Organophosphorus nerve agents are highly toxic chemicals that can cause severe adverse effects upon exposure, including respiratory failure and death. In severe cases, up to 100 mg of atropine sulfate (AS) may be required to control cholinergic symptoms. Such a requirement could not be easily met with commercially available formulations, since too many vials would be needed to deliver up to 100 mg AS. Thus, a higher concentration AS formulation would streamline logistics, since fewer vials would be needed to deliver the same total dose of AS. The proposed studies aim to evaluate and develop concentrated AS formulations (5.25 to 21 mg/mL) presented in multi-dose amber vials. CMC Pharma has significant experience developing atropine and related formulations and analytical methods and completing the stability evaluations that are needed for a new, concentrated AS formulation. Alternatively, a more concentrated formulation of AS (35 mg/mL) can be considered for use in a multi-dose pen injector intended for a single patient (e.g. similar to an insulin pen utilized by diabetic patients). CMC Pharma generated preliminary solubility data to support formulations in pharmaceutically acceptable aqueous vehicles at concentrations up to 100 mg/mL. Preliminary formulation prototypes were prepared and compared to a dilute atropine formulation and a commercial AS drug product. These stability data at accelerated temperatures support a concentrated AS formulation and suggest that a multi-year shelf life is possible when stored at room temperature and operational conditions. CMC Pharmas prior experience with atropine and the generated preliminary data support continued development of a concentrated aqueous solution formulation. CMC Pharma proposes to complete specific aims to develop prototype formulations and analytical methods that meet FDA, ICH and industry standards. A specific aim will also be executed that appropriately designs and executes stability studies to generate an initial data package to support at least a 2 year shelf life. CMC Pharma will utilize modern project management techniques to ensure efficient coordination of efforts between CMC Pharma, consultants, and the Government. CMC Pharma has the required personnel, subject matter expertise, facilities and equipment, and extensive experience in drug development from early stage research through IND submission, clinical trials, product approval, and commercialization. Specific relevant experience has focused on executing contracts to develop organophosphate medical countermeasures as both a prime and subcontractor. CMC Pharma is committed to and intends to seek FDA approval, secure the appropriate supply chain, including cGMP manufacturing, in order to provide the drug product for commercial use and the national strategic stockpile.
