The Pharmaceutical Study Of Compound Lidocaine Cream

Objective: Compound Lidocaine Cream（EMLA）is a self-sealing local anesthetic cream developed by Teva Branded Pharm in the United States.Approved by FDA,EMLA has been marketed in many countries including the United States,European Union,United Kingdom,Denmark,etc.It can be used for postoperative analgesia of various surgical operations,complete skin local analgesia,superficial genital mucosal surgery and as a pretreatment of infiltration anesthesia.Since the original research was not imported to China,the imported drugs were relatively expensive.In order to improve the accessibility of drugs for Chinese patients,reduce the economic burden of patients,and meet the needs of more patients,the imitation study of compound lidocaine cream was conducted in this study.Methods: First of all,the physical and chemical properties of lidocaine and propylamine raw materials were analyzed,the relevant literature information was fully investigated and the original research was fully analyzed to determine the type and dosage of excipients,so as to carry out the compatibility test of raw materials and excipients.Franz diffusion pool is adopted to improve the in vitro release test and in vitro transdermal test,at the same time,p H,content and related substances in traits and rheological characteristics in order to investigate the optimization selection of indicators for the prescription and technology research,and carried out in accordance with the release of prescription and process test in laboratory,amplification and enlarge the pilot in the workshop production;The determination methods of content,related substances and release in vitro were established and their systematic methodological verification was carried out respectively.With the content,related substances,rheological properties,characters,p H and release in vitro as the main indexes,the stability was studied by influencing factor test,accelerated test and long-term test.Results: In this study,a HPLC method was successfully established for the determination of compound lidocaine cream content and related substances,and all of them passed its methodological verification,indicating that the detection method is simple,accurate,sensitive and specific.Combined with the physical and chemical properties of the two apis and the analysis results of the original preparation,the type and specific dosage of the excipients were determined.Then,through the compatibility test of raw materials,it was proved that the selected excipients had good compatibility with lidocaine and promycaine and could be used as excipients for compound lidocaine cream.The properties,in vitro transdermal release rate,p H,content,related substances and rheological properties were used to screen the prescription and optimize the process.The composition and dosage of the compound lidocaine cream were determined as lidocaine and propimaine 2.5%,1.9%polyoxyethylene-54 hydrogenated castor oil as emulsifier,1.0% carbomer 974 as thickener and 0.55% sodium hydroxide as p H regulator.The preparation process is as follows: Carbomer 974 and purified water are first fully swollen into water phase,lidocaine and procaine form eutectic oil-like mixture,then polyoxyethylene 54 hydrogenated castor oil is added into the mixture,the oil phase is transferred to water phase,and a small amount of water is used to wash the residual oil phase and then transfer to water phase.In the process of oil-water two-phase emulsification,sodium hydroxide solution was added to adjust the viscosity and p H of the preparation until the uniform and stable compound lidocaine emulsion was made.The stability of the preparation was studied.Under the condition of high temperature（60℃）and light（4500±500Lx）for 30 days,the contents of the self-made preparation and the original preparation were between98.0% and 102%,the impurity limit met the requirements,and the characters and p H value did not change significantly,indicating that the stability of the preparation was good under the condition of the influencing factor test.The results of accelerated（temperature40±2℃,relative humidity 75± 5%）and long-term（temperature 25±2℃,relative humidity 60± 10%）tests showed that the content,related substances,in vitro release,p H and appearance of the product had no significant changes under accelerated and longterm test conditions of 3 month and 3 month.Conclusion: The compound lidocaine cream prepared in this study has reasonable prescription design,stable process,controllable quality,good stability and high safety,which can be used for industrial scale-up production.