TY - JOUR
T1 - Oral, ultra-long-lasting drug delivery
T2 - Application toward malaria elimination goals
AU - Bellinger, Andrew M.
AU - Jafari, Mousa
AU - Grant, Tyler M.
AU - Zhang, Shiyi
AU - Slater, Hannah C.
AU - Wenger, Edward A.
AU - Mo, Stacy
AU - Lee, Young Ah Lucy
AU - Mazdiyasni, Hormoz
AU - Kogan, Lawrence
AU - Barman, Ross
AU - Cleveland, Cody
AU - Booth, Lucas
AU - Bensel, Taylor
AU - Minahan, Daniel
AU - Hurowitz, Haley M.
AU - Tai, Tammy
AU - Daily, Johanna
AU - Nikolic, Boris
AU - Wood, Lowell
AU - Eckhoff, Philip A.
AU - Langer, Robert
AU - Traverso, Giovanni
N1 - Publisher Copyright:
© 2016 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science.
PY - 2016/11/16
Y1 - 2016/11/16
N2 - Efforts at elimination of scourges, such as malaria, are limited by the logistic challenges of reaching large rural populations and ensuring patient adherence to adequate pharmacologic treatment. We have developed an oral, ultra-long-acting capsule that dissolves in the stomach and deploys a star-shaped dosage form that releases drug while assuming a geometry that prevents passage through the pylorus yet allows passage of food, enabling prolonged gastric residence. This gastric-resident, drug delivery dosage form releases small-molecule drugs for days to weeks and potentially longer. Upon dissolution of the macrostructure, the components can safely pass through the gastrointestinal tract. Clinical, radiographic, and endoscopic evaluation of a swine largeanimal model that received these dosage forms showed no evidence of gastrointestinal obstruction or mucosal injury. We generated long-acting formulations for controlled release of ivermectin, a drug that targets malariatransmitting mosquitoes, in the gastric environment and incorporated these into our dosage form, which then delivered a sustained therapeutic dose of ivermectin for up to 14 days in our swine model. Further, by using mathematical models of malaria transmission that incorporate the lethal effect of ivermectin against malariatransmitting mosquitoes, we demonstrated that this system will boost the efficacy of mass drug administration toward malaria elimination goals. Encapsulated, gastric-resident dosage forms for ultra-long-acting drug delivery have the potential to revolutionize treatment options for malaria and other diseases that affect large populations around the globe for which treatment adherence is essential for efficacy.
AB - Efforts at elimination of scourges, such as malaria, are limited by the logistic challenges of reaching large rural populations and ensuring patient adherence to adequate pharmacologic treatment. We have developed an oral, ultra-long-acting capsule that dissolves in the stomach and deploys a star-shaped dosage form that releases drug while assuming a geometry that prevents passage through the pylorus yet allows passage of food, enabling prolonged gastric residence. This gastric-resident, drug delivery dosage form releases small-molecule drugs for days to weeks and potentially longer. Upon dissolution of the macrostructure, the components can safely pass through the gastrointestinal tract. Clinical, radiographic, and endoscopic evaluation of a swine largeanimal model that received these dosage forms showed no evidence of gastrointestinal obstruction or mucosal injury. We generated long-acting formulations for controlled release of ivermectin, a drug that targets malariatransmitting mosquitoes, in the gastric environment and incorporated these into our dosage form, which then delivered a sustained therapeutic dose of ivermectin for up to 14 days in our swine model. Further, by using mathematical models of malaria transmission that incorporate the lethal effect of ivermectin against malariatransmitting mosquitoes, we demonstrated that this system will boost the efficacy of mass drug administration toward malaria elimination goals. Encapsulated, gastric-resident dosage forms for ultra-long-acting drug delivery have the potential to revolutionize treatment options for malaria and other diseases that affect large populations around the globe for which treatment adherence is essential for efficacy.
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U2 - 10.1126/scitranslmed.aag2374
DO - 10.1126/scitranslmed.aag2374
M3 - Article
C2 - 27856796
AN - SCOPUS:84995608772
SN - 1946-6234
VL - 8
JO - Science translational medicine
JF - Science translational medicine
IS - 365
ER -