@article{7350007a60c948dfbd3843742701edb1,
title = "A deep eutectic-based, self-emulsifying subcutaneous depot system for apomorphine therapy in Parkinson{\textquoteright}s disease",
abstract = "Apomorphine, a dopamine agonist, is a highly effective therapeutic to prevent intermittent off episodes in advanced Parkinson{\textquoteright}s disease. However, its short systemic half-life necessitates three injections per day. Such a frequent dosing regimen imposes a significant compliance challenge, especially given the nature of the disease. Here, we report a deep eutectic-based formulation that slows the release of apomorphine after subcutaneous injection and extends its pharmacokinetics to convert the current three-injections-a-day therapy into an every-other-day therapy. The formulation comprises a homogeneous mixture of a deep eutectic solvent choline-geranate, a cosolvent n-methyl-pyrrolidone, a stabilizer polyethylene glycol, and water, which spontaneously emulsifies into a microemulsion upon injection in the subcutaneous space, thereby entrapping apomorphine and significantly slowing its release. Ex vivo studies with gels and rat skin demonstrate this self-emulsification process as the mechanism of action for sustained release. In vivo pharmacokinetics studies in rats and pigs further confirmed the extended release and improvement over the clinical comparator Apokyn. In vivo pharmacokinetics, supported by a pharmacokinetic simulation, demonstrate that the deep eutectic formulation reported here allows the maintenance of the therapeutic drug concentration in plasma in humans with a dosing regimen of approximately three injections per week compared to the current clinical practice of three injections per day.",
keywords = "Apomorphine, Deep eutectic, Depot, Ionic liquid, Parkinson{\textquoteright}s",
author = "Jayoung Kim and Yongsheng Gao and Zongmin Zhao and Danika Rodrigues and Tanner, {Eden E.L.} and Kelly Ibsen and Sasmal, {Pradip K.} and Rajasekhar Jaladi and Shanavas Alikunju and Samir Mitragotri",
note = "Funding Information: ACKNOWLEDGMENTS. The work was financially supported by Promius Pharma (a subsidiary of Dr. Reddy{\textquoteright}s Laboratories) and School of Engineering and Applied Sciences at Harvard University. The authors acknowledge the Harvard Center for Mass Spectrometry; the Harvard Center for Biological Imaging; the Allston-Science and Engineering Complex{\textquoteright}s Molecular and Cellular Biology Core; and Harvard University Center for Nanoscale Systems (CNS), a member of the National Nanotechnology Coordinated Infrastructure Network (NNCI) supported by National Science Foundation ECCS-2025158, for infrastructure and support. We also thank the Dana-Farber/Harvard Cancer Center in Boston, MA, for the use of the Rodent Histopathology Core and its histological section preparation service. Dana-Farber/Harvard Cancer Center is supported in part by the National Cancer Institute Cancer Center Support Grant National Institutes of Health 5P30CA06516. Funding Information: The work was financially supported by Promius Pharma (a subsidiary of Dr. Reddy{\textquoteright}s Laboratories) and School of Engineering and Applied Sciences at Harvard University. The authors acknowledge the Harvard Center for Mass Spectrometry; the Harvard Center for Biological Imaging; the Allston-Science and Engineering Complex{\textquoteright}s Molecular and Cellular Biology Core; and Harvard University Center for Nanoscale Systems (CNS), a member of the National Nanotechnology Coordinated Infrastructure Network (NNCI) supported by National Science Foundation ECCS-2025158, for infrastructure and support. We also thank the Dana-Farber/Harvard Cancer Center in Boston, MA, for the use of the Rodent Histopathology Core and its histological section preparation service. Dana-Farber/Harvard Cancer Center is supported in part by the National Cancer Institute Cancer Center Support Grant National Institutes of Health 5P30CA06516. Publisher Copyright: {\textcopyright} 2022 National Academy of Sciences. All rights reserved.",
year = "2022",
month = mar,
day = "1",
doi = "10.1073/pnas.2110450119",
language = "English",
volume = "119",
journal = "Proceedings of the National Academy of Sciences of the United States of America",
issn = "0027-8424",
publisher = "National Academy of Sciences",
number = "9",
}