| Three co-extrusion bag used for infusion, with respect to its constituent materials, production processes, the overall design and the usage method, is the best form of packaging in the infusion system nowadays, on behalf of the latest world-class level, and is the development trend of the packaging materials which directly contact with infusion in future. There are many outstanding advantages in three co-extrusion bag used for infusion, but still there are many security risks, such as the ingredients in packaging material direct contacting with the drug may migrate into the infusion, resulting in a security risk of product. In addition, three co-extrusion bag used for infusion may have adsorption effect on main drug and excipient, which can result in the contents decreased of active ingredients, and thus affecting the effectiveness of the product. Therefore, once three co-extrusion bag used for infusion is selected to be the packaging materials directly contacting with the drug for any infusion product, studies must be conducted concerning with the compatibility of the drug with 3-layer co-extrusion bags used for Infusion. This paper studied the compatibility of ketoprofen and sodium acetate injection with 3-layer co-extrusion bags used for infusion. The study aimed to provide the scientific basis for new drug registration and clinical application of the infusion.In extraction experiment, three extraction solvent were used, toluene was used for extraction of the antioxidants in 3-layer co-extrusion bags used for infusion, methanol was used for soaking and extracting the styrene monomer in 3-layer co-extrusion films used for infusion. ketoprofen and sodium acetate injection was used for extraction of 3-layer co-extrusion bags used for infusion, the extraction conditions simulated sterilization conditions and the extraction time is longer than the sterilization time. The extraction were conducted to 3-layer co-extrusion films used for infusion, polypropylene interface, and internal cover of polypropylene combination cover, respectively and the extraction solutions were determined by HPLC method. The HPLC method was established to determine the antioxidant 168,330,1010,1076 and antioxidants THP-EPQ, the GC method was established to determine the styrene monomer, all the method conducted the comprehensive method validation. According to the extraction experiment, the type and quantity of antioxidant and the quantity of styrene monomer can be cleared, so as to the degree of difficulty in migrating to the infusion. Results:The antioxidant and the styrene monomer can be detected in the toluene extraction solution and the methanol extraction solution, and all of the quantity of them were complied with the provisions of the European Pharmacopoeia about the limits of additive for 3-layer co-extrusion bags used for infusion, suggesting the established method to determine the antioxidant and styrene monomer is accurate and reliable and can be used for extraction experiment and migration experiment. The antioxidant and the styrene monomer can not be detected in the ketoprofen and sodium acetate injection, suggesting that under the simulated conditions of sterilization and longer sterilization time, The antioxidant and the styrene monomer in 3-layer co-extrusion bags used for infusion, were not dissolved in ketoprofen and sodium acetate injection.In migration experiment,3 batches test product of ketoprofen and sodium acetate injection were placed under the accelerated stability testing conditions (temperature 40℃±2℃, relative humidity 75%±5%) and the long-term stability testing conditions (temperature 25℃±2℃, relative humidity 40%±5%), respectively. At the time points of 0 months, accelerated stability test 1,2,3,6 months, and long-term stability test 3,6 months, the antioxidant and the styrene monomer in ketoprofen and sodium acetate injection were determined. Results:The antioxidant and the styrene monomer were not detected in all the test product, suggesting that all the antioxidant and the styrene monomer in 3-layer co-extrusion bags used for infusion have not migrated into ketoprofen and sodium acetate injection.In adsorption experiment,3 batches test product of ketoprofen and sodium acetate injection and the injection encapsulated with inert glass containers were placed under the accelerated stability testing conditions (temperature 40℃±2℃, relative humidity 75%±5%) and the long-term stability testing conditions (temperature 25℃±2℃, relative humidity 40%±5%), respectively. At the time points of 0 months, accelerated stability test 1,2,3,6 months, and long-term stability test 3,6 months, conducted a comprehensive testing for all the samples. The detection index were the content of ketoprofen and sodium acetate, the liquid trait, the values of pH and the like. Results: There were no significant differences about the content of ketoprofen and sodium acetate, the liquid trait, the values of pH between the injection encapsulated with 3-layer co-extrusion bags used for infusion and the injection encapsulated with inert glass containers, suggesting that 3-layer co-extrusion bags used for infusion had no adsorption effect on ketoprofen and sodium acetate in the injection.In the safety evaluation, the results of extraction experiment, migration experiment and adsorption experiment were evaluated in an scientific and systematic way. First, according to the literature, analysed and calculated permitted daily exposure (PDE) of each antioxidant and the styrene monomer, and then combined with the daily maximum dose, calculated analytical evaluation threshold (AET) of each antioxidant and the styrene monomer in the normal preparation packaging. Then according to the proportion of three co-extruded infusion bag and extraction solvent calculated the analytical evaluation threshold (AET) of each antioxidant and the styrene monomer in extraction solutions. The results showed that the content of each antioxidant in toluene extraction solutions was less than the predetermined limit of additives in European Pharmacopoeia, the content of each antioxidant in extraction solution of ketoprofen and sodium acetate injection was lower than analytical evaluation threshold (AET) of each antioxidant and the styrene monomer in corresponding extraction solutions. In migration experiment, the contents of antioxidants and styrene in ketoprofen and sodium acetate injection which placed under the accelerated stability test and the long-term stability test conditions were detected, the results were lower than the corresponding analytical evaluation threshold (AET), suggesting that all the antioxidant and the styrene monomer in 3-layer co-extrusion bags used for infusion have not migrated into ketoprofen and sodium acetate injection. In adsorption experiment, the contents of ketoprofen and sodium, the liquid trait, the values of pH of injection encapsulated with 3-layer co-extrusion bags used for infusion and injection encapsulated with inert glass containers which placed under the accelerated stability test and the long-term stability test conditions were detected, the results showed no significant differences between both injection in different packaging, suggesting that 3-layer co-extrusion bags used for infusion had no adsorption effect on ketoprofen and sodium acetate in the injection.Conclusion:ketoprofen and sodium acetate injection with 3-layer co-extrusion bags used for Infusion has good compatibility. |
PDF Full Text Request