Volume : 11, Issue : 01, January – 2024

Title:

OPTIMIZATION OF LOCAL TOBRAMYCIN DELIVERY INTO LUNGS BY CHANGING THE PHYSICOCHEMICAL PROPERTIES OF TOBRAMYCIN INHALED SOLUTION FOR IMPROVING NEBULIZER PERFORMANCE USING SELECTED HIGH-PERFORMANCE NEBULIZER DELIVERY SYSTEMS

Authors :

Marwan. H. Mashat *, Salman Alfadhel, Abdullah M. Aloufi, Fayez Abiladi, Bandar Aljahdali, B.J. Clark, K.H. Assi, H. Chrystyn

Abstract :

Chronic lung infection with Pseudomonas aeruginosa is a major cause of increased morbidity and mortality in cystic fibrosis (CF) patients. Lung function and overall quality of life have improved as a result of the tobramycin inhalation solution (TIS). For determining the optimum combinations to deliver a large amount of tobramycin at the site of infection in the lung, three sets of TIS formulations have been designed in this study by changing the physicochemical properties of the drug solution for improving nebulizer performance. The CEN methodology for the determination of particle size distribution and aerosol output characteristics has been used for in-vitro assessment of tobramycin-tested formulations. All measurements were performed at ambient conditions. Different selected high-performance nebulizer delivery systems were used: two different designs of jet nebulizers and two new nebulizers based on vibrating mesh technology. The two jet nebulizers were Pari LC Plus® and Sidestream® powered by PariBoyN® and Medix AC 2000 Hi Flow compressors, respectively, with a fill volume 5ml. The vibrating-mesh nebulizers
were high-frequency NE-U22 Omron® ultrasonic vibrating mesh and Aeroneb® Go electronic micropump nebulizers, with 2.5ml fill volume.
In conclusion, the particle size distribution and aerosol output data in this study showed that significantly affected by the physicochemical properties of the drug solution such as osmolarity, pH, ionic strength, viscosity, density, and surface tension in conjunction with the nebulizer design on droplet size as well as aerosol output of TIS to maximize tobramycin delivery into the lungs with selected jet and ultrasonic vibrating mesh nebulizers. The probability of increasing tobramycin absorption in- vivo still required more investigations.
Keywords: Cystic fibrosis; Tobramycin; TOBI®; nebulizer; jet nebulizers; ultrasonic vibrating mesh nebulizer; electronic micropump nebulizer; CEN method; surface tension; ion concentration; viscosity.

Cite This Article:

Please cite this article in press Marwan. H. Mashat et al., Optimization Of Local Tobramycin Delivery Into Lungs By Changing The Physicochemical Properties Of Tobramycin Inhaled Solution For Improving Nebulizer Performance Using Selected High-Performance Nebulizer Delivery Systems., Indo Am. J. P. Sci, 2024; 11 (01).

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References:

1. N. Hoiby, E.W, Flensborg, B. Beck, B. Friis, SV. Jacobsen, L. Jacobsen, Pseudomonas aeruginosa infection in cystic fibrosis. Diagnostic and prognostic significance of Pseudomonas aeruginosa precipitins determined by means of crossed immune electrophoresis, Scand J Respir Dis. Apr;58 (2) (1977) 65-79.
2. N. Hoiby, C. Koch, Pseudomonas aeruginosa infection in cystic fibrosis and its management, Thorax. 45 (1990) 881–884.
3. B.S. Quon, C.H. Goss, B.W. Ramsey, Inhaled antibiotics for lower airway infections, Ann Am Thorac Soc. Mar;11(3) (2014) 425-34.
4. LM, Rose, R. Neale, Development of the first inhaled antibiotic for the treatment of cystic fibrosis, Sci Transl Med 2:mr4 (2010)
5. P. Szychowiak, M. Desgrouas, & S. Ehrmann, Inhaled antibiotics in critical care: state of the art and future perspectives, Infectious Diseases Now 52 (2022) 327–333.
6. A.D, Hay, A. Bolhuis, A.L. Huntley, M.D. Jones, Inhaled antibiotics for acute lower respiratory tract infections in primary care: a hypothesis, Lancet Respir Med Aug 10(8) (2022) 731-732.
7. P.A. Flume, B.P. O’Sullivan, K.A. Robinson, C.H. Goss, PJ. Jr. Mogayzel,
D.B. Willey-Courand, J. Bujan, J. Finder, M. Lester, L. Quittell, R. Rosenblatt, R.L Vender, L. Hazle, K. Sabadosa, B. Marshall, Cystic fibrosis pulmonary guidelines: chronic medications for maintenance of lung health, Am J Respir Crit Care Med 176 (2007) 957–969.
8. PJ. Jr . Mogayzel, E.T, Naureckas, K.A. Robinson, G. Mueller, D. Hadjiliadis, JB. Hoag, L. Lubsch, L. Hazle, K. Sabadosa, B. Marshall, Pulmonary Clinical Practice Guidelines Committee. Cystic fibrosis pulmonary guidelines. Chronic medications for maintenance of lung health. Am J Respir Crit Care Med Apr 1;187(7) (2013) 680-689
9. G. Döring, P. Flume, H. Heijerman, JS. Elborn, Treatment of lung infection in patients with cystic fibrosis: current and future strategies, J Cyst Fibros 11 (2012) 461–479
10. A.R. Smyth, S.C. Bell, S. Bojcin, M. Bryon, A. Duff, P. Flume, N. Kashirskaya, A. Munck, F. Ratjen, S.J. Schwarzenberg, I. Sermet-Gaudelus,
K.W. Southern, G. Taccetti, G. Ullrich, S. Wolfe, European cystic fibrosis society standards of care: best practice guidelines. J Cyst Fibros 13(Suppl. 1) (2014) S23–S42
11. B.W. Ramsey, M.S Pepe, J.M. Quan, K.L. Otto, A.B. Montgomery, J. Williams-Warren, M Vasiljev-K, D. Borowitz, C.M Bowman, B.C. Marshall,
S. Marshall, A.L. Smith, Intermittent administration of inhaled tobramycin in patients with cystic, N Engl J Med 340 (1999) 23-30
12. J.L. Burns, J.M. Van Dalfsen, R.M Shawar, K.L Otto, R.L Garber, J.M. Quan,
A.B. Montgomery, G.M. Albers, B.W. Ramsey, A.L. Smith, Effect of chronic intermittent administration of inhaled tobramycin on respiratory microbial flora in patients with cystic fibrosis, J Infect Dis. 179 (1999) 1190-1196.
13. D.J. Touw, F.A. Jacobs, R.W. Brimicombe, H.G. Heijerman, W. Bakker, D.D Briemer, Pharmacokinetics of aerosolized tobramycin in adult patients with cystic fibrosis, Antimicrob Agents Chemother. 41 (1997) 184-187.
14. P.P. Le Brun, A.H. de Boer, D. Gjaltema, P. Hagedoorn, H.G Heijerman,
H.W. Frijlink, Inhalation of tobramycin in cystic fibrosis part 1: the choice of a nebulizer, Int J Pharm 189 (1999a) 205-214
15. P.P. Le Brun, A.H. de Boer, D. Gjaltema, P. Hagedoorn, H.G Heijerman,
H.W. Frijlink, Inhalation of tobramycin in cystic fibrosis Part 2: Optimization of the tobramycin solution for a jet and an ultrasonic nebulizer, Int J Pharm. (1999b)189 215-225
16. N. H. Trejo, In vitro aerodynamic characterization of the dose emitted during jet nebulization of high strength tobramycin solutions.” Mphil Thesis, University of Bradford. 2004.
17. AJ.van Velzen,; J.W.F. Uges, H.G.M, Heijerman, Pharmacokinetics and safety of tobramycin nebulization with the I-neb and PARI-LC Plus in children with cystic fibrosis: A randomized, crossover study. Br J Clin Pharmacol. Sep 85(9) (2019) 1984-1993
18. K. Hamed, L. Debonnett, Tobramycin inhalation powder for the treatment of pulmonary Pseudomonas aeruginosa infection in patients with cystic fibrosis: a review based on clinical evidence, Ther Adv Respir Dis. May 11(5) (2017) 193-209
19. K. Hamed, V. Conti, H. Tian, E. Loefroth, Adherence to tobramycin inhaled powder vs inhaled solution in patients with cystic fibrosis: analysis of US insurance claims data. Patient Prefer Adherence Apr 27 (11) (2017) 831-838.
20. G. Taccetti, M. Francalanci, G. Pizzamiglio, B. Messore, V. Carnovale, G. Cimino, M. Cipolli, Cystic Fibrosis: Recent Insights into Inhaled Antibiotic Treatment and Future Perspectives. Antibiotics (Basel). Mar 22,10 (3) (2021) 338
21. M.W. Konstan, P.A. Flume, M. Kappler, R. Chiron, M. Higgins, F. Brockhaus, J. Zhang, G. Angyalosi, E. He, D.E. Geller, Safety, efficacy and convenience of tobramycin inhalation powder in cystic fibrosis patients: the EAGER trial, J Cyst Fibros. 10 (2011) 54–61
22. M.W. Konstan, D.E. Geller, P. Minić, F. Brockhaus, J. Zhang, G. Angyalosi, Tobramycin inhalation powder for P. aeruginosa infection in cystic fibrosis: the EVOLVE trial, Pediatr Pulmonol. 46 (2011) 230–238
23. U. Sommerwerck, I. Virella-Lowell, G. Angyalosi, A. Viegas, W. Cao, L. Debonnett, Long-term safety of tobramycin inhalation powder in patients with cystic fibrosis: phase IV (ETOILES) study, Curr Med Res Opin. 32 (2016) 1789–1795
24. D.J. Maselli, H. Keyt, M.I. Restrepo, Inhaled Antibiotic Therapy in Chronic Respiratory Diseases, Int. J. Mol. Sci. 18 (2017) 1062
25. H.L. Lin, C.S. Chen, J.B. Fink, G.H. Lee, C.W. Huang, J.C. Chen, Z.Y. Chiang, In Vitro Evaluation of a Vibrating-Mesh Nebulizer Repeatedly Use over 28 Days, Pharmaceutics. Oct 15,12 (10) (2020) 971
26. M. Mashat, B.J. Clark, KH. Assi, H. Chrystyn, In vitro aerodynamic characterization of the dose emitted during nebulization of tobramycin high strength solution by novel and jet nebulizer delivery systems. Pulm Pharmacol Ther. 37 (2016) 37-42.
27. T. Ghazanfari, A.M. Elhissi, Z. Ding, K.M. Taylor, The influence of fluid physicochemical properties on vibrating-mesh nebulization. Int J Pharm. Jul 18;339 (1-2) (2007) 103-11
28. J. Boe, J.H. Dennis, B.R. O’Driscoll, T.T Bauer, M. Carone, B. Dautzenberg,
P. Diot, K. Heslop, L. Lannefors, European Respiratory Society Task Force on the use of nebulizers. European Respiratory Society Guidelines on the use of nebulizers, Eur Respir J. 18(1) (2001), 228-42
29. T.C. Carvalho, J.T. McConville, the function and performance of aqueous aerosol devices for inhalation therapy, J Pharm Pharmacol. 68 (5) (2016) 556- 578
30. S. Han, R.K. Mallampalli, The Role of Surfactant in Lung Disease and Host Defense against Pulmonary Infections, Ann Am Thorac Soc. 12(5) (2015) 765-774
31. B. Chassaing, O. Koren, J.K. Goodrich, A.C. Poole, S. Srinivasan, R.E. Ley,
A.T. Gewirtz, Dietary emulsifiers impact the mouse gut microbiota promoting colitis and metabolic syndrome. Nature 5, 519 (7541) (2015) 92-96
32. C. O’Callaghan, P.W. Barry, The science of nebulized drug delivery, Thorax 52 Suppl 2 (Suppl 2) (1997) S31-44
33. I.Y. Saleem, H.D. Smyth, Tuning aerosol particle size distribution of metered dose inhalers using cosolvents and surfactants, Biomed Res Int. (2013) 574310.
34. H. Steckel, F. Eskandar, Factors affecting aerosol performance during nebulization with jet and ultrasonic nebulizers, Eur J Pharm Sci. 19(5) (2003) 443-55
35. P. Byron, Some future perspectives for unit dose inhalation aerosols. Drug Dev Ind Pharm. 12 (1976) 993-1015
36. S. Suarez, A.J. Hickey, Drug properties affecting aerosol behaviour, Respir Care. Jun;45(6) (2000) 652-66
37. P.R. Byron, J.S. Patton, Drug delivery via the respiratory tract. J Aerosol Med. 7(1) (1994) 49-75
38. M.M. Clay, D. Pavia, S.P. Newman, S.W. Clarke, Factors influencing the size distribution of aerosols from jet nebulisers, Thorax. 38(10) (1983) 755-9
39. America Association for Respiratory Care. Aerosol consensus statement. Respir Care 36 (1991) 916-921
40. A. Clark, and L. Borgström, In vitro testing of pharmaceutical aerosols and predicting lung deposition from in vitro measurement, Drug Delivery to the Lung; edited by Bisgaard, Chris O, Callaghan, Gerald C. Smaldone. (2002) pp105-142
41. E.C. Smith, J. Denyer, A.H. Kendrick, Comparison of twenty-three nebuliser/compressor combinations for domiciliary use, Eur Respir J. 8 (1995) 1214–1221
42. M. Mashat, H. Chrystyn, BJ. Clark, KH. Assi. Development and validation of HPLC method for the determination of tobramycin in urine samples post- inhalation using pre-column derivatization with fluorescein isothiocyanate, J Chromatogr B Analyt Technol Biomed Life Sci. Jun 15;869(1-2) (2008) 59- 66.
43. O.N.M. McCallion, and M. Patel, Viscosity effects on nebulisation of aqueous solutions, Int J Pharm. 130 (1996) 245-249
44. O.N.M. McCallion, G. Taylor, P.A. Bridges, M.L. Thomson, and A. J. Taylor, Jet nebulizers for pulmonary drug delivery, Int J Pharm 130 (1996b) 1-11
45. O.N.M. McCallion, K.M.G. Taylor, M. Thomas, and A. J. Taylor, The influence of surface tension on aerosols produced by medical nebulisers, Int J Pharm. 129 (1996a), 123-136
46. O.N.M. McCallion, K.M.G. Taylor, M. Thomas, and A. J. Taylor, Nebulizing fluids of different physicochemical properties. Eur J Pharm Sci. 2 (1994) 183.
47. M. H. Wagener, S. Wiethoff, W. Friedrich, I. Mollenhauer, M. Obladen, and
U. Boenick, Ultrasonic surfactant nebulization with different exciting frequencies, Biophysical Chemistry 84 (2000) 35-43
48. A. Weber, G. Morlin, M. Cohen, J. William-Warren, B. Ramsey, and A. Smith, Effect of nebulizer type and antibiotic concentration on device performance. Pediatr Pulmonol. 23 (1997) 249-260
49. K.M.G. Taylor, and O. N. M. McCallion. Ultrasonic nebulizers for pulmonary drug delivery. Int J Pharm. 153 (1997) 93-104.