Koehl Niklas J, Holm René, Kuentz Martin, Griffin Brendan T
School of Pharmacy, University College Cork, Cavanagh Building, College Road, Cork, Ireland.
Drug Product Development, Janssen Research and Development, Johnson & Johnson, Turnhoutseweg 30, 2340, Beerse, Belgium.
Pharm Res. 2019 Feb 22;36(4):56. doi: 10.1007/s11095-019-2590-y.
Lipid suspensions have been shown to be a suitable bio-enabling formulation approach for highly lipophilic or 'grease ball' drug molecules, but studies on 'brick dust' drugs are lacking. This study explored the utility of lipid suspensions for enhancing oral bioavailability of the rather hydrophobic drug nilotinib in vivo in rats.
Four lipid suspensions were developed containing long chain triglycerides, medium chain triglyceride, long chain monoglycerides and medium chain monoglycerides and in vivo bioavailability was compared to an aqueous suspension. Additionally, in vitro lipolysis and wettability tests were conducted.
Nilotinib lipid suspensions did not show a bioavailability increase compared to an aqueous suspension. The bioavailability was lower for triglyceride suspensions, relative to both monoglyceride and an aqueous suspension. The long chain monoglyceride displayed a significantly higher bioavailability relative to triglycerides. In vitro lipolysis results suggested entrapment of nilotinib crystals within poorly dispersible triglycerides, leading to slower nilotinib release and absorption. This was further supported by higher wettability of nilotinib by lipids.
Monoglycerides improved oral bioavailability of nilotinib in rats, relative to triglycerides. For 'brick dust' drugs formulated as lipid suspensions, poorly dispersible formulations may delay the release of drug crystals from the formulation leading to reduced absorption. Graphical Abstract An aqueous and four lipid suspensions have been evaluated in in vitro and in vivo to gain insights into the potential benefits and limitations of lipid suspensions.
脂质混悬液已被证明是一种适用于高度亲脂性或“油球”类药物分子的生物赋形制剂方法，但缺乏针对“砖粉”类药物的研究。本研究探讨了脂质混悬液在提高大鼠体内相当疏水的药物尼洛替尼口服生物利用度方面的效用。
制备了四种含有长链甘油三酯、中链甘油三酯、长链单甘油酯和中链单甘油酯的脂质混悬液，并将其体内生物利用度与水混悬液进行比较。此外，还进行了体外脂解和润湿性测试。
与水混悬液相比，尼洛替尼脂质混悬液的生物利用度没有提高。相对于单甘油酯和水混悬液，甘油三酯混悬液的生物利用度较低。长链单甘油酯相对于甘油三酯显示出显著更高的生物利用度。体外脂解结果表明，尼洛替尼晶体被困在难分散的甘油三酯中，导致尼洛替尼释放和吸收较慢。脂质对尼洛替尼的较高润湿性进一步支持了这一点。
相对于甘油三酯，单甘油酯提高了大鼠体内尼洛替尼的口服生物利用度。对于制成脂质混悬液的“砖粉”类药物，难分散的制剂可能会延迟药物晶体从制剂中的释放，从而导致吸收减少。图形摘要 对一种水混悬液和四种脂质混悬液进行了体外和体内评估，以深入了解脂质混悬液的潜在益处和局限性。
