可吸入制剂在药学领域的基础与临床应用

doi:10.5246/jcps.2025.06.038

摘要/Abstract

摘要：

近年来, 随着呼吸系统疾病患病率上升, 以及生物工程技术和药学的发展, 吸入给药已成为肺部疾病的优选途径。吸入制剂通过局部给药的方式, 可以快速、直接地进入肺部发挥药效, 降低给药剂量, 提高药物疗效。本文通过查阅文献及检索临床试验网站, 总结了以下三个方面: (1) 临床应用的吸入装置; (2) 临床上市的可吸入制剂的应用; (3) 可吸入制剂在肺部感染、肺结核、肺癌、肺纤维化等肺部疾病和帕金森等系统性疾病中的临床前研究。目的是探讨可吸入制剂在药学领域的基础研究和临床应用, 期望推动可吸入制剂的普及和利用, 助力可吸入制剂在更多疾病的研究。

关键词: 可吸入制剂, 吸入装置, 吸入疫苗, 肺部感染, 吸入纳米药物

Abstract:

In recent years, the rising prevalence of respiratory diseases, coupled with advancements in biotechnology and pharmacology, has positioned inhalable formulations as a preferred method of drug administration. This approach enables direct and rapid delivery of medication to the lungs, maximizing therapeutic effects while minimizing dosage and potential side effects. In this review, we meticulously examined current literature and clinical trial databases to present a comprehensive overview of three key areas: (1) inhalation devices currently utilized in clinical settings; (2) the clinical applications of approved inhalable formulations; and (3) preclinical research on inhalable treatments targeting various lung conditions, including pulmonary infections, tuberculosis, lung cancer, pulmonary fibrosis, as well as systemic diseases like Parkinson’s disease. The objective was to delve into both foundational research and the clinical use of inhalable formulations within the pharmaceutical field, with the aim of fostering their broader adoption and guiding the development of inhalable therapies for a more comprehensive range of diseases.

Key words: Inhalable formulations, Inhalation device, Inhaled vaccine, Pulmonary infection, Inhalable nanomedicine

Supporting:

闫玉莹, 杨学斌, 冀召帅. 可吸入制剂在药学领域的基础与临床应用[J]. 中国药学(英文版), 2025, 34(6): 503-518.

Yuying Yan, Xuebin Yang, Zhaoshuai Ji. Inhalable formulations in pharmacy: from basic research to clinical applications[J]. Journal of Chinese Pharmaceutical Sciences, 2025, 34(6): 503-518.

图/表 9

Table 1. Advantages and disadvantages of different administrations.

Figure 1. The practical process of inhalable drugs.

Table 2. Specific information on different inhalation devices.

Table 3. Summary of commonly used inhaled drugs in the clinic.

Figure 2. Mechanism of pulmonary infection.

Figure 3. Mechanism of action of inhaled COVID-19 vaccine.

Table 4. Introduction of inhaled drugs for preclinical pulmonary infections.

Table 5. Summary of demographic data[44].

Figure 4. Particle size distribution histogram of afatinib-loaded PLGA nanoparticles. Characterization of particle size, polydispersity index, zeta potential, entrapmParticle (%) size distribution histogram of afatinib loaded PLGA nanoparticlesent efficiency and drug loading for afatinib loaded PLGA nanoparticle formulation (%). Data represent mean ± SD (n = 3)[56]. Copyright is from the PMC open access subset.

参考文献 64

[1]	Ambrosino, N.; Fracchia, C. Strategies to relieve dyspnoea in patients with advanced chronic respiratory diseases. A narrative review. Authors’ reply. Pulmonology. 2019, 25, 356–357.
[2]	Turégano-Yedro, M.; Trillo-Calvo, E.; Navarro i Ros, F.; Maya-Viejo, J.D.; González Villaescusa, C.; Echave Sustaeta, J.M.; Doña, E.; Alcázar Navarrete, B. Inhaler adherence in COPD: a crucial step towards the correct. Int. J. Chronic Obstr. Pulm. Dis. 2023, 18, 2887–2893.
[3]	Iwanaga, T.; Tohda, Y.; Nakamura, S.; Suga, Y. The respimat^® soft mist inhaler: implications of drug delivery characteristics for patients. Clin. Drug Investig. 2019, 39, 1021–1030.
[4]	Knap, K.; Kwiecień, K.; Reczyńska-Kolman, K.; Pamuła, E. Inhalable microparticles as drug delivery systems to the lungs in a dry powder formulations. Regen. Biomater. 2022, 10, rbac099.
[5]	Cho, Y.S.; Oh, Y.M. Dilemma of asthma treatment in mild patients. Tuberc. Respir. Dis. 2019, 82, 190–193.
[6]	Lommatzsch, M.; Buhl, R.; Korn, S. The treatment of mild and moderate asthma in adults. Dtsch Arztebl. Int. 2020, 117, 434–444.
[7]	Barjaktarevic, I.Z.; Milstone, A.P. Nebulized therapies in COPD: past, present, and the future. Int. J. Chronic Obstr. Pulm. Dis. 2020, 15, 1665–1677.
[8]	Terry, P.D.; Dhand, R. Inhalation therapy for stable COPD: 20 years of GOLD reports. Adv. Ther. 2020, 37, 1812–1828.
[9]	Terry, P.D.; Dhand, R. The 2023 GOLD report: updated guidelines for inhaled pharmacological therapy in patients with stable COPD. Pulm. Ther. 2023, 9, 345–357.
[10]	Bassetti, M.; Vena, A.; Russo, A.; Peghin, M. Inhaled liposomal antimicrobial delivery in lung infections. Drugs. 2020, 80, 1309–1318.
[11]	Elborn, J.S.; Blasi, F.; Burgel, P.R.; Peckham, D. Role of inhaled antibiotics in the era of highly effective CFTR modulators. Eur. Respir. Rev. 2023, 32, 220154.
[12]	Bilton, D.; Pressler, T.; Fajac, I.; Clancy, J.P.; Sands, D.; Minic, P.; Cipolli, M.; Galeva, I.; Solé, A.; Quittner, A.L.; Liu, K.; McGinnis, J.P.; Eagle, G.; Gupta, R.; Konstan, M.W.; Renner, S.; Knoop, C.; Malfroot, A.; Dupont, L.; Desager, K.; De Baets, F.; Bosheva, M.; Nedkova, V.; Galabov, I.; Galeva, I.; Freitag, A.; Morrison, N.; Wilcox, P.; Pressler, T.; Martinet, Y.; Chiron, R.; Fajac, I.; Dominique, S.; Reix, P.; Prevotat, A.; Sermet, I.; Durieu, I.; Fischer, R.; Huber, R.; Staab, D.; Mellies, U.; Sextro, W.; Welte, T.; Wilkens, H.; Sommerwerk, U.; Bewig, B.; Inglezos, I.; Doudounakis, S.E.; Bede, O.; Gönczi, F.; Újhelyi, R.; McKone, E.; McNally, P.; Lucidi, V.; Cipolli, M.; La Rosa, M.; Minicucci, L.; Padoan, R.; Pisi, G.; Gagliardini, R.; Colombo, C.; Bronsveld, I.; Sapiejka, E.; Mazurek, H.; Sands, D.; Górnicka, G.; Stelmach, I.; Batura-Gabryel, H.; Rachel, M.; Minic, P.; Orosova, J.; Takac, B.; Feketova, A.; Martinez, C.; Hernandez, G.G.; Villa-Asensi, J.R.; Gartner, S.; Sole, A.; Lindblad, A.; Ledson, M.; Bilton, D.; Whitehouse, J.; Smyth, A.; Ketchell, I.; Lee, T.; MacGregor, G. Amikacin liposome inhalation suspension for chronic Pseudomonas aeruginosa infection in cystic fibrosis. J. Cyst. Fibros. 2020, 19, 284–291.
[13]	Tan, Z.M.; Lai, G.P.; Pandey, M.; Srichana, T.; Pichika, M.R.; Gorain, B.; Bhattamishra, S.K.; Choudhury, H. Novel approaches for the treatment of pulmonary tuberculosis. Pharmaceutics. 2020, 12, 1196.
[14]	Gonzalez-Juarrero, M.; Lukka, P.B.; Wagh, S.; Walz, A.; Arab, J.; Pearce, C.; Ali, Z.; Ryman, J.T.; Parmar, K.; Temrikar, Z.; Munoz-Gutierrez, J.; Robertson, G.T.; Liu, J.Y.; Lenaerts, A.J.; Daley, C.; Lee, R.E.; Braunstein, M.; Hickey, A.J.; Meibohm, B. Preclinical evaluation of inhalational spectinamide-1599 therapy against tuberculosis. ACS Infect. Dis. 2021, 7, 2850–2863.
[15]	Wan, Q.Y.; Zhang, X.R.; Zhou, D.F.; Xie, R.; Cai, Y.; Zhang, K.H.; Sun, X.R. Inhaled nano-based therapeutics for pulmonary fibrosis: recent advances and future prospects. J. Nanobiotechnology. 2023, 21, 215.
[16]	Wong, A.W.; Ryerson, C.J.; Guler, S.A. Progression of fibrosing interstitial lung disease. Respir. Res. 2020, 21, 32.
[17]	Hauser, R.A.; Isaacson, S.H.; Ellenbogen, A.; Safirstein, B.E.; Truong, D.D.; Komjathy, S.F.; Kegler-Ebo, D.M.; Zhao, P.; Oh, C. Orally inhaled levodopa (CVT-301) for early morning OFF periods in Parkinson’s disease. Parkinsonism Relat. Disord. 2019, 64, 175–180.
[18]	Hauser, R.A.; LeWitt, P.A.; Waters, C.H.; Grosset, D.G.; Blank, B. The clinical development of levodopa inhalation powder. Clin. Neuropharmacol. 2023, 46, 66–78.
[19]	Cheng, H.Y.; Zou, Y.Y.; Shah, C.D.; Fan, N.; Bhagat, T.D.; Gucalp, R.; Kim, M.; Verma, A.; Piperdi, B.; Spivack, S.D.; Halmos, B.; Perez-Soler, R. First-in-human study of inhaled Azacitidine in patients with advanced non-small cell lung cancer. Lung Cancer. 2021, 154, 99–104.
[20]	Kosmidis, C.; Sapalidis, K.; Zarogoulidis, P.; Sardeli, C.; Koulouris, C.; Giannakidis, D.; Pavlidis, E.; Katsaounis, A.; Michalopoulos, N.; Mantalobas, S.; Koimtzis, G.; Alexandrou, V.; Tsiouda, T.; Amaniti, A.; Kesisoglou, I. Inhaled cisplatin for NSCLC: facts and results. Int. J. Mol. Sci. 2019, 20, 2005.
[21]	Kuehl, P.J.; Tellez, C.S.; Grimes, M.J.; March, T.H.; Tessema, M.; Revelli, D.A.; Mallis, L.M.; Dye, W.W.; Sniegowski, T.; Badenoch, A.; Burke, M.; Dubose, D.; Vodak, D.T.; Picchi, M.A.; Belinsky, S.A. 5-Azacytidine inhaled dry powder formulation profoundly improves pharmacokinetics and efficacy for lung cancer therapy through genome reprogramming. Br. J. Cancer. 2020, 122, 1194–1204.
[22]	Chandel, A.; Goyal, A.K.; Ghosh, G.; Rath, G. Recent advances in aerosolised drug delivery. Biomed. Pharmacother. 2019, 112, 108601.
[23]	Lavorini, F. Easyhaler^®: an overview of an inhaler device for day-to-day use in patients with asthma and chronic obstructive pulmonary disease. Drugs Context. 2019, 8, 1–8.
[24]	Hagmeyer, L.; van Koningsbruggen-Rietschel, S.; Matthes, S.; Rietschel, E.; Randerath, W. From the infant to the geriatric patient—strategies for inhalation therapy in asthma and chronic obstructive pulmonary disease. Clin. Respir. J. 2023, 17, 487–498.
[25]	Lv, X.; Gao, Z.; Tang, W.; Qin, J.; Wang, W.; Liu, J.; Li, M.; Teng, F.; Yi, Dong, J.; Wei, Y. Trends of therapy in the treatment of asthma. Ther. Adv. Respir. Dis. 2023, 17, 17534666231155748.
[26]	Chan, H.W.; Chow, S.; Zhang, X.Y.; Zhao, Y.Y.; Tong, H.H.Y.; Chow, S.F. Inhalable nanoparticle-based dry powder formulations for respiratory diseases: challenges and strategies for translational research. AAPS PharmSciTech. 2023, 24, 98.
[27]	Anderson, C.F.; Grimmett, M.E.; Domalewski, C.J.; Cui, H.G. Inhalable nanotherapeutics to improve treatment efficacy for common lung diseases. Wiley Interdiscip. Rev. Nanomed. Nanobiotechnol. 2020, 12, e1586.
[28]	Wong, W.F.; Ang, K.P.; Sethi, G.; Looi, C.Y. Recent advancement of medical patch for transdermal drug delivery. Medicina (Kaunas). 2023, 59, 778.
[29]	Hastedt, J.E.; Bäckman, P.; Cabal, A.; Clark, A.; Ehrhardt, C.; Forbes, B.; Hickey, A.J.; Hochhaus, G.; Jiang, W.L.; Kassinos, S.; Kuehl, P.J.; Prime, D.; Son, Y.J.; Teague, S.; Tehler, U.; Wylie, J. iBCS: 1. principles and framework of an inhalation-based biopharmaceutics classification system. Mol. Pharmaceutics. 2022, 19, 2032–2039.
[30]	Kaplan, A.; van Boven, J.F.M. Switching inhalers: a practical approach to keep on UR RADAR. Pulm. Ther. 2020, 6, 381–392.
[31]	Ke, W.R.; Chang, R.Y.K.; Kwok, P.C.L.; Tang, P.; Chen, L.; Chen, D.H.; Chan, H.K. Administration of dry powders during respiratory supports. Ann. Transl. Med. 2021, 9, 596.
[32]	Usmani, O.S. Choosing the right inhaler for your asthma or COPD patient. Ther. Clin. Risk Manag. 2019, 15, 461–472.
[33]	Jardim, J.R.; Nascimento, O.A. The importance of inhaler adherence to prevent COPD exacerbations. Med. Sci. 2019, 7, 54.
[34]	Cataldo, D.; Hanon, S.; Peché, R.V.; Schuermans, D.J.; Degryse, J.M.; De Wulf, I.A.; Elinck, K.; Leys, M.H.; Rummens, P.L.; Derom, E. How to choose the right inhaler using a patient-centric approach? Adv. Ther. 2022, 39, 1149–1163.
[35]	Daley-Yates, P.; Singh, D.; Igea, J.M.; Macchia, L.; Verma, M.; Berend, N.; Plank, M. Assessing the effects of changing patterns of inhaled corticosteroid dosing and adherence with fluticasone furoate and budesonide on asthma management. Adv. Ther. 2023, 40, 4042–4059.
[36]	Gao, J.X. Vaccination with CanSinoBIO’s inhaled COVID-19 vaccine has begun in China. J. Biosaf. Biosecur. 2022, 4, 163.
[37]	Kyriakidis, N.C.; López-Cortés, A.; González, E.V.; Grimaldos, A.B.; Prado, E.O. SARS-CoV-2 vaccines strategies: a comprehensive review of phase 3 candidates. NPJ Vaccines. 2021, 6, 28.
[38]	Wang, Z.Z.; Popowski, K.D.; Zhu, D.S.; de Juan Abad, B.L.; Wang, X.Y.; Liu, M.R.; Lutz, H.; De Naeyer, N.; DeMarco, C.T.; Denny, T.N.; Dinh, P.U C.; Li, Z.H.; Cheng, K. Exosomes decorated with a recombinant SARS-CoV-2 receptor-binding domain as an inhalable COVID-19 vaccine. Nat. Biomed. Eng. 2022, 6, 791–805.
[39]	Elborn, J.S.; Flume, P.A.; Van Devanter, D.R.; Procaccianti, C. Management of ChronicPseudomonas AeruginosaInfection with inhaled levofloxacin in people with cystic fibrosis. Future Microbiol. 2021, 16, 1087–1104.
[40]	Vuong, N.N.; Hammond, D.; Kontoyiannis, D.P. Clinical uses of inhaled antifungals for invasive pulmonary fungal disease: promises and challenges. J. Fungi. 2023, 9, 464.
[41]	Alshammari, M.K.; Almutairi, M.S.; Althobaiti, M.D.; Alsawyan, W.A.; Alomair, S.A.; Alwattban, R.R.; Al Khozam, Z.H.; Alanazi, T.J.; Alhuqyal, A.S.; Darwish, H.S.A.; Alotaibi, A.F.; Almutairi, F.N.; Alanazi, A.A. A systematic review of clinical pharmacokinetics of inhaled antiviral. Medicina (Kaunas). 2023, 59, 642.
[42]	Hickey, A.J. Emerging trends in inhaled drug delivery. Adv. Drug Deliv. Rev. 2020, 157, 63–70.
[43]	Zhang, C.Q.; D’Angelo, D.; Buttini, F.; Yang, M.S. Long-acting inhaled medicines: present and future. Adv. Drug Deliv. Rev. 2024, 204, 115146.
[44]	Waterer, G.; Lord, J.; Hofmann, T.; Jouhikainen, T. Phase I, dose-escalating study of the safety and pharmacokinetics of inhaled dry-powder vancomycin (AeroVanc) in volunteers and patients with cystic fibrosis: a new approach to therapy for methicillin-resistant staphylococcus aureus. Antimicrob. Agents Chemother. 2020, 64, e01776–19.
[45]	Hava, D.L.; Tan, L.S.; Johnson, P.; Curran, A.K.; Perry, J.; Kramer, S.; Kane, K.T.; Bedwell, P.; Layton, G.; Swann, C.; Henderson, D.; Khan, N.; Connor, L.; McKenzie, L.; Singh, D.; Roach, J. A phase 1/1b study of PUR1900, an inhaled formulation of itraconazole, in healthy volunteers and asthmatics to study safety, tolerability and pharmacokinetics. Br. J. Clin. Pharmacol. 2020, 86, 723–733.
[46]	Saha, T.; Sinha, S.; Harfoot, R.; Quiñones-Mateu, M.E.; Das, S.C. Manipulation of spray-drying conditions to develop an inhalable ivermectin dry powder. Pharmaceutics. 2022, 14, 1432.
[47]	Fishbein, S.R.S.; Hink, T.; Reske, K.A.; Cass, C.; Struttmann, E.; Iqbal, Z.H.; Seiler, S.; Kwon, J.H.; Burnham, C.A.; Dantas, G.; Dubberke, E.R. Randomized controlled trial of oral vancomycin treatment in clostridioides difficile-colonized patients. mSphere. 2021, 6, e00936–20.
[48]	Britt, N.S.; Hazlett, D.S.; Horvat, R.T.; Liesman, R.M.; Steed, M.E. Activity of pulmonary vancomycin exposures versus planktonic and biofilm isolates of methicillin-resistant Staphylococcus aureus from cystic fibrosis sputum. Int. J. Antimicrob. Agents 2020, 55, 105898.
[49]	Bergagnini-Kolev, M.; Kane, K.; Templeton, I.E.; Curran, A.K. Evaluation of the potential for drug-drug interactions with inhaled itraconazole using physiologically based pharmacokinetic modelling, based on phase 1 clinical data. AAPS J. 2023, 25, 62.
[50]	Formiga, F.R.; Leblanc, R.; de Souza Rebouças, J.; Farias, L.P.; de Oliveira, R.N.; Pena, L. Ivermectin: an award-winning drug with expected antiviral activity against COVID-19. J. Control. Release. 2021, 329, 758–761.
[51]	Elkholy, K.O.; Hegazy, O.; Erdinc, B.; Abowali, H. Ivermectin: a closer look at a potential remedy. Cureus. 2020, 12, e10378.
[52]	Mansour, S.M.; Shamma, R.N.; Ahmed, K.A.; Sabry, N.A.; Esmat, G.; Mahmoud, A.A.; Maged, A. Safety of inhaled ivermectin as a repurposed direct drug for treatment of COVID-19: a preclinical tolerance study. Int. Immunopharmacol. 2021, 99, 108004.
[53]	Braunstein, M.; Hickey, A.J.; Ekins, S. Why wait? the case for treating tuberculosis with inhaled drugs. Pharm. Res. 2019, 36, 166.
[54]	Mehanna, M.M.; Mohyeldin, S.M.; Elgindy, N.A. Rifampicin-carbohydrate spray-dried nanocomposite: a futuristic multiparticulate platform for pulmonary delivery. Int. J. Nanomed. 2019, 14, 9089–9112.
[55]	Al Khatib, A.O.; El-Tanani, M.; Al-Obaidi, H. Inhaled medicines for targeting non-small cell lung cancer. Pharmaceutics. 2023, 15, 2777.
[56]	Elbatanony, R.S.; Parvathaneni, V.; Kulkarni, N.S.; Shukla, S.K.; Chauhan, G.; Kunda, N.K.; Gupta, V. Afatinib-loaded inhalable PLGA nanoparticles for localized therapy of non-small cell lung cancer (NSCLC)-development and in-vitro efficacy. Drug Deliv. Transl. Res. 2021, 11, 927–943.
[57]	Gupta, C.; Jaipuria, A.; Gupta, N. Inhalable formulations to treat non-small cell lung cancer (NSCLC): recent therapies and developments. Pharmaceutics. 2022, 15, 139.
[58]	Jiang, P.; Liang, B.; Zhang, Z.; Fan, B.; Zeng, L.; Zhou, Z.Y.; Mao, Z.F.; Xu, Q.; Yao, W.R.; Shen, Q.L. New insights into nanosystems for non-small-cell lung cancer: diagnosis and treatment. RSC Adv. 2023, 13, 19540–19564.
[59]	Crintea, A.; Dutu, A.G.; Samasca, G.; Florian, I.A.; Lupan, I.; Craciun, A.M. The nanosystems involved in treating lung cancer. Life (Basel). 2021, 11, 682.
[60]	Raghu, G.; Remy-Jardin, M.; Richeldi, L.; Thomson, C.C.; Inoue, Y.; Johkoh, T.; Kreuter, M.; Lynch, D.A.; Maher, T.M.; Martinez, F.J.; Molina-Molina, M.; Myers, J.L.; Nicholson, A.G.; Ryerson, C.J.; Strek, M.E.; Troy, L.K.; Wijsenbeek, M.; Mammen, M.J.; Hossain, T.; Bissell, B.D.; Herman, D.D.; Hon, S.M.; Kheir, F.; Khor, Y.H.; Macrea, M.; Antoniou, K.M.; Bouros, D.; Buendia-Roldan, I.; Caro, F.; Crestani, B.; Ho, L.; Morisset, J.; Olson, A.L.; Podolanczuk, A.; Poletti, V.; Selman, M.; Ewing, T.; Jones, S.; Knight, S.L.; Ghazipura, M.; Wilson, K.C. Idiopathic pulmonary fibrosis (an update) and progressive pulmonary fibrosis in adults: an official ATS/ERS/JRS/ALAT clinical practice guideline. Am. J. Respir. Crit. Care Med. 2022, 205, e18–e47.
[61]	Kolb, M.; Orfanos, S.E.; Lambers, C.; Flaherty, K.; Masters, A.; Lancaster, L.; Silverstein, A.; Nathan, S.D. The antifibrotic effects of inhaled treprostinil: an emerging option for ILD. Adv. Ther. 2022, 39, 3881–3895.
[62]	Luinstra, M.; Rutgers, W.; van Laar, T.; Grasmeijer, F.; Begeman, A.; Isufi, V.; Steenhuis, L.; Hagedoorn, P.; de Boer, A.; Frijlink, H.W. Pharmacokinetics and tolerability of inhaled levodopa from a new dry-powder inhaler in patients with Parkinson’s disease. Ther. Adv. Chronic Dis. 2019, 10, doi: 10.1177/2040622319857617.
[63]	Glenardi, G.; Handayani, T.; Barus, J.; Mangkuliguna, G. Inhaled levodopa (CVT-301) for the treatment of parkinson disease: a systematic review and meta-analysis of randomized controlled trials. Neurol. Clin. Pract. 2022, 12, 139–148.
[64]	Farbman, E.S.; Waters, C.H.; LeWitt, P.A.; Rudzińska, M.; Klingler, M.; Lee, A.; Qian, J.; Oh, C.; Hauser, R.A. A 12-month, dose-level blinded safety and efficacy study of levodopa inhalation powder (CVT-301, Inbrija) in patients with Parkinson’s disease. Park. Relat. Disord. 2020, 81, 144–150.