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Science and Technology of Pressurized Metered-Dose Inhalers

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Controlled Pulmonary Drug Delivery

Part of the book series: Advances in Delivery Science and Technology ((ADST))

Abstract

The pressurized, propellant driven metered-dose inhaler is an essential technology for pulmonary drug delivery. In this chapter, both the basic scientific principles and technological advances of these systems will be discussed. A particular focus will be the physical chemistry of formulation and how this understanding allows predictable product development of these products. Lastly, based on this science, future technological advances will be discussed.

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Notes

  1. 1.

    Correlations for solution-based pMDIs have indeed been developed (with cosolvents and other nonvolatiles), but for specific hardware sets (e.g., a certain valve and actuator) (Stein 2004).

  2. 2.

    We note several publications that have discussed the possibility of electrostatic stability in nonaqueous solvents (Vakarelski 2010; Patel 2010), and this may be an important area of research for HFA-based pMDIs as we go forward. However, at this time, there is not enough fundamental studies in this area to rationalize experimental results observed to date that have argued in favor of electrostatic stabilization of colloidal domains in HFAs (Peguin 2008).

References

  1. Akasaka R (2008) An assessment of thermodynamic models for HFC refrigerant mixtures through the critical-point calculation. Int J Thermophys 29:1328–1341

    CAS  Google Scholar 

  2. Ashayer R, Luckham PF, Manimaaran S, Rogueda P (2004) Investigation of the molecular interactions in a pMDI formulation by atomic force microscopy. Eur J Pharm Sci 21(4):533–543

    PubMed  CAS  Google Scholar 

  3. AstraZeneca (2009) Symbicort product information booklet

    Google Scholar 

  4. Atkins PJ, Woodcock A, Blinova O, Khan J, Stechert R, Wright P, Yizhong Y (2006) Medical aerosols, in IPCC/TEAP special report: safeguarding the ozone layer and the global climate system, Fakes D, Seki M, Editors. pp 351–360

    Google Scholar 

  5. Azarmi S, Roa WH, Lobenberg R (2008) Targeted delivery of nanoparticles for the treatment of lung diseases. Adv Drug Deliv Rev 60(8):863–875

    PubMed  CAS  Google Scholar 

  6. Bailey MM, Berkland CJ (2009) Nanoparticle formulations in pulmonary drug delivery. Med Res Rev 29(1):196–212

    PubMed  CAS  Google Scholar 

  7. Bandi N, Wei W, Roberts CB, Kotra LP, Kompella UB (2004) Preparation of budesonide- and indomethacin-hydroxypropyl-beta-cyclodextrin (HPBCD) complexes using a single-step, organic-solvent-free supercritical fluid process. Eur J Pharm Sci 23(2):159–168

    PubMed  CAS  Google Scholar 

  8. Bell J, Newman S (2007) The rejuvenated pressurised metered dose inhaler. Expert Opin Drug Deliv 4(3):215–234

    PubMed  CAS  Google Scholar 

  9. Berger W (2009) Aerosol devices and asthma therapy. Curr Drug Deliv 6(1):38–49

    PubMed  CAS  Google Scholar 

  10. Bharatwaj B, Wu L, Whittum-Hudson J, da Rocha SRP (2010) The potential for the noninvasive delivery of polymeric nanocarriers using propellant-based inhalers in the treatment of Chlamydial respiratory infections. Biomaterials 31:7376–7385

    Google Scholar 

  11. Blondino FE, Byron PR (1998) Surfactant dissolution and water solubilization in chlorine-free liquified gas propellants. Drug Dev Ind Pharm 24(10):935–945

    PubMed  CAS  Google Scholar 

  12. Brambilla G, Ganderton D, Garzia R, Lewis D, Meakin B, Ventura P (1999) Modulation of aerosol clouds produced by pressurised inhalation aerosols. Int J Pharm 186(1):53–61

    PubMed  CAS  Google Scholar 

  13. Chokshi U, Selvam P, Porcar L, da Rocha SRP (2009) Reverse aqueous emulsions and microemulsions in HFA227 propellant stabilized by non-ionic ethoxylated amphiphiles. Int J Pharm 369:176–184

    PubMed  CAS  Google Scholar 

  14. Chow AH, Tong HH, Chattopadhyay P, Shekunov BY (2007) Particle engineering for pulmonary drug delivery. Pharm Res 24(3):411–437

    PubMed  CAS  Google Scholar 

  15. Courrier HM, Butz N, Vandamme TF (2002) Pulmonary drug delivery systems: recent developments and prospects. Crit Rev Ther Drug Carrier Syst 19(4–5):425–498

    PubMed  CAS  Google Scholar 

  16. Courrier HM, Pons F, Lessinger JM, Frossard N, Krafft MP, Vandamme TF (2004) In vivo evaluation of a reverse water-in-fluorocarbon emulsion stabilized with a semifluorinated amphiphile as a drug delivery system through the pulmonary route. Int J Pharm 282(1–2):131–140

    PubMed  CAS  Google Scholar 

  17. Cummings RH (1999) Pressurized metered dose inhalers: chlorofluorocarbon to hydrofluoroalkane transition-valve performance. J Allergy Clin Immunol 104(6):S230–S236

    PubMed  CAS  Google Scholar 

  18. Dailey LA, Wittmar M, Kissel T (2005) The role of branched polyesters and their modifications in the development of modern drug delivery vehicles. J Control Release 101(1–3):137–149

    PubMed  CAS  Google Scholar 

  19. Dalby RN, Tiano SL, Hickey AJ (2007) Medical devices for the delivery of therapeutic ­aerosols to the lungs. In: Hickey AJ (ed) Inhalation aerosols – physical and biological basis for therapy, 2nd edn. Informa Healthcare, New York

    Google Scholar 

  20. Davis ME, Chen ZG, Shin DM (2008) Nanoparticle therapeutics: an emerging treatment modality for cancer. Nat Rev Drug Discov 7(9):771–782

    PubMed  CAS  Google Scholar 

  21. de Jager D, Manning M, Kuijpers L (2006) Safeguarding the ozone layer and the global ­climate system: issues related to hydrofluorocarbons and perfluorocarbons, in IPCC/TEAP special report, Davidson O, McFarland M, Midgley P, Editors. pp 19–81

    Google Scholar 

  22. de Jager D, Manning M, Kuijpers L (2006) Safeguarding the ozone layer and the global ­climate system: issues related to hydrofluorocarbons and perfluorocarbons – summary for policymakers, in IPCC/TEAP special Report, Davidson O, McFarland M, Midgley P, Editors. pp 1–13

    Google Scholar 

  23. Dellamary LA, Tarara TE, Smith DJ, Woelk CH (2000) Hollow porous particles in metered dose inhalers. Pharm Res 17(2):168–174

    PubMed  CAS  Google Scholar 

  24. Dickinson PA, Seville PC, McHale H, Perkins NC, Taylor G (2000) An investigation of the solubility of various compounds in the hydrofluoroalkane propellants and possible model liquid propellants. J Aerosol Med 13(3):179–186

    PubMed  CAS  Google Scholar 

  25. Dickinson PA, Howells SW, Kellaway IW (2001) Novel nanoparticles for pulmonary drug administration. J Drug Target 9(4):295–302

    PubMed  CAS  Google Scholar 

  26. Edwards DA, Hanes J, Caponetti G (1997) Large porous particles for pulmonary drug ­delivery. Science 276(5320):1868–1871

    PubMed  CAS  Google Scholar 

  27. Elvassore N, Bertucco A, Wahlstrom A (1999) A cubic equation of state with group contributions for the calculation of vapor-liquid equilibria of mixtures of hydrofluorocarbons and lubricant oils. Ind Eng Chem Res 38:2110–2118

    CAS  Google Scholar 

  28. Engstrom J, Tam J, Miller M, Williams RO, Johnston K (2009) Templated open flocs of ­nanorods for enhanced pulmonary delivery with pressurized metered dose inhalers. Pharm Res 26(1):101–117

    PubMed  CAS  Google Scholar 

  29. Gupta A, Myrdal PB (2004) Novel method for the determination of solubility in aerosol propellants. J Pharm Sci 93(10):2411–2419

    PubMed  CAS  Google Scholar 

  30. Hadinoto K, Phanapavudikul P, Kewu Z, Tan BHT (2007) Drug release study of large hollow nanoparticulate aggregates carrier particles for pulmonary delivery. Int J Pharm 341:195–206

    PubMed  CAS  Google Scholar 

  31. Hans ML, Lowman AM (2002) Biodegradable nanoparticles for drug delivery and targeting. Curr Opin Solid State Mater Sci 6:319–327

    CAS  Google Scholar 

  32. Harris JA, Stein SW, Myrdal PB (2006) Evaluation of the TSI aerosol impactor 3306/3321 system using a redesigned impactor stage with solution and suspension metered-dose ­inhalers. AAPS PharmSciTech 7(1):E20

    PubMed  Google Scholar 

  33. Hitzman CJ, Wattenberg LW, Wiedmann TS (2006) Pharmacokinetics of 5-fluorouracil in the hamster following inhalation delivery of lipid-coated nanoparticles. J Pharm Sci 95(6):1196–1211

    PubMed  CAS  Google Scholar 

  34. Hoye JA, Myrdal PB (2008) Measurement and correlation of solute solubility in HFA-134a/ethanol systems. Int J Pharm 362(1–2):184–188

    PubMed  CAS  Google Scholar 

  35. Hoye JA, Gupta A, Myrdal PB (2008) Solubility of solid solutes in HFA-134a with a correlation to physico-chemical properties. J Pharm Sci 97(1):198–208

    PubMed  CAS  Google Scholar 

  36. Huber A, Lemmon EW, Friend DG (2002) Modeling bubble points of mixtures of hydrofluorocarbon refrigerants and polyol ester lubricants. Fluid Phase Equilibria 194:511–519

    Google Scholar 

  37. James J, Crean B, Davies M, Toon R, Jinks P, Roberts CJ (2008) The surface characterisation and comparison of two potential sub-micron, sugar bulking excipients for use in low-dose, suspension formulations in metered dose inhalers. Int J Pharm 361(1–2):209–221

    PubMed  CAS  Google Scholar 

  38. James J, Davies M, Toon R, Jinks P, Roberts CJ (2009) Particulate drug interactions with polymeric and elastomeric valve components in suspension formulations for metered dose inhalers. Int J Pharm 366(1–2):124–132

    PubMed  CAS  Google Scholar 

  39. Johnson KA (2007) Interfacial phenomena and phase behavior in metered dose inhaler ­formulations. In: Hickey AJ (ed) Inhalation aerosols – physical and biological basis for ­therapy, 2nd edn. Informa Healthcare, New York, pp 347–371

    Google Scholar 

  40. Jones SA, Martin GP, Brown MB (2006) Stabilisation of deoxyribonuclease in hydrofluoroalkanes using miscible vinyl polymers. J Control Release 115:1–8

    PubMed  CAS  Google Scholar 

  41. Kappl M, Butt HJ (2002) The colloidal probe technique and its application to adhesion force measurements. Part Part Syst Charact 19:129–143

    CAS  Google Scholar 

  42. Kiselev SB, Ely JF (2003) Generalized corresponding states model for bulk and interfacial properties in pure fluids and fluid mixtures. J Chem Phys 119:8645–8662

    CAS  Google Scholar 

  43. Kleinstreuer C, Zhang Z, Donohue JF (2008) Targeted drug-aerosol delivery in the human respiratory system. Annu Rev Biomed Eng 10:195–220

    PubMed  CAS  Google Scholar 

  44. Kreyling WG, Semmler-Behnke M, Seitz J, Scymczak W, Wenk A, Mayer P, Takenaka S, Oberdorster G (2009) Size dependence of the translocation of inhaled iridium and carbon nanoparticle aggregates from the lung of rats to the blood and secondary target organs. Inhal Toxicol 21(Suppl 1):55–60

    PubMed  CAS  Google Scholar 

  45. Kumari A, Yadav SK, Yadav SC (2010) Biodegradable polymeric nanoparticles based drug delivery systems. Colloids Surf B Biointerfaces 75(1):1–18

    PubMed  CAS  Google Scholar 

  46. Lai SK, O’Hanlon DE, Harrold S, Man ST, Wang YY, Cone R, Hanes J (2007) Rapid ­transport of large polymeric nanoparticles in fresh undiluted human mucus. Proc Natl Acad Sci USA 104(5):1482–1487

    PubMed  CAS  Google Scholar 

  47. Lai SK, Wang YY, Hanes J (2009) Mucus-penetrating nanoparticles for drug and gene ­delivery to mucosal tissues. Adv Drug Deliv Rev 61(2):158–171

    PubMed  CAS  Google Scholar 

  48. Lavorini F, Fontana GA (2009) Targeting drugs to the airways: the role of spacer devices. Expert Opin Drug Deliv 6(1):91–102

    PubMed  CAS  Google Scholar 

  49. Lewis D (2007) Metered-dose inhalers: actuators old and new. Expert Opin Drug Deliv 4(3):235–245

    PubMed  CAS  Google Scholar 

  50. Liao YH, Brown MB, Jones SA, Nazir T, Martin GP (2005) The effects of polyvinyl alcohol on the in vitro stability and delivery of spray-dried protein particles from surfactant-free HFA 134a-based pressurised metered dose inhalers. Int J Pharm 304(1–2):29–39

    PubMed  CAS  Google Scholar 

  51. McCallister JW, Moore WC (2008) Hydrofluoroalkane preparations of fluticasone propionate. Expert Rev Resp Med 2:433–442

    CAS  Google Scholar 

  52. McDonald KJ, Martin GP (2000) Transition to CFC-free metered dose inhalers – into the new millennium. Int J Pharm 201(1):89–107

    PubMed  CAS  Google Scholar 

  53. Mitchell JP, Nagel MW (2009) Oral inhalation therapy: meeting the challenge of developing more patient-appropriate devices. Expert Rev Med Devices 6(2):147–155

    PubMed  Google Scholar 

  54. Mogalian E, Myrdal PB (2007) Pharmaceutical solvents for pulmonary drug delivery. In: Augustijns P, Brewster M (eds) Solvent systems and their selection in pharmaceutics and biopharmaceutics, vol VI. Springer, New York, pp 427–441

    Google Scholar 

  55. Nicolini G, Scichilone N, Bizzi A, Papi A, Fabbri LM (2008) Beclomethasone/formoterol fixed combination for the management of asthma: patient considerations. Ther Clin Risk Manag 4(5):855–864

    PubMed  CAS  Google Scholar 

  56. Norwood DL, Paskiet D, Ruberto M, Feinberg T, Schroeder A, Poochikian G, Wang Q, Deng TJ, DeGrazio F, Munos MK, Nagao LM (2008) Best practices for extractables and leachables in orally inhaled and nasal drug products: an overview of the PQRI recommendations. Pharm Res 25(4):727–739

    PubMed  CAS  Google Scholar 

  57. Nyambura BK, Kellaway IW, Taylor KM (2009) Insulin nanoparticles: stability and aerosolization from pressurized metered dose inhalers. Int J Pharm 375(1–2):114–122

    PubMed  CAS  Google Scholar 

  58. Nyambura BK, Kellaway IW, Taylor KM (2009) The processing of nanoparticles containing protein for suspension in hydrofluoroalkane propellants. Int J Pharm 372(1–2):140–146

    PubMed  CAS  Google Scholar 

  59. O’Riordan TG, Smaldone GC (2008) Aerosol delivery systems. In: Kay AB, Kaplan AP, Bousquet J, Holt PG (eds) Allergy and allergic diseases, vol 1, 2nd edn. Blackwell Publishing, Maiden, pp 768–782

    Google Scholar 

  60. Overhoff KA, Engstrom JD, Chen B, Scherzer BD, Milner TE, Johnston KP, Williams RO III (2007) Novel ultra-rapid freezing particle engineering process for enhancement of dissolution rates of poorly water-soluble drugs. Eur J Pharm Biopharm 65(1):57–67

    PubMed  CAS  Google Scholar 

  61. Overhoff KA, Johnston KP, Tam J, Engstrom J, Williams RO (2009) Use of thin film freezing to enable drug delivery: a review. J Drug Deliv Sci Technol 19(2):89–98

    CAS  Google Scholar 

  62. Oversteegen L (2008) Inhaled medicines: product differentiation by device. Innov Pharm Technol 28:62–65

    Google Scholar 

  63. Oversteegen L, Rovini H, Belsey MJ (2007) Respiratory drug market dynamics. Nat Rev Drug Discov 6(9):695–696

    PubMed  CAS  Google Scholar 

  64. Panyam J, Labhasetwar V (2003) Biodegradable nanoparticles for drug and gene delivery to cells and tissue. Adv Drug Deliv Rev 55(3):329–347

    PubMed  CAS  Google Scholar 

  65. Patel N, Marlow M, Lawrence MJ (2003) Fluorinated ionic surfactant microemulsions in hydrofluorocarbon 134a (HFC 134a). J Colloid Interface Sci 258(2):354

    PubMed  CAS  Google Scholar 

  66. Patel N, Marlow M, Lawrence MJ (2003) Formation of fluorinated nonionic surfactant ­microemulsions in hydrofluorocarbon 134a (HFC 134a). J Colloid Interface Sci 258(2):345

    PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

  68. Peguin RPS, da Rocha SRP (2008) Solvent−solute interactions in hydrofluoroalkane ­propellants. J Phys Chem B 112:8084–8094

    PubMed  CAS  Google Scholar 

  69. Peguin RPS, Selvam P, da Rocha SRP (2006) Microscopic and thermodynamic properties of the HFA134a-water interface: atomistic computer simulations and tensiometry under ­pressure. Langmuir 22(21):8826–8830

    PubMed  CAS  Google Scholar 

  70. Peguin RPS, Wu L, da Rocha SRP (2007) The Ester Group: how hydrofluoroalkane-philic is it? Langmuir 23(16):8291–8294

    PubMed  CAS  Google Scholar 

  71. Peguin RP, Kamath G, Potoff JJ, da Rocha SR (2009) All-atom force field for the prediction of vapor-liquid equilibria and interfacial properties of HFA134a. J Phys Chem B 113(1):178–187

    PubMed  CAS  Google Scholar 

  72. Pison U, Welte T, Giersig M, Groneberg DA (2006) Nanomedicine for respiratory diseases. Eur J Pharmacol 533(1–3):341–350

    PubMed  CAS  Google Scholar 

  73. Prokopovich P, Theodossides S, Rahnejat H, Hodson D (2009) Friction in ultra-thin conjunction of valve seals of pressurised metered dose inhalers. Wear 268:845–852

    Google Scholar 

  74. Quinn EA, Forbes RT, Williams AC, Oliver MJ, McKenzie L, Purewal TS (1999) Protein conformational stability in the hydrofluoroalkane propellants tetrafluoroethane and heptafluoropropane analysed by Fourier transform Raman spectroscopy. Int J Pharm 186(1):31–41

    PubMed  CAS  Google Scholar 

  75. Ridder KB, Davies-Cutting CJ, Kellaway IW (2005) Surfactant solubility and aggregate ­orientation in hydrofluoroalkanes. Int J Pharm 295(1–2):57–65

    PubMed  CAS  Google Scholar 

  76. Rogueda P (2005) Novel hydrofluoroalkane suspension formulations for respiratory drug delivery. Expert Opin Drug Deliv 2(4):625–638

    PubMed  CAS  Google Scholar 

  77. Rogueda P (2007) Pharmaceutical spray formulation comprising a hydrofluoroalkane and an acylated cyclodextrin. US Patent 2007/0104652 A1

    Google Scholar 

  78. Rogueda PG, Traini D (2007) The nanoscale in pulmonary delivery. Part 1: deposition, fate, toxicology and effects. Expert Opin Drug Deliv 4(6):595–606

    PubMed  CAS  Google Scholar 

  79. Rogueda PGA, Traini D (2007) The nanoscale in pulmonary delivery. Part 2: formulation platforms. Expert Opin Drug Deliv 4(6):607–620

    PubMed  CAS  Google Scholar 

  80. Rosenholm JB (2010) Solvent and surfactant induced interactions in drug dispersions. Colloid Surface Physicochem Eng Aspects 354:197–204

    CAS  Google Scholar 

  81. Rytting E, Nguyen J, Wang X, Kissel T (2008) Biodegradable polymeric nanocarriers for pulmonary drug delivery. Expert Opin Drug Deliv 5(6):629–639

    PubMed  CAS  Google Scholar 

  82. Saiprasad S, Onyskiw P, Conti D, Wu L, da Rocha SRP (2010). DNase particle formulation for pressurized metered-dose inhalers. Manuscript in Preparation

    Google Scholar 

  83. Scheuch G, Siekmeier R (2007) Novel approaches to enhance pulmonary delivery of proteins and peptides. J Physiol Pharmacol 58(Suppl 5, Pt 2):615–625

    PubMed  Google Scholar 

  84. Selvam P, Peguin RPS, Chokshi U, da Rocha SRP (2006) Surfactant design for the 1,1,1,2-tetrafluoroethane-water interface: ab initio calculations and in situ high-pressure tensiometry. Langmuir 22(21):8675–8683

    PubMed  CAS  Google Scholar 

  85. Selvam P, Chokshi U, Gouch A, da Rocha SRP (2008) Ethoxylated copolymer surfactants for the hfa134a-water interface: interfacial activity, aggregation behavior and biomolecule. Soft Matter 4:357–366

    CAS  Google Scholar 

  86. Semmler-Behnke M, Takenaka S, Fertsch S, Wenk A, Seitz J, Mayer P, Oberdorster G, Kreyling WG (2007) Efficient elimination of inhaled nanoparticles from the alveolar region: evidence for interstitial uptake and subsequent reentrainment onto airways epithelium. Environ Health Perspect 115(5):728–733

    PubMed  CAS  Google Scholar 

  87. Sham JOH, Yu Z, Finlay WH, Roa WH, Lobenberg R (2004) Formulation and characterization of spray-dried powders containing nanoparticles for aerosol delivery to the lung. Int J Pharm 269:457–467

    PubMed  CAS  Google Scholar 

  88. Shekunov BY, Chattopadhyay P, Seitzinger J, Huff R (2006) Nanoparticles of poorly water-­soluble drugs prepared by supercritical fluid extraction of emulsions. Pharm Res 23(1):196–204

    PubMed  CAS  Google Scholar 

  89. Shekunov BY, Chattopadhyay P, Tong HH, Chow AH (2007) Particle size analysis in ­pharmaceutics: principles, methods and applications. Pharm Res 24(2):203–227

    PubMed  CAS  Google Scholar 

  90. Sherwood JK, Alex S, Salama G, Obenauer-Kutner L, Huyck S, Berry J, Sequeira J, Brouet G, Marie C (2007) Particle size coarsening induced by valve silicone in a metered dose inhaler. Drug Dev Ind Pharm 33(2):155–162

    PubMed  CAS  Google Scholar 

  91. Shoyele SA (2008) Engineering protein particles for pulmonary drug delivery. Methods Mol Biol 437:149–160

    PubMed  CAS  Google Scholar 

  92. Shoyele SA, Cawthorne S (2006) Particle engineering techniques for inhaled biopharmaceuticals. Adv Drug Deliv Rev 58(9–10):1009–1029

    PubMed  CAS  Google Scholar 

  93. Smyth HDC (2003) The influence of formulation variables on the performance of alternative propellant-driven metered dose inhalers. Adv Drug Deliv Rev 55(7):807–828

    PubMed  CAS  Google Scholar 

  94. Smyth HD (2005) Propellant-driven metered-dose inhalers for pulmonary drug delivery. Expert Opin Drug Deliv 2(1):53–74

    PubMed  Google Scholar 

  95. Soppimath KS, Aminabhavi TM, Kulkarni AR, Rudzinski WE (2001) Biodegradable ­polymeric nanoparticles as drug delivery devices. J Control Release 70(1–2):1–20

    PubMed  CAS  Google Scholar 

  96. Steckel H, Wehle S (2004) A novel formulation technique for metered dose inhaler (MDI) suspensions. Int J Pharm 284(1–2):75–82

    PubMed  CAS  Google Scholar 

  97. Stefely J (2002) Novel excipients for inhalation drug delivery: expanding the capability of the MDI. Drug Deliv Technol 2:1–8

    Google Scholar 

  98. Stein SW, Myrdal PB (2004) A theoretical and experimental analysis of formulation and device parameters affecting solution MDI size distributions. J Pharm Sci 93(8):2158–2175

    PubMed  CAS  Google Scholar 

  99. Stein SW, Stefely J (2003) Reinventing metered dose inhalers: from poorly efficient CFC MDIs to highly efficient HFA MDIs. Drug Deliv Technol 3:46–51

    CAS  Google Scholar 

  100. Steytler DC, Thorpe M, Eastoe J, Dupont A, Heenan RK (2003) Microemulsion formation in 1,1,1,2-tetrafluoroethane (R134a). Langmuir 19(21):8715

    CAS  Google Scholar 

  101. Sung JC, Pulliam BL, Edwards DA (2007) Nanoparticles for drug delivery to the lungs. Trends Biotechnol 25(12):563–570

    PubMed  CAS  Google Scholar 

  102. Tam JM, Engstrom JD, Ferrer D, Williams RO III, Johnston KP (2010) Templated open flocs of anisotropic particles for pulmonary delivery with pressurized metered dose inhalers. J Pharm Sci 99(7):3150–3165

    PubMed  CAS  Google Scholar 

  103. Tang BC, Dawson M, Lai SK, Wang YY, Suk JS, Yang M, Zeitlin P, Boyle MP, Fu J, Hanes J (2009) Biodegradable polymer nanoparticles that rapidly penetrate the human mucus ­barrier. Proc Natl Acad Sci USA 106(46):19268–19273

    PubMed  CAS  Google Scholar 

  104. Tarasova A, Burden F, Gasteiger J, Winkler DA (2010) Robust modelling of solubility in supercritical carbon dioxide using Bayesian methods. J Mol Graph Model 28(7):593–597

    PubMed  CAS  Google Scholar 

  105. Terzano C (2001) Pressurized metered dose inhalers and add-on devices. Pulm Pharmacol Ther 14(5):351–366

    PubMed  CAS  Google Scholar 

  106. Traini D, Rogueda P, Young P, Price R (2005) Surface energy and interparticle forces correlations in model pMDI formulations. Pharm Res 22(5):816–825

    PubMed  CAS  Google Scholar 

  107. Traini D, Young PM, Price R, Rogueda P (2006) A novel apparatus for the determination of solubility in pressurized metered dose inhalers. Drug Dev Ind Pharm 32(10):1159–1163

    PubMed  CAS  Google Scholar 

  108. Traini D, Young PM, Rogueda P, Price R (2006) Investigation into the influence of polymeric stabilizing excipients on inter-particulate forces in pressurised metered dose inhalers. Int J Pharm 320(1–2):58–63

    PubMed  CAS  Google Scholar 

  109. Traini D, Young PM, Rogueda P, Price R (2007) In vitro investigation of drug particulates interactions and aerosol performance of pressurised metered dose inhalers. Pharm Res 24(1):125–135

    PubMed  CAS  Google Scholar 

  110. Tsapis N, Bennett D, Jackson B, Weitz DA, Edwards DA (2002) Trojan particles: large porous carriers of nanoparticles for drug delivery. Proc Natl Acad Sci USA 99(19):12001–12005

    PubMed  CAS  Google Scholar 

  111. van Krevelen DW (1990) Properties of polymers. Their correlationwith chemical structure; their numerical estimation and prediction from additive group contributions, 3rd rev. ed.; Elsevier Scientific, Amsterdam, 1990

    PubMed  CAS  Google Scholar 

  112. Vervaet C, Byron PR (1999) Drug-surfactant-propellant interactions in HFA-formulations. Int J Pharm 186(1):13–30

    PubMed  CAS  Google Scholar 

  113. Videira MA, Botelho MF, Santos AC, Gouveia LF, de Lima JJ, Almeida AJ (2002) Lymphatic uptake of pulmonary delivered radiolabelled solid lipid nanoparticles. J Drug Target 10(8):607–613

    PubMed  CAS  Google Scholar 

  114. Wilby M (2005) pMDI performance – increasing performance consistency of pMDIs. Drug Deliv Technol 5:1–6

    Google Scholar 

  115. Williams RO III, Hu C (1997) A study of an epoxy aerosol can lining exposed to hydrofluoroalkane propellants. Eur J Pharm Biopharm 44(2):195–203

    CAS  Google Scholar 

  116. Williams RO III, Hu C (2000) Moisture uptake and its influence on pressurized metered-dose inhalers. Pharm Dev Technol 5(2):153–162

    PubMed  CAS  Google Scholar 

  117. Williams RO III, Hu C (2001) Influence of water on the solubility of two steroid drugs in hydrofluoroalkane (HFA) propellants. Drug Dev Ind Pharm 27:71–79

    PubMed  CAS  Google Scholar 

  118. Wright P (2006) Transition to CFC-free metered-dose inhalers in IPAC Submission to the Medical Technical Options Committee. pp 1–15

    Google Scholar 

  119. Wu L, da Rocha SRP (2007) Biocompatible and biodegradable copolymer stabilizers for hydrofluoroalkane dispersions: a colloidal probe microscopy investigation. Langmuir 23(24):12104–12110

    PubMed  CAS  Google Scholar 

  120. Wu L, da Rocha SRP (2008) Applications of the atomic force microscope in development of propellant-based inhalation formulations. KONA Powder Part J 26:106–128

    CAS  Google Scholar 

  121. Wu L, Al-Haydari M, da Rocha SRP (2007) Novel propellant-driven inhalation formulations: engineering polar drug particles with surface-trapped hydrofluoroalkane-philes. Eur J Pharm Sci 33(2):146–158

    PubMed  CAS  Google Scholar 

  122. Wu L, Peguin RPS, da Rocha SRP (2007) Understanding solvation in hydrofluoroalkanes: ab initio calculations and chemical force microscopy. J Phys Chem B 111:8096–8104

    PubMed  CAS  Google Scholar 

  123. Wu L, Peguin RPS, Selvam P, Chokshi U, da Rocha SRP (2007) Molecular scale behavior in alternative propellant-based inhaler formulations. In: Hickey AJ (ed) Inhalation aerosols – physical and biological basis for therapy, 2nd edn. Informa Healthcare, New York, pp 373–397

    Google Scholar 

  124. Wu L, Bharatwaj B, Panyam J, da Rocha SRP (2008) Core-shell particles for the dispersion of small polar drugs and biomolecules in hydrofluoroalkane propellants. Pharm Res 25(2):289–301

    PubMed  CAS  Google Scholar 

  125. Yamamoto H, Kuno Y, Sugimoto S, Takeuchi H, Kawashima Y (2005) Surface-modified PLGA nanosphere with chitosan improved pulmonary delivery of calcitonin by mucoadhesion and opening of the intercellular tight junctions. J Control Release 102(2):373–381

    PubMed  CAS  Google Scholar 

  126. Yang W, Peters JI, Williams RO III (2008) Inhaled nanoparticles – a current review. Int J Pharm 356(1–2):239–247

    PubMed  CAS  Google Scholar 

  127. Yang W, Tam J, Miller DA, Zhou J, McConville JT, Johnston KP, Williams RO III (2008) High bioavailability from nebulized itraconazole nanoparticle dispersions with biocompatible stabilizers. Int J Pharm 361(1–2):177–188

    PubMed  CAS  Google Scholar 

  128. Young PM, Price R, Lewis D, Edge S, Traini D (2003) Under pressure: predicting pressurized metered dose inhaler interactions using the atomic force microscope. J Colloid Interface Sci 262(1):298–302

    PubMed  CAS  Google Scholar 

  129. Zhao Y, Brown MB, Jones SA (2009) Engineering novel topical foams using hydrofluroalkane emulsions stabilised with pluronic surfactants. Eur J Pharm Sci 37(3–4):370–377

    PubMed  CAS  Google Scholar 

  130. Zhao Y, Moddaresi M, Jones SA, Brown MB (2009) A dynamic topical hydrofluoroalkane foam to induce nanoparticle modification and drug release in situ. Eur J Pharm Biopharm 72(3):521–528

    PubMed  CAS  Google Scholar 

  131. Zhao Y, Brown MB, Jones SA (2010) Pharmaceutical foams: are they the answer to the dilemma of topical nanoparticles? Nanomedicine 6(2):227–236

    PubMed  CAS  Google Scholar 

  132. Zheng JY, Fulu MY, Lee DY, Barber TE, Adjei AL (2001) Pulmonary peptide delivery: effect of taste-masking excipients on leuprolide suspension metered-dose inhalers. Pharm Dev Technol 6(4):521–530

    PubMed  CAS  Google Scholar 

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Acknowledgments

The authors would like to acknowledge the Institute of Manufacturing Research and the Graduate School at Wayne State University (WSU) for research assistantships, National Science Foundation (NSF, CBET 0933144) and Michigan University Commercialization Initiative (MUCI) for financial support.

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Authors and Affiliations

  1. Chemical Engineering and Materials Science, Wayne State University, Detroit, MI, 48202, USA

    Sandro R. P. da Rocha

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  1. Sandro R. P. da Rocha
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  2. Balaji Bharatwaj
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  3. Sowmya Saiprasad
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Correspondence to Sandro R. P. da Rocha .

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Editors and Affiliations

  1. , Pharmaceutics Division - PHR 4.214, University of Texas, University Station 1, Austin, 78712, USA

    Hugh D.C. Smyth

  2. Eshelman School of Pharmacy, Division of Molecular Pharmaceutics, University of North Carolina, Chapel Hill, 27599, North Carolina, USA

    Anthony J. Hickey

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© 2011 Controlled Release Society

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da Rocha, S.R.P., Bharatwaj, B., Saiprasad, S. (2011). Science and Technology of Pressurized Metered-Dose Inhalers. In: Smyth, H., Hickey, A. (eds) Controlled Pulmonary Drug Delivery. Advances in Delivery Science and Technology. Springer, New York, NY. https://doi.org/10.1007/978-1-4419-9745-6_8

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