In vivo evaluation of lipid-based formulations for oral delivery of apomorphine and its diester prodrugs

摘要

In the present study, the differences in oral absorption of apomorphine and its diester prodrugs and the effect of lipid-based formulations on the absorption of apomorphine or its prodrugs were investigated. Apomorphine, dilauroyl apomorphine (DLA) and dipalmitoyl apomorphine (DPA) were orally administered (0.24 mmol/kg) to rats as: DLA-o/w emulsion, DPA-o/w emulsion, apomorphine-o/w emulsion, apomorphine aqueous suspension, DLA-Maisine, DLA-soybean oil, DLA-self-emulsifying drug delivery systems (SEDDS), and DLA-w/o emulsion. The o/w and w/o emulsion consisted of Maisine 35-1 emulsified with water in 1: 3 and 4: 1 ratio, respectively. T-max of diesters was significantly increased (p <= 0.05) compared to apomorphine in o/w emulsion, suggesting that esterification yielded prolonged drug absorption. C-max, AUC and the relative bioavailability of apomorphine after DLA-SEDDS administration was higher (p <= 0.05) than after DLA-w/o administration, indicating that triglycerides and surfactants improved the oral absorption of DLA. Similarly, C-max and AUC after dosing apomorphine-o/w were significantly higher (p <= 0.05) than that of aqueous suspension. This suggested that lipids and lipolysis products possibly aided apomorphine micellar solubilization in intestinal fluids. A combination of prodrug strategy and lipid-based formulations facilitated a higher and prolonged absorption of apomorphine from its diester prodrugs. (C) 2016 Elsevier B. V. All rights reserved.