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.
Similar content being viewed by others
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
References
Barenholz Y. Doxil® - the first FDA-approved nano-drug: lessons learned. J Control Release. 2012;160(2):117–34.
Lautenschlager C, Schmidt C, Lehr CM, Fischer D, Stallmach A. PEG-functionalized microparticles selectively target inflamed mucosa in inflammatory bowel disease. Eur J Pharm Biopharm. 2013;85(3 Pt A):578–86.
Lamprecht A, Schafer U, Lehr CM. Size-dependent bioadhesion of micro- and nanoparticulate carriers to the inflamed colonic mucosa. Pharm Res. 2001;18(6):788–93.
Lammers T, Kiessling F, Hennink WE, Storm G. Drug targeting to tumors: principles, pitfalls and (pre-) clinical progress. J Control Release. 2012;161(2):175–87.
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.
Langer K, Balthasar S, Vogel V, Dinauer N, von Briesen H, Schubert D. Optimization of the preparation process for human serum albumin (HSA) nanoparticles. Int J Pharm. 2003;257(1–2):169–80.
Oleinick NL, Evans HH. The photobiology of photodynamic therapy: cellular targets and mechanisms. Radiat Res. 1998;150(5 Suppl):146–56.
Karnik R, Gu F, Basto P, Cannizzaro C, Dean L, Kyei-Manu W, et al. Microfluidic platform for controlled synthesis of polymeric nanoparticles. Nano letters. 2008;8(9):2906–12.
Zhao C-X, He L, Qiao SZ, Middelberg AP. Nanoparticle synthesis in microreactors. Chemical Engineering Science. 2011;66(7):1463–79.
Santos RJ, Sultan MA. State of the art of mini/μ Jet reactors. Chemical Engineering & Technology. 2013;36(6):937–49.
Petschacher C, Eitzlmayr A, Besenhard M, Wagner J, Barthelmes J, Bernkop-Schnürch A, et al. Thinking continuously: a microreactor for the production and scale-up of biodegradable, self-assembled nanoparticles. Polymer Chemistry. 2013;4(7):2342–52.
Henderson BW, Dougherty TJ. How does photodynamic therapy work? Photochem Photobiol. 1992;55(1):145–57.
Bechet D, Couleaud P, Frochot C, Viriot ML, Guillemin F, Barberi-Heyob M. Nanoparticles as vehicles for delivery of photodynamic therapy agents. Trends Biotechnol. 2008;26(11):612–21.
Dougherty TJ. Photodynamic therapy (PDT) of malignant tumors. Crit Rev Oncol Hematol. 1984;2(2):83–116.
Bodmeier R, Chen H, Tyle P, Jarosz P. Spontaneous formation of drug-containing acrylic nanoparticles. J Microencapsul. 1991;8(2):161–70.
Viehof A, Javot L, Beduneau A, Pellequer Y, Lamprecht A. Oral insulin delivery in rats by nanoparticles prepared with non-toxic solvents. Int J Pharm. 2013;443(1–2):169–74.
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.
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.
Bootz A, Vogel V, Schubert D, Kreuter J. Comparison of scanning electron microscopy, dynamic light scattering and analytical ultracentrifugation for the sizing of poly(butyl cyanoacrylate) nanoparticles. Eur J Pharm Biopharm. 2004;57(2):369–75.
Schuck P, Rossmanith P. Determination of the sedimentation coefficient distribution by least-squares boundary modeling. Biopolymers. 2000;54(5):328–41.
Porsch B, Hillang I, Karlsson A, Sundelof LO. Ion-exclusion controlled size-exclusion chromatography of methacrylic acid-methyl methacrylate copolymers. J Chromatogr A. 2000;872(1–2):91–9.
Dragicevic-Curic N, Scheglmann D, Albrecht V, Fahr A. Development of different temoporfin-loaded invasomes-novel nanocarriers of temoporfin: characterization, stability and in vitro skin penetration studies. Colloids Surf B Biointerfaces. 2009;70(2):198–206.
Wacker M, Zensi A, Kufleitner J, Ruff A, Schutz J, Stockburger T, et al. A toolbox for the upscaling of ethanolic human serum albumin (HSA) desolvation. Int J Pharm. 2011;414(1–2):225–32.
Wacker M. Nanocarriers for intravenous injection-the long hard road to the market. Int J Pharm. 2013;457(1):50–62.
Wacker MG. Nanotherapeutics-product development along the “nanomaterial” discussion. J Pharm Sci. 2014;103(3):777–84.
Moulari B, Pertuit D, Pellequer Y, Lamprecht A. The targeting of surface modified silica nanoparticles to inflamed tissue in experimental colitis. Biomaterials. 2008;29(34):4554–60.
Danhier F, Feron O, Preat V. To exploit the tumor microenvironment: Passive and active tumor targeting of nanocarriers for anti-cancer drug delivery. J Control Release. 2010;148(2):135–46.
Tscharnuter W. Photon correlation spectroscopy in particle sizing. In: Meyers RA, editor. Encyclopedia of analytical chemistry. Chinchester: Wiley; 2000. p. 5469–85.
Ali ME, Lamprecht A. Polyethylene glycol as an alternative polymer solvent for nanoparticle preparation. Int J Pharm. 2013;456(1):135–42.
Gratton SE, Ropp PA, Pohlhaus PD, Luft JC, Madden VJ, Napier ME, et al. The effect of particle design on cellular internalization pathways. Proc Natl Acad Sci U S A. 2008;105(33):11613–8.
Wang J, Byrne JD, Napier ME, DeSimone JM. More effective nanomedicines through particle design. Small. 2011;7(14):1919–31.
Muller RH, Jacobs C, Kayser O. Nanosuspensions as particulate drug formulations in therapy. Rationale for development and what we can expect for the future. Adv Drug Deliv Rev. 2001;47(1):3–19.33.
Günther A, Jhunjhunwala M, Thalmann M, Schmidt MA, Jensen KF. Micromixing of miscible liquids in segmented gas-liquid flow. Langmuir. 2005;21(4):1547–55.
Jensen KF. Microreaction engineering—is small better? Chemical Engineering Science. 2001;56(2):293–303.
Li W, Greener J, Voicu D, Kumacheva E. Multiple modular microfluidic (M 3) reactors for the synthesis of polymer particles. Lab on a Chip. 2009;9(18):2715–21.
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.
Wu H, White M, Khan MA. Quality-by-Design (QbD): An integrated process analytical technology (PAT) approach for a dynamic pharmaceutical co-precipitation process characterization and process design space development. Int J Pharm. 2011;405(1–2):63–78.
Yu LX, Lionberger RA, Raw AS, D’Costa R, Wu H, Hussain AS. Applications of process analytical technology to crystallization processes. Adv Drug Deliv Rev. 2004;56(3):349–69.
Wu H, Khan MA. Quality-by-design: an integrated process analytical technology approach to determine the nucleation and growth mechanisms during a dynamic pharmaceutical coprecipitation process. J Pharm Sci. 2011;100(5):1969–86.
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
Corresponding author
Rights and permissions
About this article
Cite this article
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
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s11095-014-1569-y