The IP.com Prior Art Database
English (United States)
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The present disclosure relates to stable aqueous composition comprising quaternary ammonium neuromuscular blocking agent and process of preparation thereof.
Neuromuscular-blocking agents block transmission at the neuromuscular junction, causing paralysis of the affected skeletal muscles. Clinically, neuromuscular block is used as an adjunct to anesthesia to induce paralysis, so that surgery can be carried out with fewer complications. Typically therapy by neuromuscular blocking agents is performed by i.v. administration of a suitable dosage form. Injectable preparation of neuromuscular blocking agents tend to be unstable due to hydrolysis in acidic pH, hence stability of pharmaceutical preparations comprising neuromuscular blocking agent(s) remain one of the major concern(s). The major approaches used in the art to minimize hydrolysis include use of reconstitutable powder, i.e., developing freeze-dried powder or simple admixture containing the active ingredient associated with some excipients, which are dissolved in water or another suitable solvent prior to administration. This introduces another step in the surgeon’s or anesthesiologist’s regimen. In addition, reconstitutable formulations must typically be sterilized by expensive gamma irradiation sterile fill procedures. Furthermore, the entire drug may not re-dissolve or redisperse easily during pre-injection step; leading to dangerous emboli, such as pulmonary emboli.
Preformulated aqueous solution of quarternary ammonium neuromuscular blocking agent is advantageous as it would overcome most of the drawbacks. Various methods have been used in the art to develop a stable injectable aqueous solution, i.e., addition of buffers, use of zwitterions (alanine, glycine, hydroxyproline, serine, etc.), addition of an acid and/or alkali, etc. For example, U.S. Patent No. 5,767,112 discloses an injectable formulation comprising a neuromuscular blocking agent and 2 to 30 percent of at least one zwitterionic substance. U.S. Patent No. 4,237,126 discloses parenteral aqueous composition comprising a neuromuscular blocking agent which is stabilized by addition of a pharmaceutically acceptable buffer system. These buffers are generally in the range of about pH 3 to about pH 4.5, such as an acetic acid/sodium acetate buffer or a citric acid/sodium phosphate buffer.
Zemuron® (rocuronium bromide) which is marketed by Organon USA Inc., is supplied as sterile, nonpyrogenic, isotonic solution that is clear, colorless to yellow/orange, and is ready for intravenous administration. The aqueous solution has a pH of 4 adjusted with acetic acid and/or sodium hydroxide.
Aqueous solution of neuromuscular blocking agent is more stable...