TY - JOUR
T1 - Concentration and composition dependent aggregation of Pluronic- and Poly-(2-oxazolin)-Efavirenz Formulations in Biorelevant Media
AU - Endres, Sebastian
AU - Karaev, Emil
AU - Hanio, Simon
AU - Schlauersbach, Jonas
AU - Kraft, Christian
AU - Rasmussen, Tim
AU - Luxenhofer, Robert
AU - Böttcher, Bettina
AU - Meinel, Lorenz
AU - Pöppler, Ann-Christin
N1 - Funding Information:
We thank Matthias Gr?ne for helpful discussion and his support during data collection. M. M. L?btow kindly provided the pOx/pOzi EFV formulation. We gratefully acknowledge funding by the German Research Foundation (DFG) project number 440955393. Financial support from the Verband der Chemischen Industrie (VCI) in the form of a material cost allowance as well as from the University of W?rzburg in the form of a CNC PostDoc Plus allowance (financed from Emil-Hilb-funds) is also acknowledged (A.?C.P.). Electron microscopic data were acquired at the cryo-EM facility in W?rzburg (DFG Equipment Grant INST 93/903-1 FUGG). Raw experimental data is available through the repository Zenodo via https://doi.org/10.5281/zenodo.5136465.
Funding Information:
We thank Matthias Grüne for helpful discussion and his support during data collection. M. M. Lübtow kindly provided the pOx/pOzi EFV formulation. We gratefully acknowledge funding by the German Research Foundation (DFG) project number 440955393. Financial support from the Verband der Chemischen Industrie (VCI) in the form of a material cost allowance as well as from the University of Würzburg in the form of a CNC PostDoc Plus allowance (financed from Emil-Hilb-funds) is also acknowledged (A.‐C.P.). Electron microscopic data were acquired at the cryo-EM facility in Würzburg (DFG Equipment Grant INST 93/903-1 FUGG). Raw experimental data is available through the repository Zenodo via https://doi.org/10.5281/zenodo.5136465 .
Publisher Copyright:
© 2021 The Authors
PY - 2022/1/15
Y1 - 2022/1/15
N2 - Many drugs and drug candidates are poorly water-soluble. Intestinal fluids play an important role in their solubilization. However, the interactions of intestinal fluids with polymer excipients, drugs and their formulations are not fully understood. Here, diffusion ordered spectroscopy (DOSY) and nuclear Overhauser effect spectroscopy (NOESY), complemented by cryo-TEM were employed to address this. Efavirenz (EFV) as model drug, the triblock copolymers Pluronic® F-127 (PF127) and poly(2-oxazoline) based pMeOx-b-pPrOzi-b-pMeOx (pOx/pOzi) and their respective formulations were studied in simulated fed-state intestinal fluid (FeSSIF). For the individual polymers, the bile interfering nature of PF127 was confirmed and pure pOx/pOzi was newly classified as non-interfering. A different and more complex behaviour was however observed if EFV was involved. PF127/EFV formulations in FeSSIF showed concentration dependent aggregation with separate colloids at low formulation concentrations, a merging of individual particles at the solubility limit of EFV in FeSSIF and joint aggregates above this concentration. In the case of pOx/pOzi/EFV formulations, coincident diffusion coefficients for pOx/pOzi, lipids and EFV indicate joint aggregates across the studied concentration range. This demonstrates that separate evaluation of polymers and drugs in biorelevant media is not sufficient and their mixtures need to be studied to learn about concentration and composition dependent behaviour.
AB - Many drugs and drug candidates are poorly water-soluble. Intestinal fluids play an important role in their solubilization. However, the interactions of intestinal fluids with polymer excipients, drugs and their formulations are not fully understood. Here, diffusion ordered spectroscopy (DOSY) and nuclear Overhauser effect spectroscopy (NOESY), complemented by cryo-TEM were employed to address this. Efavirenz (EFV) as model drug, the triblock copolymers Pluronic® F-127 (PF127) and poly(2-oxazoline) based pMeOx-b-pPrOzi-b-pMeOx (pOx/pOzi) and their respective formulations were studied in simulated fed-state intestinal fluid (FeSSIF). For the individual polymers, the bile interfering nature of PF127 was confirmed and pure pOx/pOzi was newly classified as non-interfering. A different and more complex behaviour was however observed if EFV was involved. PF127/EFV formulations in FeSSIF showed concentration dependent aggregation with separate colloids at low formulation concentrations, a merging of individual particles at the solubility limit of EFV in FeSSIF and joint aggregates above this concentration. In the case of pOx/pOzi/EFV formulations, coincident diffusion coefficients for pOx/pOzi, lipids and EFV indicate joint aggregates across the studied concentration range. This demonstrates that separate evaluation of polymers and drugs in biorelevant media is not sufficient and their mixtures need to be studied to learn about concentration and composition dependent behaviour.
KW - BILE-SALT MICELLES
KW - BIOPHARMACEUTICAL CLASSIFICATION
KW - Bile colloids
KW - Concentation dependent interaction
KW - DELIVERY
KW - DISSOLUTION
KW - DOSY
KW - Drug-Polymer Formulations
KW - EFAVIRENZ
KW - INTESTINAL FLUIDS
KW - POLYMERIC MICELLES
KW - POORLY SOLUBLE DRUGS
KW - SOLUBILITY
KW - WATER
KW - 116 Chemical sciences
UR - http://www.scopus.com/inward/record.url?scp=85114261755&partnerID=8YFLogxK
U2 - 10.1016/j.jcis.2021.08.040
DO - 10.1016/j.jcis.2021.08.040
M3 - Article
SN - 0021-9797
VL - 606
SP - 1179
EP - 1192
JO - Journal of Colloid and Interface Science
JF - Journal of Colloid and Interface Science
ER -