Study On Intranasal Brain-Targeting System Of Trybizine Hydrochloride

Trybizine hydrochloride (T-46) is a novel antitrypanosomal agent developed by Shanghai Institute of Pharmaceutical Industry and has completed the clinical trials as a veterinary drug. But it failed to cure the CNS-infected mice. The pharmacokinetic study in mice, monkey and camel has showed that T-46 did not pass blood-brain barrier in sufficient quantities. This could be an obstacle for developing it into the antitrypanosomal drug for human being because in the progress of the disease, trypanosomes invade the Central Nervous System (CNS) of humans. The aim of this project is to design the new T-46 preparation that would facilitate the penetration into CNS.Chapter one dealt with pre-formulation studies of T-46. Apparent solubility and apparent partition coefficient were increased with pH increase, and after pH 5.8, it begin to decrease with pH increase. Furthermore, apparent partition coefficient has the trend of increase with pH increase after pH 7.0.The focus of chapter two was to set up an assay method for t-46 in serial cerebrospinal and serum sampling in the animal model. For assay of T-46 in rat cerebrospinal fluid (CSF) and serum, high-performance liquid chromatography (HPLC) is accurate, precise, so it could be used for T-46 pharmacokinetic study.The focus of chapter three was to exploit a rat model for the nose-to -brain transfer of T-46. Cisternal cannulation was used for serial CSF sampling in the animal model.In chapter four, excised bovine olfactory mucosa and self-made Franz diffusion chambers, as an in vitro model for testing the olfactory transfer of drug was studied to try to set up an intro model to screen formulations to get the best one.In chapter five, T-46 nasal in situ gel was prepared by using poloxamer 407, a thermo-sensitive gel forming excipient. Effects of different excipient , on diffusion behavior and solution-gel transforming temperature,were studied.Using the in vitro model founded in chapter four,by orthogonal design, the effects of three factors (concentration of HP-β-CD, poloxamer 407 and PEG6000) of the formula were investigated with the trans-mucosal cumulative quantities as the brain-targeting index. And by orthogonal design...