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Quantifying In Vivo Luminal Drug Solubilization -Supersaturation-Precipitation Profiles to Explain the Performance of Lipid Based Formulations

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Abstract

Purpose

To evaluate the role of supersaturation in the in vivo absorption of fenofibrate (FFB), after oral administration in a medium-chain lipid-based formulation (MCLBF).

Methods

FFB was loaded at 90% and 20% w/w of saturated solubility in MCLBF. The two formulations were pre-dispersed in purified water at 5% w/w (ME90% and 20%, respectively) and orally administered to rats to measure in vivo luminal drug concentrations.

Results

FFB precipitated in the stomach due to lipid digestion by gastric lipases and loss of solubilization capacity. This was most significant for ME90%. For ME90%, a high degree of supersaturation was also observed in the duodenum, however, precipitated FFB crystals rapidly re-dissolved. The combination of supersaturation and rapid re-dissolution appeared to drive effective absorption in the upper intestine. For ME20%, FFB precipitated in the stomach but not in the crystalline form and rapidly re-dissolved. Supersaturation in the duodenum again appeared to be the major driver of oral absorption.

Conclusions

The data provide one of the first studies of in vivo luminal drug concentration, supersaturation and absorption from lipid based formulations and suggests that for FFB, whilst very high supersaturation may drive in vitro and in vivo precipitation, re-dissolution and drug absorption is rapid and efficient.

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Abbreviations

AP:

Aqueous phase

4-BPB:

4-bromophenylboronic acid

CPLM:

Cross polarized light microscopy

DMSO:

Dimethyl sulfoxide

FFB:

Fenofibrate

FFA:

Fenofibric acid

FD-4:

Fluorescein isothiocyanate dextran 4000

GI:

Gastrointestinal

HPLC:

High performance liquid chromatography

IS:

Internal standard

LBF:

Lipid based formulation

MCLBF:

Medium-chain lipid based formulation

ME:

Microemulsion

OP:

Oil phase

PP:

Pellet phase

PWSD:

Poorly water soluble drugs

NaTC:

Sodium taurocholate

AUC0-1440min :

The area under the plasma concentration–time curve from 0 to 1440 min

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Acknowledgments

This research was partially supported by the Nagai Foundation Tokyo research grant 2018.

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Authors and Affiliations

  1. Drug Delivery Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University, 381 Royal Parade, Parkville, Victoria, 3052, Australia

    Yusuke Tanaka, Erin Tay, Tri-Hung Nguyen & Christopher J. H. Porter

  2. Laboratory of Pharmaceutics, Faculty of Pharmaceutical Sciences, Hiroshima International University, 5-1-1 Hiro-koshingai, Kure, Hiroshima, 737-0112, Japan

    Yusuke Tanaka

  3. ARC Centre of Excellence in Convergent Bio Nano Science and Technology, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria, 3052, Australia

    Christopher J. H. Porter

Authors
  1. Yusuke Tanaka
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Correspondence to Christopher J. H. Porter.

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Tanaka, Y., Tay, E., Nguyen, TH. et al. Quantifying In Vivo Luminal Drug Solubilization -Supersaturation-Precipitation Profiles to Explain the Performance of Lipid Based Formulations. Pharm Res 37, 47 (2020). https://doi.org/10.1007/s11095-020-2762-9

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