gms | German Medical Science

Objective: Morbidity and mortality following aneurysmal subarachnoid hemorrhage (aSAH) remains substantial. Oral nimodipine is the only drug approved for use by the Food and Drug Administration for improving outcome after aSAH. It has less than optimal efficacy, causes dose-limiting hypotension in a substantial proportion of patients and is administered orally 6 times a day. We describe development of site-specific, sustained release nimodipine microparticles that can be delivered once directly into the cerebral ventricles or subarachnoid space for potential improvement in outcome of patients with aneurysmal SAH.

Method: Eight injectable microparticle formulations of nimodipine in poly(DL-lactide-co-glycolide)(PLGA) polymers of varying composition were tested in vitro, and one (EG-1962) was advanced into preclinical studies to assess toxicity in rats and beagles after intraventricular and intracisternal delivery. Pharmacological activity was tested against angiographic vasospasm in the dog double hemorrhage model (n = 40 dogs randomly allocated to oral nimodipine, placebo microparticles, 100 mg nimodipine microparticles intraventricular or 40 or 100 mg nimodipine microparticles intracisternal).

Results: Intraventricular or Intracisternal injection of the selected formulation of nimodipine-PLGA microparticles (EG-1962) in rats and beagles demonstrated dose-dependent, sustained concentrations of nimodipine in plasma and cerebrospinal fluid for up to 29 days without toxicity in the brain or systemic tissues at doses less than 2 mg in rats and 51 mg in beagles (equivalent of 612 to 1200 mg respectively in humans), based on scaling relative to cerebrospinal fluid volumes. Nimodipine-PLGA microparticles (EG-1962) significantly attenuated angiographic vasospasm compared to oral nimodipine or placebo microparticles. A phase 2 dose-finding, safety and tolerability study (NEWTON - Nimodipine microparticles to Enhance recovery While reducing Toxicity after subarachnoid hemorrhage) with EG-1962 is being completed now.

Conclusions: Both intraventricular and intracisternal delivery of nimodipine microparticles (EG-1962) show promise for improving outcome after SAH. This technology may have broader applicability for similar diseases that are confined to body cavities or spaces, are self-limited and lack effective treatments.