Improving solubility and oral bioavailability of a novel antimalarial prodrug: comparing spray-dried dispersions with self-emulsifying drug delivery systems

• Published in: Pharmaceutical development and technology Vol. 25; no. 5; p. 625
• Main Authors: Potharaju, Suresh, Mutyam, Shravan Kumar, Liu, Mingtao, Green, Carol, Frueh, Lisa, Nilsen, Aaron, Pou, Sovitj, Winter, Rolf, Riscoe, Michael K, Shankar, Gita
• Format: Journal Article
• Language: English
• Published: England 27.05.2020
• Subjects: Administration, Oral; Animals; Antimalarials - administration & dosage; Antimalarials - blood; Antimalarials - chemistry; Biological Availability; Drug Compounding - methods; Drug Delivery Systems - methods; Drug Stability; Emulsions; Excipients - chemistry; Male; Molecular Structure; Polyethylene Glycols - chemistry; Polyvinyls - chemistry; Prodrugs - administration & dosage; Prodrugs - chemistry; Quinolones - administration & dosage; Quinolones - blood; Quinolones - chemistry; Rats, Sprague-Dawley; Solubility; oral bioavailability; amorphous form; self-emulsifying drug delivery systems (SEDDS); spray-dried dispersions (SDD); Antimalarial drugs
• ISSN: 1097-9867
• DOI: 10.1080/10837450.2020.1725893

To improve the solubility and oral bioavailability of a novel antimalarial agent ELQ-331(a prodrug of ELQ-300), spray-dried dispersions (SDD) and a self-emulsifying drug delivery system (SEDDS) were developed. SDD were prepared with polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer (Soluplus ) polymer carrier and Aeroperl 300 Pharma and characterized by differential scanning calorimetry, powder X-ray diffraction. For SEDDS, solubility in oils, surfactants, and co-surfactants was determined and ternary phase diagram was constructed to show self-emulsifying area. SEDDS were characterized for spontaneous emulsification and droplet size distribution. The amorphous ELQ-331 SDD improved the solubility to 10× in fast-state simulated intestinal fluid and addition of sodium lauryl sulphate externally to SDDs further improved the solubility to ∼28.5× versus non-formulated drug. SEDDS had good self-emulsifying characteristics with small emulsion droplet sizes and narrow particle distribution. Oral pharmacokinetic studies for SDD and SEDDS formulations were performed in rats. The ELQ-331 rapidly converted to ELQ-300 soon after oral administration in rats. Exposure levels of ELQ-300 were about 1.4-fold higher (based on AUC) in SEDDS than SDD formulations. Poorly soluble drugs like ELQ-331 can be formulated using SDD or SEDDS to improve solubility and oral bioavailability.