Hou Shuguang1，2， Liao Yonghong1，3， Luan Hansen1，4， Mao Shirui1，5， Shao Qi1，6， Shen Danlei1，7， Tong Zhenbo1，8， Wang Xiaofei1，9， Wang Zhaolin1，10， Wang Zhenyu1，11， Zhang Xuejuan1，12， Liu Zhang5， Zhou Yutong3， Wang Hezhi5， Chen Tong7， Liu Dawei10
1.Chinese Society of Particuology， Inhalation Drug Delivery Association， Beijing 100190， China； 2.College of Pharmacy， Chengdu University of Traditional Chinese Medicine， Chengdu 610103， China； 3.Institute of Medicinal Plant Development， Chinese Academy of Medical Sciences & Peking Union Medical College， Beijing 100193， China； 4.Heyan （Shanghai） Medical Device Co.， Ltd.， Shanghai 201203， China； 5.School of Pharmacy， Shenyang Pharmaceutical University， Shenyang 110016， China； 6.SPH Sine Pharmaceutical Laboratories Co.， Ltd.， Shanghai 201206， China； 7.Nanjing Bailing Information Technology Co.， Ltd.， Nanjing 211100， China； 8.Joint Research Center for Particle System Simulation， Southeast University-Monash University International College （Suzhou）， Suzhou 215123， China； 9.Jiangsu Delimed Pharmaceutical Co.， Ltd.， Shanghai 201203， China； 10.Hangzhou Zhixing Pharmaceutical Co.， Ltd.， Hangzhou 311400， China； 11.Sichuan Purity Pharmaceutical Co.， Ltd.， Chengdu 610095， China； 12.College of Pharmacy， Jinan University， Guangzhou 510632， China
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
Get Citation: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）： 150-162.
Received：2026-08-04， Revised： 2026-09-13，Online： 2026-10-10。
Funding： This research was supported by the Project of the Chinese Pharmacopoeia Commission (Grant No. 2025Y41) and National Natural Science Foundation of China(Grant No. 82504719).
DOI：10.13732/j.issn.1008-5548.2027.01.011
CLC No.:R94； TQ460； TB44
Type Code:A
Serial No.:1008-5548（2027）01-0150-13
