Department of Pharmaceutical Technology, Faculty of Pharmacy, National and Kapodistrian University of Athens, Panepistimiopolis, 157 71 Zografou, Greece.
Pharm Res. 2011 Dec;28(12):3145-58. doi: 10.1007/s11095-011-0506-6. Epub 2011 Jun 15.
To evaluate precipitation in and supersaturation of intestinal contents after administration of pharmacologically relevant doses of dipyridamole and ketoconazole to 12 healthy adults.
On two separate days each subject was administered in stomach 240 ml aqueous solutions of two dipyridamole doses (30/90 mg) and two ketoconazole doses (100/300 mg). Physicochemical characteristics, total drug content, and drug concentration were measured in individual intestinal contents (≤7 ml) aspirated at specific times post-dosing. Drug concentration after incubation (37°C/48 h) and equilibrium solubility were measured. Precipitate crystallinity was evaluated by x-ray powder diffraction.
Precipitated fraction was minimal (dipyridamole, ≤7%) or limited (ketoconazole, ≤16%). Ketoconazole precipitates were mostly amorphous. Depending on dose, intestinal contents with pH > 3.6 were supersaturated with dipyridamole up to 10 and 30 min and with ketoconazole up to 30 and 50 min post-administration. Intestinal contents with pH > 5 and concentration of micellar components <5 mM were supersaturated with ketoconazole or dipyridamole, but precipitated fraction was significant only for ketoconazole. After incubation, crystalline precipitates were found in almost all samples. Slow precipitation of base and/or precipitation of other phases account for this observation.
Intralumenal precipitation of weakly alkaline, lipophilic, high permeability drugs may not be substantial. Estimating intestinal supersaturation in regard to free base is inadequate as other phases may precipitate.
评估 12 名健康成年人服用相关药理剂量双嘧达莫和酮康唑后肠道内容物的沉淀和过饱和度。
在两天的时间里，每位受试者分别服用 240ml 两种剂量（30/90mg）的双嘧达莫和两种酮康唑（100/300mg）的水溶液。在给药后特定时间，通过抽吸≤7ml 的个体肠道内容物来测量物理化学特性、总药物含量和药物浓度。测量孵育（37°C/48h）后的药物浓度和平衡溶解度。通过 X 射线粉末衍射评估沉淀物结晶度。
沉淀部分很少（双嘧达莫，≤7%）或有限（酮康唑，≤16%）。酮康唑沉淀大多为无定形。根据剂量，肠道内容物 pH 值>3.6 在给药后 10 和 30 分钟对双嘧达莫，以及 30 和 50 分钟对酮康唑过饱和。肠道内容物 pH 值>5 和胶束成分浓度<5mM 时，酮康唑或双嘧达莫过饱和，但沉淀部分仅对酮康唑显著。孵育后，几乎所有样品中都发现了结晶沉淀物。这一观察结果归因于碱性较弱、脂溶性较高、通透性较强的药物的沉淀速度较慢，或沉淀其他相。
肠道内弱碱性、脂溶性、高通透性药物的腔内沉淀可能不显著。仅估计游离碱的肠道过饱和度是不够的，因为可能会沉淀其他相。
