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Dual Formulation of Atropine/Scopolamine with Enhanced Stability

Description:

TECHNOLOGY AREA(S): Chem Bio_defense, Bio Medical 

OBJECTIVE: Develop stable, combined atropine/scopolamine formulations to exploit complementary pharmacological profiles for optimal muscarinic receptor blockade and anticholinergic activity within the peripheral and central nervous systems. The goal is to develop improved countermeasures against organophosphorus (OP) nerve agent (NA) intoxication. 

DESCRIPTION: The current United States military standard treatment for NA intoxication is immediate administration of medications by autoinjector. Up to three Antidote Treatment for Nerve Agents Autoinjectors (ATNAA), each consisting of 2.0 mg atropine and 600 mg oxime (2-pralidoxime [2-PAM]), to reactivate OP-inhibited acetylcholinesterase [AChE]) may be administered to counter nerve agent symptoms. An autoinjector containing 10 mg of the anticonvulsant diazepam (Convulsant Antidote for Nerve Agents [CANA]) is administered following three ATNAA administrations. Medics in the field can administer an additional 20-30 mg of atropine and up to 30 mg of diazepam in the first hour in cases of severe intoxication. Animal studies demonstrated scopolamine could serve as a useful adjunct treatment for NA intoxication. Scopolamine enhanced the effectiveness of human equivalent doses of the standard medical countermeasures atropine, 2-PAM and diazepam. Unlike atropine, scopolamine rapidly penetrates the blood brain barrier and has greater potency (7.5 times atropine activity in the central nervous system). The addition of scopolamine to the NA treatment regimen appears to be advantageous for reducing seizures, enhancing survival, and recovery from OP NA exposure. The Joint Chemical and Biological Defense Program would like to make the brigade combat teams leaner and more agile while retaining capability. As such, minimizing to the extent feasible, the number of soldier-carried ATNAAs and medic-carried medical countermeasures is desirable. Support medical personnel carry Atropen® autoinjectors, containing the equivalent of 2.0 mg atropine sulfate (AS), to treat personnel with severe NA intoxication. A stable, combined formulation of atropine and scopolamine would increase the therapeutic efficacy of the current treatment regimen as well as reduce the requirement for additional atropine in cases of severe NA poisoning. The objective is to develop a formulation that has, minimally, stability for two years at room temperature. The desired final formulation is to be a stable, intramuscular (IM) injectable containing both atropine and scopolamine. 

PHASE I: Establish preliminary specifications for a combined formulation under International Conference on Harmonization (ICH) Pharmaceutical Development Guidelines. Explore scopolamine hydrobromide dose ranges between 0.5 to 3.0 mg, combined with a fixed dose equivalent of 2.0 mg atropine sulfate. Generate initial specifications for a dual formulation designed to maximize compatibility and stability of the combined drug substances. The dual prototype formulation may be a single phase liquid mixture or a dual/multiphase system utilizing lyophilized drug powder(s) and vehicle/diluent components. The desired final volume is to be no more than 2.0 ml. Generate initial stability profile of the dual prototype formulation(s). 

PHASE II: Continue assessment of the dual prototype formulation stability based on mass balance techniques under ICH Pharmaceutical Development Guidelines. Studies will employ forced degradation strategies based on specific chemical degradation. Stress conditions should include heat, acid, base, light, and the presence of oxidizing agents. Conduct necessary ICH stability studies, to include room temperature and accelerated conditions. Conduct a pharmacokinetic (PK) study of the optimized dual formulation prototype in rodents. Determine plasma levels of both drugs after a single IM injection and characterize standard pharmacokinetic parameters to include Cmax, AUCtotal, Tmax, and elimination half-life. PHASE III: Conduct a 14 day toxicity and toxicokinetic (TK) study of a single dose IM dual formulation in non-human primates (Rhesus macaques). The TK of atropine/scopolamine will be evaluated using plasma drug concentrations, construction of concentration time profiles, and TK parameters. Toxicity will be evaluated using survival, clinical observations (including injection site reactions), body weights, food consumption measurements, functional observational battery assessments, clinical pathology (hematology, serum chemistry, coagulation, and urinalysis), and anatomic pathology including organ weights, gross observations at necropsy, and histopathology of selected tissues. 

PHASE III: PHASE III: Conduct a 14 day toxicity and toxicokinetic (TK) study of a single dose IM dual formulation in non-human primates (Rhesus macaques). The TK of atropine/scopolamine will be evaluated using plasma drug concentrations, construction of concentration time profiles, and TK parameters. Toxicity will be evaluated using survival, clinical observations (including injection site reactions), body weights, food consumption measurements, functional observational battery assessments, clinical pathology (hematology, serum chemistry, coagulation, and urinalysis), and anatomic pathology including organ weights, gross observations at necropsy, and histopathology of selected tissues. PHASE III DUAL USE APPLICATIONS The Department of Health and Human Services (HHS) has a similar need for next generation anticholinergics to potentially include an atropine/scopolamine dual formulation for human use. 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 U. S. Food and Drug Administration (FDA) regulatory pathway leading to commercialization. 

REFERENCES: 

1: Capacio, B.R., and Shih, T.-M. "Anticonvulsant actions of anticholinergic drugs in soman poisoning," Epilepsia, 1991, 32, 604-615.

2:  McDonough, J.H., Zoeffel, L.D., McMonagle, J., Copeland, T.L., Smith, C. D., and Shih, T.-M. "Anticonvulsant treatment of nerve agent seizures: Anticholinergics versus diazepam in soman-intoxicated guinea pigs," Epilepsy Research, 2000, 38, 1-14.

3:  Shih, T.-M., Duniho, S.M., and McDonough, J.H. "Control of nerve agent-induced seizures is critical for neuroprotection and survival," Toxicol. Appl. Pharm., 2003, 188, 69-80.

4:  Shih, T.-M., Rowland, T.C., and McDonough, J.H. "Anticonvulsants for nerve agent-induced seizures: The influence of the therapeutic dose of atropine," J. Pharm. Exp. Ther., 2007, 320 (1), 154-161.

5:  Ketchum, J., Sidell, F., Crowell Jr, E., Aghajanian, G., and Hayes Jr, A. "Atropine, scopolamine, and ditran: Comparative pharmacology and antagonists in man," Psychopharmacologia, 1973, 28 (2), 121-145.

6:  Koplovitz, I., and Schulz, S. "Perspectives on the use of scopolamine as an adjunct treatment to enhance survival following organophosphorus nerve agent poisoning," Mil. Med., 2010, 175 (11), 878-882.

7:  International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use. ICH Harmonized Tripartite Guideline. Pharmaceutical Development Q8 (R2). 2009.

KEYWORDS: Atropine, Scopolamine, Chemical Nerve Agent, Medical Countermeasure, Drug Formulation 

CONTACT(S): 

Lisa Mobley 

(301) 619-8417 

lisa.r.mobley.civ@mail.mil 

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