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Effects of the antibiotic component on in-vitro bacterial killing, physico-chemical properties, aerosolization and dissolution of a ternary-combinational inhalation powder formulation of antibiotics for pan-drug resistant Gram-negative lung infections.
Int J Pharm. 2019 Apr 20; 561:102-113.IJ

Abstract

Combinational antibiotic formulations have emerged as an important strategy to combat antibiotic resistance. The main objective of this study was to examine effects of individual components on the antimicrobial activity, physico-chemical properties, aerosolization and dissolution of powder aerosol formulations when three synergistic drugs were co-spray dried. A ternary dry powder formulation consisting of meropenem (75.5 %w/w), colistin (15.1 %w/w) and rifampicin (9.4 %w/w) at the selected ratio was produced by spray drying. The ternary formulation was characterized for in-vitro antibacterial activity, physico-chemical properties, surface composition, aerosol performance and dissolution. All of the formulations demonstrated excellent aerosolization behavior achieving a fine particle fraction of >70%, which was substantially higher than those for the Meropenem-SD and Colistin-Meropenem formulations. The results indicated that rifampicin controlled the surface morphology of the ternary and binary combination formulations resulting in the formation of highly corrugated particles. Advanced characterization of surface composition by XPS supported the hypothesis that rifampicin was enriched on the surface of the combination powder formulations. All spray-dried formulations were amorphous and absorbed substantial amount of water at the elevated humidity. Storage at the elevated humidity caused a substantial decline in aerosolization performance for the Meropenem-SD and Colistin-Meropenem, which was attributed to increased inter-particulate capillary forces or particle fusion. In contrast, the ternary combination and binary Meropenem-Rifampicin formulations showed no change in aerosol performance at the elevated storage humidity conditions; attributable to the enriched hydrophobicity of rifampicin on the particle surface that acted as a barrier against moisture condensation and particle fusion. Interestingly, in the ternary formulation rifampicin enrichment on the surface did not interfere with the dissolution of other two components (i.e. meropenem and colistin). Our study provides an insight on the impact of each component on the performance of co-spray dried combinational formulations.

Authors+Show Affiliations

Department of Industrial and Physical Pharmacy, College of Pharmacy, Purdue University, 575 Stadium Mall Drive, West Lafayette, IN 47907, USA.Department of Industrial and Physical Pharmacy, College of Pharmacy, Purdue University, 575 Stadium Mall Drive, West Lafayette, IN 47907, USA.Department of Industrial and Physical Pharmacy, College of Pharmacy, Purdue University, 575 Stadium Mall Drive, West Lafayette, IN 47907, USA.Department of Industrial and Physical Pharmacy, College of Pharmacy, Purdue University, 575 Stadium Mall Drive, West Lafayette, IN 47907, USA.Biomedicine Discovery Institute and Department of Microbiology, Monash University, Clayton, Victoria 3800, Australia.Biomedicine Discovery Institute and Department of Microbiology, Monash University, Clayton, Victoria 3800, Australia.Birck Nanotechnology Center, Purdue University, West Lafayette, IN 47907, USA.Department of Pharmacology & Therapeutics, Faculty of Medicine, Dentistry and Health Sciences, The University of Melbourne, Parkville, Victoria 3010, Australia.Biomedicine Discovery Institute and Department of Microbiology, Monash University, Clayton, Victoria 3800, Australia.Department of Industrial and Physical Pharmacy, College of Pharmacy, Purdue University, 575 Stadium Mall Drive, West Lafayette, IN 47907, USA. Electronic address: tonyzhou@purdue.edu.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

30797863

Citation

Mangal, Sharad, et al. "Effects of the Antibiotic Component On In-vitro Bacterial Killing, Physico-chemical Properties, Aerosolization and Dissolution of a Ternary-combinational Inhalation Powder Formulation of Antibiotics for Pan-drug Resistant Gram-negative Lung Infections." International Journal of Pharmaceutics, vol. 561, 2019, pp. 102-113.
Mangal S, Huang J, Shetty N, et al. Effects of the antibiotic component on in-vitro bacterial killing, physico-chemical properties, aerosolization and dissolution of a ternary-combinational inhalation powder formulation of antibiotics for pan-drug resistant Gram-negative lung infections. Int J Pharm. 2019;561:102-113.
Mangal, S., Huang, J., Shetty, N., Park, H., Lin, Y. W., Yu, H. H., Zemlyanov, D., Velkov, T., Li, J., & Zhou, Q. T. (2019). Effects of the antibiotic component on in-vitro bacterial killing, physico-chemical properties, aerosolization and dissolution of a ternary-combinational inhalation powder formulation of antibiotics for pan-drug resistant Gram-negative lung infections. International Journal of Pharmaceutics, 561, 102-113. https://doi.org/10.1016/j.ijpharm.2019.02.018
Mangal S, et al. Effects of the Antibiotic Component On In-vitro Bacterial Killing, Physico-chemical Properties, Aerosolization and Dissolution of a Ternary-combinational Inhalation Powder Formulation of Antibiotics for Pan-drug Resistant Gram-negative Lung Infections. Int J Pharm. 2019 Apr 20;561:102-113. PubMed PMID: 30797863.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Effects of the antibiotic component on in-vitro bacterial killing, physico-chemical properties, aerosolization and dissolution of a ternary-combinational inhalation powder formulation of antibiotics for pan-drug resistant Gram-negative lung infections. AU - Mangal,Sharad, AU - Huang,Jiayang, AU - Shetty,Nivedita, AU - Park,Heejun, AU - Lin,Yu-Wei, AU - Yu,Heidi H, AU - Zemlyanov,Dmitry, AU - Velkov,Tony, AU - Li,Jian, AU - Zhou,Qi Tony, Y1 - 2019/02/21/ PY - 2018/11/18/received PY - 2019/02/02/revised PY - 2019/02/08/accepted PY - 2019/2/25/pubmed PY - 2019/8/20/medline PY - 2019/2/25/entrez KW - Aerosol performance KW - Dissolution KW - Dry powder inhaler KW - Solubility KW - Spray drying KW - Ternary combination SP - 102 EP - 113 JF - International journal of pharmaceutics JO - Int J Pharm VL - 561 N2 - Combinational antibiotic formulations have emerged as an important strategy to combat antibiotic resistance. The main objective of this study was to examine effects of individual components on the antimicrobial activity, physico-chemical properties, aerosolization and dissolution of powder aerosol formulations when three synergistic drugs were co-spray dried. A ternary dry powder formulation consisting of meropenem (75.5 %w/w), colistin (15.1 %w/w) and rifampicin (9.4 %w/w) at the selected ratio was produced by spray drying. The ternary formulation was characterized for in-vitro antibacterial activity, physico-chemical properties, surface composition, aerosol performance and dissolution. All of the formulations demonstrated excellent aerosolization behavior achieving a fine particle fraction of >70%, which was substantially higher than those for the Meropenem-SD and Colistin-Meropenem formulations. The results indicated that rifampicin controlled the surface morphology of the ternary and binary combination formulations resulting in the formation of highly corrugated particles. Advanced characterization of surface composition by XPS supported the hypothesis that rifampicin was enriched on the surface of the combination powder formulations. All spray-dried formulations were amorphous and absorbed substantial amount of water at the elevated humidity. Storage at the elevated humidity caused a substantial decline in aerosolization performance for the Meropenem-SD and Colistin-Meropenem, which was attributed to increased inter-particulate capillary forces or particle fusion. In contrast, the ternary combination and binary Meropenem-Rifampicin formulations showed no change in aerosol performance at the elevated storage humidity conditions; attributable to the enriched hydrophobicity of rifampicin on the particle surface that acted as a barrier against moisture condensation and particle fusion. Interestingly, in the ternary formulation rifampicin enrichment on the surface did not interfere with the dissolution of other two components (i.e. meropenem and colistin). Our study provides an insight on the impact of each component on the performance of co-spray dried combinational formulations. SN - 1873-3476 UR - https://www.unboundmedicine.com/medline/citation/30797863/Effects_of_the_antibiotic_component_on_in_vitro_bacterial_killing_physico_chemical_properties_aerosolization_and_dissolution_of_a_ternary_combinational_inhalation_powder_formulation_of_antibiotics_for_pan_drug_resistant_Gram_negative_lung_infections_ DB - PRIME DP - Unbound Medicine ER -