Pion Inc., 10 Cook St, Billerica, Massachusetts, 01821, USA.
Technical R&D Shangai Novartis Trading Ltd., Novartis Pharma AG, Shangai, China.
Pharm Res. 2018 Jun 20;35(8):161. doi: 10.1007/s11095-018-2440-3.
The goal of the study was to evaluate a miniaturized dissolution-permeation apparatus (μFLUX™ apparatus) for its ability to benchmark several itraconazole (ITZ) formulations for which in vivo PK data was available in the literature.
Untreated and micronized powders of ITZ and various enabling formulations of ITZ (commercial Sporanox® solid dispersion, a Soluplus®-based solid dispersion and a nanosuspension) were introduced to the donor compartment of μFLUX™ apparatus. Donor and acceptor chambers were divided from each other by a lipophilic membrane. In addition to the flux evaluations, changes in solid state as a function of time were investigated to gain further insight into the flux changes observed over time for the solid dispersion formulations.
Initial flux values from Sporanox®, the nanosuspension and the micronized ITZ showed ratios of 52/4/1 with a decreasing flux from nanosuspension and both solid dispersions after 2.5-3 h. Although the initial flux from the Soluplus® formulation was 2.2 times lower than the one observed for Sporanox®, the decrease in flux observed was milder and became ~ 2 times higher than Sporanox® after approximately 2.5 h. The total amounts of ITZ in the receiver compartment after 240 min showed the same rank order as the rodent AUCs of these formulations reported in literature.
It was demonstrated that in vitro flux measurements using lipophilic artificial membranes could correctly reproduce the rank order of PK results for ITZ formulations. The drop in flux over time for solid dispersions could be backed by experimental indications of crystallization.
本研究旨在评估微型渗透溶解装置（μFLUX™ 装置）的能力，以对文献中提供体内 PK 数据的几种伊曲康唑（ITZ）制剂进行基准测试。
将未经处理和微粉化的 ITZ 粉末以及 ITZ 的各种赋形剂制剂（商业 Sporanox®固体分散体、基于 Soluplus®的固体分散体和纳米混悬剂）引入到 μFLUX™ 装置的供体室中。供体室和受体室通过亲脂性膜彼此隔开。除了通量评估外，还研究了随着时间的变化对固体状态的变化，以更深入地了解在固体分散制剂随时间观察到的通量变化。
Sporanox®、纳米混悬剂和微粉化 ITZ 的初始通量值之比为 52/4/1，在 2.5-3 小时后，纳米混悬剂和两种固体分散体的通量逐渐降低。尽管 Soluplus®制剂的初始通量比 Sporanox®低 2.2 倍，但观察到的通量下降较为温和，大约 2.5 小时后，通量比 Sporanox®高约 2 倍。在 240 分钟后接收器室中 ITZ 的总量与文献中报道的这些制剂的啮齿动物 AUC 具有相同的等级顺序。
证明使用亲脂性人工膜的体外通量测量可以正确再现 ITZ 制剂的 PK 结果的等级顺序。随着时间的推移，固体分散体的通量下降可以通过结晶的实验迹象来支持。
