| The objective of this study was to develop a good absorbed and stable preparation that can avoid the strong first-pass effect of nimodipine (NMD). NMD is a dihydropyridine calcium antagonist, strongly hydrophobic and selectively effective on cerebrovascular disorders. It readily crosses blood brain barrier (BBB). The oral bioavailability is about 13% because of the extensive first-pass metabolism in the liver. Considering its properties and the request for therapy, liposome dispersion was prepared using the simple modified ethanol injection method. To resolve the instability problem of liposome dispersion, freeze-drying (lyophilization) technique was utilized to prepare freeze-dried proliposome. Its main advantage is of high stability because of its solid form during preservation. It can be readily and quickly reconstituted by adding water and simple stirring before use to form liposome dispersion with the same characteristics as before freeze-drying. To avoid the extensive first-pass effect, intranasal administration is chose after reconstitution. Also, intranasal route can promote NMD absorption across BBB.However, freeze-drying process can induce serious and irreversible damage to liposome, including size increase, membrane rupture, liposome infusion, membrane infolding, and the drug leakage etc. So it's of great importance to investigate the every freeze-drying process and the cryoprotectant formulation which can preserve the vesicles stable in freeze-drying. Screening from the various cryoprotectant, sucrose and mannitol were ensure to protect NMD liposome during freeze-drying. According to the prevailing theories for dry membrane preservation: "glass formation mechanism" and "water replacement mechanism", a good technique and formulation were confirmed which maintainthe liposome structure and improve stability. Differential scanning calorimetry (DSC) detection was employed to validate the mechanisms.The dialysis method was developed to separate the free drug from NMD liposome, and the entrapment efficiency of liposome before and after freeze-drying were determined by UV method.The rat in situ nasal perfusion technique was utilized in this investigation to explore the nasal absorption of NMD. The analyte concentrations remaining in the nasal perfusates were quantitated by a UV method. The absorption extent of NMD of 4 concentrations (0.3, 0.6, 0.9, 1.2mg/ml) and the apparent first-order rate constants (K) were calculated. NMD is good absorbed across the nasal mucosa in 4 concentrations. The value of K were calculated to be 1.35, 1.99, 1.56, 1.46 (X10-3) min-1 respectively. The absorption characteristics exhibited passive diffusion. To compare with liposome dispersion before freeze-drying, the nasal absorption of freeze-dried and reconstituted liposome was investigated, so did NMD-HPMC suspension. K of freeze-dried liposome (0.6mg/ml) is 1.90X 10-3min-1, no difference was observed between liposome before and after freeze-drying.To assess the nasal ciliary toxicity of NMD liposome, the hoptoad in situ maxilla mucosa method was used by determining the ciliary movement time following administration. The toxicity is very little and the preparation can be used in nasal delivery system.The pharmacodynamics of intranasal liposome administration was validated using 3 experiments and indexes: complete ischaemia model, brain hypoxia model and cerebral thrombus model induced by intravenous revulsant. At the same time, oral and intraperitoneal preparations of NMD were also administrated to mouse and the effects were compared with that of intranasal route. It was concluded that i.n. and i.p. route is much more effective than oral (PO.01 ).
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