Drug Release and Targeting: the Versatility of Polymethacrylate Nanoparticles for Peroral Administration Revealed by Using an Optimized In Vitro-Toolbox
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The contribution of permeability and drug release to drug targeting were investigated in the course of development of a nanosized formulation of the anti-inflammatory compound TMP-001, for the local treatment in the gastrointestinal tract.
TMP-001 was encapsulated by nanoprecipitation into Eudragit® RS 100. The permeability of these carriers was investigated in an Ussing chamber model and the release rate was determined under biorelevant conditions. Formulation toxicity and particle-cell-interaction were investigated by flow cytometry, fluorescence and electron microscopy. Furthermore, spray drying was performed.
Effective internalization of Eudragit®-nanoparticles into cancer cells was demonstrated. A burst release of the nanoparticles implied poor interaction of TMP-001 with Eudragit®. A sustained release (70.5% release after 30 min compared to 98.0% for the API) was accomplished after spray drying yielded an increased particle size. Recovery rate of TMP-001 after spray drying was 94.2 ± 5.9%.
The release of API from polymeric nanoparticles contributes profoundly to the in vivo-performance of drug delivery devices in the gastrointestinal tract. The impact of drug-polymer interaction and particle size was analyzed. Sustained release of TMP-001 could only be achieved by increasing particle size. Therefore, biorelevant release testing has been demonstrated to be a valid tool for nanoformulation design.
KEY WORDSbiorelevant release Eudragit® RS 100 nanoparticles peroral drug delivery Ussing chamber
Active pharmaceutical ingredient
Confocal laser scanning microscopy
Dulbecco’s Modified Eagle Medium
Fetal calf serum
Molecular weight cut-off
Phosphate buffered saline
Photon correlation spectroscopy
Rotations per minute
Scanning electron microscopy
Transmission electron microscopy
Water soluble tetrazolium
ACKNOWLEDGMENTS AND DISCLOSURES
This work has been supported by the Else Kröner-Fresenius Foundation (EKFS), Research Training Group Translational Research Innovation—Pharma (TRIP). Moreover, the authors acknowledge LOEWE initiative of the State of Hessen for financial support to the Research Center for Translational Medicine and Pharmacology. The analytical part of this work was supported by the DFG (German Research Association) grant SFB1039 Z01. The authors want to acknowledge Prof. Jennifer B. Dressman and Prof. Dieter Steinhilber for their support.
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