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The First Scale-Up Production of Theranostic Nanoemulsions.

Liu L, Bagia C, Janjic JM - Biores Open Access (2015)

Bottom Line: A key ingredient for successful theranostic clinical translation is pharmaceutical process design for production on a sufficient scale for clinical testing.In this study, we report, for the first time, a successful scale-up of a model theranostic nanoemulsion.This report serves as the first example of a successful scale-up of a theranostic nanoemulsion and a model for future studies on theranostic nanomedicine production and development.

View Article: PubMed Central - PubMed

Affiliation: Graduate School of Pharmaceutical Sciences, Mylan School of Pharmacy, Duquesne University , Pittsburgh, Pennsylvania.

ABSTRACT
Theranostic nanomedicines are a promising new technological advancement toward personalized medicine. Although much progress has been made in pre-clinical studies, their clinical utilization is still under development. A key ingredient for successful theranostic clinical translation is pharmaceutical process design for production on a sufficient scale for clinical testing. In this study, we report, for the first time, a successful scale-up of a model theranostic nanoemulsion. Celecoxib-loaded near-infrared-labeled perfluorocarbon nanoemulsion was produced on three levels of scale (small at 54 mL, medium at 270 mL, and large at 1,000 mL) using microfluidization. The average size and polydispersity were not affected by the equipment used or production scale. The overall nanoemulsion stability was maintained for 90 days upon storage and was not impacted by nanoemulsion production scale or composition. Cell-based evaluations show comparable results for all nanoemulsions with no significant impact of nanoemulsion scale on cell toxicity and their pharmacological effects. This report serves as the first example of a successful scale-up of a theranostic nanoemulsion and a model for future studies on theranostic nanomedicine production and development.

No MeSH data available.


Related in: MedlinePlus

Nanoemulsion stability evaluations. Effects of scale on particle size and zeta potential measurements and pH upon storage at 4°C for 90 days. (A) Size measurements of nanoemulsions (A, C, and E) without drug; (B) Size measurements of drug-loaded nanoemulsions (B, D, and F); (C) Zeta potential measurements of nanoemulsions (A, C, and E) without drug; (D) Zeta potential measurements of drug-loaded nanoemulsions (B, D, and F); (E) pH measurements of nanoemulsions A and E without a drug; (F) pH measurements of drug-loaded nanoemulsions B and F.
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f3: Nanoemulsion stability evaluations. Effects of scale on particle size and zeta potential measurements and pH upon storage at 4°C for 90 days. (A) Size measurements of nanoemulsions (A, C, and E) without drug; (B) Size measurements of drug-loaded nanoemulsions (B, D, and F); (C) Zeta potential measurements of nanoemulsions (A, C, and E) without drug; (D) Zeta potential measurements of drug-loaded nanoemulsions (B, D, and F); (E) pH measurements of nanoemulsions A and E without a drug; (F) pH measurements of drug-loaded nanoemulsions B and F.

Mentions: Furthermore, our measurements indicated that the presence of the drug in produced nanoemulsions did not affect size, zeta potential, or pH (Fig. 3) by production of three different scales and using two types of microfluidizers. Applicability of theranostic nanoemulsions in advanced preclinical testing and clinical trials in the future relies on their quality. To evaluate their shelf life, we tested all produced nanoemulsions for droplet size, polydispersity, zeta potential, and pH at storage conditions (4°C) for 90 days. Figure 3A and B shows no significant change in droplet size after 90 days of follow-up for nanoemulsions with and without a drug at all levels of the scale (small, medium, and large). Zeta potential was also maintained during the 90-day follow-up at around −7 mV, which further supports the stability of nanoemulsions (Fig. 3C, D). Furthermore, the nanoemulsion pH remained stable at ∼6.8 (Fig. 3E, F). Once nanoemulsions are used in vivo, they come into contact with complex biological fluids. To model these stressors, we evaluated their colloidal stability in model biological media (FBS-containing cell culture media) at an elevated temperature (37°C) for 72 h. No significant changes in size and polydispersity were observed upon 72 h of incubation. This suggests that all nanoemulsions (small, medium, large scale) with or without the drug are not affected by the presence of protein, salts, or nutrients (Fig. 4A–F). To further investigate nanoemulsion stability under mechanical stress and the potential impact of the scale of production on nanoemulsion quality, we performed centrifugation and filtration stability tests. It was found that upon centrifugation at 1,100 rpm for 5 min at room temperature and in different media (water, serum-free, and serum-containing cell culture media), the largest scale nanoemulsions (E and F) showed no significant changes in size and polydispersity (Fig. 5A, B). When the nanoemulsions were tested against filtration through a 0.22-μm filter, all nanoemulsions (small, medium, large scale) prepared with or without the drug showed no changes in size and polydispersity (Fig. 5C). These data suggest that all nanoemulsions reported here at three levels of scale remain highly stable when exposed to stressors during storage and use, as we earlier reported for small-scale preparations.6,31


The First Scale-Up Production of Theranostic Nanoemulsions.

Liu L, Bagia C, Janjic JM - Biores Open Access (2015)

Nanoemulsion stability evaluations. Effects of scale on particle size and zeta potential measurements and pH upon storage at 4°C for 90 days. (A) Size measurements of nanoemulsions (A, C, and E) without drug; (B) Size measurements of drug-loaded nanoemulsions (B, D, and F); (C) Zeta potential measurements of nanoemulsions (A, C, and E) without drug; (D) Zeta potential measurements of drug-loaded nanoemulsions (B, D, and F); (E) pH measurements of nanoemulsions A and E without a drug; (F) pH measurements of drug-loaded nanoemulsions B and F.
© Copyright Policy - open-access
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC4497684&req=5

f3: Nanoemulsion stability evaluations. Effects of scale on particle size and zeta potential measurements and pH upon storage at 4°C for 90 days. (A) Size measurements of nanoemulsions (A, C, and E) without drug; (B) Size measurements of drug-loaded nanoemulsions (B, D, and F); (C) Zeta potential measurements of nanoemulsions (A, C, and E) without drug; (D) Zeta potential measurements of drug-loaded nanoemulsions (B, D, and F); (E) pH measurements of nanoemulsions A and E without a drug; (F) pH measurements of drug-loaded nanoemulsions B and F.
Mentions: Furthermore, our measurements indicated that the presence of the drug in produced nanoemulsions did not affect size, zeta potential, or pH (Fig. 3) by production of three different scales and using two types of microfluidizers. Applicability of theranostic nanoemulsions in advanced preclinical testing and clinical trials in the future relies on their quality. To evaluate their shelf life, we tested all produced nanoemulsions for droplet size, polydispersity, zeta potential, and pH at storage conditions (4°C) for 90 days. Figure 3A and B shows no significant change in droplet size after 90 days of follow-up for nanoemulsions with and without a drug at all levels of the scale (small, medium, and large). Zeta potential was also maintained during the 90-day follow-up at around −7 mV, which further supports the stability of nanoemulsions (Fig. 3C, D). Furthermore, the nanoemulsion pH remained stable at ∼6.8 (Fig. 3E, F). Once nanoemulsions are used in vivo, they come into contact with complex biological fluids. To model these stressors, we evaluated their colloidal stability in model biological media (FBS-containing cell culture media) at an elevated temperature (37°C) for 72 h. No significant changes in size and polydispersity were observed upon 72 h of incubation. This suggests that all nanoemulsions (small, medium, large scale) with or without the drug are not affected by the presence of protein, salts, or nutrients (Fig. 4A–F). To further investigate nanoemulsion stability under mechanical stress and the potential impact of the scale of production on nanoemulsion quality, we performed centrifugation and filtration stability tests. It was found that upon centrifugation at 1,100 rpm for 5 min at room temperature and in different media (water, serum-free, and serum-containing cell culture media), the largest scale nanoemulsions (E and F) showed no significant changes in size and polydispersity (Fig. 5A, B). When the nanoemulsions were tested against filtration through a 0.22-μm filter, all nanoemulsions (small, medium, large scale) prepared with or without the drug showed no changes in size and polydispersity (Fig. 5C). These data suggest that all nanoemulsions reported here at three levels of scale remain highly stable when exposed to stressors during storage and use, as we earlier reported for small-scale preparations.6,31

Bottom Line: A key ingredient for successful theranostic clinical translation is pharmaceutical process design for production on a sufficient scale for clinical testing.In this study, we report, for the first time, a successful scale-up of a model theranostic nanoemulsion.This report serves as the first example of a successful scale-up of a theranostic nanoemulsion and a model for future studies on theranostic nanomedicine production and development.

View Article: PubMed Central - PubMed

Affiliation: Graduate School of Pharmaceutical Sciences, Mylan School of Pharmacy, Duquesne University , Pittsburgh, Pennsylvania.

ABSTRACT
Theranostic nanomedicines are a promising new technological advancement toward personalized medicine. Although much progress has been made in pre-clinical studies, their clinical utilization is still under development. A key ingredient for successful theranostic clinical translation is pharmaceutical process design for production on a sufficient scale for clinical testing. In this study, we report, for the first time, a successful scale-up of a model theranostic nanoemulsion. Celecoxib-loaded near-infrared-labeled perfluorocarbon nanoemulsion was produced on three levels of scale (small at 54 mL, medium at 270 mL, and large at 1,000 mL) using microfluidization. The average size and polydispersity were not affected by the equipment used or production scale. The overall nanoemulsion stability was maintained for 90 days upon storage and was not impacted by nanoemulsion production scale or composition. Cell-based evaluations show comparable results for all nanoemulsions with no significant impact of nanoemulsion scale on cell toxicity and their pharmacological effects. This report serves as the first example of a successful scale-up of a theranostic nanoemulsion and a model for future studies on theranostic nanomedicine production and development.

No MeSH data available.


Related in: MedlinePlus