In Vivo Precipitation of Poorly Soluble Drugs from Lipid-Based Drug Delivery Systems
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In Vivo Precipitation of Poorly Soluble Drugs from Lipid-Based Drug Delivery Systems. / Sassene, P J; Michaelsen, M H; Mosgaard, M D; Jensen, M.K.; Van Den Broek, E; Wasan, K M; Mu, H; Rades, T; Müllertz, A.
In: Molecular Pharmaceutics, Vol. 13, No. 10, 03.10.2016, p. 3417-3426.Research output: Contribution to journal › Journal article › peer-review
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TY - JOUR
T1 - In Vivo Precipitation of Poorly Soluble Drugs from Lipid-Based Drug Delivery Systems
AU - Sassene, P J
AU - Michaelsen, M H
AU - Mosgaard, M D
AU - Jensen, M.K.
AU - Van Den Broek, E
AU - Wasan, K M
AU - Mu, H
AU - Rades, T
AU - Müllertz, A
PY - 2016/10/3
Y1 - 2016/10/3
N2 - Precipitation of poorly water-soluble drugs from lipid-based drug delivery systems (LbDDS) has been studied extensively during in vitro lipolysis but has never been shown in vivo. The aim of this study was therefore to investigate if drug precipitation can occur from LbDDS during transit of the gastrointestinal tract in vivo. Rats were administered 300 μL of either of two LbDDS (LbDDS I and LbDDS II) loaded with danazol or fenofibrate (or paracetamol to assess gastric emptying). The rats were euthanized at various time points after administration of both LbDDS containing either drug, and the contents of the stomach and proximal part of the small intestine were harvested. The contents were analyzed for crystalline drug by X-ray powder diffraction and polarized light microscopy. No drug precipitation was evident in the stomach or the intestine after administration of LbDDS I containing danazol at the tested time points. Fenofibrate precipitation was absent in the stomach initially after administration of LbDDS I, but was evident in the stomach 90 min after dosing. No crystalline fenofibrate was observed in the intestine. Danazol and fenofibrate precipitation was evident in the stomach following administration of LbDDS II containing either drug, but not in the intestine at the tested time point. Drug precipitation from LbDDS was observed in the stomach, but not in the intestine, which is contrary to what in vitro lipolysis data (obtained under human GI conditions) suggests. Thus, precipitation of drugs from LbDDS in vivo in rats is much lower than might be anticipated from in vitro lipolysis data.
AB - Precipitation of poorly water-soluble drugs from lipid-based drug delivery systems (LbDDS) has been studied extensively during in vitro lipolysis but has never been shown in vivo. The aim of this study was therefore to investigate if drug precipitation can occur from LbDDS during transit of the gastrointestinal tract in vivo. Rats were administered 300 μL of either of two LbDDS (LbDDS I and LbDDS II) loaded with danazol or fenofibrate (or paracetamol to assess gastric emptying). The rats were euthanized at various time points after administration of both LbDDS containing either drug, and the contents of the stomach and proximal part of the small intestine were harvested. The contents were analyzed for crystalline drug by X-ray powder diffraction and polarized light microscopy. No drug precipitation was evident in the stomach or the intestine after administration of LbDDS I containing danazol at the tested time points. Fenofibrate precipitation was absent in the stomach initially after administration of LbDDS I, but was evident in the stomach 90 min after dosing. No crystalline fenofibrate was observed in the intestine. Danazol and fenofibrate precipitation was evident in the stomach following administration of LbDDS II containing either drug, but not in the intestine at the tested time point. Drug precipitation from LbDDS was observed in the stomach, but not in the intestine, which is contrary to what in vitro lipolysis data (obtained under human GI conditions) suggests. Thus, precipitation of drugs from LbDDS in vivo in rats is much lower than might be anticipated from in vitro lipolysis data.
U2 - 10.1021/acs.molpharmaceut.6b00413
DO - 10.1021/acs.molpharmaceut.6b00413
M3 - Journal article
C2 - 27533712
VL - 13
SP - 3417
EP - 3426
JO - Molecular Pharmaceutics
JF - Molecular Pharmaceutics
SN - 1543-8384
IS - 10
ER -
ID: 168937639