Gastrointestinal lipolysis and trans-epithelial transport of SMEDDS via oral route

Self-microemulsifying drug delivery systems (SMEDDSs) have recently returned to the limelight of academia and industry due to their enormous potential in oral delivery of biomacromolecules. However, information on gastrointestinal lipolysis and trans-epithelial transport of SMEDDS is rare. Aggregation-caused quenching (ACQ) fluorescent probes are utilized to visualize the in vivo behaviors of SMEDDSs, because the released probes during lipolysis are quenched upon contacting water. Two SMEDDSs composed of medium chain triglyceride and different ratios of Tween-80 and PEG-400 are set as models, meanwhile Neoral® was used as a control. The SMEDDS droplets reside in the digestive tract for as long as 24 h and obey first order kinetic law of lipolysis. The increased chain length of the triglyceride decreases the lipolysis of the SMEDDSs. Ex vivo imaging of main tissues and histological examination confirm the trans-epithelial transportation of the SMEDDS droplets. Approximately 2%‒4% of the given SMEDDSs are transported via the lymph route following epithelial uptake, while liver is the main termination. Caco-2 cell lines confirm the cellular uptake and trans-epithelial transport. In conclusion, a fraction of SMEDDSs can survive the lipolysis in the gastrointestinal tract, permeate across the epithelia, translocate via the lymph, and accumulate mainly in the liver. Access the full open access article 

Materials
Labrafac CC was a kind gift from Gattefossé (Cedex, France), while Tween-80 and PEG-400 were from SINOPHARM (Beijing, China). Neoral® was purchased from Novartis (Basel, Switzerland). DAPI (4′,6-diamidino-2-phenylindole) and optimal cutting temperature (OCT) compound was from Shanghai Yeasen Biotech (Shanghai, China) and Leica (Mannheim, Germany), respectively. DMEM, RPMI 1640 and fetal bovine serum are from Gibco Invitrogen (Carlsbad, CA, USA). Caco-2 (human colorectal adenocarcinoma cell) and Raji (human Burkitt’s lymphoma cell) were obtained from the Cell Bank of the Chinese Academy of Sciences (Shanghai, China), while HT29-MTX cells were from China Center for Type Culture Collection (Wuhan, China). The ACQ probes, known as P2 and P4, were synthesized in the laboratory.

Conclusions
The ACQ probes render the visualization of the in vivo lipolysis and transport of intact SMEDDS droplets. SMEDDSs reside in the GIT of rats for up to 24 h, although they suffer lipolysis in a first order kinetic model. The SMEDDSs consisting of LCT have a slightly higher resistance to the lipolysis than the ones consisting of MCT. The survival SMEDDS droplets can permeate across the epithelia, where they are transported via either the blood or the lymph ducts. Around 2%‒4% administered SMEDDSs are transported via the lymphatic route. The SMEDDSs in the circulation are delivered to several organs with the liver as the major accumulating organ. In vitro Caco-2 cell models confirm the uptake and trans-monolayer transfer of the intact SMEDDS droplets. It is concluded that SMEDDSs are potential for oral delivery of labile entities as they can transport across the enterocytes and enter the circulation.

Article information: Fei Xia, Zhongjian Chen, Quangang Zhu, Jianping Qi, Xiaochun Dong, Weili Zhao, Wei Wu, Yi Lu,
Gastrointestinal lipolysis and trans-epithelial transport of SMEDDS via oral route, Acta Pharmaceutica Sinica B, 2021. https://doi.org/10.1016/j.apsb.2021.03.006.