Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2022 Nov;39(11):2781-2799.
doi: 10.1007/s11095-022-03344-5. Epub 2022 Aug 2.

Improved Aerosolization Stability of Inhalable Tobramycin Powder Formulation by Co-Spray Drying with Colistin

Vaibhav Pathak  1 , Heejun Park  1 , Dmitry Zemlyanov  2 , Sonal V Bhujbal  1 , Maizbha Uddin Ahmed  1 , Mohammad A K Azad  3 , Jian Li  3 , Qi Tony Zhou  4
Affiliations

Improved Aerosolization Stability of Inhalable Tobramycin Powder Formulation by Co-Spray Drying with Colistin

Vaibhav Pathak et al. Pharm Res. 2022 Nov.

Abstract

Purpose: Tobramycin shows synergistic antibacterial activity with colistin and can reduce the toxic effects of colistin. The purpose of this study is to prepare pulmonary powder formulations containing both colistin and tobramycin and to assess their in vitro aerosol performance and storage stability.

Methods: The dry powder formulations were manufactured using a lab-scale spray dryer. In vitro aerosol performance was measured using a Next Generation Impactor. The storage stability of the dry powder formulations was measured at 22°C and two relative humidity levels - 20 and 55%. Colistin composition on the particle surface was measured using X-ray photoelectron spectroscopy.

Results: Two combination formulations, with 1:1 and 1:5 molar ratios of colistin and tobramycin, showed fine particle fractions (FPF) of 85%, which was significantly higher than that of the spray dried tobramycin (45%). FPF of the tobramycin formulation increased significantly when stored for four weeks at both 20% and 55% RH. In contrast, FPF values of both combination formulations and spray dried colistin remained stable at both humidity levels. Particle surface of each combination was significantly enriched in colistin molecules; 1:5 combination showed 77% by wt. colistin.

Conclusions: The superior aerosol performance and aerosolization stability of 1:1 and 1:5 combination formulations of colistin and tobramycin could be attributed to enrichment of colistin on the co-spray dried particle surface. The observed powder properties may be the result of a surfactant-like assembly of these colistin molecules during spray drying, thus forming a hydrophobic particle surface.

Keywords: combination antibiotics; dry powder inhalation; respiratory infections; storage stability.

PubMed Disclaimer

Conflict of interest statement

CONFLICT OF INTEREST

MUA, MAKA, JL and QTZ are inventors of PCT/US2021/030393.

Figures

Fig. 1
Fig. 1
Representative scanning electron microscopy images of the spray dried formulations
Fig. 2
Fig. 2
X-ray diffraction patterns of the spray dried (SD) formulations and raw drug powders
Fig. 3
Fig. 3
Water vapor sorption isotherms of the spray dried formulations measured over two consecutive adsorption-desorption cycles.
Fig. 3
Fig. 3
Water vapor sorption isotherms of the spray dried formulations measured over two consecutive adsorption-desorption cycles.
Fig. 4
Fig. 4
X-ray diffraction patterns of the spray dried formulations subjected to one DVS sorption cycle
Fig. 5
Fig. 5
Dispersive, specific, and total surface energy data of the spray dried formulations. Error bars show standard deviations (n=4)
Fig. 6
Fig. 6
X-ray diffraction patterns of the spray dried formulations right after preparation, and after storage at 20% or 55% RH for 4 weeks
Fig. 6
Fig. 6
X-ray diffraction patterns of the spray dried formulations right after preparation, and after storage at 20% or 55% RH for 4 weeks
Fig. 7
Fig. 7
Representative SEM images of the SD tobramycin formulation at the start and after 2 and 4 weeks of storage at 20 and 55% RH
Fig. 8
Fig. 8
Representative SEM images of SD colistin formulation at the start and after 2 and 4 weeks of storage at 20 and 55% RH
Fig. 9
Fig. 9
Representative SEM images of SD 1:1 combination formulation at the start and after 2 and 4 weeks of storage at 20 and 55% RH
Fig. 10
Fig. 10
Representative SEM images of SD 1:5 combination formulation at the start and after 2 and 4 weeks of storage at 20 and 55% RH
Fig. 11
Fig. 11
Changes in emitted dose (ED), fine particle fraction (FPF), and emitted fine particle fraction (E-FPF) of spray dried colistin during storage at 20 and 55% RH over 4 weeks. Error bars show standard deviation (n=4). Bars marked with * are significantly different (p < 0.05) from corresponding values at week 0
Fig. 12
Fig. 12
Changes in emitted dose (ED), fine particle fraction (FPF), and emitted fine particle fraction (E-FPF) of spray dried tobramycin during storage at 20 and 55% RH over 4 weeks. Error bars show standard deviations (n=4). Bars marked with * are significantly different (p < 0.05) from corresponding values at week 0
Fig. 12
Fig. 12
Changes in emitted dose (ED), fine particle fraction (FPF), and emitted fine particle fraction (E-FPF) of spray dried tobramycin during storage at 20 and 55% RH over 4 weeks. Error bars show standard deviations (n=4). Bars marked with * are significantly different (p < 0.05) from corresponding values at week 0
Fig. 13
Fig. 13
Changes in emitted dose (ED), fine particle fraction (FPF), and emitted fine particle fraction (E-FPF) of colistin in spray dried combination formulations during storage at 20 and 55% RH over 4 weeks: 1:1 Col-Tob (left) and 1:5 Col-Tob (right). Error bars show standard deviations (n=4). Bars marked with * are significantly different (p < 0.05) from corresponding values at week 0
See this image and copyright information in PMC

References

    1. Nation RL, Li J, Cars O, Couet W, Dudley MN, Kaye KS, et al. Framework for optimisation of the clinical use of colistin and polymyxin B: The prato polymyxin consensus. Lancet Infect Dis. 2015;15(2):225–34. 10.1016/s1473-3099(14)70850-3. - DOI - PubMed
    1. Garonzik SM, Li J, Thamlikitkul V, Paterson DL, Shoham S, Jacob J, et al. Population pharmacokinetics of colistin methanesulfonate and formed colistin in critically ill patients from a multicenter study provide dosing suggestions for various categories of patients. Antimicrob Agents Chemother. 2011;55(7):3284–94. 10.1128/Aac.01733-10. - DOI - PMC - PubMed
    1. Gurjar M. Colistin for lung infection: An update. J Intensive Care. 2015;3(1):1–12. 10.1186/s40560-015-0072-9. - DOI - PMC - PubMed
    1. Yapa SWS, Li J, Patel K, Wilson JW, Dooley MJ, George J, et al. Pulmonary and systemic pharmacokinetics of inhaled and intravenous colistin methanesulfonate in cystic fibrosis patients: Targeting advantage of inhalational administration. Antimicrob Agents Chemother. 2014;58(5):2570–9. 10.1128/aac.01705-13. - DOI - PMC - PubMed
    1. Nang SC, Azad MAK, Velkov T, Zhou Q, Li J. Rescuing the last-line polymyxins: Achievements and challenges. Pharmacol Rev. 2021;73(2):679. 10.1124/pharmrev.120.000020. - DOI - PMC - PubMed

LinkOut - more resources