Bridging Laboratory and Large Scale Production: Preparation and In Vitro-Evaluation of Photosensitizer-Loaded Nanocarrier Devices for Targeted Drug Delivery
- 479 Downloads
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.
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.
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.
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.
KeywordsDesign of Experiments Drug targeting Eudragit® RS 100 Nanoparticles Photodynamic therapy
Active pharmaceutical ingredient
Dynamic light scattering
Dulbecco’s Modified Eagle Medium
Design of Experiments
Fetal calf serum
Good manufacturing practice
Molecular weight cut-off
Process analytical technology
N-methyl dibenzopyrazine methyl sulphate
Size exclusion chromatography
Scanning electron microscopy
- SNS ratio
Solvent-to-non solvent ratio
Transmission electron microscopy
Sodium 3’-[(phenylaminocarbonyl)-3,4-tetrazolium]-bis(4-methoxy-6-nitro)benzene sulfonic acid
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).
- 5.Fessi H, Puisieux F, Devissaguet JP, Ammoury N, Benita S. Nanocapsule formation by interfacial polymer deposition following solvent displacement. Int J Pharm. 1989;55(1):1–4.Google Scholar
- 17.Wacker M, Chen K, Preuss A, Possemeyer K, Roeder B, Langer K. Photosensitizer loaded HSA nanoparticles. I: Preparation and photophysical properties Int J Pharm. 2010;393(1–2):253–62.Google Scholar
- 18.Vogel V, Langer K, Balthasar S, Schuck P, Mächtle W, Haase W, et al. Characterization of serum albumin nanoparticles by sedimentation velocity analysis and electron microscopy. Analytical Ultracentrifugation VI: Springer; 2002. p. 31–36.Google Scholar
- 28.Tscharnuter W. Photon correlation spectroscopy in particle sizing. In: Meyers RA, editor. Encyclopedia of analytical chemistry. Chinchester: Wiley; 2000. p. 5469–85.Google Scholar
- 36.Türeli AE, Penth B, Langguth P, Baumstümmler B. Vorrichtung und Verfahren zur Herstellung pharmazeutisch hochfeiner Partikel sowie zur Beschichtung solcher Partikel in Mikroreaktoren. German Patent Application DE102009008478A1; 2011.Google Scholar