Natsume H, Iwata S, Ohtake K, Miyamoto M, Yamaguchi M, Hosoya K, Kobayashi D, Sugibayashi K, Morimoto Y
Faculty of Pharmaceutical Sciences, Josai University, 1-1 Keyakidai, Sakado, Saitama 350-0295, Japan.
Int J Pharm. 1999 Aug 5;185(1):1-12. doi: 10.1016/s0378-5173(99)00100-3.
Several cationic compounds were screened as potential nasal absorption enhancers to increase intranasal absorption of a model drug, fluorescein isothiocyanate labeled dextran (MW 4.4 kDa, FD-4), without nasal membrane damage in rats. Their effects were compared with those of classical enhancers. Various cationic compounds (poly-L-arginines with different molecular weights (MW 8.9, 45.5 and 92.0 kDa, poly-L-Arg (10), (50) and (100), respectively), L-arginine (L-Arg), L-lysine (L-Lys), and cetylpyridinium chloride (CPCL) were evaluated. Of the cationic compounds, poly-L-Arg and CPCL greatly enhanced the intranasal absorption of FD-4, as did chitosan, a cationic polysaccharide which has been reported to show a great effect on the transnasal delivery of peptide and protein drugs. The enhancing intensity by poly-L-Arg was dependent on its molecular weight. Rank order of the enhancing ratio, calculated from the AUC ratio for the enhancer treatment against the untreatment, was 0.5% poly-L-Arg (100) congruent with0.5% sodium dodecylsulfate congruent with0.5% CPCL?0.5% poly-L-Arg (50)?0.5% sodium deoxycholate congruent with0.5% sodium taurodihydrofusidate?0.5% polyoxyethylene-9-lauryl ether congruent with0.5% lysophosphatidylcholine?0.5% chitosan congruent with0.5% poly-L-Arg (10)>/=10% L-Arg congruent with10% L-Lys?0.5% sodium glycocholate congruent with0.5% sodium taurocholate congruent with0.5% EDTA. Only the poly-L-Args represented almost the same degree of hemolysis of cationic compounds compared with pH 7.0 phosphate buffered saline in the rat erythrocyte lysis experiment. The enhancing ratio by classical enhancers correlated with leaching of protein, phospholipids and LDH from isolated rabbit nasal mucosa. CPCL also fell on the regression lines between the enhancing ratio and their degree of leaching from classical enhancers. In contrast, the enhancing intensities by poly-L-Arg (10), (50) and (100) were greatly shifted from the regression line: the amount of leaching was markedly low in spite of a great enhancement of FD-4 absorption. These findings suggest that of the assessed enhancers only the poly-L-Args enhance the transnasal delivery of high molecular substances without severe damage to the nasal mucosal membrane. Poly-L-Arg is therefore a promising candidate having a good balance between enhancing activity and safety for nasal peptide and protein delivery.
筛选了几种阳离子化合物作为潜在的鼻腔吸收增强剂，以增加模型药物异硫氰酸荧光素标记的葡聚糖（分子量4.4 kDa，FD-4）的鼻腔吸收，且不对大鼠鼻黏膜造成损伤。将它们的效果与经典增强剂的效果进行了比较。评估了各种阳离子化合物（不同分子量（8.9、45.5和92.0 kDa）的聚-L-精氨酸，分别为聚-L-Arg (10)、(50)和(100)）、L-精氨酸（L-Arg）、L-赖氨酸（L-Lys）和十六烷基吡啶氯化物（CPCL）。在阳离子化合物中，聚-L-Arg和CPCL极大地增强了FD-4的鼻腔吸收，壳聚糖也是如此，壳聚糖是一种阳离子多糖，据报道对肽和蛋白质药物的经鼻递送有很大作用。聚-L-Arg的增强强度取决于其分子量。根据增强剂处理组与未处理组的AUC比值计算出的增强率排序为：0.5%聚-L-Arg (100)≈0.5%十二烷基硫酸钠≈0.5% CPCL＞0.5%聚-L-Arg (50)＞0.5%脱氧胆酸钠≈0.5%牛磺二氢fusidate＞0.5%聚氧乙烯-9-月桂基醚≈0.5%溶血磷脂酰胆碱≈0.5%壳聚糖≈0.5%聚-L-Arg (10)≥10% L-Arg≈10% L-Lys＞0.5%甘氨胆酸钠≈0.5%牛磺胆酸钠≈0.5% EDTA。在大鼠红细胞裂解实验中，与pH 7.0磷酸盐缓冲盐水相比，只有聚-L-Arg表现出几乎相同程度的阳离子化合物溶血作用。经典增强剂的增强率与从分离的兔鼻黏膜中浸出的蛋白质、磷脂和LDH相关。CPCL也落在增强率与其从经典增强剂中浸出程度之间的回归线上。相比之下，聚-L-Arg (10)、(50)和(100)的增强强度明显偏离回归线：尽管FD-4吸收有很大增强，但浸出量明显较低。这些发现表明，在所评估的增强剂中，只有聚-L-Arg能增强高分子物质的经鼻递送，而不会对鼻黏膜造成严重损伤。因此，聚-L-Arg是一种有前途的候选物，在增强活性和鼻腔肽与蛋白质递送安全性之间具有良好的平衡。
