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Pulmonary Spray Dried Powders of Tobramycin Containing Sodium Stearate to Improve Aerosolization Efficiency

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Abstract

Purpose

Tobramycin microparticulate powders containing the hydrophobic adjunct sodium stearate were studied for their use as pulmonary formulations in dry powder inhalers.

Methods

Spray-dried powders were characterized in terms of particle size distribution, morphology, crystallinity, drug dissolution rate, toxicity on epithelial lung cells and aerosol efficiency.

Results

The presence of the sodium stearate had a direct influence on the aerosol performance of tobramycin spray-dried powders. Powders containing 1% w/w sodium stearate had fine particle fraction FPF of 84.3 ± 2.0% compared to 27.1 ± 1.9% for powders containing no adjunct. This was attributed to the accumulation of sodium stearate at the particle surface. Powders with higher sodium stearate concentrations (2% w/w) showed significantly lower FPF (66.4 ± 0.9%) and less accumulation of sodium stearate at the particle surface. This was attributed to the formation of adjunct micelles, which remained internalised in the particle structure due to their reduced tropism toward the drying drop surface and molecular mobility. Preliminary analysis of the toxicity effect of sodium stearate on A549 cell lines showed that the adjunct, in the concentration used, had no effect on cell viability over a 24-h period compared to particles of pure tobramycin.

Conclusions

Tobramycin pulmonary powders with low level of sodium stearate, presenting high respiration performances and no overt toxicity on lung cells, could be used to improve therapeutic outcomes of patient with Cystic Fibrosis (CF).

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References

  1. L. Garcia-Contreras, and A.J. Hickey. Pharmaceutical and biotechnological aerosols for cystic fibrosis therapy. Adv. Drug. D. Rev. 54:1491–1504 (2002). doi:10.1016/S0169-409X(02)00159-X.

    Article  CAS  Google Scholar 

  2. M.E. Drobnic, P. Suñé, J.B. Montoro, A. Ferrer, and R. Orriols. Inhaled tobramycin in non-cystic fibrosis patients with bronchiectasis and chronic bronchial infection with pseudomonas aeruginosa. Ann. Pharmacother. 39:39–44 (2005). doi:10.1345/aph.1E099.

    PubMed  CAS  Google Scholar 

  3. H. Lode. Tobramycin: a review of therapeutic uses and dosing schedules. C. Ther. Res. 59:7 (1998).

    Google Scholar 

  4. V.B. Pai, and M.C. Nahata. Efficacy and safety of aerosolized tobramycin in cystic fibrosis. Ped Pneumology. 32:314–327 (2001).

    CAS  Google Scholar 

  5. 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, S. Marshall, and A.L. Smith. Intermittent administration of inhaled tobramycin in patients with cystic fibrosis. N. Engl. J. Med. 340:23–30 (1999). doi:10.1056/NEJM199901073400104.

    Article  PubMed  CAS  Google Scholar 

  6. G. Döring, S.P. Conway, H.G.M. Heijerman, M.E. Hodson, N. Hùiby, A. Smyth, and D.J. Touw. Antibiotic therapy against Pseudomonas aeruginosa in cystic fibrosis: a European consensus. Eur. Respir. J. 16:749–767 (2000). doi:10.1034/j.1399-3003.2000.16d30.x.

    Article  PubMed  Google Scholar 

  7. R.B. Moss. Administration of aerosolized antibiotics in cystic fibrosis patients. Chest. 120:107–113 (2001). doi:10.1378/chest.120.3_suppl.107S.

    Article  Google Scholar 

  8. J. Eisenberg, M. Pepe, J. Williams-Warren, M. Vasiliev, A.B. Montgomery, A.L. Smith, and B.W. Ramsey. Systems fibrosis using jet and ultrasonic nebulizer concentration in patients with cystic. A comparison of peak sputum tobramycin. Chest. 111:955–962 (1997). doi:10.1378/chest.111.4.955.

    Article  PubMed  CAS  Google Scholar 

  9. D.J. Touw, A.J. Knox, and A. Smyth. Population pharmacokinetics of tobramycin administered thrice daily and once daily in children and adults with cystic fibrosis. J. Cyst. Fibros. 6:327–333 (2007). doi:10.1016/j.jcf.2006.12.007.

    Article  PubMed  CAS  Google Scholar 

  10. L. Vidal, A. Gafter-Gvili, S. Borok, A. Fraser, L. Leibovici, and M. Paul. Efficacy and safety of aminoglycoside monotherapy: systematic review and meta-analysis of randomized controlled trials. J. Antimicrob. Chemother. 60:247–257 (2007). doi:10.1093/jac/dkm193.

    Article  PubMed  CAS  Google Scholar 

  11. 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. Adis. Drug Evaluation. 63(22):2501–2520 (2003).

    CAS  Google Scholar 

  12. M.P. Boyle. Challenge of cystic fibrosis care so many drugs, so little time: the future. Chest. 123:3–5 (2003). doi:10.1378/chest.123.1.3.

    Article  PubMed  Google Scholar 

  13. P.W. Campbell, and L. Saiman. Use of aerosolized antibiotics in patients with cystic fibrosis. Chest. 116:775–788 (1999). doi:10.1378/chest.116.3.775.

    Article  PubMed  CAS  Google Scholar 

  14. M.P. Timsina, G.P. Martin, C. Marriott, D. Ganderton, and M. Yianneskis. Drug delivery to the respiratory tract using dry powder inhalers. Int. J. Pharm. 101:1–130 (1994).

    Article  CAS  Google Scholar 

  15. I. Gonda. The ascent of pulmonary drug delivery. J. Pharm. Sci. 89:940–945 (2000). doi:10.1002/1520-6017(200007)89:7<940::AID-JPS11>3.0.CO;2-B.

    Article  PubMed  CAS  Google Scholar 

  16. D.E. Geller, M.W. Konstan, J. Smith, S.B. Noonberg, and C. Conrad. Novel tobramycin inhalation powder in cystic fibrosis subjects: pharmacokinetics and safety. Pediatric. Pneumol. 42:307–333 (2007).

    Google Scholar 

  17. A.J. Hickey, and T.B. Martonen. Behavior of hygroscopic pharmaceutical aerosol and the influence of hydrophobic additives. Pharm. Res. 10(1):1–7 (1993). doi:10.1023/A:1018952425107.

    Article  PubMed  CAS  Google Scholar 

  18. R. Veinhard. Pharmaceutical particle engineering via spray drying. Pharm. Res. 25(5):999–1022 (2008). doi:10.1007/s11095-007-9475-1.

    Article  Google Scholar 

  19. P.C. Seville, H.-Y. Li, and T.P. Learoyd. Spray-dried powders for pulmonary drug delivery. Crit. Rev. Ther. Drug Carrier Sys. 24(4):307–360 (2007).

    CAS  Google Scholar 

  20. G. Pilcer, T. Sebti, and K. Amighi. Formulation and characterization of lipid-coated tobramycin particles for dry powder inhalation. Pharm. Res. 23(5):931–940 (2006). doi:10.1007/s11095-006-9789-4.

    Article  PubMed  CAS  Google Scholar 

  21. G. Pilcer, F. Vanderbist, and K. Amighi. Preparation and characterization of spray-dried tobramycin powder containing nanoparticles for pulmonary delivery. Int. J. Pharm. 365:162–169 (2008).

    Article  PubMed  Google Scholar 

  22. 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. 124:360–366 (2003).

    Article  PubMed  CAS  Google Scholar 

  23. S. Edge, A.M. Belu, U.J. Potter, D.F. Steele, P.M. Young, R. Price, and J.N. Staniforth. Chemical characterization of sodium starch glycolate particles. Int. J. Pharm. 240:67–78 (2002). doi:10.1016/S0378-5173(02)00109-6.

    Article  PubMed  CAS  Google Scholar 

  24. J. Carmichael, W.G. DeGraff, and A.F. Gazdar. Evaluation of tetrazolium-based semiautomated colorimetric assay: assessment of radiosensitivity. Cancer Res. 47(4):943–946 (1987).

    PubMed  CAS  Google Scholar 

  25. T. Mosmann. Rapid colorimetric assay for cellular growth and survival: application to proliferation and cytotoxicity assays. J. Immunol. Methods. 65:55–63 (1983). doi:10.1016/0022-1759(83)90303-4.

    Article  PubMed  CAS  Google Scholar 

  26. D.O. Corrigan, O.I. Corrigan, and A.M. Healy. Physicochemical and in vitro deposition properties of salbutamol sulphate/ipatropium bromide and salbuthamol sulphate/excipient spray dried mixtures for use in dry powder inhalers. Int. J. Pharm. 322:22–30 (2006). doi:10.1016/j.ijpharm.2006.05.022.

    Article  PubMed  CAS  Google Scholar 

  27. FDA. Dissolution Testing of Immediate Release Solid Oral Dosage Forms. FDA, Rockville, MD, 1997.

    Google Scholar 

  28. J.H. Widdicombe. Regulation of the depth and composition of airway surface liquid. J. Anatomy. 201(4):313–318 (2002). doi:10.1046/j.1469-7580.2002.00098.x.

    Article  CAS  Google Scholar 

  29. T.J. Franz. Percutaneous absorptions. On the relevance of in vitro data. J. Investigative Dermatolog. 64:190–195 (1975). doi:10.1111/1523-1747.ep12533356.

    Article  CAS  Google Scholar 

  30. R. Salama, S. Hoe, H.K. Chan, D. Traini, and P.M. Young. Preparation and characterisation of controlled release co-spray dried drug–polymer microparticles for inhalation 1: Influence of polymer concentration on physical and in vitro characteristics. Eu. J. Pharm. Biopharm. 69:486–495 (2008).

    Article  CAS  Google Scholar 

  31. H.Y. Li, and J. Birchall. Chitosan-modified dry powder formulations for pulmonary gene delivery. Pharm. Res. 23:941–950 (2006). doi:10.1007/s11095-006-0027-x.

    Article  PubMed  Google Scholar 

  32. D. Lechuga-Ballesteros, C. Charan, C. Stults, C.L. Stevenson, D.P. Miller, R. Vehring, V. Tep, and M.C. Kuo. Trileucine improves dispersibility, aerosol performance and stability of spray-dried powders for inhalation. J. Pharm. Sci. 97(1):287–302 (2008). doi:10.1002/jps.21078.

    Article  PubMed  CAS  Google Scholar 

  33. 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). doi:10.1002/jgm.654.

    Article  PubMed  CAS  Google Scholar 

  34. H.Y. Li, H. Neill, R. Innocent, P.C. 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). doi:10.1080/10611860410001659786.

    Article  PubMed  CAS  Google Scholar 

  35. British Pharmacopoeia, 2008, Vol. 2 Sodium Stearate Monograph p. 1994, London, England.

  36. British Pharmacopoeia, 2008, Tobramycin Monograph p. 2153, London, England.

  37. H.A. Capelle, L.G. Britcher, and G.E. Morris. Sodium stearate adsorption onto titania pigment. J. Col. Int. Sci. 268:293–300 (2003).

    Article  CAS  Google Scholar 

  38. D. Myers. Surfaces, interfaces and colloids—principle and applications. Wiley-VCH, New York, 1999.

    Book  Google Scholar 

  39. A. Tabazadeh. Organic aggregate formation in aerosols and its impact on the physicochemical properties of atmospheric particles. Atmos. Env. 39:5472–5480 (2005). doi:10.1016/j.atmosenv.2005.05.045.

    Article  CAS  Google Scholar 

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Authors and Affiliations

  1. Department of Pharmacy, University of Parma, Parma, Italy

    Chiara Parlati, Paolo Colombo & Francesca Buttini

  2. Advanced Drug Delivery Group, Faculty of Pharmacy, University of Sydney, Sydney, NSW, 2006, Australia

    Paul M. Young, Handoko Adi & Daniela Traini

  3. Respiratory Research Group, Faculty of Pharmacy, University of Sydney, Sydney, NSW, 2006, Australia

    Alaina J. Ammit

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  1. Chiara Parlati
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  2. Paolo Colombo
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  3. Francesca Buttini
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Correspondence to Paolo Colombo.

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Parlati, C., Colombo, P., Buttini, F. et al. Pulmonary Spray Dried Powders of Tobramycin Containing Sodium Stearate to Improve Aerosolization Efficiency. Pharm Res 26, 1084–1092 (2009). https://doi.org/10.1007/s11095-009-9825-2

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  • DOI: https://doi.org/10.1007/s11095-009-9825-2

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