Acyclovir Permeation Enhancement Across Intestinal and Nasal Mucosae by Bile Salt-Acylcarnitine Mixed Micelles

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Abstract
The purpose of this study was to investigate the absorption enhancement of acyclovir, an antiviral agent, by means of bile salt-acylcarnitine mixed micelles. The specificity, site dependence, palmitoyl-DL-carnitine chloride (PCC) concentration dependence, and effects of absorption promoters on acyclovir absorption via the nasal cavity (N) and four different intestinal segments of the rat, i.e., duodenum (D), upper jejunum (UJ), combined lower jejunum and ileum (LJ), and colon (C) were evaluated. The present study employed the rat in situ nasal and intestinal perfusion techniques and utilized sodium glycocholate (NaGC), three acylcarnitines, and their mixed micelles as potential nasal and intestinal absorption promoters. Acylcarnitines used were DL-octanoylcarnitine chloride (OCC), palmitoyl-DL-carnitine chloride (PCC), and DL-stearoylcarnitine chloride (SCC). All acylcarnitines and NaGC by themselves produced negligible enhancement of acyclovir absorption in the rat intestine, while OCC and SCC were totally ineffective in the nasal cavity. However, the mixed micellar solutions of NaGC with PCC or SCC could significantly increase the mucosal membrane permeability of acyclovir in the colon and nasal cavity. On the other hand, NaGC-OCC mixed micelles slightly increased the absorption of acyclovir by both routes. When a mixed micellar solution of NaGC with PCC was used, the rank order of apparent acyclovir permeability (Papp; cm/sec), corrected for surface area of absorption, was N (10.54 ± 0.62 x 10−5) > D (6.82 ± 0.30 x 10−5) > LJ (2.90 ± 0.08 x 10−5) > C (2.54 ± 0.14 x 10−5) > UJ (2.30 ± 0.22 x 10−5). In contrast, the Papp rank order for acyclovir without any absorption promoter was D (2.49 ± 0.44 x 10−5) > UJ (0.64 ± 0.03 x 10−5) > LJ, C, and N (0). The effect of mixed micellar solutions was synergistic and was much greater than that with single adjuvants probably because of micellar solubilization of acylcarnitines by NaGC. The magnitude of absorption promotion was dependent on the hydrophobicity, i.e., carbon-chain length of the acylcarnitines. The enhanced permeability could be reversed within 60-120 min after removal of the adjuvant from the duodenum, colon, and nasal cavity. These results suggest that bile salt-acylcarnitine mixed micelles can be used as intestinal or nasal mucosal absorption promoters of poorly permeable agents.