Development, Characterization, and Pharmacokinetic Evaluation of a CRV431 Loaded Self-Microemulsifying Drug Delivery System

Authors

  • Daniel J Trepanier ContraVir Pharmaceuticals Inc. Edmonton, Alberta, Canada.
  • Daren R Ure ContraVir Pharmaceuticals Inc, Edmonton, Alberta, Canada.
  • Robert Thomas Foster ContraVir Pharmaceuticals Inc., Edmonton, Alberta, Canada.

DOI:

https://doi.org/10.18433/jpps30245

Abstract

PURPOSE: The objective of this study was to develop a self-microemulsifying drug delivery system (SMEDDS) formulation for the oral delivery of CRV431, a non-immunosuppressive analogue of cyclosporine A. Relative to cyclosporine A, CRV431 is poorly soluble in lipid solvents and thusly presents a challenge for the development of a formulation of sufficient oral bioavailability for clinical use. METHODS: The solubility of CRV431, a cyclosporine derivative, was determined in a range of commonly used surfactants, oils and co-solvents. A pseudo-ternary phase diagram was constructed from the most soluble excipients and prototype formulations, SERIES 1 and SERIES 2 were developed. The pharmacokinetics, following single oral doses of 1 and 3 mg/kg of CRV431 SMEDDS, was studied in healthy human volunteers using liquid chromatography-electrospray ionization-mass spectrometry (LC-ESI-MS). RESULTS: The maximum drug load for the SERIES 1 formulations was less than 40 mg/ml. Manipulation of the excipient ratios allowed for the development of SERIES 2 formulations, which had higher drug loading capacity and stability for CRV431 compared to SERIES 1. Further improvements allowed for the development of an optimized SMEDDS formulation containing up to 90 mg/ml CRV431 and which generated a microemulsion mean particle size of 25 nm when dispersed into aqueous media. The pharmacokinetics of the optimized CRV431 SMEDDS displayed excellent total body exposure and dose-proportional effects in humans, and high drug levels in the liver of rats. CONCLUSIONS: The developed SMEDDS formulation should allow for effective clinical development of CRV431, targeted to the treatment of liver diseases including hepatitis B (HBV), fibrosis, and hepatocellular carcinoma.

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Author Biography

Robert Thomas Foster, ContraVir Pharmaceuticals Inc., Edmonton, Alberta, Canada.

Chief Executive Officer

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Published

2018-11-24

How to Cite

Trepanier, D. J., Ure, D. R., & Foster, R. T. (2018). Development, Characterization, and Pharmacokinetic Evaluation of a CRV431 Loaded Self-Microemulsifying Drug Delivery System. Journal of Pharmacy &Amp; Pharmaceutical Sciences, 21(1s), 335s–348s. https://doi.org/10.18433/jpps30245

Issue

Section

Pharmaceutical Sciences; Original Research Articles