MMB4 DMS Nanoparticle Suspension Formulation With Enhanced Stability for the Treatment of Nerve Agent Intoxication

Abstract

Various oximes are currently fielded or under investigation in the United States and other countries as a component of autoinjector emergency treatment systems for organophosphate nerve agent chemical weapons. Bis-pyridinium oximes in general have greater efficacy against a broad spectrum of nerve agents, but they have poor stability due to hydrolytic degradation at elevated temperatures. 1,1'-Methylenebis-4-[(hydroxyimino)methyl]pyridinium dimethanesulfonate (MMB4 DMS) is a leading candidate for next-generation nerve agent treatment systems, because it is more stable than other bis-pyridinium oximes, but it still degrades quickly at temperatures often encountered during storage and field use. The primary goal is to increase the stability and shelf life of MMB4 while maintaining the desirable pharmacokinetic (PK) properties of the aqueous formulation. We have developed a formulation to be used in a phase 1 clinical trial consisting of MMB4 micro/nanoparticles suspended in cottonseed oil, a biocompatible vegetable oil. Through various milling techniques, the average particle size can be controlled from approximately 200 to 6000 nm to produce non-Newtonian formulations that are viscous enough to resist rapid particle sedimentation while remaining injectable at a range of concentrations from 5 to 400 mg/mL. The preliminary accelerated stability test shows that MMB4 in these formulations is stable for at least 2 years at temperatures up to 80°C. Preliminary preclinical in vivo studies have demonstrated that all concentrations and particle sizes have desirable PK properties, including high bioavailability and rapid absorption, which is critical to combat potent and fast-acting nerve agents.

Non-Newtonian Suspension Formulations for Improved Stability and Delivery of Autoinjectable CBRN Countermeasures

“…Therefore, the particle size range of samples for further studies was selected so as to optimize the physical stability and injectability of the suspensions at the chosen concentration of 100 mg/g. [6]. The primary goals for this study were to confirm that systemic exposure was independent of particle size and to compare the systemic exposure of MMB4 DMS OF to MMB4 DMS EF following an (IM) injection.…”

“…In this article, Southwest Research Institute (SwRI) presents a formulation which solves many of the problems with currently available autoinjector products. Our Enhanced Formulation (EF) [6] consists of drug microparticles and/or nanoparticles suspended in biocompatible cottonseed oil (CSO). EF is a non-Newtonian shearthinning fluid, making it injectable even at high solid concentrations (400 mg/mL or more), yet it is sufficiently viscous so as to prevent significant sedimentation of suspended particles.…”

Good Manufacturing Practice

“…We previously developed a nonaqueous formulation consisting of a suspension of 1,1 0 -methylenebis-4-[(hydroxyimino)methyl]pyridinium dimethanesulfonate (MMB4 DMS) nanoparticles in cottonseed oil (CSO). 9 This product, known as Enhanced Formulation (EF, as opposed to the aqueous Original Formulation, or OF), is a non-Newtonian fluid at sufficiently high concentrations and low particle size distributions, exhibiting shear thinning behavior. The EF has a high zero-shear viscosity that allows it to resist rapid particle sedimentation but remains injectable due to the drop in viscosity during injection caused by shear thinning.…”

“…Because the MMB4 DMS nanoparticles are insoluble in hydrophobic CSO, the chemical stability of MMB4 in EF is vastly superior to that of MMB4 in aqueous solution. The EF exhibit almost no degradation even after 2 years at temperatures up to 80 C. 9 As shown in Figures 1 and 2, various techniques were used during the development to reduce the particle size of MMB4 DMS to accommodate different concentrations in the EF. 9 Range-finding preclinical studies indicated that a solid concentration of approximately 100 mg MMB4 DMS per gram of EF was optimal.…”

“…The EF exhibit almost no degradation even after 2 years at temperatures up to 80 C. 9 As shown in Figures 1 and 2, various techniques were used during the development to reduce the particle size of MMB4 DMS to accommodate different concentrations in the EF. 9 Range-finding preclinical studies indicated that a solid concentration of approximately 100 mg MMB4 DMS per gram of EF was optimal. 10,11 For maximum physical stability at this concentration, a wet mill process was developed using an agitator bead mill to reduce the MMB4 DMS particle size distribution to the range of approximately 200 to 300 nm.…”