Gao Ping, Akrami Anna, Alvarez Francisco, Hu Jack, Li Lan, Ma Chandra, Surapaneni Sekhar
Department of Pharmaceutics, Amgen Inc, Thousand Oaks, California 91320, USA.
J Pharm Sci. 2009 Feb;98(2):516-28. doi: 10.1002/jps.21451.
Supersaturatable self-emulsifying drug delivery systems (S-SEDDS) were explored to improve the oral absorption of AMG 517, a poorly water-soluble drug candidate. In vitro characterizations indicate the level of Tween 80 in the formulation dictates the initial degree of supersaturation of AMG 517, and, therefore, its precipitation kinetics. The presence of a small amount of cellulosic polymer (e.g., HPMC) effectively sustained a metastable supersaturated state by retarding precipitation kinetics. Precipitates from the S-SEDDS formulations (with HPMC) from in vitro test media were identified as amorphous AMG 517 while crystalline AMG 517 precipitates were found when either HPMC was absent or PVP was present in the formulation. In vivo pharmacokinetic study in Cynomolgus monkeys reveals that the S-SEDDS formulation showed approximately 30% higher mean C(max) and comparable exposure (AUC) of AMG 517 as compared to an aqueous suspension at a dose of 12.5 mg. The rapid absorption characteristics of AMG 517 from the S-SEDDS formulation as evidenced by high C(max) and short T(max) are attributed to a high free drug concentration in vivo, implying a supersaturated state. This case demonstrates that S-SEDDS technology is an effective approach for improving the rate and extent of absorption of poorly soluble drugs.
为提高难溶性候选药物AMG 517的口服吸收，对过饱和自乳化药物递送系统（S-SEDDS）进行了研究。体外表征表明，制剂中吐温80的含量决定了AMG 517的初始过饱和程度，进而决定其沉淀动力学。少量纤维素聚合物（如羟丙甲纤维素）的存在通过延缓沉淀动力学有效地维持了亚稳态过饱和状态。体外试验介质中S-SEDDS制剂（含羟丙甲纤维素）的沉淀物被鉴定为无定形AMG 517，而当制剂中不存在羟丙甲纤维素或存在聚乙烯吡咯烷酮时，会形成结晶性AMG 517沉淀。食蟹猴体内药代动力学研究表明，与12.5 mg剂量的水悬浮液相比，S-SEDDS制剂的AMG 517平均C(max)高约30%，暴露量（AUC）相当。高C(max)和短T(max)所证明的AMG 517从S-SEDDS制剂中的快速吸收特性归因于体内高游离药物浓度，这意味着处于过饱和状态。该案例表明，S-SEDDS技术是提高难溶性药物吸收速率和程度的有效方法。
