Skip to main content
Log in

Particle Engineering for Pulmonary Drug Delivery

  • Expert Review
  • Published:
Pharmaceutical Research Aims and scope Submit manuscript

Abstract

With the rapidly growing popularity and sophistication of inhalation therapy, there is an increasing demand for tailor-made inhalable drug particles capable of affording the most efficient delivery to the lungs and the most optimal therapeutic outcomes. To cope with this formulation demand, a wide variety of novel particle technologies have emerged over the past decade. The present review is intended to provide a critical account of the current goals and technologies of particle engineering for the development of pulmonary drug delivery systems. These technologies cover traditional micronization and powder blending, controlled solvent crystallization, spray drying, spray freeze drying, particle formation from liquid dispersion systems, supercritical fluid processing and particle coating. The merits and limitations of these technologies are discussed with reference to their applications to specific drug and/or excipient materials. The regulatory requirements applicable to particulate inhalation products are also reviewed briefly.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

Similar content being viewed by others

References

  1. S. P. Newman and W. W. Busse. Evolution of dry powder inhaler design, formulation, and performance. Respir. Med. 96:293–304 (2002).

    PubMed  CAS  Google Scholar 

  2. R. J. Malcolmson and J. K. Embleton. Dry powder formulations for pulmonary delivery. PSTT 1:394–398 (1998).

    CAS  Google Scholar 

  3. K. Koushik and U. B. Kompella. Particle and device engineering for inhalation drug delivery. Drug Del. Technol. 4: 40–50 (2004).

    Google Scholar 

  4. B. Y. Shekunov, P. Chattopadhyay, H. H. Y. Tong, and A. H. L. Chow. Particle size analysis in pharmaceutics: principles, methods and applications. Pharm. Res. (2006) (In print).

  5. B. Y. Shekunov, J. C. Feeley, A. H. L. Chow, H. H. Y. Tong, and P. York. Aerosolisation behaviour of micronised and supercritically-processed powders. J. Aerosol Sci. 34:553–568 (2003).

    Google Scholar 

  6. B. Y. Shekunov, B. Chattopadhyay, and J. Seitzinger. Production of respirable particles using spray-freeze-drying with compressed CO2. Proceedings of the Conference on Respiratory Drug Delivery, Palm Springs, California, 2004, pp. 489–492.

  7. B. Y. Shekunov, B. Chattopadhyay, A. Gibson, and C. Lehmkuhl. Influence of spray-freezing parameters on particle size and morphology of insulin. Proceedings of the Conference on Respiratory Drug Delivery, Boca Raton, Florida, 2006, pp. 605–608.

  8. R. M. Platz, J. S. Patton, L. Foster, and M. Eljamal. Spray drying of macromolecules to produce inhalable dry powders. United States Patent. 6,582,728 (2003).

  9. S. P. Duddu, S. A. Sisk, Y. H. Walter, T. E. Tarara, K. R. Trimble, A. R. Clark, M. A. Eldon, R. C. Elton, M. Pickford, P. H. Hirst, S. P. Newman, and J. G. Weers. Improved lung delivery from a passive dry powder inhaler using an engineered PulmoSphere® powder. Pharm. Res. 19:689–695 (2002).

    PubMed  CAS  Google Scholar 

  10. D. A. Edwards, R. S. Langer, R. Vanbever, J. Mintzes, J. Wang, and D. H. Chen. Preparation of novel particles for inhalation. United States Patent. 6,652,837 (2003).

  11. V. Truong-Lee, B. V. Pham, J. F. Carpenter, R. Seid, and T. W. Randolph. Spray freeze drying of compositions for pulmonary administration. United States Patent Application. 0042971 A1 (2004).

  12. B. Y. Shekunov. Production of powders for respiratory drug delivery. In P. York, U. B. Kompella, and B. Y. Shekunov (eds.), Supercritical Fluid Technology for Drug Product Development, Marcel Dekker, New York, 2004, pp. 247–282.

    Google Scholar 

  13. H. K. Chan and I. Gonda. Physicochemical characterization of a new respirable form of nedocromil. J. Pharm. Sci. 84:692–696 (1995).

    PubMed  CAS  Google Scholar 

  14. T. M. Crowder, J. A. Rosati, J. D. Schroeter, A. J. Hichey, and T. B. Martonen. Fundamental effects of particle morphology on lung delivery: predictions of Stokes’ law and the particular relevance to dry powder inhaler formulation and development. Pharm. Res. 19:239–245 (2002).

    PubMed  CAS  Google Scholar 

  15. H. K. Chan. Dry powder aerosol delivery systems: current and future research directions. J. Aerosol Med. 19:21–27 (2006).

    PubMed  CAS  Google Scholar 

  16. K. Kendall and K. Stainton. Adhesion and aggregation of fine particles. Powder Technol. 121:223–229 (2001).

    CAS  Google Scholar 

  17. X. M. Zeng, G. P. Martin, S.-K. Tee, and C. Marriott. The role of fine particle lactose on the dispersion and deaggregation of salbutamol sulphate in the air stream in vitro. Int. J. Pharm. 176:99–110 (1998).

    CAS  Google Scholar 

  18. W. I. Li, M. Perzl, J. Heyder, R. Langer, J. D. Brain, K. H. Englmeier, R. W. Niven, and D. A. Edwards. Aerodynamics and aerosol particle deaggregation phenomena in model oral-pharyngeal cavities. J. Aerosol Sci. 27:1269–1286 (1996).

    CAS  Google Scholar 

  19. D. L. French, D. A. Edwards, and R. W. Niven. The influence of formulation on emission, deaggregation and deposition of dry powders for inhalation. J. Aerosol Sci. 27:769–783 (1996).

    CAS  Google Scholar 

  20. J. C. Keil, R. Kotian, and J. Peart. Using and interpreting aerosol electrostatic data from electrical low pressure impactor. Proceedings of the Conference on Respiratory Drug Delivery, Boca Raton, Florida, 2006, pp. 605–608.

  21. R. C. Rowe. Interaction of lubricants with microcrystalline cellulose and anhydrous lactose—a solubility parameter approach. Int. J. Pharm. 41:223–226 (1988).

    CAS  Google Scholar 

  22. H. H. Y. Tong, B. Y. Shekunov, P. York, and A. H. L. Chow. Influence of polymorphism on the surface energetics of salmeterol xinafoate crystallized from supercritical fluids. Pharm. Res. 19:640–648 (2002).

    PubMed  CAS  Google Scholar 

  23. H. H. Y. Tong, B. Y. Shekunov, P. York, and A. H. L. Chow. Predicting the aerosol performance of dry powder inhalation formulations by interparticulate interaction analysis using inverse gas chromatography. J. Pharm. Sci. 95:228–233 (2005).

    Google Scholar 

  24. B. Y. Shekunov, B. Chattopadhyay, and J. Seitzinger. Lyophilization method and apparatus for producing particles. PCT Int. Appl. WO 2004071410 A2 20040826 (2004).

    Google Scholar 

  25. M. U. Rehman, B. Y. Shekunov, P. York, and P. Colthorpe. Solubility and precipitation of nicotinic acid in supercritical carbon dioxide. J. Pharm. Sci. 90:1570–1582 (2001).

    PubMed  CAS  Google Scholar 

  26. J. N. Stanifordth. Nasal and pulmonary powder opportunities: new drugs and formulations for rapid systemic onset. Proceedings of the Conference on Respiratory Drug Delivery 10, Boca Raton, Florida, 2006, pp. 249–256.

  27. Y. Kawashima, T. Serigano, T. Hino, H. Yamamoto, and H. Takeuchi. Surface-modified antiasthmatic dry powder aerosols inhaled intratracheally reduce the pharmacologically effective dose. Pharm. Res. 15:1753–1759 (1998).

    PubMed  CAS  Google Scholar 

  28. N. Y. K. Chew, B. Y. Shekunov, H. H. Y. Tong, A. H. L. Chow, C. Savage, J. Wu, and H. K. Chan. Effect of amino acids on the dispersion of disodium cromoglycate powders. J. Pharm. Sci. 94:2289–2301 (2005).

    PubMed  CAS  Google Scholar 

  29. P. Lucas, K. Anderson, and J. N. Staniforth. Protein deposition from dry powder inhalers: fine particle multiplets as performance modifiers. Pharm. Res. 15:562–569 (1998).

    PubMed  CAS  Google Scholar 

  30. C. Bosquillon, C. Lombry, V. Preat, and R. Vanbever. Influence of formulation excipients and physical characteristics of inhalation dry powders on their aerosolization performance. J. Control. Release 70:329–339 (2001).

    PubMed  CAS  Google Scholar 

  31. S. K. Tee, C. Marriot, X. M. Zeng, and G. P. Martin. The use of different sugars as fine and coarse carriers for aerosolised salbutamol sulphate. Int. J. Pharm. 208:111–123 (2000).

    PubMed  CAS  Google Scholar 

  32. N. Y. K. Chew and H. K. Chan. Use of solid corrugated particles to enhance powder aerosol performance. Pharm. Res. 18:1570–1577 (2001).

    PubMed  CAS  Google Scholar 

  33. D. J. Ganderton and N. M. Kazem. Dry powder inhalers. In D. J. Ganderton, and T. Jones (eds.), Advances in Pharmaceutical Sciences, Academic, London, 1992, pp. 65–73.

    Google Scholar 

  34. A. H. L. Chow, H. H. Y. Tong, B. Y. Shekunov, and P. York. Use of inverse gas chromatography (IGC) to determine the surface energy and surface area of powdered materials. Pharm. Res. 21:1718–1720 (2004).

    PubMed  CAS  Google Scholar 

  35. J. Schiewe and B. Zierenberg. 2004. How easy is powder deagglomeration? A critical assessment of particle interaction measurement techniques. Proceedings of the Conference on Respiratory Drug Delivery, Palm Springs, California, 2004, pp. 303–311.

  36. A. H. L. Chow, H. Y. Tong, and B. Y. Shekunov. Control of physical forms of pharmaceutical substances. In P. York, U. B. Kompella and B. Y. Shekunov (eds.), Supercritical Fluid Technology for Drug Product Development, Marcel Dekker Series, New York, 2004, pp. 283–342.

    Google Scholar 

  37. I. Balashazy, T. B. Martonen, and W. Hofmann. Fiber deposition in airway bifurcations. J. Aerosol Med. 3:243–260 (1990).

    Google Scholar 

  38. W. G. Kreyling, M. Semmler-Behnke, and W. Moller. Ultrafine particles–lung interactions: does size matter? J. Aerosol Med. 19:74–83 (2006).

    PubMed  CAS  Google Scholar 

  39. B. Y. Shekunov. Nanoparticle technology for drug delivery—from nanoparticles to cutting-edge delivery strategies. Part I. Drugs 8:399–401 (2005).

    Google Scholar 

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

    PubMed  CAS  Google Scholar 

  41. P. Chattopadhyay, R. Huff, and B. Y. Shekunov. Drug encapsulation using supercritical fluid extraction of emulsions. J. Pharm. Sci. 95:667–679 (2006).

    PubMed  CAS  Google Scholar 

  42. V. Berard, E. Lesniewska, C. Andres, D. Pertuy, C. Laroche, and Y. Pourcelot. Affinity scale between a carrier and a drug in DPI studied by atomic force microscopy. Int. J. Pharm. 247:127–137 (2002).

    PubMed  CAS  Google Scholar 

  43. N. Rasenack and B. W. Muller. Micron-size drug particles: common and novel micronization techniques. Pharm. Dev. Technol. 9:1–13 (2004).

    PubMed  CAS  Google Scholar 

  44. K. Broda-Pfeiffer, H. Hausler, P. Grab, and P. Langguth. Conditioning following powder micronization: influence on particle growth of salbutamol sulphate. Drug Dev. Ind. Pharm. 29:1007–1084 (2003).

    Google Scholar 

  45. M. Irngartinger, V. Camuglia, M. Damm, J. Goede, and H. W. Frijlink. Pulmonary delivery of therapeutic peptides via dry powder inhalation: effects of micronisation and manufacturing. Eur. J. Pharm. Biopharm. 58:7–14 (2004).

    PubMed  CAS  Google Scholar 

  46. G. W. Hallworth. Inhalation composition containing lactose pellets. United States Patent. 6,183,782 (2001).

  47. K. Takano, K. Nishii, A. Mukoyama, Y. Iwadate, H. Kamiya, and M. Horio. Binderless granulation of pharmaceutical lactose powders. Powder Technol. 122:212–221 (2002).

    CAS  Google Scholar 

  48. Y. Kawashima, T. Serigano, T. Hino, H. Yamamoto, and H. Takeuchi. Effect of surface morphology of carrier lactose on dry powder inhalation property of pranlukast hydrate. Int. J. Pharm. 172:179–188 (1998).

    CAS  Google Scholar 

  49. F. Vanderbist, B. Wery, I. M. Pavon, and A. J. Moes. Optimization of a dry powder inhaler formulation of nacystelyn, a new mucoactive agent. J. Pharm. Pharmacol. 51:1229–1234 (1999).

    PubMed  CAS  Google Scholar 

  50. P. W. S. Heng, L. W. Chan, and L. T. Lim. Quantification of the surface morphologies of lactose carriers and their effect on the in vitro deposition of salbutamol sulphate. Chem. Pharm. Bull. 48:393–398 (2000).

    PubMed  CAS  Google Scholar 

  51. P. Harjunen, V. P. Lehto, K. Martimo, E. Suihko, T. Lankinen, P. Paronen, and K. Jarvinen. Lactose modifications enhance its drug performance in the novel multiple dose Taifun® DPI. Eur. J. Pharm. Sci. 16:313–321 (2002).

    PubMed  CAS  Google Scholar 

  52. K. Gilani, A. R. Najafabadi, M. Barghi, and M. R. Tehrani. Aerosolisation of beclomethasone dipropionate using spray dried lactose/polyethylene glycol carriers. Eur. J. Pharm. Biopharm. 58:595–606 (2004).

    PubMed  CAS  Google Scholar 

  53. M. Murtomaa, V. Mellin, P. Harjunen, T. Lankinen, E. Laine, and V. P. Lehto. Effect of particle morphology on the triboelectrification in dry powder inhalers. Int. J. Pharm. 282:107–114 (2004).

    PubMed  CAS  Google Scholar 

  54. H. Larhrib, G. P. Martin, D. Prime, and C. Marriott. Characterisation and deposition studies of engineered lactose crystals with potential for use as a carrier for aerosolised salbutamol sulfate from dry powder inhalers. Eur. J. Pharm. Sci. 19:211–221 (2003).

    Google Scholar 

  55. X. M. Zeng, G. P. Martin, C. Marriott, and J. Pritchard. The influence of carrier morphology on drug delivery by dry powder inhalers. Int. J. Pharm. 200:93–106 (2000).

    PubMed  CAS  Google Scholar 

  56. X. M. Zeng, G. P. Martin, C. Marriott, and J. Pritchard. Lactose as a carrier in dry powder formulations: the influence of surface characteristics on drug delivery. J. Pharm. Sci. 90:1424–1434 (2001).

    Google Scholar 

  57. H. Larhrib, G. P. Martin, C. Marriott, and D. Prime. The influence of carrier and drug morphology on drug delivery from dry powder formulations. Int. J. Pharm. 257:283–296 (2003).

    PubMed  CAS  Google Scholar 

  58. X. M. Zeng, G. P. Martin, C. Marriott, and J. Pritchard. The use of lactose recrystallised from carbopol gels ad a carrier for aerosolised salbutamol sulphate. Eur. J. Pharm. Biopharm. 51:55–62 (2001).

    CAS  Google Scholar 

  59. M. P. Flament, P. Leterme, and A. Gayot. The influence of carrier roughness on adhesion, content uniformity and the in vitro deposition of terbutaline sulphate from dry powder inhalers. Int. J. Pharm. 275:201–209 (2004).

    PubMed  CAS  Google Scholar 

  60. K. Iida, Y. Hayakawa, H. Okamoto, K. Danjo, and H. Leuenberger. Effect of surface covering of lactose carrier particles on dry powder inhalation properties of salbutamol sulphate. Chem. Pharm. Bull. 51:1455–1457 (2003).

    PubMed  CAS  Google Scholar 

  61. K. Iida, Y. Hayakawa, H. Okamoto, K. Danjo, and H. Leuenberger. Effect of surface layering time of lactose carrier particles on dry powder inhalation properties of salbutamol sulphate. Chem. Pharm. Bull. 52:350–353 (2004).

    PubMed  CAS  Google Scholar 

  62. K. Iida, Y. Hayakawa, H. Okamoto, K. Danjo, and H. Leuenberger. Preparation of dry powder inhalation with lactose carrier particles surface-coated using a Wurster fluidized bed. Chem. Pharm. Bull. 53:431–434 (2005).

    PubMed  CAS  Google Scholar 

  63. K. Iida, Y. Hayakawa, H. Okamoto, K. Danjo, and H. Leuenberger. Preparation of dry powder inhalation by surface treatment of lactose carrier particles. Chem. Pharm. Bull. 51:1–5 (2003).

    PubMed  CAS  Google Scholar 

  64. G. Caponetti, R. Bettini, P. Colombo, and P. Ventura. Powders consisting of particles with a perfectly smooth surface for use as carriers for the preparation of inhalation mixtures with micronized drugs and method for their preparation. WO 01/05429 (2001).

    Google Scholar 

  65. P. M. Young, D. Cocconi, P. Colombo, R Bettini, R. Price, D. F. Steele, and M. J. Tobyn. Characterization of a surface modified dry powder inhalation carrier prepared by “particle smoothing”. J. Pharm. Pharmacol. 54:1339–1344 (2002).

    PubMed  CAS  Google Scholar 

  66. F. Ferrari, D. Cocconi, R. Bettini, F. Giordano, P. Santi, M. Tobyn, R. Price, P. Young, C. J. Fiegel, J. Fu, and J. Hanes. Poly(ether-anhydride) dry powder aerosols for sustained drug delivery in the lungs. J. Control. Release 96:411–423 (2004).

    Google Scholar 

  67. F. Podczeck. The influence of particle size distribution and surface roughness of carrier particles on the in vitro properties of dry powder inhalations. Aerosol Sci. Tech. 31:301–321 (1999).

    CAS  Google Scholar 

  68. M. D. Louey and P. J. Stewart. Particle interactions involved in aerosol dispersion of ternary interactive mixtures. Pharm. Res. 19:1524–1531 (2002).

    PubMed  CAS  Google Scholar 

  69. S. P. Shah and A. Misra. Liposomal amikacin dry powder inhaler: effect of fines on in vitro performance. AAPS PharmSciTech 5:1–7 (2004).

    Google Scholar 

  70. L. W. Chan, L. T. Lim, and P. W. S. Heng. Immobilization of fine particles on lactose carrier by precision coating and its effect on the performance of dry powder formulations. J. Pharm. Sci. 92:975–984 (2003).

    PubMed  CAS  Google Scholar 

  71. H. Steckel and N. Bolzen. Alternative sugars as potential carriers for dry powder inhalations. Int. J. Pharm. 270:297–306 (2004).

    PubMed  CAS  Google Scholar 

  72. P. Harjunen, T. Lankinen, H. Salonen, V. P. Lehto, and K. Jarvinen. Effects of carriers and storage of formulation on the lung deposition of a hydrophobic and hydrophilic drug from a DPI. Int. J. Pharm. 263:151–163 (2003).

    PubMed  CAS  Google Scholar 

  73. B. E. Rabinow. Nanosuspensions in drug delivery. Nat. Rev. Drug Discov. 3:785–796 (2004).

    PubMed  CAS  Google Scholar 

  74. T. S. Weidmann, L. DeCastro, and R. Wood. Nebulization of nanocrystals: production of respirable solid-in-liquid-in-air colloidal dispersion. Pharm. Res. 14:112–116 (1997).

    Google Scholar 

  75. K. K. Kraft, B. Steiger, D. Beussink, J. N. Quiring, N. Fitzgerald, H. E. Greenberg, and S. A. Waldman. The pharmacokinetics of nebulized nanocrystal budesonide suspension in healthy volunteers. J. Clin. Pharmacol. 44:67–72 (2004).

    PubMed  CAS  Google Scholar 

  76. B. Y. Shekunov, P. Chattopadhyay, D. Yim, D. Cippola, and B. Boyd. Formulation and in vitro performance of drug-lipid nanosuspensions for pulmonary delivery. Proceedings of the Conference on Respiratory Drug Delivery, Boca Raton, Florida, 2006, pp. 609–612.

  77. P. Chattopadhyay, B. Y. Shekunov, D. Yim, D. Cipolla, B. Boyd, and S. Farr. Production of drug-lipid nanosuspensions using Supercritical Fluid Extraction of Emulsions (SFEE) for pulmonary delivery using the AERx System. Adv. Drug Deliv. Rev. (2006) (in print).

  78. L. Li, H. Chiou, D. Heng, H. K. Chan, R. Prud’homme, and J. Raper. Studies on nanopharmaceuticals formulated using confined impinging jets for pulmonary drug delivery. Proceedings of the Conference on Respiratory Drug Delivery, Boca Raton, Florida, 2006, pp. 905–907.

  79. M. Trotta, M. Gallarate, F. Pattarino, and S. Morel. Emulsions containing partially water-miscible solvents for the preparation of drug nanosuspensions. J. Control. Release 76:119–128 (2001).

    PubMed  CAS  Google Scholar 

  80. N. Rasenack, H. Steckel, and B. W. Muller. Micronization of anti-inflammatory drugs for pulmonary delivery by a controlled crystallization process. J. Pharm. Sci. 92:35–44 (2003).

    PubMed  CAS  Google Scholar 

  81. E. Mathiowitz, C. Thanos, and Z. Liu. Methods for micronization of hydrophobic drugs. United States Patent. 6,824,791 (2004).

  82. N. Rasenack, H. Steckel, and B. W. Muller. Preparation of microcrystals by in situ micronization. Powder Technol. 143144:291–296 (2004).

    Google Scholar 

  83. H. Steckel, N. Rasenack, P. Villax, and B. W. Muller. In vitro characterization of jet-milled and in-situ-micronized fluticasone-17-propionate. Int. J. Pharm. 258:65–75 (2003).

    PubMed  CAS  Google Scholar 

  84. H. Steckel, N. Rasenack, and B. W. Muller. In-situ-micronization of disodium cromoglycate for pulmonary delivery. Eur. J. Pharm. Biopharm. 55:173–180 (2003).

    PubMed  CAS  Google Scholar 

  85. S. Havelund. Pulmonary insulin crystals. United States Patent. 6,310,038 (2001).

  86. J. H. Kwon, B. H. Lee, J. J. Lee, and C. W. Kim. Insulin microcrystal suspension as a long-acting formulation for pulmonary delivery. Eur. J. Pharm. Sci. 22:107–116 (2004).

    PubMed  CAS  Google Scholar 

  87. K. Ikegami, Y. Kawashima, H. Takeuchi, H. Yamamoto, N. Isshiki, D. I. Momose, and K. Ouchi. Improved inhalation behaviour of steroid KSR-592 in vitro with Jethaler® by polymorphic transformation to needle-like crystals (β-form). Pharm. Res. 19:1439–1445 (2002).

    PubMed  CAS  Google Scholar 

  88. M. J. Clarke, M. J. Tobyn, and J. N. Staniforth. Physicochemical factors governing the performance of nedocromil sodium as a dry powder aerosol. J. Pharm. Sci. 89:1160–1169 (2000).

    PubMed  CAS  Google Scholar 

  89. K. Ikegami, Y. Kawashima, H. Takeuchi, H. Yamamoto, D. I. Momose, N. Saito, and N. Isshiki. In vitro inhalation behaviour of spherically agglomerated steroid particles with carrier lactose. Adv. Powder Technol. 11:323–332 (2000).

    CAS  Google Scholar 

  90. K. Ikegami, Y. Kawashima, H. Takeuchi, H. Yamamoto, N. Isshiki, D. I. Momose, and K. Ouchi. Primary crystal growth during spherical agglomeration in liquid: designing an ideal dry powder inhalation system. Powder Technol. 126:266–274 (2002).

    CAS  Google Scholar 

  91. K. Ikegami, Y. Kawashima, H. Takeuchi, H. Yamamoto, N. Isshiki, D. I. Momose, and K. Ouchi. Simultaneous particulate design of primary and agglomerated crystals of steroid by spherical agglomeration in liquid for dry powder inhalation. Powder Technol. 130:290–297 (2003).

    CAS  Google Scholar 

  92. K. Ikegami, Y. Kawashima, H. Takeuchi, H. Yamamoto, K. Mimura, D. I. Momose, and K. Ouchi. A new spherically agglomerated drug composite system with lactose for dry powder inhalation. Adv. Powder Technol. 14:215–229 (2003).

    CAS  Google Scholar 

  93. S. Beach, D. Latham, C. Sidgwick, M. Hanna, and P. York. Control of the physical form of salmeterol xinafoate. Org. Process Res. Dev. 3:370–376 (1999).

    CAS  Google Scholar 

  94. J. Baldyga, M. Henczka, and B. Y. Shekunov. Fluid dynamics, mass-transfer and particle formation in supercritical fluids. In P. York, U. B. Kompella, B. Y. Shekunov (eds.), Supercritical Fluid Technology for Drug Product Development, Marcel Dekker Series, 2004, pp. 91–157.

  95. S. L. Hem. The effect of ultrasonic vibrations on the crystallization processes. Ultrasonics 10:202–207 (1967).

    Google Scholar 

  96. H. Chiou, L. Li, H. K Chan, T. Hu, J. F Chen, and J. Yun. Production of salbutamol sulfate powders using high-gravity controlled precipitation. Proceedings of the Conference on Respiratory Drug Delivery, Boca Raton, Florida, 2006, pp. 893–895.

  97. L. Master. Spray Drying Handbook, 5th ed. Longman, New York, 1991.

    Google Scholar 

  98. T. Ozeki, S. Beppu, T. Mizoe, Y. Takashima, H. Yuasa, and H. Okada. Preparation pf polymeric submicron particles-containing microparticles using a 4-fluid nozzle spray drier. Pharm. Res. 23:177–183 (2006).

    PubMed  CAS  Google Scholar 

  99. Y. F. Maa, P. A. Nguyen, K. Sit, and C. C. Hsu. Spray-drying performance of a bench-top spray dryer for protein aerosol powder preparation. Biotechnol. Bioeng. 60:301–309 (1998).

    PubMed  CAS  Google Scholar 

  100. C. A. Dunbar, N. M. Concessio, and A. J. Hickey. Evaluation of atomizer performance in production of respirable spray dried particles. Pharm. Dev. Technol. 3:433–441 (1998).

    PubMed  CAS  Google Scholar 

  101. J. Elversson, A. M. Fureby, G. Alderborn, and U. Elofsson. Droplet and particle size relationship and shell thickness of inhalable lactose particles during spray drying. J. Pharm. Sci. 92:900–910 (2003).

    PubMed  CAS  Google Scholar 

  102. J. Elversson and A. M. Fureby. Particle size and density in spray drying—effects of carbohydrate properties. J. Pharm. Sci. 94:2049–2060 (2005).

    PubMed  CAS  Google Scholar 

  103. K. Gilani, A. R. Najafabadi, M. Barghi, and M. R. Tehrani. The effect of water to ethanol feed ratio on physical properties and aerosolization behaviour of spray dried cromolyn sodium particles. J. Pharm. Sci. 94:1048–1059 (2005).

    PubMed  CAS  Google Scholar 

  104. Y. F. Maa, H. R. Costantino, P. A. Nguyen, and C. C. Hsu. The effect of operating and formulation variables on the morphology of spray-dried protein particles. Pharm. Dev. Technol. 2:213–223 (1997).

    PubMed  CAS  Google Scholar 

  105. N. Y. K. Chew, P. Tang, H. K. Chan, and J. A. Raper. How much particle surface corrugation is sufficient to improve aerosol performance of powders? Pharm. Res. 22:148–152 (2005).

    PubMed  CAS  Google Scholar 

  106. S. Freitas, H. P. Merkle, and B. Gander. Ultrasonic atomisation into reduced pressure atmosphere—envisaging aseptic spray-drying for microencapsulation. J. Control. Release 95:185–195 (2004).

    PubMed  CAS  Google Scholar 

  107. D. E. Chickering, S. Narasimhan, D. Altreuter, P. Kopesky, M. Keegan, J. A. Straub, and H. Bernstrin. Methods and apparatus for making particles using spray dryer and in-line jet mill. United States Patent. 6,921,458 (2005).

  108. D. H. Chen, R. P. Batycky, L. Johnston, and J. Mintzes. Control of process humidity to produce large, porous particles. United States Patent. 6,848,197 (2005).

  109. S. P. Sellers, G. S. Clark, R. E. Sievers, and J. F. Carpenter. Dry powder of stable formulations from aqueous solutions prepared using supercritical CO2-assisted aerosolization. J. Pharm. Sci. 90:785–797 (2001).

    PubMed  CAS  Google Scholar 

  110. R. M. Platz, J. S. Patton, L. Foster, and M. Eljamal. Compositions and methods for the pulmonary delivery of aerosolized macromolecules. United States Patent. 6,797,258 (2004).

  111. R. M. Platz, J. S. Patton, L. Foster, and M. Eljamal. Composition for pulmonary administration comprising a drug and a hydrophobic amino acid. United States Patent. 6,921,527 (2005).

  112. D. J. Smith, S. Bot, L. Dellamary, and A. Bot. Evaluation of novel aerosol formulations designed for mucosal vaccination against influenza virus. Vaccine 21:2805–2812 (2003).

    PubMed  CAS  Google Scholar 

  113. M. Eljamal, J. S. Patton, L. Foster, and R. M. Platz. Compositions and methods for nucleic acid delivery to the lung. United States Patent. 5,994,314 (1999).

  114. P. C. Seville, I. W. Kellaway, and J. C. Birchall. Preparation of dry powder dispersions for non-viral gene delivery by freeze-drying and spray-drying. J. Gene Med. 4:428–437 (2002).

    PubMed  CAS  Google Scholar 

  115. A. Millqvist-Fureby, M. Malmsten, and B. Bergenstahl. Spray-drying of trypsin—surface characterisation and activity preservation. Int. J. Pharm. 188:243–253 (1999).

    PubMed  CAS  Google Scholar 

  116. K. Stahl, M. Claesson, P. Lilliehorn, H. Linden, and K. Backstrom. The effect of process variables on the degradation and physical properties of spray dried insulin intended for inhalation. Int. J. Pharm. 233:227–237 (2002).

    PubMed  CAS  Google Scholar 

  117. H. R. Costantino, J. D. Andya, P. A. Nguyen, N. Dasovich, T. D. Sweeney, S. J. Shire, C. C. Hsu, and Y. F. Maa. Effect of mannitol crystallization on the stability and aerosol performance of a spray-dried pharmaceutical protein, recombinant humanized anti-IgE monoclonal antibody. J. Pharm. Sci. 87:1406–1411 (1998).

    PubMed  CAS  Google Scholar 

  118. S. T. Tzannis and S. J. Prestrelski. Activity–stability considerations of trysinogen during spray drying: effects of sucrose. J. Pharm. Sci. 88:351–359 (1999).

    PubMed  CAS  Google Scholar 

  119. C. Stevenson, J. E. Hastedt, S. R. Lehrman, H. S. Chiang, D. B. Bennett, D. Lesikar, B. Yang, D. Gong, and K. Cabot. Inhalable spray dried 4-helix bundle protein powders having minimized aggregation. United States Patent. 6,569,406 (2003).

  120. D. A. Edwards, J. Hanes, G. Caponetti, J. Hrkach, A. B. Jebria, M. L. Eskew, J. Mintzes, D. Deaver, N. Lotan, and R. Langer. Large porous particles for pulmonary drug delivery. Science 276:1868–1871 (1997).

    PubMed  CAS  Google Scholar 

  121. L. A. Dellamary, T. E. Tarara, D. J. Smith, C. H. Woelk, A. Adractas, M. L. Costello, H. Gill, and J. G. Weers. Hollow porous particles in metered dose inhalers. Pharm. Res. 17:168–174 (2000).

    PubMed  CAS  Google Scholar 

  122. T. E. Tarara, M. S. Hartman, H. Gill, A. A. Kennedy, and J. G. Weers. Characterization of suspension-based metered dose inhaler formulations composed of spray-dried budesonide microcrystals dispersed in HFA-134a. Pharm. Res. 21:1607–1614 (2004).

    PubMed  CAS  Google Scholar 

  123. R. Vanbever, A. B. Jebria, J. D. Mintzes, R. Langer, and D. A. Edwards. Sustained release of insulin from insoluble inhaled particles. Drug Dev. Res. 48:178–185 (1999).

    CAS  Google Scholar 

  124. R. Vanbever, J. D. Mintzes, J. Wang, J. Nice, D. Chen, R. Batycky, R. Langer, and D. A. Edwards. Formulation and physical characterization of large porous particles for inhalation. Pharm. Res. 16:1735–1742 (1999).

    PubMed  CAS  Google Scholar 

  125. A. Ben-Jebria, D. H. Chen, M. L. Eskew, R. Vanbever, R. Langer, and D. A. Edwards. Large porous particles for sustained protection from carbachol-induced bronchoconstriction in guinea pigs. Pharm. Res. 16:555–561 (1999).

    PubMed  CAS  Google Scholar 

  126. J. Wang, A. B. Jebria, and D. A. Edwards. Inhalation of estradiol for sustained systemic delivery. J. Aerosol Med. 12:27–36 (1999).

    Article  PubMed  CAS  Google Scholar 

  127. R. M. Platz, S. Kimura, Y. Satoh, and L. C. Foster. Methods and compositions for the dry powder formulation of interferons. United States Patent. 6,479,049 (2002).

  128. M. W. Lipp, R. P. Batycky, and G. Caponetti. Formulation of spray-drying large porous particles. United States Patent. 6,749,835 (2004).

  129. H. Steckel and H. G. Brandes. A novel spray-drying technique to produce low density particles for pulmonary delivery. Int. J. Pharm. 278:187–195 (2004).

    PubMed  CAS  Google Scholar 

  130. J. Straub, H. Bernstein, D. E. Chickering, S. Khattak, and G. Randall. Porous drug matrices and methods of manufacture thereof. United States Patent. 6,645,528 (2003).

  131. N. Osborne, A. D. Sutton, and R. A. Johnson. Spray-drying microcapsules using an aqueous liquid containing a volatile liquid. United States Patent. 6,623,722 (2003).

  132. C. Bosquillon, P. G. Rouxhet, F. Ahimou, D. Simon, C. Culot, V. Preat, and R. Vanbever. Aerosolization properties, surface composition and physical state of spray-dried protein powders. J. Control. Release 99:357–367 (2004).

    PubMed  CAS  Google Scholar 

  133. Y. L. Lo, J. C. Tsai, and J. H. Kuo. Liposomes and disaccharides as carriers in spray-dried powder formulations of superoxide dismutase. J. Control. Release 94:259–272 (2004).

    PubMed  CAS  Google Scholar 

  134. R. P. Batycky, M. M. Lipp, and R. W. Niven. Use of simple amino acids to form porous particles during spray drying. United States Patent. 6,586,008 (2003).

  135. H. Y. Li, P. C. Seville, I. J. Williamson, and J. C. Birchall. The use of amino acids to enhance the aerosolisation of spray-dried powders for pulmonary gene therapy. J. Gene Med. 7:343–353 (2005).

    PubMed  CAS  Google Scholar 

  136. A. R. Najafabadi, K. Golani, M. Barghi, and M. R. Tehrani. The effect of vehicle on physical properties and aerosolisation behaviour of disodium cromoglycate microparticles spray dried alone or with L-leucine. Int. J. Pharm. 285:97–108 (2004).

    PubMed  CAS  Google Scholar 

  137. H. Y. Li, H. Neill, R. Innocent, P. Seville, I. Williamson, and J. C. Birchall. Enhanced dispersibility and deposition of spray-dried powders for pulmonary gene therapy. J. Drug Target. 11:425–432 (2003).

    PubMed  CAS  Google Scholar 

  138. D. J. Freeman and R. W. Niven. The influence of sodium glycocholate and other additives on the in vivo transfection of plasmid DNA in the lungs. Pharm. Res. 13:202–209 (1996).

    PubMed  CAS  Google Scholar 

  139. V. Codrons, F. Vanderbist, B. Ucakar, V. Preat, and R. Vanbever. Impact of formulation and methods of pulmonary delivery on absorption of parathyroid hormone (1–34) from rat lungs. J. Pharm. Sci. 93:1241–1252 (2004).

    PubMed  CAS  Google Scholar 

  140. C. Bosquillon, V. Preat, and R. Vanbever. Pulmonary delivery of growth hormone using dry powders and visualization of its local fate in rats. J. Control. Release 96:233–244 (2004).

    PubMed  CAS  Google Scholar 

  141. V. Codrons, F. Vanderbist, R. K. Verbeeck, M. Arras, D. Lison, V. Preat, and R. Venbever. Systemic delivery of parathyroid hormone (1–34) using inhalation dry powders in rats. J. Pharm. Sci. 92:938–950 (2003).

    PubMed  CAS  Google Scholar 

  142. H. Todo, H. Okamoto, K. Iida, and K. Danjo. Effect of additives on insulin absorption from intratracheally administered dry powders in rats. Int. J. Pharm. 220:101–110 (2001).

    PubMed  CAS  Google Scholar 

  143. H. Todo, H. Okamoto, K. Iida, and K. Danjo. Improvement of stability and absorbability of dry insulin powder for inhalation by powder-combination technique. Int. J. Pharm. 271:41–52 (2004).

    PubMed  CAS  Google Scholar 

  144. M. Sakagami, K. Sakon, W. Kinoshita, and Y. Makino. Enhanced pulmonary absorption following aerosol administration of mucoadhesive powder microspheres. J. Control. Release 77:117–129 (2001).

    PubMed  CAS  Google Scholar 

  145. H. Y. Li, P. C. Seville, I. J. Williamson, and J. C. Birchall. The use of absorption enhancers to enhance the dispersibility of spray-dried powders for pulmonary gene therapy. J. Gene Med. 7:1035–1043 (2005).

    PubMed  CAS  Google Scholar 

  146. A. Grenha, B. Seijo, and C. R. Lopez. Microencapsulated chitosan nanoparticles for lung protein delivery. Eur. J. Pharm. Sci. 25:427–437 (2005).

    PubMed  CAS  Google Scholar 

  147. J. O. H. Sham, Y. Zhang, W. H. Finlay, W. H. Roa, and R. Lobenberg. Formulation and characterization of spray-dried powders containing nanoparticles for aerosol delivery to the lung. Int. J. Pharm. 269:457–467 (2004).

    PubMed  CAS  Google Scholar 

  148. P. H. Hirst, G. R. Pitcairn, J. G. Weers, T. E. Tarara, A. R. Clark, L. A. Dellamary, G. Hall, J. Shorr, and S. P. Newman. In vivo lung deposition of hollow porous particles from a pressurized metered dose inhaler. Pharm. Res. 19:258–264 (2002).

    PubMed  CAS  Google Scholar 

  149. R. A. Beyerinck, H. L. M. Deibele, D. E. Dobry, R. J. Ray, D. M. Settell, and K. R. Spence. Method for making homogeneous spray-dried solid amorphous drug dispersions utilizing modified spray-drying apparatus. United States Patent. 6,763,607 (2004).

  150. Y. Kawashima, T. Serigano, T. Hino, H. Yamamoto, and H. Takeuchi. A new powder design method to improve inhalation efficiency of pranlukast hydrate dry powder aerosols by surface modification with hydroxypropylmethylcellulose phthalate nanospheres. Pharm. Res. 15:1748–1752 (1998).

    PubMed  CAS  Google Scholar 

  151. Y. C. Huang, M. K. Yeh, and C. H. Chiang. Formulation factors in preparing BTM-chitosan microspheres by spray drying method. Int. J. Pharm. 242:239–242 (2002).

    PubMed  CAS  Google Scholar 

  152. Y. C. Huang, M. K. Yeh, S. N. Cheng, and C. H. Chiang. The characteristics of betamethasone-loaded chitosan microparticles by spray-drying method. J. Microencapsul 20:459–472 (2003).

    PubMed  CAS  Google Scholar 

  153. M. Asada, H. Takahashi, H. Okamoto, H. Tanino, and K. Danjo. Theophylline particle design using chitosan by the spray drying. Int. J. Pharm. 270:167–174 (2004).

    PubMed  CAS  Google Scholar 

  154. K. Surendrakumar, G. P. Martyn, E. C. M. Hodgers, M. Jansen, and J. A. Blair. Sustained release of insulin from sodium hyaluronate based dry powder formulations after pulmonary delivery to beagle dogs. J. Control. Release 91:385–394 (2003).

    PubMed  CAS  Google Scholar 

  155. G. Hamdi, G. Ponchel, M. Besnard, and D. Duchene. Loading and in vitro release of salbutamol from degradable cross-linked starch microspheres intended for pulmonary administration. STP Pharma Sciences 9:573–577 (1999).

    CAS  Google Scholar 

  156. I. G. Davidson, E. J. Langner, S. V. Plowman, and J. A. Blair. Release mechanism of insulin encapsulated in trehalose ester derivative microparticles delivered via inhalation. Int. J. Pharm. 254:211–222 (2003).

    PubMed  CAS  Google Scholar 

  157. R. Alcock, J. A. Blair, D. J. O’Mahony, A. Raoof, and A. V. Quirk. Modifying the release of leuprolide from spray dried OED microparticles. J. Control. Release 82:429–440 (2002).

    PubMed  CAS  Google Scholar 

  158. J. Fiegel, J. Fu, and J. Hanes. Poly(ether-anhydride) dry powder aerosols for sustained drug delivery in the lungs. J. Control. Release 96:411–423 (2004).

    PubMed  CAS  Google Scholar 

  159. J. Fu, J. Fiegel, E. Krauland, and J. Hanes. New polymeric carriers for controlled drug delivery following inhalation or injection. Biomaterials 23:4425–4433 (2002).

    PubMed  CAS  Google Scholar 

  160. D. F. Bain, D. L. Munday, and A. Smith. Modulation of rifampicin release from spray-dried microspheres using combinations of poly-(DL-lactide). J. Microencapsul 16:369–385 (1999).

    PubMed  CAS  Google Scholar 

  161. S. Suarez, P. O’Hara, M. Kazantseva, C. E. Newcomer, R. Hopfer, D. N. McMurray, and A. J. Hickey. Airways delivery of rifampicin microparticles for the treatment of tuberculosis. J. Antimicrob. Chemother. 48:431–434 (2001).

    PubMed  CAS  Google Scholar 

  162. R. O. Cook, R. K. Pannu, and I. W. Kellaway. Novel sustained release microspheres for pulmonary drug delivery. J. Control. Release 104:79–90 (2005).

    PubMed  CAS  Google Scholar 

  163. L. Garsia-Contreras, D. Lu, and A. J. Hickey. Formulation strategies for a novel tuberculosis vaccine. Proceedings of the Conference on Respiratory Drug Delivery, Boca Raton, Florida, 2006, pp. 877–880.

  164. M. Chougule, B. K. Padhi, and A. Misra. Formulation of a nano-liposomal dry powder inhaler containing amiloride hydrochloride: preparation and characterization. Proceedings of the Conference on Respiratory Drug Delivery, Boca Raton, Florida, 2006, pp. 797–799.

  165. H. K. Chan, A. R. Clark, J. C. Feeley, M. C. Kuo, S. R. Lehrman, K. P. Cleland, D. P. Miller, R. Vehring, and D. L. Ballesteros. Physical stability of salmon calcitonin spray-dried powders for inhalation. J. Pharm. Sci. 93:792–804 (2004).

    PubMed  CAS  Google Scholar 

  166. Y. F. Maa, P. A. Nguyen, J. D. Andya, N. Dasovich, T. D. Sweeney, S. J. Shire, and C. C. Hsu. Effect of spray drying and subsequent processing conditions on residual moisture content and physical/biochemical stability of protein inhalation powders. Pharm. Res. 15:768–775 (1998).

    PubMed  CAS  Google Scholar 

  167. N. Y. K. Chew and H. K. Chan. Influence of particle size, air flow, and inhaler device on the dispersion of mannitol powders as aerosols. Pharm. Res. 16:1098–1103 (1999).

    PubMed  CAS  Google Scholar 

  168. H. K. Chan, A. Clark, I. Gonda, M. Mumenthaler, and C. Hsu. Spray dried powders and powder blends of recombinant human deoxyribonuclease (rhDNase) for aerosol delivery. Pharm. Res. 14:431–437 (1997).

    PubMed  CAS  Google Scholar 

  169. Y. Matsuda, S. Kawaguchi, H. Kobayashi, and J. Nishijo. Physicochemical characterization of spray-dried phenylbutazone polymorphs. J. Pharm. Sci. 73:173–179 (1984).

    PubMed  CAS  Google Scholar 

  170. K. Kimura, F. Hirayama, and K. Uekama. Characterization of tolbutamide polymorphs (Burger’s form II and IV) and polymorphic transition behaviour. J. Pharm. Sci. 88:385–391 (1999).

    PubMed  CAS  Google Scholar 

  171. W. Beckman and W. H. Otto. Occurrence, stability, kinetics of crystallization and polymorphic transition of the a, b and c modification of abecarnil. Influence of supersaturation, temperature, solvents and impurities. Trans IchemE. 74(A):750–758 (1996).

    Google Scholar 

  172. L. Yu and K. Ng. Glycine crystallization during spray drying: the pH effect on salt and polymorphic forms. J. Pharm. Sci. 91:2367–2375 (2002).

    PubMed  CAS  Google Scholar 

  173. T. L. Rogers, K. P. Johnston, and R. O. Williams III. Solution-based particle formation of pharmaceutical powders by supercritical or compressed fluid CO2 and cryogenic spray-freezing technologies. Drug Dev. Ind. Pharm. 27:1003–1015 (2001).

    PubMed  CAS  Google Scholar 

  174. Z. Yu, A. S. Garcia, K. P. Johnston, and R. O. Williams III. Spray freezing into liquid nitrogen for highly stable protein nanostructured microparticles. Eur. J. Pharm. Biopharm. 58:529–537 (2004).

    PubMed  CAS  Google Scholar 

  175. P. Herbert, and M. S. Healy. Production scale method of forming microparticles. United States Patent. 5,922,253 (1999).

  176. Y. F. Maa and S. J. Prestrelski. Biopharmaceutical powders: particle formation and formulation considerations. Curr. Pharm. Biotechnol. 1:283–302 (2000).

    PubMed  CAS  Google Scholar 

  177. H. Leuenberger. Spray freeze-drying—the process of choice for low water soluble drugs. J. Nanopart. Res. 4:111–119 (2002).

    CAS  Google Scholar 

  178. T. L. Rogers, A. C. Nelsen, M. Sarkari, T. J. Young, K. P. Johnston, and R. O. Williams III. Enhanced aqueous dissolution of a poorly water-soluble drug by novel particle engineering technology: spray-freezing into liquid with atmospheric freeze-drying. Pharm. Res. 20:485–493 (2003).

    PubMed  CAS  Google Scholar 

  179. Z. Yu, T. L. Rogers, J. Hu, K. P. Johnston, and R. O. Williams III. Preparation and characterization of microparticles containing peptide produced by a novel process: spray freezing into liquid. Eur. J. Pharm. Biopharm. 54:221–228 (2002).

    PubMed  CAS  Google Scholar 

  180. G. S. Zijlstra, W. L. J. Hinrichs, A. H. de Boer, and H. W. Frijlink. The role of particle engineering in relation to formulation and de-agglomeration principle in the development of a dry powder formulation for inhalation of cetrorelix. Eur. J. Pharm. Sci. 23:139–149 (2004).

    PubMed  CAS  Google Scholar 

  181. R. O. Williams III, K. P. Johnston, T. J. Young, T. L. Rogers, M. K. Barron, Z. Yu, and J. Hu. Process for production of nanoparticles and microparticles by spray freezing into liquid. United States Patent. 6,862,890 (2005).

  182. J. Hu, K. P. Johnston, and R. O. Williams III. Spray freezing into liquid (SFL) particle engineering technology to enhance dissolution of poorly water soluble drugs: organic solvent versus organic/aqueous co-solvent systems. Eur. J. Pharm. Sci. 20:295–303 (2003).

    PubMed  CAS  Google Scholar 

  183. J. Hu, K. P. Johnston, and R. O. Williams III. Stable amorphous danazol nanostructured powders with rapid dissolution rates produced by spray freezing into liquid. Drug Dev. Ind. Pharm. 30:698–704 (2004).

    Google Scholar 

  184. W. T. Leach, D. T. Simpson, T. N. Val, E. C. Anuta, Z. S. Yu, R. O. Williams III, and K. P. Johnston. Uniform encapsulation of stable protein nanoparticles produced by spray freezing for the reduction of burst release. J. Pharm. Sci. 94:56–69 (2005).

    PubMed  CAS  Google Scholar 

  185. H. R. Costantino, L. Firouzabadian, K. Hogeland, C. Wu, C. Beganski, K. G. Carrasquillo, M. Cordova, K. Griebenow, S. E. Zale, and M. A. Tracy. Protein spray-freeze drying. Effect of atomization conditions on particle size and stability. Pharm. Res. 17:1374–1383 (2000).

    PubMed  CAS  Google Scholar 

  186. H. R. Costantino, O. L. Johnson, and A. E. Zale. Relationship between encapsulated drug particle size and initial release of recombinant human growth hormone from biodegradable microspheres. J. Pharm. Sci. 93:2624–2634 (2004).

    PubMed  CAS  Google Scholar 

  187. H. R. Costantino, L. Firouzabadian, K. G. Carrasquillo, K. Griebenow, S. E. Zale, and M. A. Tracy. Protein spray freeze drying. 2. Effect of formulation variables on particle size and stability. J. Pharm. Sci. 91:388–395 (2002).

    PubMed  CAS  Google Scholar 

  188. Y. F. Maa, P. A. Nguyen, T. Sweeney, S. J. Shire, and C. C. Hsu. Protein inhalation powders: spray drying vs spray freeze drying. Pharm. Res. 16:249–254 (1999).

    PubMed  CAS  Google Scholar 

  189. Y. F. Maa and P. A. Nguyen. Method of spray freeze drying proteins for pharmaceutical administration. United States Patent. 6,284,282 (2001).

  190. J. M. Vaughn, X. Gao, M. J. Yacaman, K. P. Johnston, and R. O. Williams III. Comparison of powder produced by evaporative precipitation into aqueous solution (EPAS) and spray freezing into liquid (SFL) technologies using novel Z-contrast STEM and complimentary techniques. Eur. J. Pharm. Biopharm. 60:81–89 (2005).

    PubMed  CAS  Google Scholar 

  191. H. R. Costantino, W. E. Jaworowicz, M. A. Tracy, and C. P. Beganski. Method of producing sub-micron particles of biologically active agents and uses thereof. United States Patent. 6,284,283 (2001).

  192. H. R. Costantino, W. E. Jaworowicz, M. A. Tracy, and C. P. Beganski. Method of producing sub-micron particles of biologically active agents and uses thereof. United States Patent. 6,428,815 (2002).

  193. K. G. Carrasquillo, J. C. A. Carro, A. Alejandro, D. D. Toro, and K. Griebenow. Reduction of structural perturbations in bovine serum albumin by non-aqueous microencapsulation. J. Pharm. Pharmacol. 53:115–120 (2001).

    PubMed  CAS  Google Scholar 

  194. J. Hu, T. L. Rogers, J. Brown, T. Young, K. P. Johnston, and R. O. Williams III. Improvement of dissolution rates of poorly water soluble APIs using novel spray freezing into liquid technology. Pharm. Res. 19:1278–1284 (2002).

    PubMed  CAS  Google Scholar 

  195. T. L. Rogers, K. A. Overhoff, P. Shah, P. Santiago, M. J. Yacaman, K. P. Johnston, and R. O. Williams III. Micronized powders of a poorly water soluble drug produced by a spray-freezing into liquid-emulsion process. Eur. J. Pharm. Biopharm. 55:161–172 (2003).

    PubMed  CAS  Google Scholar 

  196. M. Joshi and A. Misra. Dry powder inhalation of liposomal ketotifen fumarate: formulation and characterization. Int. J. Pharm. 223:15–27 (2001).

    PubMed  CAS  Google Scholar 

  197. L. Sweeney, H. Chen, Z. Wang, R. Loebenberg, W. Roa, and W. Finlay. Nanoparticle doxorubicin formulated as a dry-powder aerosol. Proceedings of the Conference on Respiratory Drug Delivery, Boca Raton, Florida, 2006, pp. 829–832.

  198. Y. F. Maa, M. Ameri, C. Shu, L. G. Payne, and D. Chen. Influenza vaccine powder formulation development: spray-freeze-drying and stability evaluation. J. Pharm. Sci. 93:1912–1923 (2004).

    PubMed  CAS  Google Scholar 

  199. M. C. Heller, J. F. Carpenter, and T. W. Randolph. Protein formulation and lyophilization cycle design: Prevention of damage due to freeze-concentration induced phase separation. Biotechnol. Bioeng. 63:167–174 (1999).

    Google Scholar 

  200. J. Hu, K. P. Johnston, and R. O. Williams III. Rapid dissolving high potency danazol powders produced by spray freezing into liquid process. Int. J. Pharm. 271:145–154 (2004).

    PubMed  CAS  Google Scholar 

  201. J. H. S. Kuo and R. Hwang. Preparation of DNA dry powder for non-viral gene delivery by spray-freeze drying: effect of protective agents (polyethyleneimine and sugars) on the stability of DNA. J. Pharm. Pharmacol. 56:27–33 (2004).

    PubMed  CAS  Google Scholar 

  202. C. Sonner, Y. F. Maa, and G. Lee. Spray-freeze-drying for protein powder preparation: particle characterization and a case study with trypsinogen stability. J. Pharm. Sci. 91:2122–2139 (2002).

    PubMed  CAS  Google Scholar 

  203. X. M. Lam, E. T. Duenas, and J. L. Cleland. Encapsulation and stabilization of nerve growth factor into poly(lactic-co-glycolic) acid microspheres. J. Pharm. Sci. 90:1356–1365 (2001).

    PubMed  CAS  Google Scholar 

  204. J. Wang, K. M. Chua, and C. H. Wang. Stabilization and encapsulation of human immunoglobulin G into biodegradable microspheres. J. Colloid Interface Sci. 271:92–101 (2004).

    PubMed  CAS  Google Scholar 

  205. P. A. Burke, L. A. Klumb, J. D. Herberger, X. C. Nguyen, R. A. Harrell, and M. Aordich. Poly(lactide-co-glycolide) microsphere formulations of darbepoetin alfa: spray drying is an alternative to encapsulation by spray-freeze drying. Pharm. Res. 21:500–506 (2004).

    PubMed  CAS  Google Scholar 

  206. X. C. Nguyen, J. D. Herberger, and P. A. Burke. Protein powders for encapsulation: a comparison of spray-freeze drying and spray drying of darbepoetin alfa. Pharm. Res. 21:507–513 (2004).

    PubMed  CAS  Google Scholar 

  207. X. M. Zeng, G. P. Martin, and C. Marriott. The controlled delivery of drugs to the lung. Int. J. Pharm. 124:149–164 (1995).

    CAS  Google Scholar 

  208. Y. L. Lai, R. C. Metha, A. A. Thacker, S. D. Yoo, P. J. McMamara, and P. P. DeLuca. Sustained bronchodilation with isoproterenol poly(glycolide-co-lactide) microspheres. Pharm. Res. 10:119–125 (1993).

    PubMed  CAS  Google Scholar 

  209. M. M. El-Baseir, M. A. Phipps, and I. W. Kellaway. Preparation and subsequent degradation of poly(L-lactic acid) microspheres suitable for aerosolisation: a physico-chemical study. Int. J. Pharm. 151:145–153 (1997).

    CAS  Google Scholar 

  210. R. Sharma, D. Saxena, A. K. Dwivedi, and A. Misra. Inhalable microparticles containing drug combinations to target alveolar macrophages for treatment of pulmonary tuberculosis. Pharm. Res. 18:1405–1410 (2001).

    PubMed  CAS  Google Scholar 

  211. P. O’Hara and A. J. Hickey. Respirable PLGA microspheres containing rifampicin for the treatment of tuberculosis: manufacture and characterization. Pharm. Res. 17:955–961 (2000).

    PubMed  CAS  Google Scholar 

  212. V. A. Philip, R. C. Mehta, M. K. Mazumder, and P. P. DeLuca. Effect of surface treatment on the respirable fractions of PLGA microspheres formulated for dry powder inhalers. Int. J. Pharm. 151:165–174 (1997).

    CAS  Google Scholar 

  213. D. J. Armstrong, P. N. C. Elliott, J. L. Ford, D. Gansdon, G. P. Mccarthy, C. Rostron, and M. D. Worsley. Poly-(D,L-lactic acid) microspheres incorporating histological dyes for intra-pulmonary histopathological investigations. J. Pharm. Pharmacol. 48:258–262 (1996).

    PubMed  CAS  Google Scholar 

  214. X. M. Zeng, G. P. Martin, and C. Marriott. Preparation and in vitro evaluation of tetrandrine-entrapped albumin microspheres as an inhaled drug delivery system. Eur. J. Pharm. Sci. 3:87–93 (1995).

    CAS  Google Scholar 

  215. F. Q. Li, J. H. Hu, B. Lu, H. Yao, and W. G. Zhang. Ciprofloxacin-loaded bovine serum albumin microspheres: preparation and drug-release in vitro. J. Microencapsul 18:825–829 (2001).

    PubMed  CAS  Google Scholar 

  216. Y. Q. Tian, M. E. Klegerman, and A. J. Hickey. Evaluation of microparticles containing doxorubicin suitable for aerosol delivery to the lungs. PDA J. Pharm. Sci. Technol. 58:266–275 (2004).

    PubMed  CAS  Google Scholar 

  217. L. Brown, M. Jarpe, J. McGeehan, Y. Qin, E. Moore, and K. Hogeland. Promaxx™ microsphere characterization. Proceedings of the Conference on Respiratory Drug Delivery, Palm Springs, California, 2004, pp. 477–479.

  218. J. Rashba-Step, E. Proos, A. Sullivan, K. Hogeland, and T. Scott. Promaxx™ microsphere characterization. Proceedings of the Conference on Respiratory Drug Delivery, Palm Springs, California, 2004, pp. 481–483.

  219. A. Pfützner, A. E. Mann, and S. S. Steiner. Technosphere/insulin—a new approach for effective delivery of human insulin via the pulmonary route. Diabetes Technol. Ther. 4:589–594 (2002).

    PubMed  Google Scholar 

  220. A. Leone-Bay and M. Grant. Technosphere® technology: a platform for inhaled protein therapeutics. http://www.ondrugdelivery.com/products/current_issues.htm/ (accessed 7/14/2006).

  221. XstalBio. Advanced drug delivery of therapeutic protein, peptides, DNA & vaccines protein stabilisation http://www.XstalBio.com (accessed 7/17/2006).

  222. K. Westesen. Novel lipid based colloidal dispersions as potential drug administration systems—expectations and reality. Colloid Polym. Sci. 278:608–618 (2000).

    CAS  Google Scholar 

  223. R. H. Muller, K. Mader, and W. Gohla. Solid lipid nanoparticles (SLN) for controlled drug delivery—a review of the state of the art. Eur. J. Pharm. Biopharm. 50:161–177 (2000).

    PubMed  CAS  Google Scholar 

  224. A. R. Clark and P. York. SCF-pulmonary pharmaceuticals: the uncoated truth. Proceedings of the Conference on Respiratory Drug Delivery 10, Boca Raton, Florida, 2006, pp. 317–326.

  225. H. Steckel, J. Thies, and B. W. Müller. Micronizing of steroids for pulmonary delivery by supercritical carbon dioxide. Int. J. Pharm. 152:99–110 (1997).

    CAS  Google Scholar 

  226. H. Steckel and B. W. Müller. Metered-dose inhaler formulation of fluticasone-17-propionate micronized with supercritical carbon dioxide using the alternative propellent HFA-227. Int. J. Pharm. 173:25–33 (1998).

    CAS  Google Scholar 

  227. B. Y. Shekunov, B. Chattopadhyay, and J. Seitzinger. Supercritical fluid processing techniques: comparing the products. Proceedings of the Conference on Respiratory Drug Delivery, Palm Springs, California, 2004, pp. 289–296.

  228. S. P. Velaga, R. Ghaderi, and J. Carlfors. Preparation and characterization of hydrocortisone particles using a supercritical fluids extraction process. Int. J. Pharm. 231:155–166 (2002).

    PubMed  CAS  Google Scholar 

  229. C. H. Richardson, H. Chrystyn, I. C. K. Won, and S. Walker. Comparison of in-vitro performance of salbutamol sulphate manufactured by a supercritical fluid process micronized salbutamol in a dry powder inhaler. AAPS PharmSci 4:T3197 (2002).

    Google Scholar 

  230. M. Rehman, B. Y. Shekunov, P. York, D. Lechuga-Ballesteros, D. P. Miller, T. Tan, and P. Colphorpe. Optimization of powders for pulmonary delivery using supercritical fluid technology. Eur. J. Pharm. Sci. 22:1–18 (2004).

    PubMed  CAS  Google Scholar 

  231. S. P. Velaga, R. Berger, and J. Carlfors. Supercritical fluids crystallization of budesonide and flunisolide. Pharm. Res. 19:1564–1571 (2002).

    PubMed  CAS  Google Scholar 

  232. H. H. Y. Tong, B. Y. Shekunov, P. York, and A. H. L. Chow. Characterization of two polymorphs of salmeterol xinafoate crystallized from supercritical fluids. Pharm. Res. 18:852–858 (2001).

    PubMed  CAS  Google Scholar 

  233. H. H. Y. Tong, B. Y. Shekunov, P. York, and A. H. L. Chow. Thermal analysis of trace level of polymorphic impurity in salmeterol xinafoate samples. Pharm. Res. 20:1423–1429 (2003).

    PubMed  CAS  Google Scholar 

  234. H. Todo, K. Iida, H. Okamoto, and K. Danjo. Improvement of insulin absorption from intratracheally administrated dry powder prepared by supercritical carbon dioxide process. J. Pharm. Sci. 92:2475–2486 (2003).

    PubMed  CAS  Google Scholar 

  235. M. A. Winters, B. L. Knutson, P. G. Debenedetti, H. G. Sparks, T. M. Przybycien, C. L. Stevenson, and S. J. Prestrelski. Precipitation of proteins in supercritical carbon dioxide. J. Pharm. Sci. 85:586–594 (1996).

    PubMed  CAS  Google Scholar 

  236. R. T. Bustami, H. K. Chan, F. Dehghani, and N. R. Foster. Generation of micro-particles of proteins for aerosol delivery using high pressure modified carbon dioxide. Pharm. Res. 17:1360–1366 (2000).

    PubMed  CAS  Google Scholar 

  237. J. Jung, F. Leboeuf, and M. Perrut. Preparation of inhalable protein particles by SCF-emulsion drying. Proceedings of the 6th International Symposium on Supercritical Fluids, Versailles, France, 2003, pp. 1837–1842.

  238. M. Tservistas, M. S. Levy, M. Y. A. Lo-Yim, R. D. O’Kennedy, P. York, G. O. Humphreys, and M. Hoare. The formation of plasmid DNA loaded pharmaceutical powders using supercritical fluid technology. Biotechnol. Bioeng. 72:12–18 (2001).

    PubMed  CAS  Google Scholar 

  239. T. M. Martin, N. Bandi, R. Shultz, C. B. Roberts, and U. B. Kompella. Supercritical fluid technology-derived budesonide and budesonide-PLA microparticles for respiratory delivery. AAPS PharmSci 3 (2001).

  240. R. Falk, T. W. Randolph, J. D. Meyer, R. M. Kelly, and M. C. Manning. Controlled release of ionic compounds from poly(L-lactide) microspheres produced by precipitation with a compressed antisolvent. J. Control. Release 44:77–85 (1997).

    CAS  Google Scholar 

  241. H. Zhou, C. Lengsfeld, D. J. Claffey, J. A. Ruth, B. Hybertson, T. W. Randolph, K. Y. Ng, and M. C. Manning. Hydrophobic ion pairing of isoniazid using a prodrug approach. J. Pharm. Sci. 91:1502–1511 (2002).

    PubMed  CAS  Google Scholar 

  242. Y. S. Cheng, D. Yazzine, J. Gao, D. Muggli, J. Etter, and G. J. Rosenthal. Particle characteristics and lung deposition patterns in a human airway replica of a dry powder formulation of polylactic acid produced using supercritical fluid technology. J. Aerosol Med. 16:65–73 (2003).

    PubMed  CAS  Google Scholar 

  243. P. M. Gosselin, R. Thibert, M. Preda, and J. N. Mcmullen. Polymorphic properties of micronized carbamazepine produced by RESS. Int. J. Pharm. 252:225–235 (2003).

    PubMed  CAS  Google Scholar 

  244. S. M. Howdle, M. S. Watson, M. J. Whitaker, V. K. Popov, M. C. Davies, F. S. Mandel, J. D. Wang, and K. M. Shakesheff. Supercritical fluid mixing: preparation of thermally sensitive polymer composite containing bioactive materials. Chem. Commun. 109–110 (2001).

  245. B. Y. Shekunov, P. Chattopadhyay, and J. S. Seitzinger. Preparation of composite particles for taste masking and controlled release using liquefaction with supercritical CO2. Proceedings of the Annual Conference of AAPS, Salt Lake City (2003).

  246. K. Lee and G. Gould. Aerogel powder therapeutic agents. International patent publication. WO 02/051389. (2002).

  247. R. K. Singh, W. S. Kim, M. Ollinger, V. Craciun, I. Coowantwong, G. Hochhaus, and N. Koshizaki. Laser based synthesis of nanofunctionalized particulates for pulmonary based controlled drug delivery applications. Appl. Surf. Sci. 197:610–614 (2002).

    Google Scholar 

  248. R. S. Pillai, D. B. Yeates, I. F. Miller, and A. J. Hickey. Controlled dissolution from wax-coated aerosol particles in canine lungs. J. Appl. Physiol. 84(2):717–725 (1998).

    PubMed  CAS  Google Scholar 

  249. E. I. Kauppinen, J. Raula, D. P. Brown, and A. Lähde. Gas-phase synthesis and coating of multifunctional nano- and microparticles for drug delivery. Proceedings of the Particles 2006: Medical/Biochemical Diagnostic, Pharmaceutical and Drug Delivery Applications of particle Technology, Orlando, Florida, 66–67, 2006.

  250. G. Poochikian and V. Shah. Pharmaceutical quality assessment system (PQAS): science and risk managed approaches for inhalation drug products. Proceedings of the Conference on Respiratory Drug Delivery, Boca Raton, Florida, 2006, pp. 151–158.

  251. M. H. Golden. What does PAT means for inhalation products? Proceedings of the Conference on Respiratory Drug Delivery, Boca Raton, Florida, 2006, pp. 143–150.

  252. N. Y. K. Chew and H. K. Chan. Effect of powder polydispersity on aerosol generation. J. Pharm. Sci. 5:162–168 (2002).

    CAS  Google Scholar 

Download references

Acknowledgement

One of the authors (Henry H. Y. Tong) would like to acknowledge the financial support of Macao Polytechnic Institute (Project no.: RP/ESS-7/2005).

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Albert H. L. Chow.

Glossary

AAT

Alpha-1-antitrypsin

AFM

Atomic force microscopy

AUC

Area under the curve

CAN-BD

CO2-assisted nebulization with bubble-drying

CFD

Computational fluid dynamics

COPD

Chronic obstructive pulmonary disease

DoE

Design of experiments

DPI

Dry powder inhaler

DPPC

Dipalmitoylphosphatidylcholine

DSCG

Disodium cromoglycate

ED

Emitted dose

FCA

Force-controlled additives

FDKP

Fumaryl diketopiperazine

FPF

Fine particle fraction

HFA

Hydrofluoroalkane

HIP

Hydrophobic ion pairing

HPMC

Hydroxylpropylmethylcellulose

IGC

Inverse gas chromatography

MDI

Metered dose inhaler

MMAD

Mass median aerodynamic diameter

MSCI

Multistage cascade impactor

QbD

Quality by design

OED

Oligosaccharide ester derivatives

PAT

Process analytical technology

PSD

Particle size distribution

PCMC

Protein-coated micro-crystals

PEG

Poly(ethylene glycol)

PGA

Poly(glycolic) acid

PGSS

Particle formation from gas-saturated solutions

PLA

Poly(l-lactic acid)

PLGA

Poly(lactide-co-glycolide) acid

PQAS

Pharmaceutical quality assessment system

PVA

Polyvinyl alcohol

PTH

Parathyroid hormone

RESS

Rapid expansion of supercritical solution

RH

Relative humidity

SA

Sebacic acid

SAS

Supercritical antisolvent

SCF

Supercritical fluid

SCT

Salmon calcitonin

SD

Spray drying

SEDS

Solution enhanced dispersion with supercritical fluids

SFEE

Supercritical fluid extraction of emulsions

SFD

Spray freeze drying

SLN

Solid lipid nanoparticles

TBA

Tributyl alcohol

TOF

Time-of-flight

XPS

X-ray photoelectron spectroscopy

Rights and permissions

Reprints and permissions

About this article

Cite this article

Chow, A.H.L., Tong, H.H.Y., Chattopadhyay, P. et al. Particle Engineering for Pulmonary Drug Delivery. Pharm Res 24, 411–437 (2007). https://doi.org/10.1007/s11095-006-9174-3

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11095-006-9174-3

Key words

Navigation