(M1130-03-18) Developing In Vitro Lipolysis Model for Real-Time Analysis of Drug Concentrations during Digestion of Lipid-Based Formulations

Purpose: For poorly soluble drugs, which represent up to 80% of all small drug molecules in modern development pipelines, Lipid-Based Formulations (LBF) are an attractive enabling technology to enhance oral bioavailability for such drugs. In vitro lipolysis assays have been developed to study the impact of LBF digestion on formulation performance, predominantly using crude porcine pancreatin extract as the lipase (1). However, the presence of porcine pancreatin extract hampers the in-line analytical opportunities for monitoring drug concentration in real time, resulting in slower and resource intensive off-line analysis (2). The objective of this study was to reengineer the current in vitro lipolysis model by redefining the digestion conditions with the goal of developing in-line UV measurements to monitor drug concentrations in real time during formulation digestion.

Methods: The pH-stat setup was used to maintain the pH during digestion by continuous titration with NaOH. A range of lipases was explored to assess digestion of a long-chain and medium-chain LBF, including pancreatin, immobilized lipases (from Candida Antarctica B, Rhizomucor miehei, and Thermomyces lanuginosus), and liquid lipases (from Candida Antarctica A and B, Rhizomucor miehei, and Thermomyces lanuginosus).

Results: The results indicated that the sn-1,3 specific lipases offered a comparable extent of digestion and similar digestion kinetics compared to the crude pancreatin extract, whereas the non-specific lipases did not yield any comparable digestion.

Conclusion: These sn-1,3 specific lipases offer the advantages that they can be easily integrated for in-line UV analysis. Further studies will be explored to investigate which of these can facilitate in-line and bio-predictive evaluation of lipolysis.

References: (1) O’Dwyer, P., Box, K. J., Koehl, N. J., Bennet-Lenane, H., Reppas, C., Holm, R., Kuentz, M., and Griffin, B. T., Novel Biphasic Lipolysis Method To Predict in Vivo Performance of Lipid-Based Formulations, Mol. Pharmaceutics, Volume 17, issue 9, August 2020, pages 3342-335227
(2) Kuentz, M. Analytical technologies for real-time drug dissolution and precipitation testing on a small scale, Journal of Pharmacy and Pharmacology, Volume 67, Issue 2, February 2015, Pages 143–159

Acknowledgments: This project has received funding from the European Union’s Horizon 2020 research and innovation programme under the Marie Skłodowska-Curie grant agreement No 955756