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Advances in Device and Formulation Technologies for Pulmonary Drug Delivery

  • Review Article
  • Theme: Advances in Formulation and Device Technologies for Pulmonary Drug Delivery
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Abstract

Inhaled pharmaceuticals are formulated and delivered differently according to the therapeutic indication. However, specific device-formulation coupling is often fickle, and new medications or indications also demand new strategies. The discontinuation of chlorofluorocarbon propellants has seen replacement of older metered dose inhalers with dry powder inhaler formulations. High-dose dry powder inhalers are increasingly seen as an alternative dosage form for nebulised medications. In other cases, new medications have completely bypassed conventional inhalers and been formulated for use with unique inhalers such as the Staccato® device. Among these different devices, integration of software and electronic assistance has become a shared trend. This review covers recent device and formulation advances that are forming the current landscape of inhaled therapeutics.

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References

  1. Patton JS, Byron PR. Inhaling medicines: delivering drugs to the body through the lungs. Nat Rev Drug Discov. 2007;6(1):67–74.

    CAS  PubMed  Google Scholar 

  2. Hohenegger M. Novel and current treatment concepts using pulmonary drug delivery. Curr Pharm Des. 2010;16(22):2484–92.

    CAS  PubMed  Google Scholar 

  3. Cipolla DC, Gonda I. Formulation technology to repurpose drugs for inhalation delivery. Drug Discov Today: Ther Strateg. 2011;8(3–4):123–30. doi:10.1016/j.ddstr.2011.07.001.

    CAS  Google Scholar 

  4. Heinemann L. The failure of exubera: are we beating a dead horse? J Diabetes Sci Technol. 2008;2(3):518–29.

    PubMed Central  PubMed  Google Scholar 

  5. Zhou QT, Armstrong B, Larson I, Stewart PJ, Morton DAV. Understanding the influence of powder flowability, fluidization and de-agglomeration characteristics on the aerosolization of pharmaceutical model powders. Eur J Pharm Sci. 2010;40(5):412–21. doi:10.1016/j.ejps.2010.04.012.

    CAS  PubMed  Google Scholar 

  6. de Boer AH, Chan HK, Price R. A critical view on lactose-based drug formulation and device studies for dry powder inhalation: which are relevant and what interactions to expect? Adv Drug Deliv Rev. 2012;64(3):257–74. doi:10.1016/j.addr.2011.04.004.

    PubMed  Google Scholar 

  7. Coates MS, Chan HK, Fletcher DF, Raper JA. Effect of design on the performance of a dry powder inhaler using computational fluid dynamics. Part 2: air inlet size. J Pharm Sci. 2006;95(6):1382–92.

    CAS  PubMed  Google Scholar 

  8. Tong ZB, Zheng B, Yang RY, Yu AB, Chan HK. CFD-DEM investigation of the dispersion mechanisms in commercial dry powder inhalers. Powder Technol. 2013;240:19–24. doi:10.1016/j.powtec.2012.07.012.

    CAS  Google Scholar 

  9. Zhou QT, Tong ZB, Tang P, Citterio M, Yang RY, Chan HK. Effect of device design on the aerosolization of a carrier-based dry powder inhaler—a case study on aerolizer® Foradile®. Aaps J. 2013;15(2):511–22. doi:10.1208/s12248-013-9458-6.

    CAS  PubMed Central  PubMed  Google Scholar 

  10. Son Y-J, Longest PW, Tian G, Hindle M. Evaluation and modification of commercial dry powder inhalers for the aerosolization of a submicrometer excipient enhanced growth (EEG) formulation. Eur J Pharm Sci. 2013;49(3):390–9. doi:10.1016/j.ejps.2013.04.011.

    CAS  PubMed Central  PubMed  Google Scholar 

  11. Curtis RM, Donovan MJ, Smyth H. Inhaler to deliver substances for prophylaxis or prevention of disease or injury caused by the chemical agents. US2013/0213397 A1. 2013

  12. Ehtezazi T, Allanson DR, Jenkinson ID, Shrubb I, O’Callaghan C. Investigating improving powder deagglomeration via dry powder inhalers at a low Inspiratory flow rate by employing add-on spacers. J Pharm Sci. 2008;97(12):5212–21. doi:10.1002/jps.21375.

    CAS  PubMed  Google Scholar 

  13. Longest PW, Son YJ, Holbrook L, Hindle M. Aerodynamic factors responsible for the deaggregation of carrier-free drug powders to form micrometer and submicrometer aerosols. Pharm Res. 2013;30(6):1608–27. doi:10.1007/s11095-013-1001-z.

    CAS  PubMed Central  PubMed  Google Scholar 

  14. Harrison LI, Novak CC, Needham MJ, Ratner P. Comparative pulmonary function and pharmacokinetics of fluticasone propionate and salmeterol xinafoate delivered by two dry powder inhalers to patients with asthma. J Aerosol Med Pulm Drug Deliv. 2011;24(5):245–52. doi:10.1089/jamp.2011.0884.

    CAS  PubMed  Google Scholar 

  15. Friebel C, Steckel H. Single-use disposable dry powder inhalers for pulmonary drug delivery. Expert Opin Drug Deliv. 2010;7(12):1359–72. doi:10.1517/17425247.2010.538379.

    CAS  PubMed  Google Scholar 

  16. Selvam P, McNair D, Truman R, Smyth HDC. A novel dry powder inhaler: effect of device design on dispersion performance. Int J Pharm. 2010;401(1–2):1–6. doi:10.1016/j.ijpharm.2010.07.056.

    CAS  PubMed  Google Scholar 

  17. Behara SRB, Larson I, Kippax P, Morton DAV, Stewart P. The kinetics of cohesive powder de-agglomeration from three inhaler devices. Int J Pharm. 2011;421(1):72–81. doi:10.1016/j.ijpharm.2011.09.024.

    CAS  PubMed  Google Scholar 

  18. Coates MS, Chan HK, Fletcher DF, Raper JA. Influence of air flow on the performance of a dry powder inhaler using computational and experimental analyses. Pharm Res. 2005;22(9):1445–53. doi:10.1007/s11095-005-6155-x.

    CAS  PubMed  Google Scholar 

  19. Morton D, Staniforth J. Systemic pulmonary delivery: success through integrated formulation and device development. In: Furness G, editor. Pulmonary delivery: innovative technologies breathing new life into inhalable therapeutics. East Sussex, UK: Furness; 2006.

    Google Scholar 

  20. Zhang X, Ma Y, Zhang L, Zhu J, Jin F. The development of a novel dry powder inhaler. Int J Pharm. 2012;431(1–2):45–52. doi:10.1016/j.ijpharm.2012.04.019.

    CAS  PubMed  Google Scholar 

  21. Corcoran TE, Venkataramanan R, Hoffman RM, George MP, Petrov A, Richards T, et al. Systemic delivery of atropine sulfate by the microdose dry-powder inhaler. J Aerosol Med Pulm Drug Deliv. 2013;26(1):46–55. doi:10.1089/jamp.2011.0948.

    CAS  PubMed Central  PubMed  Google Scholar 

  22. Voshaar T, Spinola M, Linnane P, Campanini A, Lock D, Lafratta A, et al. Comparing usability of NEXThaler with other inhaled corticosteroid/long-acting beta-agonist fixed combination dry powder inhalers in asthma patients. J Aerosol Med Pulm Drug Deliv. 2013. doi:10.1089/jamp.2013.1086.

    PubMed  Google Scholar 

  23. Hofmann T, editor. Optimized steroid delivery in severe and pediatric asthma: improved compliance and efficacy. Abstracts: International Society for Aerosols in Medicine; 2013; North Carolina, USA: Journal of Aerosol Medicine and Pulmonary Drug Delivery

  24. Mainz JG, Canisius S, Shcheuch G, Mullinger B, Nocker K, Hofmann T, editors. An open-label randomized pilot trial to evaluate tolerability, safety and applicability of budesonide inhalation suspension (BIS) delivered via AKIT JET in children aged 3–11 years with mild to moderate asthma. Abstracts: International Society for Aerosols in Medicine; 2013; North Carolina, USA: Journal of Aerosol Medicine and Pulmonary Drug Delivery

  25. Young PM, Crapper J, Philips G, Sharma K, Chan HK, Traini D. Overcoming dose limitations using the orbital multi-breath dry powder inhaler. J Aerosol Med Pulm Drug Deliv. 2013. doi:10.1089/jamp.2013.1080.

    PubMed  Google Scholar 

  26. de Boer AH, Hagedoorn P, Westerman EM, Le Brun PPH, Heijerman HGM, Frijlink HW. Design and in vitro performance testing of multiple air classifier technology in a new disposable inhaler concept (Twincer®) for high powder doses. Eur J Pharm Sci. 2006;28(3):171–8. doi:10.1016/j.ejps.2005.11.013.

    PubMed  Google Scholar 

  27. de Boer AH, Hagedoorn P, Woolhouse R, Wynn E. Computational fluid dynamics (CFD) assisted performance evaluation of the Twincer™ disposable high-dose dry powder inhaler. J Pharm Pharmacol. 2012;64(9):1316–25. doi:10.1111/j.2042-7158.2012.01511.x.

    PubMed  Google Scholar 

  28. de Boer AH, Hagedoorn P, Woolhouse R, Wynn E. Computational fluid dynamics (CFD) assisted performance evaluation of the Twincer (TM) disposable high-dose dry powder inhaler. J Pharm Pharmacol. 2012;64(9):1316–25. doi:10.1111/j.2042-7158.2012.01511.x.

    PubMed  Google Scholar 

  29. Grasmeijer F, Hagedoorn P, Frijlink HW, de Boer AH. Characterisation of high dose aerosols from dry powder inhalers. Int J Pharm. 2012;437(1–2):242–9. doi:10.1016/j.ijpharm.2012.08.020.

    CAS  PubMed  Google Scholar 

  30. Bell J, Newman S. The rejuvenated pressurised metered dose inhaler. Expert Opin Drug Deliv. 2007;4(3):215–34. doi:10.1517/17425247.4.3.215.

    CAS  PubMed  Google Scholar 

  31. Stein SW, Sheth P, Hodson D, Myrdal PB. Advances in metered dose inhaler technology: hardware development. AAPS PharmSciTech. 2014.

  32. FDA. Guidance for industry: integration of dose-counting mechanisms into MDI drug products. 2003.

  33. Conner JB, Buck PO. Improving asthma management: the case for mandatory inclusion of dose counters on all rescue bronchodilators. J Asthma. 2013;50(6):658–63. doi:10.3109/02770903.2013.789056.

    PubMed Central  PubMed  Google Scholar 

  34. Giraud V, Allaert FA. Improved asthma control with breath-actuated pressurized metered dose inhaler (pMDI): the SYSTER survey. Eur Rev Med Pharmacol Sci. 2009;13(5):323–30.

    CAS  PubMed  Google Scholar 

  35. Crompton GK. Breath-activated aerosol. Br Med J. 1971;2(5762):652–3.

    CAS  PubMed Central  PubMed  Google Scholar 

  36. Cipolla D, Chan HK, Schuster J, Farina D. Personalizing aerosol medicine: development of delivery systems tailored to the individual. Ther Deliv. 2010;1(5):667–82.

    CAS  PubMed  Google Scholar 

  37. Ingerski LM, Hente EA, Modi AC, Hommel KA. Electronic measurement of medication adherence in pediatric chronic illness: a review of measures. J Pediatr. 2011;159(4):528–34. doi:10.1016/j.jpeds.2011.05.018.

    PubMed Central  PubMed  Google Scholar 

  38. Knoch M, Keller M. The customised electronic nebuliser: a new category of liquid aerosol drug delivery systems. Expert Opin Drug Deliv. 2005;2(2):377–90. doi:10.1517/17425247.2.2.377.

    CAS  PubMed  Google Scholar 

  39. Mansour MM. Overcoming jet lag: optimizing aerosol delivery with and without jet nebulizers. Espir Care. 2013;58(7):1255–6. doi:10.4187/respcare.02618.

    Google Scholar 

  40. Kesser KC, Geller DE. New aerosol delivery devices for cystic fibrosis. Respir Care. 2009;54(6):754–67. discussion 67-8.

    PubMed  Google Scholar 

  41. Cipolla DC, Clark AR, Chan HK, Gonda I, Shire SJ. Assessment of aerosol delivery systems for recombinant human deoxyribonuclease. STP Pharma Sci. 1994;4(1):50–62.

    Google Scholar 

  42. Watts AB, McConville JT, Williams 3rd RO. Current therapies and technological advances in aqueous aerosol drug delivery. Drug Dev Ind Pharm. 2008;34(9):913–22. doi:10.1080/03639040802144211.

    CAS  PubMed  Google Scholar 

  43. Arunthari V, Bruinsma RS, Lee AS, Johnson MM. A prospective, comparative trial of standard and breath-actuated nebulizer: efficacy, safety, and satisfaction. Respir Care. 2012;57(8):1242–7. doi:10.4187/respcare.01450.

    PubMed  Google Scholar 

  44. Goodman N, Morgan M, Nikander K, Hinch S, Coughlin S. Evaluation of patient-reported outcomes and quality of life with the I-neb AAD system in patients with chronic obstructive pulmonary disease. J Aerosol Med Pulmon Drug Deliv. 2010;23 Suppl 1:S61–70. doi:10.1089/jamp.2009.0767.

    Google Scholar 

  45. Rubin BK. Pediatric aerosol therapy: new devices and new drugs. Respir Care. 2011;56(9):1411–21. doi:10.4187/respcare.01246. discussion 21-3.

    PubMed  Google Scholar 

  46. Kroneberg P, Zimlich W, Muellinger B, Wenker A, Scheuch G, editors. Device output is not a predictor of lung dose. Drug Delivery to the Lung 19; 2008; Edinbugh, UK.

  47. Fischer A, Stegemann J, Scheuch G, Siekmeier R. Novel devices for individualized controlled inhalation can optimize aerosol therapy in efficacy, patient care and power of clinical trials. Eur J Med Res. 2009;14 Suppl 4:71–7.

    PubMed Central  PubMed  Google Scholar 

  48. Bakker EM, Volpi S, Salonini E, van der Wiel-Kooij EC, Sintnicolaas CJJCM, Hop WCJ, et al. Improved treatment response to dornase alfa in cystic fibrosis patients using controlled inhalation. Eur Respir J. 2011;38(6):1328–35. doi:10.1183/09031936.00006211.

    CAS  PubMed  Google Scholar 

  49. Moller W, Heimbeck I, Hofer TP, Khadem Saba G, Neiswirth M, Frankenberger M, et al. Differential inflammatory response to inhaled lipopolysaccharide targeted either to the airways or the alveoli in man. PLoS ONE. 2012;7(4):e33505. doi:10.1371/journal.pone.0033505.

    PubMed Central  PubMed  Google Scholar 

  50. Janssens HM, Overweel J, editors. Specific targeting of inhaled steroids to small airways in children with problematic severe asthma using the AKITA: a case series. Abstracts: International Society for Aerosols in Medicine; 2013; North Carolina, USA: Journal of Aerosol Medicine and Pulmonary Drug Delivery

  51. Nikander K, Prince I, Coughlin S, Warren S, Taylor G. Mode of breathing-tidal or slow and deep-through the I-neb adaptive aerosol delivery (AAD) system affects lung deposition of (99m)Tc-DTPA. J Aerosol Med Pulmon Drug Deliv. 2010;23 Suppl 1:S37–43. doi:10.1089/jamp.2009.0786.

    CAS  Google Scholar 

  52. Geller DE, Kesser KC. The I-neb adaptive aerosol delivery system enhances delivery of alpha1-antitrypsin with controlled inhalation. J Aerosol Med Pulmon Drug Deliv. 2010;23 Suppl 1:S55–9. doi:10.1089/jamp.2009.0793.

    CAS  Google Scholar 

  53. Denyer J, Black A, Nikander K, Dyche T, Prince I. Domiciliary experience of the target inhalation mode (TIM) breathing maneuver in patients with cystic fibrosis. J Aerosol Med Pulmon Drug Deliv. 2010;23 Suppl 1:S45–54. doi:10.1089/jamp.2009.0777.

    Google Scholar 

  54. McCormack P, McNamara PS, Southern KW. A randomised controlled trial of breathing modes for adaptive aerosol delivery in children with cystic fibrosis. J Cyst Fibros: Off J Eur Cyst Fibros Soc. 2011;10(5):343–9. doi:10.1016/j.jcf.2011.04.006.

    Google Scholar 

  55. Dhand R. Intelligent nebulizers in the age of the Internet: the I-neb adaptive aerosol delivery (AAD) system. J Aerosol Med Pulmon Drug Deliv. 2010;23 Suppl 1:iii–v. doi:10.1089/jamp.2010.0818.

    Google Scholar 

  56. Hodder R, Price D. Patient preferences for inhaler devices in chronic obstructive pulmonary disease: experience with Respimat Soft Mist inhaler. Int J Chron Obstructive Pulmon Dis. 2009;4:381–90.

    CAS  Google Scholar 

  57. Hodder R, Reese PR, Slaton T. Asthma patients prefer Respimat Soft Mist Inhaler to Turbuhaler. Int J Chron Obstructive Pulmon Dis. 2009;4:225–32.

    CAS  Google Scholar 

  58. Asakura Y, Nishimura N, Maezawa K, Terajima T, Kizu J, Chohnabayashi N. Effect of switching tiotropium HandiHaler® to Respimat® Soft Mist Inhaler in patients with COPD: the difference of adverse events and usability between inhaler devices. J Aerosol Med Pulmon Drug Deliv. 2013;26(1):41–5. doi:10.1089/jamp.2011.0941.

    CAS  Google Scholar 

  59. Ferguson GT, Ghafouri M, Dai L, Dunn LJ. COPD patient satisfaction with ipratropium bromide/albuterol delivered via Respimat: a randomized, controlled study. Int J Chron Obstructive Pulmon Dis. 2013;8:139–50. doi:10.2147/COPD.S38577.

    CAS  Google Scholar 

  60. van Noord JA, Cornelissen PJ, Aumann JL, Platz J, Mueller A, Fogarty C. The efficacy of tiotropium administered via Respimat Soft Mist Inhaler or HandiHaler in COPD patients. Respir Med. 2009;103(1):22–9. doi:10.1016/j.rmed.2008.10.002.

    PubMed  Google Scholar 

  61. van Noord JA, Smeets JJ, Drenth BM, Rascher J, Pivovarova A, Hamilton AL, et al. 24-Hour bronchodilation following a single dose of the novel beta(2)-agonist olodaterol in COPD. Pulmon Pharmacol Ther. 2011;24(6):666–72. doi:10.1016/j.pupt.2011.07.006.

    Google Scholar 

  62. Beasley R, Singh S, Loke YK, Enright P, Furberg CD. Call for worldwide withdrawal of tiotropium Respimat mist inhaler. BMJ. 2012;345:e7390. doi:10.1136/bmj.e7390.

    PubMed  Google Scholar 

  63. Jenkins CR, Beasley R. Tiotropium Respimat increases the risk of mortality. Thorax. 2013;68(1):5–7. doi:10.1136/thoraxjnl-2012-202482.

    PubMed  Google Scholar 

  64. Tang Y, Massey D, Zhong NS. Evaluation of the efficacy and safety of tiotropium bromide (5 microg) inhaled via Respimat in Chinese patients with chronic obstructive pulmonary disease. Chin Med J. 2013;126(19):3603–7.

    CAS  PubMed  Google Scholar 

  65. Jenkins C, Beasley R. Authors’ reply to “explaining differential effects of tiotropium on mortality in COPD”. Thorax. 2013;68(6):590–1.

    PubMed  Google Scholar 

  66. Lipworth BJ, Short PM. Explaining differential effects of tiotropium on mortality in COPD. Thorax. 2013;68(6):589–90. doi:10.1136/thoraxjnl-2012-203176.

    PubMed  Google Scholar 

  67. Jenkins CR, Beasley R. Authors’ response to Metzdorf et al. Thorax. 2013;68(8):782–3. doi:10.1136/thoraxjnl-2013-203380.

    PubMed  Google Scholar 

  68. Metzdorf N, Hallmann C, Disse B. Thorax editorial by Jenkins and Beasley related to tiotropium respimat. Thorax. 2013;68(8):782. doi:10.1136/thoraxjnl-2013-203228.

    PubMed  Google Scholar 

  69. Bateman ED. Tiotropium Respimat increases the risk of mortality: con. Eur Respir J. 2013;42(3):590–3. doi:10.1183/09031936.00042213.

    CAS  PubMed  Google Scholar 

  70. Beasley R. Tiotropium Respimat increases the risk of mortality: pro. Eur Respir J. 2013;42(3):584–9. doi:10.1183/09031936.00042113.

    CAS  PubMed  Google Scholar 

  71. Jenkins CR. More than just reassurance on Tiotropium safety. N Engl J Med. 2013;369(16):1555–6. doi:10.1056/NEJMe1310107.

    CAS  PubMed  Google Scholar 

  72. Dinh KV, Myers DJ, Noymer PD, Cassella JV. In vitro aerosol deposition in the oropharyngeal region for Staccato® Loxapine. J Aerosol Med Pulmon Drug Deliv. 2010;23(4):253–60. doi:10.1089/jamp.2009.0814.

    CAS  Google Scholar 

  73. Dinh K, Myers DJ, Glazer M, Shmidt T, Devereaux C, Simis K, et al. In vitro aerosol characterization of Staccato® Loxapine. Int J Pharm. 2011;403(1–2):101–8. doi:10.1016/j.ijpharm.2010.10.030.

    CAS  PubMed  Google Scholar 

  74. Borgstrom L, Olsson B, Thorsson L. Degree of throat deposition can explain the variability in lung deposition of inhaled drugs. J Aerosol Med: Off J Int Soc Aerosols Med. 2006;19(4):473–83. doi:10.1089/jam.2006.19.473.

    Google Scholar 

  75. Citrome L. Addressing the need for rapid treatment of agitation in schizophrenia and bipolar disorder: focus on inhaled loxapine as an alternative to injectable agents. Ther Clin Risk Manag. 2013;9:235–45. doi:10.2147/TCRM.S31484.

    CAS  PubMed Central  PubMed  Google Scholar 

  76. Kwentus J, Riesenberg RA, Marandi M, Manning RA, Allen MH, Fishman RS, et al. Rapid acute treatment of agitation in patients with bipolar I disorder: a multicenter, randomized, placebo-controlled clinical trial with inhaled loxapine. Bipolar Disord. 2012;14(1):31–40. doi:10.1111/j.1399-5618.2011.00975.x.

    CAS  PubMed  Google Scholar 

  77. Lesem MD, Tran-Johnson TK, Riesenberg RA, Feifel D, Allen MH, Fishman R, et al. Rapid acute treatment of agitation in individuals with schizophrenia: multicentre, randomised, placebo-controlled study of inhaled loxapine. Brit J Psychiatry: J Mental Sci. 2011;198(1):51–8. doi:10.1192/bjp.bp.110.081513.

    Google Scholar 

  78. Allen MH, Feifel D, Lesem MD, Zimbroff DL, Ross R, Munzar P, et al. Efficacy and safety of loxapine for inhalation in the treatment of agitation in patients with schizophrenia: a randomized, double-blind, placebo-controlled trial. J Clin Psychiatry. 2011;72(10):1313–21. doi:10.4088/JCP.10m06011yel.

    CAS  PubMed  Google Scholar 

  79. Currier G, Walsh P. Safety and efficacy review of inhaled loxapine for treatment of agitation. Clin Schizophr Relat Psychoses. 2013;7(1):25–32. doi:10.3371/CSRP.CUWA.032513.

    PubMed  Google Scholar 

  80. Denyer J. Adherence monitoring in drug delivery. Expert Opin Drug Deliv. 2010;7(10):1127–31. doi:10.1517/17425247.2010.517520.

    PubMed  Google Scholar 

  81. Wollmer P, Pieber TR, Gall MA, Brunton S. Delivering needle-free insulin using AERx® iDMS (Insulin Diabetes Management System) technology. Diabetes Technol Ther. 2007;9:S57–64. doi:10.1089/dia.2007.0206.

    CAS  PubMed  Google Scholar 

  82. Mastrandrea LD. Inhaled insulin: overview of a novel route of insulin administration. Vasc Heal Risk Manag. 2010;6:47–58.

    CAS  Google Scholar 

  83. Geller D, Thipphawong J, Otulana B, Caplan D, Ericson D, Milgram L, et al. Bolus inhalation of rhDNase with the AERx system in subjects with cystic fibrosis. J Aerosol Med Depos Clearance Eff Lung. 2003;16(2):175–82. doi:10.1089/089426803321919933.

    CAS  Google Scholar 

  84. Davis MP. Recent development in therapeutics for breakthrough pain. Expert Rev Neurother. 2010;10(5):757–73. doi:10.1586/ern.10.41.

    CAS  PubMed  Google Scholar 

  85. Cipolla D, Bruinenberg P, Eliahu P, Johansson E, Marjason J, Morishige R, editors. Development of an inhaled AERx essence nicotine product for smoking cessation. Respiratory drug delivery. Arizona: Interpharm Press; 2008.

    Google Scholar 

  86. Gonda I, Bruinenberg P, Mudumba S, Cipolla D, editors. Smoking cessation approach via deep lung delivery of ‘clean’ nicotine. RDD Europe 2009; Lisbon.

  87. Weers JG, Bell J, Chan HK, Cipolla D, Dunbar C, Hickey AJ, et al. Pulmonary formulations: what remains to be done? J Aerosol Med Pulmon Drug Deliv. 2010;23 Suppl 2:S5–23. doi:10.1089/jamp.2010.0838.

    CAS  Google Scholar 

  88. Chan H-K. Nanodrug particles and nanoformulations for drug delivery. Advanced Drug Delivery Reviews. 2011;63(6):405–492

    Google Scholar 

  89. Bhavna, Ahmad FJ, Mittal G, Jain GK, Malhotra G, Khar RK, et al. Nano-salbutamol dry powder inhalation: a new approach for treating broncho-constrictive conditions. Eur J Pharm Biopharm. 2009;71(2):282–91. doi:10.1016/j.ejpb.2008.09.018.

    CAS  PubMed  Google Scholar 

  90. Bur M, Henning A, Hein S, Schneider M, Lehr C-M. Inhalative nanomedicine—opportunities and challenges. Inhal Toxicol. 2009;21(s1):137–43. doi:10.1080/08958370902962283.

    CAS  PubMed  Google Scholar 

  91. Van Eerdenbrugh B, Van den Mooter G, Augustijns P. Top-down production of drug nanocrystals: nanosuspension stabilization, miniaturization and transformation into solid products. Int J Pharm. 2008;364(1):64–75. doi:10.1016/j.ijpharm.2008.07.023.

    PubMed  Google Scholar 

  92. Chan H-K, Kwok PCL. Production methods for nanodrug particles using the bottom-up approach. Adv Drug Deliv Rev. 2011;63(6):406–16. doi:10.1016/j.addr.2011.03.011.

    CAS  PubMed  Google Scholar 

  93. D’Addio SM, Prud'homme RK. Controlling drug nanoparticle formation by rapid precipitation. Adv Drug Deliv Rev. 2011;63(6):417–26. doi:10.1016/j.addr.2011.04.005.

    PubMed  Google Scholar 

  94. Kwok P, Tunsirikongkon A, Glover W, Chan H-K. Formation of protein nano-matrix particles with controlled surface architecture for respiratory drug delivery. Pharm Res. 2011;28(4):788–96. doi:10.1007/s11095-010-0332-2.

    CAS  PubMed  Google Scholar 

  95. Pornputtapitak W, El-gendy N, Berkland C. Nanocluster budesonide formulations enhance drug delivery through endotracheal tubes. J Pharm Sci. 2012;101(3):1063–72. doi:10.1002/jps.22818.

    CAS  PubMed  Google Scholar 

  96. El-Gendy N, Gorman EM, Munson EJ, Berkland C. Budesonide nanoparticle agglomerates as dry powder aerosols with rapid dissolution. J Pharm Sci. 2009;98(8):2731–46. doi:10.1002/jps.21630.

    CAS  PubMed  Google Scholar 

  97. El-Gendy N, Desai V, Berkland C. Agglomerates of ciprofloxacin nanoparticles yield fine dry powder aerosols. J Pharm Innov. 2010;5(3):79–87. doi:10.1007/s12247-010-9082-2.

    Google Scholar 

  98. El-Gendy N, Pornputtapitak W, Berkland C. Nanoparticle agglomerates of fluticasone propionate in combination with albuterol sulfate as dry powder aerosols. Eur J Pharm Sci. 2011;44(4):522–33. doi:10.1016/j.ejps.2011.09.014.

    CAS  PubMed  Google Scholar 

  99. Shen Z-G, Chen W-H, Jugade N, Gao L-Y, Glover W, Shen J-Y, et al. Fabrication of inhalable spore like pharmaceutical particles for deep lung deposition. Int J Pharm. 2012;430(1–2):98–103. doi:10.1016/j.ijpharm.2012.03.044.

    CAS  PubMed  Google Scholar 

  100. Bailey MM, Gorman EM, Munson EJ, Berkland C. Pure insulin nanoparticle agglomerates for pulmonary delivery. Langmuir. 2008;24(23):13614–20. doi:10.1021/la802405p.

    CAS  PubMed Central  PubMed  Google Scholar 

  101. El-Gendy N, Aillon KL, Berkland C. Dry powdered aerosols of diatrizoic acid nanoparticle agglomerates as a lung contrast agent. Int J Pharm. 2010;391(1–2):305–12. doi:10.1016/j.ijpharm.2010.03.009.

    CAS  PubMed Central  PubMed  Google Scholar 

  102. Aillon KL, El-Gendy N, Dennis C, Norenberg JP, McDonald J, Berkland C. Iodinated nanoclusters as an inhaled computed tomography contrast agent for lung visualization. Mol Pharm. 2010;7(4):1274–82. doi:10.1021/mp1000718.

    CAS  PubMed Central  PubMed  Google Scholar 

  103. Plumley C, Gorman EM, El-Gendy N, Bybee CR, Munson EJ, Berkland C. Nifedipine nanoparticle agglomeration as a dry powder aerosol formulation strategy. Int J Pharm. 2009;369(1–2):136–43. doi:10.1016/j.ijpharm.2008.10.016.

    CAS  PubMed Central  PubMed  Google Scholar 

  104. El-Gendy N, Berkland C. Combination chemotherapeutic dry powder aerosols via controlled nanoparticle agglomeration. Pharm Res. 2009;26(7):1752–63. doi:10.1007/s11095-009-9886-2.

    CAS  PubMed Central  PubMed  Google Scholar 

  105. Rytting E, Nguyen J, Wang X, Kissel T. Biodegradable polymeric nanocarriers for pulmonary drug delivery. Expert Opinion on Drug Delivery. 2008;5(6):629–39. doi:10.1517/17425247.5.6.629.

    CAS  PubMed  Google Scholar 

  106. Kurmi BD, Kayat J, Gajbhiye V, Tekade RK, Jain NK. Micro- and nanocarrier-mediated lung targeting. Expert Opin Drug Deliv. 2010;7(7):781–94. doi:10.1517/17425247.2010.492212.

    CAS  PubMed  Google Scholar 

  107. Sung JC, Pulliam BL, Edwards DA. Nanoparticles for drug delivery to the lungs. Trends Biotechnol. 2007;25(12):563–70.

    CAS  PubMed  Google Scholar 

  108. Azarmi S, Roa WH, Löbenberg R. Targeted delivery of nanoparticles for the treatment of lung diseases. Adv Drug Deliv Rev. 2008;60(8):863–75. doi:10.1016/j.addr.2007.11.006.

    CAS  PubMed  Google Scholar 

  109. Yang W, Peters JI, Williams Iii RO. Inhaled nanoparticles—a current review. Int J Pharm. 2008;356(1–2):239–47. doi:10.1016/j.ijpharm.2008.02.011.

    CAS  PubMed  Google Scholar 

  110. Rogueda PGA, Traini D. The nanoscale in pulmonary delivery. Part 2: formulation platforms. Expert Opin Drug Deliv. 2007;4(6):607–20.

    CAS  PubMed  Google Scholar 

  111. Beck-Broichsitter M, Merkel OM, Kissel T. Controlled pulmonary drug and gene delivery using polymeric nano-carriers. J Control Release. 2012;161(2):214–24. doi:10.1016/j.jconrel.2011.12.004.

    CAS  PubMed  Google Scholar 

  112. Chow AL, Tong HY, Chattopadhyay P, Shekunov B. Particle engineering for pulmonary drug delivery. Pharm Res. 2007;24(3):411–37. doi:10.1007/s11095-006-9174-3.

    CAS  PubMed  Google Scholar 

  113. Pilcer G, Amighi K. Formulation strategy and use of excipients in pulmonary drug delivery. Int J Pharm. 2010;392(1–2):1–19. doi:10.1016/j.ijpharm.2010.03.017.

    CAS  PubMed  Google Scholar 

  114. Astete CE, Sabliov CM. Synthesis and characterization of PLGA nanoparticles. J Biomater Sci Polym Ed. 2006;17(3):247–89. doi:10.1163/156856206775997322.

    CAS  PubMed  Google Scholar 

  115. Bala I, Hariharan S, Kumar MNVR. PLGA nanoparticles in drug delivery: the state of the art. Crit Rev Ther Drug Carr Syst. 2004;21(5):36. doi:10.1615/CritRevTherDrugCarrierSyst.v21.i5.20.

    Google Scholar 

  116. Dailey LA, Kissel T. New poly(lactic-co-glycolic acid) derivatives: modular polymers with tailored properties. Drug Discov Today: Technol. 2005;2(1):7–13. doi:10.1016/j.ddtec.2005.05.017.

    CAS  Google Scholar 

  117. Dailey LA, Wittmar M, Kissel T. The role of branched polyesters and their modifications in the development of modern drug delivery vehicles. J Control Release. 2005;101(1–3):137–49. doi:10.1016/j.jconrel.2004.09.003.

    CAS  PubMed  Google Scholar 

  118. Pancholi K, Stride E, Edirisinghe M. In vitro method to characterize diffusion of dye from polymeric particles: a model for drug release. Langmuir. 2009;25(17):10007–13. doi:10.1021/la900694k.

    CAS  PubMed  Google Scholar 

  119. Barichello JM, Morishita M, Takayama K, Nagai T. Encapsulation of hydrophilic and lipophilic drugs in PLGA nanoparticles by the nanoprecipitation method. Drug Dev Ind Pharm. 1999;25(4):471–6. doi:10.1081/ddc-100102197.

    CAS  PubMed  Google Scholar 

  120. Wang X, Xie X, Cai C, Rytting E, Steele T, Kissel T. Biodegradable branched polyesters poly(vinyl sulfonate-covinyl alcohol)-graft poly(d, l-lactic-coglycolic acid) as a negatively charged polyelectrolyte platform for drug delivery: synthesis and characterization. Macromolecules. 2008;41(8):2791–9. doi:10.1021/ma702705s.

    CAS  Google Scholar 

  121. Wittmar M, Unger F, Kissel T. Biodegradable brushlike branched polyesters containing a charge-modified poly(vinyl alcohol) backbone as a platform for drug delivery systems: synthesis and characterization. Macromolecules. 2006;39(4):1417–24. doi:10.1021/ma051837n.

    CAS  Google Scholar 

  122. Beck-Broichsitter M, Rytting E, Lebhardt T, Wang X, Kissel T. Preparation of nanoparticles by solvent displacement for drug delivery: a shift in the “ouzo region” upon drug loading. Eur J Pharm Sci. 2010;41(2):244–53. doi:10.1016/j.ejps.2010.06.007.

    CAS  PubMed  Google Scholar 

  123. Card JW, Zeldin DC, Bonner JC, Nestmann ER. Pulmonary applications and toxicity of engineered nanoparticles. Am J Physiol Lung Cell Mol Physiol. 2008;295(3):L400–11. doi:10.1152/ajplung.00041.2008.

    CAS  PubMed Central  PubMed  Google Scholar 

  124. Gill S, Löbenberg R, Ku T, Azarmi S, Roa W, Prenner EJ. Nanoparticles: characteristics, mechanisms of action, and toxicity in pulmonary drug delivery—a review. J Biomed Nanotechnol. 2007;3(2):107–19.

    CAS  Google Scholar 

  125. Higginson D, Theodoratou E, Nair H, Huda T, Zgaga L, Jadhav SS, et al. An evaluation of respiratory administration of measles vaccine for prevention of acute lower respiratory infections in children. BMC Public Health. 2011;11 Suppl 3:S31. doi:10.1186/1471-2458-11-S3-S31.

    PubMed Central  PubMed  Google Scholar 

  126. Omer SB, Hiremath GS, Halsey NA. Respiratory administration of measles vaccine. Lancet. 2010;375(9716):706–8. doi:10.1016/S0140-6736(09)62028-6.

    PubMed  Google Scholar 

  127. Lin W-H, Griffin DE, Rota PA, Cape SP, Bennett D. Successful respiratory immunization with dry powder live-attenuated measles virus vaccine in rhesus macaques. Proceedings of the National Academy of Sciences. PNAS. 2011. doi:10.1073/pnas.1017334108.

    Google Scholar 

  128. Bennett JV, Fernandez de Castro J, Valdespino-Gomez JL, Garcia-Garcia Mde L, Islas-Romero R, Echaniz-Aviles G, et al. Aerosolized measles and measles-rubella vaccines induce better measles antibody booster responses than injected vaccines: randomized trials in Mexican schoolchildren. Bull World Health Organ. 2002;80(10):806–12.

    PubMed Central  PubMed  Google Scholar 

  129. Castro JF, Bennett JV, Rincon HG, Munoz MT, Sanchez LA, Santos JI. Evaluation of immunogenicity and side effects of triple viral vaccine (MMR) in adults, given by two routes: subcutaneous and respiratory (aerosol). Vaccine. 2005;23(8):1079–84. doi:10.1016/j.vaccine.2004.08.018.

    PubMed  Google Scholar 

  130. Wayne Conlan J, Shen H, KuoLee R, Zhao X, Chen W. Aerosol-, but not intradermal-immunization with the live vaccine strain of Francisella tularensis protects mice against subsequent aerosol challenge with a highly virulent type A strain of the pathogen by an αβ T cell- and interferon gamma-dependent mechanism. Vaccine. 2005;23(19):2477–85. doi:10.1016/j.vaccine.2004.10.034.

    CAS  PubMed  Google Scholar 

  131. Huang J, Mikszta JA, Ferriter MS, Jiang G, Harvey NG, Dyas B, et al. Intranasal administration of dry powder anthrax vaccine provides protection against lethal aerosol spore challenge. Hum Vaccin. 2007;3(3):90–3.

    CAS  PubMed  Google Scholar 

  132. Tyne AS, Chan JG, Shanahan ER, Atmosukarto I, Chan HK, Britton WJ, et al. TLR2-targeted secreted proteins from Mycobacterium tuberculosis are protective as powdered pulmonary vaccines. Vaccine. 2013;31(40):4322–9. doi:10.1016/j.vaccine.2013.07.022.

    CAS  PubMed  Google Scholar 

  133. Garcia Contreras L, Awashthi S, Hanif S, Hickey AJ. Inhaled vaccines for the prevention of tuberculosis. J Mycobac Dis. 2013;S1(002):1–13. doi:10.4172/2161-1068.S1-002.

    Google Scholar 

  134. Hokey DA, Misra A. Aerosol vaccines for tuberculosis: a fine line between protection and pathology. Tuberculosis. 2011;91(1):82–5. Edinburgh, Scotland.

    CAS  PubMed  Google Scholar 

  135. Frois C, Wu EQ, Ray S, Colice GL. Inhaled corticosteroids or long-acting beta-agonists alone or in fixed-dose combinations in asthma treatment: a systematic review of fluticasone/budesonide and formoterol/salmeterol. Clin Ther. 2009;31(12):2779–803. doi:10.1016/j.clinthera.2009.12.021.

    CAS  PubMed  Google Scholar 

  136. Lechuga-Ballesteros D, Noga B, Vehring R, Cummings RH, Dwivedi SK. Novel cosuspension metered-dose inhalers for the combination therapy of chronic obstructive pulmonary disease and asthma. Futur Med Chem. 2011;3(13):1703–18. doi:10.4155/fmc.11.133.

    CAS  Google Scholar 

  137. Buhl R, Vogelmeier C. Budesonide/formoterol maintenance and reliever therapy: a new treatment approach for adult patients with asthma. Curr Med Res Opin. 2007;23(8):1867–78. doi:10.1185/030079907x210769.

    CAS  PubMed  Google Scholar 

  138. Morice AH, Peterson S, Beckman O, Osmanliev D. Therapeutic comparison of a new budesonide/formoterol pMDI with budesonide pMDI and budesonide/formoterol DPI in asthma. Int J Clin Pract. 2007;61(11):1874–83. doi:10.1111/j.1742-1241.2007.01574.x.

    CAS  PubMed Central  PubMed  Google Scholar 

  139. Vandevanter DR, Geller DE. Tobramycin administered by the TOBI Podhaler for persons with cystic fibrosis: a review. Med Devices. 2011;4:179–88. doi:10.2147/MDER.S16360.

    CAS  Google Scholar 

  140. Zhou Q, Morton DAV, Yu HH, Jacob J, Wang J, Li J, et al. Colistin powders with high aerosolisation efficiency for respiratory infection: preparation and in vitro evaluation. J Pharm Sci. 2013;102(10):3736–47. doi:10.1002/jps.23685.

    CAS  PubMed  Google Scholar 

  141. Duret C, Wauthoz N, Sebti T, Vanderbist F, Amighi K. New inhalation-optimized itraconazole nanoparticle-based dry powders for the treatment of invasive pulmonary aspergillosis. Int J Nanomedicine. 2012;7:5475–89. doi:10.2147/IJN.S34091.

    CAS  PubMed Central  PubMed  Google Scholar 

  142. Schuster A, Haliburn C, Doring G, Goldman MH. Safety, efficacy and convenience of colistimethate sodium dry powder for inhalation (Colobreathe DPI) in patients with cystic fibrosis: a randomised study. Thorax. 2013;68(4):344–50. doi:10.1136/thoraxjnl-2012-202059.

    PubMed Central  PubMed  Google Scholar 

  143. Geller DE, Weers J, Heuerding S. Development of an inhaled dry-powder formulation of tobramycin using PulmoSphere technology. J Aerosol Med Pulm Drug Deliv. 2011;24(4):175–82. doi:10.1089/jamp.2010.0855.

    CAS  PubMed Central  PubMed  Google Scholar 

  144. Tsifansky MD, Yeo Y, Evgenov OV, Bellas E, Benjamin J, Kohane DS. Microparticles for inhalational delivery of antipseudomonal antibiotics. AAPS J. 2008;10(2):254–60. doi:10.1208/s12248-008-9033-8.

    CAS  PubMed Central  PubMed  Google Scholar 

  145. Yang Y, Tsifansky MD, Wu CJ, Yang HI, Schmidt G, Yeo Y. Inhalable antibiotic delivery using a dry powder co-delivering recombinant deoxyribonuclease and ciprofloxacin for treatment of cystic fibrosis. Pharm Res. 2010;27(1):151–60. doi:10.1007/s11095-009-9991-2.

    CAS  PubMed  Google Scholar 

  146. Adi H, Young PM, Chan HK, Agus H, Traini D. Co-spray-dried mannitol-ciprofloxacin dry powder inhaler formulation for cystic fibrosis and chronic obstructive pulmonary disease. Eur J Pharm Sci: Off J Eur Fed Pharm Sci. 2010;40(3):239–47. doi:10.1016/j.ejps.2010.03.020.

    CAS  Google Scholar 

  147. Zhou Q, Gengenbach T, Denman J, Yu H, Li J, Chan H. Synergistic antibiotic combination powders of colistin and rifampicin provide high aerosolization efficiency and moisture protection. AAPS J. 2014;16(1):37–47. doi:10.1208/s12248-013-9537-8.

    PubMed  Google Scholar 

  148. Chan JG, Chan HK, Prestidge CA, Denman JA, Young PM, Traini D. A novel dry powder inhalable formulation incorporating three first-line anti-tubercular antibiotics. Eur J Pharm Biopharm: Off J Arbeitsgemeinschaft Pharm Verfahrenstechnik eV. 2012. doi:10.1016/j.ejpb.2012.08.007.

    Google Scholar 

  149. Dharmadhikari AS, Kabadi M, Gerety B, Hickey AJ, Fourie PB, Nardell E. Phase I, single-dose, dose-escalating study of inhaled dry powder capreomycin: a new approach to therapy of drug-resistant tuberculosis. Antimicrob Agents Chemother. 2013;57(6):2613–9. doi:10.1128/AAC.02346-12.

    CAS  PubMed Central  PubMed  Google Scholar 

  150. Golshahi L, Lynch KH, Dennis JJ, Finlay WH. In vitro lung delivery of bacteriophages KS4-M and PhiKZ using dry powder inhalers for treatment of Burkholderia cepacia complex and Pseudomonas aeruginosa infections in cystic fibrosis. J Appl Microbiol. 2011;110(1):106–17. doi:10.1111/j.1365-2672.2010.04863.x.

    CAS  PubMed  Google Scholar 

  151. Myrdal PB, Sheth P, Stein SW. Advances in metered dose inhaler technology: formulation development. AAPS PharmSciTech. 2014.

  152. Wu ZZ, Thatcher ML, Lundberg JK, Ogawa MK, Jacoby CB, Battiste JL, et al. Forced degradation studies of corticosteroids with an alumina-steroid-ethanol model for predicting chemical stability and degradation products of pressurized metered-dose inhaler formulations. J Pharm Sci. 2012;101(6):2109–22. doi:10.1002/jps.23111.

    CAS  PubMed  Google Scholar 

  153. Vervaet C, Byron PR. Drug-surfactant-propellant interactions in HFA-formulations. Int J Pharm. 1999;186(1):13–30. doi:10.1016/s0378-5173(99)00134-9.

    CAS  PubMed  Google Scholar 

  154. Wu Z.Z. GN, Johnson P.R. Steroid solution aerosol products with enhanced chemical stability. 3M Innovative Properties Company; 2011

  155. Lewis D. GD, Meakin B., Ventura P., Brambilla G.,Garzia R. Pressurized metered dose inhalers (MDI) containing a solution comprising ipratropium bromide, HFA propellant, and co-solvent and comprising a container with a specific internal surface composition and/or lining. Chiesi Farmaceutici S.p.A.; 2012.

  156. Dohmeier DM HD, Wilde T, editor. The application of a new high performance dual-layer coating to pressurized metered dose inhaler hardware. Respir Drug Deliv Eur; 2009; 2:209–212

    Google Scholar 

  157. Sukasame N, Boonme P, Srichana T. Development of budesonide suspensions for use in an HFA pressurized metered dose inhaler. Sci Asia. 2011;37(1):31–7. doi:10.2306/scienceasia1513-1874.2011.37.031.

    CAS  Google Scholar 

  158. Murata S, Izumi T, Ito H. Reformulation of Stmerin® D CFC formulation using HFA propellants. Pharm Dev Technol. 2013;18(6):1314–8. doi:10.3109/10837450.2012.680596.

    CAS  PubMed  Google Scholar 

  159. Zhu B, Traini D, Chan H-K, Young PM. The effect of ethanol on the formation and physico-chemical properties of particles generated from budesonide solution-based pressurized metered-dose inhalers. Drug Dev Ind Pharm. 2013;39(11):1625–37. doi:10.3109/03639045.2012.728230.

    CAS  PubMed  Google Scholar 

  160. Saleem IY, Smyth HDC. Tuning aerosol particle size distribution of metered dose inhalers using cosolvents and surfactants. BioMed Research International. 2013;2013:574310. doi: 10.1155/2013/574310.

  161. Ninbovorl J, Sawatdee S, Srichana T. Factors affecting the stability and performance of ipratropium bromide; fenoterol hydrobromide pressurized-metered dose inhalers. AAPS PharmSciTech. 2013;14(4):1294–302. doi:10.1208/s12249-013-0024-4.

    CAS  PubMed Central  PubMed  Google Scholar 

  162. Leach CL HW, Tomai MA, Hammerbeck DM, Stefely JS. Oligolactic acid (OLA) biomatrices for sustained release of asthma therapeutics. In: RN Dalby PB, SJ Farr, J Peart (Eds). Respiratory drug delivery VII: Serentec: Raleigh, NC; 2000. p. 75–87.

  163. Purohit D, Trehan A, Arora V. Development of room temperature stable formulation of formoterol fumarate/beclomethasone HFA pMDI. Indian J Pharm Sci. 2009;71(6):713–U13.

    PubMed Central  Google Scholar 

  164. Wu L, Al-Haydari M, da Rocha SRP. Novel propellant-driven inhalation formulations: engineering polar drug particles with surface-trapped hydrofluoroalkane-philes. Eur J Pharm Sci. 2008;33(2):146–58. doi:10.1016/j.ejps.2007.10.007.

    CAS  PubMed  Google Scholar 

  165. Dellamary LA, Tarara TE, Smith DJ, Woelk CH, Adractas A, Costello ML, et al. Hollow porous particles in metered dose inhalers. Pharm Res. 2000;17(2):168–74. doi:10.1023/a:1007513213292.

    CAS  PubMed  Google Scholar 

  166. Vehring R, Lechuga-Ballesteros D, Joshi V, Noga B, Dwivedi SK. Cosuspensions of microcrystals and engineered microparticles for uniform and efficient delivery of respiratory therapeutics from pressurized metered dose inhalers. Langmuir. 2012;28(42):15015–23. doi:10.1021/la302281n.

    CAS  PubMed  Google Scholar 

  167. Barnes PJ. Scientific rationale for using a single inhaler for asthma control. Eur Respir J. 2007;29(3):587–95. doi:10.1183/09031936.00080306.

    CAS  PubMed  Google Scholar 

  168. Bodzenta-Lukaszyk A, Pulka G, Dymek A, Bumbacea D, McIver T, Schwab B, et al. Efficacy and safety of fluticasone and formoterol in a single pressurized metered dose inhaler. Respir Med. 2011;105(5):674–82. doi:10.1016/j.rmed.2010.11.011.

    PubMed  Google Scholar 

  169. Chatterjee A, Shah M, D'Souza AO, Bechtel B, Crater G, Dalal AA. Observational study on the impact of initiating tiotropium alone versus tiotropium with fluticasone propionate/salmeterol combination therapy on outcomes and costs in chronic obstructive pulmonary disease. Respiratory Research. 2012. doi: 10.1186/1465-9921-13-15.

  170. Tashkin DP, Ferguson GT. Combination bronchodilator therapy in the management of chronic obstructive pulmonary disease. Respiratory Research. 2013. doi: 10.1186/1465-9921-14-49.

  171. Rogueda PGA, Price R, Smith T, Young PM, Traini D. Particle synergy and aerosol performance in non-aqueous liquid of two combinations metered dose inhalation formulations: an AFM and Raman investigation. J Colloid Interface Sci. 2011;361(2):649–55. doi:10.1016/j.jcis.2011.05.073.

    CAS  PubMed  Google Scholar 

  172. Salama RO, Young PM, Rogueda P, Lallement A, Iliev I, Traini D. Advances in drug delivery: is triple therapy the future for the treatment of chronic obstructive pulmonary disease? Expert Opin Pharmacother. 2011;12(12):1913–32.

    CAS  PubMed  Google Scholar 

  173. Tan YH, Yang ZW, Peng XS, Xin F, Xu YH, Feng M, et al. A novel bottom-up process to produce nanoparticles containing protein and peptide for suspension in hydrofluoroalkane propellants. Int J Pharm. 2011;413(1–2):167–73. doi:10.1016/j.ijpharm.2011.03.069.

    CAS  PubMed  Google Scholar 

  174. Li HY, Seville PC. Novel pMDI formulations for pulmonary delivery of proteins. Int J Pharm. 2010;385(1–2):73–8. doi:10.1016/j.ijpharm.2009.10.032.

    CAS  PubMed  Google Scholar 

  175. Bains BK, Birchall JC, Toon R, Taylor G. In vitro reporter gene transfection via plasm Id DNA delivered by metered dose inhaler. J Pharm Sci. 2010;99(7):3089–99. doi:10.1002/jps.22085.

    CAS  PubMed  Google Scholar 

  176. Conti DS, Bharatwaj B, Brewer D, da Rocha SRP. Propellant-based inhalers for the non-invasive delivery of genes via oral inhalation. J Control Release. 2012;157(3):406–17. doi:10.1016/j.jconrel.2011.09.089.

    CAS  PubMed  Google Scholar 

  177. Haddrell AE, Hargreaves G, Davies JF, Reid JP. Control over hygroscopic growth of saline aqueous aerosol using pluronic polymer additives. Int J Pharm. 2013;443(1–2):183–92. doi:10.1016/j.ijpharm.2012.12.039.

    CAS  PubMed  Google Scholar 

  178. Beck-Broichsitter M, Oesterheld N, Knuedeler MC, Seeger W, Schmehl T. On the correlation of output rate and aerodynamic characteristics in vibrating-mesh-based aqueous aerosol delivery. Int J Pharm. 2013;461(1–2):34–7. doi:10.1016/j.ijpharm.2013.11.036.

    PubMed  Google Scholar 

  179. Chan JG, Traini D, Chan HK, Young PM, Kwok PC. Delivery of high solubility polyols by vibrating mesh nebulizer to enhance mucociliary clearance. J Aerosol Med Pulm Drug Deliv. 2012;25(5):297–305. doi:10.1089/jamp.2011.0961.

    CAS  PubMed  Google Scholar 

  180. Carvalho TC, McCook JP, Narain NR, McConville JT. Development and characterization of phospholipid-stabilized submicron aqueous dispersions of coenzyme Q(1)(0) presenting continuous vibrating-mesh nebulization performance. J Liposome Res. 2013;23(4):276–90. doi:10.3109/08982104.2013.796976.

    CAS  PubMed  Google Scholar 

  181. Najlah M, Parveen I, Alhnan MA, Ahmed W, Faheem A, Phoenix DA, et al. The effects of suspension particle size on the performance of air-jet, ultrasonic and vibrating-mesh nebulisers. Int J Pharm. 2013;461(1–2):234–41. doi:10.1016/j.ijpharm.2013.11.022.

    PubMed  Google Scholar 

  182. Lambros MP, Beringer PM, Wong-Beringer A. Nebulizer choice affects the airway targeting of amphotericin B lipid complex aerosols. J Pharm Technol. 2013;29(5):199–204. doi:10.1177/8755122513500905.

    CAS  Google Scholar 

  183. Beck-Broichsitter M, Rieger M, Reul R, Gessler T, Seeger W, Schmehl T. Correlation of drug release with pulmonary drug absorption profiles for nebulizable liposomal formulations. Eur J Pharm Biopharm: Off J Arbeitsgemeinschaft Pharm Verfahrenstechnik eV. 2013;84(1):106–14. doi:10.1016/j.ejpb.2012.12.003.

    CAS  Google Scholar 

  184. Ong HX, Benaouda F, Traini D, Cipolla D, Gonda I, Bebawy M, et al. In vitro and ex vivo methods predict the enhanced lung residence time of liposomal ciprofloxacin formulations for nebulisation. Eur J Pharm Biopharm: Off J Arbeitsgemeinschaft Pharm Verfahrenstechnik eV. 2013. doi:10.1016/j.ejpb.2013.06.024.

    Google Scholar 

  185. Cipolla D, Wu H, Chan J, Chan H-K, Gonda I, editors. Liposomal ciprofloxacin for inhalation retains integrity following nebulization. RDD Europe 2013; 2013; Berlin.

  186. Gaspar MM, Gobbo O, Ehrhardt C. Generation of liposome aerosols with the Aeroneb Pro and the AeroProbe nebulizers. J Liposome Res. 2010;20(1):55–61. doi:10.3109/08982100903085150.

    CAS  PubMed  Google Scholar 

  187. Cipolla D, Gonda I, Chan HK. Liposomal formulations for inhalation. Ther Deliv. 2013;4(8):1047–72. doi:10.4155/tde.13.71.

    CAS  PubMed  Google Scholar 

  188. Alexander BD, Winkler TP, Shi S, Dodds Ashley ES, Hickey AJ. In vitro characterization of nebulizer delivery of liposomal amphotericin B aerosols. Pharm Dev Technol. 2011;16(6):577–82. doi:10.3109/10837450.2011.591803.

    CAS  PubMed  Google Scholar 

  189. Monforte V, Lopez-Sanchez A, Zurbano F, Ussetti P, Sole A, Casals C, et al. Prophylaxis with nebulized liposomal amphotericin B for Aspergillus infection in lung transplant patients does not cause changes in the lipid content of pulmonary surfactant. J Heart Lung Transplant: Off Publ Int Soc Heart Transplant. 2013;32(3):313–9. doi:10.1016/j.healun.2012.11.013.

    Google Scholar 

  190. Sharma K, Somavarapu S, Colombani A, Govind N, Taylor KM. Nebulised siRNA encapsulated crosslinked chitosan nanoparticles for pulmonary delivery. Int J Pharm. 2013;455(1–2):241–7. doi:10.1016/j.ijpharm.2013.07.024.

    CAS  PubMed  Google Scholar 

  191. Beck-Broichsitter M, Kleimann P, Gessler T, Seeger W, Kissel T, Schmehl T. Nebulization performance of biodegradable sildenafil-loaded nanoparticles using the Aeroneb Pro: formulation aspects and nanoparticle stability to nebulization. Int J Pharm. 2012;422(1-2):398–408. doi:10.1016/j.ijpharm.2011.10.012.

    CAS  PubMed  Google Scholar 

  192. Ichinose F, Erana-Garcia J, Hromi J, Raveh Y, Jones R, Krim L, et al. Nebulized sildenafil is a selective pulmonary vasodilator in lambs with acute pulmonary hypertension. Crit Care Med. 2001;29(5):1000–5.

    CAS  PubMed  Google Scholar 

  193. Lubamba B, Lebacq J, Reychler G, Marbaix E, Wallemacq P, Lebecque P, et al. Inhaled phosphodiesterase type 5 inhibitors restore chloride transport in cystic fibrosis mice. Eur Respir J. 2011;37(1):72–8. doi:10.1183/09031936.00013510.

    CAS  PubMed  Google Scholar 

  194. Antoniu SA, Trofor AC. Inhaled gentamicin in non-cystic fibrosis bronchiectasis: effects of long-term therapy. Expert Opin Pharmacother. 2011;12(7):1191–4. doi:10.1517/14656566.2011.563735.

    CAS  PubMed  Google Scholar 

  195. Serisier DJ, Bilton D, De Soyza A, Thompson PJ, Kolbe J, Greville HW, et al. Inhaled, dual release liposomal ciprofloxacin in non-cystic fibrosis bronchiectasis (ORBIT-2): a randomised, double-blind, placebo-controlled trial. Thorax. 2013;68(9):812–7. doi:10.1136/thoraxjnl-2013-203207.

    PubMed  Google Scholar 

  196. Zeitler K, Salvas B, Stevens V, Brown J. Aztreonam lysine for inhalation: new formulation of an old antibiotic. Am J Health Syst Pharm: AJHP: Off J Am Soc Health Syst Pharm. 2012;69(2):107–15. doi:10.2146/ajhp100624.

    CAS  Google Scholar 

  197. Cooper CJ, Denyer SP, Maillard JY. Stability and purity of a bacteriophage cocktail preparation for nebulizer delivery. Lett Appl Microbiol. 2013. doi:10.1111/lam.12161.

    PubMed  Google Scholar 

  198. Manca ML, Cassano R, Valenti D, Trombino S, Ferrarelli T, Picci N, et al. Isoniazid-gelatin conjugate microparticles containing rifampicin for the treatment of tuberculosis. J Pharm Pharmacol. 2013;65(9):1302–11. doi:10.1111/jphp.12094.

    CAS  PubMed  Google Scholar 

  199. Patlolla RR, Chougule M, Patel AR, Jackson T, Tata PN, Singh M. Formulation, characterization and pulmonary deposition of nebulized celecoxib encapsulated nanostructured lipid carriers. J Control Release: Off J Control Release Soc. 2010;144(2):233–41. doi:10.1016/j.jconrel.2010.02.006.

    CAS  Google Scholar 

  200. Reed MD, Tellez CS, Grimes MJ, Picchi MA, Tessema M, Cheng YS, et al. Aerosolised 5-azacytidine suppresses tumour growth and reprogrammes the epigenome in an orthotopic lung cancer model. Brit J Cancer. 2013;109(7):1775–81. doi:10.1038/bjc.2013.575.

    CAS  PubMed Central  PubMed  Google Scholar 

  201. Hudson R, Olson Blair B. Inhaled antibiotics for Gram-negative respiratory infections. Futur Med Chem. 2011;3(13):1663–77. doi:10.4155/fmc.11.114.

    CAS  Google Scholar 

  202. Cipolla D, Chan H-K. Inhaled antibiotics to treat lung infection. Pharm Patent Analyst. 2013;2(5):647–63. doi:10.4155/ppa.13.47.

    CAS  Google Scholar 

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Acknowledgments

This study was supported by the Australian Research Council's Discovery Projects funding scheme (DP120102778 and DP110105161).

Dr Qi Tony Zhou is the recipient of the Early Career Fellowship from National Health and Medical Research Council (APP1053528). John Chan and Jennifer Wong are recipients of the Australian Postgraduate Award from the Australian Federal Government.

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Authors and Affiliations

  1. Respiratory Technology, Woolcock Institute of Medical Research and Discipline of Pharmacology, Sydney Medical School, The University of Sydney, Sydney, 2037, NSW, Australia

    John Gar Yan Chan

  2. Advanced Drug Delivery Group, Faculty of Pharmacy, The University of Sydney, Sydney, 2006, NSW, Australia

    John Gar Yan Chan, Jennifer Wong, Qi Tony Zhou, Sharon Shui Yee Leung & Hak-Kim Chan

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  1. John Gar Yan Chan
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  2. Jennifer Wong
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  3. Qi Tony Zhou
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  4. Sharon Shui Yee Leung
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  5. Hak-Kim Chan
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Correspondence to Hak-Kim Chan.

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Guest Editors: Paul B. Myrdal and Steve W. Stein

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Chan, J.G.Y., Wong, J., Zhou, Q.T. et al. Advances in Device and Formulation Technologies for Pulmonary Drug Delivery. AAPS PharmSciTech 15, 882–897 (2014). https://doi.org/10.1208/s12249-014-0114-y

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  • DOI: https://doi.org/10.1208/s12249-014-0114-y

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