多奈哌齐经鼻给药小鼠血脑药物测定及药动学研究

Determination of Donepezil in the Plasma and Brain Tissue of Mice and Pharmacokinetics of Its Intranasal Preparations

制备了盐酸多奈哌齐鼻腔给药溶液剂和o/w型乳剂。建立了LC-MS法检测血浆和脑组织内药物浓度的方法。以雄性ICR小鼠为模型进行体内试验,给药后同步采集血浆和脑组织样品。经DAS 2.1.1软件处理数据后,比较了鼻腔溶液剂、鼻腔乳剂和静脉注射剂给药后小鼠体内的药动学参数。用经鼻给药脑靶向效率(DTE)和脑靶向潜力(DTP)指标比较了鼻腔溶液剂和鼻腔乳剂的脑靶向性。结果显示,鼻腔溶液剂和鼻腔乳剂的绝对生物利用度分别为68.3%和99.2%。但由于该药本身极易透过血脑屏障,经鼻制剂并未表现出显著的脑靶向优势。

Donepezil hydrochloride intranasal solution and oil-in-water intranasal emulsion were prepared. The composition of the intranasal emulsion was as follows： 4% of Tween-80, 1% of Span-80, 45% of sunflower seed oil and 50 % of phosphate buffer solution （PBS, pH 5） containing donepezil hydrochloride. An eligible LC-MS method for the determination of drug concentration in plasma and brain tissue was established. Rapid chromatographic separation was achieved in the mobile phase of 10 mmol/L ammonium acetate solution containing 0.1% formic acid ： methanol （24：76） with a flow rate of 0.3 ml/min. And detection was carried out using positive-ion electrospray mass spectrometry with monitoring ion pairs of m/z 380.00→m/z 91.15 for donepezil hydrochloride and m/z 383.00→m/z 337.05 for loratadine （internal standard）. Male ICR mice was randomly divided into 3 groups： intranasal solution, intranasal emulsion and intravenous injection. Blood and brain tissue were synchronously collected after administration. Then pharmacokinetic parameters were calculated by DAS 2.1.1 software based on the determination results. The results showed that the absolute bioavailability of nasal solution and nasal emulsion were 68.3 % and 99.2 %, respectively. Brain targeting effects of two intranasal preparations were evaluated with brain targeting efficiency （DTE） and brain targeting potential （DTP） as the indexes. However, these nasal preparations showed no significant brain-targeting advantages since donepezil hydrochloride could easily pass through the blood-brain barrier by intravenous injection.