Nebulised Isotonic Hydroxychloroquine Aerosols for Potential Treatment of COVID-19
Waiting Tai, Michael Yee Tak Chow, Rachel Yoon Kyung Chang, Patricia Tang, Igor Gonda, Robert B Macarthur, Hak-Kim Chan, Philip Chi Lip Kwok
Pharmaceutics, doi:10.3390/pharmaceutics13081260
The coronavirus disease 2019 (COVID-19) is an unprecedented pandemic that has severely impacted global public health and the economy. Hydroxychloroquine administered orally to COVID-19 patients was ineffective, but its antiviral and anti-inflammatory actions were observed in vitro. The lack of efficacy in vivo could be due to the inefficiency of the oral route in attaining high drug concentration in the lungs. Delivering hydroxychloroquine by inhalation may be a promising alternative for direct targeting with minimal systemic exposure. This paper reports on the characterisation of isotonic, pH-neutral hydroxychloroquine sulphate (HCQS) solutions for nebulisation for COVID-19. They can be prepared, sterilised, and nebulised for testing as an investigational new drug for treating this infection. The 20, 50, and 100 mg/mL HCQS solutions were stable for at least 15 days without refrigeration when stored in darkness. They were atomised from Aerogen Solo Ultra vibrating mesh nebulisers (1 mL of each of the three concentrations and, in addition, 1.5 mL of 100 mg/mL) to form droplets having a median volumetric diameter of 4.3-5.2 µm, with about 50-60% of the aerosol by volume < 5 µm. The aerosol droplet size decreased (from 4.95 to 4.34 µm) with increasing drug concentration (from 20 to 100 mg/mL). As the drug concentration and liquid volume increased, the nebulisation duration increased from 3 to 11 min. The emitted doses ranged from 9.1 to 75.9 mg, depending on the concentration and volume nebulised. The HCQS solutions appear suitable for preclinical and clinical studies for potential COVID-19 treatment.
Conflicts of
References
Abu-Raddad, Chemaitelly, Butt, National Study Group for COVID-19 Vaccination. Effectiveness of the BNT162b2 Covid-19 vaccine against the B.1.1.7 and B.1.351 variants, N. Engl. J. Med,
doi:10.1056/NEJMc2104974Albariqi, Chang, Tai, Ke, Chow et al., Inhalable hydroxychloroquine powders for potential treatment of COVID-19, J. Aerosol Med. Pulm. Drug Deliv,
doi:10.1089/jamp.2020.1648Beck-Broichsitter, Oesterheld, Electrolyte type and nozzle composition affect the process of vibrating-membrane nebulization, Eur. J. Pharm. Biopharm,
doi:10.1016/j.ejpb.2017.05.004Bentur, Hutt, Brassil, Bäckman, Gonda et al., Phase 1 randomized placebo-controlled study in healthy adult volunteers to evaluate the safety, tolerability, and pharmacokinetics of orally inhaled aerosolized hydroxychloroquine sulfate-A potential treatment for COVID-19, J. Allergy Clin. Immunol,
doi:10.1016/j.jaci.2020.12.011Boregowda, Gandhi, Jain, Khanna, Gupta, Comprehensive literature review and evidence evaluation of experimental treatment in COVID 19 contagion, Clin. Med. Insights Circ. Respir. Pulm. Med,
doi:10.1177/1179548420964140Chan, Kwok, Young, Chan, Traini, Mannitol delivery by vibrating mesh nebulisation for enhancing mucociliary clearance, J. Pharm. Sci,
doi:10.1002/jps.22494Chan, Traini, Chan, Young, Kwok, Delivery of high solubility polyols by vibrating mesh nebulizer to enhance mucociliary clearance, J. Aerosol Med. Pulm. Drug Deliv,
doi:10.1089/jamp.2011.0961Chang, Kwok, Ghassabian, Brannan, Koskela et al., Cough as an adverse effect on inhalation pharmaceutical products, Br. J. Pharmacol,
doi:10.1111/bph.15197Charous, Nemeth, Serebriakov, Abraham, Aerosolized hydroxychloroquine (AHCQ) protects against antigeninduced early (EAR) and late airway responses (LAR) and airway hyperresponsiveness (AHR) in allergic sheep, Am. J. Respir. Crit. Care Med
Dauby, The unfinished story of hydroxychloroquine in COVID-19: The right anti-inflammatory dose at the right moment?, Int. J. Infect. Dis,
doi:10.1016/j.ijid.2020.10.032Dayton, Owen, Cipolla, Chu, Otulana et al., Development of an inhaled hydroxychloroquine sulfate product using the AERx ® system to treat asthma
De Reus, Hagedoorn, Sturkenboom, Grasmeijer, Bolhuis et al., Tolerability and pharmacokinetic evaluation of inhaled dry powder hydroxychloroquine in healthy volunteers, meDrxiv
Desager, Van Bever, Stevens, Osmolality and pH of anti-asthmatic drug solutions, Agents Actions,
doi:10.1007/BF01997612Fan, Zhang, Liu, Yang, Zheng et al., Connecting hydroxychloroquine in vitro antiviral activity to in vivo concentration for prediction of antiviral effect: A critical step in treating COVID-19 patients, Clin. Infect. Dis,
doi:10.1093/cid/ciaa623Fantini, Di Scala, Chahinian, Yahi, Structural and molecular modelling studies reveal a new mechanism of action of chloroquine and hydroxychloroquine against SARS-CoV-2 infection, Int. J. Antimicrob. Agents,
doi:10.1016/j.ijantimicag.2020.105960Fassihi, Nabar, Fassihi, Novel approach for low-dose pulmonary delivery of hydroxychloroquine in COVID-19, Br. J. Pharmacol,
doi:10.1111/bph.15167Fink, Ehrmann, Li, Dailey, Mckiernan et al., Reducing aerosol-related risk of transmission in the era of COVID-19: An interim guidance endorsed by the International Society of Aerosols in Medicine, J. Aerosol Med. Pulm. Drug Deliv,
doi:10.1089/jamp.2020.1615Finkbeiner, Charous, Dolganov, Widdicombe, Hydroxychloroquine (HCQ) inhibits rhinovirus (RV) replication in cultured human tracheal epithelial cells, J. Allergy Clin. Immunol,
doi:10.1016/j.jaci.2004.01.416Finlay, Stapleton, Undersizing of droplets from a vented nebulizer caused by aerosol heating during transit through an Andersen impactor, J. Aerosol Sci,
doi:10.1016/S0021-8502(98)00024-XGhazanfari, Elhissi, Dong, Taylor, The influence of fluid physicochemical properties on vibrating-mesh nebulization, Int. J. Pharm,
doi:10.1016/j.ijpharm.2007.02.035Hinds, Aerosol Technology: Properties, Behavior, and Measurement of Airborne Particles
Iacobucci, Covid-19: Single vaccine dose is 33% effective against variant from India, data show, BMJ,
doi:10.1136/bmj.n1346Idkaidek, Hawari, Dodin, Obeidat, Development of a physiologically-based pharmacokinetic (PBPK) model of nebulized hydroxychloroquine for pulmonary delivery to COVID-19 patients, Drug Res
Jang, Choi, Byun, Jue, Chloroquine inhibits production of TNF-alpha, IL-1beta and IL-6 from lipopolysaccharide-stimulated human monocytes/macrophages by different modes, Rheumatology,
doi:10.1093/rheumatology/kei282Jordan, Brookes, Nikolic, Le Couteur, Hydroxychloroquine overdose: Toxicokinetics and management, Clin. Toxicol,
doi:10.1081/CLT-100102466Juul, Nielsen, Feinberg, Siddiqui, Jørgensen et al., Interventions for treatment of COVID-19: A living systematic review with meta-analyses and trial sequential analyses (The LIVING Project), PLoS Med,
doi:10.1371/journal.pmed.1003293Karlsson, Soveri, Lewandowsky, Karlsson, Karlsson et al., Fearing the disease or the vaccine: The case of COVID-19, Personal. Individ. Differ,
doi:10.1016/j.paid.2020.110590Karnad, Mhaisekar, Moralwar, Respiratory mucus pH in tracheostomized intensive care unit patients: Effects of colonization and pneumonia, Crit. Care Med,
doi:10.1097/00003246-199007000-00003Kaur, Kaushal, Kaushal, Therapeutic status of hydroxychloroquine in COVID-19: A review, J. Anaesthesiol. Clin. Pharmacol
Klimke, Hefner, Will, Voss, Hydroxychloroquine as an aerosol might markedly reduce and even prevent severe clinical symptoms after SARS-CoV-2 infection, Med. Hypotheses,
doi:10.1016/j.mehy.2020.109783Kostoff, Briggs, Porter, Spandidos, Tsatsakis, COVID-19 vaccine safety, Int. J. Mol. Med
Kwong, Ho, Coates, Comparison of nebulized particle size distribution with Malvern laser diffraction analyzer versus Andersen cascade impactor and low-flow Marple personal cascade impactor, J. Aerosol Med,
doi:10.1089/jam.2000.13.303Lammers, Brohet, Theunissen, Koster, Rood et al., Early hydroxychloroquine but not chloroquine use reduces ICU admission in COVID-19 patients, Int. J. Infect. Dis,
doi:10.1016/j.ijid.2020.09.1460Liu, Cao, Xu, Wang, Zhang et al., Hydroxychloroquine, a less toxic derivative of chloroquine, is effective in inhibiting SARS-CoV-2 infection in vitro, Cell Discov,
doi:10.1038/s41421-020-0156-0Luchsinger, Hillyer, Vaccine efficacy probable against COVID-19 variants, Science
Madhi, Baillie, Cutland, Voysey, Koen et al., Efficacy of the ChAdOx1 nCoV-19 Covid-19 vaccine against the B.1.351 variant, N. Engl. J. Med,
doi:10.1056/NEJMoa2102214Maisonnasse, Guedj, Contreras, Behillil, Solas et al., Hydroxychloroquine use against SARS-CoV-2 infection in non-human primates, Nature,
doi:10.1038/s41586-020-2558-4Martindale, The Complete Drug Reference
Mitchell, Berlinski, Canisius, Cipolla, Dolovich et al., Urgent appeal from International Society for Aerosols in Medicine (ISAM) during COVID-19: Clinical decision makers and governmental agencies should consider the inhaled route of administration: A statement from the ISAM Regulatory and Standardization Issues Networking Group, J. Aerosol. Med. Pulm. Drug Deliv
Moffat, Osselton, Widdop, Clarke's Analysis of Drugs and Poisons
Morris, Tisi, Tan, Worthington, Development and palatability assessment of Norvir ® (ritonavir) 100 mg powder for pediatric population, Int. J. Mol. Sci,
doi:10.3390/ijms20071718Pastick, Okafor, Wang, Lofgren, Skipper et al., Review: Hydroxychloroquine and chloroquine for treatment of SARS-CoV-2 (COVID-19), Open Forum Infect. Dis,
doi:10.1093/ofid/ofaa130Pauli, Joshi, Vasavada, Brackett, Towa, Evaluation of an immediate-release formulation of hydroxychloroquine sulfate with an interwoven pediatric taste-masking system, J. Pharm. Sci,
doi:10.1016/j.xphs.2019.12.014Phipps, Gonda, Droplets produced by medical nebulizers: Some factors affecting their size and solute concentration, Chest,
doi:10.1378/chest.97.6.1327Phipps, Gonda, Evaporation of aqueous aerosols produced by jet nebulizers: Effects on particle size and concentration of solution in the droplets, J. Aerosol Med,
doi:10.1089/jam.1994.7.239Schuster, Cipolla, Farr, Processes for Taste-Masking of Inhaled Formulations, U.S. Patent Application
Siemieniuk, Bartoszko, Ge, Zeraatkar, Izcovich et al., Drug treatments for covid-19: Living systematic review and network meta-analysis, BMJ,
doi:10.1136/bmj.m2980Sperber, Quraishi, Kalb, Panja, Stecher et al., Selective regulation of cytokine secretion by hydroxychloroquine: Inhibition of interleukin 1 alpha (IL-1-alpha) and IL-6 in human monocytes and T cells, J. Rheumatol
Sun, Wang, Cai, Hu, Chen et al., Cytokine storm intervention in the early stages of COVID-19 pneumonia, Cytokine Growth Factor Rev,
doi:10.1016/j.cytogfr.2020.04.002Tai, Wu, Wu, Tsai, Wang et al., A strategy to treat COVID-19 disease with targeted delivery of inhalable liposomal hydroxychloroquine: A preclinical pharmacokinetic study, Clin. Transl. Sci,
doi:10.1111/cts.12923Taylor, None
Tett, Cutler, Day, Brown, A dose-ranging study of the pharmacokinetics of hydroxy-chloroquine following intravenous administration to healthy volunteers, Br. J. Clin. Pharmacol,
doi:10.1111/j.1365-2125.1988.tb05281.xWang, Cao, Zhang, Yang, Liu et al., Remdesivir and chloroquine effectively inhibit the recently emerged novel coronavirus (2019-nCoV) in vitro, Cell Res,
doi:10.1038/s41422-020-0282-0Warhurst, Steele, Adagu, Craig, Cullander, Hydroxychloroquine is much less active than chloroquine against chloroquine-resistant Plasmodium falciparum, in agreement with its physicochemical properties, J. Antimicrob. Chemother,
doi:10.1093/jac/dkg319Yao, Ye, Zhang, Cui, Huang et al., In vitro antiviral activity and projection of optimized dosing design of hydroxychloroquine for the treatment of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), Clin. Infect. Dis,
doi:10.1093/cid/ciaa237Zander, Intrakranieller Druck und hypotone Infusionslösungen (Intracranial pressure and hypotonic infusion solutions), Anaesthesist,
doi:10.1007/s00101-009-1524-1{ 'indexed': {'date-parts': [[2024, 2, 5]], 'date-time': '2024-02-05T10:05:14Z', 'timestamp': 1707127514943},
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'abstract': '<jats:p>The coronavirus disease 2019 (COVID-19) is an unprecedented pandemic that has '
'severely impacted global public health and the economy. Hydroxychloroquine administered '
'orally to COVID-19 patients was ineffective, but its antiviral and anti-inflammatory actions '
'were observed in vitro. The lack of efficacy in vivo could be due to the inefficiency of the '
'oral route in attaining high drug concentration in the lungs. Delivering hydroxychloroquine '
'by inhalation may be a promising alternative for direct targeting with minimal systemic '
'exposure. This paper reports on the characterisation of isotonic, pH-neutral '
'hydroxychloroquine sulphate (HCQS) solutions for nebulisation for COVID-19. They can be '
'prepared, sterilised, and nebulised for testing as an investigational new drug for treating '
'this infection. The 20, 50, and 100 mg/mL HCQS solutions were stable for at least 15 days '
'without refrigeration when stored in darkness. They were atomised from Aerogen Solo Ultra '
'vibrating mesh nebulisers (1 mL of each of the three concentrations and, in addition, 1.5 mL '
'of 100 mg/mL) to form droplets having a median volumetric diameter of 4.3–5.2 µm, with about '
'50–60% of the aerosol by volume < 5 µm. The aerosol droplet size decreased (from 4.95 to '
'4.34 µm) with increasing drug concentration (from 20 to 100 mg/mL). As the drug concentration '
'and liquid volume increased, the nebulisation duration increased from 3 to 11 min. The '
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{'given': 'Igor', 'family': 'Gonda', 'sequence': 'additional', 'affiliation': []},
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'reference': [ { 'key': 'ref1',
'unstructured': 'COVID-19 Dashboard by the Center for Systems Science and Engineering '
'(CSSE) at Johns Hopkins University '
'(JHU)https://coronavirus.jhu.edu/map.html'},
{'key': 'ref2', 'doi-asserted-by': 'publisher', 'DOI': '10.1016/j.clim.2020.108634'},
{'key': 'ref3', 'doi-asserted-by': 'publisher', 'DOI': '10.1038/s41586-020-2798-3'},
{'key': 'ref4', 'doi-asserted-by': 'publisher', 'DOI': '10.1016/S0140-6736(20)31976-0'},
{ 'key': 'ref5',
'first-page': '1599',
'article-title': 'COVID-19 vaccine safety',
'volume': '46',
'author': 'Kostoff',
'year': '2020',
'journal-title': 'Int. J. Mol. Med.'},
{'key': 'ref6', 'doi-asserted-by': 'publisher', 'DOI': '10.1016/j.paid.2020.110590'},
{'key': 'ref7', 'doi-asserted-by': 'publisher', 'DOI': '10.1136/bmj.n359'},
{'key': 'ref8', 'doi-asserted-by': 'publisher', 'DOI': '10.1136/bmj.n1346'},
{'key': 'ref9', 'doi-asserted-by': 'publisher', 'DOI': '10.1056/NEJMc2104974'},
{ 'key': 'ref10',
'doi-asserted-by': 'crossref',
'first-page': '1116',
'DOI': '10.1126/science.abg9461',
'article-title': 'Vaccine efficacy probable against COVID-19 variants',
'volume': '371',
'author': 'Luchsinger',
'year': '2021',
'journal-title': 'Science'},
{'key': 'ref11', 'doi-asserted-by': 'publisher', 'DOI': '10.1056/NEJMoa2102214'},
{'key': 'ref12'},
{ 'key': 'ref13',
'unstructured': 'Treatments and Vaccines for COVID-19: Authorised '
'Medicineshttps://www.ema.europa.eu/en/human-regulatory/overview/public-health-threats/coronavirus-disease-covid-19/treatments-vaccines/treatments-covid-19/covid-19-treatments-authorised'},
{'key': 'ref14'},
{ 'key': 'ref15',
'unstructured': 'Assessment of Evidence for COVID-19-Related '
'Treatmentshttps://www.ashp.org/-/media/assets/pharmacy-practice/resource-centers/Coronavirus/docs/ASHP-COVID-19-Evidence-Table.ashx'},
{'key': 'ref16', 'doi-asserted-by': 'publisher', 'DOI': '10.1208/s12248-020-00532-2'},
{'key': 'ref17', 'doi-asserted-by': 'publisher', 'DOI': '10.1136/bmj.m2980'},
{'key': 'ref18', 'doi-asserted-by': 'publisher', 'DOI': '10.1177/1179548420964140'},
{'key': 'ref19', 'doi-asserted-by': 'publisher', 'DOI': '10.1371/journal.pmed.1003293'},
{'key': 'ref20', 'doi-asserted-by': 'publisher', 'DOI': '10.1093/jac/dkg319'},
{'key': 'ref21', 'series-title': 'Martindale: The Complete Drug Reference', 'year': '2021'},
{ 'key': 'ref22',
'series-title': 'Clarke’s Analysis of Drugs and Poisons',
'author': 'Moffat',
'year': '2003'},
{ 'key': 'ref23',
'doi-asserted-by': 'publisher',
'DOI': '10.1111/j.1365-2125.1989.tb03439.x'},
{ 'key': 'ref24',
'doi-asserted-by': 'crossref',
'first-page': 'S160',
'DOI': '10.4103/joacp.JOACP_313_20',
'article-title': 'Therapeutic status of hydroxychloroquine in COVID-19: A review',
'volume': '36',
'author': 'Kaur',
'year': '2020',
'journal-title': 'J. Anaesthesiol. Clin. Pharmacol.'},
{'key': 'ref25', 'doi-asserted-by': 'publisher', 'DOI': '10.1016/j.mehy.2020.109783'},
{'key': 'ref26', 'doi-asserted-by': 'publisher', 'DOI': '10.1038/s41422-020-0282-0'},
{'key': 'ref27', 'doi-asserted-by': 'publisher', 'DOI': '10.1093/cid/ciaa237'},
{'key': 'ref28', 'doi-asserted-by': 'publisher', 'DOI': '10.1038/s41421-020-0156-0'},
{'key': 'ref29', 'doi-asserted-by': 'publisher', 'DOI': '10.1016/j.ijantimicag.2020.105960'},
{'key': 'ref30', 'doi-asserted-by': 'publisher', 'DOI': '10.1093/ofid/ofaa130'},
{'key': 'ref31', 'doi-asserted-by': 'publisher', 'DOI': '10.1152/physrev.00020.2020'},
{'key': 'ref32', 'doi-asserted-by': 'publisher', 'DOI': '10.1016/j.cytogfr.2020.04.002'},
{ 'key': 'ref33',
'first-page': '803',
'article-title': 'Selective regulation of cytokine secretion by hydroxychloroquine: '
'Inhibition of interleukin 1 alpha (IL-1-alpha) and IL-6 in human '
'monocytes and T cells',
'volume': '20',
'author': 'Sperber',
'year': '1993',
'journal-title': 'J. Rheumatol.'},
{'key': 'ref34', 'doi-asserted-by': 'publisher', 'DOI': '10.1093/rheumatology/kei282'},
{'key': 'ref35', 'doi-asserted-by': 'publisher', 'DOI': '10.1016/j.ijid.2020.10.032'},
{'key': 'ref36', 'doi-asserted-by': 'publisher', 'DOI': '10.1016/j.ijid.2020.09.1460'},
{'key': 'ref37', 'doi-asserted-by': 'publisher', 'DOI': '10.1038/s41586-020-2558-4'},
{ 'key': 'ref38',
'doi-asserted-by': 'publisher',
'DOI': '10.1111/j.1365-2125.1988.tb05281.x'},
{ 'key': 'ref39',
'first-page': 'A859',
'article-title': 'Aerosolized hydroxychloroquine (AHCQ) protects against antigen-induced '
'early (EAR) and late airway responses (LAR) and airway '
'hyperresponsiveness (AHR) in allergic sheep',
'volume': '163',
'author': 'Charous',
'year': '2001',
'journal-title': 'Am. J. Respir. Crit. Care Med.'},
{ 'key': 'ref40',
'series-title': 'Respiratory Drug Delivery 2006',
'first-page': '429',
'article-title': 'Development of an inhaled hydroxychloroquine sulfate product using the '
'AERx® system to treat asthma',
'volume': 'Volume 2',
'author': 'Dayton',
'year': '2006'},
{'key': 'ref41', 'doi-asserted-by': 'publisher', 'DOI': '10.1016/j.jaci.2004.01.416'},
{'key': 'ref42', 'doi-asserted-by': 'publisher', 'DOI': '10.1111/bph.15167'},
{'key': 'ref43', 'doi-asserted-by': 'publisher', 'DOI': '10.1089/jamp.2020.1648'},
{ 'key': 'ref44',
'doi-asserted-by': 'crossref',
'first-page': '235',
'DOI': '10.1089/jamp.2020.1622',
'article-title': 'Urgent appeal from International Society for Aerosols in Medicine '
'(ISAM) during COVID-19: Clinical decision makers and governmental '
'agencies should consider the inhaled route of administration: A '
'statement from the ISAM Regulatory and Standardization Issues '
'Networking Group',
'volume': '33',
'author': 'Mitchell',
'year': '2020',
'journal-title': 'J. Aerosol. Med. Pulm. Drug Deliv.'},
{'key': 'ref45', 'doi-asserted-by': 'publisher', 'DOI': '10.1093/cid/ciaa623'},
{'key': 'ref46', 'doi-asserted-by': 'publisher', 'DOI': '10.1111/bph.15197'},
{ 'key': 'ref47',
'first-page': '12.03.20243162',
'article-title': 'Tolerability and pharmacokinetic evaluation of inhaled dry powder '
'hydroxychloroquine in healthy volunteers',
'author': 'de Reus',
'year': '2020',
'journal-title': 'meDrxiv'},
{'key': 'ref48', 'doi-asserted-by': 'publisher', 'DOI': '10.1016/j.jaci.2020.12.011'},
{ 'key': 'ref49',
'series-title': 'K-7000 Vapor Pressure Osmometer User Manual V7109',
'year': '2007'},
{'key': 'ref50', 'doi-asserted-by': 'publisher', 'DOI': '10.1016/j.addr.2014.08.013'},
{ 'key': 'ref51',
'doi-asserted-by': 'publisher',
'DOI': '10.1111/j.1365-2125.1988.tb03305.x'},
{ 'key': 'ref52',
'series-title': 'United States Pharmacopeia 43—National Formulary 38',
'year': '2020'},
{'key': 'ref53', 'series-title': 'CRC Handbook of Chemistry and Physics', 'year': '2020'},
{ 'key': 'ref54',
'series-title': 'Aerosol Technology: Properties, Behavior, and Measurement of Airborne '
'Particles',
'author': 'Hinds',
'year': '1999'},
{ 'key': 'ref55',
'series-title': 'Guidance for Industry—Q2B Validation of Analytical Procedures: '
'Methodology',
'year': '1996'},
{'key': 'ref56', 'doi-asserted-by': 'publisher', 'DOI': '10.1378/chest.97.6.1327'},
{'key': 'ref57', 'doi-asserted-by': 'publisher', 'DOI': '10.1089/jam.1994.7.239'},
{'key': 'ref58'},
{'key': 'ref59', 'doi-asserted-by': 'publisher', 'DOI': '10.1016/j.xphs.2019.12.014'},
{'key': 'ref60', 'doi-asserted-by': 'publisher', 'DOI': '10.3390/ijms20071718'},
{'key': 'ref61'},
{'key': 'ref62', 'doi-asserted-by': 'publisher', 'DOI': '10.1111/cts.12923'},
{'key': 'ref63', 'series-title': 'Aerogen® Solo System Instruction Manual', 'year': '2016'},
{'key': 'ref64', 'doi-asserted-by': 'publisher', 'DOI': '10.3390/pharmaceutics12100971'},
{'key': 'ref65', 'doi-asserted-by': 'publisher', 'DOI': '10.1089/jamp.2020.1615'},
{'key': 'ref66', 'doi-asserted-by': 'publisher', 'DOI': '10.1007/BF01997612'},
{'key': 'ref67', 'doi-asserted-by': 'publisher', 'DOI': '10.1007/s00101-009-1524-1'},
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