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Pharmaceutical Research

, Volume 32, Issue 5, pp 1714–1726 | Cite as

Bridging Laboratory and Large Scale Production: Preparation and In Vitro-Evaluation of Photosensitizer-Loaded Nanocarrier Devices for Targeted Drug Delivery

  • Susanne Beyer
  • Li Xie
  • Susanna Gräfe
  • Vitali Vogel
  • Kerstin Dietrich
  • Arno Wiehe
  • Volker Albrecht
  • Werner Mäntele
  • Matthias G. WackerEmail author
Research Paper

Abstract

Purpose

Industrial production of nanosized drug delivery devices is still an obstacle to the commercialization of nanomedicines. This study encompasses the development of nanoparticles for peroral application in photodynamic therapy, optimization according to the selected product specifications, and the translation into a continuous flow process.

Methods

Polymeric nanoparticles were prepared by nanoprecipitation of Eudragit® RS 100 in presence and in absence of glycofurol. The photosensitizer temoporfin has been encapsulated into these carrier devices. Process parameters were optimized by means of a Design of Experiments approach and nanoparticles with optimal characteristics were manufactured by using microreactor technology. The efficacy was determined by means of cell culture models in A-253 cells.

Results

Physicochemical properties of nanoparticles achieved by nanoprecipitation from ethanolic solutions were superior to those obtained from a method based upon glycofurol. Nanoencapsulation of temoporfin into the matrix significantly reduced toxicity of this compound, while the efficacy was maintained. The release profiles assured a sustained release at the site of action. Finally, the transfer to continuous flow technology was achieved.

Conclusion

By adjusting all process parameters, a potent formulation for application in the GI tract was obtained. The essential steps of process development and scale-up were part of this formulation development.

Keywords

Design of Experiments Drug targeting Eudragit® RS 100 Nanoparticles Photodynamic therapy 

Abbreviations

API

Active pharmaceutical ingredient

AUC

Analytical ultracentrifugation

DLS

Dynamic light scattering

DMEM

Dulbecco’s Modified Eagle Medium

DoE

Design of Experiments

FCS

Fetal calf serum

GI

Gastrointestinal

GMP

Good manufacturing practice

mTHPC

meso-tetrakis(3-hydroxyphenyl)chlorin

MWCO

Molecular weight cut-off

PAT

Process analytical technology

PDI

Polydispersity index

PDT

Photodynamic therapy

PEG

Polyethylene glycol

PMS

N-methyl dibenzopyrazine methyl sulphate

S.D.

Standard deviation

SEC

Size exclusion chromatography

SEM

Scanning electron microscopy

SNS ratio

Solvent-to-non solvent ratio

TEM

Transmission electron microscopy

XTT

Sodium 3’-[(phenylaminocarbonyl)-3,4-tetrazolium]-bis(4-methoxy-6-nitro)benzene sulfonic acid

Notes

Acknowledgments and Disclosures

The authors want to acknowledge Prof. Dr. Jennifer B. Dressman, Prof. Dr. Dieter Steinhilber, and Dr. Astrid Kahnt for their support and Evonik Industries AG for reagent supply.

This work has been supported by the Else Kröner-Fresenius Foundation (EKFS), Research Training Group Translational Research Innovation – Pharma (TRIP).

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Copyright information

© Springer Science+Business Media New York 2014

Authors and Affiliations

  • Susanne Beyer
    • 1
  • Li Xie
    • 2
  • Susanna Gräfe
    • 3
  • Vitali Vogel
    • 2
  • Kerstin Dietrich
    • 1
  • Arno Wiehe
    • 3
  • Volker Albrecht
    • 3
  • Werner Mäntele
    • 2
  • Matthias G. Wacker
    • 4
    Email author
  1. 1.Institute of Pharmaceutical Technology,Goethe UniversityFrankfurt (Main)Germany
  2. 2.Institute of BiophysicsGoethe UniversityFrankfurt (Main)Germany
  3. 3.biolitec research GmbH,JenaGermany
  4. 4.Department of Pharmaceutical TechnologyFraunhofer-Institute for Molecular Biology and Applied Ecology IME, Project group for Translational Medicine & Pharmacology TMPFrankfurt (Main)Germany

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