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Extended Release Formulations for Fielded Nerve Agent Pretreatment

Description:

TECHNOLOGY AREA(S): Chem Bio_defense, Bio Medical 

OBJECTIVE: Develop formulations of pyridostigmine bromide (PB) that afford pretreatment to nerve agent exposure by reducing the number of daily administrations of the fielded product, while maintaining a consistent reduction in blood acetylcholinesterase activity. 

DESCRIPTION: Military operations occur under a wide-range of temperatures and austere conditions. The current and future joint service members are globally deployed and are executing missions across the full spectrum of military operations. A rebalancing of forces will focus on Asia-Pacific and Middle Eastern regions. The Joint Chemical and Biological Defense Program wants to make the brigade combat teams leaner and more nimble while retaining capability. Expeditionary missions require medical solutions that allow maximum flexibility and agility. These members must protect themselves against all nerve agent threats during deployments, sustainment operations, and re-deployments. Non-state actors and terrorists may develop or acquire nerve agents, and may use them abroad and in the homeland, and joint forces may be the first to respond. Prophylaxes used in conjunction with other treatments, would counter the threat of performance degradation and death caused by nerve agent threats. Organophosphorus nerve agents exert their toxic effects by binding to and inactivating the enzyme acetylcholinesterase (AChE). These nerve agents bind very tightly to AChE, and after a certain amount of time, ranging from minutes to hours, this binding becomes irreversible. If sufficient amount of the enzyme is bound up, the effects can be lethal. The rationale behind the use of PB is that it temporarily binds to AChE, thereby preventing nerve agents from binding to, and permanently inactivating AChE. However, unlike the nerve agents, PB binding is reversible. Thus PB creates a pool of reversibly bound AChE that is essentially protected against the irreversible binding of nerve agents. The only pretreatment medication currently FDA-approved for use against the lethal effects of nerve agent (e.g., soman) poisoning is pyridostigmine bromide (PB) tablets. PB tablets are procured by the DoD as Soman Nerve Agent Pretreatment Pyridostigmine (SNAPP). PB is an orally active cholinesterase inhibitor. The dose of pyridostigmine is one 30 mg tablet every 8 hours, to be started at least several hours prior to nerve agent exposure. In humans, this dosing of PB inhibits red blood cell cholinesterase (i.e., AChE) by 20-40%, a level that protects animals from the lethal effects of soman. The product must be stored in refrigeration between 2-8°C (36-46°F) and protected from light. A unit of issue is one blister pack of 21 tablets. NSN 6505-01-178-7903 represents a package of 10 blister packs. The tablets are hygroscopic. Once issued to a soldier, the blister pack must be discarded after three months as it is no longer maintained under refrigerated temperatures. Pyridostigmine also has been approved by the Medicines Control Agency, the United Kingdom equivalent of the U. S. Food and Drug Administration (FDA), for the Ministry of Defence as a pretreatment for organophosphorus inhibitors of AChE. Based on current operation tempo, there is interest in obtaining a solution for administering a nerve agent pretreatment with reduced frequency than the SNAPP product, as well as a product/packaging that could maintain activity during prolonged exposure to both desert temperatures and high humidity. Mestinon® TIMESPAN® tablets contain 180 mg PB in a specially coated tablet for sustained release. The product is stored at 25°C (77°F), with excursions permitted to 15-30°C (59-86°F). This form provides uniformly slow release, hence prolonged duration of drug action; it facilitates control of myasthenic symptoms with fewer individual doses daily. However, dosing of this product to achieve the desired 20-40% reduction in blood AChE activity for use as a nerve agent pretreatment has not been conducted. The ultimate goal is to develop PB formulation data that could be used in a future supplement to the pyridostigmine bromide tablet New Drug Application 20-414. 

PHASE I: Alterations to the PB tablet formulation will be studied that provide a prolonged blood level of PB, sufficient to generate a steady-state 20-40% reduction in red blood cell AChE activity. The initial goal is a single oral administration sufficient to maintain these levels minimally up to 24 hours. Proof-of-concept formulations should be tested in appropriate animal models (e.g., guinea pig, rat). The route of administration should be justified if other than oral in the animal model. Preclinical pharmacokinetic and pharmacodynamics data for proof-of-concept formulations will be assessed for suitability to meet steady-state 20-40% reduction in blood AChE activity for minimally 24 hrs. Ideally, candidate formulations will be assessed for stability at elevated temperatures encountered by military personnel operating overseas. 

PHASE II: Establish formulation strategy to accelerate entry into early stage clinical development. Design and perform formulation prototype development studies. Use FDA quality by design approach to formulation concept design based upon clinical targets. The desired goal is to use excipients that are clinical route of administrate appropriate, and generally recognized as safe. Produce prototype formulation(s) using state-of-the-art and scalable technologies in particle processing and drug physical form manipulation. Screen for and manufacture soluble intermediates. Perform risk assessment to identify potentially high risk formulation and process variables; propose/conduct studies to increase knowledge and reduce risk. Identify and mitigate any stability and processing issues during small scale-up manufacture of prototype formulation. Initiate real-time stability data to support 6-month stability of prototype formulations across a range of temperatures and humidity; define excursion limits. PHASE III: Develop a tablet formulation and manufacturing process that ensures the quality, safety and efficacy of modified-release tablet. Define the quality target product profile (QTPP) of the modified-release PB tablet based on drug substance properties, consideration of the PB label and intended population. Continue risk assessment and propose a control strategy, which should include in-process and finished product specifications. Develop and optimize modified-release tablets compressed into scored tablets to achieve all of the attributes in the PB QTPP. Conduct necessary ICH stability studies. Optimize the extended-release final tablet process development using drug layering, ER polymer coating, blending and lubrication, and compression, as appropriate. 

PHASE III: PHASE III: Develop a tablet formulation and manufacturing process that ensures the quality, safety and efficacy of modified-release tablet. Define the quality target product profile (QTPP) of the modified-release PB tablet based on drug substance properties, consideration of the PB label and intended population. Continue risk assessment and propose a control strategy, which should include in-process and finished product specifications. Develop and optimize modified-release tablets compressed into scored tablets to achieve all of the attributes in the PB QTPP. Conduct necessary ICH stability studies. Optimize the extended-release final tablet process development using drug layering, ER polymer coating, blending and lubrication, and compression, as appropriate. PHASE III DUAL USE APPLICATIONS: Given the unforeseen/unanticipated use of nerve agents on the homeland, and in contrast to military personnel, civilians are unlikely to be pretreated with pyridostigmine and protected by personal protective equipment. Extended pretreatment of a civilian population is not desirable nor feasible given the possibility of overdose and toxic effects in special populations. However, there may be instances where it would be desirable to pretreat both medical and emergency aid personnel (e.g., first responders) and first receivers (e.g., hospital personnel) following a known/suspected nerve agent attack. Healthcare-providers, as valuable assets, would have an additional layer of protection against the lethal effects of nerve agents during mass casualty decontamination (possibility for secondary contamination of medical personnel), evacuation and medical intervention activities. The military counterparts to the DoD, notably the United Kingdom and NATO allies, along with members of the CBR MOU, use pyridostigmine bromide tablets. The armed forces of these countries would reap the benefits of a less frequent dosing regimen as well as a formulation that could withstand extended elevated temperatures and humidity. Finally, additional PB extended release formulations for the treatment of myasthenia gravis could be of commercial interest to benefit this patient population. 

REFERENCES: 

1: ATP 4-02.285 Multiservice Tactics, Techniques, and Procedures for Treatment of Chemical Agent Casualties and Conventional Military Chemical Injuries, 19 Aug 2015. Chapter 3:Nerve Agents.

2:  Capstone Concept for Joint Operations: Joint Forces 2020. 10 Sep 2012.

3:  Drug Approval Package, Pyridostigmine bromide tablet, NDA 20-414.

4:  https://www.accessdata.fda.gov/drugsatfda_docs/nda/2003/20414_pyridostigmine.cfm

5:  Herkert NM, Eckert S, Eyer P, Bumm R, Weber G, Thiermann H, et al. Identical kinetics of human erythrocyte and muscle acetylcholinesterase with respect to carbamate pre-treatment, residual activity upon soman challenge and spontaneous reactivation after withdrawal of the inhibitors. Toxicology 2008, 246:188–192.

6:  International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use. Q1A-F Stability.

7:  Scott, L. 2007 Pretreatment for Nerve Agent Poisoning. In: Marrs, T.C., Maynard, R.L., Sidell, F.R. (Eds.), Chemical Warfare Agents: Toxicology and Treatment. John Wiley & Sons Ltd., Chichester, pp. 343–353.

8:  Quality by Design for ANDAs: an Example for Modified-Release Dosage Forms. Available at FDA.gov: https://www.fda.gov/downloads/drugs/developmentapprovalprocess/howdrugsaredevelopedandapproved/approvalapplications/abbreviatednewdrugapplicationandagenerics/ucm286595.pdf

9:  Thompson J, Rehn M, Lossius HM, Lockey D. Risks to emergency medical responders at terrorist incidents: a narrative review of the medical literature. Critical Care 2014, 18:521.

10:  TRADOC Pamphlet 525-3-1 The U.S. Army Operating Concept:2020-2040, Win in a Complex World. 31 Oct 14.

KEYWORDS: Chemical Nerve Agent, Pretreatment, Extended-release, Drug Delivery, Medical Countermeasure 

CONTACT(S): 

Renae Malek 

(301) 619-8426 

renae.l.malek.civ@mail.mil 

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