Rationally designed lipid- and food-based drug formulations to enhance oral bioavailability

摘要 超过40%的上市药物和约90%的开发管道中的药物存在不良的水性 溶解性和相关的低生物利用度。食物，特别是脂质，可以显著增强 这些药物的生物利用度。这种“食物效应”可以通过开发基于脂质和食物的 这些制剂表现出增强的吸收效率，并且因此可以以降低的 药物剂量，同时保持相同的全身暴露。值得注意的是，使用食品成分作为配方 赋形剂还可以减轻食物对生物利用度的影响，从而使患者能够服用这些药物， 不考虑食物，减少药物治疗方案的复杂性，并最终解决重大的 患者依从性低的问题。然而，脂质和食物在口服药物递送中的使用是有限的，部分原因是缺乏脂质和食物。 能够预测胃肠道中的先验脂质功能及其对药物吸收的影响。我们的团队开发了 一种可以预测食物数量和成分对药物吸收和生物利用度影响的算法 从机械的角度来看。具体来说，我们的算法考虑了多个并行的动态过程（药物 溶解、脂质和蛋白质消化、药物在胶体中的分配、吸收）来定量预测影响 食物相关脂质和蛋白质对口服生物利用度的影响。这种方法提供了巨大的价值， 在开发使用脂质和其他食品成分的改进剂型方面提供合理的定量指导， 制剂辅料。在这个项目中，我们的目标是开发一种生物利用度差的口服上市的新制剂， 已知受食物显著影响的药物，仅限于餐后服用。小说 剂型将表现出增强的能力，因为它们可以以较低的剂量给药， 相同的治疗效果和与食物一起或不与食物一起给药不会影响生物利用度。发展 这些制剂将证明我们的算法在改善口服递送差的药物方面的实际应用。 通过利用食物效应来开发生物可利用的药物。在第一个目标中，现有的算法将适于预测 在施用基于水性脂质/蛋白质乳液的递送载体后的药物药代动力学。动力学 参数将在体外测量，并用作模型输入参数，以选择最佳的 与市售制剂生物等效的药物剂量和脂质-蛋白质混合物组合物。在第二 目的，建模框架将被用来选择一种脂质-表面活性剂-助溶剂系统， 作为胶囊内的基于脂质的制剂施用。制剂参数（例如，药物剂量，辅料 组合物）将进行优化，以告知与上市制剂生物等效的制剂的开发 剂型。将通过犬药代动力学研究证明所有制剂之间的生物等效性。 这些目标的成功完成将证明我们的模型可以1）有效地告知合理的设计， 具有增强的生物利用度的新的基于食物和脂质的制剂，和2）可以允许开发更低的 剂量制剂，同时保持与市售剂型相同的暴露量和治疗效果。

Abstract More than 40% of marketed drugs and about 90% of drugs in development pipelines suffer from poor aqueous solubility and associated low bioavailability. Food, and lipids in particular, can significantly enhance the bioavailability of such drugs. This “food effect” could be exploited by developing lipid- and food-based formulations that demonstrate enhanced efficiency absorption, and as a result can be designed at a reduced drug dose while maintaining the same systemic exposure. Notably, using food components as formulation excipients would also mitigate food effects on bioavailability, thus allowing patients to take these medications irrespective of food, reducing the complexity of medication regiments, and ultimately addressing the significant issue of low patient adherence. However, lipid and food use in oral drug delivery is limited, in part, due to lack of ability to predict a priori lipid function in the GI tract and its effect on drug absorption. Our team has developed an algorithm that can predict the impact of food quantity and composition on drug absorption and bioavailability from a mechanistic point of view. Specifically, our algorithm considers multiple parallel, dynamic processes (drug dissolution, lipid and protein digestion, drug partitioning in colloids, absorption) to quantitatively predict the impact of food-associated lipids and proteins on oral bioavailability. This approach offers tremendous value by enabling rational quantitative guidance in developing improved dosage forms using lipids and other food ingredients as formulation excipients. In this project, we aim to develop novel formulations of a poorly bioavailable oral marketed drug that is known to be significantly impacted by food and is restricted to be taken only after a meal. The novel dosage forms will demonstrate enhanced capabilities in that they can be administered at a lower dose for the same therapeutic effect and administration with or without food will not impact bioavailability. Development of these formulations will demonstrate the practical application of our algorithm to improve oral delivery of poorly bioavailable drugs by exploiting the food effect. In the first aim, the existing algorithm will be adapted to predict drug pharmacokinetics after administration of an aqueous lipid/protein emulsion-based delivery vehicle. Kinetic parameters will be measured in vitro and used as model input parameters to inform selection of the most optimal drug dose and lipid-protein mixture composition that is bioequivalent to the marketed formulation. In the second aim, the modeling framework will be employed to select a lipid-surfactant-cosolvent system that can be administered as a lipid-based formulation inside a capsule. Formulation parameters (e.g., drug dose, excipient composition) will be optimized to inform development of a formulation that is bioequivalent to the marketed dosage form. Bioequivalence among all formulations will be demonstrated via pharmacokinetic studies in dogs. Successful completion of these aims will demonstrate that our model can 1) effectively inform rational design of novel food- and lipid-based formulations with enhanced bioavailability, and 2) can allow development of lower dose formulations while maintaining the same exposure and therapeutic effect as the marketed dosage form.