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Novel physiological depot formulations for long-term butyrylcholinesterase delivery


OBJECTIVE: A capability is sought to deliver human butyrylcholinesterase (BuChE) into blood circulation from a depot that can be administered intramuscularly or subcutaneously and which can maintain blood BuChE concentrations above 80 micrograms/milliliter for periods exceeding 10 days. The ability to maintain elevated blood BuChE concentrations is an operationally desirable capability that allows for extended prophylactic protection from the effects of organophosphorous agents while minimizing the need for repeated administration. DESCRIPTION: Elevated BuChE plasma levels confer prophylactic protection from the effects of organophosphorous agents by scavenging these agents in the blood stream before they can reach terminal nerve synapses. We seek a capability to deliver butyrylcholinesterase into blood circulation in a timed-release manner in order to maintain elevated BuChE concentrations over extended periods of time. Operational requirements for certain types of missions make it impractical for health care providers to administer repeated intravenous doses of BuChE 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 BuChE concentration 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 in areas where health care providers are not available to administer this prophylaxis. The proposed system must allow for subcutaneous or intramuscular administration of a stable depot that can sustain delivery of butyrylcholinesterase into circulation over the course of at least 10 days. The depot should be able to maintain a BuChE plasma concentration of 80 micrograms/mL over the 10 day period. The proposed solution may be composed of any suitable material(s) to achieve the required performance characteristics. Administration at multiple injection sites is acceptable. Unless otherwise exempted, the proposed design must be informed by requirements for eventual approval under the Food and Drug Administration regulatory pathways for drugs, biologics, or medical devices. PHASE I: The performer will demonstrate the formulation of BuChE into a depot system that is capable of delivering BuChE at the proper release rate to sustain blood concentrations over the time period specified above. Demonstration using an in vitro model system is acceptable. Modeling and simulation of depot performance to support in vitro or in vivo study design(s) is highly encouraged. PHASE II: The performer will evaluate performance and conduct early animal trials in an established animal model in collaboration with an entity capable of working with nerve agents and in consultation with the US Army Medical Research Institute of Chemical Defense (USMRICD). Conduct detailed characterization of depot performance in a suitable animal model, demonstrate in vivo efficacy against nerve agent challenge using an established animal model, and conduct toxicology and safety studies required to support an IND, 510(k), or related FDA filing. PHASE III: The performer or a suitable partner will conduct a Phase 1 clinical trial to establish human safety and obtain pharmacokinetic performance data. PHASE III DUAL USE APPLICATIONS: Sustained delivery of large molecule therapeutics is an open problem with a large potential market and with direct applicability to dozens of FDA-licensed biologics. Successful completion of all three phases under this solicitation will support small business valuation by confirming technical merit that invites further investment. This award mechanism will bridge the gap between laboratory-scale innovation and entry into a recognized FDA regulatory pathway leading to commercialization. REFERENCES: 1. D. E. Lenz et al., Toxicology 233, 31-39 (2007). 2. L. Raveh, E. Grauer, J. Grunwald, E. Cohen, Y. Ashani, Toxicol Appl Pharmacol 145, 43-53 (1997). 3. P. Masson, O. Lockridge, Archives of Biochemistry and Biophysics 494, 107-120 (2010). 4. D. E. Lenz, E. D. Clarkson, S. M. Schulz, D. M. Cerasoli, Chemicobiological interactions 187, 249-252 (2010). 5. A. Altunbas, S. J. Lee, S. A. Rajasekaran, J. P. Schneider, D. J. Pochan, Biomaterials 32, 5906-5914 (2011). 6. R. Huang, W. Qi, L. Feng, R. Su, Z. He, Soft Matter 7, 6222 (2011). 7. S. Y. Fung et al., Advanced Functional Materials 19, 74-83 (2009).
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