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Stability Characterization of a Polysorbate 80-Dimethyl Trisulfide Formulation, a Cyanide Antidote Candidate.

ABSTRACT: Novel cyanide countermeasures are needed for cases of a mass-exposure cyanide emergency. A lead candidate compound is dimethyl trisulfide (DMTS), which acts as a sulfur donor for rhodanese, thereby assisting the conversion of cyanide into thiocyanate. DMTS is a safe compound for consumption and, in a 15% polysorbate 80 (DMTS-PS80) formulation, has demonstrated good efficacy against cyanide poisoning in several animal models. We performed a stability study that investigated the effect of temperature, location of formulation preparation, and pH under buffered conditions. We found that while the stability of the DMTS component was fairly independent of which laboratory prepared the formulation, the concentration of DMTS in the formulation was reduced 36-58% over the course of 29 weeks when stored at room temperature. This loss typically increased with increasing temperatures, although we did not find statistical differences between the stability at different storage temperatures in all formulations. Further, we found that addition of a light buffer negatively impacted the stability, whereas the pH of that buffer did not impact stability. We investigated the factors behind the reduction of DMTS over time using various techniques, and we suggest that the instability of the formulation is governed at least partially by precipitation and evaporation, although a combination of factors is likely involved.

SUBMITTER: Bartling CM

PROVIDER: S-EPMC4767715 | biostudies-literature | 2016 Mar

REPOSITORIES: biostudies-literature

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Stability Characterization of a Polysorbate 80-Dimethyl Trisulfide Formulation, a Cyanide Antidote Candidate.

Bartling Craig M CM Andre Jon C JC Howland Carrie A CA Hester Mark E ME Cafmeyer Jeffrey T JT Kerr Andrew A Petrel Trevor T Petrikovics Ilona I Rockwood Gary A GA

Drugs in R&D 20160301 1

Novel cyanide countermeasures are needed for cases of a mass-exposure cyanide emergency. A lead candidate compound is dimethyl trisulfide (DMTS), which acts as a sulfur donor for rhodanese, thereby assisting the conversion of cyanide into thiocyanate. DMTS is a safe compound for consumption and, in a 15% polysorbate 80 (DMTS-PS80) formulation, has demonstrated good efficacy against cyanide poisoning in several animal models. We performed a stability study that investigated the effect of temperat ...[more]

PMID: 26861644

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Project description:Acetylcholinesterase (AChE) inhibitors such as donepezil, galantamine and rivastigmine are used for the management of dementia in Alzheimer's Disease (AD). These drugs elevate endogenous acetylcholine (ACh) levels at the M1 muscarinic receptor in the brain to achieve therapeutic benefits. However, their side effects, such as nausea, vomiting, dizziness, insomnia, loss of appetite, altered heart rate, etc., are related to non-specific peripheral activation of M2-M5 muscarinic subtypes. It is logical, therefore, to develop drugs that selectively activate brain M1 receptors. Unfortunately, the orthosteric site homology among the receptor subtypes does not permit this approach. An alternative approach is to use positive allosteric modulator (PAM) of M1 receptors like benzyl quinolone carboxylic acid (BQCA). PAMs although devoid of M1 agonist activity, however, when bound, enhance the binding affinity of orthosteric ligand, Ach. The current challenge with PAMS is their low brain half-life, permeability, and higher elimination rates. This study reports active targeting of brain M1 receptors using surface modified nano lipid-drug conjugates (LDC) of M1 PAM, BQCA, to treat AD. Polysorbate-80 (P-80) surface modified stearylamine (SA)-BQCA conjugated nanoparticles (BQCA-SA-P80-NPs) were prepared by conjugating BQCA to SA, followed by the formation of nanoparticles (NPs) using P-80 by solvent injection method. The BQCA-SA-P80-NPs are near-spherical with a particle size (PS) of 166.62 ± 1.24 nm and zeta potential (ZP) of 23.59 ± 0.37 mV. In the in vitro cytotoxicity (SH-SY5Y cells) and hemolysis assays, BQCA-SA-P80-NPs, show acceptable safety and compatibility. In mice, Alzheimer's model, BQCA-SA-P80-NPs significantly prevent STZ induced changes in memory, neuronal Aβ1-42, p-Tau, APP, NF-κB, and BACE levels and neuronal cell death, when compared to untreated disease control and naïve BQCA treated group. Further, BQCA-SA-P80-NPs significantly improve the therapeutic efficacy of AChE inhibitor, donepezil (DPZ), indicating its potentiating effects. In vivo biodistribution studies in mice show selective accumulation of BQCA-SA-P80-NPs in the brain, suggesting an improved brain bioavailability and reduced peripheral side effects of BQCA. The study results demonstrate that BQCA-SA-P80-NPs can improve brain bioavailability and therapeutic efficacy of BQCA in AD.

Dataset Information

Stability Characterization of a Polysorbate 80-Dimethyl Trisulfide Formulation, a Cyanide Antidote Candidate.

Publications

Stability Characterization of a Polysorbate 80-Dimethyl Trisulfide Formulation, a Cyanide Antidote Candidate.

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