A Site-Specific, Sustained-Release Drug Delivery System for Aneurysmal Subarachnoid Hemorrhage.

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.

Intracranial drug delivery for subarachnoid hemorrhage.

Tice and colleagues pioneered site-specific, sustained-release drug delivery to the brain almost 30 years ago. Currently there is one drug approved for use in this manner. Clinical trials in subarachnoid hemorrhage have led to approval of nimodipine for oral and intravenous use, but other drugs, such as clazosentan, hydroxymethylglutaryl CoA reductase inhibitors (statins) and magnesium, have not shown consistent clinical efficacy. We propose that intracranial delivery of drugs such as nimodipine, formulated in sustained-release preparations, are good candidates for improving outcome after subarachnoid hemorrhage because they can be administered to patients that are already undergoing surgery and who have a self-limited condition from which full recovery is possible.