SBIR-STTR Award

This program plans to develop a drug delivery system that provides maximum oxime drug exposure and improve cholinesterase reactivation in the brain and tissues of central nervous system (CNS) of a warfighter after exposure to organophosphate (OP) poisoning. The greatest need for improvement in cholinesterase reactivation is the ability to deliver charged cholinesterase reactivators to the CNS that do not readily cross the blood-brain barier (BBB). The current combination drug therapy requires infusion of high doses of drugs and is not well-suited for battlefield administration. Impel NeuroPharma has developed a novel non-invasive intranasal drug delivery technology that will bypass the BBB thereby allowing a maximum drug exposure and cholinesterase reactivation. Instead of depositing drugs to the lower nasal cavity (achieved with traditional nasal delivery devices), this technology deposits drugs into the upper 1/3 of the nasal cavity and provides direct access to the brain and CNS (via the olfactory cells), thereby improving the efficiency of CNS delivery. This proposed program will formulate oximes for delivery into the brain and CNS using this device and evaluating it in appropriate animal models. We envision that this product will be used in theater to counteract the effects of OP poisoning.

Keywords:
Liposomes, Nanoparticles, Oximes, Blood Brain Barrier, Status Epilepticus, Intranasal, Device, Non-Invasive

Technical Abstract Impel NeuroPharma has developed a novel non-invasive delivery system, the POD device that targets drug to the upper third of the nasal cavity which results in direct and rapid transport of drug to the CNS via the olfactory perineural pathways, effectively bypassing the BBB. In Phase I of this research contract Impel successfully characterized and tested both an aqueous and a dry powder form of 2-PAM for administration via Impel’s POD device, which led to dramatic increases in 2-PAM brain concentrations and lower plasma concentrations compared to IV administration. In Phase 2 of this research contract, Impel will conduct critical studies in order to ready this product for clinical trials and ultimately for use in the battlefield setting as an effective treatment for nerve gas exposure. Impel’s four main objectives are 1) Determine doses of POD administered 2-PAM and MMB-4 with optimal CNS exposure in rats; 2) Demonstrate the CNS protective effects of POD administered 2-PAM and MMB-4 in rats exposed to the nerve agents sarin and soman; 3) Develop optimized POD device for battlefield oxime use; and 4) Determine tolerability and drug distribution of POD administered oxime in non-human primates.

Keywords:
Central Nervous System, Drug Delivery, Intranasal, Nose-To-Brain, Oximes, Mmb-4, 2-Pam, Organophosphate Posioning,