Borkar Nrupa, Holm René, Yang Mingshi, Müllertz Anette, Mu Huiling
Department of Pharmacy, Faculty of Health and Medical Sciences, University of Copenhagen, Universitetsparken 2, 2100 Copenhagen, Denmark.
Department of Pharmacy, Faculty of Health and Medical Sciences, University of Copenhagen, Universitetsparken 2, 2100 Copenhagen, Denmark; Pharmaceutical Science and CMC Biologics, H. Lundbeck A/S, Ottiliavej 9, 2500, Valby, Denmark.
Int J Pharm. 2016 Nov 20;513(1-2):211-217. doi: 10.1016/j.ijpharm.2016.09.024. Epub 2016 Sep 9.
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 (0.24mmol/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 of diesters was significantly increased (p≤0.05) compared to apomorphine in o/w emulsion, suggesting that esterification yielded prolonged drug absorption. C, 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 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.
在本研究中，对阿扑吗啡及其二酯前药的口服吸收差异以及脂质体制剂对阿扑吗啡或其前药吸收的影响进行了研究。将阿扑吗啡、二月桂酰阿扑吗啡（DLA）和二棕榈酰阿扑吗啡（DPA）以0.24mmol/kg的剂量口服给予大鼠，给药形式如下：DLA-o/w乳剂、DPA-o/w乳剂、阿扑吗啡-o/w乳剂、阿扑吗啡水混悬液、DLA-Maisine、DLA-大豆油、DLA-自乳化药物递送系统（SEDDS）和DLA-w/o乳剂。o/w和w/o乳剂分别由Maisine 35-1与水按1:3和4:1的比例乳化而成。与o/w乳剂中的阿扑吗啡相比，二酯的T显著增加（p≤0.05），这表明酯化作用使药物吸收延长。DLA-SEDDS给药后阿扑吗啡的C、AUC和相对生物利用度高于DLA-w/o给药后（p≤0.05），表明甘油三酯和表面活性剂改善了DLA的口服吸收。同样，阿扑吗啡-o/w给药后的C和AUC显著高于水混悬液（p≤0.05）。这表明脂质和脂解产物可能有助于阿扑吗啡在肠液中的胶束增溶。前药策略和脂质体制剂的结合促进了阿扑吗啡从其二酯前药中更高且更持久的吸收。
