Abstract
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.
Highlights
Ultrasound (US) imaging is frequently employed in clinical practice because of its non-invasive nature, easy handling, low cost, real-time feedback, and broad applicability
We evaluated the feasibility of lyophilizing Poly(n-butyl cyanoacrylate) microbubbles (PBCA-MB), using the commonly employed cryoprotectants glucose, sucrose, PVP, and polyethylene glycol (PEG) (Figure 1)
The amount of dissolved gas in aqueous media decreases more rapidly, which indirectly promotes the diffusion of gas from the MB core into the dispersion medium, leading to MB shrinkage and collapse [16]. These results demonstrate that poly(n-butyl cyanoacrylate) (PBCA)-MB are properly stable for up to 20 weeks at 4 ◦C and 25 ◦C, and that increasing the temperature to 37 ◦C results in relatively rapid disintegration
Summary
Ultrasound (US) imaging is frequently employed in clinical practice because of its non-invasive nature, easy handling, low cost, real-time feedback, and broad applicability. To enable the commercial use of PBCA-MB, either for preclinical or for clinical applications, it is important to study and optimize key pharmaceutical properties, such as formulation stability and shelf-life. We here set out to systematically study the stability, shelf-life, and lyophilization of PBCA-MB (Figure 1) This was done by storing them for up to 20 weeks at 4 ◦C, 25 ◦C, and 37 ◦C, and monitoring changes in their concentration and physicochemical properties (size, acoustic signal generation). Sucrose and PVP were found to be suitable cryoprotectants for freeze-drying both standard and dye-loaded PBCA-MB, providing a basis for the pharmaceutical development of lyophilized PBCA-MB for future preclinical and clinical applications. Sucrose and PVP were found to be suitable cryoprotectants for freeze-drying both Pstharnmdaacerudticsa2n0d19,d1y1,e4-3l3oaded PBCA-MB, providing a basis for the pharmaceutical developme3notf o13f lyophilized PBCA-MB for future preclinical and clinical applications
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