUSP）作为参考。LbDDS 的口服生物利用度范围为 27%至 35%。模拟大鼠胃肠消化的两步体外脂肪分解模型提供了体外 FF 增溶数据，以了解口服吸收情况。在体外脂肪分解过程中，SUSP 中大部分 FF 未溶解，而 SBO 中 FF 分布在分散性差的油相中。对于不含 MAPC 的 SNEDDS，FF 在分散和消化过程中几乎全部增溶到水相中。向 SBO 中添加 MAPC 增强了油相在消化介质中的分散性，而向 SNEDDS 中添加 MAPC 则导致 FF 在体外脂肪分解开始时 29%分配到油相中。FF 分布在油相和水相解释了含有 MAPC 的 LbDDS 更高和更持久的口服吸收。为了解释所有制剂相对较低的生物利用度，FF 和三油酸甘油酯分别用 I 和 I 标记，以在双同位素 SPECT/CT 体内成像研究中研究药物和脂质赋形剂的体内分布。放射性标记药物浓度随时间的变化与血浆曲线相关。在给药后 24 小时，胃中观察到大量放射性标记的药物和脂质（即，分别为放射性标记的药物和脂质的 28-59%和 24-60%），这与制剂的低生物利用度有关。本研究首次将体外脂肪分解和双同位素体内成像相结合，以找到 LbDDS 和水混悬剂中不同非诺贝特吸收曲线的根本原因。
