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Coating and Pharmacokinetic Evaluation of Air Spray Coated Drug Coated Balloons

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Abstract

Drug coated balloons (DCB) are becoming the standard-care treatment for peripheral arterial disease (PAD). DCB use excipients to transfer and retain anti-proliferative drugs, such as paclitaxel. Excipients thus play a vital role in the design and function of DCB, however methods to coat balloons with excipients and anti-proliferative drugs remain unknown. The goal of this study was to thus develop an approach to coat and evaluate DCB for various excipients. An air sprayer method was developed to deposit paclitaxel and various excipients onto non-coated commercially available angioplasty balloons. The coating of the angioplasty balloons was evaluated for drug deposition and coating efficiency using high performance liquid chromatography tandem mass spectrometry. Drug transfer and retention of the coated angioplasty balloons into arterial segments were evaluated ex vivo using harvested pig arteries in a pulsatile flow bioreactor. The air sprayer method successfully delivered varying excipients including bovine serum albumin (BSA), urea and iohexol. The air spray method was configured to coat four angioplasty balloons simultaneously with paclitaxel and iohexol with an average paclitaxel load of 4.0 ± 0.70 µg/mm2. The intra-day (within) and inter-day (between) coating precisions, defined as relative standard deviation (RSD), was 17.2 and 15.5%, respectively. Ex vivo deployment of iohexol-paclitaxel DCB yielded an arterial paclitaxel concentration of 123.4 ± 44.68 ng/mg (n = 3) at 1 h, 126.7 ± 25.27 ng/mg (n = 3) at 1 day, and 12.9 ± 12.88 ng/mg (n = 3) at 7 days. This work provides proof-of-concept of a quick, inexpensive approach to coat commercially available angioplasty balloons with paclitaxel and various excipients.

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References

  1. Anderson, J. A., S. Lamichhane, T. Remund, P. Kelly, and G. Mani. Preparation, characterization, in vitro drug release, and cellular interactions of tailored paclitaxel releasing polyethylene oxide films for drug-coated balloons. Acta Biomater. 29:333–351, 2016.

    Article  Google Scholar 

  2. Ansari, F., L. K. Pack, S. S. Brooks, and T. M. Morrison. Design considerations for studies of the biomechanical environment of the femoropopliteal arteries. J. Vasc. Surg. 58:804–813, 2013.

    Article  Google Scholar 

  3. Atigh, M. K., E. A. Turner, U. Christians, and S. K. Yazdani. The use of an occlusion perfusion catheter to deliver paclitaxel to the arterial wall. Cardiovasc. Therap. 2017. https://doi.org/10.1111/1755-5922.12269.

    Google Scholar 

  4. Axel, D. I., W. Kunert, C. Goggelmann, M. Oberhoff, C. Herdeg, A. Kuttner, D. H. Wild, B. R. Brehm, R. Riessen, F. Koveker, and K. R. Karsch. Paclitaxel inhibits arterial smooth muscle cell proliferation and migration in vitro and in vivo using local drug delivery. Circulation 96:636–645, 1997.

    Article  Google Scholar 

  5. Blessing, E. The next generation of drug-coated balloons: the PANTHER study. Suppl. Endovasc. Today Eur. 3:12–14, 2015.

    Google Scholar 

  6. Bosiers, M., K. Deloose, J. Callaert, K. Keirse, J. Verbist, and P. Peeters. Drug-eluting stents below the knee. J. Cardiovasc. Surg. 52:231–234, 2011.

    Google Scholar 

  7. Buszman, P. P., A. Tellez, M. Afari, Y. Cheng, G. B. Conditt, J. C. McGregor, K. Milewski, M. Stenoien, G. L. Kaluza, and J. F. Granada. Stent healing response following delivery of paclitaxel via durable polymeric matrix versus iopromide-based balloon coating in the familial hypercholesterolaemic swine model of coronary injury. EuroIntervention. 9:510–516, 2013.

    Article  Google Scholar 

  8. Chesher, D. Evaluating assay precision. Clin. Biochem. Rev. 29:S23–S26, 2008.

    Google Scholar 

  9. Cortese, B., A. Micheli, A. Picchi, A. Coppolaro, L. Bandinelli, S. Severi, and U. Limbruno. Paclitaxel-coated balloon versus drug-eluting stent during PCI of small coronary vessels, a prospective randomized clinical trial. Heart. 96:1291–1296, 2010.

    Article  Google Scholar 

  10. Cremers, B., Y. Clever, S. Schaffner, U. Speck, M. Böhm, and B. Scheller. Treatment of coronary in-stent restenosis with a novel paclitaxel urea coated balloon. Minerva Cardioangiol. 58:583–588, 2010.

    Google Scholar 

  11. Fan, Y., L. Marlin, R. A. Sahatjian, and S. A. Schultz. Medical device with lubricious coating., 1996.

  12. Fernandez-Parra, R., A. Laborda, C. Lahuerta, F. Lostale, J. Aramayona, I. de Blas, and M. A. de Gregorio. Pharmacokinetic study of paclitaxel concentration after drug-eluting balloon angioplasty in the iliac artery of healthy and atherosclerotic rabbit models. J. Vasc. Interv. Radiol. 26(1380–7):e1, 2015.

    Google Scholar 

  13. Fortier, A., V. Gullapalli, and R. A. Mirshams. Review of biomechanical studies of arteries and their effect on stent performance. IJC Heart Vessel. 4:12–18, 2014.

    Article  Google Scholar 

  14. Gandhi, P. J., and Z. V. P. Murthy. Kinetic study of ultrasonic antisolvent crystallization of sirolimus. Cryst. Res. Technol. 45:321–327, 2010.

    Article  Google Scholar 

  15. Gandhi, P. J., and Z. V. P. Murthy. Investigation of different drug deposition techniques on drug releasing properties of cardiovascular drug coated balloons. Ind. Eng. Chem. Res. 51:10800–10823, 2012.

    Article  Google Scholar 

  16. Go, A. S., D. Mozaffarian, V. L. Roger, E. J. Benjamin, J. D. Berry, M. J. Blaha, S. Dai, E. S. Ford, C. S. Fox, S. Franco, H. J. Fullerton, C. Gillespie, S. M. Hailpern, J. A. Heit, V. J. Howard, M. D. Huffman, S. E. Judd, B. M. Kissela, S. J. Kittner, D. T. Lackland, J. H. Lichtman, L. D. Lisabeth, R. H. Mackey, D. J. Magid, G. M. Marcus, A. Marelli, D. B. Matchar, D. K. McGuire, E. R. Mohler, 3rd, C. S. Moy, M. E. Mussolino, R. W. Neumar, G. Nichol, D. K. Pandey, N. P. Paynter, M. J. Reeves, P. D. Sorlie, J. Stein, A. Towfighi, T. N. Turan, S. S. Virani, N. D. Wong, D. Woo, and M. B. Turner. American Heart Association Statistics C and Stroke Statistics S. Executive summary: heart disease and stroke statistics-2014 update: a report from the American Heart Association. Circulation 129:399–410, 2014.

    Article  Google Scholar 

  17. Granada, J. F., M. Stenoien, P. P. Buszman, A. Tellez, D. Langanki, G. L. Kaluza, M. B. Leon, W. Gray, M. R. Jaff, and R. S. Schwartz. Mechanisms of tissue uptake and retention of paclitaxel-coated balloons: impact on neointimal proliferation and healing. Open Heart. 1:e000117, 2014.

    Article  Google Scholar 

  18. Hehrlein, C., G. Richardt, M. Wiemer, H. Schneider, C. Naber, E. Hoffmann, and U. Dietz. Description of Pantera Lux paclitaxel-releasing balloon and preliminary quantitative coronary angiography (QCA) results at six months in patients with coronary in-stent restenosis. EuroIntervention. 7(Suppl K):K119–K1124, 2011.

    Article  Google Scholar 

  19. Hirsch, A. T., L. Hartman, R. J. Town, and B. A. Virnig. National health care costs of peripheral arterial disease in the Medicare population. Vasc. Med. 13:209–215, 2008.

    Article  Google Scholar 

  20. Kaule, S., I. Minrath, F. Stein, U. Kragl, W. Schmidt, K. P. Schmitz, K. Sternberg, and S. Petersen. Correlating coating characteristics with the performance of drug-coated balloons: a comparative in vitro investigation of own established hydrogel- and ionic liquid-based coating matrices. PLoS ONE 10:e0116080, 2015.

    Article  Google Scholar 

  21. Kelsch, B., B. Scheller, M. Biedermann, Y. P. Clever, S. Schaffner, D. Mahnkopf, U. Speck, and B. Cremers. Dose response to Paclitaxel-coated balloon catheters in the porcine coronary overstretch and stent implantation model. Invest. Radiol. 46:255–263, 2011.

    Article  Google Scholar 

  22. Kothwala, D., A. Raval, A. Choubey, C. Engineer, and H. Kotadia. Paclitaxel drug delivery from cardoivascular stent. Trends Biomater. Artif. Organs. 19:88–92, 2006.

    Google Scholar 

  23. Kumar, G. N., U. K. Walle, K. N. Bhalla, and T. Walle. Binding of taxol to human plasma, albumin and alpha 1-acid glycoprotein. Res. Commun. Chem. Pathol. Pharmacol. 80:337–344, 1993.

    Google Scholar 

  24. Lamichhane, S., J. Anderson, T. Remund, P. Kelly, and G. Mani. Dextran sulfate as a drug delivery platform for drug-coated balloons: preparation, characterization, in vitro drug elution, and smooth muscle cell response. J. Biomed. Mater. Res. B Appl. Biomater. 104:1416–1430, 2016.

    Article  Google Scholar 

  25. Liistro, F. Drug-eluting balloons are better for below-knee lesions than sirolimus-eluting stents. Cath. Lab. Digest. 21, 2013.

  26. Maca, T., R. Ahmadi, K. Derfler, W. Hörl, R. Koppensteiner, E. Minar, B. Schneider, A. Stümpflen, and H. Ehringer. Elevated lipoprotein(a) and increased incidence of restenosis after femoropopliteal PTA: rationale for the higher risk of recurrence in females? Atherosclerosis. 127:27–34, 1996.

    Article  Google Scholar 

  27. Margolis, J., J. McDonald, R. Heuser, P. Klinke, R. Waksman, R. Virmani, N. Desai, and D. Hilton. Systemic nanoparticle paclitaxel (nab-paclitaxel) for in-stent restenosis I (SNAPIST-I): a first-in-human safety and dose-finding study. Clin. Cardiol. 30:165–170, 2007.

    Article  Google Scholar 

  28. Melder, R. J. IN.PACT drug-eluting balloon: technology and pre-clinical findings. EuroPCR., 2012.

  29. Nikol, S., T. Y. Heuehns, and B. Höfling. Molecular biology and post-angioplasty restenosis. Atherosclerosis. 123:17–31, 1996.

    Article  Google Scholar 

  30. Pan, Ch J, J. J. Tang, Y. J. Weng, J. Wang, and N. Huang. Preparation, characterization and anticoagulation of curcumin-eluting controlled biodegradable coating stents. J. Control. Release 116:42–49, 2006.

    Article  Google Scholar 

  31. Pósa, A., N. Nyolczas, R. Hemetsberger, N. Pavo, O. Petnehazy, Z. Petrasi, G. Sangiorgi, and M. Gyongyosi. Optimization of drug-eluting balloon use for safety and efficacy: evaluation of the 2nd generation paclitaxel-eluting DIOR-balloon in porcine coronary arteries. Catheter. Cardiovasc. Interv. 76:395–403, 2010.

    Article  Google Scholar 

  32. Raval, A., A. Choubey, C. Engineer, H. Kotadia, and D. Kothwala. Novel biodegradable polymeric matrix coated cardiovascular stent for controlled drug delivery. Trends Biomater. Artif. Organs. 20:101–110, 2007.

    Google Scholar 

  33. Raval, A., J. Parikh, and C. Engineer. Mechanism of controlled release kinetics from medical devices. Braz. J. Chem. Eng. 27:211–225, 2010.

    Article  Google Scholar 

  34. Rits, J., J. A. van Herwaarden, A. K. Jahrome, D. Krievins, and F. L. Moll. The incidence of arterial stent fractures with exclusion of coronary, aortic, and non-arterial settings. J. Vasc. Surg. 48:773, 2008.

    Article  Google Scholar 

  35. Scheinert, D., S. Duda, T. Zeller, H. Krankenberg, J. Ricke, M. Bosiers, G. Tepe, S. Naisbitt, and K. Rosenfield. The LEVANT I (Lutonix paclitaxel-coated balloon for the prevention of femoropopliteal restenosis) trial for femoropopliteal revascularization: first-in-human randomized trial of low-dose drug-coated balloon versus uncoated balloon angioplasty. JACC Cardiovasc. Interv. 7:10–19, 2014.

    Article  Google Scholar 

  36. Scheinert, D., S. Scheinert, J. Sax, C. Piorkowski, S. Braunlich, M. Ulrich, G. Biamino, and A. Schmidt. Prevalence and clinical impact of stent fractures after femoropopliteal stenting. J. Am. Coll. Cardiol. 45:312–315, 2005.

    Article  Google Scholar 

  37. Scheller, B. Contrast media as carriers for local drug delivery Successful inhibition of neointimal proliferation in the porcine coronary stent model. Eur. Heart J. 24:1462–1467, 2003.

    Article  Google Scholar 

  38. Scheller, B., U. Speck, C. Abramjuk, U. Bernhardt, M. Bohm, and G. Nickenig. Paclitaxel balloon coating, a novel method for prevention and therapy of restenosis. Circulation 110:810–814, 2004.

    Article  Google Scholar 

  39. Scheller, B., U. Speck, B. Romeike, A. Schmitt, M. Sovak, M. Böhm, and H. P. Stoll. Contrast media as carriers for local drug delivery: successful inhibition of neointimal proliferation in the porcine coronary stent model. Eur. Heart J. 24:1462–1467, 2003.

    Article  Google Scholar 

  40. Scheller, B., U. Speck, A. Schmitt, M. Böhm, and G. Nickenig. Addition of paclitaxel to contrast media prevents restenosis after coronary stent implantation. J. Am. Coll. Cardiol. 42:1415–1420, 2003.

    Article  Google Scholar 

  41. Schillinger, M., M. Haumer, G. Schlerka, W. Mlekusch, and M. Exner. Restenosis after percutaneous transluminal angioplasty in the femoropopliteal segment: the role of inflammation. J. Endovasc. Therapy. 8:477–483, 2001.

    Article  Google Scholar 

  42. Schroeder, H., D. R. Meyer, B. Lux, F. Ruecker, M. Martorana, and S. Duda. Two-year results of a low-dose drug-coated balloon for revascularization of the femoropopliteal artery: outcomes from the ILLUMENATE first-in-human study. Catheter. Cardiovasc. Interv. 86:278–286, 2015.

    Article  Google Scholar 

  43. Scientific, B. The next generation of drug-coated balloons. Endovasc. Today Eur. 2, 2015.

  44. Speck, U., N. Stolzenburg, D. Peters, and B. Scheller. How does a drug-coated balloon work? Overview of coating techniques and their impact. J. Cardiovasc. Surg. 51:3–11, 2016.

    Google Scholar 

  45. Sternberg, K., S. Kramer, C. Nischan, N. Grabow, T. Langer, G. Hennighausen, and K. P. Schmitz. In vitro study of drug-eluting stent coatings based on poly(l-lactide) incorporating cyclosporine A: drug release, polymer degradation and mechanical integrity. J. Mater. Sci. 18:1423–1432, 2007.

    Google Scholar 

  46. Stolzenburg, N., J. Breinl, S. Bienek, M. Jaguszewski, M. Lochel, M. Taupitz, U. Speck, S. Wagner, and J. Schnorr. Paclitaxel-coated balloons: investigation of drug transfer in healthy and atherosclerotic arteries—first experimental results in rabbits at low inflation pressure. Cardiovasc. Drugs Ther. 30:263–270, 2016.

    Article  Google Scholar 

  47. Tepe, G., B. Schnorr, T. Albrecht, K. Brechtel, C. D. Claussen, B. Scheller, U. Speck, and T. Zeller. Angioplasty of femoral-popliteal arteries with drug-coated balloons: 5-year follow-up of the THUNDER Trial. JACC Cardiovasc. Interv. 8:102–108, 2015.

    Article  Google Scholar 

  48. Tepe, G., T. Zeller, T. Albrecht, S. Heller, U. Schwarzwälder, J. Beregi, C. D. Claussen, A. Oldenburg, B. Scheller, and U. Speck. Local delivery of paclitaxel to inhibit restenosis during angioplasty of the leg. N. Engl. J. Med. 358:689–699, 2008.

    Article  Google Scholar 

  49. Turner, E. A., A. C. Stenson, and S. K. Yazdani. HPLC-MS/MS method for quantification of paclitaxel from keratin containing samples. J. Pharm. Biomed. Anal. 139:247–251, 2017.

    Article  Google Scholar 

  50. Wang, L. Drug releasing coatings for medical devices., 2016.

  51. Werk, M., T. Albrecht, D. R. Meyer, M. N. Ahmed, A. Behne, U. Dietz, G. Eschenbach, H. Hartmann, C. Lange, B. Schnorr, H. Stiepani, G. B. Zoccai, and E. L. Hanninen. Paclitaxel-coated balloons reduce restenosis after femoro-popliteal angioplasty: evidence from the randomized PACIFIER trial. Circ. Cardiovasc. Interv. 5:831–840, 2012.

    Article  Google Scholar 

  52. Werk, M., S. Langner, B. Reinkensmeier, H. F. Boettcher, G. Tepe, U. Dietz, N. Hosten, B. Hamm, U. Speck, and J. Ricke. Inhibition of restenosis in femoropopliteal arteries: paclitaxel-coated versus uncoated balloon: femoral paclitaxel randomized pilot trial. Circulation 118:1358–1365, 2008.

    Article  Google Scholar 

  53. Yazdani, S. K., E. Pacheco, M. Nakano, F. Otsuka, S. Naisbitt, F. D. Kolodgie, E. Ladich, S. Rousselle, and R. Virmani. Vascular, downstream, and pharmacokinetic responses to treatment with a low dose drug-coated balloon in a swine femoral artery model. Catheter. Cardiovasc. Interv. 83:132–140, 2014.

    Article  Google Scholar 

  54. Zhang, Y. L., J. Bendrick-Peart, T. Strom, M. Haschke, and U. Christians. Development and validation of a high-throughput assay for quantification of the proliferation inhibitor ABT-578 Using LC/LC-MS/MS in blood and tissue samples. Ther. Drug Monit. 27:770–778, 2005.

    Article  Google Scholar 

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Funding

This work was supported by the American Heart Association [#15SDG25880000, #16PRE27350003], National Institute of Health [#1R15HL127596] and a research grant from the University of South Alabama Office and Research Development.

Conflict of interest

Saami K. Yazdani serves on the Scientific Advisory Board of Advanced Catheter Therapies and Toray Industries and has received grant support from Advanced Catheter Therapies, Toray Industries and Lutonix, Inc., and is a shareholder in Advanced Catheter Therapies. Other co-authors have no conflict of interest to report.

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This article does not contain any studies with human participants or animals performed by any of the authors.

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Authors and Affiliations

  1. Mechanical Engineering Department, University of South Alabama, Mobile, AL, 36688, USA

    Emily A. Turner, Marzieh K. Atigh, Megan M. Erwin & Saami K. Yazdani

  2. iC42 Clinical Research and Development, University of Colorado, Aurora, CO, 80045, USA

    Uwe Christians

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  1. Emily A. Turner
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Associate Editors Baruch Barry Lieber and Ajit P. Yoganathan oversaw the review of this article.

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Deposition of coating on mounted balloons using air spraying. Supplementary material 1 (MP4 1645 kb)

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Turner, E.A., Atigh, M.K., Erwin, M.M. et al. Coating and Pharmacokinetic Evaluation of Air Spray Coated Drug Coated Balloons. Cardiovasc Eng Tech 9, 240–250 (2018). https://doi.org/10.1007/s13239-018-0346-1

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