Pulmonary Spray Dried Powders of Tobramycin Containing Sodium Stearate to Improve Aerosolization Efficiency
Tobramycin microparticulate powders containing the hydrophobic adjunct sodium stearate were studied for their use as pulmonary formulations in dry powder inhalers.
Spray-dried powders were characterized in terms of particle size distribution, morphology, crystallinity, drug dissolution rate, toxicity on epithelial lung cells and aerosol efficiency.
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.
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).
KEY WORDSantibiotic dry powder inhaler spray drying pulmonary delivery NGI tobramycin
- 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).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.PubMedCrossRefGoogle 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.PubMedCrossRefGoogle 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).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.PubMedCrossRefGoogle 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
- 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).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.PubMedCrossRefGoogle Scholar
- 27.FDA. Dissolution Testing of Immediate Release Solid Oral Dosage Forms. FDA, Rockville, MD, 1997.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).CrossRefGoogle 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.PubMedCrossRefGoogle Scholar
- 35.British Pharmacopoeia, 2008, Vol. 2 Sodium Stearate Monograph p. 1994, London, England.Google Scholar
- 36.British Pharmacopoeia, 2008, Tobramycin Monograph p. 2153, London, England.Google Scholar