Preparation Process?Quality Control Of Terazosin Hydrochloride Capsule And Bioequivalence In Beagle

Terazosin hydrochloride is a selective?1 receptor blocker,which can reduce peripheral vascular resistance and lower systolic and diastolic blood pressure.The original development company is Abbott Company,and the commonly used clinical dosage form is capsule,which is mainly used for patients with benign prostatic hyperplasia and hypertension.In China,the number of those patients is increasing year by year.The way to make a reasonable imitation of terazosin hydrochloride capsule under the relevant medical policies in China,to alleviate the demand of domestic patients for the original research preparation,to reduce the cost of patients'treatment,and to explore the experience of developping generic drugs,has become the focus of this study.Objective?1?Based on the requirements for the consistency evaluation of oral solid preparations,combined with the concept of quality originating from design?QBD?and relevant requirements in ICH,the preparation process and quality study of terazosin hydrochloride capsules?establishing content,dissolution,Related substance detection methods and methodological verification?,so that the quality of the product is not inferior to the reference preparation in pharmaceutical indicators?Sandoz's terazosin hydrochloride capsules?.?2?Establish LC-MS/MS method to determine the concentration of terazosin in plasma of Beagle dogs,and study the pharmacokinetics of terazosin hydrochloride capsules in healthy Beagle dogs.Differences in pharmacokinetic parameters in the body,predict whether the test and reference preparations meet the requirements in human bioequivalence experiments,improve research efficiency and reduce research investment.Method?1?Preparation processThrough reverse engineering analysis,the formulation composition of terazosin hydrochloride capsules was obtained,and the quality target profile?QTPP?and key quality attributes?CQA?were formulated.Determine the key process parameters?CPP?of the product through compatibility test of raw materials and optimization of prescription process,and through in vitro dissolution test,the f2 factor of the in vitro dissolution curve with the reference preparation is greater than 50.Process amplification and production process verification of the identified prescription process,so that it can be used in industrial production.?2?Quality controlEstablish HPLC methods for the detection of related substances,contents,and dissolution.The established methods were verified and can be used for quality control of terazosin hydrochloride capsules.?3?Pharmacokinetics of Beagle dogs in vivoUse ammonium acetate-methanol?65:35?as mobile phase,flow rate was 0.2ml/min,and carbon octadecyl bonded silica gel Column?2.1×50mm,1.8?m?for separation.The mass spectrometer used an ESI source to detect by positive ion detection and multi-reactive ion monitoring?MRM?scanning.The detection ion was m/z388.2?m/z290.4?terazosin hydrochloride,to be measured Material?,m/z384.2?m/z247.3?prazosin,internal standard?.;Double cross experimental design was used for two cycles and two preparations,that is,10 healthy Beagle dogs according to weight.The dogs randomly divided into two groups,cross-feded the test preparation?medicine A?terazosin hydrochloride capsule and the reference preparation?medicine R?terazosin hydrochloride capsule?Sandoz.lnc?.2mg.Plasma samples were collected at different time points after administration,and the concentration of terazosin drug in plasma was determined by LC-MS/MS method.The main pharmacokinetic parameters were calculated by DAS3.2.8 software and equivalent analysis was performed.Results?1?Preparation processThrough the screening of the prescription process,the formulation composition and process parameters of the preparation were determined,and the production process was verified on the production line.The verification results showed that the established prescription process can produce products that meet the expected quality goals.?2?Quality controlThrough methodological verification of related substances,dissolution,content,and microbial limits,the established quality standards can be applied to the quality control of terazosin hydrochloride capsules.?3?Pharmacokinetics of Beagle dogs in vivoThe LC-MS/MS method was established and systematic method verification was performed.The established LC-MS/MS method can meet the requirements of biological sample analysis.The main pharmacokinetic parameters of the test and reference preparations are as follows:T1/2 is?8.697±1.377?and?9.202±2.925?h,C_maxis?19.19±5.623?and?17.900±3.826?ng/m L,T_maxis?2.6±1.519?and?2.575±1.519?h,AUC0-t is?230.81±37.361?and?215.505±21.725?ng·h/m L,and AUC0-?is?238.094±36.879?and?224.920±23.025?ng·h/m L;using the reference preparation as a control,the AUC_0-trelative bioavailability of the test preparation is estimated to be 106.9±11.5%,and the AUC_0-?relative bioavailability is 105.9±12.5%,both Bioequivalent in Beagle dogs.Conclusion?1?Based on the concept of QBD,this study determined the CQA and CPP of the product.The obtained process recipe was scaled up by the production process,and the product quality was in line with the expected goals.?2?The related substances,content,dissolution and other detection methods established by this research can meet the quality control of the products.?3?The LC-MS/MS method established in this study is simple,fast,sensitive and accurate,and is suitable for studying the pharmacokinetic behavior of terazosin in Beagle dogs.