Study On Micellar Dosing System For Promoting Oral Lymphatic Absorption

The majority of orally administered drugs gain access to the systemic circulation by absorption into the portal blood. However, some highly lipophilic compounds, whose absorption often limited by their low rate of dissolution and poor solubility, could access to systemic circulation by transported by lymph as the intestinal lymphatic system drains through the thoracic lymph duct into the left internal jugular vein and then to the systemic circulation. These drugs include CSA, probucol, halofantrine, testosterone undecanoate and so on. Advantages of drug transport via the intestinal lymphatics include improved drug absorption, avoidance of potential first-pass metabolism and selectively target of specific drugs to particular regions of lymphatic circulation.In this article, probucol and halofantrine were selected as the model drugs and drug-loaded micelle was prepared with lipid excipient which could facilitate the drug lymphatic transport. The aim of the study was to find lipid materials which could enhance drug lymphatic transport and promote drug lymphatic transport via a formulation way.There’re five main parts in this study.1. Establishment of analysis methods for probucol and halofantrine.Analysis methods of probucol and halofantrine using HPLC were established. The methodological study proved the methods were simple and short-time consuming with good resolution, precision and accuracy, which could be used in the following experiment.2. Investigation of the effect of different excipients on the drug intestinal lymphatic transportThere are two main mechanisms of lipid-based vehicles enhancing intestinal lymphatic drug transport:stimulation of chylomicron production and association of the drug with the triglyceride core of the lipoprotein.Two experiments were endowed, the first one is the investigation of the effect of different excipients on CM’s synthesis and secretion. TA, Pluronic L61 and mPHG-DSPE were found to enhance the CM’s secretion. Then the investigation of effects of TA, Pluronic L61 and mPEG-DSPE on drug uptake and transport in Caco-2 cell were carried out. According to the results, mEG-DSPE and TA can improve the drug uptake and transport. Thus, they were chosen as the lipid material for the micelle formulation.3. Preparation and characterization of micellar delivery systemProbucol and halofantrine micelles were prepared with a film formation method using mPEG-DPSE as the vehicle material. The formulation was optimized by a single factor test. Encapsulation efficiency and drug loading were set as the indicators. The effects of evaporation temperature, water amount, ration of drug and lipid and filter membrane was investigated. ER of micelle prepared is higher than 90% and particle size was between 10～20nm.4.In vitro evaluation of drug-loaded micelle on drug lymphatic transportIn vitro evaluation of drug-loaded micelle was conducted in Caco-2 cell model. The effects of drug solution, drug and mPEG-DSPE solution and drug-loaded micelle on drug uptake and transport were compared. The results showed that comparing with the drug solution, drug-loaded micelle could improve the drug uptake and transport significantly.5. In vivo evaluation of drug-loaded micelle on drug lymphatic transportIn vivo evaluation of probucol micelle was conducted both in anesathia rat model and conscious rat model. Results showed that probucol micelle enhanced the lymphatic transport of probucol significantly in the two models comparing with the drug suspension. Evaluation of halofantrine micelle was conducted in conscious rat model. The results showed that drug-loaded micelle could improve the drug lymphatic transport significantly in contrast with the drug solution.