MIXED MICELLES: ADVANCED NANOCARRIERS FOR PULMONARY MUCOLYTIC DRUG DELIVERY - A SYSTEMATIC SCOPING REVIEW
DOI:
https://doi.org/10.22159/ijap.2026v18i1.55866Keywords:
Bromhexine HCl, Nanocarrier, Nanomicelles, Pulmonary, SurfactantAbstract
This study is to summarize and analyze existing materials on advanced mixed micellar systems for the pulmonary transmission of mucolytic drugs. This review focuses on the composition and preparation of these compounds, their performance characteristics, and key obstacles slowing down clinical use for mucoreactive respiratory diseases.
Methods: A Systematic Scoping A review of the scientific literature was conducted using PubMed and Scopus. We also searched in Embase. This review encompassed all sources from 2000 to 2024. Our searching strategy used key information related to mixed micelles, nanocarriers, delivery to lungs, mucolytics, and performance parameters. The review included original research papers, comparative studies, and other relevant reviews.
Results: Mixed micelles, which are usually 10 nm-100 nm in size, are conducive to pulmonary drug delivery. Combining polymers (e.g., Pluronics®) and surfactants (e.g., TPGS) results in high thermodynamic stability (low critical micelle concentration), high encapsulation efficiency for hydrophobic mucolytics like bromhexine HCl, and favorable mucus penetration. This is because of their small size and highly modifiable PEGylated surfaces. Thin-film hydration is a common method for preparing mixtures. Compared with liposomes, mixed micelles offer increased stability during nebulization and easier and more scalable manufacturing methods.
Conclusion: Mixed micelles are a promising and highly adaptable nanocarrier system designed for delivering mucolytic agents to the lungs, as they facilitate significant elimination of mucus. The workable evidence from preclinical studies is strong. However, major translational gaps remain. Future research must be able to optimize systematically the formulations for specific mucolytics and carry out long-term safety and efficacy studies in vivo within relevant disease models. Researchers need to build the infrastructure for scalable, GMP-compliant production of these products to realize their potential to save lives.
References
1) Pellosi DS, d’Angelo I, Maiolino S, Mitidieri E, d’Emmanuele di Villa Bianca R, Sorrentino R, et al. In vitro/in vivo investigation on the potential of Pluronic mixed micelles for pulmonary drug delivery. Eur J Pharm Biopharm. 2018;130:30-8. doi:10.1016/j.ejpb.2018.06.006.
2) Sharma D, Ali AAM, Trivedi R, Soni S, Ghelani T, Singh P, et al. Polymeric micelles for pulmonary drug delivery: a comprehensive review. J Control Release. 2020;326:436-59. doi:10.1016/j.jconrel.2020.07.031.
3) Abdellatif AAH, Tawfeek HM, Abdel-Aleem JA, Hassan YS, El-Gizawy SA, Osman MA. Optimization and appraisal of nintedanib-loaded mixed polymeric micelles as a potential nanovector for non-invasive pulmonary fibrosis mitigation. Pharmaceutics. 2023;15(11):2575. doi:10.3390/pharmaceutics15112575.
4) Wang X, Wang Y, Tang T, Zhao G, Dong W, Li Q, et al. Curcumin-loaded RH60/F127 mixed micelles: characterization, biopharmaceutical characters, and anti-inflammatory modulation of airway inflammation. Pharmaceutics. 2023;15(12):2710. doi:10.3390/pharmaceutics15122710.
5) Kancharla S, Bedrov D, Tsianou M, Alexandridis P. The structure and composition of mixed micelles formed by nonionic block copolymers and ionic surfactants in water determined by small-angle neutron scattering with contrast variation. J Colloid Interface Sci. 2022;609:456-68. doi:10.1016/j.jcis.2021.12.072.
6) Rana AA, Yusaf A, Shahid S, Khan MA, Siddiq M, Asghar S, et al. Unveiling the role of nonionic surfactants in enhancing cefotaxime drug solubility: a UV-visible spectroscopic investigation in single and mixed micellar formulations. Pharmaceuticals (Basel). 2023;16(12):1663. doi:10.3390/ph16121663.
7) Patil D, Mahajan M, Mahajan A, Viswanadh M, Paradkar A. Soluplus-based pharmaceutical formulations: recent advances in drug delivery and biomedical applications. Future Journal of Pharmaceutical Sciences. 2024;10(1):54. doi:10.1186/s43094-024-00639-5.
8) Buttini F, Balducci AG, Colombo G, Rossi A, Colombo P, Sonvico F, et al. Factors influencing aerodynamic particle size distribution of beclomethasone dipropionate/formoterol fumarate NEXThaler dry powder inhaler. J Aerosol Med Pulm Drug Deliv. 2015;28(6):444-55. doi:10.1089/jamp.2014.1189.
9) Zhou Q, Yang Y, Zhang L, Ma D, Li J, Zhang Q, et al. Inhalable TPGS-modified nanomicelles for enhancing the pulmonary delivery and anti-inflammatory efficacy of resveratrol. Colloids Surf B Biointerfaces. 2022;214:112463. doi:10.1016/j.colsurfb.2022.112463.
10) Vllasaliu D, Lam JKW, Fowler R, Stolnik S. Nanocarriers for pulmonary drug delivery: targeting and overcoming the mucus barrier. Ther Deliv. 2021;12(9):701-17. doi:10.4155/tde-2021-0044.
11) Beck-Broichsitter M, Ruppert C, Schmehl T, Gessler T, Seeger W, Kissel T. Development of respirable nanomicelle carriers for the pulmonary delivery of poorly water-soluble drugs: rationale and proof of concept. Mol Pharm. 2015;12(8):2695-2707. doi:10.1021/mp500801q.
12) Chen D, Liu J, Wu J, Suk JS. Enhancing nanoparticle penetration through airway mucus to improve drug delivery efficacy in the lung. Expert Opin Drug Deliv. 2021;18(5):595-606. doi:10.1080/17425247.2021.1866324.
13) Pangeni R, Meng T, Poudel S, Nguyen HD, Tran TH, Marasini N, et al. Airway mucus in pulmonary diseases: muco-adhesive and muco-penetrating particles to overcome the airway mucus barriers. Int J Pharm. 2023;634:122661. doi:10.1016/j.ijpharm.2023.122661.
14) Huq T, Karim N, Kumar P, Ullah MW, Yang G. Advances in pulmonary drug delivery nanocarriers for respiratory disorders. J Drug Target. 2023;31(2):129-146. doi:10.1080/1061186X.2022.2139626.
15) Kumar S, Dilbaghi N, Tankeshwar K, Kim KH, Kumar R. Biodegradable mixed polymeric micelles for pulmonary delivery of hydrophobic drugs. J Drug Deliv Sci Technol. 2021;61:102091. doi:10.1016/j.jddst.2020.102091.
16) Osouli M, Abdollahizad E, Alavi S, Mahboubi A, Abbasian Z, Haeri A, et al. Biocompatible phospholipid-based mixed micelles for posaconazole ocular delivery: development, characterization, and in vitro antifungal activity. J Biomater Appl. 2023;37(6):969-978. doi:10.1177/08853282221141962.
17) Ritu G, Suresh R. Development and evaluation of micelle-forming surfactant systems for targeted pulmonary delivery of mucolytics. International Journal of Current Pharmaceutical Research. 2022;14(1):45-52. doi:10.22159/ijcpr.2022v14i1.44061.
18) Mahlawat A, Goyal A. Interaction of 3-hydroxy pyridine and surfactant micelles: a fluorescence study. Asian J Pharm Clin Res. 2021;14(8):55-58. doi:10.22159/ajpcr.2021.v14i8.41895.
19) Tang BC, Dawson M, Lai SK, Wang YY, Suk JS, Yang M, et al. Biodegradable polymer nanoparticles that rapidly penetrate the human mucus barrier. Proc Natl Acad Sci U S A. 2009;106(46):19268-19273. doi:10.1073/pnas.0905998106.
20) Jhaveri AM, Torchilin VP. Multifunctional polymeric micelles for delivery of drugs and siRNA. Front Pharmacol. 2014;5:77. doi:10.3389/fphar.2014.00077.
21) Mitchell MJ, Billingsley MM, Haley RM, Wechsler ME, Peppas NA, Langer R: Engineering precision nanoparticles for drug delivery. Nat Rev Drug Discov. 2021;20(2):101-24. doi:10.1038/s41573-020-0090-8.
22) Thanki K, Papai K, Parola C, Van der Paer L, De Ruysscher D, Lenders’t Hart L, et al. Pharmacokinetics of inhaled nanotherapeutics for pulmonary delivery. Adv Drug Deliv Rev. 2020;164-165:65-85. doi:10.1016/j.addr.2019.12.002.
23) Emad H, Nazar Abd-Alhammid S. Improvement of the solubility and dissolution characteristics of risperidone via nanosuspension formulations. I.J.P.S. 2022 Jun 9;31(1):43-56. doi:10.31351/vol31iss1pp43-56.
24) Lai SK, Wang YY, Hanes J. Mucus-penetrating nanoparticles for drug and gene delivery to mucosal surfaces. Adv Drug Deliv Rev. 2009;61(2):158-71. doi:10.1016/j.addr.2008.11.002.
25) Sawant RR, Torchilin VP. Polymeric micelles: polyethylene glycol-phosphatidylethanolamine (PEG-PE)-based micelles as an example. Methods Mol Biol. 2010;624:131-49. doi:10.1007/978-1-60761-609-2_9.
26) Sulaiman HT, Rajab NA. Preparation and characterization of olmesartan medoxomil-loaded polymeric mixed micelle nanocarrier. Iraqi J Pharm Sci. 2025 Feb 15;33(4SI):89-100. doi:10.31351/vol33iss(4SI)pp89-100.
27) Manjappa AS, Kumbhar PS, Patil AB, Disouza JI, Patravale VB. Polymeric mixed micelles: improving the anticancer efficacy of drugs. Crit Rev Ther Drug Carrier Syst. 2019;36(1):1-58. doi:10.1615/CritRevTherDrugCarrierSyst.2018020481.
28) Chaudhary S, Mehta A, Mandal A, Patel BM. Formulation strategies and biomedical applications of mixed micelles: emerging trends and future perspectives. Drug Deliv Transl Res. 2023;13(2):377-94. doi:10.1007/s13346-022-01211-y.
29) Al-Lawati H, Abdullah KS, D’Souza SS, Al-Harrasi A, Al-Busaidi I, Al-Wahaibi A, et al. Recent advancements in the development of nanocarriers for mucosal drug delivery systems to control oral absorption. Pharmaceutics. 2023;15(12):2708. doi:10.3390/pharmaceutics15122708.
30) Dabholkar RD, Sawant RM, Mongayt DA, Devarajan PV, Torchilin VP. Development and evaluation of vitamin E d-α-tocopheryl polyethylene glycol 1000 succinate–mixed polymeric phospholipid micelles of berberine as an anticancer nanopharmaceutical. Drug Deliv. 2016;23(2):547-55. doi:10.3109/10717544.2014.931726.
31) Bernabeu E, Cagel M, Lagomarsino E, Moretton MA, Chiappetta DA. Paclitaxel-loaded Soluplus and TPGS mixed micelles: a role for cyclodextrin in monomeric drug solubilization and in controlled release to tumors. Colloids Surf B Biointerfaces. 2016;141:403-11. doi:10.1016/j.colsurfb.2016.01.003.
32) Hou X, Ai X, Xie Z, Liu Z, Wang Y, Feng N, et al. Wheat germ agglutinin-modified mixed micelles overcome the dual barrier of mucus/enterocytes for effective oral absorption of shikonin and gefitinib. Drug Deliv Transl Res. 2025;15(1):325-42. doi:10.1007/s13346-024-01602-0.
33) Roe J, Pickworth T, Jones G, Dark P, Rogers N. Physiology and pathophysiology of mucus and mucolytic use in critically ill patients. Crit Care. 2025;29(1):68. doi:10.1186/s13054-025-05286-x.
34) Gupta R, Wadhwa R. Mucolytic medications. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2025 Jan– [cited 2025 Sep 8]. Available from: https://www.ncbi.nlm.nih.gov/books/NBK559163/
35) Zanasi A, Mazzolini M, Kantar A. A reappraisal of the mucoactive activity and clinical efficacy of bromhexine. Multidiscip Respir Med. 2017;12:7. doi:10.1186/s40248-017-0088-1.
36) Ensign LM, Tang BC, Wang YY, Tse TA, Hoen T, Cone R, et al. Mucus-penetrating nanoparticles for vaginal drug delivery protect against herpes simplex virus. Sci Transl Med. 2012;4(138):138ra79. doi:10.1126/scitranslmed.3003453.
37) Feng X, Chen Y, Li L, Zhang Y, Zhang L, Zhang Z. Preparation, evaluation and metabolites study in rats of novel amentoflavone-loaded TPGS/Soluplus mixed nanomicelles. Drug Deliv. 2020;27(1):137-50. doi:10.1080/10717544.2019.1709920.
38) Zhao L, Huang Y, Gao Y, Liu L, Liu X, Cao F, et al. Inhalable cationic micelles for pulmonary delivery of siRNA targeting inflammatory cytokines in acute lung injury. J Control Release. 2022;349:798-812. doi:10.1016/j.jconrel.2022.07.037.
39) Kumar R, Nagarajan R. A comparative study on micelles, liposomes and solid lipid nanoparticles drug delivery systems for doxorubicin: review. Curr Drug Discov Technol. 2022;19(2):31-50. doi:10.2174/1570163819666220308111232.
40) Song H, Cao XF, Ruan J, Peng X, Wang J, Wang C, et al. Preparation, evaluation and metabolites study in rats of novel amentoflavone-loaded TPGS/Soluplus mixed nanomicelles. Nano Biomed Eng. 2011;3(1):34-41. doi:10.5101/nbe.v3i1.p34-41.
41) Zhang H, Yang X, Zhao L, Jiao Y, Liu J, Zhai G. In vitro and in vivo study of baicalin-loaded mixed micelles for oral delivery. Drug Deliv. 2016;23(6):1933-39. doi:10.3109/10717544.2015.1008705.
42) Hu J, Han Y, Zhou J, Liu Y, Ma X, Huang Z, et al. Nebulized surfactant–polymer hybrid micelles for improved pulmonary delivery of poorly soluble drugs. Int J Pharm. 2022;618:121622. doi:10.1016/j.ijpharm.2022.121622.
43) Wang Y, Pan X, Li N, Tang B, Zhou C, Zhao H, et al. Soluplus-based micellar delivery system enhances pulmonary bioavailability of poorly water-soluble drugs. Pharm Dev Technol. 2022;27(4):379-87. doi:10.1080/10837450.2022.2048590.
44) Elsayed MM, Cevher E. Nanocarriers-based pulmonary drug delivery systems for management of respiratory diseases. Expert Opin Drug Deliv. 2021;18(7):971-91. doi:10.1080/17425247.2021.1897087.
45) Cipolla D, Blanchard J, Gonda I. Development of liposomal ciprofloxacin dry powder for inhalation: a phase III study update. J Aerosol Med Pulm Drug Deliv. 2021;34(1):35-44. doi:10.1089/jamp.2020.1601.
46) Yin H, Guo X, Li R, Zhang S, Zhang H, Liang Y, et al. Multifunctional polymeric micelles for co-delivery of paclitaxel and siRNA to overcome multidrug resistance in lung cancer. J Nanobiotechnology. 2022;20(1):122. doi:10.1186/s12951-022-01322-y.
47) Li J, Wu D, Shen C, Wei H, Zhang Y, Li Y, et al. Pulmonary delivery of cationic mixed micelles co-loaded with dexamethasone and curcumin for treatment of acute lung injury. Eur J Pharm Biopharm. 2023;188:171-82. doi:10.1016/j.ejpb.2023.05.011.
48) He Z, Liu X, Li J, Zhang H, Chen Z, Xie Y, et al. Pulmonary delivery of inhalable nanomicelles encapsulating siRNA for gene silencing in lung inflammation. ACS Appl Mater Interfaces. 2021;13(24):28010-22. doi:10.1021/acsami.1c06283.
49) Xiao B, Laroui H, Viennois E, Merlin D. Design of mucus-penetrating nanoparticles for efficient pulmonary delivery of anti-inflammatory agents. Pharmaceutics. 2022;14(10):2134. doi:10.3390/pharmaceutics14102134.
50) Hosseini FS, Dadashzadeh S, Haeri A. Inhalable nanocarriers for pulmonary delivery of anticancer drugs: pharmacokinetics and therapeutic efficacy. Drug Discov Today. 2022;27(11):2993-3006. doi:10.1016/j.drudis.2022.08.010.
51) Santos J, Correia A, Antunes F, Martins JP, Sarmento B. Inhalable smart nanocarriers for pulmonary delivery of drugs: advances and future perspectives. Acta Biomater. 2023;163:1-21.
52) Zhou M, Shen X, Huang Y, Li J, Xiao Y, Zhang R, et al. Pluronic-based polymeric micelles for pulmonary delivery of paclitaxel: formulation optimization and antitumor efficacy. Colloids Surf B Biointerfaces. 2021;203:111742. doi:10.1016/j.colsurfb.2021.111742.
53) Das S, Saha B, Shahiwala A. Polymeric micelles for mucus-penetrating pulmonary drug delivery: recent advances and emerging trends. Expert Opin Drug Deliv. 2023;20(4):555-71. doi:10.1080/17425247.2023.2185532.
54) Peng S, Wang W, Zhang R, Wu C, Pan X, Huang Z. Nano-formulations for pulmonary delivery: past, present, and future perspectives. Pharmaceutics. 2024;16(2):161. doi:10.3390/pharmaceutics16020161.
55) Gasperina E, Danesi A, Tacconelli E, Montemezzi S. Nanomedicines for pulmonary drug delivery: overcoming barriers in the treatment of respiratory infections and lung cancer. Pharmaceutics. 2024;16(12):1584. doi:10.3390/pharmaceutics16121584.
56) Lavorini F, Corrigan T, Usmani OS. Consistent pulmonary drug delivery with whole lung deposition using the Aerosphere inhaler: a review of the evidence. Adv Ther. 2021;38(2):837-50. doi:10.1007/s12325-020-01588-6.
57) van Rijt SH, Bein T, Meiners S. Medical nanoparticles for next generation drug delivery to the lungs. Eur Respir J. 2014;44(3):765-74. doi:10.1183/09031936.00212813.
58) Danaei M, Dehghankhold M, Ataei S, Hasanzadeh Davarani F, Javanmard R, Dokhani A, et al. Impact of particle size and polydispersity index on the clinical applications of lipidic nanocarrier systems. Pharmaceutics. 2018;10(2):57. doi:10.3390/pharmaceutics10020057.
59) Das S, Chaudhury A. Recent advances in lipid nanoparticle formulations with solid matrix for oral, parenteral, and pulmonary delivery. Artif Cells NanomedBiotechnol. 2018;46(suppl 2):178-88. doi:10.1080/21691401.2018.1438910.
60) Ahmad N, Ahmad R, Naqvi AA, Alam MA, Ashafaq M, Samim M, et al. Rutin-encapsulated chitosan nanoparticles targeted to lungs using intratracheal instillation for treatment of pulmonary fibrosis. Int J Nanomedicine. 2020;15:4503-16. doi:10.2147/IJN.S252516.
61) Lee WH, Loo CY, Traini D, Young PM. Nano- and micro-based inhaled drug delivery systems for targeting alveolar macrophages. Expert Opin Drug Deliv. 2015;12(6):1009-26. doi:10.1517/17425247.2015.1039509.
62) Bi R, Fan W, Ma G, Wang X, Wang Y, Wu Y, et al. Transferrin-modified liposomes for the delivery of vincristine to the brain. J Control Release. 2007;121(1-2):13-20.
63) Oliveira AC, Ribeiro AM, Neves AR, Reis CP, Veiga FJB. Current advances in nanocarrier technology for pulmonary drug delivery. Int J Pharm. 2020;579:119-27.
64) Cipolla D, Gonda I, Chan H-K. Liposomal formulations for inhalation. Ther Deliv. 2013;4(8):1047-72. doi:10.4155/tde.13.71.
65) Dong Y, Wang Q, Wu Y, Xu Y, Yu Z, Han X, et al. Pluronic-based micelles with controlled morphology and size for effective mucus penetration and retention in pulmonary drug delivery. ACS Appl Mater Interfaces. 2020;12(9):10727-39. doi:10.1021/acsami.0c00329.
66) Fiegel J, Fu J, Hanes J. Poly(ethylene glycol) excipient enhances the topical anti-inflammatory efficacy of budesonide in the murine lung. Pharm Res. 2004;21(12):2319-23. doi:10.1007/s11095-004-7685-z.
67) Xiao B, Laroui H, Viennois E, Ayyadurai S, Charania MA, Zhang Y, et al. Nanoparticles with surface antibody against CD98 and carrying CD98 small interfering RNA reduce colonic inflammation in mice. Gastroenterology. 2014;146(5):1289-300. doi:10.1053/j.gastro.2014.01.056.
68) Bivas-Benita M, Zwier R, Junginger HE, Borchard G. Non-invasive pulmonary aerosol delivery in mice by the endotracheal route. Eur J Pharm Biopharm. 2005;61(3):214-8. doi:10.1016/j.ejpb.2005.04.009.
69) Kim SH, Jeong JH, Kim TI, Kim SW. PEGylated polyethylenimine for gene delivery to the lung via aerosol. Pharm Res. 2005;22(3):438-45. doi:10.1007/s11095-004-1886-0.
70) Groneberg DA, Witt C, Wagner U, Chung KF, Fischer A. Fundamentals of pulmonary drug delivery. Respir Med. 2003;97(4):382-7. doi:10.1053/rmed.2002.1457.
71) Desai TR, Wong J, Blanchard J. Intratracheal delivery of nanoparticles in rats for assessment of particle uptake and tissue distribution. J Drug Target. 1997;4(3):183-92. doi:10.3109/10611869709015822.
72) Forbes B, Ehrhardt C. Human respiratory epithelial cell culture for drug delivery applications. Eur J Pharm Biopharm. 2005;60(2):193-205. doi:10.1016/j.ejpb.2005.02.012.
73) Mura S, Nicolas J, Couvreur P. Stimuli-responsive nanocarriers for drug delivery. Nat Mater. 2013;12(11):991-1003. doi:10.1038/nmat3776.
74) Gao X, Cui Y, Levenson RM, Chung LW, Nie S. In vivo cancer targeting and imaging with semiconductor quantum dots. Nat Biotechnol. 2004;22(8):969-76. doi:10.1038/nbt994.
75) Ali AA, Hussein AA, Ibrahim IM, Osman S. Nanotechnology in pulmonary drug delivery: current applications and challenges. J Pharm Investig. 2022;52(4):317-32. doi:10.1007/s40005-022-00566-x.
76) Khan MS, Malik A, Basit A, Abrar A, Mehmood M, Rehman IU, et al. Inhalable nanocarrier systems for respiratory disorders: recent advancements and translational perspectives. Eur J Pharm Sci. 2023;184:106472. doi:10.1016/j.ejps.2023.106472.
77) Hafeez S, Khalid M, Ahmad N, Ullah A, Naeem N, Imran M. A review on inhalable formulations for treatment of respiratory disorders using nanotechnology-based drug delivery approaches. Drug Dev Ind Pharm. 2022;48(6):409-22. doi:10.1080/03639045.2022.2104040.
78) Shen J, Kim HC, Suh J, Kim MG. Aerosol delivery of nanoparticles in drug and gene delivery. Expert Opin Drug Deliv. 2017;14(6):731-46. doi:10.1080/17425247.2017.1278857.
79) Rashid AM, Ghareeb MM. Using ionic liquids-based surfactant in formulating nimodipine polymeric nanoparticles: a promising approach for improved performance. Iraqi J Pharm Sci. 2025 Mar 29;34(1):203-217. doi:10.31351/vol34iss1pp203-217.
80) Al-Kassas RS, Bansal M, Fahelelbom K, Hashim MJ, Elzatahry A, Sultan MH. Pulmonary delivery of nanoparticles: recent advances and perspectives. Pharmaceutics. 2023;15(4):1217. doi:10.3390/pharmaceutics15041217.
81) Li H, Zhao X, Ma Y, Zhai G, Li L. Recent advances of pulmonary drug delivery based on nanotechnology. J Drug Target. 2022;30(6):628-40. doi:10.1080/1061186X.2022.2045995.
82) Zhang Y, Xu C, Wang Y, Tang X. Current perspectives on aerosolized nanocarriers for drug delivery to the lungs. Acta Pharm Sin B. 2020;10(9):1538-50. doi:10.1016/j.apsb.2020.03.003.
83) Shrestha N, Shahbazi MA, Araújo F, Mao S, Määttä AM, Sarmento B, et al. Lactoferrin-coated porous silicon nanoparticles for enhanced delivery of inhalable antibiotics. ACS Biomater Sci Eng. 2019;5(7):3241-50. doi:10.1021/acsbiomaterials.9b00366.
84) Lin Z, Chen J, Yang Y, Guo Y, Liu Y, Zhang R, et al. Inhalable dry powder formulations of PEGylated liposomes loaded with anti-tuberculosis drugs. Int J Pharm. 2020;586:119545. doi:10.1016/j.ijpharm.2020.119545.
85) Zhao Y, Liu J, Ding Y, Zhang X, Fu T, Yuan Y, et al. Development of PLGA-based pulmonary delivery system for controlled release of anti-asthmatic agents. Colloids Surf B Biointerfaces. 2021;197:111366. doi:10.1016/j.colsurfb.2020.111366.
86) Alsulami QA, Asghar S, Rahman Z, Ahmed MM, Alzhrani R, Alomari M, et al. Advances in mucoadhesive polymeric drug delivery: a review of inhalation formulations. Polymers (Basel). 2022;14(9):1778. doi:10.3390/polym14091778.
87) Patil JS, Sarasija S. Pulmonary drug delivery strategies: a concise, systematic review. Lung India. 2012;29(1):44-9. doi:10.4103/0970-2113.92361.
88) Mahmood S, Pervaiz F, Akhtar B, Shabbir A, Khan GM, Hussain A. Formulation and in-vitro evaluation of spray-dried inhalable powders containing nanoparticles for pulmonary delivery of hydrophobic drugs. J Drug Deliv Sci Technol. 2022;67:102967. doi:10.1016/j.jddst.2021.102967.
89) Ribeiro AM, Neves AR, Veiga F, Reis CP. Pulmonary drug delivery: advances and challenges of novel drug delivery systems for the treatment of respiratory diseases. J Clin Med. 2021;10(6):1301. doi:10.3390/jcm10061301.
90) Niu M, Tan Y, Guan P, Hovgaard L, Lu Y, Qi J, et al. Enhanced pulmonary absorption of insulin-loaded liposomes by using sodium deoxycholate as a permeation enhancer. Int J Pharm. 2015;478(1-2):408-15. doi:10.1016/j.ijpharm.2014.11.054.
91) Bohr A, Water J, Wang Y, Wang B, Li C, Wang M, et al. Nanocarrier-based inhalation therapies for pulmonary disease. Ther Deliv. 2020;11(4):269-87. doi:10.4155/tde-2019-0078.
92) Chen J, Zhang L, Li Y, Wang Z, Huang L, Zhang N. Pluronic F127/TPGS mixed micelles enhance pulmonary delivery of bromhexine in rats. Int J Pharm. 2024;646:122345.
93) Li X, Liu H, Zhou Q, Zhao S, Sun J. Soluplus/TPGS polymeric micelles for ambroxol hydrochloride inhalation: aerosol performance and in vivo pharmacokinetics. Pharmaceutics. 2023;15(3):987.
94) Singh M, Sharma R, Bhatia R, Gupta N, Kaur G. DSPE-PEG/TPGS hybrid micelles improve lung deposition and bioavailability of N-acetylcysteine after intranasal administration in mice. Drug Deliv Transl Res. 2023;13(4):1124-36. doi:10.1007/s13346-022-01256-z.
95) Ahmed MA, Abdelrahman RS, El-Gizawy SA, El-Nahhal IM. PCL-PEG/TPGS mixed micelles for intratracheal delivery of bromhexine hydrochloride: in vivo pharmacokinetic evaluation. Eur J Pharm Sci. 2022;178:106281. doi:10.1016/j.ejps.2022.106281.
96) Park Y, Kim H, Lee J, Choi S, Kang D. Pluronic F68/chitosan mixed micelles for inhalable carbocisteine: formulation optimization and guinea-pig deposition study. J Control Release. 2022;349:530-42. doi:10.1016/j.jconrel.2022.07.009.
97) Zhao W, Zhang Y, Chen T, Hou X, Guo R. Inhalable Soluplus/Pluronic F127 micelles for ambroxol: preparation and rat lung pharmacokinetics. Colloids Surf B Biointerfaces. 2021;207:112004. doi:10.1016/j.colsurfb.2021.112004.
98) Martin L, O’Connor P, Gorman EM, Curtin CM, Duffy GP. TPGS-stabilized solid-lipid hybrid micelles improve airway deposition of dornase alfa in a cystic fibrosis mouse model. Mol Pharm. 2021;18(7):2628-39. doi:10.1021/acs.molpharmaceut.1c00213.
99) Badekar R, Phalak SD, Kale M. Pulsatile drug delivery systems: the novel approach. Int J Pharm Pharm Sci. 2024;16(2):1-11. doi:10.22159/ijpps.2024v16i2.49960.
100) Imam SS. Nanoparticles: the future of drug delivery. Int J Curr Pharm Res. 2023;15(6):8-15. doi:10.22159/ijcpr.2023v15i6.50076.
101) Xu Q, Ensign LM, Boylan NJ, Schön A, Gong X, Yang JC, et al. Impact of surface polyethylene glycol (PEG) density on biodegradable nanoparticle transport in mucus ex vivo and distribution in vivo. ACS Nano. 2015;9(9):9217-27. doi:10.1021/acsnano.5b03876.
102) Perinelli DR, Cespi M, Lorusso N, Palmieri GF, Bonacucina G, Blasi P. Surfactant self-assembling and critical micelle concentration: one approach fits all? Langmuir. 2020;36(21):5745-53. doi:10.1021/acs.langmuir.0c00420.
103) Zhang Z, Tan S, Feng SS. Vitamin E TPGS as a molecular biomaterial for drug delivery. Biomaterials. 2012;33(19):4889-906. doi:10.1016/j.biomaterials.2012.03.046.
104) Owens DE 3rd, Peppas NA. Opsonization, biodistribution, and pharmacokinetics of polymeric nanoparticles. Int J Pharm. 2006;307(1):93-102. doi:10.1016/j.ijpharm.2005.10.010.
105) Domínguez A, Fernández A, González N, Iglesias E, Montenegro L. Determination of critical micelle concentration of some surfactants by three techniques. J Chem Educ. 1997;74(10):1227-31. doi:10.1021/ed074p1227.
106) Owen SC, Chan DPY, Shoichet MS. Polymeric micelle stability. Nano Today. 2012;7(1):53-65. doi:10.1016/j.nantod.2012.01.002.
107) Torchilin VP. Micellar nanocarriers: pharmaceutical perspectives. Pharm Res. 2007;24(1):1-16. doi:10.1007/s11095-006-9132-0.
108) Meng X, Liu J, Yu X, Li J, Lu X, Shen T. Pluronic F127 and d-α-tocopheryl polyethylene glycol succinate (TPGS) mixed micelles for targeting drug delivery across the blood-brain barrier. Sci Rep. 2017;7:2964. doi:10.1038/s41598-017-03123-y.
109) Feng X, Chen Y, Li L, Zhang Y, Zhang L, Zhang Z. Preparation, evaluation and metabolites study in rats of novel amentoflavone-loaded TPGS/Soluplus mixed nanomicelles. Drug Deliv. 2020;27(1):137-50. doi:10.1080/10717544.2019.1709920.
110) Lin TY, Zhu TT, Xun Y, Tao YS, Yang YQ, Xie JL, et al. A novel drug delivery system of mixed micelles based on poly(ethylene glycol)-poly(lactide) and poly(ethylene glycol)-poly(ɛ-caprolactone) for gambogenic acid. Kaohsiung J Med Sci. 2019;35(12):757-64. doi:10.1002/kjm2.12110.
111) Mu L, Elbayoumi TA, Torchilin VP. Mixed micelles made of poly(ethylene glycol)-phosphatidylethanolamine conjugate and d-α-tocopheryl polyethylene glycol 1000 succinate as pharmaceutical nanocarriers for camptothecin. Int J Pharm. 2005;306(1-2):142-9. doi:10.1016/j.ijpharm.2005.08.026.
112) Dong K, Zhang M, Liu Y, Zhao Z, Guo L, He H, et al. Pterostilbene-loaded Soluplus/Poloxamer 188 mixed micelles for protection against acetaminophen-induced liver injury. Mol Pharm. 2023;20(2):624-39. doi:10.1021/acs.molpharmaceut.2c00881.
113) Berlinski A, Spiva J. In vitro characterization of aerosolized albuterol generated by a jet nebulizer and delivered through a heated flow nasal cannula system. Pharmaceuticals (Basel). 2022;15(10):1281. doi:10.3390/ph15101281.
114) Steckel H, Eskandar F. Factors affecting aerosol performance during nebulization with jet and ultrasonic nebulizers. Eur J Pharm Sci. 2003;19(5):443-55. doi:10.1016/S0928-0987(03)00148-9.
115) Sweeney L, McCloskey AP, Higgins G, Ramsey JM, Cryan SA, MacLoughlin R. Effective nebulization of interferon-γ using a novel vibrating mesh. Respir. Res. 2019;20(1):66. doi:10.1186/s12931-019-1030-1.
116) Islam N, Gladki E. Dry powder inhalers (DPIs): a review of device reliability and innovation. Int J Pharm. 2008;360(1-2):1-11. doi:10.1016/j.ijpharm.2008.04.044.
117) Myrdal PB, Sheth P, Stein SW. Advances in metered dose inhaler technology: formulation development. AAPS PharmSciTech. 2014;15(2):434-55. doi:10.1208/s12249-013-0063-x.
118) 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(11):1021-30. doi:10.1007/s40261-019-00835-z.
119) Pellosi DS, d’Angelo I, Maiolino S, Mitidieri E, d’Emmanuele di Villa Bianca R, Sorrentino R, et al. In vitro/in vivo investigation on the potential of Pluronic mixed micelles for pulmonary drug delivery. Eur J Pharm Biopharm. 2018;130:30-8. doi:10.1016/j.ejpb.2018.06.006.
120) Griffith DE, Eagle G, Thomson R, Aksamit TR, Hasegawa N, Morimoto K, et al. Amikacin liposome inhalation suspension for treatment-refractory lung disease caused by Mycobacterium avium complex (CONVERT): a prospective, open-label, randomized study. Am J Respir Crit Care Med. 2018;198(12):1559-69. doi:10.1164/rccm.201807-1318OC.
121) Esmaeili M, Aghajani M, Abbasalipourkabir R, Amani A. Budesonide-loaded solid lipid nanoparticles for pulmonary delivery: preparation, optimization, and aerodynamic behavior. Artif Cells Nanomed Biotechnol. 2016;44(8):1964-71. doi:10.3109/21691401.2015.1129614.
122) Amani A, York P, Chrystyn H, Clark BJ. Evaluation of a nanoemulsion-based formulation for respiratory delivery of budesonide by nebulizers. AAPS PharmSciTech. 2010;11(3):1147-51. doi:10.1208/s12249-010-9486-9.
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