title: Capreomycin supergenerics for pulmonary tuberculosis treatment: preparation, in vitro, and in vivo characterization.
abstract: The pulmonary route is one of the main strategies investigated to improve tuberculosis therapy. The aim of this study was to develop a simple and scalable method to produce capreomycin inhalable powders to use as supergeneric. In vitro antimycobacterial activity and in vivo acute toxicity were assessed using agar proportion susceptibility test on Mycobacterium tuberculosis and chicken chorioallantoic membrane assay, respectively. Capreomycin and three different hydrophobic counterions, namely oleate, linoleate, and linolenate, were combined in solution to obtain hydrophobic ion-pairs that were successively spray-dried. Ion-pairing efficiency was influenced by the spray-dryer employed to produce the powder. In the case of capreomycin oleate, both instruments, mini and nano spray-dryer, were suitable to maintain a high ion-paired content, while for capreomycin linoleate and linolenate, mini spray-dryer was the most appropriate instrument. The three formulations showed morphology and particle sizes potentially suitable for inhalation. Capreomycin oleate and linoleate showed the same efficacy of capreomycin sulfate against M. tuberculosis, while capreomycin linolenate showed a reduced efficacy, even though strain growth was inhibited at 10(-4) mycobacterial inoculum. In vivo acute toxicity studies evidenced the lowest toxic potential for capreomycin oleate when compared to the single components or the other two salts. Overall, capreomycin oleate seems to possess the most promising characteristics to be used as supergenerics in pulmonary tuberculosis treatment.
authors.affiliation: Dipartimento di Chimica e Tecnologia del Farmaco, Università degli Studi di Perugia, Perugia, Italy. lululi@unipg.it
authors.forename: Aurélie
authors.initials: A
authors.lastname: Schoubben
authors.forename: Paolo
authors.initials: P
authors.lastname: Blasi
authors.forename: Maria Luisa
authors.initials: ML
authors.lastname: Marenzoni
authors.forename: Lanfranco
authors.initials: L
authors.lastname: Barberini
authors.forename: Stefano
authors.initials: S
authors.lastname: Giovagnoli
authors.forename: Carlo
authors.initials: C
authors.lastname: Cirotto
authors.forename: Maurizio
authors.initials: M
authors.lastname: Ricci
mesh_terms: D000818:Animals; D000995:Antitubercular Agents / Q000737:chemistry / Q000627:therapeutic use*; D002207:Capreomycin / Q000737:chemistry / Q000627:therapeutic use*; D002642:Chick Embryo; D006801:Humans; D066298:In Vitro Techniques; D008826:Microbial Sensitivity Tests; D008855:Microscopy, Electron, Scanning; D009169:Mycobacterium tuberculosis / Q000187:drug effects; D011208:Powders; D014397:Tuberculosis, Pulmonary / Q000188:drug therapy* / Q000382:microbiology
chemical_list: D000995:Antitubercular Agents; D011208:Powders; D002207:Capreomycin