TY - JOUR
T1 - Improving solubility and oral bioavailability of a novel antimalarial prodrug
T2 - comparing spray-dried dispersions with self-emulsifying drug delivery systems
AU - Potharaju, Suresh
AU - Mutyam, Shravan Kumar
AU - Liu, Mingtao
AU - Green, Carol
AU - Frueh, Lisa
AU - Nilsen, Aaron
AU - Pou, Sovitj
AU - Winter, Rolf
AU - Riscoe, Michael K.
AU - Shankar, Gita
N1 - Funding Information:
US Department of Defense Peer Reviewed Medical Research Program10.13039/501100004477 United States National Institutes of Health Veterans Affairs Merit Review Program Research funds reported for this publication were provided by the US Department of Defense Peer Reviewed Medical Research Program (Log #PR130649; Contract #W81XWH-14-1-0447; MKR and GS). Funds were also provided by the United States National Institutes of Health award number AI100569 (MKR) and by the Veterans Affairs Merit Review Program Award number i01 BX003312 (MKR). Authors wish to thank Dr. Susan A. Charman of Centre for Drug Candidate Optimization, Monash Institute of Pharmaceutical Sciences, Australia for providing intravenous pharmacokinetic data of ELQ-300 in rats, which was used for calculating bioavailability of SEDDS and SDD formulations. Authors also wish to thank Dr. Chun Yang for the bioanalytical analysis and Kathleen O’Loughlin for the coordinating pharmacokinetic study activities with the oral formulations. Authors further acknowledge the following:‘The US Army Medical Research Acquisition Activity, 820 Chandler Street, Fort Detrick MD 21702-5014 is the awarding and administering acquisition office.’ ‘Opinions, interpretations, conclusions and recommendation are of those of the author and are not necessarily endorsed by the Department of Defense.’ ‘In conducting research using animals, the investigator(s) adheres to the laws of the United States and regulations of the Department of Agriculture.’ Include required assurances, approvals, documents, and information specified on the Animal Care and Use Review Office (ACURO) website (https://mrmc.detrick.army.mil/index.cfm?pageid=Research_Protections.acuro&rn=1).
Publisher Copyright:
© 2020, © 2020 Informa UK Limited, trading as Taylor & Francis Group.
PY - 2020/5/27
Y1 - 2020/5/27
N2 - 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.
AB - 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.
KW - Antimalarial drugs
KW - amorphous form
KW - oral bioavailability
KW - self-emulsifying drug delivery systems (SEDDS)
KW - spray-dried dispersions (SDD)
UR - http://www.scopus.com/inward/record.url?scp=85079426921&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85079426921&partnerID=8YFLogxK
U2 - 10.1080/10837450.2020.1725893
DO - 10.1080/10837450.2020.1725893
M3 - Article
C2 - 32031478
AN - SCOPUS:85079426921
SN - 1083-7450
VL - 25
SP - 625
EP - 639
JO - Pharmaceutical Development and Technology
JF - Pharmaceutical Development and Technology
IS - 5
ER -