TY - JOUR

T1 - Interaction of liposomes with bile salts investigated by asymmetric flow field-flow fractionation (AF4)

T2 - A novel approach for stability assessment of oral drug carriers

AU - Bohsen, Mette Sloth

AU - Tychsen, Sofie Tandrup

AU - Kadhim, Ali Abdul Hussein

AU - Grohganz, Holger

AU - Treusch, Alexander H.

AU - Brandl, Martin

N1 - Funding Information: The authors would like to acknowledge Assoc. Prof. Judith Kuntsche from SDU for her AF4/MALLS/dRI-expertise and guidance. This study was funded by a Phospholipid Research Center grant to AHT (ATR-2019–074/1–1) and received support from the Nordic University Hub project (#85352, MB) (NordicPOP, Patient Oriented Products).

PY - 2023

Y1 - 2023

N2 - For oral drug delivery the stability of liposomes against intestinal bile salts is of key importance. Here, asymmetric flow field-flow fractionation (AF4) coupled to multi-angle laser light scattering (MALLS) and a differential refractive index (dRI) detector was employed to monitor structural re-arrangement of liposomes upon exposure to the model bile salt taurocholate. For comparison, a conventional stability assay was employed using a hydrophilic marker and size exclusion chromatography (SEC) to separate released from liposome-entrapped dye. Calcein-containing liposomes with and without cholesterol were compared in terms of their in vitro stability upon exposure to bile salts by separating liposomes from co-existing colloidal species emerging after stress test using AF4/MALLS/dRI. Dynamic light scattering (DLS) was utilized in parallel. Our AF4/MALLS/dRI results suggested that exposure of egg-phospholipid liposomes to bile salts at physiological concentrations led to the formation of two new species of colloidal associates, likely (mixed) micelles. Subjecting cholesterol-containing liposomes to the same bile media did not lead to any new colloidal structures, indicating increased stability of these liposomes. Our SEC-based release assay largely confirmed these findings, indicating that AF4/MALLS/dRI is a suitable technique for prediction of in vitro oral stability of liposomal formulations. Moreover, the powerful AF4/MALLS/dRI technique appears promising to improve the understanding of the underlying mechanisms during bile salt-induced liposomal breakdown.

AB - For oral drug delivery the stability of liposomes against intestinal bile salts is of key importance. Here, asymmetric flow field-flow fractionation (AF4) coupled to multi-angle laser light scattering (MALLS) and a differential refractive index (dRI) detector was employed to monitor structural re-arrangement of liposomes upon exposure to the model bile salt taurocholate. For comparison, a conventional stability assay was employed using a hydrophilic marker and size exclusion chromatography (SEC) to separate released from liposome-entrapped dye. Calcein-containing liposomes with and without cholesterol were compared in terms of their in vitro stability upon exposure to bile salts by separating liposomes from co-existing colloidal species emerging after stress test using AF4/MALLS/dRI. Dynamic light scattering (DLS) was utilized in parallel. Our AF4/MALLS/dRI results suggested that exposure of egg-phospholipid liposomes to bile salts at physiological concentrations led to the formation of two new species of colloidal associates, likely (mixed) micelles. Subjecting cholesterol-containing liposomes to the same bile media did not lead to any new colloidal structures, indicating increased stability of these liposomes. Our SEC-based release assay largely confirmed these findings, indicating that AF4/MALLS/dRI is a suitable technique for prediction of in vitro oral stability of liposomal formulations. Moreover, the powerful AF4/MALLS/dRI technique appears promising to improve the understanding of the underlying mechanisms during bile salt-induced liposomal breakdown.

KW - Asymmetric flow field-flow fractionation

KW - Bile salt

KW - Dynamic light scattering

KW - Liposome

KW - Oral administration

KW - Size exclusion chromatography

U2 - 10.1016/j.ejps.2023.106384

DO - 10.1016/j.ejps.2023.106384

M3 - Journal article

C2 - 36642346

AN - SCOPUS:85146635309

VL - 182

JO - European Journal of Pharmaceutical Sciences

JF - European Journal of Pharmaceutical Sciences

SN - 0928-0987

M1 - 106384

ER -