| Nimodipine (NM) is a dihydropyridine calcium-channel blocker that has been shown to selectively dilate cerebral vessels and increase cerebral blood flow (CBF) in animals and human. It is clinically applied in cerebral ischemia and hypoxia. NM is currently approved for its benefit to ameliorate memory degeneration and prevent senile dementia in old age. However, oral bioavailability of NM is very low due to its extensive first-pass metabolism in liver, which causes lower amount of NM in brain. Therefore, looking for alternative routes of administration to improve therapeutic effects is indispensable. Delivery by the nasal route has received a lot of attention recently, because it offers such advantages as rapid absorption, avoidance of liver first-pass metabolism, ease of convenience and self- medication. Moreover, it has also been reported that nasal administration may provide access to the brain via the olfactory area. So we were interested in seeing whether these advantages would apply to NM. The first purpose of this study was to investigate the distribution of NM in rats and find out whether the nasal route could improve NM bioavailability and whether the drug could be transported directly from the nasal cavity to the brain so as to improve the prophylactic effect of dementia. The second purpose was to ferret the possibilities to increase the brain delivery of drug by formulating NM with an appropriate nasal delivery system.First, rat model for nasal application of drugs was established and the collection methods of CSF and brain tissue samples were described.Second, a high-performance liquid chromatographic assay for the determination of NM concentrations in rat plasma, brain tissue and CSF were established. The linear range for NM in three kinds of samples were 20~1000 ng/ml, 25~3500 ng/g and 15-150 ng/ml, respectively. The limit of detection was 15 ng/ml. Method recovery was 98.71% ~103.86%, the inter-assay precision was less than 6% and the intra-assay precision was less than 5%. Plasma and brain tissue NM extraction recoveries were 91.3213.30% and83.33+3.12%, respectively. The selectivity of the assay is good without any interfering peak. Accordingly, the method was suitable to study the pharmacokinetic profiles of NM in blood and brain following intranasal administration in rats.Third, NM solution was prepared by using ethanol-PEG400-water (4:3:3) mixture, and it was administered intravenously (iv), orally, and nasally to rats. At different times post dose, blood, CSF and brain tissue samples were collected and NM concentrations were analyzed. Oral bioavailability of NM was 1.17% whereas nasal dosing improved bioavailability to 67.22%. Following iv administration, similar NM concentrations in different brain regions were observed. However NM concentration in olfactory bulb within 15min post dose was found significantly higher than the other brain tissue after nasal administration, whose AUC0-360 was about 138.91% compared with iv route. The brain tissue-to-plasma AUC ratios in four brain tissues following intranasal administration were significantly higher than those obtained after iv dosing. It was concluded that nasally administered NM could markedly improve the bioavailability, and a fraction of the NM dose could be transported directly from the nasal cavity into the CNS.Fourth, Carbopol 934P was used to prepare NM hydrogel. The effect of incorporating various excipients into gel base was also tested. The solubility and in vitro release studies were carried out , and in-situ toad palate model was used to evaluate the ciliotoxicity of various gel formulations. The optimized formulation contained methylated p-cyclodextrin which exhibited fine consistency and stability, and with the pH value between 6.5 and 7.5. NM could homogeneous disperse in gel base. After nasal administration, a sustained absorption effect was observed in rats.Fifth, two non-ion surfactants, Cremophor RH-40 and Labrasol, were adopted in the formation of O/W microemulsion. The phase behavior was depicted on a pseu...
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