Liposomal carrier systems have emerged as a promising technology for pulmonary drug delivery. This study focuses on two selected liposomal systems, namely, dipalmitoylphosphatidylcholine stabilized by phosphatidic acid and cholesterol (DPPC-PA-Chol) and dipalmitoylphosphatidylcholine stabilized by polyethylene glycol and cholesterol (DPPC-PEG-Chol). First, the research investigates the stability of these liposomal systems during the atomization process using different kinds of nebulizers (air-jet, vibrating mesh, and ultrasonic). The study further explores the aerodynamic particle size distribution of the aerosol generated by the nebulizers. The nebulizer that demonstrated optimal stability and particle size was selected for more detailed investigation, including Andersen cascade impactor measurements, an assessment of the influence of flow rate and breathing profiles on aerosol particle size, and an in vitro deposition study on a realistic replica of the upper airways. The most suitable combination of a nebulizer and liposomal system was DPPC-PA-Chol nebulized by a Pari LC Sprint Star in terms of stability and particle size. The influence of the inspiration flow rate on the particle size was not very strong but was not negligible either (decrease of Dv50 by 1.34 μm with the flow rate increase from 8 to 60 L/min). A similar effect was observed for realistic transient inhalation. According to the in vitro deposition measurement, approximately 90% and 70% of the aerosol penetrated downstream of the trachea using the stationary flow rate and the realistic breathing profile, respectively. These data provide an image of the potential applicability of liposomal carrier systems for nebulizer therapy. Regional lung drug deposition is patient-specific; therefore, deposition results might vary for different airway geometries. However, deposition measurement with realistic boundary conditions (airway geometry, breathing profile) brings a more realistic image of the drug delivery by the selected technology. Our results show how much data from cascade impactor testing or estimates from the fine fraction concept differ from those of a more realistic case.

Department of Thermodynamics and Environmental Engineering Faculty of Mechanical Engineering Brno University of Technology Technicka 2896 2 616 69 Brno Czech Republic

Institute of Physical and Applied Chemistry Faculty of Chemistry Brno University of Technology Purkyňova 464 118 Královo Pole 612 00 Brno Czech Republic

Zobrazit více v PubMed

Pilcer G.; Amighi K. Formulation strategy and use of excipients in pulmonary drug delivery. Int. J. Pharm. 2010, 392, 1–19. 10.1016/j.ijpharm.2010.03.017. PubMed DOI

Misra A.; Jinturkar K.; Patel D.; et al. Recent advances in liposomal dry powder formulations: preparation and evaluation. Expert Opin Drug Deliv 2009, 6, 71–89. 10.1517/17425240802652309. PubMed DOI

Elhissi A. Liposomes for Pulmonary Drug Delivery: The Role of Formulation and Inhalation Device Design. Curr. Pharm. Des 2017, 23, 362–372. 10.2174/1381612823666161116114732. PubMed DOI

Patton J. S.; Byron P. R. Inhaling medicines: Delivering drugs to the body through the lungs. Nat. Rev. Drug Discov 2007, 6, 67–74. 10.1038/nrd2153. PubMed DOI

Cipolla D.; Gonda I.; Chan H.-K. Liposomal formulations for inhalation. Ther Deliv 2013, 4, 1047–1072. 10.4155/tde.13.71. PubMed DOI

Szabová J.; Mišík O.; Fučík J.; Mrázová K.; Mravcová L.; Elcner J.; Lízal F.; Krzyžánek V.; Mravec F. Liposomal form of erlotinib for local inhalation administration and efficiency of its transport to the lungs. Int. J. Pharmaceutics 2023, 634, 122695.10.1016/j.ijpharm.2023.122695. PubMed DOI

Anabousi S.; Kleemann E.; Bakowsky U.; et al. Effect of PEGylation on the Stability of Liposomes During Nebulisation and in Lung Surfactant. J. Nanosci Nanotechnol 2006, 6, 3010–3016. 10.1166/jnn.2006.461. PubMed DOI

Zhang T.; Chen Y.; Ge Y.; et al. Inhalation treatment of primary lung cancer using liposomal curcumin dry powder inhalers. Acta Pharm. Sin B 2018, 8, 440–448. 10.1016/j.apsb.2018.03.004. PubMed DOI PMC

Rudokas M.; Najlah M.; Alhnan M. A.; et al. Liposome Delivery Systems for Inhalation: A Critical Review Highlighting Formulation Issues and Anticancer Applications. Med. Princ Pract 2016, 25, 60–72. 10.1159/000445116. PubMed DOI PMC

Lamichhane N.; Udayakumar T. S.; D’Souza W. D.; Simone C. II; Raghavan S.; Polf J.; Mahmood J. Liposomes: Clinical applications and potential for image-guided drug delivery. Molecules 2018, 23, 288.10.3390/molecules23020288. PubMed DOI PMC

Tseng W. C.; Huang L. Liposome-based gene therapy. Pharm. Sci. Technol. Today 1998, 1, 206–213. 10.1016/S1461-5347(98)00054-6. DOI

Kraft J. C.; Freeling J. P.; Wang Z.; et al. Emerging Research and Clinical Development Trends of Liposome and Lipid Nanoparticle Drug Delivery Systems. J. Pharm. Sci. 2014, 103, 29–52. 10.1002/jps.23773. PubMed DOI PMC

Large D. E.; Abdelmessih R. G.; Fink E. A.; et al. Liposome composition in drug delivery design, synthesis, characterization, and clinical application. Adv. Drug Deliv Rev. 2021, 176, 113851.10.1016/j.addr.2021.113851. PubMed DOI

Sercombe L.; Veerati T.; Moheimani F.; Wu S. Y.; Sood A. K.; Hua S. Advances and Challenges of Liposome Assisted Drug Delivery. Front. Pharmacol. 2015, 6, 286.10.3389/fphar.2015.00286. PubMed DOI PMC

Gilbert B. E.; Knight C.; Alvarez F. G.; et al. Tolerance of Volunteers to Cyclosporine A-dilauroylphosphatidylcholine Liposome Aerosol. Am. J. Respir Crit Care Med. 1997, 156, 1789–1793. 10.1164/ajrccm.156.6.9702101. PubMed DOI

Beltrán-Gracia E.; López-Camacho A.; Higuera-Ciapara I.; Velázquez-Fernández J. B.; Vallejo-Cardona A. A. Nanomedicine review: clinical developments in liposomal applications. Cancer Nanotechnol. 2019, 10, 11.10.1186/s12645-019-0055-y. DOI

Lehofer B.; Bloder F.; Jain P. P.; et al. Impact of atomization technique on the stability and transport efficiency of nebulized liposomes harboring different surface characteristics. Eur. J. Pharm. Biopharm 2014, 88, 1076–1085. 10.1016/j.ejpb.2014.10.009. PubMed DOI

Elhissi A.; Gill H.; Ahmed W.; et al. Vibrating-mesh nebulization of liposomes generated using an ethanol-based proliposome technology. J. Liposome Res. 2011, 21, 173–180. 10.3109/08982104.2010.505574. PubMed DOI

Hickey A. J.Pharmaceutical Inhalation Aerosol Technology; CRC Press, 2019.

Ari A. Jet, Ultrasonic, and Mesh Nebulizers: An Evaluation of Nebulizers for Better Clinical Outcomes. Eurasian J. Pulmonol 2014, 16, 1–7. 10.5152/ejp.2014.00087. DOI

Taffet G. E.; Donohue J. F.; Altman P. R. Clinical Interventions in Aging Dovepress Considerations for managing chronic obstructive pulmonary disease in the elderly. Clin Interv Aging 2013, 9, 23–30. 10.2147/CIA.S52999. PubMed DOI PMC

Nerbrink O. Nebulizers: Past to present platforms and future possibilities. Inhalation 2016, 10, 1–6.

Pritchard J. N.; Hatley R. H.; Denyer J.; et al. Mesh nebulizers have become the first choice for new nebulized pharmaceutical drug developments. Ther Deliv 2018, 9, 121–136. 10.4155/tde-2017-0102. PubMed DOI

Szabová J.; Mišík O.; Havlíková M.; Lízal F.; Mravec F. Influence of liposomes composition on their stability during the nebulization process by vibrating mesh nebulizer. Colloids Surf., B 2021, 204, 111793.10.1016/j.colsurfb.2021.111793. PubMed DOI

Zaru M.; Manca M.-L.; Fadda A. M.; et al. Chitosan-coated liposomes for delivery to lungs by nebulisation. Colloids Surfaces B Biointerfaces 2009, 71, 88–95. 10.1016/j.colsurfb.2009.01.010. PubMed DOI

Lehofer B.; Bloder F.; Jain P. P.; et al. Impact of atomization technique on the stability and transport efficiency of nebulized liposomes harboring different surface characteristics. Eur. J. Pharm. Biopharm 2014, 88, 1076–1085. 10.1016/j.ejpb.2014.10.009. PubMed DOI

European Pharmacopoeia 2.9.18. Preparations for inhalation: Aerodynamic assessment of fine particles. In European Pharmacopoeia, 5th ed.; Council of Europe, European Pharmacopoeia Commission, European Directorate for the Quality of Medicines & Healthcare, 2005; pp 2799–2811.

Chaurasiya B.; Zhao Y. Y. Dry powder for pulmonary delivery: A comprehensive review. Pharmaceutics 2021, 13, 31.10.3390/pharmaceutics13010031. PubMed DOI PMC

Malcolmson R. J.; Embleton J. K. Dry powder formulations for pulmonary delivery. Pharm. Sci. Technol. Today 1998, 1, 394–398. 10.1016/S1461-5347(98)00099-6. DOI

Haughney J.; Price D.; Barnes N. C.; et al. Choosing inhaler devices for people with asthma: Current knowledge and outstanding research needs. Respir Med. 2010, 104, 1237–1245. 10.1016/j.rmed.2010.04.012. PubMed DOI

Chow A. H. L.; Tong H. H. Y.; Chattopadhyay P.; et al. Particle engineering for pulmonary drug delivery. Pharm. Res. 2007, 24, 411–437. 10.1007/s11095-006-9174-3. PubMed DOI

Williams R. O.; Carvalho T. C.; Peters J. I. Influence of particle size on regional lung deposition - What evidence is there?. Int. J. Pharm. 2011, 406, 1–10. 10.1016/j.ijpharm.2010.12.040. PubMed DOI

Newman S. P.; Chan H. K. In vitro/in vivo comparisons in pulmonary drug delivery. J. Aerosol Med. Pulm Drug Deliv 2008, 21, 77–84. 10.1089/jamp.2007.0643. PubMed DOI

Glover W.; Chan H. K.; Eberl S.; et al. Lung deposition of mannitol powder aerosol in healthy subjects. J. Aerosol Med. Depos Clear Eff Lung 2006, 19, 522–532. 10.1089/jam.2006.19.522. PubMed DOI

Darquenne C. Aerosol deposition in health and disease. J. Aerosol Med. Pulm Drug Deliv 2012, 25, 140–147. 10.1089/jamp.2011.0916. PubMed DOI PMC

Hinds W. C.Aerosol Technology: Properties, Behavior, and Measurement of Airborne Particles, 2nd ed.; Wiley: New York, 1999.

Storey-Bishoff J.; Noga M.; Finlay W. H. Deposition of micrometer-sized aerosol particles in infant nasal airway replicas. J. Aerosol Sci. 2008, 39, 1055–1065. 10.1016/j.jaerosci.2008.07.011. DOI

Darquenne C.; Prisk K. G. Deposition of inhaled particles in the human lung is more peripheral in lunar than in normal gravity. Eur. J. Appl. Physiol 2008, 103, 687–695. 10.1007/s00421-008-0766-y. PubMed DOI

Mitchell J.; Newman S.; Chan H.-K. In vitro and in vivo aspects of cascade impactor tests and inhaler performance: A review. AAPS PharmSciTech 2007, 8, 237–248. 10.1208/pt0804110. PubMed DOI PMC

Kaul H. Respiratory healthcare by design: Computational approaches bringing respiratory precision and personalised medicine closer to bedside. Morphologie 2019, 103, 194–202. 10.1016/j.morpho.2019.10.042. PubMed DOI

Wittgen B. P.H.; Kunst P. W.A.; van der Born K.; van Wijk A. W.; Perkins W.; Pilkiewicz F. G.; Perez-Soler R.; Nicholson S.; Peters G. J.; Postmus P. E. Phase I study of aerosolized SLIT cisplatin in the treatment of patients with carcinoma of the lung. Clin. Cancer Res. 2007, 13, 2414–2421. 10.1158/1078-0432.CCR-06-1480. PubMed DOI

Verschraegen C. F.; Gilbert B. E.; Loyer E.; et al. Clinical Evaluation of the Delivery and Safety of Aerosolized Liposomal 9-Nitro-20(S)-Camptothecin in Patients with Advanced Pulmonary Malignancies. Clin. Cancer Res. 2004, 10, 2319–2326. 10.1158/1078-0432.CCR-0929-3. PubMed DOI

Moradpour Z.; Barghi L. Novel Approaches for Efficient Delivery of Tyrosine Kinase Inhibitors. J. Pharm. Pharm. Sci. 2018, 22, 37–48. 10.18433/jpps29891. PubMed DOI

Elhissi A. M. A.; Taylor K. M. G. Delivery of liposomes generated from proliposomes using air-jet, ultrasonic, and vibrating-mesh nebulisers. J. Drug Deliv Sci. Technol. 2005, 15, 261–265. 10.1016/S1773-2247(05)50047-9. DOI

Leung K. K. M.; Bridges P. A.; Taylor K. M. G. The stability of liposomes to ultrasonic nebulisation. Int. J. Pharm. 1996, 145, 95–102. 10.1016/S0378-5173(96)04730-8. DOI

Young P, Ong H. X., Traini D.. Liposomes for Inhalation. In The ISAM Textbook of Aerosol Medicine; International Society of Aerosols in Medicine (ISAM)/Mary Ann Libert Publishing, Inc., 2015; pp 303–329.

Finlay W. H.; Wong J. P. Regional lung deposition of nebulized liposome-encapsulated ciprofloxacin. Int. J. Pharm. 1998, 167, 121–127. 10.1016/S0378-5173(98)00055-6. DOI

Hu J.; Zhang R.; Beng H.; et al. Effects of flow pattern, device and formulation on particle size distribution of nebulized aerosol. Int. J. Pharm. 2019, 560, 35–46. 10.1016/j.ijpharm.2019.01.025. PubMed DOI

Dobrowolska K.; Sosnowski T. R. Evolution of droplet size distribution in selected nebulizers. Physicochem Probl Miner Process 2020, 56, 32–40. 10.37190/ppmp/126312. DOI

Liu Q.; Guan J.; Qin L.; et al. Physicochemical properties affecting the fate of nanoparticles in pulmonary drug delivery. Drug Discov Today 2020, 25, 150–159. 10.1016/j.drudis.2019.09.023. PubMed DOI

Bernhard W. Lung surfactant: Function and composition in the context of development and respiratory physiology. Ann. Anat 2016, 208, 146–150. 10.1016/j.aanat.2016.08.003. PubMed DOI

Niven R. W.; Schreier H. Nebulization of liposomes. I. Effects of lipid composition. Pharm. Res. 1990, 7, 1127–1133. 10.1023/A:1015924124180. PubMed DOI

Wang Y.; Li J.; Leavey A.; et al. Comparative Study on the Size Distributions, Respiratory Deposition, and Transport of Particles Generated from Commonly Used Medical Nebulizers. J. Aerosol Med. Pulm Drug Deliv 2017, 30, 132–140. 10.1089/jamp.2016.1340. PubMed DOI

Finlay W. H.The Mechanics of Inhaled Pharmaceutical Aerosols; Academic Press, 2001.

Roy M.; Courtay C. Daily activities and breathing parameters for use in respiratory tract dosimetry. Radiat. Prot. Dosim. 1991, 35, 179–186. 10.1093/oxfordjournals.rpd.a080947. DOI

Lizal F.; Elcner J.; Hopke P. K.; et al. Development of a realistic human airway model. Proc. Inst Mech Eng. Part H J. Eng. Med. 2012, 226, 197–207. 10.1177/0954411911430188. PubMed DOI

Zhou Y.; Cheng Y. S. Particle deposition in a cast of human tracheobronchial airways. Aerosol Sci. Technol. 2005, 39, 492–500. 10.1080/027868291001385. DOI

Farkas A.; Lizal F.; Jedelsky J.; Elcner J.; Karas J.; Belka M.; Misik O.; Jicha M. The role of the combined use of experimental and computational methods in revealing the differences between the micron-size particle deposition patterns in healthy and asthmatic subjects. J. Aerosol Sci. 2020, 147, 105582.10.1016/j.jaerosci.2020.105582. DOI

Jedelsky J.; Belka M.; Jícha M.; Lizal F.. Breathing simulator. CZ 306136 B6, 2016.

Copley M. Improving the realism and relevance of mouth-throat models for inhaled product testing. ONdrugDelivery 2015, 32–37.

Berkenfeld K.; Hauschild K.; McConville J. T.; et al. Cascade Impactor Performance of Commercial pMDI Formulations Using Modified Induction Ports. Mol. Pharmaceutics 2020, 17, 1491–1501. 10.1021/acs.molpharmaceut.9b01171. PubMed DOI

Mitchell J.; Copley M.; Sizer Y.; et al. Adapting the Abbreviated Impactor Measurement (AIM) concept to make appropriate inhaler aerosol measurements to compare with clinical data: A scoping study with the ‘alberta’ idealized throat (AIT) inlet. J. Aerosol Med. Pulm Drug Deliv 2012, 25, 188–197. 10.1089/jamp.2011.0925. PubMed DOI

Lizal F.; Belka M.; Adam J.; et al. A method for in vitro regional aerosol deposition measurement in a model of the human tracheobronchial tree by the positron emission tomography. Proc. Inst Mech Eng. Part H J. Eng. Med. 2015, 229, 750–757. 10.1177/0954411915600005. PubMed DOI

Heyder J.; Gebhart J.; Rudolf G.; et al. Deposition of particles in the human respiratory tract in the size range 0.005–15 μm. J. Aerosol Sci. 1986, 17, 811–825. 10.1016/0021-8502(86)90035-2. DOI

Häussermann S.; Sommerer K.; Scheuch G. Regional Lung Deposition in Vivo Data. J. Aerosol Med. Pulm Drug Deliv 2020, 33, 291–299. 10.1089/jamp.2020.29032.sh. PubMed DOI

Chan T. L.; Lippmann M. Experimental measurements and empirical modelling of the regional deposition of inhaled particles in humans. Am. Ind. Hyg Assoc J. 1980, 41, 399–409. 10.1080/15298668091424942. PubMed DOI

Lippmann M.; Albert R. E. The Effect of Particle Size on the Regional Deposition of Inhaled Aerosols in the Human Respiratory Tract. Am. Ind. Hyg Assoc J. 1969, 30, 257–275. 10.1080/00028896909343120. PubMed DOI

Golshahi L.; Noga M. L.; Vehring R.; et al. An in vitro study on the deposition of micrometer-sized particles in the extrathoracic airways of adults during tidal oral breathing. Ann. Biomed Eng. 2013, 41, 979–989. 10.1007/s10439-013-0747-0. PubMed DOI