预测 fed 态生物相关介质中药物的体外溶出度：溶解度增强和相对较低胶体扩散性的贡献。
Prediction of In Vitro Drug Dissolution into Fed-state Biorelevant Media: Contributions of Solubility Enhancement and Relatively Low Colloid Diffusivity.
机构信息
University of Maryland, Department of Pharmaceutical Sciences, 20 Penn Street, Baltimore, MD 21201, USA.
University of Maryland, Department of Pharmaceutical Sciences, 20 Penn Street, Baltimore, MD 21201, USA.
出版信息
Eur J Pharm Sci. 2022 Jun 1;173:106179. doi: 10.1016/j.ejps.2022.106179. Epub 2022 Mar 30.
A model was previously derived to predict in vitro dissolution of drug into surfactant solution and showed good predictability for pharmaceutical surfactants, where surfactant-mediated enhanced drug dissolution was several fold less than enhanced solubility (about 3-fold or less) due to drug-loaded micelles exhibiting slower diffusivity than free drug. The present objective was to quantitatively assess the contributions of biorelevant media-mediated solubility and diffusivity on enhanced drug dissolution in FeSSGF and FeSSIF-V2. Three poorly water soluble drugs were subjected to dissolution into FeSSGF and FeSSIF-V2, as well as their corresponding "surfactant-free" media. Solubility and laser diffraction analysis of drug in FeSSGF and dynamic light-scattering studies (DLS) of drug in FeSSIF-V2 were conducted. Results showed drug-saturated FeSSGF globules and FeSSIF-V2 mixed micelles were large and slow diffusing (diffusivities of about 1×10 and 7×10 cm/s, respectively), compared to free drug (about 7×10 cm/s) and drug-bound micelles from pharmaceutical surfactants (about 0.5-1×10 cm/s). Of the three drugs, griseofulvin exhibited the greatest biorelevant media-enhanced solubility and dissolution (652-fold and 6.23-fold respectively in FeSSGF, and 190-fold and 12.7-fold respectively in FeSSIF-V2), but slow colloid diffusivity markedly attenuated large solubility benefits, particularly in FeSSGF.
先前已经建立了一个模型，用于预测药物在表面活性剂溶液中的体外溶解情况，并且对医药用表面活性剂具有良好的预测能力，其中由于载药胶束的扩散性比游离药物慢，因此表面活性剂介导的药物增溶作用（增强溶解度约 3 倍或更少）远小于药物增溶作用。本研究的目的是定量评估生物相关介质介导的溶解度和扩散性对 FeSSGF 和 FeSSIF-V2 中药物增溶的贡献。将三种疏水性差的药物分别溶解在 FeSSGF 和 FeSSIF-V2 中，以及它们各自的“无表面活性剂”介质中。在 FeSSGF 和 FeSSIF-V2 中进行了药物的溶解度和激光衍射分析，以及在 FeSSIF-V2 中进行了药物的动态光散射（DLS）研究。结果表明，与游离药物（约 7×10 cm/s）和药物结合的药用表面活性剂胶束（约 0.5-1×10 cm/s）相比，药物饱和的 FeSSGF 胶束和 FeSSIF-V2 混合胶束较大且扩散缓慢（扩散系数分别约为 1×10 和 7×10 cm/s）。在这三种药物中，灰黄霉素表现出最大的生物相关介质增强的溶解度和溶解（在 FeSSGF 中分别为 652 倍和 6.23 倍，在 FeSSIF-V2 中分别为 190 倍和 12.7 倍），但胶体扩散缓慢明显削弱了大溶解度的优势，尤其是在 FeSSGF 中。
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