Department of Pharmaceutics and Center for Translational Drug Delivery, College of Pharmacy, University of Minnesota, 308 Harvard Street SE, Minneapolis, MN, 55455, USA.
Albany Molecular Research Inc., 21 Corporate Circle, Albany, NY, 12203, USA.
Drug Deliv Transl Res. 2018 Apr;8(2):375-386. doi: 10.1007/s13346-017-0383-6.
Lipid-based drug delivery systems, a well-tolerated class of formulations, have been evaluated extensively to enhance the bioavailability of poorly soluble drugs. However, it has been difficult to predict the in vivo performance of lipid dosage forms based on conventional in vitro techniques such as cell monolayer permeability studies because of the complexity of the gastrointestinal processing of lipid formulations. In the current study, we explored the feasibility of coupling Caco-2 and Madin-Darby canine kidney monolayer permeability studies with lipolysis, a promising in vitro technique to evaluate lipid systems. A self-emulsifying lipid delivery system was formulated using a blend of oil (castor oil), surfactant (Labrasol® or PL497), and co-surfactant (lecithin). Formulations demonstrating high drug solubility and rapid self-emulsification were selected to study the effect of lipolysis on in vitro cell permeability. Lipolysis of the formulations was carried out using pancreatin as the digestive enzyme. All the digested formulations compromised monolayer integrity as indicated by lowered trans-epithelial electrical resistance (TEER) and enhanced Lucifer yellow (LY) permeability. Further, the changes in TEER value and LY permeability were attributable to the digestion products of the formulation rather than the individual lipid excipients, drug, digestion enzyme, or the digestion buffer. The digested formulations were fractionated into pellet, oily phase, and aqueous phase, and the effect of each of these on cell viability was examined. Interestingly, the aqueous phase, which is considered important for in vivo drug absorption, was responsible for cytotoxicity. Because lipid digestion products lead to disruption of cell monolayer, it may not be appropriate to combine lipolysis with cell monolayer permeability studies. Additional in vivo studies are needed to determine any potential side effects of the lipolysis products on the intestinal permeability barrier, which could determine the suitability of lipid-based systems for oral drug delivery.
基于脂质的药物递送系统是一类耐受性良好的制剂，已被广泛评估用于提高难溶性药物的生物利用度。然而，由于脂质制剂在胃肠道中的复杂处理过程，基于传统的体外技术（如细胞单层渗透率研究）难以预测脂质剂型的体内性能。在本研究中，我们探讨了将 Caco-2 和 Madin-Darby 犬肾单层渗透率研究与脂肪酶解相结合的可行性，脂肪酶解是一种有前途的评估脂质系统的体外技术。使用油（蓖麻油）、表面活性剂（Labrasol® 或 PL497）和助表面活性剂（卵磷脂）的混合物配制自乳化脂质递药系统。选择具有高药物溶解度和快速自乳化性能的制剂来研究脂肪酶解对体外细胞通透性的影响。使用胰酶作为消化酶进行制剂的脂肪酶解。所有消化的制剂均破坏了单层完整性，表现为跨上皮电阻（TEER）降低和荧光素黄（LY）通透性增强。此外，TEER 值和 LY 通透性的变化归因于制剂的消化产物，而不是单独的脂质赋形剂、药物、消化酶或消化缓冲液。将消化的制剂分离为沉淀、油性相和水相，并检查了这些相中的每一种对细胞活力的影响。有趣的是，被认为对体内药物吸收很重要的水相是导致细胞毒性的原因。由于脂质消化产物导致细胞单层破裂，因此将脂肪酶解与细胞单层渗透率研究结合可能并不合适。需要进行额外的体内研究，以确定脂肪酶解产物对肠道通透性屏障的任何潜在副作用，这可能决定基于脂质的系统是否适合口服药物递送。
