Objective

The current study aimed to develop a novel milk-based formulation of docetaxel, a sparingly soluble antineoplastic agent, administered so far exclusively by the intravenous route and evaluate its oral bioavailability.

Methods

Pre-formulation studies included the determination of docetaxel solubility in water-alcohol mixtures as well as short-term content uniformity experiments of the final formulation. The pharmacokinetic (PK) performance of the developed milk-based formulations was further evaluated in vivo in mice using ritonavir, a potent P-glycoprotein inhibitor, as an absorption enhancer of docetaxel and the marketed intravenous docetaxel formulation, Taxotere®, as a control.

Results

In vivo PK results in mice showed that all the administered oral docetaxel formulations had limited absorption in the absence of ritonavir. On the contrary, ritonavir co-administration given as pre-treatment significantly enhanced oral bioavailability of both the marketed and milk-based docetaxel formulations; an even more marked increase in drug exposure was observed when ritonavir was incorporated within the docetaxel milk-based formulation. The fixed-dose combination also showed a more prolonged absorption of the drug compared to separate administrations.

Conclusions

The current study provides insights for the discovery of a novel milk-based formulation that could potentially serve as an alternative, non-toxic and patient-friendly carrier for an acceptable docetaxel oral chemotherapy.

中文翻译：

---

在基于口服乳的配方中使用利托那韦增强多西紫杉醇的吸收

客观的

目前的研究旨在开发一种新的基于牛奶的多西紫杉醇制剂，一种微溶性抗肿瘤剂，迄今为止仅通过静脉途径给药，并评估其口服生物利用度。

方法

预制剂研究包括确定多西紫杉醇在水-醇混合物中的溶解度以及最终制剂的短期含量均匀性实验。使用利托那韦（一种有效的 P 糖蛋白抑制剂）作为多西紫杉醇的吸收促进剂和已上市的静脉注射多西紫杉醇制剂 Taxotere® 作为对照，在小鼠体内进一步评估了开发的基于牛奶的制剂的药代动力学（PK）性能。

结果

小鼠体内 PK 结果表明，在没有利托那韦的情况下，所有口服多西紫杉醇制剂的吸收有限。相反，作为预处理给予利托那韦联合给药显着提高了市售和基于牛奶的多西紫杉醇制剂的口服生物利用度；当将利托那韦加入多西紫杉醇乳制剂中时，观察到药物暴露量的增加更为显着。与单独给药相比，固定剂量组合也显示出更长时间的药物吸收。

结论

目前的研究为发现一种新的基于牛奶的配方提供了见解，该配方可能作为可接受的多西紫杉醇口服化疗的替代、无毒和对患者友好的载体。