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).
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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.
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.
H. Lode. Tobramycin: a review of therapeutic uses and dosing schedules. C. Ther. Res. 59:7 (1998).
V.B. Pai, and M.C. Nahata. Efficacy and safety of aerosolized tobramycin in cystic fibrosis. Ped Pneumology. 32:314–327 (2001).
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.
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.
R.B. Moss. Administration of aerosolized antibiotics in cystic fibrosis patients. Chest. 120:107–113 (2001). doi:10.1378/chest.120.3_suppl.107S.
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.
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.
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.
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).
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.
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.
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).
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.
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).
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.
R. Veinhard. Pharmaceutical particle engineering via spray drying. Pharm. Res. 25(5):999–1022 (2008). doi:10.1007/s11095-007-9475-1.
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).
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.
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).
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).
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.
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).
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.
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.
FDA. Dissolution Testing of Immediate Release Solid Oral Dosage Forms. FDA, Rockville, MD, 1997.
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.
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.
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).
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.
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.
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.
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.
British Pharmacopoeia, 2008, Vol. 2 Sodium Stearate Monograph p. 1994, London, England.
British Pharmacopoeia, 2008, Tobramycin Monograph p. 2153, London, England.
H.A. Capelle, L.G. Britcher, and G.E. Morris. Sodium stearate adsorption onto titania pigment. J. Col. Int. Sci. 268:293–300 (2003).
D. Myers. Surfaces, interfaces and colloids—principle and applications. Wiley-VCH, New York, 1999.
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.
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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
- dry powder inhaler
- spray drying
- pulmonary delivery