TY - JOUR

T1 - Development of a high-throughput in vitro intestinal lipolysis model for rapid screening of lipid-based drug delivery systems

AU - Mosgaard, Mette D

AU - Sassene, Philip

AU - Mu, Huiling

AU - Rades, Thomas

AU - Müllertz, Anette

N1 - Copyright © 2015. Published by Elsevier B.V.

PY - 2015/8

Y1 - 2015/8

N2 - PURPOSE: To develop a high-throughput in vitro intestinal lipolysis (HTP) model, without any means of pH-stat-titration, to enable a fast evaluation of lipid-based drug delivery systems (LbDDS).MATERIAL AND METHOD: The HTP model was compared to the traditionally used dynamic in vitro lipolysis (DIVL) model with regard to the extent of lipid digestion and drug distribution of two poorly soluble model drugs (cinnarizine and danazol), during digestion of three LbDDS (LbDDS I-III).RESULT: The HTP model was able to maintain pH around 6.5 during digestion, without the addition of NaOH to neutralize the free fatty acids (FFAs), due to an increased buffer capacity. Cinnarizine was primarily located in the aqueous phase during digestion of all three LbDDS and did not differ significantly between the two models. The distribution of danazol varied from formulation to formulation, but no significant difference between the models was observed. The triacylglycerides (TAG) in LbDDS III were digested to the same extent in both models, whereas the TAG present in LbDDS II was digested slightly less in the HTP model. No TAG was present in LbDDS I and digestion was therefore not analyzed.CONCLUSION: The HTP model is able to predict drug distribution during digestion of LbDDS containing poorly water soluble drugs in the same manner as the DIVL model. Thus the HTP model might prove applicable for high-throughput evaluation of LbDDS in e.g. 96 well plates or small scale dissolution equipment.

AB - PURPOSE: To develop a high-throughput in vitro intestinal lipolysis (HTP) model, without any means of pH-stat-titration, to enable a fast evaluation of lipid-based drug delivery systems (LbDDS).MATERIAL AND METHOD: The HTP model was compared to the traditionally used dynamic in vitro lipolysis (DIVL) model with regard to the extent of lipid digestion and drug distribution of two poorly soluble model drugs (cinnarizine and danazol), during digestion of three LbDDS (LbDDS I-III).RESULT: The HTP model was able to maintain pH around 6.5 during digestion, without the addition of NaOH to neutralize the free fatty acids (FFAs), due to an increased buffer capacity. Cinnarizine was primarily located in the aqueous phase during digestion of all three LbDDS and did not differ significantly between the two models. The distribution of danazol varied from formulation to formulation, but no significant difference between the models was observed. The triacylglycerides (TAG) in LbDDS III were digested to the same extent in both models, whereas the TAG present in LbDDS II was digested slightly less in the HTP model. No TAG was present in LbDDS I and digestion was therefore not analyzed.CONCLUSION: The HTP model is able to predict drug distribution during digestion of LbDDS containing poorly water soluble drugs in the same manner as the DIVL model. Thus the HTP model might prove applicable for high-throughput evaluation of LbDDS in e.g. 96 well plates or small scale dissolution equipment.

KW - Chromatography, High Pressure Liquid

KW - Cinnarizine

KW - Danazol

KW - Drug Carriers

KW - High-Throughput Screening Assays

KW - Intestines

KW - Kinetics

KW - Lipids

KW - Lipolysis

KW - Models, Biological

KW - Particle Size

U2 - 10.1016/j.ejpb.2015.06.028

DO - 10.1016/j.ejpb.2015.06.028

M3 - Journal article

C2 - 26159837

VL - 94

SP - 493

EP - 500

JO - European Journal of Pharmaceutics and Biopharmaceutics

JF - European Journal of Pharmaceutics and Biopharmaceutics

SN - 0939-6411

ER -