Improvement of intestinal absorption of human calcitonin by chemical modification with fatty acids: Synergistic effects of acylation and absorption enhancers

To improve the intestinal absorption of human calcitonin (hCT), novel lipophilic derivatives of hCT were synthesized by chemical modification with short-chain length fatty acids such as acetic acid and caproic acid, and the intestinal absorption and stability of these derivatives were examined in rats. The intestinal absorption properties of hCT and its acyl derivatives, acetylated hCT (Ac-hCT) and caproylated hCT (Cap-hCT), were estimated by measuring its hypocalcemic effects. Their intestinal absorption and stability in the intestinal mucosal homogenates were improved by increasing the carbon number of the fatty acid. Furthermore, we investigated the effects of co-administered absorption enhancers, sodium glycocholate (Na-GC), N-lauryl-beta-D-maltoside (LM), sodium deoxycholate (Na-DC) and sodium salicylate (Na-Sal), on the intestinal absorption of hCT and its acyl derivatives. Their intestinal absorption was slightly enhanced by the addition of various absorption enhancers except for Na-Sal. However, the extent of the promoting effect was a little higher for a native hCT rather than for acyl-hCT derivatives. These results suggested that it may be possible to achieve the further absorption enhancement of hCT by using a combination of acylation and absorption enhancers.