The present invention 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 US Pat. No. 5,767,112 discloses an injectable formulation comprising a neuromuscular blocking agent and 2 to 30 percent of at least one zwitterionic substance. US Pat. 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 at an acidic pH. So a pH adjusting agent (acid or buffer) is needed to be added in aqueous compositions of quarternary neuromuscular blocking agents to develop a stable composition having an acidic pH.
Apart from factors affecting the stability of aqueous compositions of quarternary ammonium neuromuscular blocking agent disclosed in the art, method of preparation of the composition may also critically affect the stability of aqueous composition of quarternary ammonium neuromuscular blocking agent as well as the level of impurities in final composition. While formulating aqueous compositions comprising at least one quarternary ammonium neuromuscular blocking agent it was surprisingly found that the order of addition of buffer acid in the manufacturing process is critical for the stability of the final composition.
Hence in one general aspect there is provided a stable aqueous composition of quarternary ammonium neuromuscular blocking agent comprising quarternary ammonium neuromuscular blocking agent, buffer, and one or more pharmaceutically acceptable excipients wherein the pH of the composition is adjusted with addition of buffer acid in multiple steps.
In another general aspect there is provided a process for the preparation of a stable aqueous composition of quarternary ammonium neuromuscular blocking agent, wherein the said process comprises
1. Dissolving buffer salt in aqueous solvent,
2. Adding a part of buffer acid to solution of step 1 and mixing with stirring,
3. Adding quarternary ammonium neuromuscular blocking agent to solution of step 2, and
4. Adjusting the pH of the composition of step 3 to about 2 to about 6 with the remaining amount of
buffer acid.
In another general aspect there is provided a process for the preparation of a stable aqueous composition of rocuronium bromide, wherein the said process comprises
1. Dissolving sodium acetate trihydrate in water for injection,
2. Adding a part of acetic acid to solution of step 1 and mixing with stirring,
3. Adding quraternary ammonium neuromuscular blocking agent to solution of step 2, and
4. Adjusting the pH of the composition of step 3 to pH of about 2 to pH of about 6 with the
remaining amount of acetic acid.
In another general aspect there is provided a method of producing muscular relaxation in a mammal in need thereof by administering to the said mammal a stable aqueous composition of quarternary ammonium neuromuscular blocking agent comprising a quarternary ammonium neuromuscular blocking agent, buffer, and one or more pharmaceutically acceptable excipients wherein the pH of the composition is adjusted with addition of buffer acid in multiple steps.
Incorporation of an acid and / or alkali or buffer (to maintain pH) in aqueous composition of quarternary ammonium neuromuscular blocker has been the main strategy in past for the development of a stable aqueous composition of the same, because quarternary ammonium neuromuscular blocking agent remain stable in acidic pH. The improved stability resultant from the lower pH solutions is related to the basic nature of the reaction of quarternary ammonium neuromuscular blocking agent with water. Typically the pH of the solutions obtained according to the methods of the present invention is between about 2 to about 6, preferably between about 3 to about 5. In all compositions available in the art, the buffer acid was added in a single step after the addition of drug into aqueous vehicle. However, in the present invention buffer acid is added in multiple steps which lead to a composition which are more stable than earlier compositions of the art. Stability study data of representative compositions showing improved stability of composition of the present invention are incorporated herein later in this document.
The term "quarternary ammonium neuromuscular blocking agent" as used herein includes neuromuscular blockers having chemical structures which comprise quarternary ammonium ion and androstane nucleus.
Specific examples include mivacurium, rapacuronium, rocuronium, atracurium, cistracurium, pancuronium, vacuronium, doxacurium, and pipecuronium. The term also include complexes, salts, solvates, hydrates, isomers and other derivatives thereof. The concentration of neuromuscular blocking agent in the composition may vary from about 0.5 % w/v to about 2.5 % w/v.
The term "buffer" as used herein comprises two components i.e. buffer acid and buffer salt, which provide pH to the composition to the composition in the range of about 2 to about 6. In particular the pH of final composition may vary from about 3 to about 5. Examples of these buffers include; maleate buffer (pK^.97) pH range 1.2-2.6, phosphate buffer (pK, 2.15) pH range 1.7-2.9, glycine buffer (pK, 2.35) pH range 2.2-3.6, citrate buffer (pK, 3.13) pH range 2.2-6.5, glycylglycine buffer (pK, 3.14) pH range 2.5-3.8, malate buffer (pt