Category: Formulation and Quality
Purpose: We improved aqueous solubility and oral bioavailability of a novel antimalarial agent (ELQ-331, an alkoxy carbonate alkyl ester of ELQ-300) by developing spray-dried dispersions (SDDs) and a self-emulsifying drug delivery system (SEDDS).
Methods: We prepared the SDDs by blending ELQ-331 with Soluplus® polymer carrier and Aeroperl® 300 Pharma excipient at 1:4:2 (w:w:w) ratio. We characterized drug content and saturation solubility in biorelevant buffers at time =0 and after storing at 25°C/60%RH and 40°C/75%RH for 12 weeks. For SEDDS, we dissolved ELQ-331 in oils, surfactants, and cosurfactants and characterized drug content, spontaneous emulsification, dilution effect, and droplet size distribution using laser diffraction. We studied pharmacokinetics of oral SDD and SEDDS formulations in rats.
Results: The SDD ELQ-331 formed stable amorphous solid dispersions with 10X greater solubility in FaSSIF (fast stated simulated intestinal fluid) buffer than non-formulated pure drug controls. Sodium lauryl sulfate (20% w/w) was added externally to ELQ-331 SDDs, improving solubility ~28.5X vs. non-formulated drug. ELQ-331 SDD was stable for at least 12 weeks at 25°C/60%RH and 40°C/75%RH. The SEDDS had good self-emulsifying characteristics (spontaneous formation of bluish emulsion, clarity) and were stable on further dilution with small emulsion droplet sizes and a narrow particle distribution. The ELQ-331 rapidly converted to ELQ-300 (base form) soon after oral administration in rats. Exposure levels of ELQ-300 based on AUClast and AUCinf were about 1.4-fold higher in SEDDS than SDD formulations.
Conclusion: Poorly soluble drugs like ELQ-331 can be formulated using SDDs or SEDDS to improve solubility and oral bioavailability.
Gita Shankar– Menlo Park, California
Suresh Potharaju– Menlo Park, California
Shravan Mutyam– Menlo Park, California
Michael Riscoe– Portland, Oregon
Gita Shankar– Director, Formulation R&D, SRI International, Menlo Park, CA