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The AAPS Journal

, 10:254 | Cite as

Microparticles for Inhalational Delivery of Antipseudomonal Antibiotics

  • Michael D. Tsifansky
  • Yoon Yeo
  • Oleg V. Evgenov
  • Evangelia Bellas
  • John Benjamin
  • Daniel S. KohaneEmail author
Research Article

Abstract

Chronic pseudomonal bronchopulmonary infections in cystic fibrosis patients are frequently controlled with inhaled antibiotics. Dry-powder inhalable antibiotics are an attractive alternative to nebulized medications. We produced and evaluated microparticles composed of dipalmitoylphosphatidylcholine, albumin, and lactose as a model system for intrapulmonary delivery of ceftazidime, ciprofloxacin, and several combinations of the two, none of which is presently available for inhalation. Microparticles containing one or both antibiotics were prepared by spray-drying. Their Anderson cascade impactor deposition profiles showed 10–30% fine particle fractions of the nominal dose. Microparticles containing varying amounts of each antibiotic showed statistically different deposition profiles. Aerodynamics and deposition of microparticles co-encapsulating both antibiotics were similar to those of single-drug microparticles with the same proportion of ciprofloxacin alone. The antipseudomonal activities of microparticles co-encapsulating half of the 50% effective concentration (EC50) of both ceftazidime and ciprofloxacin (5 mg of particles containing 5% ceftazidime and 10% ciprofloxacin) were at least additive compared to particles containing the EC50 of each antibiotic separately (5 mg of particles containing 10% ceftazidime or 5 mg of particles containing 20% ciprofloxacin). Co-encapsulation of the antibiotics in microparticles ensures co-deposition at desired ratios, improves the particles’ aerodynamics and fine particle fraction, as compared to microparticles with equivalent amounts of ceftazidime alone, and achieves additive antipseudomonal activity.

KEY WORDS

co-encapsulation cystic fibrosis dry-powder inhalational delivery of antibiotics microparticles 

Notes

ACKNOWLEDGMENT

We would like to express our gratitude to Henry Dorkin, MD for helpful insights. This work was supported by Cystic Fibrosis Foundation Research and Clinical Fellowship grant (TSIFAN02B0) to MDT and NIH GM073626 to DSK.

References

  1. 1.
    A. R. Penketh, A. Wise, M. B. Mearns, M. E. Hodson, and J. C. Batten. Cystic fibrosis in adolescents and adults. Thorax. 42(7):526–532 (1987).PubMedCrossRefGoogle Scholar
  2. 2.
    M. I. Gomez, and A. Prince. Opportunistic infections in lung disease: Pseudomonas infections in cystic fibrosis. Curr Opin Pharmacol (2007).Google Scholar
  3. 3.
    M. E. Hodson, and C. G. Gallagher. New clinical evidence from the European tobramycin trial in cystic fibrosis. J. Cyst. Fibros. 1(Suppl 2):199–202 (2002).PubMedCrossRefGoogle Scholar
  4. 4.
    B. W. Ramsey, M. S. Pepe, J. M. Quan, K. L. Otto, A. B. Montgomery, J. Williams-Warren, K. M. Vasiljev, D. Borowitz, C. M. Bowman, B. C. Marshall et al. Intermittent administration of inhaled tobramycin in patients with cystic fibrosis. Cystic Fibrosis Inhaled Tobramycin Study Group. N. Engl. J. Med. 340(1):23–30 (1999).PubMedCrossRefGoogle Scholar
  5. 5.
    M. E. Hodson. Antibiotic treatment. Aerosol therapy. Chest. 94(2 Suppl):156S–162S (1988).PubMedCrossRefGoogle Scholar
  6. 6.
    P. W. Campbell 3rd, and L. Saiman. Use of aerosolized antibiotics in patients with cystic fibrosis. Chest. 116(3):775–788 (1999).PubMedCrossRefGoogle Scholar
  7. 7.
    L. Weathers, D. Riggs, M. Santeiro, and R. E. Weibley. Aerosolized vancomycin for treatment of airway colonization by methicillin-resistant Staphylococcus aureus. Pediatr. Infect. Dis. J. 9(3):220–221 (1990).PubMedCrossRefGoogle Scholar
  8. 8.
    L. Máiz, R. Cantón, N. Mir, F. Baquero, and H. Escobar. Aerosolized vancomycin for the treatment of methicillin-resistant Staphylococcus aureus infection in cystic fibrosis. Pediatric. Pulmonology. 26(4):287–289 (1998).PubMedCrossRefGoogle Scholar
  9. 9.
    J. D. Gradon, E. H. Wu, and L. I. Lutwick. Aerosolized vancomycin therapy facilitating nursing home placement. Ann. Pharmacother. 26(2):209–210 (1992).PubMedGoogle Scholar
  10. 10.
    B. Laube. Aerosol delivery systems. In G. Loughlin, and H. Eigen (eds.), Respiratory Disease in Children: Diagnosis and Management, Williams and Wilkins, Baltimore, MD, 1994, pp. 721–729.Google Scholar
  11. 11.
    R. S. Bernard, and L. L. Cohen. Increasing adherence to cystic fibrosis treatment: a systematic review of behavioral techniques. Pediatr. Pulmonol. 37(1):8–16 (2004).PubMedCrossRefGoogle Scholar
  12. 12.
    M. A. Wall, A. B. Terry, J. Eisenberg, M. McNamara, and R. Cohen. Inhaled antibiotics in cystic fibrosis. Lancet. 1(8337):1325 (1983).PubMedCrossRefGoogle Scholar
  13. 13.
    R. L. Elmore, M. E. Contois, J. Kelly, A. Noe, and A. Poirier. Stability and compatibility of admixtures of intravenous ciprofloxacin and selected drugs. Clin. Ther. 18(2):246–255 (1996).PubMedCrossRefGoogle Scholar
  14. 14.
    C. G. Prober, P. D. Walson, and J. Jones. Technical report: precautions regarding the use of aerosolized antibiotics. Committee on Infectious Diseases and Committee on Drugs. Pediatrics. 106(6):E89 (2000).PubMedCrossRefGoogle Scholar
  15. 15.
    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(3):329–339 (2001).PubMedCrossRefGoogle Scholar
  16. 16.
    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(3):357–367 (2004).PubMedCrossRefGoogle Scholar
  17. 17.
    R. E. Dostal, J. P. Seale, and B. J. Yan. Resistance to ciprofloxacin of respiratory pathogens in patients with cystic fibrosis. Med. J. Aust. 156(1):20–24 (1992).PubMedGoogle Scholar
  18. 18.
    J. Watkins, J. Francis, and J. A. Kuzemko. Does monotherapy of pulmonary infections in cystic fibrosis lead to early development of resistant strains of Pseudomonas aeruginosa? Scand. J. Gastroenterol. Suppl. 143:81–85 (1988).PubMedCrossRefGoogle Scholar
  19. 19.
    S. M. Cheer, J. Waugh, and S. Noble. Inhaled tobramycin (TOBI): a review of its use in the management of Pseudomonas aeruginosa infections in patients with cystic fibrosis. Drugs. 63(22):2501–2520 (2003).PubMedCrossRefGoogle Scholar
  20. 20.
    A. L. Smith, B. W. Ramsey, D. L. Hedges, B. Hack, J. Williams-Warren, A. Weber, E. J. Gore, and G. J. Redding. Safety of aerosol tobramycin administration for 3 months to patients with cystic fibrosis. Pediatr. Pulmonol. 7(4):265–271 (1989).PubMedCrossRefGoogle Scholar
  21. 21.
    J. L. Burns, J. M. Van Dalfsen, R. M. Shawar, K. L. Otto, R. L. Garber, J. M. Quan, A. B. Montgomery, G. M. Albers, B. W. Ramsey, and A. L. Smith. Effect of chronic intermittent administration of inhaled tobramycin on respiratory microbial flora in patients with cystic fibrosis. J. Infect. Dis. 179(5):1190–1196 (1999).PubMedCrossRefGoogle Scholar
  22. 22.
    D. N. Fish, M. K. Choi, and R. Jung. Synergic activity of cephalosporins plus fluoroquinolones against Pseudomonas aeruginosa with resistance to one or both drugs. J. Antimicrob. Chemother. 50(6):1045–1049 (2002).PubMedCrossRefGoogle Scholar
  23. 23.
    S. L. Pendland, C. R. Messick, and R. Jung. In vitro synergy testing of levofloxacin, ofloxacin, and ciprofloxacin in combination with aztreonam, ceftazidime, or piperacillin against Pseudomonas aeruginosa. Diagn. Microbiol. Infect. Dis. 42(1):75–78 (2002).PubMedCrossRefGoogle Scholar
  24. 24.
    D. A. Edwards, A. Ben-Jebria, and R. Langer. Recent advances in pulmonary drug delivery using large, porous inhaled particles. J. Appl. Physiol. 85(2):379–385 (1998).PubMedGoogle Scholar
  25. 25.
    D. S. Kohane, M. Lipp, R. C. Kinney, N. Lotan, and R. Langer. Sciatic nerve blockade with lipid–protein–sugar particles containing bupivacaine. Pharm. Res. 17(10):1243–1249 (2000).PubMedCrossRefGoogle Scholar
  26. 26.
    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. V16(11):1735 (1999).CrossRefGoogle Scholar
  27. 27.
    D. S. Kohane, S. E. Smith, D. N. Louis, G. Colombo, P. Ghoroghchian, N. G. M. Hunfeld, C. B. Berde, and R. Langer. Prolonged duration local anesthesia from tetrodotoxin-enhanced local anesthetic microspheres. Pain. 104(1,2):415–421 (2003).PubMedCrossRefGoogle Scholar
  28. 28.
    J. Castillo, J. Curley, J. Hotz, M. Uezono, J. Tigner, M. Chasin, R. Wilder, R. Langer, and C. Berde. Glucocorticoids prolong rat sciatic nerve blockade in vivo from bupivacaine microspheres. Anesthesiology. 85(5):1157–1166 (1996).PubMedCrossRefGoogle Scholar
  29. 29.
    G. Colombo, R. Padera, R. Langer, and D. Kohane. Prolonged duration local anesthesia with lipid–protein–sugar particles containing bupivacaine and dexamethasone. J. Biomed. Mater. Res. A. 75(2):458–464 (2005).PubMedGoogle Scholar
  30. 30.
    J. P. Mitchell, and M. W. Nagel. Cascade impactors for the size characterization of aerosols from medical inhalers: their uses and limitations. J. Aerosol. Med. 16(4):341–377 (2003).PubMedCrossRefGoogle Scholar
  31. 31.
    J. M. Goldman, S. M. Bayston, S. O’Connor, and R. E. Meigh. Inhaled micronised gentamicin powder: a new delivery system. Thorax. 45(12):939–940 (1990).PubMedGoogle Scholar
  32. 32.
    N. R. Crowther Labiris, A. M. Holbrook, H. Chrystyn, S. M. Macleod, and M. T. Newhouse. Dry powder versus intravenous and nebulized gentamicin in cystic fibrosis and bronchiectasis. A pilot study. Am. J. Respir. Crit. Care Med. 160(5 Pt 1):1711–1716 (1999).PubMedGoogle Scholar
  33. 33.
    M. T. Newhouse, P. H. Hirst, S. P. Duddu, Y. H. Walter, T. E. Tarara, A. R. Clark, and J. G. Weers. Inhalation of a dry powder tobramycin PulmoSphere formulation in healthy volunteers. Chest. 124(1):360–366 (2003).PubMedCrossRefGoogle Scholar
  34. 34.
    H. Adi, P. M. Young, H. K. Chan, P. Stewart, H. Agus, and D. Traini. Cospray dried antibiotics for dry powder lung delivery. J Pharm Sci. (2007).Google Scholar
  35. 35.
    Gentamicin. Micromedex® Healthcare Series. Thomson MicromedexGoogle Scholar
  36. 36.
    Ciprofloxacin. Micromedex® Healthcare Series. Thomson MicromedexGoogle Scholar
  37. 37.
    Ceftazidime. Micromedex® Healthcare Series. Thomson MicromedexGoogle Scholar

Copyright information

© American Association of Pharmaceutical Scientists 2008

Authors and Affiliations

  • Michael D. Tsifansky
    • 1
  • Yoon Yeo
    • 2
  • Oleg V. Evgenov
    • 3
  • Evangelia Bellas
    • 4
  • John Benjamin
    • 5
  • Daniel S. Kohane
    • 6
    Email author
  1. 1.Department of Pediatrics, Division of Pediatric Intensive Care MedicineLutheran General Children’s HospitalPark RidgeUSA
  2. 2.Industrial and Physical Pharmacy and Biomedical EngineeringPurdue UniversityWest LafayetteUSA
  3. 3.Department of Anesthesia and Critical Care Medicine, Massachusetts General HospitalHarvard Medical SchoolBostonUSA
  4. 4.Department of Chemical EngineeringMassachusetts Institute of TechnologyCambridgeUSA
  5. 5.Shriners Hospital for Children-BostonBostonUSA
  6. 6.Laboratory for Biomaterials and Drug Delivery, Dept of Anesthesiology, Children’s HospitalHarvard Medical SchoolBostonUSA

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