Echinomycin is quinoxaline-containing depsipeptide antibiotic and proposed to treat acute myeloid leukemia (AML) as molecular targeting HIF-1a in cancer stem cells (CSCs). Through targeting HIF-1a, echinomycin selectively eliminates CSCs in hematological tumors. Formulation of echinomycin for injection was challenging due to its hydrophobic nature. Cyclodextrins (CDs) are a group of cyclic oligiosaccharides, consisting of 6 or more 1-4 linked aanhydroglucose moieties. CDs have hydrophobic cavity and hydrophilic exterior. Here we report preformulation study in development of echinomycin for injection formulation using various CDs. Also stability studies of the drug in the formulation over years using HPLC assay method will be reported. Cavasol and Captisol (CDs) were tested and Cavasol was chosen for further study. Study variations to modify the proper formulation method were including stirring time with magnetic stirrer, type of syringe filter, concentration of solution, and type of diluent. Stress condition analysis performed with echinomycin-cavasol formulation stored in 0.1N HCl, 0.1N NaOH, and 3% H2O2 at RT and 60°C for 24 hours. HPLC assay procedure is a gradient assay using water and acetonitrile as mobile phase. A Waters XBridge BEH C18 Column was used for elution in 40°C and detection was set at 254 nm. The analyses of echinomycin-cavasol formulation under stress conditions indicated that the assay procedure is stability indicating and linearity of the procedure was established with six points over the concentration range of 0.004 to 0.227 mg/mL (R2=0.9998). Echinomycin injection (2mL of 20 mcg/mL in pre-siliconized 2mL clear type I vial) was made and on going stability study performs using products stored in two different temperature conditions. Echinomycin injections are stable for at least eighteen months when stored in freezer while for only one month in refrigerated condition. Continuous stability monitoring over the course of the clinical trial will be conducted.

Preformulation analysis and stability of hydrophobic small molecular echinomycin for injection formulation

2019 Fall National Meeting

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