Inhalation Drug Therapy: Emerging Trends in Nasal and Pulmonary Drug Delivery

  • Manisha Lalan
  • Hemal Tandel
  • Rohan Lalani
  • Vivek Patel
  • Ambikanandan Misra


The success of drug therapy is highly dependent on route of administration, and oral route of administration is the most successful, popular, and patient friendly. However, the bioavailability of many drugs is less due to first-pass metabolism which paved a way for development of innovative drug formulations and routes of administration. Biologics and antineoplastic therapeutics are restricted to parenteral route only due to bioavailability issues in other routes of administration which often leads to off-target toxicities; therefore inhalational route for therapeutic delivery has been gaining attention recently to enhance bioavailability by taking advantage of rich blood supply of lungs. This route is used for delivering agents locally to the lungs during diseased states such as chronic obstructive pulmonary disease, asthma, or cystic fibrosis. It also acts as a portal to access blood and lymphatic systems. Nasal route has been explored since the beginning of human civilization, and Indian Ayurvedic system of medicine uses this route since long. Rapid onset of action of systemically acting products is an important advantage. The present chapter covers factors affecting absorption, drug repositioning strategies, characterization tests, and clinical trials of nasal as well as pulmonary therapeutics.


Inhalation drug therapy Dry powder inhaler Intranasal drug delivery devices Metered dose inhaler Nasal and pulmonary drug delivery 


  1. 1.
    Suman J (2015) Leveraging old drugs: A critical review of delivery systems and lifecycle management. Proc RDD Europe 2015 (Nice, France) 1:109–120Google Scholar
  2. 2.
    Graul A, Cruces E, Dulsat C, Arias E, Stringer M (2012) The year’s new drugs & biologics, 2011. Drugs Today (Barcelona, Spain: 1998) 48(1):33–77CrossRefGoogle Scholar
  3. 3.
    Škalko-Basnet N (2014) Biologics: the role of delivery systems in improved therapy. Biologics 8:107PubMedPubMedCentralGoogle Scholar
  4. 4.
    Tiwari G, Tiwari R, Sriwastawa B, Bhati L, Pandey S, Pandey P et al (2012) Drug delivery systems: an updated review. Int J Pharm Invest 2(1):2CrossRefGoogle Scholar
  5. 5.
    Patil J, Sarasija S (2012) Pulmonary drug delivery strategies: a concise, systematic review. Lung India 29(1):44PubMedPubMedCentralCrossRefGoogle Scholar
  6. 6.
    Amrutiya J, Lalani R, Bhatt P, Siddhapura K, Misra A (2015) Nucleic acid carriers for pulmonary gene delivery. J Pharm Sci Tech Mgmt 1(2)Google Scholar
  7. 7.
    Patil S, Vhora I, Amrutiya J, Lalani R, Misra A (2015) Role of nanotechnology in delivery of protein and peptide drugs. Curr Pharm Des 21(29):4155–4173PubMedCrossRefGoogle Scholar
  8. 8.
    Labiris N, Dolovich MB (2003) Pulmonary drug delivery. Part I: physiological factors affecting therapeutic effectiveness of aerosolized medications. Br J Clin Pharmacol 56(6):588–599PubMedPubMedCentralCrossRefGoogle Scholar
  9. 9.
    Sou T, Meeusen EN, de Veer M, Morton DA, Kaminskas LM, McIntosh MP (2011) New developments in dry powder pulmonary vaccine delivery. Trends Biotechnol 29(4):191–198PubMedCrossRefGoogle Scholar
  10. 10.
    Gonda I, Schuster J (2003) Pulmonary delivery of drugs by inhalation. Drugs Pharm Sci 126:807–816Google Scholar
  11. 11.
    Yu J, Chien YW (1997) Pulmonary drug delivery: physiologic and mechanistic aspects. Crit Rev Ther Drug Carrier Syst 14(4)CrossRefGoogle Scholar
  12. 12.
    Groneberg D, Witt C, Wagner U, Chung K, Fischer A (2003) Fundamentals of pulmonary drug delivery. Respir Med 97(4):382–387PubMedCrossRefGoogle Scholar
  13. 13.
    Marriott C (1990) Mucus and mucociliary clearance in the respiratory tract. Adv Drug Deliv Rev 5(1–2):19–35CrossRefGoogle Scholar
  14. 14.
    Rubin BK (2007) Mucolytics, expectorants, and mucokinetic medications. Respir Care 52(7):859–865PubMedGoogle Scholar
  15. 15.
    Lansley AB (1993) Mucociliary clearance and drug delivery via the respiratory tract. Adv Drug Deliv Rev 11(3):299–327CrossRefGoogle Scholar
  16. 16.
    Hastings RH, Folkesson HG, Matthay MA (2004) Mechanisms of alveolar protein clearance in the intact lung. Am Physiol Soc 286(4):L679–LL89Google Scholar
  17. 17.
    Corboz MR, Zhang J, LaSala D, DiPetrillo K, Li Z, Malinin V et al (2018) Therapeutic administration of inhaled ins1009, a treprostinil prodrug formulation, inhibits bleomycin-induced pulmonary fibrosis in rats. Pulm Pharmacol Ther 49:95–103PubMedCrossRefGoogle Scholar
  18. 18.
    Ishizuka H, Toyama K, Yoshiba S, Okabe H, Furuie H (2012) Intrapulmonary distribution and pharmacokinetics of laninamivir, a neuraminidase inhibitor, after a single inhaled administration of its prodrug, laninamivir octanoate, in healthy volunteers. Antimicrob Agents Chemother:AAC.06456-11Google Scholar
  19. 19.
    Abdelaziz HM, Gaber M, Abd-Elwakil MM, Mabrouk MT, Elgohary MM, Kamel NM et al (2018) Inhalable particulate drug delivery systems for lung cancer therapy: nanoparticles, microparticles, nanocomposites and nanoaggregates. J Control Release 269:374–392PubMedCrossRefGoogle Scholar
  20. 20.
    Levet V, Rosière R, Merlos R, Fusaro L, Berger G, Amighi K et al (2016) Development of controlled-release cisplatin dry powders for inhalation against lung cancers. Int J Pharm 515(1–2):209–220PubMedCrossRefGoogle Scholar
  21. 21.
    Mohtar N, Taylor KM, Sheikh K, Somavarapu S (2017) Design and development of dry powder sulfobutylether-β-cyclodextrin complex for pulmonary delivery of fisetin. Eur J Pharm Biopharm 113:1–10PubMedCrossRefGoogle Scholar
  22. 22.
    Loira-Pastoriza C, Todoroff J, Vanbever R (2014) Delivery strategies for sustained drug release in the lungs. Adv Drug Deliv Rev 75:81–91PubMedCrossRefGoogle Scholar
  23. 23.
    Sivadas N, Cryan SA (2011) Inhalable, bioresponsive microparticles for targeted drug delivery in the lungs. J Pharm Pharmacol 63(3):369–375PubMedCrossRefGoogle Scholar
  24. 24.
    Secret E, Kelly SJ, Crannell KE, Andrew JS (2014) Enzyme-responsive hydrogel microparticles for pulmonary drug delivery. ACS Appl Mater Interfaces 6(13):10313–10321PubMedCrossRefGoogle Scholar
  25. 25.
    Gaspar MM, Bakowsky U, Ehrhardt C (2008) Inhaled liposomes–current strategies and future challenges. J Biomed Nanotechnol 4(3):245–257CrossRefGoogle Scholar
  26. 26.
    Willis L, Hayes D, Mansour HM (2012) Therapeutic liposomal dry powder inhalation aerosols for targeted lung delivery. Lung 190(3):251–262PubMedCrossRefGoogle Scholar
  27. 27.
    Kellaway IW, Farr SJ (1990) Liposomes as drug delivery systems to the lung. Adv Drug Deliv Rev 5(1–2):149–161CrossRefGoogle Scholar
  28. 28.
    Clancy J, Dupont L, Konstan M, Billings J, Fustik S, Goss C et al (2013) Phase II studies of nebulised Arikace in CF patients with Pseudomonas aeruginosa infection. Thorax 68:818–825. thoraxjnl-2012-202230PubMedPubMedCentralCrossRefGoogle Scholar
  29. 29.
    Bi R, Shao W, Wang Q, Zhang N (2008) Spray-freeze-dried dry powder inhalation of insulin-loaded liposomes for enhanced pulmonary delivery. J Drug Target 16(9):639–648PubMedCrossRefGoogle Scholar
  30. 30.
    Paranjpe M, Müller-Goymann C (2014) Nanoparticle-mediated pulmonary drug delivery: a review. Int J Mol Sci 15(4):5852–5873PubMedPubMedCentralCrossRefGoogle Scholar
  31. 31.
    Zhou QT, Leung SSY, Tang P, Parumasivam T, Loh ZH, Chan H-K (2015) Inhaled formulations and pulmonary drug delivery systems for respiratory infections. Adv Drug Deliv Rev 85:83–99PubMedCrossRefPubMedCentralGoogle Scholar
  32. 32.
    El-Sherbiny IM, El-Baz NM, Yacoub MH (2015) Inhaled nano- and microparticles for drug delivery. Glob Cardiol Sci Pract 2015:2PubMedPubMedCentralCrossRefGoogle Scholar
  33. 33.
    Mangal S, Gao W, Li T, Zhou QT (2017) Pulmonary delivery of nanoparticle chemotherapy for the treatment of lung cancers: challenges and opportunities. Acta Pharmacol Sin 38(6):782PubMedPubMedCentralCrossRefGoogle Scholar
  34. 34.
    Jaafar-Maalej C, Andrieu V, Elaissari A, Fessi H (2011) Beclomethasone-loaded lipidic nanocarriers for pulmonary drug delivery: preparation, characterization and in vitro drug release. J Nanosci Nanotechnol 11(3):1841–1851PubMedCrossRefPubMedCentralGoogle Scholar
  35. 35.
    Elhissi A, Islam M, Arafat B, Taylor M, Ahmed W (2010) Development and characterisation of freeze-dried liposomes containing two anti-asthma drugs. IET Micro Nano Lett 5(3):184–188CrossRefGoogle Scholar
  36. 36.
    Zhang P, Tu Y, Wang S, Wang Y, Xie Y, Li M et al (2011) Preparation and characterization of budesonide-loaded solid lipid nanoparticles for pulmonary delivery. J Chin Pharm Sci 20:390–396Google Scholar
  37. 37.
    Wang W, Zhu R, Xie Q, Li A, Xiao Y, Li K et al (2012) Enhanced bioavailability and efficiency of curcumin for the treatment of asthma by its formulation in solid lipid nanoparticles. Int J Nanomedicine 7:3667PubMedPubMedCentralCrossRefGoogle Scholar
  38. 38.
    Kumar SSD, Surianarayanan M, Vijayaraghavan R, Mandal AB, MacFarlane D (2014) Curcumin loaded poly (2-hydroxyethyl methacrylate) nanoparticles from gelled ionic liquid–In vitro cytotoxicity and anti-cancer activity in SKOV-3 cells. Eur J Pharm Sci 51:34–44PubMedCrossRefGoogle Scholar
  39. 39.
    Castelli F, Puglia C, Sarpietro MG, Rizza L, Bonina F (2005) Characterization of indomethacin-loaded lipid nanoparticles by differential scanning calorimetry. Int J Pharm 304(1–2):231–238PubMedCrossRefGoogle Scholar
  40. 40.
    Ali R, Mittal G, Ali R, Kumar M, Kishan Khar R, Ahmad FJ et al (2013) Development, characterisation and pharmacoscintigraphic evaluation of nano-fluticasone propionate dry powder inhalation as potential antidote against inhaled toxic gases. J Microencapsul 30(6):546–558PubMedCrossRefPubMedCentralGoogle Scholar
  41. 41.
    Trivedi R, Redente EF, Thakur A, Riches DW, Kompella UB (2012) Local delivery of biodegradable pirfenidone nanoparticles ameliorates bleomycin-induced pulmonary fibrosis in mice. Nanotechnology 23(50):505101PubMedCrossRefPubMedCentralGoogle Scholar
  42. 42.
    Suzuki ÉY, Amaro MI, de Almeida GS, Cabral LM, Healy AM, de Sousa VP (2018) Development of a new formulation of roflumilast for pulmonary drug delivery to treat inflammatory lung conditions. Int J Pharm 550(1–2):89–99PubMedCrossRefPubMedCentralGoogle Scholar
  43. 43.
    Rao K, Shrikhande S, Bajaj A (2013) Development of cisplatin nanoparticles as dry powder inhalers for lung cancer. Curr Nanosci 9(4):447–450CrossRefGoogle Scholar
  44. 44.
    Xie Y, Aillon KL, Cai S, Christian JM, Davies NM, Berkland CJ et al (2010) Pulmonary delivery of cisplatin–hyaluronan conjugates via endotracheal instillation for the treatment of lung cancer. Int J Pharm 392(1–2):156–163PubMedPubMedCentralCrossRefGoogle Scholar
  45. 45.
    Li M, Neoh K-G, Wang R, Zong B-Y, Tan JY, Kang E-T (2013) Methotrexate-conjugated and hyperbranched polyglycerol-grafted Fe3O4 magnetic nanoparticles for targeted anticancer effects. Eur J Pharm Sci 48(1–2):111–120PubMedCrossRefPubMedCentralGoogle Scholar
  46. 46.
    Gill KK, Nazzal S, Kaddoumi A (2011) Paclitaxel loaded PEG5000–DSPE micelles as pulmonary delivery platform: formulation characterization, tissue distribution, plasma pharmacokinetics, and toxicological evaluation. Eur J Pharm Biopharm 79(2):276–284PubMedCrossRefPubMedCentralGoogle Scholar
  47. 47.
    Yang R, Yang S-G, Shim W-S, Cui F, Cheng G, Kim I-W et al (2009) Lung-specific delivery of paclitaxel by chitosan-modified PLGA nanoparticles via transient formation of microaggregates. J Pharm Sci 98(3):970–984PubMedCrossRefPubMedCentralGoogle Scholar
  48. 48.
    Xu P, Yin Q, Shen J, Chen L, Yu H, Zhang Z et al (2013) Synergistic inhibition of breast cancer metastasis by silibinin-loaded lipid nanoparticles containing TPGS. Int J Pharm 454(1):21–30PubMedCrossRefPubMedCentralGoogle Scholar
  49. 49.
    Yoo D, Guk K, Kim H, Khang G, Wu D, Lee D (2013) Antioxidant polymeric nanoparticles as novel therapeutics for airway inflammatory diseases. Int J Pharm 450(1–2):87–94PubMedCrossRefPubMedCentralGoogle Scholar
  50. 50.
    Hoesel LM, Flierl MA, Niederbichler AD, Rittirsch D, McClintock SD, Reuben JS et al (2008) Ability of antioxidant liposomes to prevent acute and progressive pulmonary injury. Antioxid Redox Signal 10(5):963–972CrossRefGoogle Scholar
  51. 51.
    Varshosaz J, Ghaffari S, Mirshojaei S, Jafarian A, Atyabi F, Kobarfard F et al (2013) Biodistribution of amikacin solid lipid nanoparticles after pulmonary delivery. Biomed Res Int 2013:1–8Google Scholar
  52. 52.
    Cipolla D, Gonda I, Chan H-K (2013) Liposomal formulations for inhalation. Ther Deliv 4(8):1047–1072PubMedCrossRefGoogle Scholar
  53. 53.
    Liu C, Shi J, Dai Q, Yin X, Zhang X, Zheng A (2015) In-vitro and in-vivo evaluation of ciprofloxacin liposomes for pulmonary administration. Drug Dev Ind Pharm 41(2):272–278PubMedCrossRefGoogle Scholar
  54. 54.
    Duan J, Vogt FG, Li X, Hayes D Jr, Mansour HM (2013) Design, characterization, and aerosolization of organic solution advanced spray-dried moxifloxacin and ofloxacin dipalmitoylphosphatidylcholine (DPPC) microparticulate/nanoparticulate powders for pulmonary inhalation aerosol delivery. Int J Nanomedicine 8:3489PubMedPubMedCentralGoogle Scholar
  55. 55.
    Park C-W, Li X, Vogt FG, Hayes D Jr, Zwischenberger JB, Park E-S et al (2013) Advanced spray-dried design, physicochemical characterization, and aerosol dispersion performance of vancomycin and clarithromycin multifunctional controlled release particles for targeted respiratory delivery as dry powder inhalation aerosols. Int J Pharm 455(1–2):374–392PubMedCrossRefPubMedCentralGoogle Scholar
  56. 56.
    Pilcer G, Rosière R, Traina K, Sebti T, Vanderbist F, Amighi K (2013) New co-spray-dried tobramycin nanoparticles–clarithromycin inhaled powder systems for lung infection therapy in cystic fibrosis patients. J Pharm Sci 102(6):1836–1846PubMedCrossRefPubMedCentralGoogle Scholar
  57. 57.
    Sinha B, Mukherjee B, Pattnaik G (2013) Poly-lactide-co-glycolide nanoparticles containing voriconazole for pulmonary delivery: in vitro and in vivo study. Nanomedicine 9(1):94–104PubMedCrossRefPubMedCentralGoogle Scholar
  58. 58.
    Wu X, Hayes D Jr, Zwischenberger JB, Kuhn RJ, Mansour HM (2013) Design and physicochemical characterization of advanced spray-dried tacrolimus multifunctional particles for inhalation. Drug Design Dev Ther 7:59Google Scholar
  59. 59.
    Pardeike J, Weber S, Haber T, Wagner J, Zarfl H, Plank H et al (2011) Development of an itraconazole-loaded nanostructured lipid carrier (NLC) formulation for pulmonary application. Int J Pharm 419(1–2):329–338PubMedCrossRefPubMedCentralGoogle Scholar
  60. 60.
    Verma RK, Germishuizen WA, Motheo MP, Agrawal AK, Singh AK, Mohan M et al (2013) Inhaled microparticles containing clofazimine are efficacious in treatment of experimental tuberculosis in mice. Antimicrob Agents Chemother 57(2):1050–1052PubMedPubMedCentralCrossRefGoogle Scholar
  61. 61.
    Kumar PV, Asthana A, Dutta T, Jain NK (2006) Intracellular macrophage uptake of rifampicin loaded mannosylated dendrimers. J Drug Target 14(8):546–556PubMedCrossRefGoogle Scholar
  62. 62.
    Deol P, Khuller G, Joshi K (1997) Therapeutic efficacies of isoniazid and rifampin encapsulated in lung-specific stealth liposomes against Mycobacterium tuberculosis infection induced in mice. Antimicrob Agents Chemother 41(6):1211–1214PubMedPubMedCentralCrossRefGoogle Scholar
  63. 63.
    Varma JR, Kumar TS, Prasanthi B, Ratna JV (2015) Formulation and characterization of pyrazinamide polymeric nanoparticles for pulmonary tuberculosis: Efficiency for alveolar macrophage targeting. Indian J Pharm Sci 77(3):258PubMedPubMedCentralCrossRefGoogle Scholar
  64. 64.
    Pandey R, Sharma A, Zahoor A, Sharma S, Khuller G, Prasad B (2003) Poly (DL-lactide-co-glycolide) nanoparticle-based inhalable sustained drug delivery system for experimental tuberculosis. J Antimicrob Chemother 52(6):981–986PubMedCrossRefGoogle Scholar
  65. 65.
    Takeuchi H, Sugihara H (2010) Absorption of calcitonin in oral and pulmonary administration with polymer-coated liposomes. Yakugaku zasshi 130(9):1135–1142PubMedCrossRefGoogle Scholar
  66. 66.
    Trapani A, Di Gioia S, Ditaranto N, Cioffi N, Goycoolea FM, Carbone A et al (2013) Systemic heparin delivery by the pulmonary route using chitosan and glycol chitosan nanoparticles. Int J Pharm 447(1–2):115–123PubMedCrossRefGoogle Scholar
  67. 67.
    Liu J, Gong T, Fu H, Wang C, Wang X, Chen Q et al (2008) Solid lipid nanoparticles for pulmonary delivery of insulin. Int J Pharm 356(1–2):333–344PubMedCrossRefGoogle Scholar
  68. 68.
    Zhao Y-Z, Li X, Lu C-T, Xu Y-Y, Lv H-F, Dai D-D et al (2012) Experiment on the feasibility of using modified gelatin nanoparticles as insulin pulmonary administration system for diabetes therapy. Acta Diabetol 49(4):315–325PubMedCrossRefGoogle Scholar
  69. 69.
    Lee C, Choi JS, Kim I, Oh KT, Lee ES, Park E-S et al (2013) Long-acting inhalable chitosan-coated poly (lactic-co-glycolic acid) nanoparticles containing hydrophobically modified exendin-4 for treating type 2 diabetes. Int J Nanomedicine 8:2975PubMedPubMedCentralGoogle Scholar
  70. 70.
    Kleemann E, Schmehl T, Gessler T, Bakowsky U, Kissel T, Seeger W (2007) Iloprost-containing liposomes for aerosol application in pulmonary arterial hypertension: formulation aspects and stability. Pharm Res 24(2):277–287PubMedCrossRefGoogle Scholar
  71. 71.
    Beck-Broichsitter M, Schmehl T, Gessler T, Seeger W, Kissel T (2012) Development of a biodegradable nanoparticle platform for sildenafil: formulation optimization by factorial design analysis combined with application of charge-modified branched polyesters. J Control Release 157(3):469–477PubMedCrossRefGoogle Scholar
  72. 72.
    Paranjpe M, Neuhaus V, Finke J, Richter C, Gothsch T, Kwade A et al (2013) In vitro and ex vivo toxicological testing of sildenafil-loaded solid lipid nanoparticles. Inhal Toxicol 25(9):536–543PubMedCrossRefGoogle Scholar
  73. 73.
    Varshosaz J, Taymouri S, Hamishehkar H (2014) Fabrication of polymeric nanoparticles of poly (ethylene-co-vinyl acetate) coated with chitosan for pulmonary delivery of carvedilol. J Appl Polym Sci 131(1):39694CrossRefGoogle Scholar
  74. 74.
    Park S, Jeong EJ, Lee J, Rhim T, Lee SK, Lee KY (2013) Preparation and characterization of nonaarginine-modified chitosan nanoparticles for siRNA delivery. Carbohydr Polym 92(1):57–62PubMedCrossRefGoogle Scholar
  75. 75.
    Sharma K, Somavarapu S, Colombani A, Govind N, Taylor KM (2013) Nebulised siRNA encapsulated crosslinked chitosan nanoparticles for pulmonary delivery. Int J Pharm 455(1–2):241–247PubMedCrossRefGoogle Scholar
  76. 76.
    Jobe AH (1993) Pulmonary surfactant therapy. N Engl J Med 328(12):861–868PubMedCrossRefGoogle Scholar
  77. 77.
    Ribeiro A, Souza A, Amaral A, Vasconcelos N, Jeronimo M, Carneiro F et al (2013) Nanobiotechnological approaches to delivery of DNA vaccine against fungal infection. J Biomed Nanotechnol 9(2):221–230PubMedCrossRefGoogle Scholar
  78. 78.
    Srinivasan AR, Shoyele SA (2013) Self-associated submicron IgG1 particles for pulmonary delivery: effects of non-ionic surfactants on size, shape, stability, and aerosol performance. AAPS PharmSciTech 14(1):200–210PubMedCrossRefGoogle Scholar
  79. 79.
    Zou Y, Tornos C, Qiu X, Lia M, Perez-Soler R (2007) p53 aerosol formulation with low toxicity and high efficiency for early lung cancer treatment. Clin Cancer Res 13(16):4900–4908PubMedCrossRefGoogle Scholar
  80. 80.
    Ibrahim M, Verma R, Garcia-Contreras L (2015) Inhalation drug delivery devices: technology update. Med Devices (Auckland, NZ) 8:131Google Scholar
  81. 81.
    Newman SP (2005) Principles of metered-dose inhaler design. Respir Care 50(9):1177–1190PubMedGoogle Scholar
  82. 82.
    Steuer G, Prais D, Mussaffi H, Mei-Zahav M, Bar-On O, Levine H et al (2018) Inspiromatic-safety and efficacy study of a new generation dry powder inhaler in asthmatic children. Pediatr Pulmonol 53:1348–1355PubMedCrossRefGoogle Scholar
  83. 83.
    De Boer A, Hagedoorn P, Gjaltema D, Goede J, Frijlink H (2003) Air classifier technology (ACT) in dry powder inhalation: part 1. Introduction of a novel force distribution concept (FDC) explaining the performance of a basic air classifier on adhesive mixtures. Int J Pharm 260(2):187–200PubMedCrossRefGoogle Scholar
  84. 84.
    Ehtezazi T (2012) Recent patents in pressurised metered dose inhalers. Recent Pat Drug Deliv Formul 6(1):31–44PubMedCrossRefGoogle Scholar
  85. 85.
    Hoppentocht M, Akkerman OW, Hagedoorn P, Frijlink HW, de Boer AH (2015) The Cyclops for pulmonary delivery of aminoglycosides; a new member of the Twincer™ family. Eur J Pharm Biopharm 90:8–15PubMedCrossRefGoogle Scholar
  86. 86.
    Shaji J, Shaikh MJ (2016) Current development in the evaluation methods of pulmonary drug delivery system. Indian J Pharm Sci 78(3):294–306CrossRefGoogle Scholar
  87. 87.
    Barnett AH, Bellary S (2007) Inhaled human insulin (Exubera®): clinical profile and patient considerations. Vasc Health Risk Manag 3(1):83PubMedPubMedCentralGoogle Scholar
  88. 88.
    Nuffer W, Trujillo JM, Ellis SL (2015) Technosphere insulin (afrezza) a new, inhaled prandial insulin. Ann Pharmacother 49(1):99–106PubMedCrossRefGoogle Scholar
  89. 89.
    McElroy MC, Kirton C, Gliddon D, Wolff RK (2013) Inhaled biopharmaceutical drug development: nonclinical considerations and case studies. Inhal Toxicol 25(4):219–232PubMedCrossRefGoogle Scholar
  90. 90.
    Walvoord EC, De La Peña A, Park S, Silverman B, Cuttler L, Rose SR et al (2009) Inhaled growth hormone (GH) compared with subcutaneous GH in children with GH deficiency: pharmacokinetics, pharmacodynamics, and safety. J Clin Endocrinol Metab 94(6):2052–2059PubMedCrossRefGoogle Scholar
  91. 91.
    Markovic SN, Suman VJ, Nevala WK, Geeraerts L, Creagan ET, Erickson LA et al (2008) A dose-escalation study of aerosolized sargramostim in the treatment of metastatic melanoma: an NCCTG Study. Am J Clin Oncol 31(6):573PubMedPubMedCentralCrossRefGoogle Scholar
  92. 92.
    Bulbake U, Doppalapudi S, Kommineni N, Khan W (2017) Liposomal formulations in clinical use: an updated review. Pharmaceutics 9(2):12PubMedCentralCrossRefPubMedGoogle Scholar
  93. 93.
    Vardakas KZ, Voulgaris GL, Samonis G, Falagas ME (2018) Inhaled colistin monotherapy for respiratory tract infections in adults without cystic fibrosis: a systematic review and meta-analysis. Int J Antimicrob Agents 51(1):1–9PubMedCrossRefGoogle Scholar
  94. 94.
    Vazquez-Espinosa E, Marcos C, Alonso T, Giron R, Gomez-Punter R, Garcia-Castillo E et al (2016) Tobramycin inhalation powder (TOBI Podhaler®) for the treatment of lung infection in patients with cystic fibrosis. Expert Rev Anti-Infect Ther 14(1):9–17PubMedCrossRefGoogle Scholar
  95. 95.
    Richter MJ, Stollfuß B, Roitenberg A, Kleinjung F, Graeff V, Berghaus S et al (2018) Switching inhaled iloprost formulations in patients with pulmonary arterial hypertension: the VENTASWITCH Trial. Pulm Circ 8(4):2045894018798921PubMedPubMedCentralCrossRefGoogle Scholar
  96. 96.
    Gessler T (2018) Inhalation of repurposed drugs to treat pulmonary hypertension. Adv Drug Deliv Rev 133:34–44PubMedCrossRefGoogle Scholar
  97. 97.
    Moss RB, Milla C, Colombo J, Accurso F, Zeitlin PL, Clancy JP et al (2007) Repeated aerosolized AAV-CFTR for treatment of cystic fibrosis: a randomized placebo-controlled phase 2B trial. Hum Gene Ther 18(8):726–732PubMedCrossRefGoogle Scholar
  98. 98.
    Verschraegen CF, Gilbert BE, Loyer E, Huaringa A, Walsh G, Newman RA et al (2004) Clinical evaluation of the delivery and safety of aerosolized liposomal 9-nitro-20 (s)-camptothecin in patients with advanced pulmonary malignancies. Clin Cancer Res 10(7):2319–2326PubMedCrossRefGoogle Scholar
  99. 99.
    Wittgen BP, Kunst PW, Van Der Born K, Van Wijk AW, Perkins W, Pilkiewicz FG et al (2007) Phase I study of aerosolized SLIT cisplatin in the treatment of patients with carcinoma of the lung. Clin Cancer Res 13(8):2414–2421PubMedCrossRefGoogle Scholar
  100. 100.
    Ward ME, Woodhouse A, Mather LE, Farr SJ, Okikawa JK, Lloyd P et al (1997) Morphine pharmacokinetics after pulmonary administration from a novel aerosol delivery system. Clin Pharmacol Ther 62(6):596–609PubMedCrossRefGoogle Scholar
  101. 101.
    Mather LE, Woodhouse A, Ward ME, Farr SJ, Rubsamen RA, Eltherington LG (1998) Pulmonary administration of aerosolised fentanyl: pharmacokinetic analysis of systemic delivery. Br J Clin Pharmacol 46(1):37–43PubMedPubMedCentralCrossRefGoogle Scholar
  102. 102.
    Farr SJ, McElduff A, Mather LE, Okikawa J, Ward ME, Gonda I et al (2000) Pulmonary insulin administration using the AERx® system: physiological and physicochemical factors influencing insulin effectiveness in healthy fasting subjects. Diab Technol Ther 2(2):185–197CrossRefGoogle Scholar
  103. 103.
    Gonda IJ (1988) Drugs administered directly into the respiratory tract: modeling of the duration of effective drug levels. J Pharm Sci 77(4):340–346PubMedCrossRefGoogle Scholar
  104. 104.
    Gizurarson S (1993) The relevance of nasal physiology to the design of drug absorption studies. Adv Drug Deliv Rev 11(3):329–347CrossRefGoogle Scholar
  105. 105.
    Wermeling DP, Miller JL (2003) Intranasal drug delivery. Drugs Pharm Sci 126:727–748Google Scholar
  106. 106.
  107. 107.
    Talegaonkar S, Mishra P (2004) Intranasal delivery: An approach to bypass the blood brain barrier. Indian J Pharm 36(3):140Google Scholar
  108. 108.
    Pires A, Fortuna A, Alves G, Falcão A (2009) Intranasal drug delivery: how, why and what for? J Pharm Pharm Sci 12(3):288–311PubMedCrossRefGoogle Scholar
  109. 109.
    Vyas TK, Shahiwala A, Marathe S, Misra A (2005) Intranasal drug delivery for brain targeting. Curr Drug Deliv 2(2):165–175PubMedCrossRefGoogle Scholar
  110. 110.
    Mygind N, Änggård A (1984) Anatomy and physiology of the nose—pathophysiologic alterations in allergic rhinitis. Clin Rev Allergy 2(3):173–188PubMedGoogle Scholar
  111. 111.
    Arora P, Sharma S, Garg S (2002) Permeability issues in nasal drug delivery. Drug Discov Today 7(18):967–975PubMedCrossRefGoogle Scholar
  112. 112.
    Dahl A, Lewis J (1993) Respiratory tract uptake of inhalants and metabolism of xenobiotics. Annu Rev Pharmacol Toxicol 33(1):383–407PubMedCrossRefGoogle Scholar
  113. 113.
    Sarkar MA (1992) Drug metabolism in the nasal mucosa. Pharm Res 9(1):1–9PubMedCrossRefGoogle Scholar
  114. 114.
    Tos M (1983) Distribution of mucus producing elements in the respiratory tract. Differences between upper and lower airway. Eur J Respir Dis Suppl 128:269–279PubMedGoogle Scholar
  115. 115.
    Misawa M (1988) A new rhinitis model using chemical mediators in rats. Jpn J Pharm 48(1):15–22CrossRefGoogle Scholar
  116. 116.
    Yang P (1991) The effect of nasal sensory nerve on the enhanced nasal blood vessel permeability caused by histamine. Zhonghua er bi yan hou ke za zhi 26(4):207–208, 52PubMedGoogle Scholar
  117. 117.
    Philip G, Baroody FM, Proud D, Naclerio RM, Togias AG (1994) for publication June A. The human nasal response to capsaicin. J Allergy Clin Immunol 94(6):1035–1045PubMedCrossRefGoogle Scholar
  118. 118.
    Newman S, Moren F, Clarke S (1987) Deposition pattern from a nasal pump spray. Rhinology 25(2):77–82PubMedGoogle Scholar
  119. 119.
    Newman S, Moren F, Clarke S (1988) Deposition pattern of nasal sprays in man. Rhinology 26(2):111–120PubMedGoogle Scholar
  120. 120.
    Costantino HR, Illum L, Brandt G, Johnson PH, Quay SC (2007) Intranasal delivery: physicochemical and therapeutic aspects. Int J Pharm 337(1–2):1–24PubMedCrossRefGoogle Scholar
  121. 121.
    Graff CL, Pollack GM (2005) Functional evidence for P-glycoprotein at the nose-brain barrier. Pharm Res 22(1):86–93PubMedCrossRefGoogle Scholar
  122. 122.
    Graff CL, Pollack GM (2003) P-Glycoprotein attenuates brain uptake of substrates after nasal instillation. Pharm Res 20(8):1225–1230PubMedCrossRefGoogle Scholar
  123. 123.
    Westin U, Piras E, Jansson B, Bergström U, Dahlin M, Brittebo E et al (2005) Transfer of morphine along the olfactory pathway to the central nervous system after nasal administration to rodents. Eur J Pharm Sci 24(5):565–573PubMedCrossRefGoogle Scholar
  124. 124.
    Mortazavi SA, Smart JD (1994) Factors influencing gel-strengthening at the mucoadhesive-mucus interface. J Pharm Pharmacol 46(2):86–90PubMedCrossRefGoogle Scholar
  125. 125.
    Marttin E, Schipper NG, Verhoef JC, Merkus FW (1998) Nasal mucociliary clearance as a factor in nasal drug delivery. Adv Drug Deliv Rev 29(1–2):13–38PubMedCrossRefGoogle Scholar
  126. 126.
    Schipper NG, Verhoef JC, Merkus FW (1991) The nasal mucociliary clearance: relevance to nasal drug delivery. Pharm Res 8(7):807–814PubMedCrossRefGoogle Scholar
  127. 127.
    Merkus P, Romeijn SG, Verhoef JC, Merkus FW, Schouwenburg PF (2001) Classification of cilio-inhibiting effects of nasal drugs. Laryngoscope 111(4):595–602PubMedCrossRefGoogle Scholar
  128. 128.
    Corbo DC, Liu JC, Chienx YW (1990) Characterization of the barrier properties of mucosal membranes. J Pharm Sci 79(3):202–206PubMedCrossRefGoogle Scholar
  129. 129.
    Corbo DC, J-c L, Chien YW (1989) Drug absorption through mucosal membranes: effect of mucosal route and penetrant hydrophilicity. Pharm Res 6(10):848–852PubMedCrossRefGoogle Scholar
  130. 130.
    Huang CH, Kimura R, Bawarshi-Nassar R, Hussain A (1985) Mechanism of nasal absorption of drugs II: absorption of L-tyrosine and the effect of structural modification on its absorption. J Pharm Sci 74(12):1298–1301PubMedCrossRefGoogle Scholar
  131. 131.
    Hussain A, Kimura R, Chong-Heng H, Kashihara T (1984) Nasal absorption of naloxone and buprenorphine in rats. Int J Pharm 21(2):233–237CrossRefGoogle Scholar
  132. 132.
    Bawarshi-Nassar R, Hussain A, Crooks P (1989) Nasal absorption of 17α-ethinyloestradiol in the rat. J Pharm Pharmacol 41(3):214–215PubMedCrossRefGoogle Scholar
  133. 133.
    Hussain A, Hamadi S, Kagashima M, Iseki K, Dittert L (1991) Does increasing the lipophilicity of peptides enhance their nasal absorption? J Pharm Sci 80(12):1180–1181PubMedCrossRefGoogle Scholar
  134. 134.
    Doelker E (ed) (2002) Crystalline modifications and polymorphism changes during drug manufacture. Ann Pharm Fr 60:161–176Google Scholar
  135. 135.
    Morissette SL, Almarsson Ö, Peterson ML, Remenar JF, Read MJ, Lemmo AV et al (2004) High-throughput crystallization: polymorphs, salts, co-crystals and solvates of pharmaceutical solids. Adv Drug Deliv Rev 56(3):275–300PubMedCrossRefGoogle Scholar
  136. 136.
    Raw AS, Furness MS, Gill DS, Adams RC, Holcombe FO Jr, Lawrence XY (2004) Regulatory considerations of pharmaceutical solid polymorphism in Abbreviated New Drug Applications (ANDAs). Adv Drug Deliv Rev 56(3):397–414PubMedCrossRefGoogle Scholar
  137. 137.
    Türker S, Onur E, Ózer Y (2004) Nasal route and drug delivery systems. Pharm World Sci 26(3):137–142PubMedCrossRefPubMedCentralGoogle Scholar
  138. 138.
    Hussain AA (1998) Intranasal drug delivery. Adv Drug Deliv Rev 29(1–2):39–49PubMedCrossRefGoogle Scholar
  139. 139.
    Fisher A, Brown K, Davis S, Parr G, Smith D (1987) The effect of molecular size on the nasal absorption of water-soluble compounds in the albino rat. J Pharm Pharmacol 39(5):357–362PubMedCrossRefGoogle Scholar
  140. 140.
    Matsuyama T, Morita T, Horikiri Y, Yamahara H, Yoshino H (2006) Enhancement of nasal absorption of large molecular weight compounds by combination of mucolytic agent and nonionic surfactant. J Control Release 110(2):347–352PubMedCrossRefPubMedCentralGoogle Scholar
  141. 141.
    Fisher A, Illum L, Davis S, Schacht E (1992) Di-iodo-l-tyrosine-labelled dextrans as molecular size markers of nasal absorption in the rat. J Pharm Pharmacol 44(7):550–554PubMedCrossRefPubMedCentralGoogle Scholar
  142. 142.
    Yamamoto A, Iseki T, Ochi-Sugiyama M, Okada N, Fujita T, Muranishi S (2001) Absorption of water-soluble compounds with different molecular weights and [Asu1. 7]-eel calcitonin from various mucosal administration sites. J Control Release 76(3):363–374PubMedCrossRefGoogle Scholar
  143. 143.
    Yamamoto A, Morita T, Hashida M, Sezaki H (1993) Effect of absorption promoters on the nasal absorption of drugs with various molecular weights. Int J Pharm 93(1–3):91–99CrossRefGoogle Scholar
  144. 144.
    Shinichiro H, Takatsuka Y, Tai M, Hiroyuki M (1981) Absorption of drugs from the nasal mucosa of rat. Int J Pharm 7(4):317–325CrossRefGoogle Scholar
  145. 145.
    Huang CH, Kimura R, Nassar RB, Hussain A (1985) Mechanism of nasal absorption of drugs I: physicochemical parameters influencing the rate of in situ nasal absorption of drugs in rats. J Pharm Sci 74(6):608–611PubMedCrossRefGoogle Scholar
  146. 146.
    Jiang X, Lu X, Cui J, Qiu L, Xi N (1997) Studies on octanol-water partition coefficient and nasal drug absorption. Yao xue xue bao= Acta pharmaceutica Sinica 32(6):458–460PubMedGoogle Scholar
  147. 147.
    McMartin C, Hutchinson LE, Hyde R, Peters GE (1987) Analysis of structural requirements for the absorption of drugs and macromolecules from the nasal cavity. J Pharm Sci 76(7):535–540PubMedCrossRefGoogle Scholar
  148. 148.
    Rathbone M, Davies N, Tucker I (1994) Nasal systemic drug delivery. N Z Pharm 14:37–39Google Scholar
  149. 149.
    Ohwaki T, Ando H, Watanabe S, Miyake Y (1985) Effects of dose, pH, and osmolarity on nasal absorption of secretin in rats. J Pharm Sci 74(5):550–552PubMedCrossRefGoogle Scholar
  150. 150.
    Ohwaki T, Ando H, Kakimoto F, Uesugi K, Watanabe S, Miyake Y et al (1987) Effects of dose, pH, and osmolarity on nasal absorption of secretin in rats II: histological aspects of the nasal mucosa in relation to the absorption variation due to the effects of pH and osmolarity. J Pharm Sci 76(9):695–698PubMedCrossRefGoogle Scholar
  151. 151.
    Ohwaki T, Ishii M, Aoki S, Tatsuishi K, Kayano M (1989) Effect of dose, pH, and osmolarity on nasal absorption of secretin in rats. III.: in vitro membrane permeation test and determination of apparent partition coefficient of secretin. Chem Pharm Bull 37(12):3359–3362PubMedCrossRefGoogle Scholar
  152. 152.
    Jansson B, Hägerström H, Fransén N, Edsman K, Björk E (2005) The influence of gellan gum on the transfer of fluorescein dextran across rat nasal epithelium in vivo. Eur J Pharm Biopharm 59(3):557–564PubMedCrossRefGoogle Scholar
  153. 153.
    Suzuki Y, Makino Y (1999) Mucosal drug delivery using cellulose derivatives as a functional polymer. J Control Release 62(1–2):101–107PubMedCrossRefPubMedCentralGoogle Scholar
  154. 154.
    Hounam R, Black A, Walsh M (1971) The deposition of aerosol particles in the nasopharyngeal region of the human respiratory tract. J Aerosol Sci 2(1):47–61CrossRefGoogle Scholar
  155. 155.
    Romeo V, DeMeireles J, Sileno A, Pimplaskar H, Behl C (1998) Effects of physicochemical properties and other factors on systemic nasal drug delivery. Adv Drug Deliv Rev 29(1–2):89PubMedPubMedCentralGoogle Scholar
  156. 156.
    Kublik H, Vidgren M (1998) Nasal delivery systems and their effect on deposition and absorption. Adv Drug Deliv Rev 29(1–2):157–177PubMedCrossRefPubMedCentralGoogle Scholar
  157. 157.
    Gonda I, Gipps E (1990) Model of disposition of drugs administered into the human nasal cavity. Pharm Res 7(1):69–75PubMedCrossRefPubMedCentralGoogle Scholar
  158. 158.
  159. 159.
    Jones N, Quraishi S, Mason J (1997) The nasal delivery of systemic drugs. Int J Clin Pract 51(5):308–311PubMedPubMedCentralGoogle Scholar
  160. 160.
    Agarwal V, Mishra B (1999) Recent trends in drug delivery systems: intranasal drug delivery. Indian J Exp Biol 37(1):6–16PubMedGoogle Scholar
  161. 161.
    Shimoda N, Maitani Y, Machida Y, Nagai T (1995) Effects of dose, pH and osmolarity on intranasal absorption of recombinant human erythropoietin in rats. Biol Pharm Bull 18(5):734–739PubMedCrossRefGoogle Scholar
  162. 162.
    Hussain A, Bawarshi-Nassar R, Huang C (1985) Physicochemical considerations in intranasal drug administration. Transnasal systemic medications. Elsevier, Amsterdam, pp 121–137Google Scholar
  163. 163.
    Conley SF (1994) Comparative trial of acceptability of beclomethasone dipropionate and a new formulation of flunisolide. Ann Allergy 72(6):529–532PubMedGoogle Scholar
  164. 164.
    Denyer S (1999) 4. Pharmaceutical properties of fluticasone propionate nasal drops: a new formulation. Allergy 54:17–20PubMedCrossRefGoogle Scholar
  165. 165.
    Quadir M, Zia H, Needham TE (2000) Development and evaluation of nasal formulations of ketorolac. Drug Deliv 7(4):223–229PubMedCrossRefGoogle Scholar
  166. 166.
    Park G-B, Lee Y-S, Lee K-P (1992) Recent advances in intranasal drug delivery. J Pharm Investig 22(2):77–96Google Scholar
  167. 167.
    Wing L (1977) Tobispray in nasal surgery. Med J Aust 1(20):751PubMedCrossRefPubMedCentralGoogle Scholar
  168. 168.
    Borum P, Mygind N (1979) Nasal methacholine challenge and ipratropium therapy. Laboratory studies and a clinical trial in perennial rhinitis. Acta Otorhinolaryngol Belg 33(4):528–535PubMedPubMedCentralGoogle Scholar
  169. 169.
    Van Dyke C, Jatlow P, Ungerer J, Barash P, Byck R (1978) Oral cocaine: plasma concentrations and central effects. Science 200(4338):211–213PubMedCrossRefPubMedCentralGoogle Scholar
  170. 170.
    Schaffer N, Seidmon E (1952) The intranasal use of prophenpyridamine maleate and chlorprophenpyridamine maleate in allergic rhinitis. Ann Allergy 10(2):194PubMedPubMedCentralGoogle Scholar
  171. 171.
    Illum L, Farraj N, Critchley H, Johansen B, Davis S (1989) Enhanced nasal absorption of insulin in rats using lysophosphatidylcholine. Int J Pharm 57(1):49–54CrossRefGoogle Scholar
  172. 172.
    Misra A, Kher G (2012) Drug delivery systems from nose to brain. Curr Pharm Biotechnol 13(12):2355–2379PubMedCrossRefPubMedCentralGoogle Scholar
  173. 173.
    Pisal SS, Paradkar AR, Mahadik KR, Kadam SS (2004) Pluronic gels for nasal delivery of Vitamin B12. Part I: preformulation study. Int J Pharm 270(1–2):37–45PubMedCrossRefPubMedCentralGoogle Scholar
  174. 174.
    Ugwoke MI, Agu RU, Verbeke N, Kinget R (2005) Nasal mucoadhesive drug delivery: background, applications, trends and future perspectives. Adv Drug Deliv Rev 57(11):1640–1665PubMedCrossRefPubMedCentralGoogle Scholar
  175. 175.
    Wattanathorn J, Phachonpai W, Priprem A, Suthiparinyanont S (2007) Intranasal administration of quercetin liposome decreases anxiety-like behavior and increases spatial memory. Am J Agric Biol Sci 2(1):31–35CrossRefGoogle Scholar
  176. 176.
    Frey W (2002) Method for administering fibroblast growth factor to the brainGoogle Scholar
  177. 177.
    Vyas S, Goswami S, Singh R (1995) Liposomes based nasal delivery system of nifedipine: Development and characterization. Int J Pharm 118(1):23–30CrossRefGoogle Scholar
  178. 178.
    Mistry A, Stolnik S, Illum L (2009) Nanoparticles for direct nose-to-brain delivery of drugs. Int J Pharm 379(1):146–157PubMedCrossRefGoogle Scholar
  179. 179.
    Wang X, Chi N, Tang X (2008) Preparation of estradiol chitosan nanoparticles for improving nasal absorption and brain targeting. Eur J Pharm Biopharm 70(3):735–740PubMedCrossRefGoogle Scholar
  180. 180.
    Barst RJ, Rubin LJ, Long WA, McGoon MD, Rich S, Badesch DB et al (1996) A comparison of continuous intravenous epoprostenol (prostacyclin) with conventional therapy for primary pulmonary hypertension. N Engl J Med 334(5):296–301PubMedCrossRefGoogle Scholar
  181. 181.
    Galiè N, Ghofrani HA, Torbicki A, Barst RJ, Rubin LJ, Badesch D et al (2005) Sildenafil citrate therapy for pulmonary arterial hypertension. N Engl J Med 353(20):2148–2157PubMedCrossRefGoogle Scholar
  182. 182.
    Nava S, Karakurt S, Rampulla C, Braschi A, Fanfulla F (2001) Salbutamol delivery during non-invasive mechanical ventilation in patients with chronic obstructive pulmonary disease: a randomized, controlled study. Intensive Care Med 27(10):1627–1635PubMedCrossRefGoogle Scholar
  183. 183.
    Illum L (2002) Nasal drug delivery: new developments and strategies. Drug Discov Today 7(23):1184–1189PubMedCrossRefGoogle Scholar
  184. 184.
    Consortium IPA. Ensuring patient care – the role of the HFC MDI. Washington, DC: The Consortium. 1997.Google Scholar

Copyright information

© Springer Nature Singapore Pte Ltd. 2019

Authors and Affiliations

  • Manisha Lalan
    • 1
  • Hemal Tandel
    • 2
  • Rohan Lalani
    • 2
  • Vivek Patel
    • 2
  • Ambikanandan Misra
    • 2
  1. 1.Department of PharmaceuticsBabaria Institute of PharmacyVadodaraIndia
  2. 2.Faculty of PharmacyThe Maharaja Sayajirao University of BarodaVadodaraIndia

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