Dry powder inhalers: An overview of the in vitro dissolution methodologies and their correlation with the biopharmaceutical aspects of the drug products

European Journal of Pharmaceutical Sciences

Volumn 113, Issue , 2018, Pages 18-28

  Velaga, Sitaram P ^a   Djuris, Jelena ^b   Cvijic, Sandra ^b   Rozou, Stavroula ^c   Russo, Paola ^d   Colombo, Gaia ^e   Rossi, Alessandra ^f  

^a LULEÅ UNIVERSITY OF TECHNOLOGY   (Sweden)

^b UNIVERSITY OF BELGRADE   (Serbia)

^c ELPEN Pharmaceutical Co Inc   (Greece)

^d UNIVERSITY OF SALERNO   (Italy)

^e UNIVERSITY OF FERRARA   (Italy)

^f UNIVERSITY OF PARMA   (Italy)

Author keywords

Biopharmaceutical classification; Dissolution methods; Dry powder inhalation; Pulmonary delivery; Solubility

Indexed keywords

ABSORPTION RATE CONSTANT; ARTICLE; BIOEQUIVALENCE; CORRELATIONAL STUDY; DRUG ABSORPTION; DRUG CLEARANCE; DRUG DELIVERY SYSTEM; DRUG MANUFACTURE; DRUG SOLUBILITY; HUMAN; HYDRODYNAMICS; IN VITRO DISSOLUTION; IN VITRO STUDY; INHALATION; MEAN RESIDENCE TIME; PHARMACOKINETIC PARAMETERS; PRIORITY JOURNAL; TREATMENT DURATION; CHEMISTRY; DRUG RELEASE; DRY POWDER INHALER; INHALATIONAL DRUG ADMINISTRATION; KINETICS; MEDICINAL CHEMISTRY; PHARMACEUTICS; POWDER; PROCEDURES; RESPIRATORY FUNCTION; SOLUBILITY;

ADMINISTRATION, INHALATION; BIOPHARMACEUTICS; CHEMISTRY, PHARMACEUTICAL; DRUG LIBERATION; DRY POWDER INHALERS; HUMANS; KINETICS; POWDERS; RESPIRATORY TRACT ABSORPTION; SOLUBILITY;

EID: 85029717101     PISSN: 09280987     EISSN: 18790720     Source Type: Journal    
DOI: 10.1016/j.ejps.2017.09.002     Document Type: Article

References (90)

1. Amidon, G.L., Lennernas, H., Shah, V.P., Crison, J.R., A theoretical basis for a biopharmaceutic drug classification: the correlation of in vitro drug product dissolution and in vivo bioavailability. Pharm. Res. 12 (1995), 413–420.
2. Arora, D., Shah, K.A., Halquist, M.S., Sakagami, M., In vitro aqueous fluid-capacity-limited dissolution testing of respirable aerosol drug particles generated from inhaler products. Pharm. Res. 27 (2010), 786–795.
3. Arora, S., Haghi, M., Loo, C.Y., Traini, D., Young, P.M., Jain, S., Development of an inhaled controlled release voriconazole dry powder formulation for the treatment of respiratory fungal infection. Mol. Pharm. 12 (2015), 2001–2009.
4. Balducci, A.G., Steckel, H., Guarneri, F., Rossi, A., Colombo, G., Sonvico, F., Cordts, E., Bettini, R., Colombo, P., Buttini, F., High shear mixing of lactose and salmeterol xinafoate dry powder blends: biopharmaceutic and aerodynamic performances. J. Drug Delivery Sci. Technol. 30 (2015), 443–449.
5. Berkenfeld, K., Lamprecht, A., McConville, J.T., Devices for dry powder drug delivery to the lung. AAPS PharmSciTech 16 (2015), 479–490.
6. de Boer, A.H., Chan, H.K., Price, R., A critical view on lactose-based drug formulation and device studies for powder inhalation; which are relevant and what interactions to expect. Adv. Drug Deliv. Rev. 64 (2012), 257–274.
7. Borghardt, J.M., Weber, B., Staab, A., Kloft, C., Pharmacometric models for characterizing the pharmacokinetics of orally inhaled drugs. AAPS J. 17 (2015), 853–870.
8. Buttini, F., Miozzi, M., Balducci, A.G., Royall, P.G., Brambilla, G., Colombo, P., Bettini, R., Forbes, B., Differences in physical chemistry and dissolution rate of solid particle aerosols from solution pressurised inhalers. Int. J. Pharm. 465 (2014), 42–51.
9. Byron, P.R., Patton, J.S., Drug delivery via the respiratory tract. J. Aerosol Med. 7 (1994), 49–75.
10. Chan, J.G.Y., Chan, H.K., Prestidge, C.A., Denman, J.A., Young, P.M., Triani, D., A novel dry powder inhalable formulation incorporating three first-line anti-tubercular antibiotics. Eur. J. Pharm. Biopharm. 83 (2013), 285–292.
11. Clark, A., Eldon, M., Dwivedi, S., Wolff, R., The application of pulmonary inhalation technology to drug discovery. Annu. Rep. Med. Chem. 41 (2006), 383–393.
12. Corradi, M., Chrystyn, H., Cosio, B.G., Pirozynski, M., Loukides, S., Louis, R., Spinola, M., Usmani, O.S., NEXThaler, an innovative dry powder inhaler delivering an extrafine fixed combination of beclometasone and formoterol to treat large and small airways in asthma. Expert Opin. Drug Deliv. 11 (2014), 1497–1506.
13. Davies, N.M., Feddah, M.R., A novel method for assessing dissolution of aerosol inhaler products. Int. J. Pharm. 255 (2003), 175–187.
14. De Souza Carvalho, C., Daum, N., Lehr, C.-M., Carrier interactions with the biological barriers of the lung: advanced in vitro models and challenges for pulmonary drug delivery. Adv. Drug Deliv. Rev. 75 (2014), 129–140.
15. Demoly, P., Hagedoorn, P., de Boer, A.H., Frijlink, H.W., The clinical relevance of dry powder inhaler performance for drug delivery. Respir. Med. 108 (2014), 1195–1203.
16. Dokoumetzidis, A., Macheras, P., A century of dissolution research: from Noyes and Whitney to the biopharmaceutics classification system. Int. J. Pharm. 321 (2006), 1–11.
17. Duret, C., Wauthoz, N., Sebti, T., Vanderbist, F., Amighi, K., Solid dispersions of itraconazole for inhalation with enhanced dissolution, solubility and dispersion properties. Int. J. Pharm. 428 (2012), 103–113.
18. Eixarch, H., Haltner-Ukomadu, E., Beisswenger, C., Bock, U., Drug delivery to the lung: permeability and physicochemical characteristics of drugs as the basis for a pulmonary biopharmaceutical classification system (pBCS). J. Epithel. Biol. Pharmacol. 3 (2010), 1–14.
19. EMA, Guideline on the pharmaceutical quality of inhalation and nasal products. http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2009/09/WC500003568.pdf, 2006 (accessed 14.09.2016).
20. EMA, Guideline on the requirements for clinical documentation for orally inhaled products (OIP) including the requirements for demonstration of therapeutic equivalence between two inhaled products for use in the treatment of asthma and chronic obstructive pulmonary disease (COPD) in adults and for use in the treatment of asthma in children and adolescents. http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2009/09/WC500003504.pdf, 2009 (accessed 14.09.2016).
21. FDA, Guidance for industry: Metered Dose Inhaler (MDI) and Dry Powder Inhaler (DPI) drug products, chemistry, manufacturing, and controls documentation. http://www.fda.gov/downloads/Drugs/…/Guidances/ucm070573.pdf, 1998 (accessed 14.09.2016).
22. Forbes, B., O'Lone, R., Pribul Allen, P., Cahan, A., Clarke, C., Collinge, M., Dailey, L.A., Donnelly, L.E., Dybowski, J., Hassall, D., Hildebrand, D., Jones, R., Reed, M.D., Robinson, I., Tomlinson, L., Wolfreys, A., Challenges for inhaled drug discovery and development: induced alveolar macrophage responses. Adv. Drug Deliv. Rev. 71 (2014), 15–33.
23. Forbes, B., Bäckman, P., Christopher, D., Dolovich, M., Li, B.V., Morgan, B., In vitro testing for orally inhaled products: developments in science-based regulatory approaches. AAPS J. 17 (2015), 837–852.
24. Forbes, B., Richer, N.H., Buttini, F., Dissolution: a critical performance characteristic of inhaled products?. Nokhodchi, A., Martin, G.P., (eds.) Pulmonary Drug Delivery Advances and Challenges, 2015, Wiley, United Kingdom, 223–240.
25. Freiwald, M., Valotis, A., Kirschbaum, A., McClellan, M., Mürdter, T., Fritz, P., Friedel, G., Thomas, M., Högger, P., Monitoring the initial pulmonary absorption of two different beclomethasone dipropionate aerosols employing a human lung reperfusion model. Respir. Res. 6 (2005), 21–33.
26. Fronius, M., Clauss, W.G., Althaus, M., Why do we have to move fluid to be able to breathe?. Front. Physiol. 3 (2012), 1–9.
27. Garcia-Arieta, A., A European perspective on orally inhaled products: in vitro requirements for a biowaiver. J. Aerosol. Med. Pulm. Drug Deliv. 27 (2014), 419–429.
28. Geiser, M., Update on macrophage clearance of inhaled micro- and nanoparticles. J. Aerosol Med. Pulm. Drug Deliv. 23 (2010), 207–217.
29. Gerde, P., Malmlöf, Havsborn, L., Sjöberg, C.-O., Ewing, P., Eirefelt, S., Ekelund, K., DissolvIt: an in vitro method for simulating the dissolution and absorption of inhaled dry powder drugs in the lungs. Assay Drug Dev. Technol. 15 (2017), 77–88.
30. Grainger, C.I., Saunders, M., Buttini, F., Telford, R., Merolla, L.L., Martin, G.P. et al., Critical characteristics for corticosteroid solution metered dose inhaler bioequivalence. Mol. Pharm. 9 (2012), 563–569.
31. Gray, V.A., Hickey, A.J., Balmer, P., Davies, N.M., Dunbar, C., Foster, T.S., Olsson, B.L., Sakagami, M., Shah, V.P., Smurthwaite, M.J., Veranth, J.M., Zaidi, K., The Inhalation Ad Hoc Advisory Panel for the USP performance tests of inhalation dosage forms. Pharm. Forum. 34 (2008), 1068–1074.
32. Gumbleton, M., Al-Jayyoussi, G., Crandon-Lewis, A., Francombe, D., Kreitmeyr, K., Morris, C.J., Smith, M.W., Spatial expression and functionality of drug transporters in the intact lung: objectives for further research. Adv. Drug Deliv. Rev. 63 (2011), 110–118.
33. Haghi, M., Traini, D., Bebawy, M., Young, P.M., Deposition, diffusion and transport mechanism of dry powder microparticulate salbutamol, at the respiratory epithelia. Mol. Pharm. 9 (2012), 1717–1726.
34. Haghi, M., Traini, D., Young, P., In vitro cell integrated impactor deposition methodology for the study of aerodynamically relevant size fractions from commercial pressurised metered dose inhalers. Pharm. Res. 31 (2014), 1779–1787.
35. Hancock, B.C., Parks, M., What is the true solubility advantage for amorphous pharmaceuticals?. Pharm. Res. 17 (2000), 397–404.
36. Hastedt, J.E., The lung as a dissolution vessel?. Inhalation 8 (2014), 18–22.
37. Hastedt, J.E., Bäckman, P., Clark, A.R., Doub, W., Hicey, A., Hochhaus, G., Kuehl, P.J., Lehr, C., Mauser, P., McConville, J., Niven, R., Sakagimi, M., Weers, J.G., Scope and Relevance of a Pulmonary Biopharmaceutical Classification System AAPS/FDA/USP Workshop March 16–17th, 2015 in Baltimore, MD. AAPS Open. 2, 2016, 1–20.
38. Hayduk, W., Laudie, H., Prediction of diffusion coefficients for non- electrolytes in dilute aqueous solutions. AICHE J. 20 (1974), 611–615.
39. Hintz, R.J., Johnson, K.C., The effect of particle size distribution on dissolution rate and oral absorption. Int. J. Pharm. 51 (1989), 9–17.
40. Hochhaus, G., Horhota, S., Hendeles, L., Suarez, S., Rebello, J., Pharmacokinetics of orally inhaled drug products. AAPS J. 17 (2015), 769–775.
41. Horhota, S.T., van Noord, J.A., Verkleij, C.B., Bour, L.J., Sharma, A., Trunk, M., Cornelissen, P.J., In vitro, pharmacokinetic, pharmacodynamic, and safety comparisons of single and combined administration of tiotropium and salmeterol in COPD patients using different dry powder inhalers. AAPS J. 17 (2015), 871–880.
42. Jaspart, S., Bertholet, P., Piel, G., Dogne, J.M., Delattre, L., Evrard, B., Solid lipid microparticles as a sustained release system for pulmonary drug delivery. Eur. J. Pharm. Biopharm. 65 (2007), 47–56.
43. Kalkwarf, D.R., Dissolution rates of uranim compounds in simulated lung fluid. Sci. Total Environ. 28 (1983), 405–414.
44. Khadka, P., Ro, J., Kim, H., Kim, I., Kim, J.T., Kim, H., Cho, J.M., Yun, G., Lee, J., Pharmaceutical particle technologies: an approach to improve drug solubility, dissolution and bioavailability. Asian J. Pharm. Sci. 9 (2014), 304–316.
45. Kippax, P., Huck-Jones, D., Suman, J.D., Hochhaus, G., Bhagwat, S., Dissolution Testing – Exploring the Link between Particle Size & Dissolution Behavior for OINDPs. Drug Development & Delivery. http://drug-dev.com/Main/Back-Issues/DISSOLUTION-TESTING-Exploring-the-Link-Between-Par-1077.aspx, 2016 (accessed 26.05.2016).
46. Maretti, E., Rustichelli, C., Romagnoli, M., Balducci, A.G., Buttini, F., Sacchetti, F., Leo, E., Iannuccelli, V., Solid lipid nanoparticle assemblies (SLNas) for an anti-TB inhalation treatment - a design of experiments approach to investigate the influence of pre-freezing conditions on the powder respirability. Int. J. Pharm. 511 (2016), 669–679.
47. Marques, M.R.C., Loebenberg, R., Almukainzi, M., Simulated biological fluids with possible application in dissolution testing. Dissolut. Technol. 18 (2011), 15–28.
48. May, S., Jensen, B., Wolkenhauer, M., Schneider, M., Lehr, C.M., Dissolution techniques for in vitro testing of dry powders for inhalation. Pharm. Res. 29 (2012), 2157–2166.
49. May, S., Jensen, B., Weiler, C., Wolkenhauer, M., Schneider, M., Lehr, C.M., Dissolution testing of powders for inhalation: influence of particle deposition and modeling of dissolution profiles. Pharm. Res. 31 (2014), 3211–3224.
50. May, S., Kind, S., Jensen, B., Wolkenhauer, M., Schneider, M., Lehr, C.M., Miniature in vitro dissolution testing of powders for inhalation. Dissolut. Technol. 8 (2015), 40–51.
51. Mees, J., Fulton, C., Wilson, S., Bramwell, N., Lucius, M., Cooper, A., Development of Dissolution Methodology for Dry Powder Inhalation Aerosols, Poster at IPAC-RS. 2011, 2011 http://ipacrs.org/assets/uploads/outputs/23-Pfizer.pdf (accessed 20.06.2016).
52. Meindl, C., Stranzinger, S., Dzidic, N., Salar-Behzadi, S., Mohr, S., Zimmer, A., Fröhlich, E., Permeation of therapeutic drugs in different formulations across the airway epithelium in vitro. PLoS One, 10, 2015, e0135690.
53. Mendes Lima Santos, G., Considerations for Generic OIPs in Brazil. IPAC-RS/UF Orlando Inhalation Conference. https://custom.cvent.com/7BA2EE65E8B64AEBB1E77F19E7FD30BC/files/event/8a749091c2c741228907ca5c70b619eb/98f6e2e31b024eed9c8f81c31b3e9242.pdf, 2014 (accessed 13.04.2016).
54. Möbus, K., Siepmann, J., Bodmeier, R., Zinc–alginate microparticles for controlled pulmonary delivery of proteins prepared by spray-drying. Eur. J. Pharm. Biopharm. 81 (2012), 121–130.
55. Muralidharan, P., Haves, D. Jr., Mansour, H.M., Dry powder inhalers in COPD, lung inflammation and pulmonary infections. Expert Opin. Drug Deliv. 12 (2015), 947–962.
56. Nahar, K., Gupta, N., Gauvin, R., Absar, S., Patel, B., Gupta, V., Khademhosseini, Ahsan, F., In vitro, in vivo and ex vivo models for studying particle deposition and drug absorption of inhaled pharmaceuticals. Eur. J. Pharm. Sci. 49 (2013), 805–818.
57. Nel, A., Xia, T., Madler, L., Li, N., Toxic potential of materials at the nanolevel. Science 311 (2006), 622–627.
58. Okazaki, A., Mano, T., Sugano, K., Theoretical dissolution model of poly-disperse drug particles in biorelevant media. J. Pharm. Sci. 97 (2008), 1843–1852.
59. Olsson, B., Bäckman, P., Mouth-throat models for realistic in vitro testing: a proposal for debate. Dalby, R., Byron, P.R., Peart, J., Suman, J.D., Farr, S.J., Young, P.M., Traini, D., (eds.) Respiratory Drug Delivery 2014, Fajardo, 2014, Puerto Rico. DHI Publishing, LLC, River Grove, Il, 287–894.
60. Ong, H.X., Traini, D., Loo, C.Y., Sarkissian, L., Lauretani, G., Scalia, S., Young, P.M., Is the cellular uptake of respiratory aerosols delivered from different devices equivalent?. Eur. J. Pharm. Biopharm. 93 (2015), 320–327.
61. Ortiz, M., Jornada, D.S., Pohlmann, A.R., Gueterres, S.S., Development of novel chitosan microcapsules for pulmonary delivery of Dapsone: characterization, aerosol performance, and in vivo toxicity evaluation. AAPS PhamSciTech. 16 (2015), 1033–1040.
62. Pai, R.V., Jain, R.R., Bannalikar, A.S., Menon, M.D., Development and evaluation of chitosan microparticles based dry powder inhalation formulations of rifampicin and rifabutin. J. Aerosol Med. Pulm. Drug Deliv. 28 (2015), 1–17.
63. Parikh, R., Dalwadi, S., Preparation and characterization of controlled release poly-ɛ -caprolactone microparticles of isoniazid for drug delivery through pulmonary route. Powder Technol. 264 (2014), 158–165.
64. Patton, J.S., Mechanisms of macromolecule absorption by the lungs. Adv. Drug Deliv. Rev. 19 (1996), 3–36.
65. Patton, J.S., Byron, P.R., Inhaling medicines: delivering drugs to the body through the lungs. Drug Des. Discov. 6 (2007), 67–74.
66. Patton, J.S., Fishburn, C.S., Weers, J.G., The lungs as a portal of entry for systemic drug delivery. Proc. Am. Thorac. Soc. 1 (2004), 338–344.
67. Pilcer, G., Rosiere, R., Traina, K., Sebti, T., Vanderbist, F., Amighi, K., New co-spray-dried tobramycin nanoparticles–clarithromycin inhaled powder systems for lung infection therapy in cystic fibrosis patients. J. Pharm. Sci. 102:6 (2013), 1836–1846.
68. Reisner, C., In-vitro/in-vivo Comparisons of Formoterol MDI to Formoterol DPI: Lessons Learned. IPAC-RS/UF Orlando Inhalation Conference. http://ipacrs.org/assets/uploads/outputs/03-Day_3_OIC_2014_Reisner.pdf, 2014 (accessed 13.04.2016).
69. Riley, T., Christopher, D., Arp, J., Casazza, A., Colombani, A. et al., Challenges with developing in vitro dissolution tests for orally inhaled products (OIPs). AAPS PharmSciTech 13 (2012), 978–989.
70. Rohrschneider, M., Bhagwat, S., Krampe, R., Michler, V., Breitkreutz, J., Hochhaus, G., Evaluation of the transwell system for characterization of dissolution behavior of inhalation drugs: effects of membrane and surfactant. Mol. Pharm. 12 (2015), 2618–2624.
71. Russo, P., Stigliani, M., Prota, L., Auriemma, G., Crescenzi, C., Porta, A., Aquino, R.P., Gentamicin and leucine inhalable powder: what about antipseudomonal activity and permeation through cystic fibrosis mucus?. Int. J. Pharm. 440 (2013), 250–255.
72. Sadler, R.C., Prime, D., Burnell, P.K., Martin, G.P., Forbes, B., Integrated in vitro experimental modelling of inhaled drug delivery: deposition, dissolution and absorption. J. Drug Delivery Sci. Technol. 21 (2011), 331–338.
73. Sakagami, M., Arora Lakhani, D., Understanding dissolution in the presence of competing cellular uptake and absorption in the airways. Resp. Drug Deliv. 1 (2012), 185–192.
74. Salama, R.O., Traini, D., Chan, H.K., Young, P.M., Preparation and characterisation of controlled release co-spray dried drug–polymer microparticles for inhalation 2: evaluation of in vitro release profiling methodologies for controlled release respiratory aerosols. Eur. J. Pharm. Biopharm. 70 (2008), 145–152.
75. Scalia, S., Salama, R., Young, P., Traini, D., Preparation and in vitro evaluation of salbutamol-loaded lipid microparticles for sustained release pulmonary therapy. J. Microencapsul. 29 (2012), 225–233.
76. Schulz, H., Brand, P., Heyder, J., Particle deposition in the respiratory tract. Gehr, P., Heyder, J., (eds.) Particle-Lung Interactions, 2000, Marcel Dekker, Inc., New York, Basel, 229–290.
77. Sheng, J.J., Sirois, P.J., Dressman, J.B., Amidon, G.L., Particle diffusional layer thickness in a USP dissolution apparatus II: a combined function of particle size and paddle speed. J. Pharm. Sci. 97 (2008), 4815–4829.
78. Sigurdsson, H.H., Kirch, J., Lehr, C.M., Mucus as a barrier to lipophilic drugs. Int. J. Pharm. 453 (2013), 56–64.
79. Smart, J.D., The basics and underlying mechanisms of mucoadhesion. Adv. Drug Deliv. Rev. 57 (2005), 1556–1568.
80. Son, Y.J., McConville, J.T., Development of a standardized dissolution test method for inhaled pharmaceutical formulations. Int. J. Pharm. 382 (2009), 15–22.
81. Son, Y.J., Horng, M., Copley, M., McConville, J.T., Optimization of an in vitro dissolution test method for inhalation formulations. Dissolut. Technol. 6 (2010), 6–13.
82. Son, Y.-J., Mitchell, J.P., McConville, J.T., In vitro performance testing for pulmonary drug delivery. Smith, H.D.C., Hickey, A.J., (eds.) Controlled Pulmonary Drug Delivery, Advances in Delivery Science and Technology, 2011, Controlled Release Society, 383–415.
83. Spiekermann, G.M., Finn, P.W., Ward, E.S., Dumont, J., Dickinson, B.L., Blumberg, R.S., Lencer, W.I., Receptor-mediated immunoglobulin G transport across mucosal barriers in adult life: functional expression of FcRn in the mammalian lung. J. Exp. Med. 196 (2002), 303–310.
84. Stigliani, M., Manniello, M.D., Zegarra-Moran, O., Galietta, L., Minicucci, L., Casciaro, R., Garofalo, E., Incarnato, L., Aquino, R.P., Del Gaudio, P., Russo, P., Rheological properties of cystic fibrosis bronchial secretion and in vitro drug permeation study: the effect of sodium bicarbonate. J. Aerosol Med. Pulm. Drug Deliv. 29 (2016), 1–9.
85. Tolman, J.A., Williams, R.O., Advances in the pulmonary delivery of poorly water-soluble drugs: influence of solubilization on pharmacokinetic properties. Drug Dev. Ind. Pharm. 36 (2010), 1–30.
86. Transwell® Permeable Supports, Instructions for Use. 2003, Corning Incorporated, One Riverfront Plaza, Corning, NY.
87. Usmani, O.S., Biddiscombe, M.F., Barnes, P.J., Regional lung deposition and bronchodilator response as a function of beta2-agonist particle size. Am. J. Respir. Crit. Care Med. 172 (2005), 1497–1504.
88. Virchov, J.C., What plays a role in the choice of inhaler device for asthma therapy. Curr. Med. Res. Opin. 21 (2005), S19–25.
89. Wu, S., Salar-Behzadi, S., Frohlich, E., Role of in-silico modeling in drug development for inhalation treatment. J. Mol. Pharm. Org. Process Res., 1, 2013, 106.
90. Yang, W., Peters, J.I., Williams, R.O. III, Inhaled nanoparticles–a current review. Int. J. Pharm. 356 (2008), 239–247.