Study On The Nasal Absorption And Brain Targeting Property Of IDHP

Nasal administration has potential advantage in treatment of brain diseases due to its rapid drug absorption, no hepatic first-pass effect, and convenience to administration. In addition, bypassing the blood brain barrier, the drug can be absorbed by the olfactory mucosa directly into the brain tissue to obtain the brain targeting. IDHP is the effective constituent of the salvia miltiorrhiza metabolites and it has obvious effect for preventing cerebral anoxia and cerebral ischemia. In this thesis, the Nasal administration and brain targeting of IDHP have been investigated, and the date may provide a basis for the development and application of IDHP.The main contents and results are as follows:1. The physical and chemical properties (stability, solubility and oil-water partition coefficient) of IDHP at different pH value have been studied. The results demonstrate that the drug shows good stability in PBS buffer when pH is5.8or6.5. Meanwhile, the apparent solubility and oil-water partition coefficient reach maximum simultaneously.2.The rat nasal cavity recirculating perfusion methods were used to investigate the regulation of nasal absorption. The effects of perfusion rate, drug concentration, promote penetrant and P-gp inhibitors on the absorption were examined. Perfusion rate in the range of1.5~2.5mL/min has no effect on nasal absorption. Concentration of IDHP on400μg/mL gave a maximalnasal absorption rate. β-cyclodextrin (1.25%) can significantly improve nasal absorption rate of IDHP. However, β-cyclodextrin was more potent than sodium deoxycholate, poloxamer188and Tween80. Verapamil, a P-glycoprotein inhibitor, could increase the nasal absorption of IDHP.3.A high performance liquid chromatography (HPLC) method for analysis of the IDHP in plasma after intranasal administration and intragastric administration is established. These results showed that the plasma profile of IDHP was confirmed to be two-compartment open models by intranasal and intravenous administration, while the pharmacokinetic behavior of IDHP was in line with one-compartment open model by oral administration. IDHP was rapidly absorbed by intranasal administration, and has higher bioavailability than it by oral administration.4.Using HPLC-FLD method, the concentration of IDHP and DanShenSu in cerebrospinal fluid was detected. These results showed that cerebrospinal fluid of rats could detect IDHP and DanShenSu within30min after intranasal administration and the Tmax was lOmin. On the same dose of IDHP by intravenous administration, it could not detect IDHP and DanShenSu in rat cerebrospinal fluid. It reflected IDHP has a good targeting brain by intranasal administration.