Doxazosin_mesylate_COA_15705_MedChemExpress
稳定性英文版
HPLC ASSAY with DETERMINATION OF META-FLUOXETINE HCl.ANALYTICAL METHOD VALIDATION10 and 20mg Fluoxetine Capsules HPLC DeterminationFLUOXETINE HClC17H18F3NO•HClM.W. = 345.79CAS — 59333-67-4STABILITY INDICATINGA S S A Y V A L I D A T I O NMethod is suitable for:ýIn-process controlþProduct ReleaseþStability indicating analysis (Suitability - US/EU Product) CAUTIONFLUOXETINE HYDROCHLORIDE IS A HAZARDOUS CHEMICAL AND SHOULD BE HANDLED ONLY UNDER CONDITIONS SUITABLE FOR HAZARDOUS WORK.IT IS HIGHLY PRESSURE SENSITIVE AND ADEQUATE PRECAUTIONS SHOULD BE TAKEN TO AVOID ANY MECHANICAL FORCE (SUCH AS GRINDING, CRUSHING, ETC.) ON THE POWDER.ED. N0: 04Effective Date:APPROVED::HPLC ASSAY with DETERMINATION OF META-FLUOXETINE HCl.ANALYTICAL METHOD VALIDATION10 and 20mg Fluoxetine Capsules HPLC DeterminationTABLE OF CONTENTS INTRODUCTION........................................................................................................................ PRECISION............................................................................................................................... System Repeatability ................................................................................................................ Method Repeatability................................................................................................................. Intermediate Precision .............................................................................................................. LINEARITY................................................................................................................................ RANGE...................................................................................................................................... ACCURACY............................................................................................................................... Accuracy of Standard Injections................................................................................................ Accuracy of the Drug Product.................................................................................................... VALIDATION OF FLUOXETINE HCl AT LOW CONCENTRATION........................................... Linearity at Low Concentrations................................................................................................. Accuracy of Fluoxetine HCl at Low Concentration..................................................................... System Repeatability................................................................................................................. Quantitation Limit....................................................................................................................... Detection Limit........................................................................................................................... VALIDATION FOR META-FLUOXETINE HCl (POSSIBLE IMPURITIES).................................. Meta-Fluoxetine HCl linearity at 0.05% - 1.0%........................................................................... Detection Limit for Fluoxetine HCl.............................................................................................. Quantitation Limit for Meta Fluoxetine HCl................................................................................ Accuracy for Meta-Fluoxetine HCl ............................................................................................ Method Repeatability for Meta-Fluoxetine HCl........................................................................... Intermediate Precision for Meta-Fluoxetine HCl......................................................................... SPECIFICITY - STABILITY INDICATING EVALUATION OF THE METHOD............................. FORCED DEGRADATION OF FINISHED PRODUCT AND STANDARD..................................1. Unstressed analysis...............................................................................................................2. Acid Hydrolysis stressed analysis..........................................................................................3. Base hydrolysis stressed analysis.........................................................................................4. Oxidation stressed analysis...................................................................................................5. Sunlight stressed analysis.....................................................................................................6. Heat of solution stressed analysis.........................................................................................7. Heat of powder stressed analysis.......................................................................................... System Suitability stressed analysis.......................................................................................... Placebo...................................................................................................................................... STABILITY OF STANDARD AND SAMPLE SOLUTIONS......................................................... Standard Solution...................................................................................................................... Sample Solutions....................................................................................................................... ROBUSTNESS.......................................................................................................................... Extraction................................................................................................................................... Factorial Design......................................................................................................................... CONCLUSION...........................................................................................................................ED. N0: 04Effective Date:APPROVED::HPLC ASSAY with DETERMINATION OF META-FLUOXETINE HCl.ANALYTICAL METHOD VALIDATION10 and 20mg Fluoxetine Capsules HPLC DeterminationBACKGROUNDTherapeutically, Fluoxetine hydrochloride is a classified as a selective serotonin-reuptake inhibitor. Effectively used for the treatment of various depressions. Fluoxetine hydrochloride has been shown to have comparable efficacy to tricyclic antidepressants but with fewer anticholinergic side effects. The patent expiry becomes effective in 2001 (US). INTRODUCTIONFluoxetine capsules were prepared in two dosage strengths: 10mg and 20mg dosage strengths with the same capsule weight. The formulas are essentially similar and geometrically equivalent with the same ingredients and proportions. Minor changes in non-active proportions account for the change in active ingredient amounts from the 10 and 20 mg strength.The following validation, for the method SI-IAG-206-02 , includes assay and determination of Meta-Fluoxetine by HPLC, is based on the analytical method validation SI-IAG-209-06. Currently the method is the in-house method performed for Stability Studies. The Validation was performed on the 20mg dosage samples, IAG-21-001 and IAG-21-002.In the forced degradation studies, the two placebo samples were also used. PRECISIONSYSTEM REPEATABILITYFive replicate injections of the standard solution at the concentration of 0.4242mg/mL as described in method SI-IAG-206-02 were made and the relative standard deviation (RSD) of the peak areas was calculated.SAMPLE PEAK AREA#15390#25406#35405#45405#55406Average5402.7SD 6.1% RSD0.1ED. N0: 04Effective Date:APPROVED::HPLC ASSAY with DETERMINATION OF META-FLUOXETINE HCl.ANALYTICAL METHOD VALIDATION10 and 20mg Fluoxetine Capsules HPLC DeterminationED. N0: 04Effective Date:APPROVED::PRECISION - Method RepeatabilityThe full HPLC method as described in SI-IAG-206-02 was carried-out on the finished product IAG-21-001 for the 20mg dosage form. The method repeated six times and the relative standard deviation (RSD) was calculated.SAMPLENumber%ASSAYof labeled amountI 96.9II 97.8III 98.2IV 97.4V 97.7VI 98.5(%) Average97.7SD 0.6(%) RSD0.6PRECISION - Intermediate PrecisionThe full method as described in SI-IAG-206-02 was carried-out on the finished product IAG-21-001 for the 20mg dosage form. The method was repeated six times by a second analyst on a different day using a different HPLC instrument. The average assay and the relative standard deviation (RSD) were calculated.SAMPLENumber% ASSAYof labeled amountI 98.3II 96.3III 94.6IV 96.3V 97.8VI 93.3Average (%)96.1SD 2.0RSD (%)2.1The difference between the average results of method repeatability and the intermediate precision is 1.7%.HPLC ASSAY with DETERMINATION OF META-FLUOXETINE HCl.ANALYTICAL METHOD VALIDATION10 and 20mg Fluoxetine Capsules HPLC DeterminationLINEARITYStandard solutions were prepared at 50% to 200% of the nominal concentration required by the assay procedure. Linear regression analysis demonstrated acceptability of the method for quantitative analysis over the concentration range required. Y-Intercept was found to be insignificant.RANGEDifferent concentrations of the sample (IAG-21-001) for the 20mg dosage form were prepared, covering between 50% - 200% of the nominal weight of the sample.Conc. (%)Conc. (mg/mL)Peak Area% Assayof labeled amount500.20116235096.7700.27935334099.21000.39734463296.61500.64480757797.52000.79448939497.9(%) Average97.6SD 1.0(%) RSD 1.0ED. N0: 04Effective Date:APPROVED::HPLC ASSAY with DETERMINATION OF META-FLUOXETINE HCl.ANALYTICAL METHOD VALIDATION10 and 20mg Fluoxetine Capsules HPLC DeterminationED. N0: 04Effective Date:APPROVED::RANGE (cont.)The results demonstrate linearity as well over the specified range.Correlation coefficient (RSQ)0.99981 Slope11808.3Y -Interceptresponse at 100%* 100 (%) 0.3%ACCURACYACCURACY OF STANDARD INJECTIONSFive (5) replicate injections of the working standard solution at concentration of 0.4242mg/mL, as described in method SI-IAG-206-02 were made.INJECTIONNO.PEAK AREA%ACCURACYI 539299.7II 540599.9III 540499.9IV 5406100.0V 5407100.0Average 5402.899.9%SD 6.10.1RSD, (%)0.10.1The percent deviation from the true value wasdetermined from the linear regression lineHPLC ASSAY with DETERMINATION OF META-FLUOXETINE HCl.ANALYTICAL METHOD VALIDATION10 and 20mg Fluoxetine Capsules HPLC DeterminationED. N0: 04Effective Date:APPROVED::ACCURACY OF THE DRUG PRODUCTAdmixtures of non-actives (placebo, batch IAG-21-001 ) with Fluoxetine HCl were prepared at the same proportion as in a capsule (70%-180% of the nominal concentration).Three preparations were made for each concentration and the recovery was calculated.Conc.(%)Placebo Wt.(mg)Fluoxetine HCl Wt.(mg)Peak Area%Accuracy Average (%)70%7079.477.843465102.27079.687.873427100.77079.618.013465100.0101.0100%10079.6211.25476397.910080.8011.42491799.610079.6011.42485498.398.6130%13079.7214.90640599.413080.3114.75632899.213081.3314.766402100.399.618079.9920.10863699.318079.3820.45879499.418080.0820.32874899.599.4Placebo, Batch Lot IAG-21-001HPLC ASSAY with DETERMINATION OF META-FLUOXETINE HCl.ANALYTICAL METHOD VALIDATION10 and 20mg Fluoxetine Capsules HPLC DeterminationED. N0: 04Effective Date:APPROVED::VALIDATION OF FLUOXETINE HClAT LOW CONCENTRATIONLINEARITY AT LOW CONCENTRATIONSStandard solution of Fluoxetine were prepared at approximately 0.02%-1.0% of the working concentration required by the method SI-IAG-206-02. Linear regression analysis demonstrated acceptability of the method for quantitative analysis over this range.ACCURACY OF FLUOXETINE HCl AT LOW CONCENTRATIONThe peak areas of the standard solution at the working concentration were measured and the percent deviation from the true value, as determined from the linear regression was calculated.SAMPLECONC.µg/100mLAREA FOUND%ACCURACYI 470.56258499.7II 470.56359098.1III 470.561585101.3IV 470.561940100.7V 470.56252599.8VI 470.56271599.5(%) AverageSlope = 132.7395299.9SD Y-Intercept = -65.872371.1(%) RSD1.1HPLC ASSAY with DETERMINATION OF META-FLUOXETINE HCl.ANALYTICAL METHOD VALIDATION10 and 20mg Fluoxetine Capsules HPLC DeterminationSystem RepeatabilitySix replicate injections of standard solution at 0.02% and 0.05% of working concentration as described in method SI-IAG-206-02 were made and the relative standard deviation was calculated.SAMPLE FLUOXETINE HCl AREA0.02%0.05%I10173623II11503731III10103475IV10623390V10393315VI10953235Average10623462RSD, (%) 5.0 5.4Quantitation Limit - QLThe quantitation limit ( QL) was established by determining the minimum level at which the analyte was quantified. The quantitation limit for Fluoxetine HCl is 0.02% of the working standard concentration with resulting RSD (for six injections) of 5.0%. Detection Limit - DLThe detection limit (DL) was established by determining the minimum level at which the analyte was reliably detected. The detection limit of Fluoxetine HCl is about 0.01% of the working standard concentration.ED. N0: 04Effective Date:APPROVED::HPLC ASSAY with DETERMINATION OF META-FLUOXETINE HCl.ANALYTICAL METHOD VALIDATION10 and 20mg Fluoxetine Capsules HPLC DeterminationED. N0: 04Effective Date:APPROVED::VALIDATION FOR META-FLUOXETINE HCl(EVALUATING POSSIBLE IMPURITIES)Meta-Fluoxetine HCl linearity at 0.05% - 1.0%Relative Response Factor (F)Relative response factor for Meta-Fluoxetine HCl was determined as slope of Fluoxetine HCl divided by the slope of Meta-Fluoxetine HCl from the linearity graphs (analysed at the same time).F =132.7395274.859534= 1.8Detection Limit (DL) for Fluoxetine HClThe detection limit (DL) was established by determining the minimum level at which the analyte was reliably detected.Detection limit for Meta Fluoxetine HCl is about 0.02%.Quantitation Limit (QL) for Meta-Fluoxetine HClThe QL is determined by the analysis of samples with known concentration of Meta-Fluoxetine HCl and by establishing the minimum level at which the Meta-Fluoxetine HCl can be quantified with acceptable accuracy and precision.Six individual preparations of standard and placebo spiked with Meta-Fluoxetine HCl solution to give solution with 0.05% of Meta Fluoxetine HCl, were injected into the HPLC and the recovery was calculated.HPLC ASSAY with DETERMINATION OF META-FLUOXETINE HCl.ANALYTICAL METHOD VALIDATION10 and 20mg Fluoxetine Capsules HPLC DeterminationED. N0: 04Effective Date:APPROVED::META-FLUOXETINE HCl[RECOVERY IN SPIKED SAMPLES].Approx.Conc.(%)Known Conc.(µg/100ml)Area in SpikedSampleFound Conc.(µg/100mL)Recovery (%)0.0521.783326125.735118.10.0521.783326825.821118.50.0521.783292021.55799.00.0521.783324125.490117.00.0521.783287220.96996.30.0521.783328526.030119.5(%) AVERAGE111.4SD The recovery result of 6 samples is between 80%-120%.10.7(%) RSDQL for Meta Fluoxetine HCl is 0.05%.9.6Accuracy for Meta Fluoxetine HClDetermination of Accuracy for Meta-Fluoxetine HCl impurity was assessed using triplicate samples (of the drug product) spiked with known quantities of Meta Fluoxetine HCl impurity at three concentrations levels (namely 80%, 100% and 120% of the specified limit - 0.05%).The results are within specifications:For 0.4% and 0.5% recovery of 85% -115%For 0.6% recovery of 90%-110%HPLC ASSAY with DETERMINATION OF META-FLUOXETINE HCl.ANALYTICAL METHOD VALIDATION10 and 20mg Fluoxetine Capsules HPLC DeterminationED. N0: 04Effective Date:APPROVED::META-FLUOXETINE HCl[RECOVERY IN SPIKED SAMPLES]Approx.Conc.(%)Known Conc.(µg/100mL)Area in spikedSample Found Conc.(µg/100mL)Recovery (%)[0.4%]0.4174.2614283182.66104.820.4174.2614606187.11107.370.4174.2614351183.59105.36[0.5%]0.5217.8317344224.85103.220.5217.8316713216.1599.230.5217.8317341224.81103.20[0.6%]0.6261.3918367238.9591.420.6261.3920606269.81103.220.6261.3920237264.73101.28RECOVERY DATA DETERMINED IN SPIKED SAMPLESHPLC ASSAY with DETERMINATION OF META-FLUOXETINE HCl.ANALYTICAL METHOD VALIDATION10 and 20mg Fluoxetine Capsules HPLC DeterminationED. N0: 04Effective Date:APPROVED::REPEATABILITYMethod Repeatability - Meta Fluoxetine HClThe full method (as described in SI-IAG-206-02) was carried out on the finished drug product representing lot number IAG-21-001-(1). The HPLC method repeated serially, six times and the relative standard deviation (RSD) was calculated.IAG-21-001 20mg CAPSULES - FLUOXETINESample% Meta Fluoxetine % Meta-Fluoxetine 1 in Spiked Solution10.0260.09520.0270.08630.0320.07740.0300.07450.0240.09060.0280.063AVERAGE (%)0.0280.081SD 0.0030.012RSD, (%)10.314.51NOTE :All results are less than QL (0.05%) therefore spiked samples with 0.05% Meta Fluoxetine HCl were injected.HPLC ASSAY with DETERMINATION OF META-FLUOXETINE HCl.ANALYTICAL METHOD VALIDATION10 and 20mg Fluoxetine Capsules HPLC DeterminationED. N0: 04Effective Date:APPROVED::Intermediate Precision - Meta-Fluoxetine HClThe full method as described in SI-IAG-206-02 was applied on the finished product IAG-21-001-(1) .It was repeated six times, with a different analyst on a different day using a different HPLC instrument.The difference between the average results obtained by the method repeatability and the intermediate precision was less than 30.0%, (11.4% for Meta-Fluoxetine HCl as is and 28.5% for spiked solution).IAG-21-001 20mg - CAPSULES FLUOXETINESample N o:Percentage Meta-fluoxetine% Meta-fluoxetine 1 in spiked solution10.0260.06920.0270.05730.0120.06140.0210.05850.0360.05560.0270.079(%) AVERAGE0.0250.063SD 0.0080.009(%) RSD31.514.51NOTE:All results obtained were well below the QL (0.05%) thus spiked samples slightly greater than 0.05% Meta-Fluoxetine HCl were injected. The RSD at the QL of the spiked solution was 14.5%HPLC ASSAY with DETERMINATION OF META-FLUOXETINE HCl.ANALYTICAL METHOD VALIDATION10 and 20mg Fluoxetine Capsules HPLC DeterminationSPECIFICITY - STABILITY INDICATING EVALUATIONDemonstration of the Stability Indicating parameters of the HPLC assay method [SI-IAG-206-02] for Fluoxetine 10 & 20mg capsules, a suitable photo-diode array detector was incorporated utilizing a commercial chromatography software managing system2, and applied to analyze a range of stressed samples of the finished drug product.GLOSSARY of PEAK PURITY RESULT NOTATION (as reported2):Purity Angle-is a measure of spectral non-homogeneity across a peak, i.e. the weighed average of all spectral contrast angles calculated by comparing all spectra in the integrated peak against the peak apex spectrum.Purity Threshold-is the sum of noise angle3 and solvent angle4. It is the limit of detection of shape differences between two spectra.Match Angle-is a comparison of the spectrum at the peak apex against a library spectrum.Match Threshold-is the sum of the match noise angle3 and match solvent angle4.3Noise Angle-is a measure of spectral non-homogeneity caused by system noise.4Solvent Angle-is a measure of spectral non-homogeneity caused by solvent composition.OVERVIEWT he assay of the main peak in each stressed solution is calculated according to the assay method SI-IAG-206-02, against the Standard Solution, injected on the same day.I f the Purity Angle is smaller than the Purity Threshold and the Match Angle is smaller than the Match Threshold, no significant differences between spectra can be detected. As a result no spectroscopic evidence for co-elution is evident and the peak is considered to be pure.T he stressed condition study indicated that the Fluoxetine peak is free from any appreciable degradation interference under the stressed conditions tested. Observed degradation products peaks were well separated from the main peak.1® PDA-996 Waters™ ; 2[Millennium 2010]ED. N0: 04Effective Date:APPROVED::HPLC ASSAY with DETERMINATION OF META-FLUOXETINE HCl.ANALYTICAL METHOD VALIDATION10 and 20mg Fluoxetine Capsules HPLC DeterminationFORCED DEGRADATION OF FINISHED PRODUCT & STANDARD 1.UNSTRESSED SAMPLE1.1.Sample IAG-21-001 (2) (20mg/capsule) was prepared as stated in SI-IAG-206-02 and injected into the HPLC system. The calculated assay is 98.5%.SAMPLE - UNSTRESSEDFluoxetine:Purity Angle:0.075Match Angle:0.407Purity Threshold:0.142Match Threshold:0.4251.2.Standard solution was prepared as stated in method SI-IAG-206-02 and injected into the HPLC system. The calculated assay is 100.0%.Fluoxetine:Purity Angle:0.078Match Angle:0.379Purity Threshold:0.146Match Threshold:0.4272.ACID HYDROLYSIS2.1.Sample solution of IAG-21-001 (2) (20mg/capsule) was prepared as in method SI-IAG-206-02 : An amount equivalent to 20mg Fluoxetine was weighed into a 50mL volumetric flask. 20mL Diluent was added and the solution sonicated for 10 minutes. 1mL of conc. HCl was added to this solution The solution was allowed to stand for 18 hours, then adjusted to about pH = 5.5 with NaOH 10N, made up to volume with Diluent and injected into the HPLC system after filtration.Fluoxetine peak intensity did NOT decrease. Assay result obtained - 98.8%.SAMPLE- ACID HYDROLYSISFluoxetine peak:Purity Angle:0.055Match Angle:0.143Purity Threshold:0.096Match Threshold:0.3712.2.Standard solution was prepared as in method SI-IAG-206-02 : about 22mg Fluoxetine HCl were weighed into a 50mL volumetric flask. 20mL Diluent were added. 2mL of conc. HCl were added to this solution. The solution was allowed to stand for 18 hours, then adjusted to about pH = 5.5 with NaOH 10N, made up to volume with Diluent and injected into the HPLC system.Fluoxetine peak intensity did NOT decrease. Assay result obtained - 97.2%.ED. N0: 04Effective Date:APPROVED::HPLC ASSAY with DETERMINATION OF META-FLUOXETINE HCl.ANALYTICAL METHOD VALIDATION10 and 20mg Fluoxetine Capsules HPLC DeterminationSTANDARD - ACID HYDROLYSISFluoxetine peak:Purity Angle:0.060Match Angle:0.060Purity Threshold:0.099Match Threshold:0.3713.BASE HYDROLYSIS3.1.Sample solution of IAG-21-001 (2) (20mg/capsule) was prepared as per method SI-IAG-206-02 : An amount equivalent to 20mg Fluoxetine was weight into a 50mL volumetric flask. 20mL Diluent was added and the solution sonicated for 10 minutes. 1mL of 5N NaOH was added to this solution. The solution was allowed to stand for 18 hours, then adjusted to about pH = 5.5 with 5N HCl, made up to volume with Diluent and injected into the HPLC system.Fluoxetine peak intensity did NOT decrease. Assay result obtained - 99.3%.SAMPLE - BASE HYDROLYSISFluoxetine peak:Purity Angle:0.063Match Angle:0.065Purity Threshold:0.099Match Threshold:0.3623.2.Standard stock solution was prepared as per method SI-IAG-206-02 : About 22mg Fluoxetine HCl was weighed into a 50mL volumetric flask. 20mL Diluent was added. 2mL of 5N NaOH was added to this solution. The solution was allowed to stand for 18 hours, then adjusted to about pH=5.5 with 5N HCl, made up to volume with Diluent and injected into the HPLC system.Fluoxetine peak intensity did NOT decrease - 99.5%.STANDARD - BASE HYDROLYSISFluoxetine peak:Purity Angle:0.081Match Angle:0.096Purity Threshold:0.103Match Threshold:0.3634.OXIDATION4.1.Sample solution of IAG-21-001 (2) (20mg/capsule) was prepared as per method SI-IAG-206-02. An equivalent to 20mg Fluoxetine was weighed into a 50mL volumetric flask. 20mL Diluent added and the solution sonicated for 10 minutes.1.0mL of 30% H2O2 was added to the solution and allowed to stand for 5 hours, then made up to volume with Diluent, filtered and injected into HPLC system.Fluoxetine peak intensity decreased to 95.2%.ED. N0: 04Effective Date:APPROVED::HPLC ASSAY with DETERMINATION OF META-FLUOXETINE HCl.ANALYTICAL METHOD VALIDATION10 and 20mg Fluoxetine Capsules HPLC DeterminationSAMPLE - OXIDATIONFluoxetine peak:Purity Angle:0.090Match Angle:0.400Purity Threshold:0.154Match Threshold:0.4294.2.Standard solution was prepared as in method SI-IAG-206-02 : about 22mg Fluoxetine HCl were weighed into a 50mL volumetric flask and 25mL Diluent were added. 2mL of 30% H2O2 were added to this solution which was standing for 5 hours, made up to volume with Diluent and injected into the HPLC system.Fluoxetine peak intensity decreased to 95.8%.STANDARD - OXIDATIONFluoxetine peak:Purity Angle:0.083Match Angle:0.416Purity Threshold:0.153Match Threshold:0.4295.SUNLIGHT5.1.Sample solution of IAG-21-001 (2) (20mg/capsule) was prepared as in method SI-IAG-206-02 . The solution was exposed to 500w/hr. cell sunlight for 1hour. The BST was set to 35°C and the ACT was 45°C. The vials were placed in a horizontal position (4mm vials, National + Septum were used). A Dark control solution was tested. A 2%w/v quinine solution was used as the reference absorbance solution.Fluoxetine peak decreased to 91.2% and the dark control solution showed assay of 97.0%. The difference in the absorbance in the quinine solution is 0.4227AU.Additional peak was observed at RRT of 1.5 (2.7%).The total percent of Fluoxetine peak with the degradation peak is about 93.9%.SAMPLE - SUNLIGHTFluoxetine peak:Purity Angle:0.093Match Angle:0.583Purity Threshold:0.148Match Threshold:0.825 ED. N0: 04Effective Date:APPROVED::HPLC ASSAY with DETERMINATION OF META-FLUOXETINE HCl.ANALYTICAL METHOD VALIDATION10 and 20mg Fluoxetine Capsules HPLC DeterminationSUNLIGHT (Cont.)5.2.Working standard solution was prepared as in method SI-IAG-206-02 . The solution was exposed to 500w/hr. cell sunlight for 1.5 hour. The BST was set to 35°C and the ACT was 42°C. The vials were placed in a horizontal position (4mm vials, National + Septum were used). A Dark control solution was tested. A 2%w/v quinine solution was used as the reference absorbance solution.Fluoxetine peak was decreased to 95.2% and the dark control solution showed assay of 99.5%.The difference in the absorbance in the quinine solution is 0.4227AU.Additional peak were observed at RRT of 1.5 (2.3).The total percent of Fluoxetine peak with the degradation peak is about 97.5%. STANDARD - SUNLIGHTFluoxetine peak:Purity Angle:0.067Match Angle:0.389Purity Threshold:0.134Match Threshold:0.8196.HEAT OF SOLUTION6.1.Sample solution of IAG-21-001-(2) (20 mg/capsule) was prepared as in method SI-IAG-206-02 . Equivalent to 20mg Fluoxetine was weighed into a 50mL volumetric flask. 20mL Diluent was added and the solution was sonicated for 10 minutes and made up to volume with Diluent. 4mL solution was transferred into a suitable crucible, heated at 105°C in an oven for 2 hours. The sample was cooled to ambient temperature, filtered and injected into the HPLC system.Fluoxetine peak was decreased to 93.3%.SAMPLE - HEAT OF SOLUTION [105o C]Fluoxetine peak:Purity Angle:0.062Match Angle:0.460Purity Threshold:0.131Match Threshold:0.8186.2.Standard Working Solution (WS) was prepared under method SI-IAG-206-02 . 4mL of the working solution was transferred into a suitable crucible, placed in an oven at 105°C for 2 hours, cooled to ambient temperature and injected into the HPLC system.Fluoxetine peak intensity did not decrease - 100.5%.ED. N0: 04Effective Date:APPROVED::。
多西他赛注射液说明书多帕菲
多西他赛注射液说明书药品名称通用名称：多西他赛注射液商品名称：多帕菲英文名称：Docetaxel Injection汉语拼音：Duoxitasai Zhusheye成份本品主要成份为多西他赛,其化学名称为:｛2aR-2aα,4β,4aβ,6β,9ααR,βS,11α,12α,12aα,12bα｝-β-｛1,1-二甲基乙氧基羰基氨基｝-α-羟基苯丙酸12b-乙酰氧-12-苯甲酰氧-2a,3,4,4a,5,6,9,10,11,12,12a,12b-十二氢-4,6,11-三羟基-4a,8,13,13-四甲基-5-氧代-7,11-亚甲基-1H-环癸五烯并3,4苯并1,2-b氧杂丁环-9-基酯;化学结构式：分子式：C43H53NO14分子量：Cas No：分子量：辅料名称：柠檬酸,吐温-80,乙醇性状本品为黄色至棕黄色澄明油状液体;适应症1.适用于局部晚期或转移性乳腺癌的治疗;2.适用于局部晚期或转移性非小细胞肺癌的治疗,即使是在以顺铂为主的化疗失败后;规格20mg用法用量多西他赛只能用于静脉滴注;所有病人在接受多西他赛治疗前均必须口服糖皮质激素类药物,如地塞米松,在多西他赛滴注一天前服用,每天16mg,持续至少3天,以预防过敏反应和体液潴留;多西他赛的推荐剂量为70-75mg/m2,静脉滴注一小时,每三周一次;多西他赛注射液及溶剂使用说明：1.制备多西他赛预注射液1若从冰箱中取出所需数目的多西他赛,需在室温下放置5分钟;2用一装有针头的刻度注射器将与多西他赛注射液对应的溶剂吸出;3将装药液的瓶子倾斜,将注射器中全部溶剂注入对应的多西他赛注射液瓶中;4拔出针管及针头,手工反复倒置混合至少45秒,不能摇动;5将混合后的药瓶室温放置5分钟,然后检查溶液是否均匀澄明由于处方中含吐温-80,放置5分钟后通常还会有泡沫;此预注射液应于配制后立即使用;然而其理化性质表明不论是在2-8℃或室温保存,预注射液的稳定性为8小时;2.注射液的制备1病人所需剂量可能要超过一瓶预注射液的药量,根据计算所得病人所用药量的毫克数,用标有刻度带针头的注射器从已混合好的药瓶中每毫升含多西他赛10mg抽出所需药量,如120mg剂量多西他赛需抽取预注射液12ml;2将所抽取的预注射液注入装有5％葡萄糖液或％生理盐水的注射袋或瓶中,如果要求剂量超过多西他赛200mg,则要选择容量大一些的注射容器,以使多西他赛的最终浓度不超过ml;3用手摇动注射袋或瓶以混合注射液;4配制好的多西他赛注射用溶液,应在室温及正常光线下,于4小时内使用,无菌静脉滴注1小时;5同其它注射用药一样,多西他赛预注射液及注射液要使用前都需目测,含有沉淀的注射液即废弃不用;3.弃置所有被用于稀释、注射用的物品全部按标准操作程序弃置;不良反应1.骨髓抑制：中性粒细胞减少是最常见的不良反应而且通常较严重低于500个/mm3;可逆转且不蓄积;据文献报道,有与中性粒细胞减少相关的发热及感染发生;贫血可见于多数病例,少数病例发生重度血小板减少;2.过敏反应：部分病例可发生严重过敏反应,其特征为低血压与支气管痉挛,需要中断治疗;停止滴注并立即治疗后病人可恢复正常;部分病例也可发生轻度过敏反应;如脸红、伴有或不伴有搔痒的红斑、胸闷、背痛、呼吸困难、药物热或寒颤;3.皮肤反应常表现为红斑,主要见于手、足,或发生在臂部、脸部及胸部的局部皮疹,有时伴有搔痒;皮疹通常可能在滴注多西他赛后一周内发生,但可在下次滴注前恢复;严重症状如皮疹后出现脱皮则极少发生;可能会发生指趾甲病变,以色素沉著或变淡为特点,有时发生疼痛和指甲脱落;4.体液潴留包括水肿,也有报道极少数病例发生胸腔积液、腹水、心包积液、毛细血管通透性增加以及体重增加;经过4周期治疗或累计剂量400mg/m2后,下肢发生体液潴留,并可能发展至全身水肿,同时体重增加3公斤或3公斤以上;在停止多西他赛治疗后,体液潴留逐渐消失;为了减少体液潴留,应给病人预防性使用皮质类固醇;5.可能发生恶心、呕吐或腹泻等胃肠道反应;6.临床试验中曾有神经毒性的报道;7.心血管不良反应如低血压、窦性心动过速、心悸、肺水肿及高血压等有可能发生;8.其它不良反应包括：脱发、无力、粘膜炎、关节痛和肌肉痛、低血压和注射部位反应;9.肝功能正常者在治疗期间也有出现转氨酶升高、胆红素升高者,其与多西他赛的关系尚不明确;禁忌以下患者禁用：1.对多西他赛或吐温-80有严重过敏史的病人;2.白细胞数目小于1500个/mm3的病人;3.肝功能有严重损害的病人;注意事项1.多西他赛必须在有癌症化疗药物应用经验的医生指导下使用;由于可能发生较严重的过敏反应,应具备相应的急救设施,注射期间建议密切监测主要功能指标;2.在肝功能异常患者、使用本品高剂量治疗患者和既往接受铂类药物治疗的非小细胞肺癌患者,使用多西他赛剂量达100mg/m2时,与治疗相关的死亡发生率会增加;3.所有病人在接受多西他赛治疗前需预服药物以减轻体液潴留的发生,预服药物包括糖皮质激素类,如地塞米松,在多西他赛滴注前一天开始服用,每天16mg,服用至少3天;4.中性粒细胞减少是最常见的不良反应,多西他赛治疗期间应经常对血细胞数目进行监测;当病人中性粒细胞数目恢复至＞1500个/mm3以上时才能接受多西他赛的治疗;多西他赛治疗期间如发生严重的中性粒细胞减少＜500个/mm3并持续7天或7天以上,在下一个疗程中建议减低剂量,如仍有相同问题发生,则建议再减低剂量或停止治疗;5.在多西他赛开始滴注的最初几分钟内有可能发生过敏反应;如果发生的过敏反应的症状轻微,如脸红或局部皮肤反应,则不需终止治疗;如果发生严重过敏反应,如血压下降超过20mmHg,支气管痉挛或全身皮疹/红斑,则需立即停止滴注并进行对症治疗;对已发生严重不良反应的病人不能再次应用多西他赛;6.多西他赛治疗期间可能发生外周神经毒性反应;如果反应严重,则建议在下一疗程中减低剂量;7.已观察到的皮肤反应有肢端手心或足底局限性红斑伴水肿、脱皮等;此类毒性可能导致中断或停止治疗;8.肝功能有损害的病人：如果血清转氨酶ALT和/或AST超过正常值上限倍,同时伴有碱性磷酸酶超过正常值上限倍,存在发生严重不良反应的高度危险,如毒性死亡,包括致死的脓毒症、胃肠道出血以及发热性中性粒细胞减少症、感染、血小板减少症、口炎和乏力;因此,这些病人不应使用,并且在基线和每个化疗周期前要检测肝功能;9.本品为细胞毒类药物,药物配制要注意安全防护;建议使用手套;如果多西他赛溶液、预注射液或注射液碰到了皮肤,立即彻底地用肥皂及水冲洗；若碰到了粘膜,则要立即彻底地用水冲洗;10.本品每瓶多西他赛药液配有1瓶专用溶剂,使用前需先用溶剂稀释后,再与％生理盐水或5％葡萄糖配伍稀释,稀释后立即使用;11.为避免药物过量引起毒副反应,切勿用溶剂洗刷西林瓶及注射器孕妇及哺乳期妇女用药尚无多西他赛用于妊娠妇女的资料,多西他赛在兔及鼠中显示有胚胎及胎儿毒性,及在鼠中降低其生育的能力;象其他细胞毒药物一样,当妊娠妇女使用多西他赛时可能对胎儿有损伤;因此,多西他赛不能用于妊娠妇女;应告诫育龄期妇女在接受多西他赛治疗时应避免怀孕,一旦怀孕应立即通知治疗医生;多西他赛为亲脂性物质,但尚未知是否能从人体乳汁中排出;而且,由于其潜在的对哺乳婴儿的不良反应,在多西他赛治疗期间应停止母乳喂养;儿童用药多西他赛应用于儿童的有效性及安全性尚未确定;老年用药根据人群的药代动力学数据结果,对老年人用药没有特殊说明;药物相互作用尚无正式临床资料评估多西他赛与其他药物的相互作用;体外研究表明,多西他赛的代谢可能因合并用药而改变,这些能诱导、抑制或被细胞色素P450-3A代谢从而可能竞争性抑制该酶,如环孢素,特非那定,酮康唑,红霉素及醋竹桃霉素;当患者合并使用以上药物时,因为潜在的显著药物间作用,应加以注意;多西他赛的蛋白结合率高95％;尽管尚未正式研究过多西他赛与其他药物的体内相互作用,体外试验显示易与蛋白结合的药物如红霉素,苯海拉明,普萘洛尔,普罗帕酮,苯妥英,水杨酸盐,磺胺甲噁唑及丙戊酸钠不影响多西他赛与蛋白的结合;此外,地塞米松不影响多西他赛的蛋白结合率;多西他赛不影响洋地黄毒苷的蛋白结合率;在阿霉素/多西他赛联合用药时,多西他赛清除率增加见药代动力学;一项单药无对照研究的有限的资料提示在多西他赛与卡铂存在相互作用;当联合多西他赛时,卡铂的清除率比以前报导的单独应用卡铂的数据增高约50％;药物过量过量使用的已知症状及处理方法：多西他赛过量时,尚无解毒药可用;一旦发生过量,应将病人移至特殊监护病房内并严密监测生命体征,可预料到的过量主要并发症包括骨髓抑制,外周神经毒性及粘膜炎;发现患者用药过量后应尽快进行G-CSF治疗;如有需要,应采取其他对症治疗;药理毒理药理作用多西他赛为紫杉醇类抗肿瘤药,通过干扰细胞有丝分裂和分裂间期细胞功能所必需的微管网络而起抗肿瘤作用;多西他赛可与游离的微管蛋白结合,促进微管蛋白装配成稳定的微管,同时抑制其解聚,导致丧失了正常功能的微管束的产生和微管的固定,从而抑制细胞的有丝分裂;多西他赛与微管的结合不改变原丝的数目;毒理研究遗传毒性：在CHO-K1细胞染色体畸变试验和小鼠骨髓微核试验中,多西他赛表现出致断裂作用,但在Ames试验和CHO/HGPRT基因突变试验中未见致突变作用;生殖毒性：在大鼠静脉注射多西他赛kg按体表面积折算,约为临床推荐剂量的1/50,未见对生育力的损伤,但可引起睾丸重量减轻;该结果与大鼠和犬10个周期每21天给药1次,连续6个月的重复给药试验结果有相关性；大鼠和犬静脉注射剂量分别为5mg/kg和kg时按体表面积折算,分别约相当于临床推荐剂量的1/3和1/15,可见睾丸萎缩和变性,大鼠在低剂量时增加给药次数也表现出相似的作用;怀孕时使用多西他赛可导致胎儿损伤;大鼠和家兔在器官形成期分别给予多西他赛≥kg/日和kg/日按体表面积折算,分别相当于临床日推荐剂量的1/50和1/300,可见胚胎毒性和胎仔毒性表现为子宫内死亡、吸收胎增加、胎仔体重减轻和骨化延迟;以上剂量亦可引起母体毒性;目前尚无足够的和严格控制的孕妇临床研究资料;如果患者在孕期使用本品,或在使用本品期间怀孕,应被告之对胎儿的潜在危害和流产的潜在危险;有生育可能的妇女在使用本品治疗期间应避免怀孕;尚不清楚多西他赛是否从人乳中排泄;鉴于许多药物都可从人乳中排泄,且多西他赛可能引起哺乳婴儿的严重不良反应,母亲在使用本品前应停止哺乳;药代动力学文献报道,对癌症病人进行了剂量为20-115mg/m2的药代动力学研究;当剂量为75-115mg/m2,静脉滴注1-2小时时,其AUC呈剂量相关性;本品的药代特点符合三室药代动力学模型,α、β、γ半衰期分别为4分钟、36分钟及小时;初始阶段浓度迅速降低表明药物分布至周边室,后一时相部分原因是由于药物从周边室相对缓慢地消除;在1小时内静脉滴注给予多西他赛100mg/m2,平均峰浓度为μg/ml,AUC为μg/ml·h,总体清除率和稳态分布容积分别为21L/h/m2和113L;多西他赛及其代谢产物主要从粪便排泄;经粪便和尿排出的量分别约占所给剂量的75%和6%,仅有少部分以原型排出;体外研究表明,多西他赛的血浆蛋白结合率超过约94%,地塞米松并不影响多西他赛与蛋白的结合;体外研究表明,多西他赛被CYP3A4同功酶所代谢,这种代谢可以被CYP3A4抑制剂所抑制;贮藏密闭、遮光,2～8℃保存;包装玻璃瓶包装,每小盒内装多西他赛注射液1支和专用溶剂1支;有效期18个月。
白血病新药达沙替尼
白血病新药达沙替尼达沙替尼简介：通用名称：达沙替尼片商品名称：施达赛，SPRYCEL英文名称：Dasatinib Capsules汉语拼音：DashatiniPian成分：本品主要成分为达沙替尼，化学名称为：N-（2-氯-6甲基苯基）-2（{6-[4-（2-羟基乙基）哌嗪基-1]-2-甲基嘧啶基-4}氨基）-1,3-噻唑-5-酰胺-水合物。
化学结构式：分子式：C22H26ClN2O2S·H2O分子量：488.01（无水游离基）；506.02（水合物）临床应用：达沙替尼（Dasatinib/Sprycel），用于已经治疗，包括甲磺酸伊马替尼（Imatinibmesylate/Gleevec）耐药或不能耐受的慢性骨髓性白血病所有病期（慢性期、加速期、淋巴系细胞急变期和髓细胞急变期）的成人患者。
同时，FDA也经正常程序批准达沙替尼治疗对其他疗法耐药或不能耐受的费城染色体阳性的急性淋巴细胞性白血病成人患者。
达沙替尼属多酪氨酸激酶抑制剂，此次主要是依据来自总计包括911例患者的4项国际性、多中心Ⅱ期试验的安全性和疗效结果及其他支持性数据而获准用于上述两适应证的。
它在临床研究中最常报告的副反应有体液潴留、胃肠道症状和出血事件等；最常报告的严重副反应是发热、胸膜积液、发热性中性白)用于粒细胞白血病(CML)6月29日，FDA批准了百时美施贵宝的Sprycel(dasatinib)用于成年患者，治疗两种新的适应症：对伊马替尼等一线药物化疗不敏感的各期慢性粒细胞白血病(CML)，以及对其他疗法无效或不能耐受的Ph染色体阳性的急性淋巴细胞白血病(ALL)。
在已批准上市的药物中，Sprycel是第一种能够抑制多种构型酪氨酸蛋白激酶Abl的口服化疗药。
在纳摩尔浓度，该药能抑制Bcr-Abl, SRC 激酶家族(SRC, LCK, YES, FYN), c-KIT, EPHA2, 和PDGFR-B等多种激酶。
通过抑制上述激酶的作用，Sprycel可抑制CML和Ph+ ALL骨髓中白血病细胞的增殖，但正常红细胞、白细胞和血小板仍可继续增殖。
阿司咪唑
合成方法
合成方法
化合物(I)和碘甲烷在乙醇中回流8h，环合得到化合物(Ⅱ)。再水解脱去酯基，得到化合物(Ⅲ)。用对甲氧 基苯乙基溴进行N-烷基化，得化合物(Ⅳ)。再用对氟苄基溴烷基化，得阿司咪唑。
1. 1-[(4-氟苯基)甲基]-苯并咪唑-2-(3H)-酮的制备
在反应瓶中加入2-羟基苯并咪唑5.0g(37.3mmol)和NaH 1.6g(53mmol)(NaH含量大约为80%,浸入矿物油中) 的DMF 100ml的悬浮液.加毕.在60ºC.(最好有N2保护)搅拌反应1h.再加入4-氟苄基氯(FBC)5.4g(37mmol),加热 ( 6 0 ºC ) 搅 拌 反 应 5 . 5 h . 冷 却 至 室 温 后 加 入 冰 水 7 0 0 m l , 用 二 氯 甲 烷 ( 5 0 0 m l × 2 ) 提 取 . 有 机 层 用 食 盐 水 洗 . 无 水 N a 2 S O 4 干燥.过滤.滤液减压浓缩.剩余物用石油醚析晶.得1-[(4-氟苯基)甲基]-苯并咪唑-2-(3H)-酮固体8.0g,为无色 结 晶 m p 1 7 8 ~ 1 7 9 ºC , 收 率 8 8 % .
治疗措施
阿司咪唑中毒的治疗要点为： 1.大量摄入者予洗胃，后灌服活性炭和导泻。 2.对心肌抑制和Q-T间期延长者予5%碳酸氢钠250ml静注可能有效。 3.对症、支持治疗。
专家点评
专家点评
阿司咪阿司咪唑自1983年上市以来，在许多国家得到了广泛应用。国外研究显示阿司咪唑治疗荨麻疹的总有 效率为74%。国内的一项多中心双盲安慰剂对照试验表明阿司咪唑对急性荨麻疹的总有效率为82.9%，对慢性荨麻 疹的总有效率为86.0%，均显著高于安慰剂，主要不良反应为嗜睡、倦怠、口干等，连续用药3个月的患者中，半 数有食欲及体重增加。阿司咪唑的心脏毒性虽然发生率较低，但由于后果严重，已限制了它的应用。阿司咪唑为 强效和长效的H1受体拮抗剂，无中枢镇静和抗毒蕈碱样作用。代谢产物去甲阿司咪唑仍有抗胆胺作用。长期服用 可增进食欲和增加体重，服用过量可引起心脏Q-T间期延长和室性心律失常。适用于各种原因引起过敏性疾病。
重组贻贝粘蛋白的表征及功效评价
生物技术进展 2023 年 第 13 卷 第 4 期 596 ~ 603Current Biotechnology ISSN 2095‑2341研究论文Articles重组贻贝粘蛋白的表征及功效评价李敏 ， 魏文培 ， 乔莎 ， 郝东 ， 周浩 ， 赵硕文 ， 张立峰 ， 侯增淼 *西安德诺海思医疗科技有限公司，西安 710000摘要：为了推进重组贻贝粘蛋白在医疗、化妆品领域的应用，对大肠杆菌规模化发酵及纯化生产获得的重组贻贝粘蛋白进行了表征及功效评价。
经Edman 降解法、基质辅助激光解吸电离飞行时间质谱、PITC 法、非还原型SDS -聚丙烯酰胺凝胶电泳法、凝胶法、改良的Arnow 法对重组贻贝粘蛋白进行氨基酸N 端测序、相对分子量分析、氨基酸组成分析、蛋白纯度分析、内毒素含量测定、多巴含量测定；通过细胞迁移、斑马鱼尾鳍修复效果对重组贻贝粘蛋白进行功效评价。
结果显示，获得的重组贻贝粘蛋白与理论的一级结构一致，蛋白纯度达95%以上，内毒素<10 EU ·mg -1,多巴含量大于5%；重组贻贝粘蛋白浓度为60 μg ·mL -1时能够显著促进细胞增殖的活性（P <0.01）；斑马鱼尾鳍面积样品组与模型对照组相比极显著增加（P <0.001）。
研究结果表明，重组贻贝粘蛋白具有显著的促细胞迁移和修复愈合的功效，具备作为生物医学材料的潜质。
关键词：贻贝粘蛋白；基因重组；生物材料；表征；功效评价DOI ：10.19586/j.20952341.2023.0021 中图分类号：S985.3+1 文献标志码：ACharacterization and Efficacy Evaluation of Recombinant Mussel Adhesive ProteinLI Min ， WEI Wenpei ， QIAO Sha ， HAO Dong ， ZHOU Hao ， ZHAO Shuowen ， ZHANG Lifeng ，HOU Zengmiao *Xi'an DeNovo Hith Medical Technology Co.， Ltd ， Xi'an 710000， ChinaAbstract ：In order to promote the application of recombinant mussel adhesive protein in the medical and cosmetics field ， the recombi⁃nant mussel adhesive protein obtained from scale fermentation and purification of Escherichia coli was characterized and its efficacy was evaluated. Amino acid N -terminal sequencing ， relative molecular weight analysis ， amino acid composition analysis ， protein purityanalysis ， endotoxin content ， dihydroxyphenylalanine （DOPA ） content of recombinant mussel adhesive protein were determined by the following methods ： Edman degradation ， matrix -assisted laser desorption ionization time -of -flight mass spectrometry （MALDI -TOF -MS ）， phenyl -isothiocyanate （PITC ）， nonreductive SDS -polyacrylamide gel electrophoresis （SDS -PAGE ）， gel method ， modified Ar⁃now. The efficacy of recombinant mussel adhesive protein was evaluated by cell migration and repairing effect of zebrafish tail fin. Re⁃sults showed that the obtained recombinant mussel adhesive protein was confirmed to be consistent with the theoretical primary structure ， protein purity of more than 95%， endotoxin <10 EU ·mg -1， DOPA content above 5%. When the recombinant mussel adhesive protein concentration was 60 μg ·mL -1， the effect of promoting cell proliferation was the most obvious ， and it had very significant activity （P <0.01）. The caudal fin area of zebrafish in sample group was significantly increased compared with model control group （P <0.001）. The results indicated that recombinant mussel adhesive protein can promote cell migration and repair healing and has the potential to be used as biomedical materials.Key words ：mussel adhesive protein ； gene recombination ； biological materials ； representation ； efficacy evaluation贻贝粘蛋白（mussel adhesive protein ， MAP ）也称作贻贝足丝蛋白（mussel foot protein ，Mfps ），收稿日期：2023⁃02⁃24； 接受日期：2023⁃03⁃31联系方式：李敏 E -mail:*******************;*通信作者 侯增淼 E -mail:***********************.cn李敏，等：重组贻贝粘蛋白的表征及功效评价是海洋贝类——紫贻贝（Mytilus galloprovincalis）、厚壳贻贝（Mytilus coruscus）、翡翠贻贝（Perna viri⁃dis）等分泌的一种特殊的蛋白质，贻贝中含有多种贻贝粘蛋白，包括贻贝粘蛋白（Mfp 1～6）、前胶原蛋白（precollagens）和基质蛋白（matrix proteins）等［1］。
阿维巴坦钠合成工艺
阿维巴坦钠合成工艺
阿维巴坦钠（Avibactam Sodium）是一种新型的β-内酰胺减肥剂。
它是一种多疗效的抗生素助剂，可以与各种β-内酰胺抗生素和其
他非β-内酰胺类抗生素形成耐药性修饰，以达到有效抑制多重耐药性
细菌。
由于其独特的作用机制，阿维巴坦钠可有效抑制各种多重耐药
细菌，如耐甲氧西林金黄色葡萄球菌（MRSA）、耐米诺索菌（MRSE）、乙醇胺耐药铜绿假单胞菌（CRE）等。
阿维巴坦钠的合成工艺大致分为以下几个步骤：
1. 2-乙氧基-5-氯-4-甲氧基苯甲酸的生成：将异氰酸苯甲酰亚胺（NCA）和溴甲醇通过乙酰胺化反应，在冷却条件下进行手性环化反应，得到2-乙氧基-5-氯-4-甲氧基苯甲酸。
2. 2-氯-5-乙氧基苯甲酸内酯的生成：将2-乙氧基-5-氯-4-甲氧
基苯甲酸通过切口氨反应，转化成2-氯-5-乙氧基苯甲酸内酯。
3. 留吡啶的生成：将2-氯-5-乙氧基苯甲酸内酯进行水合反应，
由氯和水经历过酶原体介导的反应，最终得到留吡啶。
4. 阿维巴坦钠的生成：将留吡啶和2-氟乙酸（HFA）进行反应，
经过原料处理、反应、精制和稀释等步骤，最终得到阿维巴坦钠，即
合成完成。
阿维巴坦钠合成工艺准备好后，可用于抑制多重耐药细菌的增殖，弥补传统抗生素的不足之处，缩短感染患者的恢复期，降低病情的发
展风险。
仿制药参比制剂目录(第六十三批)
欧盟上市
63-27
匹伐他汀钙片
Pitavastatin Caical Europe GmbH
未进口原研药品
欧盟上市
63-28
匹伐他汀钙片
Pitavastatin Calcium Tablets
2mg
Kowa Pharmaceutical Europe GmbH
未进口原研药品
增加持证商Angelini Pharma Česká Republika s.r.o.
27-423
左甲状腺素钠片
Levothyroxine Sodium Tablets/Euthyrox;Levothyrox
100μg（以左甲状腺素钠计）
Merck Serono GmbH/Merck Sante/Merck GesellschaftmbH/Merck Healthcare Germany GmbH
100ml:1g（10mg/ml）
B Braunmedical Inc
未进口原研药品
美国橙皮书
63-14
钆特醇注射液
Gadoteridol Injection
/ProHance
279.3mg/mL（1.3965 g/5mL）
Bracco Diagnostics Inc
未进口原研药品
美国橙皮书
63-15
63-241
依折麦布瑞舒伐他汀锌胶囊
Ezetimibe rosuvastatin zinc hard capsule/Cholecomb
20mg/10mg
Proterapia Hungary Ltd
未进口原研药品
欧盟上市
63-251
盐酸氨酮戊酸凝胶
aminolevulinic acid hydrochloride gel/AMELUZ
唑拉西泮原料药质量标准
唑拉西泮原料药质量标准
唑拉西泮是一种常用的抗焦虑药物，其原料药的质量标准通常包括以下几个方面:
1.外观:唑拉西泮原料药应为白色或类白色结晶性粉末，无臭，无味。
2.纯度:唑拉西泮原料药的纯度应达到98%以上，其中杂质含量不得超过0.5%。
3.水分含量:唑拉西泮原料药的水分含不得超过0.5%。
4.熔点:唑拉西泮原料药的熔点应不低于140°C,熔融时无色或类白色。
5.溶解度:唑拉西泮原料药在水中应易溶，在乙醇中溶解,在乙醚中几乎不溶。
6.有关物质:唑拉西泮原料药中的有关物质，如降解产物、合成副产物等，应符合相关规定。
7.微生物限度:唑拉西泮原料药应符合微生物限度的规定，无菌、细菌内毒素、霉菌及酵母菌等应符合相关要求。
8.稳定性:唑拉西泮原料药应经过稳定性试验，证明其在一定条件下可保持其物理、化学和生物学性质。
这些标准是确保唑拉西泮原料药质量的基本要求，具体标准可能因生产商和国家标准而异。
在使用唑拉西泮原料药时，应遵循相关的药品法规和生产商提供的标准。
如有需要，可咨询专业医生或药剂师。
制定：审核：批准：。
阿莫沙平说明书
阿莫沙平说明书通用名称：阿莫沙平英文名称：Amoxapine中文别名：氯氧平、氯哌氧卓、哔氯苯氧氮卓英文别名：Anamox、Asendin、Demolox、Dimolax、Moxadil、Omnipress【药理】本品为二苯并氧氮卓三环类抗抑郁药，与丙米嗪相比，具有相似的抗抑郁作用，但起效快，对心脏毒性低，抗胆碱作用与镇静作用弱。
本品可通过抑制脑内突触前膜对NA的再摄取对5-HT的再摄取影响小，产生较强的抗抑郁与精神兴奋作用。
口服后吸收迅速而完全，l—2小时达血药峰浓度，在肺、心、肾、脑、脾组织中浓度较高。
组织内浓度比血浆浓度高10倍。
经肝脏代谢为7—羟基阿莫沙平和8羟基阿莫沙平，均有抗抑郁活性，其t1/2分别为6.5小时和30小时。
大部分代谢产物与葡萄糖醛酸结合，最后从肾脏排出，小量自粪便排出。
【适应症】本品适用于治疗各型抑郁症，对其它抗抑郁药治疗无效的内源性抑郁症病人亦有效，但对精神病性抑郁症疗效差。
【用法用量】口服：开始每次50mg每日3次，以后渐加量至每次100mg严重病例可增至每日600mg。
[制剂]片剂：每片50mg;100mg;150mg。
【禁用慎用】禁用于严重心、肝、肾功能不良者。
【不良反应】不良反应较轻，常见的有消化道反应：口干、便秘。
偶见眩晕、嗜睡、肌震颤。
长期大量应用时可见锥体外系症状。
罕见心率轻度升高、体位性低血压。
阿莫沙平的药物相互作用1.醋硝香豆素、茴茚二酮、双香豆素、苯茚二酮、苯丙香豆素、华法林等抗凝药与本品合用时，抗凝药的代谢减少、吸收增加，增加了出血的风险。
2.奋乃静、醋奋乃静、奋乃静/阿米替林、氯丙嗪、氟哌噻吨、氟奋乃静、氟哌啶醇、美索达嗪、五氟利多、哌泊塞嗪、丙氯拉嗪、丙嗪、硫利达嗪、三氟丙嗪等药物与本品合用时，可相互干扰代谢。
导致各种药物血药浓度的升高和毒性的加大。
因为两类药物都具有抗胆碱能活性，可增加抗胆碱能效应。
3.苯丙胺类药物与本品合用时，由于去甲肾上腺素神经传递的协同效应，可导致高血压、其他心脏影响和兴奋中枢神经系统等不良反应。
去乙酰毛花苷注射液说明模板之欧阳法创编
去乙酰毛花苷注射液【药品名称】通用名：去乙酰毛花苷注射液英文名：Deslanoside Injection汉语拼音：QuyixianMaohuaganZhsheye本品主要成分及其化学名称：为3-［(O-β-D-药吡喃糖基-（１→4）-0-2，6-二脱氧-β-D-核-己吡喃糖基-(1→4)-0-2，6-二脱氧-β-D-核-己吡喃糖基-(1→4)-0-2，6-二脱氧-β-D-核-己吡喃糖基)氧化］-12，14-二羟基-心甾-20(22)-烯内酯。
其结构式为：分子式：C47H74O19分子量：943.09辅料：乙醇，甘油，注射用水。
【适应症】（1）主要用于心力衰竭。
由于其作用较快，适用于急性心功能不全或慢性心功能不全急性加重的患者。
（2）亦可用于控制伴快速心室率的心房颤动、心房扑动患者的心室率。
（3）终止室上性心动过速起效慢，已少用。
【规格】2ml:0.4mg【用法和用量】静脉注射成人常用量：用5%葡萄糖注射液稀释后缓慢注射，首剂0.4－0.6㎎，以后每2－4小时可再给0.2－0.4㎎，总量1－1.6㎎。
小儿常用量：按下列剂量分2－3次间隔3－4小时给予。
早产儿和足月新生儿或肾功能减退、心肌炎患儿，肌内或静脉注射按体重0.022㎎/㎏，2周－3岁，按体重0.025㎎/㎏。
本品静脉注射获满意疗效后，可改用地高辛常用维持量以保持疗效。
【不良反应】（1）常见的不良反应包括：新出现的心律失常、胃纳不佳或恶心、呕吐（刺激延髓中枢）、下腹痛、异常的无力、软弱。
（2）少见的反应包括：视力模糊或“黄视”（中毒症状）、腹泻、中枢神经系统反应如精神抑郁或错乱。
（3）罕见的反应包括：嗜睡、头痛及皮疹、寻麻疹（过敏反应）。
（4）在洋地黄的中毒表现中，心律失常最重要，最常见者为室性早搏，约占心脏反应的33%。
其次为房室传导阻滞，阵发性或加速性交界性心动过速，阵发性房性心动过速伴房室传导阻滞，室性心动过速、窦性停搏、心室颤动等。
艾迪莎
美沙拉秦【药物名称】中文通用名称：美沙拉秦英文通用名称：Mesalazine其它名称：5-氨基水杨酸、艾迪莎、氨水杨酸、美少胺、颇得斯安、5-Aminosalicylic Acid、5-ASA、Asacolitin、Claversal、Enterasin、Etiasa、Fisalamine、Mesalamine、Mesalazinum、Mesasal、Pentasa、Pentasa-R、Rowasa、Salofalk、Saloflk【临床应用】用于治疗溃疡性结肠炎、Crohn病(节段性肠炎)。
【药理】1.药效学本药为抗溃疡药，通过作用于肠道炎症粘膜，抑制引起炎症的前列腺素合成及炎性介质白三烯的形成，从而对肠道壁起显著的抗炎作用，对发炎的肠壁结缔组织效果尤佳。
试验表明本药对维持溃疡性结肠炎的缓解与柳氮磺吡啶同样有效，但不发生后者通常引起的不良反应(如骨髓抑制和男性不育)。
2.药动学本药口服在结肠释放后转化为乙酰水杨酸。
乙酸水杨酸一部分被肠道内细菌分解，从粪便中排出。
另一部分由肠粘膜吸收，约40%与血浆蛋白结合，在体内代谢生成乙酰化物，此乙酰化物约80%与血浆蛋白结合，从尿中排出，半衰期为5-10小时，很少透过胎盘和分泌入乳汁。
本药缓释片由乙基纤维素包衣的美沙拉秦微颗粒(直径为0.7-1mm)组成。
在胃中开始崩解，微颗粒通过幽门进入小肠，在肠道内可持续均匀地释放美沙拉秦，约50%在小肠内释放，50%在大肠内释放。
口服缓释片无需胃排空，无药物大量倾释现象，无血药峰浓度，在胃中残留时间短，服药后20分钟内血中即可测出美沙拉秦。
缓释片还可防止美沙拉秦在近端小肠被过早吸收，从而保证它在远端小肠具有较高的生物利用度。
本药栓剂由缓释微囊组成，可直接到达作用部位，缓慢释放，局部浓度高。
【注意事项】1.禁忌症 (1)对本药成分或水杨酸类药物过敏者。
(2)消化性溃疡活动期。
(3)严重肾衰竭。
(以上均选自国外资料)2.慎用 (1)血尿素氮升高或蛋白尿患者。
拉氧头孢钠
拉氧头孢钠【中文品名】拉氧头孢钠【药效类别】抗生素＞头孢霉素衍生物类【通用药名】LATAMOXEF DISODIUM【另U 名】氧杂头霉素二钠,Lamoxactan disodium ，Moxalactam disodium , Shiomarin , Moxam Festamoxin , LY127935【化学名称】5-Oxa-1-azabicyclo[4.2.0]oct-2-e ne-2-carboxylic acid, 7-[[(2R)-carboxy(4-hydroxyphey nl )acetyl]ami no]-7-methoxy-3-[[(1 -methyl-1H-tetrazol-5-yl)thio] methyl]-8-oxo-, disodium salt,(6R,7R)-【CA登记号】[64953-12-4]【结构式】【分子式】Q O H W NN Q OS分子量】【收录药典】JP14【开发单位】盐野义制药株式会社（日本），ELiLilly （美国）【首次上市】1981 年，德国【性状】白色或淡黄色粉末，无臭。
极易溶于水、甲醇，难溶于乙醇，几乎不溶于丙酮、乙酸乙酯、乙醚、三氯甲烷和己烷。
mp170C（dec）【用途】本品是半合成的氧头孢烯（Oxacephen）类新型抗生素，基本结构与头霉素类接近。
但母核1位上S原子为O原子所取代，抗菌性能与第三代头孢菌素相近，抗菌谱与头孢噻肟相似。
对多种格兰氏阴性菌有良好抗菌作用。
大肠杆菌、流感杆菌、克雷白杆菌、各型变形杆菌、肠杆菌属、枸橼酸杆菌、沙雷杆菌等对本品高度敏感。
对厌氧菌（拟杆菌）亦有良好的抗菌作用。
本品的耐B内酰胺酶的性能强，耐药性低。
肌注1g，经1小时血药浓度达峰值，为49ug/ml，到第8小时仍可维持ml。
静注1g，即时的血浓度为170ug/ml。
本品在体内分布广，可进入痰液、腹水、羊水、脑脊液中。
通过肾和肝排泄，在尿液和胆汁中浓度高。
盐酸西那卡塞杂质结构式
盐酸西那卡塞杂质结构式：杂质A:F 3C HN.HCl A杂质B:F 3C HN.HCl B杂质C(CAS: 1229224-93-4):F 3CHN.HCl C杂质D(CAS:1229224-94-5):F 3C N.HCl DOH 杂质E(CAS:955373-56-5):F 3CHN.HCl E杂质F(CAS:694495-47-1):F 3C HN.HCl F杂质G(CAS:1428185-71-0): H N.HCl F 3CG杂质H:H N .HCl CF 3H杂质I(CAS:1025064-33-8):F 3CH N .HCl I杂质JF 3C H N .HClJ杂质K(CAS: 253337-60-9):H N.HCl K杂质L(CAS:1185097-33-9):F 3C H N .HCl DD D L杂质M(CAS:1813-96-3):F 3CM杂质N(CAS:1271930-15-4):F 3CN .HCl F 3CN深圳市恒丰万达医药科技有限公司盐酸西那卡塞是一种钙离子受体异构激动剂，作用于G-蛋白共轭型受体的钙受体，与钙离子受体结合后通过别构效应增强细胞外钙离子的作用，抑制PTH的分泌及甲状旁腺细胞的增殖，口服给药后可使血清PTH浓度降低，达到控制继发性甲状旁腺功能亢进症患者PTH水平的作用，而且本品具有在iPTH下降的同时不升高血钙的特点。