Isoxyl Aerosols for Tuberculosis Treatment: Preparation and Characterization of Particles

Abstract

Abstract. Isoxyl is a potent antituberculosis drug effective in treating various multidrug-resistant strains in the absence of known side effects. Isoxyl has been used exclusively, but infrequently, via the oral route and has exhibited very poor and highly variable bioavailability due to its sparing solubility in water. These properties resulted in failure of some clinical trials and, consequently, isoxyl's use has been limited. Delivery of isoxyl to the lungs, a major site of Mycobacterium tuberculosis infection, is an attractive alternative route of administration that may rescue this abandoned drug for a disease that urgently requires new therapies. Particles for pulmonary delivery were prepared by antisolvent precipitation. Nanofibers with a width of 200 nm were obtained by injecting isoxyl solution in ethanol to water at a volume ratio of solvent to antisolvent of 1:5. Based on this preliminary result, a well-controlled method, involving nozzle mixing, was employed to prepare isoxyl particles. All the particles were 200 to 400 nm in width but had different lengths depending on properties of the solvents. However, generating these nanoparticles by simultaneous spray drying produced isoxyl microparticles (Feret's diameter, 1.19-1.77 μm) with no discernible nanoparticle substructure. The bulking agent, mannitol, helped to prevent these nanoparticles from agglomeration during process and resulted in nanoparticle aggregates in micron-sized superstructures. Future studies will focus on understanding difference of these isoxyl microparticles and nanoparticles/nanoparticle aggregates in terms of in vivo disposition and efficacy.

Importance of the Genetic Diversity within the Mycobacterium tuberculosis Complex for the Development of Novel Antibiotics and Diagnostic Tests of Drug Resistance

“…The same applies to the duplication of the racemase Alr (Rv3423c), the target of cycloserine (17,44). Third, MICs for isoxyl, an antibiotic which was used in the 1960s for the treatment of TB and has since then emerged as a potential candidate for the treatment of drug-resistant TB, might be affected due to the duplication of DesA3 (Rv3229c), a stearoyl coenzyme A ⌬ 9 -desaturase required for oleic acid biosynthesis that is inhibited by this drug (46, 88,116,125,163). Fourth and last, the effect of the duplication of fbiA (Rv3261) and fbiB (Rv3262) on susceptibility to the three nitroimidazoles (metronidazole, delamanid, and PA-824), which are currently in phase 2 and 3 clinical trials, has to be clarified (33,65).…”

Optimization of inhaled therapies for tuberculosis: The role of macrophages and dendritic cells

“…[12], [58], [59] and [61] Thus, aerosol delivery of BCG vaccine prepared as a spray-dried nanomicroparticle aerosol, [57], [58] and [59] or liposome, chitosan and PLGA-PEI DNA vaccine [56] and [62] have also been used in mice and guinea pigs to enhance pulmonary anti-microbial activity against M. tuberculosis infection. Aerosol delivery of the BCG nanomicroparticle to normal guinea pigs subsequently challenged with virulent M. tuberculosis significantly reduced bacterial burden and lung pathology both relative to untreated animals and to control animals immunized with the standard parenteral BCG.…”

Pharmacokinetic and pharmacodynamic implications in inhalable antimicrobial therapy

“…The aerosol inhalation of kanamycin, an aminoglycoside, was found to be safe in 200 bronchopulmonary suppurative tuberculosis patients [18]. Kanamycin, clofazimine, gentamicin, ofloxacin, streptomycin and neomycin were found to be safe and effective in smaller clinical studies [19][20][21].…”