Formulation studies of InhA inhibitors and combination therapy to improve efficacy against Mycobacterium tuberculosis

Abstract

Summary Previously, structure-based drug design was used to develop substituted diphenyl ethers with potency against the Mycobacterium tuberculosis (Mtb) enoyl-ACP reductase (InhA), however, the highly lipophilic centroid compound, SB-PT004, lacked sufficient efficacy in the acute murine Mtb infection model. A next generation series of compounds were designed with improved specificity, potency against InhA, and reduced cytotoxicity in vitro, but these compounds also had limited solubility. Accordingly, solubility and pharmacokinetics studies were performed to develop formulations for this class and other experimental drug candidates with high logP values often encountered in drug discovery. Lead diphenyl ethers were formulated in co-solvent and Self-Dispersing Lipid Formulations (SDLFs) and evaluated in a rapid murine Mtb infection model that assesses dissemination to and bacterial burden in the spleen. In vitro synergy studies were performed with the lead diphenyl ether compounds, SB-PT070 and SB-PT091, and rifampin (RIF), which demonstrated an additive effect, and that guided the in vivo studies. Combinatorial therapy in vivo studies with these compounds delivered in our Self-Micro Emulsifying Drug Delivery System (SMEDDS) resulted in an additional 1.4 log10 CFU reduction in the spleen of animals co-treated with SB-PT091 and RIF and an additional 1.7 log10 reduction in the spleen with animals treated with both SB-PT070 and RIF.

Rationalizing the Binding Kinetics for the Inhibition of the Burkholderia pseudomallei FabI1 Enoyl-ACP Reductase

“…This inoculum was then delivered dropwise in alternating nostrils. Ceftazidime was formulated in PBS and test compounds in a lipid-based delivery system as previously described. , Compounds were delivered intraperitoneally, b.i.d. (twice daily) starting at the time of infection.…”

Sistemas de entrega de fármacos autoemulsificables: una plataforma de desarrollo alternativa para la industria farmacéutica colombiana

“…La fase oleosa representa uno de los principales componentes en los SEDDS puesto que es la encargada de solubilizar el principio activo y de esta dependerá la cantidad máxima que puede soportar el sistema [94][95][96]. Una mayor solubilidad del principio activo en la fase oleosa reduce los requerimientos de tensioactivos minimizando así los efectos tóxicos causados por las altas concentraciones de estos [97].…”

“…A menudo se agregan cosolventes a la formulación para facilitar el proceso de dispersión o aumentar la solubilidad del principio activo en el sistema [75]. Sin embargo, un problema potencial con los cosolventes es su alta miscibilidad con la fase acuosa, lo que significa que el sistema puede perder su capacidad solvente al entrar en contacto con los fluidos gastrointestinales y aumentar el riesgo de precipitación del principio activo [81,95]. Por lo tanto, es recomendable usar pequeñas proporciones de cosolventes en las formulaciones de SEDDS y seleccionar aquellos que permanezcan en la interfaz aceite-agua [19].…”

“…La tasa y el grado de absorción de los principios activos poco solubles en agua está controlada y limitada por el proceso de disolución [135]. Uno de los mecanismos por los cuales los SEDDS aumentan la biodisponibilidad de los principios activos se da debido a que estas formulaciones los presentan en un estado disuelto previo a la administración, lo que evita el paso de disolución que generalmente, limita la tasa de absorción de las formas cristalinas debido a las interacciones soluto-soluto [95,136].…”