Skip to main content
SpringerLink
Log in

Initial Characterization of Micafungin Pulmonary Delivery via Two Different Nebulizers and Multivariate Data Analysis of Aerosol Mass Distribution Profiles

  • Research Article
  • Published:
AAPS PharmSciTech Aims and scope Submit manuscript

Abstract

Pharmaceutical aerosols have been targeted to the lungs for the treatment of asthma and pulmonary infectious diseases successfully. Micafungin (Astellas Pharma US, Deerfield, IL, USA) has been shown to be an effective antifungal agent when administrated intravenously. Pulmonary delivery of micafungin has not previously been reported. In the present pilot study, we characterize the performance of two nebulizers and their potential for delivering micafungin to the lungs as well as the use of multivariate data analysis for mass distribution profile comparison. The concentration of micafungin sodium increased by 21% when delivered by the Acorn II nebulizer and by 20% when delivered by the LC Plus nebulizer, respectively, from the first to the second sampling period. The Acorn II nebulizer delivered a fine particle fraction FPF5.8 (%<5.8 μm) of 92.5 ± 0.8 and FPF3.3 (%<3.3 μm) of 82.3 ± 2.1 during the first sampling period. For the LC Plus nebulizer, FPF5.8 was 92.3 ± 0.1 and FPF3.3 was 67.0 ± 0.7 during the first sampling period. The mass median aerodynamic diameter (MMAD) increased from 1.67 ± 0.05 to 1.77 ± 0.04 μm (Acorn II nebulizer) and from 2.09 ± 0.01 to 2.20 ± 0.01 μm (Pari LC Plus nebulizer) from the first to the second sampling periods. These changes in MMAD were statistically significant by paired t test. Multivariate data analysis showed that this could be explained systematically by greater drug deposition on stages with larger cutoff sizes and reduced drug deposition on stages with smaller cutoff sizes rather than multimodal deposition or other anomalies in size distribution.

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

Access this article

Log in via an institution

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

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

References

  1. J. J. Vehreschild, and O.A. Cornely. Micafungin sodium, the second of the echinocandin class of antifungals: theory and practice. Future Microbiol. 1:161–170 (2006).

    Article  PubMed  CAS  Google Scholar 

  2. Astellas Pharma US. Mycamine (micafungin sodium) package insert. Deerfield, IL (2005).

  3. H. Mikamo, Y. Sato, and T. Tamaya. In vitro antifungal activity of FK463, a new water-soluble echinocandin-like lipopeptide. J. Antimicrob. Chemother. 46:485–487 (2000).

    Article  PubMed  CAS  Google Scholar 

  4. P. H. Chandrasekar, and J. D. Sobel. Micafungin: a new echinocandin. Clin. Infect. Dis. 42:1171–1178 (2006).

    Article  PubMed  CAS  Google Scholar 

  5. J. M. Joseph, R. Jain, and L. H. Danziger. Micafungin: a new echinocandin antifungal. Pharmacotherapy. 27:53–67 (2007).

    Article  PubMed  CAS  Google Scholar 

  6. T. Nakai, J. Uno, K. Otomo, F. Ikeda, S. Tawara, T. Goto, K. Nishimura, and M. Miyaji. In vitro activity of FK463, a novel lipopeptide antifungal agent, against a variety of clinically important molds. Chemotherapy. 48:78–81 (2002).

    Article  PubMed  CAS  Google Scholar 

  7. V. Petraitis, R. Petraitiene, A. H. Groll, K. Roussillon, M. Hemmings, C. A. Lyman, T. Sein, J. Bacher, I. Bekersky, and T. J. Walsh. Comparative antifungal activities and plasma pharmacokinetics of micafungin (FK463) against disseminated candidiasis and invasive pulmonary aspergillosis in persistently neutropenic rabbits. Antimicrob. Agents Chemother. 46:1857–1869 (2002).

    Article  PubMed  CAS  Google Scholar 

  8. T. Nakai, J. Uno, F. Ikeda, S. Tawara, K. Nishimura, and M. Miyaji. In vitro antifungal activity of Micafungin (FK463) against dimorphic fungi: comparison of yeast-like and mycelial forms. Antimicrob. Agents Chemother. 47:1376–1281 (2003).

    Article  PubMed  CAS  Google Scholar 

  9. K. Tabata, M. Katashima, A. Kawamura, Y. Tanigawara, and K. Sunagawa. Linear pharmacokinetics of micafungin and its active metabolites in Japanese pediatric patients with fungal infections. Biol. Pharm. Bull. 29:1706–1711 (2006).

    Article  PubMed  CAS  Google Scholar 

  10. M. F. Hebert, H. E. Smith, T. C. Marbury, S. K. Swan, W. B. Smith, R. W. Townsend, D. Buell, J. Keirns, and I. Bekersky. Pharmacokinetics of micafungin in healthy volunteers, volunteers with moderate liver disease, and volunteers with renal dysfunction. J. Clin. Pharmacol. 45:1145–1152 (2005).

    Article  PubMed  CAS  Google Scholar 

  11. T. Niwa, Y. Yokota, A. Tokunaga, Y. Yamato, A. Kagayama, T. Fujiwara, J. Hatakeyama, M. Anezaki, Y. Ohtsuka, and A. Takagi. Tissue distribution after intravenous dosing of micafungin, an antifungal drug, to rats. Biol. Pharm. Bull. 27:1154–1156 (2004).

    Article  PubMed  CAS  Google Scholar 

  12. A. H. Groll, D. Mickiene, V. Petraitis, R. Petraitiene, K. H. Ibrahim, S. C. Piscitelli, I. Bekersky, and T. J. Walsh. Compartmental pharmacokinetics and tissue distribution of the antifungal echinocandin lipopeptide micafungin (FK463) in rabbits. Antimicrob. Agents Chemother. 45:3322–3327 (2001).

    Article  PubMed  CAS  Google Scholar 

  13. A. J. Hickey. Pulmonary drug delivery—pharmaceutical chemistry and aerosol technology. In B. Wang, T. Siahaan, and R. Soltero (eds.), Drug Delivery: Principles and Applications, Wiley, New York, 2005, pp. 341–361.

    Google Scholar 

  14. A. J. Hickey, D. Lu, E. D. Ashley, and J. Stout. Inhaled azithromycin therapy. J. Aerosol. Med. 19:54–60 (2006).

    Article  PubMed  CAS  Google Scholar 

  15. A. J. Hickey. Summary of common approaches to pharmaceutical aerosol administration. In A. J. Hickey (ed.), Pharmaceutical Inhalation Aerosol Technology, 2nd ed., Marcel Dekker, New York, 2004, pp. 385–421.

    Google Scholar 

  16. D. Christopher, W. P. Adams, D. S. Lee, B. Morgan, Z. Pan, G. J. Singh, Y. Tsong, and S. Lyapustina. Product Quality Research Institute evaluation of cascade impactor profiles of pharmaceutical aerosols, part 2: evaluation of a method for determining equivalence. AAPS PharmSciTech. 8:5 (2007).

    Article  PubMed  Google Scholar 

  17. D. Christopher, W. Adams, A. Amann, C. Bertha, P. R. Byron, W. Doub, C. Dunbar, W. Hauck, S. Lyapustina, J. Mitchell, B. Morgan, S. Nichols, Z. Pan, G. J. Singh, T. Tougas, Y. Tsong, R. Wolff, and B. Wyka. Product Quality Research Institute evaluation of cascade impactor profiles of pharmaceutical aerosols, part 3: final report on a statistical procedure for determining equivalence. AAPS PharmSciTech. 8:E90 (2007).

    Article  PubMed  Google Scholar 

  18. W. P. Adams, D. Christopher, D. S. Lee, B. Morgan, Z. Pan, G. J. Singh, Y. Tsong, and S. Lyapustina. Product Quality Research Institute evaluation of cascade impactor profiles of pharmaceutical aerosols, part 1: background for a statistical method. AAPS PharmSciTech. 8:4 (2007).

    Article  PubMed  Google Scholar 

  19. R. S. Plumb, M. D. Jones, P. D. Rainville, and J. K. Nicholson. A rapid simple approach to screening pharmaceutical products using ultra-performance LC coupled to time-of-flight mass spectrometry and pattern recognition. J. Chromatogr. Sci. 46:193–198 (2008).

    PubMed  CAS  Google Scholar 

  20. J. C. Lindon, E. Holmes, and J. K. Nicholson. Metabonomics in pharmaceutical R&D. FEBS J. 274:1140–1151 (2007).

    Article  PubMed  CAS  Google Scholar 

  21. S. Rochfort. Metabolomics reviewed: a new “omics” platform technology for systems biology and implications for natural products research. J. Nat. Prod. 68:1813–1820 (2005).

    Article  PubMed  CAS  Google Scholar 

  22. The United States Pharmacopeial, General Chapter <601> Aerosols, Nasal Sprays, Metered-Dose Inhalers, and Dry Powder Inhalers. (2008).

  23. R. W. Niven, M. Speer, and H. Schreier. Nebulization of liposomes. II. The effects of size and modeling of solute release profiles. Pharm. Res. 8:217–221 (1991).

    Article  PubMed  CAS  Google Scholar 

  24. R. W. Niven, T. M. Carvajal, and H. Schreier. Nebulization of liposomes. III. The effects of operating conditions and local environment. Pharm. Res. 9:515–520 (1991).

    Article  Google Scholar 

Download references

Acknowledgements

This research was conducted with the support of an investigator (BDA)-initiated research grant from Astellas Pharma. The authors also gratefully acknowledge the gift of micafungin from Astellas Pharma.

Author information

Authors and Affiliations

  1. School of Pharmacy, University of North Carolina at Chapel Hill, CB# 7360 Kerr Hall Room 1310, Chapel Hill, North Carolina, 27599, USA

    Shuai Shi & Anthony J. Hickey

  2. Division of Infectious Diseases and International Health, Duke University Medical Center, Durham, North Carolina, 27710, USA

    Elizabeth S. Dodds Ashley & Barbara D. Alexander

  3. University of Rochester Medical Center, Rochester, New York, 14642, USA

    Elizabeth S. Dodds Ashley

Authors
  1. Shuai Shi
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Elizabeth S. Dodds Ashley
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Barbara D. Alexander
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Anthony J. Hickey
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Anthony J. Hickey.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Shi, S., Dodds Ashley, E.S., Alexander, B.D. et al. Initial Characterization of Micafungin Pulmonary Delivery via Two Different Nebulizers and Multivariate Data Analysis of Aerosol Mass Distribution Profiles. AAPS PharmSciTech 10, 129–137 (2009). https://doi.org/10.1208/s12249-009-9185-6

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1208/s12249-009-9185-6

Key words

Search

Navigation