侯曙光1，2， 廖永红1，3， 栾瀚森1，4， 毛世瑞1，5， 邵奇1，6， 沈丹蕾1，7， 佟振博1，8， 王晓飞1，9， 王兆霖1，10， 王震宇1，11， 张雪娟1，12， 刘畅5， 周嘉彤3， 王贺之5， 陈彤7， 刘大为10
1.中国颗粒学会 吸入颗粒专委会， 北京 100190 2.成都中医药大学 药学院， 四川 成都 610103；
3.中国医学科学院北京协和医学院 药用植物研究所， 北京 100193； 4.和妍（上海）医疗器械有限公司， 上海 201203；
5.沈阳药科大学 药学院， 辽宁 沈阳 110016； 6.上海上药信谊药厂有限公司， 上海 201206；
7.南京白令信息科技有限公司， 江苏 南京 211100； 8.东南大学-蒙纳士大学国际学院 颗粒系统仿真联合研究中心， 江苏 苏州 215123； 9.江苏德迈药业有限公司， 上海 201203； 10.杭州知兴制药有限公司， 浙江 杭州 311400；
11.四川普锐特药业有限公司， 四川 成都 610095； 12.暨南大学 药学院， 广东 广州 510632
引用格式：
侯曙光， 廖永红， 栾瀚森， 等. 吸入颗粒与吸入给药：从基础科学到产业转化研究进展［J］. 中国粉体技术， 2027， 33（1）： 1-13.
Hou Shuguang， Liao Yonghong， Luan Hansen， et al. Inhalable particles and inhalation drug delivery： a panoramic perspective from fundamental science to industrial translation［J］. China Powder Science and Technology， 2027， 33（1）： 1-13.
DOI：10.13732/j.issn.1008-5548.2027.01.011
收稿日期： 2026-08-04， 修回日期： 2026-09-13， 上线日期： 2026-10-网上出版日期:10。
基金项目： 国家药典委项目，编号：2025Y41；国家自然科学基金项目，编号：82504719。
第一作者： 侯曙光（1969—），男，教授，博士，博士生导师，享受国务院特殊津贴专家，研究方向为肺部吸入递药系统与经鼻递送系统。E-mail：2538606432@qq.com。
通信作者： 毛世瑞（1969—），女，教授，博士，博士生导师，享受国务院特殊津贴专家，省特聘教授，研究方向为肺部吸入递药系统、鼻脑靶向、粉体学等。E-mail：maoshirui@vip.sina.com。
摘要： 【目的】 为了推动吸入制剂产业化落地，基于颗粒工程、 装置创新、 质量评价及监管科学4个维度开展研究，为吸入给药高质量发展提供策略参考。 【研究现状】 综述吸入制剂产业化落地的技术进展，概括其在颗粒工程、 质量评价及装置创新方面的研究进展。在颗粒工程方面，喷雾干燥、超临界流体结晶及微流控组装等制备技术通过精准调控粒径、密度与形貌优化空气动力学粒径分布。在质量评价方面，新一代药用撞击器、 拉曼化学成像辅助的多模态数据融合，正推动关键质量属性与设计空间的科学构建。在装置创新层面，干粉吸入器流道阻力优化、 软雾装置的低速气溶胶工程及智能吸入器的使用监测与反馈，共同提升了递送一致性。临床适应证已从慢性阻塞性肺疾病和哮喘的维持治疗拓展至核酸药物、蛋白质及疫苗等大分子药物全身性适应证，但载体安全性与重复给药耐受性仍是生物大分子转化的关键瓶颈。 【结论与展望】提出以连续制造替代传统批次生产，以药械一体化设计替代分段开发，并建立覆盖原辅料、 装置与质量控制的产业链协同机制； 认为通过深化质量源于设计理念、 完善基于增强型体外表征与生理药代动力学模型的生物等效性评价路径，以及推进低全球变暖潜能值抛射剂的应用，可为吸入制剂的理性设计、 精准评价及合规开发提供可操作的策略框架。
关键词： 吸入给药； 空气动力学粒径； 监管科学； 生物大分子递送
Abstract
Significance Inhalation therapy has evolved from an empirically driven modality for local pulmonary diseases into an engineered platform that enables both targeted lung delivery and non-invasive systemic administration of biologics. Its advantages are attributed to the vast alveolar surface area， ultra-thin epithelial barrier， and the ability to circumvent hepatic first-pass metabolism. However， clinical translation is impeded by mucociliary clearance， alveolar macrophage uptake， nonlinear process scale-up， and fragmented drug-device integration. This review presents advances in particle engineering， characterization methodologies， device innovation， and regulatory science.
Progress In particle engineering， jet milling has long served as a cornerstone technology for micronizing drugs to respirable sizes. However， excessive mechanical energy frequently induces lattice disorder and electrostatic aggregation. Spray drying is widely adopted to engineer particles with controlled morphology and porosity， although thermal stress during scale-up remains challenging for biologics. Uniform microcrystals are produced under mild conditions by supercritical fluid crystallization， thereby better preserving macromolecular integrity. Highly porous， low-density particles are produced through spray freeze-drying， thereby enhancing the dissolution of poorly soluble active ingredients. Precise tuning of particle geometry is enabled by microfluidic platforms through controlled mixing strategies. Pharmacone microparticles are fabricated via additive manufacturing， achieving significantly enhanced inhalable fractions compared with spherical carriers. A solvent-free high-energy mixing process has also been developed， yielding solid dispersions with improved fine particle fractions. For proteins， spray drying into amorphous trehalose or mannitol matrices is preferred， whereas lactose is avoided due to Maillard reactions. RNA is protected from airway nucleases through condensation into polymeric or lipid nanocomplexes. For quality evaluation， aerodynamic particle size distribution is established as a critical quality attribute. The Next Generation Impactor （NGI） is recognized as the gold standard for aerodynamic assessment， providing distinct stage cutoffs with low interstage losses. Rapid single-particle sizing for early screening is enabled by time-of-flight analyzers. Chemical composition and morphology are simultaneously characterized by Raman chemical imaging， while surface elemental composition is quantified by X-ray photoelectron spectroscopy. Device innovation has been marked by the development of vibrating mesh nebulizers， which reduce residual volume and improve size consistency compared with conventional jet nebulizers. Minimization of exhalation loss is achieved through adaptive aerosol delivery and breath-triggered actuation technologies. For pressurized metered-dose inhalers， the transition to low-global-warming-potential propellants （HFA-152a and hydrofluoroolefin-1234ze） is driven by environmental requirements. Clinical equivalence with conventional formulations is established by the first recently approved hydrofluoroolefin （HFO）-based product. Optimization of dry powder inhalers is achieved through flow-path resistance engineering to accommodate varying inspiratory capacities. Slow-moving aerosols are generated by soft mist inhalers through mechanical energy without propellants， thereby reducing oropharyngeal deposition. Real-time monitoring of adherence is enabled by smart inhalers equipped with sensors. Improved asthma control and reduced rescue medication use are demonstrated through the correction of poor inhalation technique. Clinically， expansion beyond chronic obstructive pulmonary disease （COPD） and asthma maintenance therapy to systemic indications has been observed， including inhaled insulin， antibiotics for cystic fibrosis， and messenger RNA vaccines. Science-driven frameworks have been advanced by regulatory agencies. Enhanced in vitro characterization and physiologically based pharmacokinetic （PBPK） modeling are promoted by the United States Food and Drug Administration as alternative pathways for bioequivalence assessment， and clinical endpoint studies may be waived when formulation sameness is demonstrated. A revised guideline has been issued by the European Medicines Agency， by which inhalation products are modularized and a stepwise review framework is established. Enhanced requirements for fine particle dose mass balance and spray characterization have been introduced in the 2025 edition of the Chinese Pharmacopoeia.
Conclusions and Prospects Substantial progress has been achieved over the past decade， characterized by diversified particle engineering platforms， refined multiscale characterization， and progressive global regulatory harmonization. Nevertheless， challenges remain for advanced formulations related to nonlinear process scale-up， insufficient drug-device integration， and limited upstream industrial-chain support. The performance parameters of emerging systems in reproducible large-scale production and long-term pulmonary tolerability remain less established than those of conventional small-molecule inhalers， and further improvement is required through continuous manufacturing and process analytical technology. The extension of model-informed drug development and digital twin frameworks represents a critical direction for personalized dosing. Therefore， the development toward integrated drug-device co-design， continuous manufacturing， and adaptive life-cycle regulatory frameworks represents a prevailing trend.
Keywords： inhalation drug delivery； aerodynamic particle size； regulatory science； biomacromolecule delivery
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