Novel physiological depot formulations for long-term butyrylcholinesterase delivery

Oraganophosphorus poisons are potent nerve agents that function by inhibiting the action of acetylcholinestrase in nerve cells. Of these, G-class nerve agents including: Taubin, Soman and Saurin, and, V class agents such as VX represent a significant threat to US military personnel. Human plasma enzyme, Butyrylcholinesterase detoxifies organophosphates by making a covalent bond with them at stoichiometric ratios. The organophosphate nerve agents and butyrylcholinesterase are both inactivated in the bonding process; this inactivation of butyrylcholinesterase has no physiologically or psychologically adverse effects. Military operational requirements for certain types of missions make it impractical for health care providers to administer repeated intravenous doses of Butyrylcholinesterase in order to maintain a sufficiently high plasma concentration to afford protection over the duration of a mission. The ability to deliver and maintain sufficiently high concentration of Butyrylcholinesterase in the blood without repeated dosing is a capability that would enhance the operational utility of BuChE as a prophylactic, particularly in support of extended-duration missions. The goal of this proposal is to develop novel sustained-release formulation to deliver human plasma derived butyrylcholinesterase into blood circulation in order to maintain elevated HuBuChE concentrations of 80µg/mL for at least 10 days.