蛋白及多肽类药物口服递送策略的研究现状及思考

Current Research Status and Perspectives on Oral Delivery Strategies for Protein and Peptide Drugs

摘要

蛋白及多肽类药物具有较高的靶点选择性和生物活性，已广泛应用于糖尿病、肿瘤等重大疾病的临床治疗；但该类药物口服生物利用度普遍低于1%，临床给药方式仍以注射途径为主。近年来，口服递送技术为蛋白及多肽类药物实现非侵入给药提供了可行路径；然而，不同蛋白及多肽类药物口服给药的主要限制因素存在差异，常随药物的分子特征及吸收、分布和清除等体内处置过程发生改变。仅针对单一吸收屏障进行工艺优化，难以稳定提升且精准调控口服生物利用度。综述从吸收、分布和清除3个环节解析口服蛋白及多肽类药物的体内行为，总结归纳其口服吸收效率受限的内在机制，明确不同递送策略的适用范围与作用条件，以期为蛋白及多肽类药物口服制剂的理性设计及临床转化研究提供理论参考。

Abstract

With high target selectivity and biological activity, protein and peptide drugs have been widely applied in the clinical treatment of major diseases such as diabetes and tumors. However, the oral bioavailability of these drugs is mostly less than 1%, and injection still remains the dominant clinical route of administration. In recent years, oral delivery technology has provided a feasible approach for the non-invasive administration of protein and peptide drugs, however, the main limiting factors for oral delivery vary among different protein and peptide drugs and often change depending on their molecular characteristics as well asin vivodisposal processes including absorption, distribution and clearance. Optimization the process for a single absorption barrier alone makes it difficult to steadily enhance and precisely modulate oral bioavailability. This review analyzes the in vivobehaviors of orally administered protein and peptide drugs from the perspectives of absorption, distribution and clearance, summarizes the underlying mechanisms restricting their oral absorption efficiency, and clarifies the applicable ranges and conditions for various delivery strategies, aiming to provide some theoretical reference for the rational design and clinical translation of oral formulations of protein and peptide drugs.

关键词

蛋白及多肽类药物 / 口服递送 / 胃肠屏障 / 全身暴露 / 临床转化

Key words

protein and peptide drug / oral delivery / gastrointestinal barrier / systemic exposure / clinical translation

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基金资助

国家重点研发计划项目(2024YFA1210100)

国家自然科学基金资助项目(82025032)