低水溶性药物口服增溶促吸收制剂的研究进展与临床转化展望

Research Progresses and Clinical Translation Prospects of Solubilization and Absorption Enhancement Oral Preparations for Poorly Water-Soluble Drugs

摘要: 口服给药是小分子药物的理想给药途径，但低水溶性导致的生物利用度低已成为新药研发与临床转化的共性难题。统计研究提示，相当比例的候选化合物存在不同程度的溶解度不足，多集中于生物药剂学分类系统(biopharmaceutics classification system, BCS) II类或IV类。传统增加剂量或改换给药途径的策略难以兼顾疗效与安全性。目前已发展出固体形态工程、纳米制剂、脂质载体、环糊精包合等多种增溶促吸收策略，作用于溶出、过饱和、跨膜转运及淋巴吸收等环节。本文以完整吸收链条为主线，系统梳理难溶性药物口服吸收的限制环节，整合目前主要制剂策略的作用机制、优势与局限，并从临床转化视角提出一体化设计与评价思路。

Abstract: Oral administration is an ideal route for small-molecule drugs. However, poor oral bioavailability caused by low water solubility has become a common challenge in the research and development and clinical translation of new drugs. Statistical studies indicate that a considerable proportion of drug candidates suffer from insufficient solubility to varying degrees, most of which are classified as Class II or Class IV in the biopharmaceutics classification system (BCS). Traditional strategies such as dose escalation or alternative administration routes can hardly balance efficacy and safety. To date, various strategies for solubility enhancement and absorption promotion have been developed, including solid-state engineering, nanoformulations, lipid-based carriers, and cyclodextrin inclusion complexes. These strategies exert effects on drug dissolution, supersaturation, transmembrane transport, and lymphatic absorption. Taking the complete oral absorption cascade as the main line, this review systematically summarizes the limiting factors of oral absorption for poorly soluble drugs, integrates the mechanisms, advantages, and limitations of current mainstream formulation strategies, and proposes an integrated design and evaluation paradigm from the perspective of clinical translation.