Digestion and Drug Permeation/Re-Dissolution on Absorption of Orally Administered Ritonavir as Different Lipid-Based Formulations.
Digestion and Drug Permeation/Re-Dissolution on Absorption of Orally Administered Ritonavir as Different Lipid-Based Formulations.
复制标题
不同脂质制剂口服利托那韦吸收的消化和药物渗透/再溶解。
DOI：
10.1016/j.ejps.2020.105604
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发表时间：
2021
期刊：
影响因子：
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通讯作者：
Satoshi Kasaoka.
中科院分区：
文献类型：
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作者：
Yusuke Tanaka;Hirotaka Doi;Takeru Katano;Satoshi Kasaoka.
本研究的目的是阐明利托那韦（RTV）从不同类型的脂质制剂（LBF）口服给药后的吸收机制，特别强调脂质消化和药物渗透/再溶出对口服吸收的影响。编制了四份地方预算框架;三种含有长链（LC）或中链（MC）脂质[脂质制剂分类系统（LFCS）II-LC型、IIIA-MC型和IIIB-MC型]，第四种仅含有表面活性剂和共溶剂（IV型）。测定RTV在这些LBF中的溶解度，随后以制剂中饱和溶解度的85%w/w负载药物。然后，将每种含LBF的药物以约2.5%w/v加入到模型大鼠肠液中，用于使用体外消化模型进行评价。体外消化研究表明，II型LC和IIIA-MC能够支持RTV的持续增溶，并且在IIIA-MC中观察到适度的过饱和。与此相反，RTV部分沉淀在类型IIIB-MC在消化过程中，和IV型配方失去其溶解能力迅速分散，导致剧烈沉淀。与对照混悬液相比，将RTV作为IIIA-MC口服给药至大鼠显示出显著更高的血浆浓度-时间曲线下面积，而II-LC给药并未改善，尽管RTV在消化过程中完全溶解。从体外渗透穿过透析膜的结果（截留分子量> 1000 Da）来看，这可能是由于RTV掺入未消化的LC脂质导致胃肠道中游离浓度降低。尽管分别观察到中度和剧烈沉淀，但IIIB-MC型和IV型的口服吸收显著增加。粉末X射线衍射分析表明，沉淀物是无定形的。因此，改善的再溶解可能部分有助于改善吸收。本研究揭示了详细的吸收机制，从LBF与不同的组成。我们的研究结果可能有助于选择合适的赋形剂，设计最佳的LBF的水溶性差的药物。
The aim of this study is to clarify absorption mechanisms after oral administration of ritonavir (RTV) from different types of lipid-based formulations (LBFs) with particular emphasis on the effect of lipid digestion and drug permeation/re-dissolution on the oral absorption. Four LBFs were prepared; three contained either long-chain (LC) or medium-chain (MC) lipids [lipid formulation classification system (LFCS) Type II-LC, Type IIIA-MC, and Type IIIB-MC] and the fourth contained only surfactant and co-solvent (Type IV). The solubility of RTV in those LBFs was determined and drug subsequently loaded at 85% w/w of the saturated solubility in the formulations. Then, each LBF containing drug was added into a model rat intestinal fluid at approximately 2.5% w/v for evaluation using anin vitrodigestion model.In vitrodigestion study showed the ability of Type II-LC and Type IIIA-MC to support continued solubilization of RTV, and moderate supersaturation was observed in Type IIIA-MC. In contrast, RTV partly precipitated in the Type IIIB-MC during digestion, and the Type IV formulation lost its solubilization capacity rapidly upon dispersion, leading to drastic precipitation. Oral administration of RTV as Type IIIA-MC to rats showed significantly higher area under the plasma concentration-time curve compared to control suspension, whereas it was not improved with Type II-LC administration despite complete solubilization of RTV during digestion. From the results ofin vitropermeation across dialysis membrane (a molecular weight cutoff of > 1000 Da), this may be attributed to the lowered free concentration in the gastrointestinal tract owing to incorporation of RTV into the undigested LC lipid. Oral absorption drastically increased with Type IIIB-MC and Type IV despite the observed moderate and drastic precipitation, respectively. Powder X-ray diffraction analysis revealed that the precipitate was amorphous. Therefore, improved re-solubilization may partly contribute to improved absorption. The present study revealed detailed absorption mechanisms from LBFs with different compositions. Our findings may be useful for selecting appropriate excipients to design optimal LBFs for poorly water-soluble drugs.