Long chain triglyceride-lipid formulation promotes the oral absorption of the lipidic prodrugs through coincident intestinal behaviors

Oral administration of chemotherapy agents, such as docetaxel (DTX), is expected to reduce side effects significantly and increase dosing frequency. However, they often suffer from poor oral bioavailability, impeding their oral application. Dietary lipids such as triglycerides favor lymphatic transport nor vein system, bypassing the first-pass metabolism. Inspired by this concept, we developed a triglyceride-like prodrug of DTX (named as OATG) and explored the effect of lipid types on the OATG oral delivery. The plasma profile in rats revealed that long chain triglyceride (LCT)-based lipid formulations (LBLF) were more promising for OATG delivery than medium chain triglyceride (MCT) ones. The OATG LBLF elicited a markedly enhanced absorption compared with oral Taxotere or DTX LBLF, resulting in relative bioavailability 6.11 or 2.47-fold higher, respectively. The coincident intestinal behaviors of lipid excipients and TG-like prodrug facilitate the oral absorption of the prodrug. The effectiveness of the prodrug formulation was also examined in beagles with absolute bioavailability up to 41.08%, in sharp contrast to that of control DTX group (8%). Besides, the OATG oral formulation could be schedule-intensively administrated with no hypersensitivity, gastrointestinal and hematological toxicity. The current strategy provides an effective lipid formulation and a promising chance for chemotherapy at home.