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

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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.

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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

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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).

Author information

Authors and Affiliations

  1. Institute of Pharmaceutical Technology,, Goethe University, Max-von-Laue-Str. 9,, 60438, Frankfurt (Main), Germany

    Susanne Beyer & Kerstin Dietrich

  2. Institute of Biophysics, Goethe University, Max-von-Laue-Str. 1, 60438, Frankfurt (Main), Germany

    Li Xie, Vitali Vogel & Werner Mäntele

  3. biolitec research GmbH,, Otto-Schott-Str. 15,, 07745, Jena, Germany

    Susanna Gräfe, Arno Wiehe & Volker Albrecht

  4. Department of Pharmaceutical Technology, Fraunhofer-Institute for Molecular Biology and Applied Ecology IME, Project group for Translational Medicine & Pharmacology TMP, Max-von-Laue-Str. 9, 60438, Frankfurt (Main), Germany

    Matthias G. Wacker

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  1. Susanne Beyer
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Correspondence to Matthias G. Wacker.

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Beyer, S., Xie, L., Gräfe, S. et al. Bridging Laboratory and Large Scale Production: Preparation and In Vitro-Evaluation of Photosensitizer-Loaded Nanocarrier Devices for Targeted Drug Delivery. Pharm Res 32, 1714–1726 (2015). https://doi.org/10.1007/s11095-014-1569-y

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  • DOI: https://doi.org/10.1007/s11095-014-1569-y

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