McMartin C, Hutchinson L E, Hyde R, Peters G E
Research Centre, CIBA-GEIGY Pharmaceuticals, Horsham, Sussex.
J Pharm Sci. 1987 Jul;76(7):535-40. doi: 10.1002/jps.2600760709.
An octapeptide and a protein, of molecular weights 800 and 34,000, respectively, were found to have nasal bioavailabilities of 73 and 0.6%, respectively, in the rat. This data, combined with reported values for 23 other compounds, indicated good availability without adjuvants for all molecules up to 1000 molecular weight (mean 70%, SD between compounds 26%, n = 15) with a decline in availability above this value. The relationship between absorption and molecular weight was modeled assuming competition between constant clearance from the nasal cavity and molecular weight-dependent transport through the mucosa. Deviations of absorption from values predicted by this model did not correlate with factors such as charge, hydrophobicity, or susceptibility to aminopeptidases, but the relative absorption of cyclic and cross-linked peptides and proteins was significantly greater than that of linear peptides. It is argued that the most likely route for transport is through junctions between cells and that surface-active adjuvants (MW 6000) which markedly enhance insulin uptake may act by rendering hydrophobic areas of contact of the junctional proteins temporarily hydrophilic. The nasal route is suitable for efficient, rapid delivery of many molecules of molecular weight less than 1000. With the use of adjuvants, this limit can be extended to at least 6000 and possibly much higher.
在大鼠体内，分别发现一种分子量为800的八肽和一种分子量为34,000的蛋白质的鼻腔生物利用度分别为73%和0.6%。这些数据，再加上其他23种化合物的报告值，表明分子量高达1000的所有分子在无佐剂情况下具有良好的生物利用度（平均70%，化合物之间的标准差为26%，n = 15），高于此值生物利用度会下降。假设鼻腔恒定清除率与分子量依赖性黏膜转运之间存在竞争，对吸收与分子量之间的关系进行了建模。吸收值与该模型预测值的偏差与电荷、疏水性或对氨肽酶的敏感性等因素无关，但环状和交联肽及蛋白质的相对吸收明显大于线性肽。有人认为，最可能的转运途径是通过细胞间连接，而显著增强胰岛素摄取的表面活性佐剂（分子量6000）可能通过使连接蛋白的疏水接触区域暂时变为亲水性而起作用。鼻腔途径适用于高效、快速递送许多分子量小于1000的分子。使用佐剂后，这个限制可以至少扩展到6000，甚至可能更高。
