Schittny Andreas, Waldner Samuel, Duthaler Urs, Vorobyev Alexander, Abramovich Rimma, Krähenbühl Stephan, Puchkov Maxim, Huwyler Jörg
Division of Pharmaceutical Technology, Department of Pharmaceutical Sciences, University of Basel, 4056 Basel, Switzerland.
Division of Clinical Pharmacology and Toxicology, Department of Biomedicine, University Hospital Basel and University of Basel, 4056 Basel, Switzerland.
Pharmaceutics. 2021 Mar 17;13(3):401. doi: 10.3390/pharmaceutics13030401.
Amorphous solid dispersions (ASDs) are a promising drug-delivery strategy to overcome poor solubility through formulation. Currently, the understanding of drug absorption mechanisms from ASDs in humans is incomplete. Aiming to gain insights in this matter, we conducted a randomized cross-over design open-label clinical study (NCT03886766) with 16 healthy male volunteers in an ambulatory setting, using micro-dosed efavirenz as a model drug. In three phases, subjects were administered (1) solid ASD of efavirenz 50 mg or (2) dissolved ASD of efavirenz 50 mg or (3) a molecular solution of efavirenz 3 mg (non-ASD) as a control in block-randomized order. Endpoints were the pharmacokinetic profiles (efavirenz plasma concentration vs. time curves) and derived pharmacokinetic parameters thereof (, , , and ). Results showed that the dissolved ASD (intervention 2) exhibited properties of a supersaturated solution (compared to aqueous solubility) with rapid and complete absorption of the drug from the drug-rich particles. All interventions showed similar and were well tolerated by subjects. The findings highlight the potential of particle forming ASDs as an advanced drug-delivery system for poorly soluble drugs and provide essential insights into underlying mechanisms of ASD functioning in humans, partially validating current conceptual models.
无定形固体分散体（ASDs）是一种很有前景的药物递送策略，可通过制剂来克服药物溶解度差的问题。目前，对ASDs在人体内的药物吸收机制的了解尚不完整。为了深入了解这一问题，我们开展了一项随机交叉设计的开放标签临床研究（NCT03886766），在门诊环境中纳入16名健康男性志愿者，使用微剂量的依非韦伦作为模型药物。在三个阶段中，受试者按区组随机顺序接受以下处理：（1）50毫克依非韦伦的固体ASD，或（2）50毫克依非韦伦的溶解ASD，或（3）3毫克依非韦伦的分子溶液（非ASD）作为对照。观察终点为药代动力学曲线（依非韦伦血浆浓度与时间曲线）及其导出的药代动力学参数（，，，和）。结果表明，溶解的ASD（干预2）表现出过饱和溶液的性质（与水溶性相比），药物从富含药物的颗粒中快速且完全吸收。所有干预措施的 相似，受试者耐受性良好。这些发现突出了形成颗粒的ASDs作为难溶性药物的先进药物递送系统的潜力，并为ASDs在人体内发挥作用的潜在机制提供了重要见解，部分验证了当前的概念模型。
