The Potential Use of Cyclosporine Ultrafine Solution Pressurised Metered-
Dose Inhaler in the Treatment of COVID-19 Patients

Touraj       Ehtezazi
Abstract

Introduction: Serious COVID-19 respiratory problems start when the virus reaches the alveolar level, where type II cells get infected and die. Therefore, virus inhibition at the alveolar level would help preventing these respiratory complications.
Method: A literature search was conducted to collect physicochemical properties of small molecule compounds that could be used for the COVID-19 treatment. Compounds with low melting points were selected along with those soluble in ethanol, hydrogen-bond donors, and acceptors.
Results: There are severe acute respiratory syndrome coronavirus inhibitors with physicochemical properties suitable for the formulation as an ultrafine pressurised metered-dose inhaler (pMDI). Mycophenolic acid, Debio 025, and cyclosporine A are prime candidates among these compounds. Cyclosporine A (hereafter cyclosporine) is a potent SARS-CoV-2 inhibitor, and it has been used for the treatment of COVID-19 patients, demonstrating an improved survival rate. Also, inhalation therapy of nebulised cyclosporine was tolerated, which was used for patients with lung transplants. Finally, cyclosporine has been formulated as a solution ultrafine pMDI. Although vaccine therapy has started in most countries, inhalation therapies with non-immunological activities could minimise the spread of the disease and be used in vaccine-hesitant individuals.
Conclusion: Ultrafine pMDI formulation of cyclosporine or Debio 025 should be investigated for the inhalation therapy of COVID-19.
Keywords: COVID-19, cyclosporine A, inhalation, pressurised metered-dose inhaler, regulatory tests, approved drugs.
[1] 
Codagnone C, Bogliacino F, Gómez C, et al. Assessing concerns for the economic consequence of the COVID-19 response and mental health problems associated with economic vulnerability and negative economic shock in Italy, Spain, and the United Kingdom. PLoS One  2020; 15(10): e0240876.
[http://dx.doi.org/10.1371/journal.pone.0240876] [PMID: 33108374] 
[2] 
V’kovski P, Kratzel A, Steiner S, Stalder H, Thiel V. Coronavirus biology and replication: Implications for SARS-CoV-2. Nat Rev Microbiol  2021; 19(3): 155-70.
[http://dx.doi.org/10.1038/s41579-020-00468-6] [PMID: 33116300] 
[3] 
Thunders M, Delahunt B. Gene of the month: TMPRSS2 (transmembrane serine protease 2). J Clin Pathol  2020; 73(12): 773-6.
[http://dx.doi.org/10.1136/jclinpath-2020-206987] [PMID: 32873700] 
[4] 
Paoloni-Giacobino A, Chen H, Peitsch MC, Rossier C, Antonarakis SE. Cloning of the TMPRSS2 gene, which encodes a novel serine protease with transmembrane, LDLRA, and SRCR domains and maps to 21q22.3. Genomics  1997; 44(3): 309-20.
[http://dx.doi.org/10.1006/geno.1997.4845] [PMID: 9325052] 
[5] 
Hoffmann M, Schroeder S, Kleine-Weber H, Müller MA, Drosten C, Pöhlmann S. Nafamostat mesylate blocks activation of SARS-CoV-2: New treatment option for COVID-19. Antimicrob Agents Chemother  2020; 64(6): e00754-20.
[http://dx.doi.org/10.1128/AAC.00754-20] [PMID: 32312781] 
[6] 
Tanaka Y, Sato Y, Sasaki T. Suppression of coronavirus replication by cyclophilin inhibitors. Viruses  2013; 5(5): 1250-60.
[http://dx.doi.org/10.3390/v5051250] [PMID: 23698397] 
[7] 
Dittmar M, Lee JS, Whig K, et al. Drug repurposing screens reveal FDA approved drugs active against SARS-Cov-2. bioRxiv  2020; 2020.06.19.161042.
[8] 
Softic L, Brillet R, Berry F, et al. Inhibition of SARS-CoV-2 infection by the cyclophilin inhibitor alisporivir (Debio 025). Antimicrob Agents Chemother  2020; 64(7): e00876-20.
[http://dx.doi.org/10.1128/AAC.00876-20] [PMID: 32376613] 
[9] 
Polack FP, Thomas SJ, Kitchin N, et al. Safety and efficacy of the BNT162b2 mRNA Covid-19 vaccine. N Engl J Med  2020; 383(27): 2603-15.
[http://dx.doi.org/10.1056/NEJMoa2034577] [PMID: 33301246] 
[10] 
Voysey M, Costa Clemens SA, Madhi SA, et al. Single-dose administration and the influence of the timing of the booster dose on immunogenicity and efficacy of ChAdOx1 nCoV-19 (AZD1222) vaccine: A pooled analysis of four randomised trials. Lancet  2021; 397(10277): 881-91.
[http://dx.doi.org/10.1016/S0140-6736(21)00432-3] [PMID: 33617777] 
[11] 
Baden LR, El Sahly HM, Essink B, et al. Efficacy and safety of the mRNA-1273 SARS-CoV-2 vaccine. N Engl J Med  2021; 384(5): 403-16.
[http://dx.doi.org/10.1056/NEJMoa2035389] [PMID: 33378609] 
[12] 
Blumenthal KG, Freeman EE, Saff RR, et al. Delayed large local reactions to mRNA-1273 vaccine against SARS-CoV-2. N Engl J Med  2021; 384(13): 1273-7.
[http://dx.doi.org/10.1056/NEJMc2102131] [PMID: 33657292] 
[13] 
Burki TK. Challenges in the rollout of COVID-19 vaccines worldwide. Lancet Respir Med  2021; 9(4): e42-3.
[http://dx.doi.org/10.1016/S2213-2600(21)00129-6] [PMID: 33684355] 
[14] 
SteelFisher GK, Blendon RJ, Caporello H. An uncertain public -encouraging acceptance of covid-19 vaccines. N Engl J Med  2021; 384(16): 1483-7.
[15] 
Mullur J, Wang A, Feldweg A. A fatal case of coronavirus disease 2019 in a patient with common variable immunodeficiency. Ann Allergy Asthma Immunol  2021; 126(1): 90-2.
[PMID: 33880776] 
[16] 
Kemp SA, Collier DA, Datir R, et al. Neutralising antibodies in Spike mediated SARS-CoV-2 adaptation. medRxiv 2020.
[http://dx.doi.org/10.1101/2020.12.05.20241927] 
[17] 
Weisblum Y, Schmidt F, Zhang F, et al. Escape from neutralizing antibodies by SARS-CoV-2 spike protein variants. eLife  2020; 9: 9.
[http://dx.doi.org/10.7554/eLife.61312] [PMID: 33112236] 
[18] 
Korber B, Fischer WM, Gnanakaran S, et al. Tracking changes in SARS-CoV-2 spike: evidence that D614G increases infectivity of the COVID-19 virus. Cell  2020; 182(4): 812-27.
[http://dx.doi.org/10.1016/j.cell.2020.06.043] [PMID: 32697968] 
[19] 
Hou YJ, Chiba S, Halfmann P, et al. SARS-CoV-2 D614G variant exhibits efficient replication ex vivo and transmission in vivo. Science  2020; 370(6523): 1464-8.
[http://dx.doi.org/10.1126/science.abe8499] [PMID: 33184236] 
[20] 
Wang P, Nair MS, Liu L, et al. Antibody resistance of SARS-CoV-2 variants B.1.351 and B.1.1.7. Nature  2021; 593(7857): 130-5.
[http://dx.doi.org/10.1038/s41586-021-03398-2] [PMID: 33684923] 
[21] 
Volz E, Mishra S, Chand M, et al. Transmission of SARS-CoV-2 Lineage B.1.1.7 in England: Insights from linking epidemiological and genetic data. medRxiv  2021; 2020.12.30.20249034.
[22] 
Davies NG, Jarvis CI, Edmunds WJ, Jewell NP, Diaz-Ordaz K, Keogh RH. Increased hazard of death in community-tested cases of SARS-CoV-2 Variant of Concern 202012/01. medRxiv  2021; 2021.02.01.21250959.
[23] 
Tegally H, Wilkinson E, Giovanetti M, et al. Emergence and rapid spread of a new severe acute respiratory syndrome-related coronavirus 2 (SARS-CoV-2) lineage with multiple spike mutations in South Africa. medRxiv  2020; 2020.12.21.20248640.
[24] 
Twohig KA, Nyberg T, Zaidi A, et al. Hospital admission and emergency care attendance risk for SARS-CoV-2 delta (B.1.617.2) compared with alpha (B.1.1.7) variants of concern: A cohort study. Lancet Infect Dis  2021; S1473-3099(2): 00475-8.
[PMID: 34461056] 
[25] 
Williams TC, Burgers WA. SARS-CoV-2 evolution and vaccines: cause for concern? Lancet Respir Med  2021; 9(4): 333-5.
[http://dx.doi.org/10.1016/S2213-2600(21)00075-8] [PMID: 33524316] 
[26] 
Monk PD, Marsden RJ, Tear VJ, et al. Safety and efficacy of inhaled nebulised interferon beta-1a (SNG001) for treatment of SARS-CoV-2 infection: A randomised, double-blind, placebo-controlled, phase 2 trial. Lancet Respir Med  2020; 9(2): 196-206.
[http://dx.doi.org/10.1016/S2213-2600(20)30511-7] [PMID: 33189161] 
[27] 
van Haren FMP, Page C, Laffey JG, et al. Nebulised heparin as a treatment for COVID-19: Scientific rationale and a call for randomised evidence. Crit Care  2020; 24(1): 454.
[http://dx.doi.org/10.1186/s13054-020-03148-2] [PMID: 32698853] 
[28] 
Perico L, Benigni A, Casiraghi F, Ng LFP, Renia L, Remuzzi G. Immunity, endothelial injury and complement-induced coagulopathy in COVID-19. Nat Rev Nephrol  2021; 17(1): 46-64.
[http://dx.doi.org/10.1038/s41581-020-00357-4] [PMID: 33077917] 
[29] 
Carcaterra M, Caruso C. Alveolar epithelial cell type II as main target of SARS-CoV-2 virus and COVID-19 development via NF-Kb pathway deregulation: A physio-pathological theory. Med Hypotheses  2021; 146: 110412-2.
[http://dx.doi.org/10.1016/j.mehy.2020.110412] [PMID: 33308936] 
[30] 
Morris G, Bortolasci CC, Puri BK, et al. The pathophysiology of SARS-CoV-2: A suggested model and therapeutic approach. Life Sci  2020; 258: 118166-6.
[http://dx.doi.org/10.1016/j.lfs.2020.118166] [PMID: 32739471] 
[31] 
Lavorini F, Pedersen S, Usmani OS. Dilemmas, confusion, and misconceptions related to small airways directed therapy. Chest  2017; 151(6): 1345-55.
[http://dx.doi.org/10.1016/j.chest.2016.07.035] [PMID: 27522955] 
[32] 
Leach CL, Kuehl PJ, Chand R, McDonald JD. Respiratory tract deposition of HFA–beclomethasone and HFA–fluticasone in asthmatic patients. J Aerosol Med Pulm Drug Deliv  2016; 29(2): 127-33.
[http://dx.doi.org/10.1089/jamp.2014.1199] [PMID: 26061801] 
[33] 
Vanden Burgt JA, Busse WW, Martin RJ, Szefler SJ, Donnell D. Efficacy and safety overview of a new inhaled corticosteroid, QVAR (hydrofluoroalkane-beclomethasone extrafine inhalation aerosol), in asthma. J Allergy Clin Immunol  2000; 106(6): 1209-26.
[http://dx.doi.org/10.1067/mai.2000.111582] [PMID: 11112914] 
[34] 
Hoye JA, Gupta A, Myrdal PB. Solubility of solid solutes in HFA-134a with a correlation to physico-chemical properties. J Pharm Sci  2008; 97(1): 198-208.
[http://dx.doi.org/10.1002/jps.21080] [PMID: 17828733] 
[35] 
Hoye JA, Myrdal PB. Measurement and correlation of solute solubility in HFA-134a/ethanol systems. Int J Pharm  2008; 362(1-2): 184-8.
[http://dx.doi.org/10.1016/j.ijpharm.2008.06.020] [PMID: 18647644] 
[36] 
Saijo M, Morikawa S, Fukushi S, et al. Inhibitory effect of mizoribine and ribavirin on the replication of Severe Acute Respiratory Syndrome (SARS)-associated coronavirus. Antiviral Res  2005; 66(2-3): 159-63.
[http://dx.doi.org/10.1016/j.antiviral.2005.01.003] [PMID: 15911031] 
[37] 
Chan JFW, Chan K-H, Kao RYT, et al. Broad-spectrum antivirals for the emerging Middle East respiratory syndrome coronavirus. J Infect  2013; 67(6): 606-16.
[http://dx.doi.org/10.1016/j.jinf.2013.09.029] [PMID: 24096239] 
[38] 
Edalatifard M, Akhtari M, Salehi M, et al. Intravenous methylprednisolone pulse as a treatment for hospitalised severe COVID-19 patients: Results from a randomised controlled clinical trial. Eur Respir J  2020; 56(6): 2002808.
[http://dx.doi.org/10.1183/13993003.02808-2020] [PMID: 32943404] 
[39] 
Bleasel MD, Peterson GM. Emetine, ipecac, ipecac alkaloids and analogues as potential antiviral agents for coronaviruses. Pharmaceuticals (Basel)  2020; 13(3): E51.
[http://dx.doi.org/10.3390/ph13030051] [PMID: 32245264] 
[40] 
Kato F, Matsuyama S, Kawase M, Hishiki T, Katoh H, Takeda M. Antiviral activities of mycophenolic acid and IMD-0354 against SARS-CoV-2. Microbiol Immunol  2020; 64(9): 635-9.
[http://dx.doi.org/10.1111/1348-0421.12828] [PMID: 32579258] 
[41] 
McDonagh P, Sheehy PA, Norris JM. Identification and characterisation of small molecule inhibitors of feline coronavirus replication. Vet Microbiol  2014; 174(3-4): 438-47.
[http://dx.doi.org/10.1016/j.vetmic.2014.10.030] [PMID: 25465182] 
[42] 
Wilson L, Gage P, Ewart G. Hexamethylene amiloride blocks E protein ion channels and inhibits coronavirus replication. Virology  2006; 353(2): 294-306.
[http://dx.doi.org/10.1016/j.virol.2006.05.028] [PMID: 16815524] 
[43] 
Pillaiyar T, Meenakshisundaram S, Manickam M. Recent discovery and development of inhibitors targeting coronaviruses. Drug Discov Today  2020; 25(4): 668-88.
[http://dx.doi.org/10.1016/j.drudis.2020.01.015] [PMID: 32006468] 
[44] 
Shin JS, Jung E, Kim M, Baric RS, Go YY. Saracatinib inhibits Middle East respiratory syndrome-coronavirus replication in vitro. Viruses  2018; 10(6): 283.
[http://dx.doi.org/10.3390/v10060283] [PMID: 29795047] 
[45] 
Dyall J, Coleman CM, Hart BJ, et al. Repurposing of clinically developed drugs for treatment of Middle East respiratory syndrome coronavirus infection. Antimicrob Agents Chemother  2014; 58(8): 4885-93.
[http://dx.doi.org/10.1128/AAC.03036-14] [PMID: 24841273] 
[46] 
Choudhry N, Zhao X, Xu D, et al. Chinese therapeutic strategy for fighting COVID-19 and potential small-molecule inhibitors against Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2). J Med Chem  2020; 63(22): 13205-27.
[http://dx.doi.org/10.1021/acs.jmedchem.0c00626] [PMID: 32845145] 
[47] 
Shen L, Niu J, Wang C, et al. High-throughput screening and identification of potent broad-spectrum inhibitors of coronaviruses. J Virol  2019; 93(12): e00023-19.
[http://dx.doi.org/10.1128/JVI.00023-19] [PMID: 30918074] 
[48] 
Pizzorno A, Padey B, Dubois J, et al. In vitro evaluation of antiviral activity of single and combined repurposable drugs against SARS-CoV-2. Antiviral Res  2020; 181: 104878.
[http://dx.doi.org/10.1016/j.antiviral.2020.104878] [PMID: 32679055] 
[49] 
Kim JC, Spence RA, Currier PF, Lu X, Denison MR. Coronavirus protein processing and RNA synthesis is inhibited by the cysteine proteinase inhibitor E64d. Virology  1995; 208(1): 1-8.
[http://dx.doi.org/10.1006/viro.1995.1123] [PMID: 11831690] 
[50] 
Ekins S, Mottin M, Ramos PRPS, et al. Déjà vu: Stimulating open drug discovery for SARS-CoV-2. Drug Discov Today  2020; 25(5): 928-41.
[http://dx.doi.org/10.1016/j.drudis.2020.03.019] [PMID: 32320852] 
[51] 
Chan JF, Lau SK, To KK, Cheng VC, Woo PC, Yuen KY. Middle East respiratory syndrome coronavirus: Another zoonotic betacoronavirus causing SARS-like disease. Clin Microbiol Rev  2015; 28(2): 465-522.
[http://dx.doi.org/10.1128/CMR.00102-14] [PMID: 25810418] 
[52] 
Müller C, Schulte FW, Lange-Grünweller K, et al. Broad-spectrum antiviral activity of the eIF4A inhibitor silvestrol against corona- and picornaviruses. Antiviral Res  2018; 150: 123-9.
[http://dx.doi.org/10.1016/j.antiviral.2017.12.010] [PMID: 29258862] 
[53] 
Lin MH, Moses DC, Hsieh CH, et al. Disulfiram can inhibit MERS and SARS coronavirus papain-like proteases via different modes. Antiviral Res  2018; 150: 155-63.
[http://dx.doi.org/10.1016/j.antiviral.2017.12.015] [PMID: 29289665] 
[54] 
Lee H, Lei H, Santarsiero BD, et al. Inhibitor recognition specificity of MERS-CoV papain-like protease may differ from that of SARS-CoV. ACS Chem Biol  2015; 10(6): 1456-65.
[http://dx.doi.org/10.1021/cb500917m] [PMID: 25746232] 
[55] 
Kim Y, Lovell S, Tiew K-C, et al. Broad-spectrum antivirals against 3C or 3C-like proteases of picornaviruses, noroviruses, and coronaviruses. J Virol  2012; 86(21): 11754-62.
[http://dx.doi.org/10.1128/JVI.01348-12] [PMID: 22915796] 
[56] 
Adedeji AO, Severson W, Jonsson C, Singh K, Weiss SR, Sarafianos SG. Novel inhibitors of severe acute respiratory syndrome coronavirus entry that act by three distinct mechanisms. J Virol  2013; 87(14): 8017-28.
[http://dx.doi.org/10.1128/JVI.00998-13] [PMID: 23678171] 
[57] 
Matsuyama S, Kawase M, Nao N, et al. The inhaled steroid ciclesonide blocks SARS-CoV-2 RNA replication by targeting the viral replication-transcription complex in cultured cells. J Virol  2020; 95(1): e01648-20.
[http://dx.doi.org/10.1128/JVI.01648-20] [PMID: 33055254] 
[58] 
Marijani R, Shaik MS, Chatterjee A, Singh M. Evaluation of Metered Dose Inhaler (MDI) formulations of ciclosporin. J Pharm Pharmacol  2007; 59(1): 15-21.
[http://dx.doi.org/10.1211/jpp.59.1.0003] [PMID: 17227616] 
[59] 
Myrdal PB, Karlage KL, Stein SW, Brown BA, Haynes A. Optimized dose delivery of the peptide cyclosporine using hydrofluoroalkane-based metered dose inhalers. J Pharm Sci  2004; 93(4): 1054-61.
[http://dx.doi.org/10.1002/jps.20025] [PMID: 14999741] 
[60] 
Iacono AT, Johnson BA, Grgurich WF, et al. A randomized trial of inhaled cyclosporine in lung-transplant recipients. N Engl J Med  2006; 354(2): 141-50.
[http://dx.doi.org/10.1056/NEJMoa043204] [PMID: 16407509] 
[61] 
Groves S, Galazka M, Johnson B, et al. Inhaled cyclosporine and pulmonary function in lung transplant recipients. J Aerosol Med Pulm Drug Deliv  2010; 23(1): 31-9.
[http://dx.doi.org/10.1089/jamp.2009.0748] [PMID: 19580368] 
[62] 
Wu X, Zhang W, Hayes D Jr, Mansour HM. Physicochemical characterization and aerosol dispersion performance of organic solution advanced spray-dried cyclosporine A multifunctional particles for dry powder inhalation aerosol delivery. Int J Nanomedicine  2013; 8: 1269-83.
[PMID: 23569375] 
[63] 
Guisado-Vasco P, Valderas-Ortega S, Carralón-González MM, et al. Clinical characteristics and outcomes among hospitalized adults with severe COVID-19 admitted to a tertiary medical center and receiving antiviral, antimalarials, glucocorticoids, or immunomodulation with tocilizumab or cyclosporine: A retrospective observational study (COQUIMA cohort). EClinicalMedicine  2020; 28: 100591.
[http://dx.doi.org/10.1016/j.eclinm.2020.100591] [PMID: 33078138] 
[64] 
Poulsen NN, von Brunn A, Hornum M, Blomberg Jensen M. Cyclosporine and COVID-19: Risk or favorable? Am J Transplant  2020; 20(11): 2975-82.
[http://dx.doi.org/10.1111/ajt.16250] [PMID: 32777170] 
[65] 
Sanchez-Pernaute O, Romero-Bueno FI, Selva-O'Callaghan A. Why choose cyclosporin A as first-line therapy in COVID-19 pneumonia. Reumatol Clin  2020; S1699-258X(20): 30044-9.
[http://dx.doi.org/10.1016/j.reuma.2020.03.001] 
[66] 
Newman S, Salmon A, Nave R, Drollmann A. High lung deposition of 99mTc-labeled ciclesonide administered via HFA-MDI to patients with asthma. Respir Med  2006; 100(3): 375-84.
[http://dx.doi.org/10.1016/j.rmed.2005.09.027] [PMID: 16275052] 
[67] 
Committee-for-medicinal-products-for-human-use. Guideline on the pharmaceutical quality of inhalation and nasal products. European Medicines Agency 2006.
[68] 
Podczeck F. The influence of particle size distribution and surface roughness of carrier particles on the in vitro properties of dry powder inhalations. Aerosol Sci Technol  1999; 31(4): 301-21.
[http://dx.doi.org/10.1080/027868299304174] 
[69] 
Wakankar AA, Wang YJ, Canova-Davis E, et al. On developing a process for conducting extractable-leachable assessment of components used for storage of biopharmaceuticals. J Pharm Sci  2010; 99(5): 2209-18.
[http://dx.doi.org/10.1002/jps.22012] [PMID: 20039383] 
[70] 
Norwood DL, Paskiet D, Ruberto M, et al. Best practices for extractables and leachables in orally inhaled and nasal drug products: An overview of the PQRI recommendations. Pharm Res  2008; 25(4): 727-39.
[http://dx.doi.org/10.1007/s11095-007-9521-z] [PMID: 18183477] 
[71] 
Stein SW, Sheth P, Hodson PD, Myrdal PB. Advances in metered dose inhaler technology: Hardware development. AAPS PharmSciTech  2014; 15(2): 326-38.
[http://dx.doi.org/10.1208/s12249-013-0062-y] [PMID: 24357110] 
[72] 
Norwood DL, Nagao LM, Stults CL. Perspectives on the PQRI extractables and leachables “safety thresholds and best practices” recommendations for inhalation drug products. PDA J Pharm Sci Technol  2013; 67(5): 413-29.
[http://dx.doi.org/10.5731/pdajpst.2013.00934] [PMID: 24084658] 
[73] 
Andrew D, Feilden AR. Analytical Leachables Studies. In: Ball DJ, Stults CLM, Nagao LM, Eds.  Leachable and Extractable Handbook.  USA: John Wiley & Sons 2012; pp. 417-47.
[74] 
Stults CL, Ansell JM, Shaw AJ, Nagao LM. Evaluation of extractables in processed and unprocessed polymer materials used for pharmaceutical applications. AAPS PharmSciTech  2015; 16(1): 150-64.
[http://dx.doi.org/10.1208/s12249-014-0188-6] [PMID: 25227309] 
[75] 
Sheth P, Sandell D, Conti DS, Holt JT, Hickey AJ, Saluja B. Influence of formulation factors on the aerosol performance of suspension and solution metered dose inhalers: A systematic approach. AAPS J  2017; 19(5): 1396-410.
[http://dx.doi.org/10.1208/s12248-017-0095-3] [PMID: 28593514] 
[76] 
Pharmacopeia U. General chapters: Inhalation and nasal drug products : Aerosols , sprays , and powders—performance quality tests 2015.
[77] 
Tsong Y, Dong X, Shen M, Lostritto RT. Quality assurance test of delivered dose uniformity of multiple-dose inhaler and dry powder inhaler drug products. J Biopharm Stat  2015; 25(2): 328-38.
[http://dx.doi.org/10.1080/10543406.2014.972510] [PMID: 25357132] 
[78] 
Asmus MJ, Liang J, Coowanitwong I, Hochhaus G. In vitro performance characteristics of valved holding chamber and spacer devices with a fluticasone metered-dose inhaler. Pharmacotherapy  2004; 24(2): 159-66.
[http://dx.doi.org/10.1592/phco.24.2.159.33147] [PMID: 14998215] 
[79] 
Ehtezazi T, Saleem I, Shrubb I, Allanson DR, Jenkinson ID, O’Callaghan C. The interaction between the oropharyngeal geometry and aerosols via pressurised metered dose inhalers. Pharm Res  2010; 27(1): 175-86.
[http://dx.doi.org/10.1007/s11095-009-9994-z] [PMID: 19902336] 
[80] 
Morton RW, Mitchell JP. Design of facemasks for delivery of aerosol-based medication via pressurized metered dose inhaler with valved holding chamber: Key issues that affect performance. J Aerosol Med  2007; 20(Suppl. 1): S29-42.
[http://dx.doi.org/10.1089/jam.2007.0571] [PMID: 17411403] 
[81] 
Suggett J, Nagel M, Schneider H, Mitchell JP. 
                        Clinically Appropriate Testing of Different Valved Holding Chamber (VHC)-Facemask Combinations investigating Delivered Mass to Carina for a Widely Prescribed Inhaled Corticosteroid Delivered by Pressurized Metered-Dose Inhaler (pMDI).
                     Drug Deliv Lungs  2015; 1: 350-3.
[82] 
Szychowiak P, Gensburger S, Bocar T, et al. Pressurized metered dose inhaler aerosol delivery within nasal high-flow circuits: A bench study. J Aerosol Med Pulm Drug Deliv  2021; 34(5): 303-10.
[http://dx.doi.org/10.1089/jamp.2020.1643] [PMID: 33761286] 
[83] 
Klinger-Strobel M, Lautenschläger C, Fischer D, et al. Aspects of pulmonary drug delivery strategies for infections in cystic fibrosis-where do we stand? Expert Opin Drug Deliv  2015; 12(8): 1351-74.
[http://dx.doi.org/10.1517/17425247.2015.1007949] [PMID: 25642831] 
[84] 
Guo C, Ngo D, Ahadi S, Doub WH. Evaluation of an abbreviated impactor for Fine Particle Fraction (FPF) determination of Metered Dose Inhalers (MDI). AAPS PharmSciTech  2013; 14(3): 1004-11.
[http://dx.doi.org/10.1208/s12249-013-9984-7] [PMID: 23780781] 
[85] 
Cripps A, Riebe M, Schulze M, Woodhouse R. Pharmaceutical transition to non-CFC pressurized metered dose inhalers. Respir Med  2000; 94(Suppl B): S3-9.
[86] 
Kakade PP, Versteeg HK, Hargrave GK, Genova P, Williams III RC, Deaton D. Design optimization of a novel pMDI actuator for systemic drug delivery. J Aerosol Med  2007; 20(4): 460-74.
[http://dx.doi.org/10.1089/jam.2007.0595] [PMID: 18158718] 
[87] 
Berry J, Heimbecher S, Hart JL, Sequeira J. Influence of the metering chamber volume and actuator design on the aerodynamic particle size of a metered dose inhaler. Drug Dev Ind Pharm  2003; 29(8): 865-76.
[http://dx.doi.org/10.1081/DDC-120024182] [PMID: 14570307] 
[88] 
Chen Y, Young PM, Fletcher DF, et al. The influence of actuator materials and nozzle designs on electrostatic charge of pressurised Metered Dose Inhaler (pMDI) formulations. Pharm Res  2014; 31(5): 1325-37.
[http://dx.doi.org/10.1007/s11095-013-1253-7] [PMID: 24297072] 
[89] 
Lewis D, Shea H, Johnson R, Church T. Predicting HFA-MDI Dose Retention Properties: Engineering the Marriage Between Canisters, Valves and Formulations. Conf RDD Eur  2011; 1: 89-100.
[90] 
Lewis DA, O’Shea H, Mason F, Church TK. Exploring the impact of formulation and temperature shock on metered dose inhaler priming. Aerosol Sci Technol  2017; 51(1): 84-90.
[http://dx.doi.org/10.1080/02786826.2016.1240354] 
[91] 
Ding B, Siddiqui S, DePietro M, Petersson G, Martin UJ. Inhaler usability of a pressurized metered dose inhaler and a soft mist inhaler in patients with COPD: A simulated-use study. Chron Respir Dis  2019; 16: 1479972318787914-.
[http://dx.doi.org/10.1177/1479972318787914] [PMID: 30016880] 
[92] 
Hoe S, Traini D, Chan HK, Young PM. The influence of flow rate on the aerosol deposition profile and electrostatic charge of single and combination metered dose inhalers. Pharm Res  2009; 26(12): 2639-46.
[http://dx.doi.org/10.1007/s11095-009-9979-y] [PMID: 19806433] 
[93] 
Glover W, Chan H-K. Electrostatic charge characterization of pharmaceutical aerosols using Electrical Low-Pressure Impaction (ELPI). J Aerosol Sci  2004; 35(6): 755-64.
[http://dx.doi.org/10.1016/j.jaerosci.2003.12.003] 
[94] 
Mitchell JP, Coppolo DP, Nagel MW. Electrostatics and inhaled medications: influence on delivery via pressurized metered-dose inhalers and add-on devices. Respir Care  2007; 52(3): 283-300.
[PMID: 17328827] 
[95] 
Wildhaber JH, Devadason SG, Eber E, et al. Effect of electrostatic charge, flow, delay and multiple actuations on the in vitro delivery of salbutamol from different small volume spacers for infants. Thorax  1996; 51(10): 985-8.
[http://dx.doi.org/10.1136/thx.51.10.985] [PMID: 8977597] 
[96] 
Wilson AF, Mukai DS, Ahdout JJ. Effect of canister temperature on performance of metered-dose inhalers. Am Rev Respir Dis  1991; 143(5 Pt 1): 1034-7.
[http://dx.doi.org/10.1164/ajrccm/143.5_Pt_1.1034] [PMID: 1850965] 
[97] 
Morin CMD, Ivey JW, Titosky JTF, et al. Performance of pressurized metered-dose inhalers at extreme temperature conditions. J Pharm Sci  2014; 103(11): 3553-9.
[http://dx.doi.org/10.1002/jps.24145] [PMID: 25252183] 
[98] 
Hoye WL, Mogalian EM, Myrdal PB. Effects of extreme temperatures on drug delivery of albuterol sulfate hydrofluoroalkane inhalation aerosols. Am J Health Syst Pharm  2005; 62(21): 2271-7.
[http://dx.doi.org/10.2146/ajhp050067] [PMID: 16239418] 
[99] 
Ramón M, Juan G, Torrejón JM, et al. Influence of storage at low temperatures on the aerosol output from metered-dose and dry-powder inhalation devices. J Pharm Technol  2000; 16(1): 12-7.
[http://dx.doi.org/10.1177/875512250001600105] 
[100] 
Brambilla G, Church T, Lewis D, Meakin B. Plume temperature emitted from metered dose inhalers. Int J Pharm  2011; 405(1-2): 9-15.
[http://dx.doi.org/10.1016/j.ijpharm.2010.11.037] [PMID: 21129465] 
[101] 
Vervaet C, Byron PR. Drug-surfactant-propellant interactions in HFA-formulations. Int J Pharm  1999; 186(1): 13-30.
[http://dx.doi.org/10.1016/S0378-5173(99)00134-9] [PMID: 10469920] 
[102] 
Myrdal PB, Sheth P, Stein SW. Advances in metered dose inhaler technology: formulation development. AAPS PharmSciTech  2014; 15(2): 434-55.
[http://dx.doi.org/10.1208/s12249-013-0063-x] [PMID: 24452499] 
[103] 
FDA. (MDI) and Dry Powder Inhaler (DPI). Products - Quality Considerations Guidance for Industry 2018.
[104] 
Lange CF, Finlay WH. Overcoming the adverse effect of humidity in aerosol delivery via pressurized metered-dose inhalers during mechanical ventilation. Am J Respir Crit Care Med  2000; 161(5): 1614-8.
[http://dx.doi.org/10.1164/ajrccm.161.5.9909032] [PMID: 10806164] 
[105] 
Martin AR, Kwok DY, Finlay WH. Investigating the evaporation of metered-dose inhaler formulations in humid air: Single droplet experiments. J Aerosol Med  2005; 18(2): 218-24.
[http://dx.doi.org/10.1089/jam.2005.18.218] [PMID: 15966776] 
[106] 
Shemirani FM, Hoe S, Lewis D, Church T, Vehring R, Finlay WH. In vitro investigation of the effect of ambient humidity on regional delivered dose with solution and suspension MDIs. J Aerosol Med Pulm Drug Deliv  2013; 26(4): 215-22.
[http://dx.doi.org/10.1089/jamp.2012.0991] [PMID: 23094687] 
[107] 
Martin AR, Finlay WH. The effect of humidity on the size of particles delivered from metered-dose inhalers. Aerosol Sci Technol  2005; 39(4): 283-9.
[http://dx.doi.org/10.1080/027868290929314] 
[108] 
Ivey JW, Bhambri P, Church TK, et al. Humidity affects the morphology of particles emitted from beclomethasone dipropionate pressurized metered dose inhalers. Int J Pharm  2017; 520(1-2): 207-15.
[http://dx.doi.org/10.1016/j.ijpharm.2017.01.062] [PMID: 28167262] 
[109] 
Sheth P, Grimes MR, Stein SW, Myrdal PB. Impact of droplet evaporation rate on resulting in vitro performance parameters of pressurized metered dose inhalers. Int J Pharm  2017; 528(1-2): 360-71.
[http://dx.doi.org/10.1016/j.ijpharm.2017.06.014] [PMID: 28599855] 
[110] 
Nithyanandan P, Hoag SW, Dalby RN. The analysis and prediction of functional robustness of inhaler devices. J Aerosol Med  2007; 20(1): 19-37.
[http://dx.doi.org/10.1089/jam.2006.0564] [PMID: 17388750] 
[111] 
Roche N, Dekhuijzen PN. The evolution of pressurized metered-dose inhalers from early to modern devices. J Aerosol Med Pulm Drug Deliv  2016; 29(4): 311-27.
[http://dx.doi.org/10.1089/jamp.2015.1232] [PMID: 26824873] 
[112] 
Weinstein C, Staudinger H, Scott I, Amar NJ, LaForce C. Dose counter performance of mometasone furoate/formoterol inhalers in subjects with asthma or COPD. Respir Med  2011; 105(7): 979-88.
[http://dx.doi.org/10.1016/j.rmed.2011.01.013] [PMID: 21398104] 
[113] 
LaForce C, Weinstein C, Nathan RA, Weinstein SF, Staudinger H, Meltzer EO. Patient satisfaction with a pressurized metered-dose inhaler with an integrated dose counter containing a fixed-dose mometasone furoate/formoterol combination. J Asthma  2011; 48(6): 625-31.
[http://dx.doi.org/10.3109/02770903.2011.587579] [PMID: 21726121] 
[114] 
Wasserman RL, Sheth K, Lincourt WR, Locantore NW, Rosenzweig JC, Crim C. Real-world assessment of a metered-dose inhaler with integrated dose counter. Allergy Asthma Proc  2006; 27(6): 486-92.
[http://dx.doi.org/10.2500/aap.2006.27.2921] [PMID: 17176783] 
[115] 
Doty A, Schroeder J, Vang K, et al. Drug delivery from an innovative LAMA/LABA co-suspension delivery technology fixed-dose combination MDI: Evidence of consistency, robustness, and reliability. AAPS PharmSciTech  2018; 19(2): 837-44.
[http://dx.doi.org/10.1208/s12249-017-0891-1] [PMID: 29019170] 
[116] 
Bandholm T, Christensen R, Thorborg K, Treweek S, Henriksen M. Preparing for what the reporting checklists will not tell you: The PREPARE Trial guide for planning clinical research to avoid research waste. Br J Sports Med  2017; 51(20): 1494-501.
[http://dx.doi.org/10.1136/bjsports-2017-097527] [PMID: 28882839] 
[117] 
Terada-Hirashima J, Suzuki M, Uemura Y, et al. Efficacy and safety of inhaled ciclesonide in treating patients with asymptomatic or mild COVID-19 in the RACCO trial: Protocol for a multicenter, open-label, randomized controlled trial. JMIR Res Protoc  2020; 9(12): e23830-0.
[http://dx.doi.org/10.2196/23830] [PMID: 33206053] 
[118] 
Arnaout R, Lee RA, Lee GR, et al. SARS-CoV2 Testing: The Limit of Detection Matters. bioRxiv  2020; 2020.06.02.131144.
[http://dx.doi.org/10.1101/2020.06.02.131144] 
Cite As
Recent Advances in Drug Delivery and Formulation

The Potential Use of Cyclosporine Ultrafine Solution Pressurised Metered- Dose Inhaler in the Treatment of COVID-19 Patients

Abstract
