Preparation And Evaluation Of Oridonin Loaded Nanostructured Lipid Carriers

Background and Purposes: Oridonin(Ori) is a natural compound with significant anti-cancer activities. However, the therapeutic uses of this compound are limited by poor bioavailability. Thus, it is of great clinical significance to enhance oral absorption of oridonin. This thesis aims to design a novel biotin-modified nanostructured lipid carrier(NLC) which can be used to enhance oral bioavailability of oridonin.Methods: 1. Melt dispersion-high pressure homogenization method was used to prepare Ori-loaded NLCs(Ori-NLCs). Biotin-decorated Ori-NLCs(Bio-Ori-NLCs) were obtained by amide modification of Ori-NLCs in the aqueous phase. 2. Particle size and ζ potential of NLCs were determined by Nanosizer. The morphology of NLCs were evaluated by transmission electron microscope(TEM). Entrapment efficacy(EE) and drug loading(DL) were determined by ultrafiltration method. Drug release properties were evaluated by dialysis method. In vitro lipid digestion model was established to investigate the impact of gastrointestinal lipases on NLCs. 3. Pharmacokinetic experiment was performed with rat to evaluate oral absorption of NLCs. Rats were orally administered with Ori-NLCs, Bio-Ori-NLCs and Orisuspensions. Blood samples were collected at different time points. Rat in situ intestinal perfusion was performed to determine the permeability of oridonin NLCs.Results: The obtained biotin-decorated Ori-NLCs(Bio-Ori-NLCs) were 136.5 nm in size with an entrapment efficiency of 49.54 % and a drug load of 4.81 %. Oral bioavailability was enhanced by use of Bio-Ori-NLCs with a relative bioavailability of 171.01 %, while the value of non-modified Ori-NLCs was improved to 143.48 %. Moreover, Bio-Ori-NLCs shortened the Tmax from 1.5 h to 15 min. Bio-Ori-NLCs performed best in the oridonin permeability enhancement. In duodenum, Bio-Ori-NLCs was three times the Peff value of Ori-solution, and 1.5 times the Peff value of Ori-NLCs.Conclusion: Bio-Ori-NLCs are capable of enhancing the oral bioavailability of oridonin by facilitating its permeation through intestinal membrane. This thesis has provided a promising strategy for the future development of oridonin oral dosage forms.