Isoxyl aerosols for tuberculosis treatment: preparation and characterization of particles

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 microm) 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.

Fig. 1

Scanning electron photomicrographs of a commercial isoxyl (lot no. 130365–149120) at ×50 magnification, b commercial isoxyl (lot no. 130365–149120) at ×1,400 magnification, c commercial isoxyl (lot no. 165311–167669) at ×100 magnification, and the isoxyl particles from antisolvent precipitation by injection method: d VRSA = 1:1 at ×700 magnification, e VRSA = 1:2 at ×700 magnification, and f VRSA = 1:5 at ×15,000 magnification

Fig. 2

Scanning electron micrographs of isoxyl particles precipitated from ethanol a, isopropanol b, acetone c, and tetrahydrofuran d. The micrographs were taken at ×500 magnification

Fig. 3

Scanning electron photomicrographs of the spray-dried isoxyl particles produced by nozzle mixing of isoxyl solutions and water. a–h The particles from conditions 1–8, respectively, in Table I, and i is those from using tetrahydrofuran as solvent. The photomicrographs were taken at ×3,000 magnification

Fig. 4

Particle size distributions of the isoxyl particles measured by laser diffraction (LD). a–h represent particles from spray drying condition 1–8

Fig. 5

Half normal plot of effects of processing parameters on count median diameter a, geometric standard deviation b, circularity c, and yield d of spray-dried isoxyl particles. In the selected range, only yield was influenced by the processing parameters, N₂ flow rate (P = 0.0025), and isoxyl concentration (P = 0.0005). e Square plot of effect of these two parameters on yield

Fig. 6

Particle size distribution a and scanning electron microscopy b of the spray-dried isoxyl particles produced by addition of mannitol (mannitol:isoxyl = 1:4.4)

Fig. 7

Differential scanning calorimetry thermograms of commercial isoxyl (gray) and isoxyl microparticles (black) prepared by spray drying using condition 8. The scanning rates were 40°C/min a and 5°C/min b