The purpose of this study was to improve the solubility and enhance the brain uptake of nimodipine (NM) in an o/w microemulsion, which was suitable for intranasal delivery. Three microemulsion systems stabilized by the nonionic surfactants either Cremophor RH 40 or Labrasol, and containing a variety of oils, namely isopropyl myristate, Labrafil M 1944CS and Maisine 35-1 were developed and characterized. The nasal absorption of NM from microemulsion formulation was investigated in rats. The optimal icroemulsion formulation consisted of 8% Labrafil M 1944CS, 30% Cremophor RH 40/ethanol (3:1) and water, with a maximum solubility of NM up to 6.4mg/ml, droplet size of 30.3

A monolithic osmotic tablet system (MOTS) with two orifices in both side surfaces has been studied. Water-insoluble naproxen was selected as the model drug. Gum arabic was used as an osmotic, suspending and expanding agent, and cellulose acetate (CA) was used as semipermeable membrane. Polyethylene glycol 400 (PEG-400) was employed as plasticizer for controlling membrane porosity. The influences of gum arabic, PEG-400, membrane thickness and orifice size on the naproxen release profiles were investigated, and the optimal MOTS was evaluated in different environment media and stirring rates. The optimal MOTS was found to be able to deliver naproxen at a rate of approximately zero order up to 12 h in pH 6.8, cumulative release at 12 h is 81%, independent on environment media and stirring rate. Therefore, this MOTS can be used in oral drugcontrolled delivery field, especially for water-insoluble drug.

A high-performance liquid chromatographic (HPLC) method with fluorescence detection has been developed for the determination of rizatriptan in human plasma. Following a single-step liquid-liquid extraction with methyl tertiarybutyl ether, the analytes were separated using a mobile phase consisting of 0.05% (v/v) triethylamine in water (adjusting to pH 2.75 with 85% phosphoric acid) and acetonitrile (92:8, v/v). Fluorescence detection was performed at an excitation wavelength of 225nm and an emission wavelength of 360nm. The linearity for rizatriptan was within the concentration range of 0.5-50ng/ml. The intra-and inter-day precisions of the method were not more than 8.0%. The lower limit of quantification (LLOQ) was 0.5ng/ml for rizatriptan. The method was sensitive, simple and repeatable enough to be used in pharmacokinetic studies.

A simple, rapid and sensitive high-performance liquid chromatographic (HPLC) method has been developed to quantify zolmitriptan in plasma using an isocratic system with fluorescence detection. The method included a single-step liquid-liquid extraction with methyl tertiary butyl ether. HPLC separation was carried out by reversed phase chromatography with a mobile phase composed of 0.05% (v/v) triethylamine in water (adjusting to pH 2.75 with 85% phosphoric acid) and acetonitrile (92:8, v/v), pumped at lowrate of 1.5ml/min. Fluorescence detectionwas performed at 225nm (excitation) and 360nm (emission). The calibration curve for zolmitriptan was linear from 0.2 to 40ng/ml. The validation method yielded good results regarding linearity, precision, accuracy, specificity and recoveries. The values of the limit of detection (LOD) and limit of quantification (LOQ) were 20 and 40pg, respectively. The method was sensitive, simple and repeatable enough to be used in pharmacokinetic studies.

A sensitive and specific method for the determination of the active primary amine metabolite of sibutramine, N-didesmethylsibutramine (BTS 54 505), in human plasma was developed, based on high-performance liquid chromatography (HPLC)-electrospray ionization tandem mass spectrometry (MS-MS). The samples were extracted from plasma with methyl tert.-butyl ether, followed by separation and evaporation after addition of the internal standard, propranolol, and basification with sodium hydroxide. The residue was reconstituted in mobile phase and injected into the HPLC-MS-MS system. Chromatography was performed on an ODS MS column with a mobile phase consisting of acetonitrile (containing 0.1%trifluoroacetic acid, v/v)-0.1% trifluoroacetic acid (55:45, v/v) at a flow-rate of 0.3ml/min. Multiple reaction monitoring using precursor→product ion combinations at m/z 252.00→125.00 and 260.00→115.70 was applied to determine BTS 54 505 and propranolol, respectively. Linearity was confirmed in the concentration range 0.328-32.8ng/ml in human plasma and the imprecision of this assay was less than 19.90% over the entire concentration range. The method is sufficiently sensitive and repeatable to be used in pharmacokinetic studies. 2002 Elsevier Science B.V. All rights reserved.

The aim of this paper was to investigate the levels of methotrexate (MTX) in blood and the cerebrospinal fluid (CSF) in rats to find out whether there is any direct drug transport from nasal cavity to CSF following intranasal administration. Methotrexate was administered to male Sprague-Dawley rats either intranasally or intravenously. Drug concentrations were determined from CSF and plasma samples collected from the cisterna magna and caudal vein, respectively. To collect CSF sample continuously, blank artificial CSF was infused into the lateral ventricle. The plasma levels achieved following intranasal administration were significantly lower than those after intravenous administration (P<0.01) were, while CSF concentrations achieved after intranasal administration were significantly higher than those after intravenous administration (P<0.01). The ratio of the AUCCSF value between the intranasal route and the intravenous injection was 13.76, whereas the absolute bioavailability was only 6.3%, the drug targeting index (DTI) of nasal route was 21.7. In conclusion, these results showed that the antineoplastic MTX must be directly transported from the nasal cavity into the CSF in rats.

Our newly developed drug delivery carrier, cationic bovine serum albumin (CBSA) conjugated with poly (ethyleneglycol)-poly (lactide) (PEG-PLA) nanoparticle (CBSA-NP), was designed for brain drug delivery. CBSA, as a brain specific targetor, was covalently conjugated with the maleimide function group at the distal of poly (ethyleneglycol) (PEG) surrounding the nanoparticles. To evaluate its blood-brain barrier (BBB) transcytosis and toxicity against the BBB endothelial tight junction, we have explored a method of coculture with brain capillary endothelial cells (BCECs) on the top of micro-porous membrane of cell culture insert and astrocytes on the bottom side. The permeability of 14C-labeled sucrose was determined. For the CBSA-NP transcytosis study, a lipophilic fluorescent probe, 6-coumarin, was incorporated into nanoparticles. The BBB permeability of CBSA-NP in vitro was calculated and compared with native bovine serum albumin (BSA) conjugated pegylated nanoparticles (BSA-NP). As the coculture model, the transendothelial electrical resistance reached up to 313

The aim of this paper is to investigate the pharmacokinetic behavior of hydrochloride meptazinol (MEP) in plasma, cerebrospinal fluid (CSF) and cerebral cortex after intranasal administration (8mg/kg) in male Sprague-Dawley rats. The pharmacokinetic study of intravenous administration (8mg/kg) was also performed in rats. CSF and cerebral cortex samples were collected by serial CSF sampling and intracerebral microdialysis, respectively. The concentration of MEP in the biological samples was measured by high performance liquid chromatography (HPLC). It was determined that the absorption of MEP from the nasal cavity to systemic circulation was rapid and complete. The concentration-time profile showed a prolonged duration of MEP concentration in CSF and cortex following intranasal administration. The ratios of AUC values of intranasal to intravenous administrations were 0.96, 1.07 and 1.81 in plasma, CSF and cortex dialysate, respectively. In conclusion, intranasal administration of MEP is a promising alternative to traditional administration modes. Olfactory mucosa did not present intranasal MEP another pathway, in addition to systemic absorption, for transport to the brain.

目的：用环糊精改善鼻腔吸收促进剂去氧胆酸钠（SDC）的鼻纤毛毒性方法：分别用红细胞溶血实验、蟾除上模型和扫描电镜观察环糊精对SDC细胞膜破坏作用和鼻纤毛毒性的影响 SDC和β环糊精（β-CD）之间的包合作用采用差示热分析法和X-衍射法进行验证。结果：当SDC与β-CD或二基β环糊精（DM-β-CD）的摩尔比为 1:1 和 1:2 时能完全掩盖SDC的溶血作用。用蟾除上模型评价时，加入摩尔比 1:2 或 1:3 的SDC与β-CD或DM-βCD的混合液使SDC的相对纤毛持续运动时间由原来的0%提高至50%以上，大鼠鼻腔连续给予1:2摩尔比的SDC-β-CD溶液一周后，扫描电镜显示粘膜纤毛无明显改变，差示热分析和X-衍射结果显示SDC能与β-CD开成包合物。结论：加入β-CD或DM-β-CD能显著降低SDC的溶血作用和鼻纤毛毒性，两者的最佳比例是SDC与环糊精摩尔比 1:2。环糊精的这种保护作用与形成包合物有关。