Effects of dilution and prolonged storage with preservative in a polyethylene container on Bevacizumab (Avastin™) for topical delivery as a nasal spray in anti-hereditary hemorrhagic telangiectasia and related therapies
Affiliations: [a] Vision Research Center and Department of Ophthalmology, University of Missouri – Kansas City, School of Medicine, Kansas City, MO, USA | [b] O'Brien Pharmacy, Mission, KS, USA | [c] HHT Foundation International, Monkton, MD, USA | [d] Georgia Health Sciences University, Section of Pulmonary and Critical Care Medicine, Augusta, GA, USA
Correspondence:
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Corresponding author: Peter Koulen, Ph.D., University of Missouri – Kansas City, School of Medicine, Vision Research Center, 2411 Holmes St. Kansas City, MO 64108, USA. Tel.: +1 816 404 1834; Fax: +1 816 404 1825; E-mail: koulenp@umkc.edu.
Abstract: Background: Hereditary hemorrhagic telangiectasia (HHT) is an autosomal dominant vascular dysplasia and severe, recurrent epistaxis is a common clinical phenotype associated with HHT. An intranasal treatment regime of diluted Avastin™ (Bevacizumab; recombinant humanized anti-vascular epithelial growth factor immunoglobin G1) using apulsatile nasal irrigator has proven efficacious in clinical practice. However, concerns regarding the stability of Avastin™ following dilution and prolonged storage in standard containers used for drug delivery, such as polyethylene bottles, have so far prevented a more widespread clinical use. Compatibility with the preservative benzalkonium chloride was also unknown. Objective: This study aimed at determining, whether dilution, prolonged refrigerated storage and the presence of the preservative benzalkonium chloride – as required for novel Avastin™ formulations – affected the biochemical and electrochemical properties of the drug. Methods: We performed a detailed biochemical and electrochemical analysis of Avastin™, including native and sodium dodecyl sulfate polyacrylamide gel electrophoresis, enzyme-linked immunosorbent assay and isoelectric focusing. Results: We did not detect any evidence of degeneration or aggregation following dilution and prolonged, refrigerated storage or from the presence of benzalkonium chloride. All biochemical and electrochemical properties of Avastin™ after dilution and prolonged, refrigerated storage were undistinguishable from control. Conclusions: Our data provide important insight into the stability of Avastin™ and allow the consideration of novel Avastin™ formulations, including its use in a metered-dose nasal spray for the treatment of HHT and other applications.
