Preparation And Quality Control Of Insulin Glargine Injection U300

Insulin glargine is a long-acting human insulin analogue used in type I and type II diabetes.Insulin glargine injection U300 is a new type of ultra-long-acting insulin injection.Due to the complicated preparation process,it is still not launched in China.As a multi-injection preparation,the preparation process is complicated.In addition to insulin glargine,preservatives,stabilizers,and p H buffers are also required.The choice of ingredients and the order of preparation directly affect the quality and stability of insulin glargine injection.At the same time,the stability of insulin glargine in acidic or alkaline environment will be greatly reduced,and the tendency of coagulation due to heat and p Hysical and mechanical stress will also increase.Through the selection of product prescription and preparation methods and the selection of production and preparation conditions,this paper finally determines the prescription and preparation process,and successfully produces three batches of production batch(100L)products.Through the stability test,it is determined that the products produced by the process have less impurities and good stability.The specific research contents are as follows:1.Establishment and verification of analytical methodsIn this paper,methods for the determination and high molecular weight protein of insulin glargine injection U300 were established.Methodological verification showed that the content of insulin glargine in insulin glargine injection U300 was determined by HPLC.The content was detected by using octadecylsilane-bonded silica gel as a filler,the detection wavelength was 214 nm,and the column temperature was 35 ?.The limit of quantification was 0.93?g/ml and the limit of detection was 0.31 ?g/ml.This method can accurately determine the content of insulin glargine in insulin glargine injection U300,and the applicability,specificity and quantitative limit of detection of the method meet the requirements.2.Study on the prescription of insulin glargine injection U300After compatibility test and single factor test screening of each excipient,the formula of insulin glargine injection U300 was finally determined.The formula of insulin glargine injection U300 was insulin glargine 10.92 mg/ml,glycerin 16 mg/ml,M-cresol 2.7 %,Zinc Chloride 90?g/ml(Zinc content),dilute hydrochloric acid and sodium hydroxide appropriate amount.3.Study on preparation method of insulin glargine injection U300By changing the dissolution mode of insulin glargine and the operation of inverting thep H value,and screening the mixing sequence,the final screening method has greatly improved the product quality.The results of the 10-day high temperature challenge at 40 ?showed that the related substances and high-molecular-weight proteins in the optimized prescription decreased by more than 30% compared with the original prescription.The optimized preparation process shortens the preparation time by more than 60%.The preparation method of insulin glargine injection U300 : add glycerin and water for injection,adjust p H to 2.5-3.5.Insulin glycine,M-cresol,and zinc chloride were predissolved in glycerine solution respectively.After mixing,add water for injection to the total amount of preparation 100%,adjust p H to 3.8?4.2,sterilize by filter finally.4.Scale-up of insulin glargine injection U300Three batches of raw materials were used to produce three batches of injection continuously according to the optimized process,and the stability of three batches of products was investigated.The experimental data for 6 months of acceleration and 24 months of long-term showed that the properties,p H,and osmotic pressure remained stable,the related substances increased,the polymer protein increased slightly,and the content decreased slightly.All indicators were within the standard range and the quality met the requirements.