Lipophilic salts of poorly soluble compounds to enable high-dose lipidic SEDDS formulations in drug discovery

Abstract Self-emulsifying drug delivery systems (SEDDS) have been used to solubilize poorly water-soluble drugs to improve exposure in high-dose pharmacokinetic (PK) and toxicokinetic(TK) studies. However, the absorbable dose is often limited by drug solubility in the lipidic SEDDS vehicle. This study focuses on increasing solubility and drug loading of ionizable drugs in SEDDS vehicles using lipophiliccounterions to prepare lipophilicsalts of drugs. SEDDS formulations of two lipophilicsalts— atazanavir-2-naphthalene sulfonic acid (ATV-2-NSA) and atazanavir-dioctyl sulfosuccinic acid (ATV-Doc)—were characterized and their performance compared to atazanavir(ATV) free baseformulated as an aqueous crystalline suspension, an organic solution, and a SEDDS suspension, using in vitro , in vivo , and in silico methods. ATV-2-NSA exhibited ∼6-fold increased solubility in a SEDDS vehicle, allowing emulsion dosing at 12 mg/mL. In rat PK studies at 60 mg/kg, the ATV-2-NSA SEDDS emulsion had comparable exposure to the free-basesolution, but with less variability, and had better exposure at high dose than aqueous suspensions of ATV free base. Trends in dose-dependent exposure for various formulations were consistent with GastroPlus™ modeling. Results suggest use of lipophilicsalts is a valuable approach for delivering poorly soluble compounds at high doses in Discovery.