Pharmaceutical Research

, 27:151 | Cite as

Inhalable Antibiotic Delivery Using a Dry Powder Co-delivering Recombinant Deoxyribonuclease and Ciprofloxacin for Treatment of Cystic Fibrosis

  • Yan Yang
  • Michael D. Tsifansky
  • Chia-Jung Wu
  • Hae In Yang
  • Gudrun Schmidt
  • Yoon Yeo
Research Paper

Abstract

Purpose

To achieve efficient antibiotic delivery to the cystic fibrosis (CF) airway using a single inhalable powder co-encapsulating a mucolytic and an antibiotic.

Methods

Inhalable dry powders containing deoxyribonuclease and/or ciprofloxacin (DNase, Cipro, and DNase/Cipro powders) were produced by spray-drying with dipalmitylphosphatidylcholine, albumin, and lactose as excipients, and their antibacterial effects were evaluated using the artificial sputum model.

Results

All powders showed mass median aerodynamic diameters below 5 µm. Both drugs were loaded in the dry powders without loss in quantity and activity. Dry powders containing DNase significantly decreased the storage modulus of the artificial sputum medium in less than 30 min. When applied to artificial sputum laden with Pseudomonas aeruginosa, Cipro/DNase powder showed better antibacterial activity than Cipro powder. The higher activity of the Cipro/DNase powder is attributable to the mucolytic activity of DNase, which promotes penetration of the dry powder into the artificial sputum and efficient dissolution and diffusion of ciprofloxacin.

Conclusions

Inhalational delivery of antibiotics to the CF airway can be optimized when the sputum barrier is concomitantly addressed. Co-delivery of antibiotics and DNase using an inhalable particle system may be a promising strategy for local antipseudomonal therapy in the CF airway.

KEY WORDS

artificial sputum co-delivery cystic fibrosis DNase inhalable dry powder 

Supplementary material

11095_2009_9991_MOESM1_ESM.pdf (20 kb)
Supplementary Fig. 1(PDF 19 kb)
11095_2009_9991_MOESM2_ESM.pdf (20 kb)
Supplementary Fig. 2(PDF 19 kb)
11095_2009_9991_MOESM3_ESM.pdf (28 kb)
Supplementary Fig. 3(PDF 27 kb)
11095_2009_9991_MOESM4_ESM.pdf (22 kb)
Supplementary Fig. 4(PDF 22 kb)

References

  1. 1.
    Orenstein DM, Rosenstein BJ, Stern RC. Diagnosis of Cystic Fibrosis. Cystic Fibrosis Medical Care. Philadelphia: Lippincott Williams and Wilkins; 2000. p. 21–53.Google Scholar
  2. 2.
    Genetic Testing for Cystic Fibrosis. NIH Consens Statement Online. 1997;15:1–37.Google Scholar
  3. 3.
    Ramsey BW. Management of pulmonary disease in patients with cystic fibrosis. New Engl J Med. 1996;335:179–88.CrossRefPubMedGoogle Scholar
  4. 4.
    Murphy TM, Rosenstein BJ. Advances in the science and treatment of cystic fibrosis lung diseases: A continuing medical education resource, Duke University Medical Center & Health System, Durham, North Carolina.Google Scholar
  5. 5.
    Sanders NN, De Smedt SC, Van Rompaey E, Simoens P, De Baets F, Demeester J. Cystic fibrosis sputum. A barrier to the transport of nanospheres. Am J Respir Crit Care Med. 2000;162:1905–11.PubMedGoogle Scholar
  6. 6.
    Cotran RS, Kumar V, Collins T, Robbins SL. Robbins pathologic basis of disease. Philadelphia: Saunders; 1999.Google Scholar
  7. 7.
    Hodson ME, Gallagher CG, Govan JR. A randomised clinical trial of nebulised tobramycin or colistin in cystic fibrosis. Eur Respir J. 2002;20:658–64.CrossRefPubMedGoogle Scholar
  8. 8.
    Hodson ME. Antibiotic treatment. Aerosol therapy. Chest. 1988;94:156S–62.PubMedGoogle Scholar
  9. 9.
    Goa KL, Lamb H. Dornase alfa. A review of pharmacoeconomic and quality-of-life aspects of its use in cystic fibrosis. Pharmacoeconomics. 1997;12:409–22.CrossRefPubMedGoogle Scholar
  10. 10.
    Hodson ME, McKenzie S, Harms HK, Koch C, Mastella G, Navarro J, et al. Dornase alfa in the treatment of cystic fibrosis in Europe: a report from the Epidemiologic Registry of Cystic Fibrosis. Pediatr Pulmonol. 2003;36:427–32.CrossRefPubMedGoogle Scholar
  11. 11.
    Garcia-Contreras L, Hickey AJ. Pharmaceutical and biotechnological aerosols for cystic fibrosis therapy. Adv Drug Deliv Rev. 2002;54:1491–504.CrossRefPubMedGoogle Scholar
  12. 12.
    Parks Q, Young R, Poch K, Malcolm K, Vasil M, Nick J. Neutrophil enhancement of Pseudomonas aeruginosa biofilm development: human F-actin and DNA as targets for therapy. J Med Microbiol. 2009;58:492–502.CrossRefPubMedGoogle Scholar
  13. 13.
    Vanbever R, Mintzes JD, Wang J, Nice J, Chen D, Batycky R, et al. Formulation and physical characterization of large porous particles for inhalation. Pharm Res. 1999;16:1735.CrossRefPubMedGoogle Scholar
  14. 14.
    Yu X, Zipp GL, Davidson Iii GWR. The effect of temperature and pH on the solubility of quinolone compounds: estimation of heat of fusion. Pharm Res. 1994;11:522–7.CrossRefPubMedGoogle Scholar
  15. 15.
    Sinicropi D, Baker DL, Prince WS, Shiffer K, Shak S. Colorimetric determination of DNase I activity with a DNA-methyl green substrate. Anal Biochem. 1994;222:351–8.CrossRefPubMedGoogle Scholar
  16. 16.
    Lichtinghagen R. Determination of Pulmozyme (dornase alpha) stability using a kinetic colorimetric DNase I activity assay. Eur J Pharm Biopharm. 2006;63:365–8.CrossRefPubMedGoogle Scholar
  17. 17.
    Clinical and Laboratory Standards Institute. Methods for dilution antimicrobial susceptibility tests for bacteria that grow aerobically; Approved standard—Eighth edition (M07-A8); 2009.Google Scholar
  18. 18.
    Sriramulu DD, Lunsdorf H, Lam JS, Romling U. Microcolony formation: a novel biofilm model of Pseudomonas aeruginosa for the cystic fibrosis lung. J Med Microbiol. 2005;54:667–76.CrossRefPubMedGoogle Scholar
  19. 19.
    Shur J, Nevell TG, Ewen RJ, Price R, Smith A, Barbu E, et al. Cospray-dried unfractionated heparin with L-leucine as a dry powder inhaler mucolytic for cystic fibrosis therapy. J Pharm Sci. 2008;97:4857–68.CrossRefPubMedGoogle Scholar
  20. 20.
    Chan HK, AuYeung KL, Gonda I. Effects of additives on heat denaturation of rhDNase in solutions. Pharm Res. 1996;13:756–61.CrossRefPubMedGoogle Scholar
  21. 21.
    Cipolla DC, Gonda I, Meserve KC, Weck S, Shire SJ. Formulation and aerosol delivery of recombinant deoxyribonucleac-acid derived human deoxyribonuclease-I. In: Cleland JLLR (ed.) Symposium on Formulation and Delivery of Proteins and Peptides, at the 205th National Meeting of the American-Chemical-Society. Denver, Co; 1993. pp. 322–42.Google Scholar
  22. 22.
    Tsifansky MD, Yeo Y, Evgenov OV, Bellas E, Benjamin J, Kohane DS. Microparticles for inhalational delivery of antipseudomonal antibiotics. AAPS J. 2008;10:254–60.CrossRefPubMedGoogle Scholar
  23. 23.
    Bosquillon C, Lombry C, Preat V, Vanbever R. Influence of formulation excipients and physical characteristics of inhalation dry powders on their aerosolization performance. J Control Release. 2001;70:329.CrossRefPubMedGoogle Scholar
  24. 24.
    Bosquillon C, Lombry C, Preat V, Vanbever R. Comparison of particle sizing techniques in the case of inhalation dry powders. J Pharm Sci. 2001;90:2032–41.CrossRefPubMedGoogle Scholar
  25. 25.
    Rabbani NR, Seville PC. The influence of formulation components on the aerosolisation properties of spray-dried powders. J Control Release. 2005;110:130–40.CrossRefPubMedGoogle Scholar
  26. 26.
    Madaras-Kelly KJ, Larsson AJ, Rotschafer JC. A pharmacodynamic evaluation of ciprofloxacin and ofloxacin against two strains of Pseudomonas aeruginosa. J Antimicrob Chemother. 1996;37:703–10.CrossRefPubMedGoogle Scholar
  27. 27.
    Ghani M, Soothill JS. Ceftazidime, gentamicin, and rifampicin, in combination, kill biofilms of mucoid Pseudomonas aeruginosa. Can J Microbiol. 1997;43.Google Scholar
  28. 28.
    Sanders N, Rudolph C, Braeckmans K, De Smedt SC, Demeester J. Extracellular barriers in respiratory gene therapy. Adv Drug Deliv Rev. 2009;61:115–27.CrossRefPubMedGoogle Scholar
  29. 29.
    Thomas SR, Ray A, Hodson ME, Pitt TL. Increased sputum amino acid concentrations and auxotrophy of Pseudomonas aeruginosa in severe cystic fibrosis lung disease. Thorax. 2000;55:795–7.CrossRefPubMedGoogle Scholar
  30. 30.
    Zahm JM, GiroddeBentzmann S, Deneuville E, Perrot-Minnot C, Dabadie A, Pennaforte F, et al. Dose-dependent in vitro effect of recombinant human DNase on rheological and transport properties of cystic fibrosis respiratory mucus. Eur Respir J. 1995;8:381–6.CrossRefPubMedGoogle Scholar
  31. 31.
    Hodson ME, Geddes DM, Bush A. Cystic fibrosis. London: Hodder Arnold; 2007.Google Scholar
  32. 32.
    Walker TS, Tomlin KL, Worthen GS, Poch KR, Lieber JG, Saavedra MT, et al. Enhanced Pseudomonas aeruginosa biofilm development mediated by human neutrophils. Infect Immun. 2005;73:3693–701.CrossRefPubMedGoogle Scholar
  33. 33.
    Tomkiewicz R, Kishore C, Freeman J, Rubin B. DNA and actin filament ultrastructure in cystic fibrosis sputum. In: Baum G, Priel Z, Roth Y, Liron N, Ostield E, editors. Cilia, Mucus, and Mucociliary Interactions. New York: Marcel Dekker Inc; 1998. p. 333–41.Google Scholar
  34. 34.
    Sheils CA, Kas J, Travassos W, Allen PG, Janmey PA, Wohl ME, et al. Actin filaments mediate DNA fiber formation in chronic inflammatory airway disease. Am J Pathol. 1996;148:919–27.PubMedGoogle Scholar
  35. 35.
    Broughton-Head VJ, Shur J, Carroll MP, Smith JR, Shute JK. Unfractionated heparin reduces the elasticity of sputum from patients with cystic fibrosis. Am J Physiol Lung Cell Mol Physiol. 2007;293:L1240–9.CrossRefPubMedGoogle Scholar
  36. 36.
    Whitchurch CB, Tolker-Nielsen T, Ragas PC, Mattick JS. Extracellular DNA required for bacterial biofilm formation. Science. 2002;295:1487.CrossRefPubMedGoogle Scholar
  37. 37.
    Prosser BL, Taylor D, Dix BA, Cleeland R. Method of evaluating effects of antibiotics on bacterial biofilm. Antimicrob Agents Chemother. 1987;31:1502–6.PubMedGoogle Scholar
  38. 38.
    Costerton JW, Cheng KJ, Geesey GG, Ladd TI, Nickel JC, Dasgupta M, et al. Bacterial biofilms in nature and disease. Annu Rev Microbiol. 1987;41:435–64.CrossRefPubMedGoogle Scholar
  39. 39.
    Bates RD, Nahata MC. Aerosolized dornase alpha (rhDNase) in cystic fibrosis. J Clin Pharm Ther. 1995;20:313–5.CrossRefPubMedGoogle Scholar
  40. 40.
    Ratjen F. Treatment of early Pseudomonas aeruginosa infection in patients with cystic fibrosis. Curr Opin Pulm Med. 2006;12:428–32.CrossRefPubMedGoogle Scholar
  41. 41.
    Chalumeau MM, Tonnelier SS, D’Athis PP, Trluyer JJ-M, Gendrel DD, Brart GG, et al. Fluoroquinolone safety in pediatric patients: a prospective, multicenter, comparative cohort study in France. Pediatrics. 2003;111:e714–9.CrossRefPubMedGoogle Scholar
  42. 42.
    Lee CKK, Boyle MP, Diener-West M, Brass-Ernst L, Noschese M, Zeitlin PL. Levofloxacin pharmacokinetics in adult cystic fibrosis. Chest. 2007;131:796–802.CrossRefPubMedGoogle Scholar
  43. 43.
    Geller DEDE. Aerosol antibiotics in cystic fibrosis. Respir Care. 2009;54:658–70.CrossRefPubMedGoogle Scholar
  44. 44.
    Pearson J. Inhalation Technologies—A Breath of Fresh Air. Drug Delivery Report. 2006;19–21. Spring/Summer).Google Scholar
  45. 45.
    Sweeney LG, Wang Z, Loebenberg R, Wong JP, Lange CF, Finlay WH. Spray-freeze-dried liposomal ciprofloxacin powder for inhaled aerosol drug delivery. Int J Pharm. 2005;305:180–5.CrossRefPubMedGoogle Scholar
  46. 46.
    Bosquillon C, Rouxhet PG, Ahimou F, Simon D, Culot C, Preat V, et al. Aerosolization properties, surface composition and physical state of spray-dried protein powders. J Control Release. 2004;99:357–67.CrossRefPubMedGoogle Scholar
  47. 47.
    Ben-Jebria A, Chen D, Eskew ML, Vanbever R, Langer R, Edwards DA. Large porous particles for sustained protection from carbachol-induced bronchoconstriction in guinea pigs. Pharm Res. 1999;16:555–61.CrossRefPubMedGoogle Scholar
  48. 48.
    Codrons V, Vanderbist F, Verbeeck RK, Arras M, Lison D, Préat V, et al. Systemic delivery of parathyroid hormone (1–34) using inhalation dry powders in rats. J Pharm Sci. 2003;92:938–50.CrossRefPubMedGoogle Scholar
  49. 49.
    The United States Pharmacopeia: The National Formulary (USP32/NF27), The United States Pharmacopeial Convention, 2009.Google Scholar
  50. 50.
    Bosquillon C, Préat V, Vanbever R. Pulmonary delivery of growth hormone using dry powders and visualization of its local fate in rats. J Control Release. 2004;96:233–44.CrossRefPubMedGoogle Scholar
  51. 51.
    Weuthen T, Roeder S, Brand P, Mllinger B, Scheuch G. In vitro testing of two formoterol dry powder inhalers at different flow rates. J Aerosol Med. 2002;15:297–303.CrossRefPubMedGoogle Scholar
  52. 52.
    Tsapis N, Bennett D, Jackson B, Weitz DA, Edwards DA. Trojan particles: large porous carriers of nanoparticles for drug delivery. PNAS. 2002;99:12001–5.CrossRefPubMedGoogle Scholar
  53. 53.
    Vehring R. Pharmaceutical particle engineering via spray drying. Pharm Res. 2008;25:999–1022.CrossRefPubMedGoogle Scholar
  54. 54.
    Sung JC, Padilla DJ, Garcia-Contreras L, Verberkmoes JL, Durbin D, Peloquin CA, Elbert KJ, Hickey AJ, Edwards DA. Formulation and Pharmacokinetics of Self-Assembled Rifampicin Nanoparticle Systems for Pulmonary Delivery. Pharm Res. 2009.Google Scholar
  55. 55.
    Sung JC, Pulliam BL, Edwards DA. Nanoparticles for drug delivery to the lungs. Trends Biotechnol. 2007;25:563–70.CrossRefPubMedGoogle Scholar
  56. 56.
    Ameri M, Maa Y-F. Spray drying of biopharmaceuticals: stability and process considerations. Drying Technol. 2006;24:763–8.CrossRefGoogle Scholar
  57. 57.
    Shak S, Capon DJ, Hellmiss R, Marsters SA, Baker CL. Recombinant human DNase I reduces the viscosity of cystic fibrosis sputum. Proc Natl Acad Sci USA. 1990;87:9188–92.CrossRefPubMedGoogle Scholar
  58. 58.
    Sauer K, Camper AK, Ehrlich GD, Costerton JW, Davies DG. Pseudomonas aeruginosa displays multiple phenotypes during development as a biofilm. J Bacteriol. 2002;184:1140–54.CrossRefPubMedGoogle Scholar
  59. 59.
    Anwar H, Dasgupta M, Lam K, Costerton JW. Tobramycin resistance of mucoid Pseudomonas aeruginosa biofilm grown under iron limitation. J Antimicrob Chemother. 1989;24:647–55.CrossRefPubMedGoogle Scholar
  60. 60.
    Høiby N, Johansen HK, Moser C, Song Z, Ciofu O, Kharazmi A. Pseudomonas aeruginosa and the in vitro and in vivo biofilm mode of growth. Microbes Infect. 2001;3:23–35.CrossRefPubMedGoogle Scholar
  61. 61.
    Tsifansky MD, Yeo Y, Evgenov OV, Bellas E, Benjamin J, Kohane DS. Microparticles for Inhalational Delivery of Antipseudomonal Antibiotics. AAPS J. 2008.Google Scholar
  62. 62.
    Tré-Hardy M, Macé C, Manssouri NE, Vanderbist F, Traore H, Devleeschouwer MJ. Effect of antibiotic co-administration on young and mature biofilms of cystic fibrosis clinical isolates: the importance of the biofilm model. Int J Antimicrob Agents. 2009;33:40–5.CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2009

Authors and Affiliations

  • Yan Yang
    • 1
    • 2
  • Michael D. Tsifansky
    • 3
  • Chia-Jung Wu
    • 4
  • Hae In Yang
    • 1
  • Gudrun Schmidt
    • 4
  • Yoon Yeo
    • 1
    • 4
  1. 1.School of Pharmacy and Pharmaceutical SciencesPurdue UniversityWest LafayetteUSA
  2. 2.Research Center for Drug Metabolism, College of Life ScienceJilin UniversityChangchunPeople’s Republic of China
  3. 3.Department of Pediatrics, Divisions of Pediatric Critical Care Medicine and Pediatric PulmonologyAdvocate Lutheran General Children’s HospitalPark RidgeUSA
  4. 4.Weldon School of Biomedical EngineeringPurdue UniversityWest LafayetteUSA

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