The Development Of Carbinoxamine Maleate Extended-release Oral Suspension

Objective:Karbinal ERTM oral sustained-release suspension from Tris Pharm was used as the reference preparation to prepare the self-made preparation,adjust the prescription and optimize the preparation process,investigate the in vitro release of the self-made preparation and the reference preparation,and evaluate the consistency of the self-made preparation and the reference preparation.Methods:1.The solubility,stability,impurities and compatibility of raw materials and excipients are studied to ensure that the selected raw materials and excipients meet the requirements;2,Preliminary design of the formulation and preparation process of the self-made preparation was made through literature search and information investigation of the reference preparation;3,Using single factor test method,the drug loading process was evaluated by drug loading(drug loading = API content in 1-supernatant)and drug resin binding rate[(API content in 1-supernatant)/initial dosage];The swelling degree P(P=V/V0)was used as the evaluation index to investigate the impregnation process;The formulation technology of granule coating was investigated by taking the coating effect and sample release as evaluation indexes;The formulation technology of suspension was investigated by taking sample viscosity,sedimentation volume ratio,related substances and microbial quantity as evaluation indexes.to determine the formulation and preparation process of the self-made preparation;4,The release curves of self-made preparation and reference preparation in 0.4M potassium chloride 0.1M hydrochloric acid solution,0.4M potassium dihydrogen phosphate solution,pH 6.8 phosphate buffer solution and water were as follows:50,56 and 51,respectively.The release behavior of the two substances is similar in four dissolution media,and the species and levels of the related substances are basically the same;5,With reference preparation as control group and self-made preparation as experimental group,the blood concentration of beagle dogs was determined by HPLC-MS.The pharmacokinetic parameters were studied by using DAS 2.0 pharmacokinetic software,and their bioequivalence was evaluated.Results:1.The self-made APIs and excipients can meet the requirements without special treatment;2.Optimum prescription technology:drug loading process:drug concentration 40 mg/ml,drug resin ratio 1:2,stirring for 2 hours at 40 water bath,washing with deionized water twice,drying for less than 4 hours at 50-60 impregnation process:40%PEG-4000 stirring for 30 minutes;coating process:using fluidized bed coating,coating weight gain controlled between 30%and 50%.The coated granules were obtained by curing at 40 C for 8 hours.The ratio of xanthan gum to maltodextrin in suspension was 0.3%and 20%,the content of antioxidant sodium pyrosulfite was 0.05%,and the dosage of antimicrobial agent was 0.2(hydroxybenyl methyl ester:hydroxyphenyl propyl ester = 9:1).3.The pH value,viscosity,sedimentation volume ratio and releasability of the self-made preparation meet the requirements.The release curves of the self-made preparation and the reference preparation in 0.4M potassium chloride 0.1M hydrochloric acid solution,0.4M potassium dihydrogen phosphate solution and pH 6.8 phosphate buffer solution are 50,56 and 51,respectively,and almost no release in water.The results show that the release behavior of the two solvents is consistent in four dissolution media.4.The pharmacokinetic parameters of self-made preparations and reference preparations were similar in vivo:T1/2 ratio was 4.264 h and 5.629 h,Cmax was 22.244 ng/ml and 19.596 ng/ml,AUC(0-t)was 126.499 ng/ml.h and 139.700 ng/ml.h,and AUC(0-)was 146.606 ng/ml.h and 131.113ng/ml.h,respectively.The bioavailability was 115.3%,103.6%and 103.9%respectively.Conclusion:The formulation of the self-made preparation is reasonable,the production process has good stability and reproducibility,and the quality is controllable.The self-made preparation meets the quality standard of carbixamine maleate oral sustained-release suspension.The appearance of the self-made preparation is consistent with that of the reference preparation and the release behavior in vitro is consistent.However,there are some differences in biology,and the prescription technology needs to be further improved.