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Nebulizer systems: a new frontier for therapeutics and targeted delivery

    Sakshi V Khairnar

    Institute of Chemical Technology, Department of Pharmaceutical Science & Technology, Mumbai 400019, India

    ,
    Divya D Jain

    Institute of Chemical Technology, Department of Pharmaceutical Science & Technology, Mumbai 400019, India

    ,
    Srushti M Tambe

    Institute of Chemical Technology, Department of Pharmaceutical Science & Technology, Mumbai 400019, India

    ,
    Yashashri R Chavan

    Institute of Chemical Technology, Department of Pharmaceutical Science & Technology, Mumbai 400019, India

    &
    Purnima D Amin

    *Author for correspondence: Tel.: +91 9820966358; 

    E-mail Address: pd.amin@ictmumbai.ed.in

    Institute of Chemical Technology, Department of Pharmaceutical Science & Technology, Mumbai 400019, India

    Published Online:https://doi.org/10.4155/tde-2021-0070

    Drug delivery via the pulmonary route is a cornerstone in the pharmaceutical sector as an alternative to oral and parenteral administration. Nebulizer inhalation treatment offers multiple drug administration, easily employed with tidal breathing, suitable for children and elderly, can be adapted for severe patients and visible spray ensures patient satisfaction. This review discusses the operational and mechanical characteristics of nebulizer delivery devices in terms of aerosol production processes, their usage, benefits and drawbacks that are currently shaping the contemporary landscape of inhaled drug delivery. With the advent of particle engineering, novel inhaled nanosystems can be successfully developed to increase lung deposition and decrease pulmonary clearance. The above-mentioned advances might pave the path for treating a life-threatening disorder like severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) which is also discussed in the current state of the art.

    Graphical abstract

    Papers of special note have been highlighted as: • of interest; •• of considerable interest

    References

    • 1. Singh A, Malviya R, Sharma PK. Pulmonary drug delivery system: a novel approach for drug delivery. Curr. Drug Ther. 6(2), 137–151 (2011).
    • 2. Labiris NR, Dolovich MB. Pulmonary drug delivery. Part I: physiological factors affecting therapeutic effectiveness of aerosolized medications. Br. J. Clin. Pharmacol. 56(6), 588–599 (2003). •• A useful review highlighting critical factors to consider when developing aerosolized medications.
    • 3. Hickey AJ. Emerging trends in inhaled drug delivery. Adv. Drug Deliv. Rev. 157, 63–70 (2020).
    • 4. Labiris NR, Dolovich MB. Pulmonary drug delivery. Part II: the role of inhalant delivery devices and drug formulations in therapeutic effectiveness of aerosolized medications. Br. J. Clin. Pharmacol. 56(6), 600–612 (2003). •• Sheds light on the important factors that influence the type of aerosol delivery system and drug formulation on a drug's therapeutic effectiveness.
    • 5. Christie T. On inhaling the smoke of datura in asthma. Edinb. Med. Surg. J. 7(26), 158–160 (1811).
    • 6. Yıldız-Peköz A, Ehrhardt C. Advances in pulmonary drug delivery. Pharmaceutics 12(10), 911 (2020).
    • 7. Javadzadeh Y, Yaqoubi S. Therapeutic nanostructures for pulmonary drug delivery. In: Nanostructures for Drug Delivery. Andronescu EGrumezescu AM (Eds). 619–638 Elsevier Inc, Amsterdam, Netherlands (2017).
    • 8. Groneberg DA, Witt C, Wagner U, Chung KF, Fischer A. Fundamentals of pulmonary drug delivery. Respir. Med. 97(4), 382–387 (2003).
    • 9. Patton JS, Byron PR. Inhaling medicines: delivering drugs to the body through the lungs. Nat. Rev. Drug Discov. 6(1), 67–74 (2007).
    • 10. Hock SC, Ying YM, Wah CL. A review of the current scientific and regulatory status of nanomedicines and the challenges ahead. PDA J. Pharm. Sci. Technol. 65(2), 177–195 (2011).
    • 11. Newman SP. Drug delivery to the lungs: challenges and opportunities. Ther. Deliv. 8(8), 647–661 (2017).
    • 12. Pritchard JN. Nebulized drug delivery in respiratory medicine: what does the future hold? Ther. Deliv. 8(6), 391–399 (2017).
    • 13. Thorat S, Meshram S. Formulation and product development of pressurised metered dose inhaler: an overview. PharmaTutor 3(9), 53–64 (2015).
    • 14. Kwok PCL, Chan HK. Pulmonary drug delivery. Ther. Deliv. 4(8), 877–878 (2013).
    • 15. Le Brun PPH, De Boer AH, Frijlink HW, Heijerman HGM. A review of the technical aspects of drug nebulization. Pharm. World Sci. 22(3), 75–81 (2000). • Review presents the technical features of the nebulization of drug solutions.
    • 16. Geller DE. Comparing clinical features of the nebulizer, metered-dose inhaler, and dry powder inhaler. Respir. Care. 50(10), 1313–1322 (2005).
    • 17. Pirozynski M, Sosnowski TR. Inhalation devices: from basic science to practical use, innovative vs generic products. Expert Opin. Drug Deliv. 13(11), 1559–1571 (2016).
    • 18. Djupesland PG. Nasal drug delivery devices: characteristics and performance in a clinical perspective—a review. Drug Deliv. Transl. Res. 3(1), 42–62 (2013).
    • 19. Cho H-S, Wan G-H, Hsieh M-J. Performance of different types of nebulizer with spontaneous adult breathing pattern. Presented at: American Thoracic Society 2016 International Conference. San Francisco, CA, USA (2016).
    • 20. Pilcer G, Amighi K. Formulation strategy and use of excipients in pulmonary drug delivery. Int. J. Pharm. 392(1–2), 1–19 (2010).
    • 21. Ibrahim M, Verma R, Garcia-Contreras L. Inhalation drug delivery devices: technology update. Med. Devices (Auckl). 8, 131–139 (2015).
    • 22. Dolovich MB, Dhand R. Aerosol drug delivery: developments in device design and clinical use. Lancet 377(9770), 1032–1045 (2011). • Focuses on the significant advances in the design and clinical application of aerosol devices.
    • 23. Ari A. Jet, ultrasonic, and mesh nebulizers: an evaluation of nebulizers for better clinical outcomes. Eurasian J. Pulmonol. 16, 1–7 (2014).
    • 24. Elphick M, Hollen DV, Pritchard JN, Nikander K, Hardaker LEA, Hatley RHM. Factors to consider when selecting a nebulizer for a new inhaled drug product development program. Expert Opin. Drug Deliv. 12(8), 1375–1387 (2015). •• Summarizes the different types of nebulizer technologies and discusses the factors to be considered when selecting a technology for a new inhaled drug.
    • 25. Page CP, Barnes PJ. In: Pharmacology and Therapeutics of Asthma and COPD. Springer, NY, USA (2017).
    • 26. Sethi S, Barjaktarevic IZ, Tashkin DP. The use of nebulized pharmacotherapies during the COVID-19 pandemic. Ther. Adv. Respir. Dis. 14, 1753466620954366 (2020).
    • 27. Respaud R, Vecellio L, Diot P, Heuzé-Vourc'h N. Nebulization as a delivery method for mAbs in respiratory diseases. Expert Opin Drug Deliv. 12(6), 1027–1039 (2015).
    • 28. Pritchard JN, Hatley RH, Denyer J, Hollen DV. Mesh nebulizers have become the first choice for new nebulized pharmaceutical drug developments. Ther. Deliv. 9(2), 121–136 (2018).
    • 29. Tashkin DP. A review of nebulized drug delivery in COPD. Int. J. Chron. Obstruct. Pulmon. Dis. 11, 2585–2596 (2016).
    • 30. Prajapati S, Saha S, Sahoo B. Nebulized drug delivery: an overview. Int. J. Pharm. Sci. Res. 10(8), 3575–3582 (2019).
    • 31. Newman SP. Delivering drugs to the lungs: the history of repurposing in the treatment of respiratory diseases. Adv. Drug Deliv. Rev. 133, 5–18 (2018).
    • 32. Dhand R. Intelligent nebulizers in the age of the internet: the I-neb Adaptive Aerosol Delivery (AAD) System. J. Aerosol Med. Pulm. Drug Deliv. 23(Suppl. 1), iii–v (2010).
    • 33. Geller DE. The science of aerosol delivery in cystic fibrosis. Pediatr. Pulmonol. 43(S9), S5–S17 (2008).
    • 34. Weber A, Morlin G, Cohen M, Williams-Warren J, Ramsey B, Smith A. Effect of nebulizer type and antibiotic concentration on device performance. Pediatr. Pulmonol. 23(4), 249–260 (1997).
    • 35. Eschenbacher WL, Boushey HA, Sheppard D. Alteration in osmolarity of inhaled aerosols cause bronchoconstriction and cough, but absence of a permeant anion causes cough alone. Am. Rev. Respir. Dis. 129(2), 211–215 (1984).
    • 36. Beasley R, Fishwick D, Miles JF, Hendeles L. Preservatives in nebulizer solutions: risks without benefit. Pharmacotherapy 18(1), 130–139 (1998).
    • 37. Poulakou G, Siakallis G, Tsiodras S, Arfaras-Melainis A, Dimopoulos G. Nebulized antibiotics in mechanically ventilated patients: roadmap and challenges. Expert Rev. Anti Infect. Ther. 15(3), 211–229 (2017).
    • 38. Fonceca AM, Fox Ditcham WG, Everard ML, Devadason S. 16 - Drug Administration by Inhalation in Children. In: Kendig's Disorders of the Respiratory Tract in Children. Wilmot RDeterding RLi A et al. Eds). 257–271 Elsevier Inc, Amsterdam, Netherlands (2019).
    • 39. Dunbar C, Mitchell J. Analysis of cascade impactor mass distributions. J. Aerosol Med. 18(4), 439–451 (2005).
    • 40. Mitchell J, Newman S, Chan H-K. In vitro and in vivo aspects of cascade impactor tests and inhaler performance: a review. AAPS PharmSciTech. 8(4), 237–248 (2007).
    • 41. Mitchell JP, Nagel MW. Cascade impactors for the size characterization of aerosols from medical inhalers: their uses and limitations. J. Aerosol Med. 16(4), 341–377 (2003).
    • 42. Martin AR, Finlay WH. Nebulizers for drug delivery to the lungs. Expert Opin. Drug Deliv. 12(6), 889–900 (2015). • This review features in vivo, in vitro and ex vivo models currently available for studying lung absorption and disposition and several challenges associated with these techniques.
    • 43. Sakagami M. In vivo, in vitro and ex vivo models to assess pulmonary absorption and disposition of inhaled therapeutics for systemic delivery. Adv. Drug Deliv. Rev. 58(9–10), 1030–1060 (2006).
    • 44. Cobben NAM, Drent M, Jonkers M, Wouters EFM, Vaneechoutte M, Stobberingh EE. Outbreak of severe Pseudomonas aeruginosa respiratory infections due to contaminated nebulizers. J. Hosp. Infect. 33(1), 63–70 (1996).
    • 45. Amirav I, Newhouse MT. Transmission of coronavirus by nebulizer: a serious, underappreciated risk. CMAJ 192(13), E346–E346 (2020).
    • 46. Le Brun P, Brimicombe R, Van Doorne H, Heijerman H. The cleaning and disinfection of nebulizers used at home and in a cystic fibrosis centre. Eur. Hosp. Pharm. 6(2), 58–63 (2000). • Summarizes the advancement in nebulizer drug delivery and discusses its application in treatment of various respiratory ailments.
    • 47. Li Q, Zhan S, Liu Q et al. Preparation of a sustained-release nebulized aerosol of r-terbutaline hydrochloride liposome and evaluation of its anti-asthmatic effects via pulmonary delivery in guinea pigs. AAPS PharmSciTech. 19(1), 232–241 (2018).
    • 48. Zhang J, Liang X, Li X et al. Ocular delivery of cyanidin-3-glycoside in liposomes and its prevention of selenite-induced oxidative stress. Drug Dev. Ind. Pharm. 42(4), 546–553 (2016).
    • 49. Cipolla D, Blanchard J, Gonda I. Development of liposomal ciprofloxacin to treat lung infections. Pharmaceutics. 8(1), 6 (2016).
    • 50. Godet C, Cateau E, Rammaert B et al. Nebulized liposomal amphotericin B for treatment of pulmonary infection caused by hormographiella aspergillata: case report and literature review. Mycopathologia 182(7), 709–713 (2017).
    • 51. Tagami T, Ando Y, Ozeki T. Fabrication of liposomal doxorubicin exhibiting ultrasensitivity against phospholipase A2 for efficient pulmonary drug delivery to lung cancers. Int. J. Pharm. 517(1), 35–41 (2017).
    • 52. Subramanian S, Khan I, Korale O et al. A simple approach to predict the stability of phospholipid vesicles to nebulization without performing aerosolization studies. Int. J. Pharm. 502(1), 18–27 (2016).
    • 53. Tai T-T, Wu T-J, Wu H-D et al. A strategy to treat COVID-19 disease with targeted delivery of inhalable liposomal hydroxychloroquine: a preclinical pharmacokinetic study. Clin. Transl. Sci. 14(1), 132–136 (2021).
    • 54. Schreier H, Gonzalez-Rothi RJ, Stecenko AA. Pulmonary delivery of liposomes. J. Control. Rel. 24(1–3), 209–223 (1993).
    • 55. Makled S, Nafee N, Boraie N. Nebulized solid lipid nanoparticles for the potential treatment of pulmonary hypertension via targeted delivery of phosphodiesterase-5-inhibitor. Int. J. Pharm. 517(1), 312–321 (2017).
    • 56. Jansook P, Fülöp Z, Ritthidej GC. Amphotericin B loaded solid lipid nanoparticles (SLNs) and nanostructured lipid carrier (NLCs): physicochemical and solid-solution state characterizations. Drug Dev. Ind. Pharm. 45(4), 560–567 (2019).
    • 57. Arora R, Katiyar SS, Kushwah V, Jain S. Solid lipid nanoparticles and nanostructured lipid carrier-based nanotherapeutics in treatment of psoriasis: a comparative study. Expert Opin. Drug Deliv. 14(2), 165–177 (2017).
    • 58. Yue-Xing C, Fei-Fei Y, Han W et al. The effect of l-leucine on the stabilization and inhalability of spray-dried solid lipid nanoparticles for pulmonary drug delivery. J. Drug Deliv. Sci. Technol. 46, 474–481 (2018).
    • 59. Esmaeili M, Aghajani M, Abbasalipourkabir R, Amani A. Budesonide-loaded solid lipid nanoparticles for pulmonary delivery: preparation, optimization, and aerodynamic behavior. Artif. Cells Nanomed. Biotechnol. 44(8), 1964–1971 (2016).
    • 60. Buhecha MD, Lansley AB, Somavarapu S, Pannala AS. Development and characterization of PLA nanoparticles for pulmonary drug delivery: co-encapsulation of theophylline and budesonide, a hydrophilic and lipophilic drug. J. Drug Deliv. Sci. Technol. 53, 101128 (2019).
    • 61. Al Malyan M, Becchi C, Nikkola L et al. Polymer-based biodegradable drug delivery systems in pain management. J. Craniofac. Surg. 17(2), 302–13 (2006).
    • 62. Moreno-Sastre M, Pastor M, Salomon CJ, Esquisabel A, Pedraz JL. Pulmonary drug delivery: a review on nanocarriers for antibacterial chemotherapy. J. Antimicrob. Chemother. 70(11), 2945–2955 (2015).
    • 63. Doroudian M, Macloughlin R, Poynton F, Prina-Mello A, Donnelly SC. Nanotechnology based therapeutics for lung disease. Thorax 74(10), 965–976 (2019).
    • 64. Rogueda PGA, Traini D. The nanoscale in pulmonary delivery. Part 2: formulation platforms. Expert Opin. Drug Deliv. 4(6), 607–620 (2007).
    • 65. Joshi N, Shirsath N, Singh A, Joshi KS, Banerjee R. Endogenous lung surfactant inspired pH responsive nanovesicle aerosols: pulmonary compatible and site-specific drug delivery in lung metastases. Sci. Rep. 4(1), 7085 (2014).
    • 66. Kumar A, Chen F, Mozhi A et al. Innovative pharmaceutical development based on unique properties of nanoscale delivery formulation. Nanoscale 5(18), 8307–8325 (2013).
    • 67. Van Rijt SH, Bein T, Meiners S. Medical nanoparticles for next generation drug delivery to the lungs. Eur. Respi. J. 44(3), 765 (2014).
    • 68. Kaminskas LM, Mcleod VM, Ryan GM et al. Pulmonary administration of a doxorubicin-conjugated dendrimer enhances drug exposure to lung metastases and improves cancer therapy. J. Control. Rel. 183, 18–26 (2014).
    • 69. Bailey MM, Berkland CJ. Nanoparticle formulations in pulmonary drug delivery. 29(1), 196–212 (2009).
    • 70. Rutsaert L, Steinfort N, Van Hunsel T et al. COVID-19-associated invasive pulmonary aspergillosis. Ann. Intensive Care 10, 1–4 (2020).
    • 71. Kaur R, Dennison SR, Burrow AJ et al. Nebulised surface-active hybrid nanoparticles of voriconazole for pulmonary Aspergillosis demonstrate clathrin-mediated cellular uptake, improved antifungal efficacy and lung retention. J. Nanobiotechnol. 19(1), 19 (2021).
    • 72. Zachar O. Formulations for COVID-19 early stage treatment via silver nanoparticles inhalation delivery at home and hospital. ScienceOpen Preprints (2020).
    • 73. Weber S, Zimmer A, Pardeike J. Solid lipid nanoparticles (SLN) and nanostructured lipid carriers (NLC) for pulmonary application: a review of the state of the art. Eur. J. Pharm. Biopharm. 86(1), 7–22 (2014).
    • 74. Zhang L, Yang L, Zhang X et al. Sustained therapeutic efficacy of budesonide-loaded chitosan swellable microparticles after lung delivery: influence of in vitro release, treatment interval and dose. J. Control. Rel. 283, 163–174 (2018).
    • 75. Amore E, Ferraro M, Manca ML et al. Mucoadhesive solid lipid microparticles for controlled release of a corticosteroid in the chronic obstructive pulmonary disease treatment. Nanomedicine 12(19), 2287–2302 (2017).
    • 76. Chen Y, Du S, Zhang Z et al. Compatible stability and aerosol characteristics of Atrovent® (Ipratropium Bromide) mixed with salbutamol sulfate, terbutaline sulfate, budesonide, and acetylcysteine. 12(8), 776 (2020).
    • 77. Yarragudi SB, Kumar H, Jain R, Tawhai M, Rizwan S. Olfactory targeting of microparticles through inhalation and bi-directional airflow: effect of particle size and nasal anatomy. J. Aerosol Med. Pulm. Drug Deliv. 33(5), 258–270 (2020).
    • 78. Pulivendala G, Bale S, Godugu C. Inhalation of sustained release microparticles for the targeted treatment of respiratory diseases. Drug Deliv. Transl. Res. 10(2), 339–353 (2020).
    • 79. Ali ZA, El-Mallakh RS. Nebulized lidocaine in COVID-19, an hypothesis. Med. Hypotheses 144, 109947 (2020).
    • 80. Chaccour C, Abizanda G, Irigoyen-Barrio Á et al. Nebulized ivermectin for COVID-19 and other respiratory diseases, a proof of concept, dose-ranging study in rats. Sci. Rep. 10(1), 17073 (2020).
    • 81. Lin Y-R, Wu F-Y, Xiao H et al. Mycobacterium vaccae nebulization in the treatment of COVID-19: a randomized, double-blind, placebo-controlled trial. J. Aerosol. Med. Pulm. Drug Deliv. 34(2), 108–114 (2021).