title: A Site-Specific, Sustained-Release Drug Delivery System for Aneurysmal Subarachnoid Hemorrhage.
abstract: Nimodipine is the only drug approved for use by the Food and Drug Administration for improving outcome after aneurysmal subarachnoid hemorrhage (SAH). It has less than optimal efficacy, causes dose-limiting hypotension in a substantial proportion of patients, and is administered enterally 6 times daily. We describe development of site-specific, sustained-release nimodipine microparticles that can be delivered once directly into the subarachnoid space or cerebral ventricles for potential improvement in outcome of patients with aneurysmal SAH. Eight injectable microparticle formulations of nimodipine in poly(DL-lactide-co-glycolide) (PLGA) polymers of varying composition were tested in vitro, and 1 was advanced into preclinical studies and clinical application. Intracisternal or intraventricular injection of nimodipine-PLGA microparticles in rats and beagles demonstrated dose-dependent, sustained concentrations of nimodipine in plasma and cerebrospinal fluid for up to 29 days with minimal toxicity in the brain or systemic tissues at doses <2 mg in rats and 51 mg in beagles, which would be equivalent of up to 612-1200 mg in humans, based on scaling relative to cerebrospinal fluid volumes. Efficacy was tested in the double-hemorrhage dog model of SAH. Nimodipine-PLGA microparticles significantly attenuated angiographic vasospasm. This therapeutic approach shows promise for improving outcome after SAH and may have broader applicability for similar diseases that are confined to body cavities or spaces, are self-limited, and lack effective treatments.
authors.affiliation: Department of Neurosurgery, University Medical Center Mannheim, Ruprecht-Karls-University Heidelberg, Germany, Mannheim, Germany. daniel.haenggi@medma.uni-heidelberg.de.
authors.forename: Daniel
authors.initials: D
authors.lastname: Hänggi
authors.affiliation: Department of Neurosurgery, University Medical Center Mannheim, Ruprecht-Karls-University Heidelberg, Germany, Mannheim, Germany.
authors.forename: Nima
authors.initials: N
authors.lastname: Etminan
authors.affiliation: Department of Neurosurgery, Medical Faculty, Heinrich-Heine-University, Düsseldorf, Germany.
authors.forename: Hans Jakob
authors.initials: HJ
authors.lastname: Steiger
authors.affiliation: MPI Research, Mattawan, MI, USA.
authors.forename: Mark
authors.initials: M
authors.lastname: Johnson
authors.affiliation: MPI Research, Mattawan, MI, USA.
authors.forename: M Melissa
authors.initials: MM
authors.lastname: Peet
authors.affiliation: Evonik Industries, Birmingham, AL, USA.
authors.forename: Tom
authors.initials: T
authors.lastname: Tice
authors.affiliation: Evonik Industries, Birmingham, AL, USA.
authors.forename: Kevin
authors.initials: K
authors.lastname: Burton
authors.affiliation: Evonik Industries, Birmingham, AL, USA.
authors.forename: Bruce
authors.initials: B
authors.lastname: Hudson
authors.affiliation: Evonik Industries, Birmingham, AL, USA.
authors.forename: Michele
authors.initials: M
authors.lastname: Turner
authors.affiliation: Pharmaceutical Associates, LLC, Tampa, FL, USA.
authors.forename: Angela
authors.initials: A
authors.lastname: Stella
authors.affiliation: Google, Mountain View, CA, USA.
authors.forename: Parissa
authors.initials: P
authors.lastname: Heshmati
authors.affiliation: Evonik Industries, Birmingham, AL, USA.
authors.forename: Cara
authors.initials: C
authors.lastname: Davis
authors.affiliation: Edge Therapeutics, Inc., Berkeley Heights, NJ, USA.
authors.forename: Herbert J
authors.initials: HJ
authors.lastname: Faleck
authors.affiliation: Edge Therapeutics, Inc., Berkeley Heights, NJ, USA.|Division of Neurosurgery, St. Michael's Hospital, Labatt Family Centre of Excellence in Brain Injury and Trauma Research, Keenan Centre for Biomedical Science, Li Ka Shing Knowledge Institute, St. Michael's Hospital, Department of Surgery, University of Toronto, Toronto, ON, Canada.
authors.forename: R Loch
authors.initials: RL
authors.lastname: Macdonald
mesh_terms: D000818:Animals; D001921:Brain / Q000187:drug effects / Q000473:pathology; D003692:Delayed-Action Preparations; D004285:Dogs; D005260:Female; D015918:Infusion Pumps, Implantable; D008297:Male; D009553:Nimodipine / Q000008:administration & dosage / Q000627:therapeutic use; D051381:Rats; D013345:Subarachnoid Hemorrhage / Q000188:drug therapy* / Q000473:pathology; D016896:Treatment Outcome
chemical_list: D003692:Delayed-Action Preparations; D009553:Nimodipine
keywords: Angiographic vasospasm; delayed cerebral ischemia.; nimodipine; subarachnoid hemorrhage; sustained release