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A Spray-Dried Combination of Capreomycin and CPZEN-45 for Inhaled Tuberculosis Therapy.
J Pharm Sci. 2019 10; 108(10):3302-3311.JP

Abstract

Tuberculosis (TB) remains the single most serious infectious disease attributable to a single-causative organism. A variety of drugs have been evaluated for pulmonary delivery as dry powders: capreomycin sulfate has shown efficacy and was safely delivered by inhalation at high doses to human volunteers, whereas CPZEN-45 is a new drug that has also been shown to kill resistant TB. The studies here combine these drugs-acting by different mechanisms-as components of single particles by spray-drying, yielding a new combination drug therapy. The spray-dried combination powder was prepared in an aerodynamic particle size range suitable for pulmonary delivery. Physicochemical storage stability was demonstrated for a period of 6 months. The spray-dried combination powders of capreomycin and CPZEN-45 have only moderate affinity for mucin, indicating that delivered drug will not be bound by these mucins in the lung and available for microbicidal effects. The pharmacokinetics of disposition in guinea pigs demonstrated high local concentrations of drug following direct administration to the lungs and subsequent systemic bioavailability. Further studies are required to demonstrate the in vivo efficacy of the combination to confirm the therapeutic potential of this novel combination.

Authors+Show Affiliations

PAI Life Sciences, Seattle, Washington 98102; Department of Immunology, University of Washington School of Medicine, Seattle, Washington 98109.RTI International, Research Triangle Park, North Carolina 27709; Department of Pharmacoengineering and Molecular Pharmaceutics, Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, North Carolina 27599.RTI International, Research Triangle Park, North Carolina 27709.Infectious Disease Research Institute (IDRI), Seattle, Washington 98102.Infectious Disease Research Institute (IDRI), Seattle, Washington 98102.RTI International, Research Triangle Park, North Carolina 27709; Department of Pharmacoengineering and Molecular Pharmaceutics, Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, North Carolina 27599.PAI Life Sciences, Seattle, Washington 98102; Infectious Disease Research Institute (IDRI), Seattle, Washington 98102. Electronic address: darrick.carter@pailifesciences.com.

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Research Support, U.S. Gov't, P.H.S.

Language

eng

PubMed ID

31152746

Citation

Pitner, Ragan A., et al. "A Spray-Dried Combination of Capreomycin and CPZEN-45 for Inhaled Tuberculosis Therapy." Journal of Pharmaceutical Sciences, vol. 108, no. 10, 2019, pp. 3302-3311.
Pitner RA, Durham PG, Stewart IE, et al. A Spray-Dried Combination of Capreomycin and CPZEN-45 for Inhaled Tuberculosis Therapy. J Pharm Sci. 2019;108(10):3302-3311.
Pitner, R. A., Durham, P. G., Stewart, I. E., Reed, S. G., Cassell, G. H., Hickey, A. J., & Carter, D. (2019). A Spray-Dried Combination of Capreomycin and CPZEN-45 for Inhaled Tuberculosis Therapy. Journal of Pharmaceutical Sciences, 108(10), 3302-3311. https://doi.org/10.1016/j.xphs.2019.05.024
Pitner RA, et al. A Spray-Dried Combination of Capreomycin and CPZEN-45 for Inhaled Tuberculosis Therapy. J Pharm Sci. 2019;108(10):3302-3311. PubMed PMID: 31152746.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - A Spray-Dried Combination of Capreomycin and CPZEN-45 for Inhaled Tuberculosis Therapy. AU - Pitner,Ragan A, AU - Durham,Phillip G, AU - Stewart,Ian E, AU - Reed,Steven G, AU - Cassell,Gail H, AU - Hickey,Anthony J, AU - Carter,Darrick, Y1 - 2019/05/29/ PY - 2019/02/14/received PY - 2019/05/17/revised PY - 2019/05/21/accepted PY - 2019/6/4/pubmed PY - 2020/8/20/medline PY - 2019/6/2/entrez KW - CPZEN-45 KW - aerosols KW - capreomycin KW - drug combination KW - spray-drying KW - tuberculosis SP - 3302 EP - 3311 JF - Journal of pharmaceutical sciences JO - J Pharm Sci VL - 108 IS - 10 N2 - Tuberculosis (TB) remains the single most serious infectious disease attributable to a single-causative organism. A variety of drugs have been evaluated for pulmonary delivery as dry powders: capreomycin sulfate has shown efficacy and was safely delivered by inhalation at high doses to human volunteers, whereas CPZEN-45 is a new drug that has also been shown to kill resistant TB. The studies here combine these drugs-acting by different mechanisms-as components of single particles by spray-drying, yielding a new combination drug therapy. The spray-dried combination powder was prepared in an aerodynamic particle size range suitable for pulmonary delivery. Physicochemical storage stability was demonstrated for a period of 6 months. The spray-dried combination powders of capreomycin and CPZEN-45 have only moderate affinity for mucin, indicating that delivered drug will not be bound by these mucins in the lung and available for microbicidal effects. The pharmacokinetics of disposition in guinea pigs demonstrated high local concentrations of drug following direct administration to the lungs and subsequent systemic bioavailability. Further studies are required to demonstrate the in vivo efficacy of the combination to confirm the therapeutic potential of this novel combination. SN - 1520-6017 UR - https://www.unboundmedicine.com/medline/citation/31152746/A_Spray_Dried_Combination_of_Capreomycin_and_CPZEN_45_for_Inhaled_Tuberculosis_Therapy_ DB - PRIME DP - Unbound Medicine ER -