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Article

Shelf-Life Evaluation and Lyophilization of PBCA-Based Polymeric Microbubbles

1
Department of Pharmaceutics, Utrecht Institute for Pharmaceutical Sciences (UIPS), Utrecht University, 3584 CG Utrecht, The Netherlands
2
Institute for Experimental Molecular Imaging, Faculty of Medicine, RWTH Aachen University, 52074 Aachen, Germany
3
DWI—Leibniz Institute for Interactive Materials, Aachen, Germany AVT—Biochemical Engineering, RWTH Aachen University, 52074 Aachen, Germany
4
Electron Microscope Facility, University Hospital RWTH, RWTH Aachen University, 52074 Aachen, Germany
5
AVT—Biochemical Engineering, RWTH Aachen University, 52074 Aachen, Germany
6
Department of Targeted Therapeutics, MIRA Institute for Biomedical Technology and Technical Medicine, University of Twente, 7500 AE Enschede, The Netherlands
*
Authors to whom correspondence should be addressed.
These authors contributed equally to this work.
Pharmaceutics 2019, 11(9), 433; https://doi.org/10.3390/pharmaceutics11090433
Received: 30 June 2019 / Revised: 12 August 2019 / Accepted: 22 August 2019 / Published: 26 August 2019
(This article belongs to the Special Issue Micro/Nano-Bubbles as a New Ultrasound Imaging and Drug Delivery Tool)
Poly(n-butyl cyanoacrylate) microbubbles (PBCA-MB) are extensively employed for functional and molecular ultrasound (US) imaging, as well as for US-mediated drug delivery. To facilitate the use of PBCA-MB as a commercial platform for biomedical applications, it is important to systematically study and improve their stability and shelf-life. In this context, lyophilization (freeze drying) is widely used to increase shelf-life and promote product development. Here, we set out to analyze the stability of standard and rhodamine-B loaded PBCA-MB at three different temperatures (4 °C, 25 °C, and 37 °C), for a period of time of up to 20 weeks. In addition, using sucrose, glucose, polyvinylpyrrolidone (PVP), and polyethylene glycol (PEG) as cryoprotectants, we investigated if PBCA-MB can be lyophilized without affecting their size, concentration, US signal generation properties, and dye retention. Stability assessment showed that PBCA-MB remain largely intact for three and four weeks at 4 °C and 25 °C, respectively, while they disintegrate within one to two weeks at 37 °C, thereby compromising their acoustic properties. Lyophilization analyses demonstrated that PBCA-MB can be efficiently freeze-dried with 5% sucrose and 5% PVP, without changing their size, concentration, and US signal generation properties. Experiments involving rhodamine-B loaded MB indicated that significant dye leakage from the polymeric shell takes place within two to four weeks in case of non-lyophilized PBCA-MB. Lyophilization of rhodamine-loaded PBCA-MB with sucrose and PVP showed that the presence of the dye does not affect the efficiency of freeze-drying, and that the dye is efficiently retained upon MB lyophilization. These findings contribute to the development of PBCA-MB as pharmaceutical products for preclinical and clinical applications. View Full-Text
Keywords: PBCA; microbubbles; ultrasound; lyophilization; storage stability; drug retention PBCA; microbubbles; ultrasound; lyophilization; storage stability; drug retention
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MDPI and ACS Style

Ojha, T.; Pathak, V.; Drude, N.; Weiler, M.; Rommel, D.; Rütten, S.; Geinitz, B.; van Steenbergen, M.J.; Storm, G.; Kiessling, F.; Lammers, T. Shelf-Life Evaluation and Lyophilization of PBCA-Based Polymeric Microbubbles. Pharmaceutics 2019, 11, 433. https://doi.org/10.3390/pharmaceutics11090433

AMA Style

Ojha T, Pathak V, Drude N, Weiler M, Rommel D, Rütten S, Geinitz B, van Steenbergen MJ, Storm G, Kiessling F, Lammers T. Shelf-Life Evaluation and Lyophilization of PBCA-Based Polymeric Microbubbles. Pharmaceutics. 2019; 11(9):433. https://doi.org/10.3390/pharmaceutics11090433

Chicago/Turabian Style

Ojha, Tarun, Vertika Pathak, Natascha Drude, Marek Weiler, Dirk Rommel, Stephan Rütten, Bertram Geinitz, Mies J. van Steenbergen, Gert Storm, Fabian Kiessling, and Twan Lammers. 2019. "Shelf-Life Evaluation and Lyophilization of PBCA-Based Polymeric Microbubbles" Pharmaceutics 11, no. 9: 433. https://doi.org/10.3390/pharmaceutics11090433

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