title: Oral, ultra-long-lasting drug delivery: Application toward malaria elimination goals.
abstract: 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 large-animal 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 malaria-transmitting 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 malaria-transmitting 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.
authors.affiliation: Department of Chemical Engineering and Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.|Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.|Lyndra Inc., Watertown, MA 02472, USA.
authors.forename: Andrew M
authors.initials: AM
authors.lastname: Bellinger
authors.affiliation: Department of Chemical Engineering and Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
authors.forename: Mousa
authors.initials: M
authors.lastname: Jafari
authors.affiliation: Department of Chemical Engineering and Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.|Lyndra Inc., Watertown, MA 02472, USA.
authors.forename: Tyler M
authors.initials: TM
authors.lastname: Grant
authors.affiliation: Department of Chemical Engineering and Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
authors.forename: Shiyi
authors.initials: S
authors.lastname: Zhang
authors.affiliation: Department of Infectious Disease Epidemiology, MRC (Medical Research Council) Centre for Outbreak Analysis and Modelling, Imperial College London, London, U.K.
authors.forename: Hannah C
authors.initials: HC
authors.lastname: Slater
authors.affiliation: Institute for Disease Modeling, Bellevue, WA 98005, USA.
authors.forename: Edward A
authors.initials: EA
authors.lastname: Wenger
authors.affiliation: Department of Chemical Engineering and Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
authors.forename: Stacy
authors.initials: S
authors.lastname: Mo
authors.affiliation: Department of Chemical Engineering and Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
authors.forename: Young-Ah Lucy
authors.initials: YL
authors.lastname: Lee
authors.affiliation: Department of Chemical Engineering and Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
authors.forename: Hormoz
authors.initials: H
authors.lastname: Mazdiyasni
authors.affiliation: Department of Chemical Engineering and Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
authors.forename: Lawrence
authors.initials: L
authors.lastname: Kogan
authors.affiliation: Department of Chemical Engineering and Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
authors.forename: Ross
authors.initials: R
authors.lastname: Barman
authors.affiliation: Department of Chemical Engineering and Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.|Division of Gastroenterology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Cody
authors.initials: C
authors.lastname: Cleveland
authors.affiliation: Department of Chemical Engineering and Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
authors.forename: Lucas
authors.initials: L
authors.lastname: Booth
authors.affiliation: Department of Chemical Engineering and Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
authors.forename: Taylor
authors.initials: T
authors.lastname: Bensel
authors.affiliation: Department of Chemical Engineering and Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
authors.forename: Daniel
authors.initials: D
authors.lastname: Minahan
authors.affiliation: Department of Chemical Engineering and Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
authors.forename: Haley M
authors.initials: HM
authors.lastname: Hurowitz
authors.affiliation: Department of Chemical Engineering and Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
authors.forename: Tammy
authors.initials: T
authors.lastname: Tai
authors.affiliation: Division of Infectious Diseases, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
authors.forename: Johanna
authors.initials: J
authors.lastname: Daily
authors.affiliation: Biomatics Capital, 1107 1st Avenue, Apartment 1305, Seattle, WA 98101, USA.
authors.forename: Boris
authors.initials: B
authors.lastname: Nikolic
authors.affiliation: Institute for Disease Modeling, Bellevue, WA 98005, USA.
authors.forename: Lowell
authors.initials: L
authors.lastname: Wood
authors.affiliation: Institute for Disease Modeling, Bellevue, WA 98005, USA.
authors.forename: Philip A
authors.initials: PA
authors.lastname: Eckhoff
authors.affiliation: Department of Chemical Engineering and Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA. rlanger@mit.edu ctraverso@partners.org.|Media Lab, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.|Institute for Medical Engineering and Science, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
authors.forename: Robert
authors.initials: R
authors.lastname: Langer
authors.affiliation: Department of Chemical Engineering and Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA. rlanger@mit.edu ctraverso@partners.org.|Division of Gastroenterology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.|Division of Gastroenterology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA.
authors.forename: Giovanni
authors.initials: G
authors.lastname: Traverso
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000962:Antimalarials / Q000008:administration & dosage*; D002214:Capsules; D009033:Culicidae; D003692:Delayed-Action Preparations; D016503:Drug Delivery Systems; D065546:Drug Liberation; D004724:Endoscopy; D020342:Finite Element Analysis; D006801:Humans; D007559:Ivermectin / Q000008:administration & dosage*; D008288:Malaria / Q000188:drug therapy* / Q000635:transmission; D008962:Models, Theoretical; D011108:Polymers / Q000737:chemistry; D013270:Stomach / Q000187:drug effects*; D013552:Swine
chemical_list: D000962:Antimalarials; D002214:Capsules; D003692:Delayed-Action Preparations; D011108:Polymers; D007559:Ivermectin