Screening of cationic compounds as an absorption enhancer for nasal drug delivery

Several cationic compounds were screened as potential nasal absorption enha ncers to increase intranasal absorption of a model drug, fluorescein isothi ocyanate labeled dextran (MW 4.4 kDa, FD-4), without nasal membrane damage in rats. Their effects were compared with those of classical enhancers. Var ious 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 enha nced the intranasal absorption of FD-4, as did chitosan, a cationic polysac charide which has been reported to show a great effect on the transnasal de livery of peptide and protein drugs. The enhancing intensity by poly-L-Arg was dependent on its molecular weight. Rank order of the enhancing ratio, c alculated from the AUC ratio for the enhancer treatment against the untreat ment, was 0.5% poly-L-Arg (100) congruent to 0.5% sodium dodecylsulfate con gruent to 0.5% CPCL > 0.5% poly-L-Arg (50) > 0.5% sodium deoxycholate congr uent to 0.5% sodium taurodihydrofusidate > 0.5% polyoxyethylene-9-lauryl et her congruent to 0.5% lysophosphatidylcholine > 0.5% chitosan congruent to 0.5% poly-L-Arg (10) greater than or equal to 10% L-Arg congruent to 10% L- Lys > 0.5% sodium glycocholate congruent to 0.5% sodium taurocholate congru ent to 0.5% EDTA. Only the poly-L-Args represented almost the same degree o f hemolysis of cationic compounds compared with pH 7.0 phosphate buffered s aline in the rat erythrocyte lysis experiment. The enhancing ratio by class ical enhancers correlated with leaching of protein, phospholipids and LDH f rom isolated rabbit nasal mucose. CPCL also fell on the regression lines be tween the enhancing ratio and their degree of leaching from classical enhan cers. 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 enhanc e the transnasal delivery of high molecular substances without severe damag e to the nasal mucosal membrane. Poly-L-Arg is therefore a promising candid ate having a good balance between enhancing activity and safety for nasal p eptide and protein delivery. (C) 1999 Elsevier Science B.V. All rights rese rved.