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Drug Dev Ind Pharm. 2017 Feb;43(2):338-346. doi: 10.1080/03639045.2016.1251449. Epub 2016 Nov 6.

Optimization of the Ussing chamber setup with excised rat intestinal segments for dissolution/permeation experiments of poorly soluble drugs.

Author information

1
a Department of Pharmaceutical Technology and Biopharmaceutics , Johannes Gutenberg University , Mainz , Germany.
2
b Department of Pharmacy , Uppsala University , Uppsala , Sweden.
3
c Department of Biopharmaceutics, Pharmaceutical Sciences and Clinical Supply , Merck & Co. Inc ., Kenilworth , NJ , USA.
4
d Institute of Clinical and Functional Anatomy , University Medical Center Johannes Gutenberg University , Mainz , Germany.
5
e Institute of Medical Biostatistics, Epidemiology and Informatics , University Medical Center Johannes Gutenberg University , Mainz , Germany.

Abstract

CONTEXT:

Prediction of the in vivo absorption of poorly soluble drugs may require simultaneous dissolution/permeation experiments. In vivo predictive media have been modified for permeation experiments with Caco-2 cells, but not for excised rat intestinal segments.

OBJECTIVE:

The present study aimed at improving the setup of dissolution/permeation experiments with excised rat intestinal segments by assessing suitable donor and receiver media.

METHODS:

The regional compatibility of rat intestine in Ussing chambers with modified Fasted and Fed State Simulated Intestinal Fluids (Fa/FeSSIFmod) as donor media was evaluated via several parameters that reflect the viability of the excised intestinal segments. Receiver media that establish sink conditions were investigated for their foaming potential and toxicity. Dissolution/permeation experiments with the optimized conditions were then tested for two particle sizes of the BCS class II drug aprepitant.

RESULTS:

Fa/FeSSIFmod were toxic for excised rat ileal sheets but not duodenal sheets, the compatibility with jejunal segments depended on the bile salt concentration. A non-foaming receiver medium containing bovine serum albumin (BSA) and Antifoam B was nontoxic. With these conditions, the permeation of nanosized aprepitant was higher than of the unmilled drug formulations.

DISCUSSION:

The compatibility of Fa/FeSSIFmod depends on the excised intestinal region. The chosen conditions enable dissolution/permeation experiments with excised rat duodenal segments. The experiments correctly predicted the superior permeation of nanosized over unmilled aprepitant that is observed in vivo.

CONCLUSION:

The optimized setup uses FaSSIFmod as donor medium, excised rat duodenal sheets as permeation membrane and a receiver medium containing BSA and Antifoam B.

KEYWORDS:

Intestinal segments; antifoaming; aprepitant; cholesterol; fasted state simulated intestinal fluid; nanosized API; rat; sink conditions

PMID:
27762631
DOI:
10.1080/03639045.2016.1251449
[Indexed for MEDLINE]

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