Eshelman School of Pharmacy, Division of Molecular Pharmaceutics, University of North Carolina at Chapel Hill, Campus Box #7571, 1310 Kerr Hall, Chapel Hill, North Carolina 27599, USA.
AAPS PharmSciTech. 2010 Jun;11(2):538-49. doi: 10.1208/s12249-010-9415-y. Epub 2010 Mar 26.
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.
异羟肟酸是一种有效的抗结核药物，可有效治疗各种已知无副作用的多药耐药株。异羟肟酸一直被专门但很少通过口服途径使用，由于其在水中的溶解度低，其生物利用度非常差且高度可变。这些特性导致一些临床试验失败，因此异羟肟酸的使用受到限制。将异羟肟酸递送到肺部，这是结核分枝杆菌感染的主要部位，是一种有吸引力的替代给药途径，可能会挽救这种被废弃的药物，因为这种疾病迫切需要新的治疗方法。用于肺部给药的颗粒通过反溶剂沉淀制备。通过将异羟肟酸溶液以溶剂与反溶剂的体积比为 1:5 注入乙醇至水中，获得宽度为 200nm 的纳米纤维。基于这一初步结果，采用喷嘴混合的方法，采用一种可控性好的方法制备异羟肟酸颗粒。所有颗粒的宽度均为 200 至 400nm，但根据溶剂的性质，长度不同。然而，通过同时喷雾干燥产生的这些纳米颗粒产生了异羟肟酸微米颗粒（Feret 直径为 1.19-1.77 微米），没有明显的纳米颗粒亚结构。填充剂甘露醇有助于防止这些纳米颗粒在过程中聚集，并导致微米级超结构中的纳米颗粒聚集体。未来的研究将集中于理解这些异羟肟酸微米颗粒和纳米颗粒/纳米颗粒聚集体在体内处置和功效方面的差异。
