4/15/2016 Disclosures Limitations of current DCBs and The presenter has • US 14/244126 intellectual property filed • US 15/57103 the future direction of vascular which can be associated with this local drug delivery presentation. None of the rights to the associated intellectual property have been Patrick W. Kelly, licensed. Vascular Surgeon Sanford Health Questions How does the drug work? • Paclitaxel (Taxol) inhibits smooth muscle cell • How do DCBs work? proliferations • Where does the drug work? – Sticks to the endothelium? • Crystal or Amorphous – Pressed into the endothelium under pressure? • What’s the right dose? – Dissolves and permeates across the endothelium? • How long does the drug effect last? • Urea/sorbitol – excipient – Helps transport Taxol into the subendothelial layer 1
4/15/2016 What is the right dose? Where does it work? • 2.5 or 3 microgram per square mm of • Sub-endothelial layer of the artery Taxol on the balloon surface • Endothelium?? • 2 minute – 3 minute inflation • Number of treatments per balloon • Tissue concentrations and curves We’ve tried to answer some of Cell Cultures these questions • Cell culture test – Smooth muscle cells – Endothelial cells • Animal testing – Infusion under pressure – Drug coated balloon 2
4/15/2016 Human aortic endothelial cells cultured in the Human aortic smooth muscle cells cultured in the presence of various taxol and/or excipient presence of various combinations of taxol and/or combinations excipients 1000 7 Relative fluorescence units (RFUs) Aspect ratio (length/width) 6 5 100 4 3 1 day 1 day 10 2 3 days 3 days 5 days 1 5 days 1 0 Tissue penetration Animal Drug Infusion Test phase contrast microscopy (drug infusion) • Taxol had minimal penetration in a cremaphor solution • Taxol had moderate penetration in a urea solution • Taxol had maximal penetration in an albumin bound nanoparticle (Abraxane) 3
4/15/2016 Concentrations of Paclitaxel in the aorta of Rabbits at time zero when infused in the presence of various excipients Developing Next Generation DCB 50 45 40 Paclitaxel (ng) per mg of rabbit aorta 35 30 25 20 15 10 5 0 Cremaphor Abraxane Cremaphor and Urea Cremaphor and Contrast Agent PEO/Taxol next generation DCBs PEO/Taxol next generation DCBs • Require uniform • Require minimal coating and thickness crystal formation/even distribution • Multiple use would throughout polymer to require coating prevent particulate adhesion through formation/distal multiple stretch/relax embolization cycles • Require uniform material properties throughout 4
4/15/2016 Timed release of taxol from various paclitaxel and PEO formulations Particulate formation is at least 5 theoretically important 4.5 • Particulates could Amount of taxol released (ug per mm^2) 4 embolize to distal micro 3.5 vessels during tracking 3 • Paclitaxel dissolves 10% taxol slowly in aqueous 2.5 15% taxol 20% taxol environments Endovascular Today Volume 2 number 6. 2015 2 25% taxol 1.5 1 0.5 0 Demonstration of a multi-use balloon being used for one inflation in a Amount of drug needed in the rabbit aorta 3 arterial tissue 2.5 • Each device has differing 1921 ng per mg tissue levels of drug in the 2 arterial tissue throughout 414.4 ng per mg tissue the restenotic cascade 1.5 period 414 ng per mg tissue • Amount of drug present 1 at time zero is not as 61.6 ng per mg 169.1 ng per tissue mg tissue important as the amount 0.5 of drug present at day 7, 0 14, 21, and 28. Drug loaded on balloon (ug per mm^2) drug released from balloon (ug per mm^2) Endovascular Today Volume 2 number 6. 2015 drug left on balloon (ug per mm^2) 5
4/15/2016 Closing thoughts Thank you • DCBs Acknowledgements, Collaborator: • DIBs Tyler Remund PhD and Kathryn Pohlson • Are we targeting the right cellular process Gopi Mani, PhD and his team • Are we using the right drug or drugs? [Jordan Anderson, Sujan Lamichhane, PhD] • Should it be Crystal or Amorphous Thank You 6
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