Skip to main content

Advertisement

SpringerLink
Log in

Formulation and Pharmacokinetics of Self-Assembled Rifampicin Nanoparticle Systems for Pulmonary Delivery

  • Research Paper
  • Published:
Pharmaceutical Research Aims and scope Submit manuscript

Abstract

Purpose

To formulate rifampicin, an anti-tuberculosis antibiotic, for aerosol delivery in a dry powder ‘porous nanoparticle-aggregate particle’ (PNAP) form suited for shelf stability, effective dispersibility and extended release with local lung and systemic drug delivery.

Methods

Rifampicin was encapsulated in PLGA nanoparticles by a solvent evaporation process, spray dried into PNAPs containing varying amounts of nanoparticles, and characterized for physical and aerosol properties. Pharmacokinetic studies were performed with formulations delivered to guinea pigs by intratracheal insufflation and compared to oral and intravenous delivery of rifampicin.

Results

The PNAP formulations possessed properties suitable for efficient deposition in the lungs. In vitro release showed an initial burst of rifampicin, with the remainder available for release beyond eight hours. PNAPs delivered to guinea pigs by insufflation achieved systemic levels of rifampicin detected for six to eight hours. Moreover, rifampicin concentrations remained detectable in lung tissue and cells up to and beyond eight hours. Conversely, after pulmonary delivery of an aerosol without nanoparticles, rifampicin could not be detected in the lungs at eight hours.

Conclusions

Our results indicate that rifampicin can be formulated into an aggregated nanoparticle form that, once delivered to animals, achieves systemic exposure and extends levels of drug in the lungs.

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

Abbreviations

BAL:

Bronchoalveolar lavage

DCM:

Dichloromethane

FPFTD :

Fine particle fraction of the total dose less than 5.8 μm

NP:

Nanoparticles

PK:

Pharmacokinetics

PLGA:

Poly (lactide-co-glycolide)

PNAP:

Porous nanoparticle-aggregate particle

PNAP40:

PNAPs containing 40% NP by weight

PNAP80:

PNAPs containing 80% NP by weight

PP:

Porous particles

PVA:

Poly(vinyl alcohol)

TB:

Tuberculosis

References

  1. WHO. Tuberculosis fact sheet. Geneva: World Health Organization; 2006.

    Google Scholar 

  2. Riley RL, Mills CC, Nyka W, Weinstock N, Storey PB, Sultan LU, et al. Aerial dissemination of pulmonary tuberculosis: a two-year study of contagion in a tuberculosis ward. Am J Epidemiol 1959;70:185–96.

    Google Scholar 

  3. Russell DG. Mycobacterium tuberculosis: here today and here tomorrow. Nat Rev Mol Cell Biol 2001;2:569–86. doi:10.1038/35085034.

    Article  PubMed  CAS  Google Scholar 

  4. Fox W, Ellard GA, Mitchison DA. Studies on the treatment of tuberculosis undertaken by the British Medical Research Council Tuberculosis Units, 1946–1986, with relevant subsequent publications. Int J Tuberc Lung Dis 1999;3:S231–79.

    PubMed  CAS  Google Scholar 

  5. Thomas C. A literature review of the problems of delayed presentation for treatment and non-completion of treatment for tuberculosis in less developed countries and ways of addressing these problems using particular implementations of the DOTS strategy. J Manage Med 2002;16:371–400. doi:10.1108/02689230210446544.

    Article  Google Scholar 

  6. Patton JS. Mechanisms of macromolecule absorption by the lungs. Adv Drug Deliv Rev 1996;19:3–36.

    Article  CAS  Google Scholar 

  7. Patton JS, Fishburn CS, Weers JG. The lungs as a portal of entry for systemic drug delivery. Proc Am Thorac Soc 2004;1:338–44. doi:10.1513/pats.200409-049TA.

    Article  PubMed  CAS  Google Scholar 

  8. Heyder J, Gebhart J, Rudolf G, Schiller CF, Stahlhofen W. Deposition of particles in the human respiratory tract in the size range 0.005–15 um. J Aerosol Sci 1986;17:811–25. doi:10.1016/0021-8502(86)90035-2.

    Article  Google Scholar 

  9. Edwards DA, Hanes J, Caponetti G, Hrkach J, Ben-Jebria A, Eskew ML, et al. Large porous particles for pulmonary drug delivery. Science 1997;276:1868–72. doi:10.1126/science.276.5320.1868.

    Article  PubMed  CAS  Google Scholar 

  10. Tsapis N, Bennett D, O'Driscoll K, Shea K, Lipp MM, Fu K, et al. Direct lung delivery of para-aminosalicylic acid by aerosol particles. Tuberculosis 2003;83:379–85. doi:10.1016/j.tube.2003.08.016.

    Article  PubMed  CAS  Google Scholar 

  11. Fiegel J, Garcia-Contreras L, Thomas M, VerBerkmoes J, Elbert K, Hickey A, et al. Preparation and in vivo evaluation of a dry powder for inhalation of capreomycin. Pharm Res 2007;25:805–11.

    Article  PubMed  Google Scholar 

  12. Garcia-Contreras L, Fiegel J, Telko MJ, Elbert K, Hawi A, Thomas M, et al. Inhaled large porous particles of capreomycin for treatment of tuberculosis in a guinea pig model. Antimicrob Agents Chemother 2007;51:2830–6. doi:10.1128/AAC.01164-06.

    Article  PubMed  CAS  Google Scholar 

  13. Gelperina S, Kisich K, Iseman MD, Heifets L. The potential advantages of nanoparticle drug delivery systems in chemotherapy of tuberculosis. Am J Respir Crit Care Med 2005;172:1487–90. doi:10.1164/rccm.200504-613PP.

    Article  PubMed  Google Scholar 

  14. Hansand ML, Lowman AM. Biodegradable nanoparticles for drug delivery and targeting. Curr Opin Solid State Mater Sci 2002;6:319–27. doi:10.1016/S1359-0286(02)00117-1.

    Article  Google Scholar 

  15. Kawashima Y, Yamamoto H, Takeuchi H, Fujioka S, Hino T. Pulmonary delivery of insulin with nebulized -lactide/glycolide copolymer (PLGA) nanospheres to prolong hypoglycemic effect. J Control Release 1999;62:279–87. doi:10.1016/S0168-3659(99)00048-6.

    Article  PubMed  CAS  Google Scholar 

  16. Yamamoto H, Kuno Y, Sugimoto S, Takeuchi H, Kawashima Y. Surface-modified PLGA nanosphere with chitosan improved pulmonary delivery of calcitonin by mucoadhesion and opening of the intercellular tight junctions. J Control Release 2005;102:373–81. doi:10.1016/j.jconrel.2004.10.010.

    Article  PubMed  CAS  Google Scholar 

  17. Vaughn JM, McConville JT, Burgess D, Peters JI, Johnston KP, Talbert RL, et al. Single dose and multiple dose studies of itraconazole nanoparticles. Eur J Pharm Biopharma 2006;63:95–102. doi:10.1016/j.ejpb.2006.01.006.

    Article  CAS  Google Scholar 

  18. Dailey LA, Schmehl T, Gessler T, Wittmar M, Grimminger F, Seeger W, et al. Nebulization of biodegradable nanoparticles: impact of nebulizer technology and nanoparticle characteristics on aerosol features. J Control Release 2003;86:131–44. doi:10.1016/S0168-3659(02)00370-X.

    Article  PubMed  CAS  Google Scholar 

  19. Le Brun PPH, de Boer AH, Frijlink HW, Heijerman HGM. A review of the technical aspects of drug nebulization. Pharm World Sci 2000;22:75–81. doi:10.1023/A:1008786600530.

    Article  PubMed  Google Scholar 

  20. Wendorf J, Singh M, Chesko J, Kazzaz J, Soewanan E, Ugozzoli M, et al. A practical approach to the use of nanoparticles for vaccine delivery. J Pharm Sci 2006;95:2738–50. doi:10.1002/jps.20728.

    Article  PubMed  CAS  Google Scholar 

  21. Saez A, Guzman M, Molpeceres J, Aberturas MR. Freeze-drying of polycaprolactone and poly(-lactic-glycolic) nanoparticles induce minor particle size changes affecting the oral pharmacokinetics of loaded drugs. Eur J Pharm Biopharma 2000;50:379–87. doi:10.1016/S0939-6411(00)00125-9.

    Article  CAS  Google Scholar 

  22. Heyder J, Rudolf G. Mathematical models of particle deposition in the human respiratory tract. J Aerosol Sci 1984;15:697–707. doi:10.1016/0021-8502(84)90007-7.

    Article  Google Scholar 

  23. Tsapis N, Bennett D, Jackson B, Weitz DA, Edwards DA. Trojan particles: large porous carriers of nanoparticles for drug delivery. Proc Natl Acad Sci U S A 2002;99. doi:10.1073/pnas.182233999.

  24. Sung JC, Pulliam BL, Edwards DA. Nanoparticles for drug delivery to the lungs. Trends Biotechnol 2007;25:563–70. doi:10.1016/j.tibtech.2007.09.005.

    Article  PubMed  CAS  Google Scholar 

  25. Chew NYK, Shekunov BY, Tong HHY, Chow AHL, Savage C, Wu J, et al. Effect of amino acids on the dispersion of disodium cromoglycate powders. J Pharm Sci 2005;94:2289–300. doi:10.1002/jps.20426.

    Article  PubMed  CAS  Google Scholar 

  26. Li H-Y, Seville PC, Williamson IJ, Birchall JC. The use of amino acids to enhance the aerosolisation of spray-dried powders for pulmonary gene therapy. J Gene Med 2005;7:343–53. doi:10.1002/jgm.654.

    Article  PubMed  CAS  Google Scholar 

  27. Azarmi S, Tao X, Chen H, Wang Z, Finlay WH, Lobenberg R, et al. Formulation and cytotoxicity of doxorubicin nanoparticles carried by dry powder aerosol particles. Int J Pharm 2006;319:155–61. doi:10.1016/j.ijpharm.2006.03.052.

    Article  PubMed  CAS  Google Scholar 

  28. Hadinoto K, Zhu K, Tan RBH. Drug release study of large hollow nanoparticulate aggregates carrier particles for pulmonary delivery. Int J Pharm 2007;341:195–2061. doi:10.1016/j.ijpharm.2007.03.035.

    Article  PubMed  CAS  Google Scholar 

  29. Grenha A, Seijo B, Remunan-Lopez C. Microencapsulated chitosan nanoparticles for lung protein delivery. Eur J Pharm Sci 2005;25:427–37. doi:10.1016/j.ejps.2005.04.009.

    Article  PubMed  CAS  Google Scholar 

  30. O'Hara P, Hickey AJ. Respirable PLGA microspheres containing rifampicin for the treatment of tuberculosis: manufacture and characterization. Pharm Res 2000;V17:955–61. doi:10.1023/A:1007527204887.

    Article  Google Scholar 

  31. Joshi DP, Lan-Chun-Fung YL, Pritchard JG. Determination of poly(vinyl alcohol) via its complex with boric acid and iodine. Anal Chim Acta 1979;104:153–60. doi:10.1016/S0003-2670(01)83825-3.

    Article  CAS  Google Scholar 

  32. Garcia-Contreras L, Hickey AJ. Pharmacokinetics of aerosolized rifampicin in the guinea pig. In: Dalby RN, Byron PR, Peart J, Farr S, editors. Respiratory drug delivery VIII. Raleigh, NC: Horwood; 2002.

    Google Scholar 

  33. Peloquin CA, Namdar R, Singleton MD, Nix DE. Pharmacokinetics of rifampin under fasting conditions, with food, and with antacids. Chest 1999;115:12–8. doi:10.1378/chest.115.1.12.

    Article  PubMed  CAS  Google Scholar 

  34. Garcia-Contreras L, Sethuraman V, Kazantseva M, Godfrey V, Hickey AJ. Evaluation of dosing regimen of respirable rifampicin biodegradable microspheres in the treatment of tuberculosis in the guinea pig. J Antimicrob Chemother 2006;58:980–6. doi:10.1093/jac/dkl369.

    Article  PubMed  CAS  Google Scholar 

  35. Suarez S, O'Hara P, Kazantseva M, Newcomer CE, Hopfer R, McMurray DN, et al. Respirable PLGA microspheres containing rifampicin for the treatment of tuberculosis: screening in an infectious disease model. Pharm Res 2001;V18:1315–9. doi:10.1023/A:1013094112861.

    Article  Google Scholar 

  36. Suarez S, O'Hara P, Kazantseva M, Newcomer CE, Hopfer R, McMurray DN, et al. Airways delivery of rifampicin microparticles for the treatment of tuberculosis. J Antimicrob Chemother 2001;48:431–4. doi:10.1093/jac/48.3.431.

    Article  PubMed  CAS  Google Scholar 

  37. Coowanitwong I, Arya V, Kulvanich P, Hochhaus GN. Slow release formulations of inhaled rifampin. AAPS J 2008;10:342–8. doi:10.1208/s12248–008–9044–5.

    Article  PubMed  CAS  Google Scholar 

  38. Pandey R, Sharma A, Zahoor A, Sharma S, Khuller GK, Prasad B. Poly (DL-lactide-co-glycolide) nanoparticle-based inhalable sustained drug delivery system for experimental tuberculosis. J Antimicrob Chemother 2003;52:981–6. doi:10.1093/jac/dkg477.

    Article  PubMed  CAS  Google Scholar 

  39. Sharma A, Sharma S, Khuller GK. Lectin-functionalized poly (lactide-co-glycolide) nanoparticles as oral/aerosolized antitubercular drug carriers for treatment of tuberculosis. J Antimicrob Chemother 2004;54:761–6. doi:10.1093/jac/dkh411.

    Article  PubMed  CAS  Google Scholar 

  40. Zahoor A, Sharma S, Khuller GK. Inhalable alginate nanoparticles as antitubercular drug carriers against experimental tuberculosis. Int J Antimicrobial Agents 2005;26:298–303. doi:10.1016/j.ijantimicag.2005.07.012.

    Article  CAS  Google Scholar 

  41. Esmaeili F, Hosseini-Nasr M, Rad-Malekshahi M, Samadi N, Atyabi F, Dinarvand R. Preparation and antibacterial activity evaluation of rifampicin-loaded poly lactide-co-glycolide nanoparticles. Nanomed Nanotechnol Biol Med 2007;3:161–7. doi:10.1016/j.nano.2007.03.003.

    Article  CAS  Google Scholar 

  42. Birnbaum DT, Kosmala JD, Brannon-Peppas L. Optimization of preparation techniques for poly(lactic acid-co-glycolic acid) nanoparticles. J Nanopart Res 2000;V2:173–81. doi:10.1023/A:1010038908767.

    Article  Google Scholar 

  43. Dailey LA, Jekel N, Fink L, Gessler T, Schmehl T, Wittmar M, et al. Investigation of the proinflammatory potential of biodegradable nanoparticle drug delivery systems in the lung. Toxicol Appl Pharmacol 2006;215:100–8. doi:10.1016/j.taap.2006.01.016.

    Article  PubMed  CAS  Google Scholar 

  44. Birnbaum DT, Brannon-Peppas L. Molecular weight distribution changes during degradation and release of PLGA nanoparticles containing epirubicin HCl. J Biomater Sci Polym Ed 2003;14:87–102. doi:10.1163/15685620360511155.

    Article  PubMed  CAS  Google Scholar 

  45. Peloquin C, Vernon A. Antimycobacterial agents: rifamycins for mycobacterial infections. In: Yu V, Edwards G, McKinnon P, Peloquin C, Morse G, editors. Antimicrobial chemotherapy and vaccines, vol. II: antimicrobial agents. 2nd ed. Pittsburg: Esun Technologies; 2005. p. 383–402.

    Google Scholar 

  46. Peloquin C. Clinical pharmacology of the anti-tuberculosis drugs. In: Davies P, Barnes P, Gordon S, editors. Clinical tuberculosis. 4th ed. London: Hodder Arnold; 2008.

    Google Scholar 

  47. Dickinson JM, Mitchison DA. Suitability of rifampicin for intermittent administration in the treatment of tuberculosis. Tubercle 1970;51:82–94. doi:10.1016/0041-3879(70)90131-5.

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgements

The authors thank Plastiape for their generous donation of inhaler devices and Shionogi for supplying capsules, Prof. Patrick Couvreur for fruitful discussions and Annalicia Poehler for research assistance. Electron microscopy work was performed at the Center for Nanoscale Systems (CNS), part of the Faculty of Arts and Sciences at Harvard University. This work was supported by a grant from the National Institute of Health/NIAID under Grant Number 5 U01 61336-02 and a National Science Foundation Graduate Research Fellowship.

Author information

Authors and Affiliations

  1. Harvard School of Engineering and Applied Sciences, 29 Oxford Street, Pierce 322, Cambridge, Massachusetts, 02138, USA

    Jean C. Sung, Jarod L. VerBerkmoes, Katharina J. Elbert & David A. Edwards

  2. School of Pharmacy, University of North Carolina at Chapel Hill, Kerr Hall, Chapel Hill, North Carolina, 27599, USA

    Danielle J. Padilla, Lucila Garcia-Contreras & Anthony J. Hickey

  3. National Jewish Medical and Research Center, Denver, Colorado, 80206, USA

    David Durbin & Charles A. Peloquin

Authors
  1. Jean C. Sung
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Danielle J. Padilla
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Lucila Garcia-Contreras
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Jarod L. VerBerkmoes
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. David Durbin
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Charles A. Peloquin
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Katharina J. Elbert
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Anthony J. Hickey
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. David A. Edwards
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to David A. Edwards.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Sung, J.C., Padilla, D.J., Garcia-Contreras, L. et al. Formulation and Pharmacokinetics of Self-Assembled Rifampicin Nanoparticle Systems for Pulmonary Delivery. Pharm Res 26, 1847–1855 (2009). https://doi.org/10.1007/s11095-009-9894-2

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11095-009-9894-2

KEY WORDS

Search

Navigation