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Article(id=1239238140922221065, tenantId=1146029695717560320, journalId=1205117023404326918, issueId=1239238136711139764, articleNumber=null, orderNo=null, doi=10.16155/j.0254-1793.2024-0089, pmid=null, cstr=null, oa=null, hot=null, price=null, onlineType=0, articleFormat=0, articleType=null, articleTypeStr=null, receivedDate=1707148800000, receivedDateStr=2024-02-06, revisedDate=null, revisedDateStr=null, acceptedDate=null, acceptedDateStr=null, onlineDate=1773386996727, onlineDateStr=2026-03-13, pubDate=1722355200000, pubDateStr=2024-07-31, doiRegisterDate=null, doiRegisterDateStr=null, onlineIssueDate=1773386996727, onlineIssueDateStr=2026-03-13, onlineJustAcceptDate=null, onlineJustAcceptDateStr=null, onlineFirstDate=null, onlineFirstDateStr=null, sourceXml=null, magXml=null, createTime=1773386996727, creator=13701087609, updateTime=1773386996727, updator=13701087609, issue=Issue{id=1239238136711139764, tenantId=1146029695717560320, journalId=1205117023404326918, year='2024', volume='44', issue='7', pageStart='1105', pageEnd='1284', issueExtLink='null', onlineDate='null', pubDate='null', beforeIssueId=null, nextIssueId=null, price=null, status=1, issueComplete=1, articleOrder=1, issueType=-1, specialIssue=null, createTime=1773386995723, creator=13701087609, updateTime=1773387118529, updator=13701087609, preIssue=null, nextIssue=null, ext={EN=IssueExt(id=1239238651851370909, tenantId=1146029695717560320, journalId=1205117023404326918, issueId=1239238136711139764, language=EN, specialIssueTitle=, coverIllustrator=null, specialIssueEditor=, specialIssueAbout=), CN=IssueExt(id=1239238651851370910, tenantId=1146029695717560320, journalId=1205117023404326918, issueId=1239238136711139764, language=CN, specialIssueTitle=, coverIllustrator=null, specialIssueEditor=, specialIssueAbout=)}, issueFiles=null}, startPage=1212, endPage=1221, ext={EN=ArticleExt(id=1239238142193095256, articleId=1239238140922221065, tenantId=1146029695717560320, journalId=1205117023404326918, language=EN, title=Study on bioequivalence exemption for levofloxacin tablets post-excipient modification, columnId=1206272757852074373, journalTitle=Chinese Journal of Pharmaceutical Analysis, columnName=Safety Monitoring, runingTitle=null, highlight=null, articleAbstract=
Objective:

To investigate the feasibility of applying for bioequivalence exemption based on parallel artificial membrane permeability assay (PAMPA) data by evaluating the solubility and in vitro permeability of levofloxacin, comparing the prescription differences between the generic and reference formulations, assessing the impact of disparate excipients on the permeation behavior of the active pharmaceutical ingredient (API), and predicting the bioequivalence of the two formulations.

Methods:

The dissolution of the raw material at pH 1.0 to pH 6.8 was determined using high-performance liquid chromatography. The μFluxTM system was employed to determine the permeability of the raw material and the mixture of raw material with sodium stearyl fumarate in various media. pH 5.0 fed-state intestinal fluid, pH 6.5 fasted-state intestinal fluid, and pH 7.4 phosphate buffer (16 mL) were precisely added to the donor chamber, while 16 mL of Accepter Sink Buffer was added to the receptor chamber. The rotor speed was set at 200 r·min-1, and the collection time was 180 min. Determine the permeability of the raw material and the mixture of raw material with sodium stearyl fumarate in various media, as well as the permeability of the raw material in the reference and generic formulations powders. The impact of newly added excipients and other changed excipients on API was evaluated through a two-tailed t-test. The Macro FluxTM system was used to measure the dissolution-permeation curves of the reference and generic formulations, intestinal simulation fluids at pH 5.0 and pH 6.5 (1 000 mL) were added to the dissolution cup as dissolution media, with a stirring speed of 75 r·min-1 using a paddle method, 12 mL of Accepter Sink Buffer was added to the receptor chamber, and the stirring speed of the micro-stirring rod was set at 450 r·min-1, one tablet of each reference or generic formulation was placed in the dissolution cup, and the dissolution-permeation curves of the formulations were measured. The similarity of dissolution curves was compared, and the permeability rate (JFlux) and cumulative drug permeation amount (AMT) were calculated to predict the bioequivalence of the two formulations, ensuring that the 90% confidence interval for the geometric mean ratio of JFlux and AMT of the two formulations fell within the range of 80% to 125%.

Results:

Levofloxacin solubility ranged from 16.4 mg·mL-1 to 62.7 mg·mL-1 across different mediums, its permeability in pH 5.0 fed-state simulated intestinal fluid, pH 6.5 fasted-state simulated intestinal fluid, and pH 7.4 phosphate-buffered saline was 2.92×10-6 cm·s-1, 1.01×10-5 cm·s-1, and 1.07×10-5 cm·s-1, respectively. The addition of sodium stearyl fumarate showed no significant difference in permeability compared to the original API (P<0.05), and there were no significant differences between the powder API of the reference and generic formulations (P<0.05). The dissolution curves of both formulations were similar, with the 90% confidence interval for JFlux and AMT within the predefined range.

Conclusion:

Levofloxacin tablets, classified as BCS Class Ⅰ, demonstrated that the altered excipients in the formulation did not impact on the API’s permeability, confirming bioequivalence between the reference and generic formulations. The bioequivalence exemption study based on PAMPA can be utilized for permeability studies of raw materials, excipient screening and optimization, and prediction of formulation bioequivalence, effectively reducing drug development costs and time. This study provides reference data for pharmaceutical companies applying for bioequivalence exemptions.

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目的：

通过测定左氧氟沙星的溶解性和体外渗透性，对比仿制与参比制剂的处方差异，考察差异性辅料对原料渗透行为的影响，并预测2种制剂的生物等效性，旨在探究基于平行人工膜渗透试验（PAMPA）的体外渗透性数据申请生物等效性豁免的可行性。

方法：

采用高效液相色谱法测定原料在pH 1.0~pH 6.8的溶解性；采用μFluxTM系统，在供体室中分别精密加入pH 5.0的饱腹小肠模拟液、pH 6.5的空腹小肠模拟液和pH 7.4的磷酸盐缓冲液16 mL，受体室中精密加入Accepter Sink Buffer 16 mL，转子速度200 r·min-1，采集时间180 min，测定各介质中原料和原料与硬脂富马酸钠混合物中原料的渗透性，以及参比和仿制制剂粉末中原料的渗透性，通过双侧t检验考察是否有显著性差异，以评估处方中新增辅料和其他变更辅料对原料的影响；采用Macro FluxTM系统，在溶出杯中加入pH 5.0和pH 6.5的肠模拟液1 000 mL作为溶出介质，使用桨法转速为75 r·min-1，受体室中精密加入Accepter Sink Buffer 12 mL，微搅拌棒的转速为450 r·min-1，分别取参比制剂和仿制制剂1片置溶出杯中，测定制剂的溶出-渗透曲线，比较溶出曲线相似性，计算渗透速率（JFlux）和终点时的药物累计渗透量（AMT），以2种制剂JFlux和AMT几何均值比值的90%置信区间是否落在80%~125%范围内为依据，预测制剂的生物等效性。

结果：

左氧氟沙星在不同介质的溶解性为16.4~62.7 mg·mL-1，其渗透性在pH 5.0的饱腹小肠模拟液、pH 6.5的空腹小肠模拟液和pH 7.4的磷酸盐缓冲液中分别为2.92×10-6、1.01×10-5和1.07×10-5 cm·s-1；加入硬脂富马酸钠后与原料的渗透性相比无显著差异（P<0.05），参比和仿制制剂粉末中原料渗透性无显著差异（P<0.05）；2种制剂的溶出曲线相似，JFlux和AMT几何均值比值的90%置信区间结果均在限度范围之内。

结论：

左氧氟沙星为BCSⅠ类药物，处方变更后的辅料均不影响原料的渗透吸收，仿制与参比制剂生物等效，国产仿制制剂满足生物等效性豁免的核心要求。基于PAMPA的生物等效性研究，可用于原料的渗透性研究、处方的筛选和优化以及制剂的生物等效性预测等，能有效降低仿制药开发的成本和时间，加速高质量药品的研发。

, correspAuthors=张晓明, authorNote=null, correspAuthorsNote=
** Tel：（0971）7822983；E-mail：
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Tel：（0971）7822983；E-mail：

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Pharmaceutics， 2023， 15(2)： 592, articleTitle=Commercially available cell-free permeability tests for industrial drug development： increased sustainability through reduction of in vivo studies, refAbstract=null), Reference(id=1239238161927295263, tenantId=1146029695717560320, journalId=1205117023404326918, articleId=1239238140922221065, doi=null, pmid=null, pmcid=null, year=2012, volume=17, issue=15-16, pageStart=905, pageEnd=null, url=null, language=null, rfNumber=[28], rfOrder=36, authorNames=DI L, ARTURSSON P, AVDEEF A, journalName=Drug Discov Today, refType=null, unstructuredReference=DI L， ARTURSSON P， AVDEEF A， et al. Evidence-based approach to assess passive diffusion and carrier-mediated drug transport[J]. Drug Discov Today， 2012， 17(15-16)： 905, articleTitle=Evidence-based approach to assess passive diffusion and carrier-mediated drug transport, refAbstract=null), Reference(id=1239238162027958562, tenantId=1146029695717560320, journalId=1205117023404326918, articleId=1239238140922221065, doi=null, pmid=null, pmcid=null, year=2010, volume=9, issue=8, pageStart=597, pageEnd=null, url=null, language=null, rfNumber=[29], rfOrder=37, authorNames=SUGANO K, KANSY M, ARTURSSON P, journalName=Nat Rev Drug Discov, refType=null, unstructuredReference=SUGANO K， KANSY M， ARTURSSON P， et al. Coexistence of passive and carrier-mediated processes in drug transport[J]. 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articleId=1239238140922221065, language=EN, label=Fig.5, caption=Pe(Papp) comparison and t-test, figureFileSmall=N++4Ze20qM1ryhFRWcIxEw==, figureFileBig=LdgBjaqp+9FS3fWJB5FjmQ==, tableContent=null), ArticleFig(id=1239238154625011830, tenantId=1146029695717560320, journalId=1205117023404326918, articleId=1239238140922221065, language=CN, label=图5, caption=Pe(Papp)比较和t检验, figureFileSmall=N++4Ze20qM1ryhFRWcIxEw==, figureFileBig=LdgBjaqp+9FS3fWJB5FjmQ==, tableContent=null), ArticleFig(id=1239238154788589691, tenantId=1146029695717560320, journalId=1205117023404326918, articleId=1239238140922221065, language=EN, label=Fig.6, caption=Dissolution（A） and permeation（B） curves(pH 5.0), figureFileSmall=UtqFs33Y4cEISY7LDoQjWw==, figureFileBig=bdtGLrBHJWeoG4JhShrkNA==, tableContent=null), ArticleFig(id=1239238154910224512, tenantId=1146029695717560320, journalId=1205117023404326918, articleId=1239238140922221065, language=CN, label=图6, caption=溶出（A）-渗透（B）曲线(pH 5.0), figureFileSmall=UtqFs33Y4cEISY7LDoQjWw==, figureFileBig=bdtGLrBHJWeoG4JhShrkNA==, tableContent=null), ArticleFig(id=1239238155073802374, tenantId=1146029695717560320, journalId=1205117023404326918, articleId=1239238140922221065, language=EN, label=Fig.7, caption=Dissolution（A） and permeation（B） curves(pH 6.5), figureFileSmall=PqIAln/tkjgjFcRkJUAa/A==, figureFileBig=pqwsOUpWj+UVLOpJT8x/Qw==, tableContent=null), ArticleFig(id=1239238155178659980, tenantId=1146029695717560320, journalId=1205117023404326918, articleId=1239238140922221065, language=CN, label=图7, caption=溶出（A）-渗透（B）曲线(pH 6.5), figureFileSmall=PqIAln/tkjgjFcRkJUAa/A==, figureFileBig=pqwsOUpWj+UVLOpJT8x/Qw==, tableContent=null), ArticleFig(id=1239238155279323280, tenantId=1146029695717560320, journalId=1205117023404326918, articleId=1239238140922221065, language=EN, label=Tab.1, caption=

Solubility of levofloxacin

, figureFileSmall=null, figureFileBig=null, tableContent=
试验次数
(number of tests)		溶解度(solubility)/(mg·mL-1)
pH 1.0pH 3.0pH 4.5pH 5.0pH 6.0pH 6.8
162.750.129.418.920.916.4
262.849.829.418.420.816.4
362.649.629.818.520.816.5
均值(average)62.749.829.518.620.816.4
RSD/%0.160.510.781.40.280.35
Vsingle-dose/mL*121525403646
), ArticleFig(id=1239238155379986579, tenantId=1146029695717560320, journalId=1205117023404326918, articleId=1239238140922221065, language=CN, label=表1, caption=

左氧氟沙星的溶解度(37 ℃±0.5 ℃，n=3)

, figureFileSmall=null, figureFileBig=null, tableContent=
试验次数
(number of tests)		溶解度(solubility)/(mg·mL-1)
pH 1.0pH 3.0pH 4.5pH 5.0pH 6.0pH 6.8
162.750.129.418.920.916.4
262.849.829.418.420.816.4
362.649.629.818.520.816.5
均值(average)62.749.829.518.620.816.4
RSD/%0.160.510.781.40.280.35
Vsingle-dose/mL*121525403646
), ArticleFig(id=1239238155493232792, tenantId=1146029695717560320, journalId=1205117023404326918, articleId=1239238140922221065, language=EN, label=Tab.2, caption=

Regression equations of standard curves of donor chamber and receiver chamber

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室
(chamber)		介质
(medium)		光程
(probe)/mm		回归方程(regression equation)
通道1(channel 1)通道2(channel 2)通道3(channel 3)
供体室(donor chamber)pH 5.02Y=2 796.73X-7.54Y=2 539.01X-9.41Y=3 452.90X-7.70
pH 6.52Y=1 793.92X-5.97Y=1 625.97X-7.39Y=1 838.00X-7.32
pH 7.42Y=1 586.60X-7.62Y=1 438.70X-9.03Y=1 631.58X-9.09
受体室(receiver chamber)ASB10Y=16.70X-0.017Y=16.62X-0.012Y=16.76X-0.014
20Y=31.36X-0.016Y=32.39X-0.018Y=31.94X-0.014
), ArticleFig(id=1239238155614867611, tenantId=1146029695717560320, journalId=1205117023404326918, articleId=1239238140922221065, language=CN, label=表2, caption=

供体室和受体室标准曲线的回归方程

, figureFileSmall=null, figureFileBig=null, tableContent=
室
(chamber)		介质
(medium)		光程
(probe)/mm		回归方程(regression equation)
通道1(channel 1)通道2(channel 2)通道3(channel 3)
供体室(donor chamber)pH 5.02Y=2 796.73X-7.54Y=2 539.01X-9.41Y=3 452.90X-7.70
pH 6.52Y=1 793.92X-5.97Y=1 625.97X-7.39Y=1 838.00X-7.32
pH 7.42Y=1 586.60X-7.62Y=1 438.70X-9.03Y=1 631.58X-9.09
受体室(receiver chamber)ASB10Y=16.70X-0.017Y=16.62X-0.012Y=16.76X-0.014
20Y=31.36X-0.016Y=32.39X-0.018Y=31.94X-0.014
), ArticleFig(id=1239238155732308127, tenantId=1146029695717560320, journalId=1205117023404326918, articleId=1239238140922221065, language=EN, label=Tab.3, caption=

Pe(Papp) of API and mixtures

, figureFileSmall=null, figureFileBig=null, tableContent=
编号
(No.)		原料(API) Pe/(×10-6 cm·s-1)原料(API)＋硬脂富马酸钠(sodium stearyl fumarate) Papp/(×10-6 cm·s-1)
pH 5.0pH 6.5pH 7.4pH 5.0pH 6.5pH 7.4
13.19.811.32.99.912.0
22.910.911.02.910.410.9
32.910.08.82.89.411.5
42.99.711.62.79.510.9
52.810.011.12.910.710.4
63.09.910.62.811.511.6
均值(mean)±SD2.9±0.110.1±0.510.7±1.02.8±0.110.2±0.811.2±0.6
RSD/%3.84.59.33.17.85.2
), ArticleFig(id=1239238155816194209, tenantId=1146029695717560320, journalId=1205117023404326918, articleId=1239238140922221065, language=CN, label=表3, caption=

原料与混合物的Pe(Papp)(n=6)

, figureFileSmall=null, figureFileBig=null, tableContent=
编号
(No.)		原料(API) Pe/(×10-6 cm·s-1)原料(API)＋硬脂富马酸钠(sodium stearyl fumarate) Papp/(×10-6 cm·s-1)
pH 5.0pH 6.5pH 7.4pH 5.0pH 6.5pH 7.4
13.19.811.32.99.912.0
22.910.911.02.910.410.9
32.910.08.82.89.411.5
42.99.711.62.79.510.9
52.810.011.12.910.710.4
63.09.910.62.811.511.6
均值(mean)±SD2.9±0.110.1±0.510.7±1.02.8±0.110.2±0.811.2±0.6
RSD/%3.84.59.33.17.85.2
), ArticleFig(id=1239238155925246117, tenantId=1146029695717560320, journalId=1205117023404326918, articleId=1239238140922221065, language=EN, label=Tab.4, caption=

Papp of reference and generic formulation powders

, figureFileSmall=null, figureFileBig=null, tableContent=
编号
(No.)		Papp/(×10-6 cm·s-1)
参比制剂粉末(reference formulation powder)仿制制剂粉末(generic formulation powder)
pH 5.0pH 6.5pH 7.4pH 5.0pH 6.5pH 7.4
12.910.110.93.010.111.2
22.910.411.02.910.511.3
32.810.610.02.911.411.5
42.88.711.33.010.611.5
52.810.010.62.810.711.3
62.910.011.82.910.312.1
均值(mean)±SD2.8±010.0±0.610.9±0.72.9±0.110.6±0.411.5±0.3
RSD/%1.46.75.62.64.22.8
), ArticleFig(id=1239238156059463849, tenantId=1146029695717560320, journalId=1205117023404326918, articleId=1239238140922221065, language=CN, label=表4, caption=

仿制制剂和参比制剂粉末的Papp(n=6)

, figureFileSmall=null, figureFileBig=null, tableContent=
编号
(No.)		Papp/(×10-6 cm·s-1)
参比制剂粉末(reference formulation powder)仿制制剂粉末(generic formulation powder)
pH 5.0pH 6.5pH 7.4pH 5.0pH 6.5pH 7.4
12.910.110.93.010.111.2
22.910.411.02.910.511.3
32.810.610.02.911.411.5
42.88.711.33.010.611.5
52.810.010.62.810.711.3
62.910.011.82.910.312.1
均值(mean)±SD2.8±010.0±0.610.9±0.72.9±0.110.6±0.411.5±0.3
RSD/%1.46.75.62.64.22.8
), ArticleFig(id=1239238156139155629, tenantId=1146029695717560320, journalId=1205117023404326918, articleId=1239238140922221065, language=EN, label=Tab.5, caption=

JFlux and AMT of reference and generic formulation

, figureFileSmall=null, figureFileBig=null, tableContent=
编号
(No.)		JFlux /(μg·min-1·cm-2)AMT/μg
pH 5.0pH 6.5pH 5.0pH 6.5
参比
(reference)		仿制
(generic)		参比
(reference)		仿制
(generic)		参比
(reference)		仿制
(generic)		参比
(reference)		仿制
(generic)
10.089 70.090 60.209 70.209 456.6659.49132.00133.72
20.087 20.090 90.228 60.218 055.9559.87142.01136.54
30.087 50.092 20.210 30.233 851.2755.37135.08138.85
40.084 40.086 00.209 40.217 753.6756.81133.41138.48
50.082 60.087 80.208 80.212 854.4358.62130.15134.20
60.079 50.095 30.207 20.214 047.5356.05123.86133.03
平均(mean)0.085 20.090 50.212 30.217 653.2557.70132.75135.80
SD0.003 70.003 30.008 00.008 63.381.885.972.51
RSD/%4.43.63.83.96.43.34.51.9
), ArticleFig(id=1239238156235624625, tenantId=1146029695717560320, journalId=1205117023404326918, articleId=1239238140922221065, language=CN, label=表5, caption=

仿制制剂和参比制剂的JFlux和AMT

, figureFileSmall=null, figureFileBig=null, tableContent=
编号
(No.)		JFlux /(μg·min-1·cm-2)AMT/μg
pH 5.0pH 6.5pH 5.0pH 6.5
参比
(reference)		仿制
(generic)		参比
(reference)		仿制
(generic)		参比
(reference)		仿制
(generic)		参比
(reference)		仿制
(generic)
10.089 70.090 60.209 70.209 456.6659.49132.00133.72
20.087 20.090 90.228 60.218 055.9559.87142.01136.54
30.087 50.092 20.210 30.233 851.2755.37135.08138.85
40.084 40.086 00.209 40.217 753.6756.81133.41138.48
50.082 60.087 80.208 80.212 854.4358.62130.15134.20
60.079 50.095 30.207 20.214 047.5356.05123.86133.03
平均(mean)0.085 20.090 50.212 30.217 653.2557.70132.75135.80
SD0.003 70.003 30.008 00.008 63.381.885.972.51
RSD/%4.43.63.83.96.43.34.51.9
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左氧氟沙星片辅料变更后的生物等效性豁免研究*
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王文丽 1 , 张小燕 1 , 王小晶 1 , 庾莉菊 2 , 张晓明 1, ** , 孙莺 1
药物分析杂志 | 安全监测 2024,44(7): 1212-1221
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药物分析杂志 | 安全监测 2024, 44(7): 1212-1221
左氧氟沙星片辅料变更后的生物等效性豁免研究*
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王文丽1 , 张小燕1, 王小晶1, 庾莉菊2, 张晓明1, ** , 孙莺1
作者信息
  • 1.甘肃省药品检验研究院，兰州 730070
  • 2.中国食品药品检定研究院，北京 102629

    • Tel：（0971）7822983；E-mail：

通讯作者:

** Tel：（0971）7822983；E-mail：
Study on bioequivalence exemption for levofloxacin tablets post-excipient modification
Wen-li WANG1 , Xiao-yan ZHANG1, Xiao-jing WANG1, Li-ju YU2, Xiao-ming ZHANG1, ** , Ying SUN1
Affiliations
  • 1.Gansu Institute for Drug Control, Lanzhou 730070, China
  • 2.National Institutes for Food and Drug Control, Beijing 102629, China
出版时间: 2024-07-31 doi: 10.16155/j.0254-1793.2024-0089
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摘要
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目的：

通过测定左氧氟沙星的溶解性和体外渗透性，对比仿制与参比制剂的处方差异，考察差异性辅料对原料渗透行为的影响，并预测2种制剂的生物等效性，旨在探究基于平行人工膜渗透试验（PAMPA）的体外渗透性数据申请生物等效性豁免的可行性。

方法：

采用高效液相色谱法测定原料在pH 1.0~pH 6.8的溶解性；采用μFluxTM系统，在供体室中分别精密加入pH 5.0的饱腹小肠模拟液、pH 6.5的空腹小肠模拟液和pH 7.4的磷酸盐缓冲液16 mL，受体室中精密加入Accepter Sink Buffer 16 mL，转子速度200 r·min-1，采集时间180 min，测定各介质中原料和原料与硬脂富马酸钠混合物中原料的渗透性，以及参比和仿制制剂粉末中原料的渗透性，通过双侧t检验考察是否有显著性差异，以评估处方中新增辅料和其他变更辅料对原料的影响；采用Macro FluxTM系统，在溶出杯中加入pH 5.0和pH 6.5的肠模拟液1 000 mL作为溶出介质，使用桨法转速为75 r·min-1，受体室中精密加入Accepter Sink Buffer 12 mL，微搅拌棒的转速为450 r·min-1，分别取参比制剂和仿制制剂1片置溶出杯中，测定制剂的溶出-渗透曲线，比较溶出曲线相似性，计算渗透速率（JFlux）和终点时的药物累计渗透量（AMT），以2种制剂JFlux和AMT几何均值比值的90%置信区间是否落在80%~125%范围内为依据，预测制剂的生物等效性。

结果：

左氧氟沙星在不同介质的溶解性为16.4~62.7 mg·mL-1，其渗透性在pH 5.0的饱腹小肠模拟液、pH 6.5的空腹小肠模拟液和pH 7.4的磷酸盐缓冲液中分别为2.92×10-6、1.01×10-5和1.07×10-5 cm·s-1；加入硬脂富马酸钠后与原料的渗透性相比无显著差异（P<0.05），参比和仿制制剂粉末中原料渗透性无显著差异（P<0.05）；2种制剂的溶出曲线相似，JFlux和AMT几何均值比值的90%置信区间结果均在限度范围之内。

结论：

左氧氟沙星为BCSⅠ类药物，处方变更后的辅料均不影响原料的渗透吸收，仿制与参比制剂生物等效，国产仿制制剂满足生物等效性豁免的核心要求。基于PAMPA的生物等效性研究，可用于原料的渗透性研究、处方的筛选和优化以及制剂的生物等效性预测等，能有效降低仿制药开发的成本和时间，加速高质量药品的研发。

生物等效性  /  豁免  /  左氧氟沙星  /  溶解性  /  渗透性  /  平行人工膜渗透试验  /  渗透速率  /  累计渗透量
Objective:

To investigate the feasibility of applying for bioequivalence exemption based on parallel artificial membrane permeability assay (PAMPA) data by evaluating the solubility and in vitro permeability of levofloxacin, comparing the prescription differences between the generic and reference formulations, assessing the impact of disparate excipients on the permeation behavior of the active pharmaceutical ingredient (API), and predicting the bioequivalence of the two formulations.

Methods:

The dissolution of the raw material at pH 1.0 to pH 6.8 was determined using high-performance liquid chromatography. The μFluxTM system was employed to determine the permeability of the raw material and the mixture of raw material with sodium stearyl fumarate in various media. pH 5.0 fed-state intestinal fluid, pH 6.5 fasted-state intestinal fluid, and pH 7.4 phosphate buffer (16 mL) were precisely added to the donor chamber, while 16 mL of Accepter Sink Buffer was added to the receptor chamber. The rotor speed was set at 200 r·min-1, and the collection time was 180 min. Determine the permeability of the raw material and the mixture of raw material with sodium stearyl fumarate in various media, as well as the permeability of the raw material in the reference and generic formulations powders. The impact of newly added excipients and other changed excipients on API was evaluated through a two-tailed t-test. The Macro FluxTM system was used to measure the dissolution-permeation curves of the reference and generic formulations, intestinal simulation fluids at pH 5.0 and pH 6.5 (1 000 mL) were added to the dissolution cup as dissolution media, with a stirring speed of 75 r·min-1 using a paddle method, 12 mL of Accepter Sink Buffer was added to the receptor chamber, and the stirring speed of the micro-stirring rod was set at 450 r·min-1, one tablet of each reference or generic formulation was placed in the dissolution cup, and the dissolution-permeation curves of the formulations were measured. The similarity of dissolution curves was compared, and the permeability rate (JFlux) and cumulative drug permeation amount (AMT) were calculated to predict the bioequivalence of the two formulations, ensuring that the 90% confidence interval for the geometric mean ratio of JFlux and AMT of the two formulations fell within the range of 80% to 125%.

Results:

Levofloxacin solubility ranged from 16.4 mg·mL-1 to 62.7 mg·mL-1 across different mediums, its permeability in pH 5.0 fed-state simulated intestinal fluid, pH 6.5 fasted-state simulated intestinal fluid, and pH 7.4 phosphate-buffered saline was 2.92×10-6 cm·s-1, 1.01×10-5 cm·s-1, and 1.07×10-5 cm·s-1, respectively. The addition of sodium stearyl fumarate showed no significant difference in permeability compared to the original API (P<0.05), and there were no significant differences between the powder API of the reference and generic formulations (P<0.05). The dissolution curves of both formulations were similar, with the 90% confidence interval for JFlux and AMT within the predefined range.

Conclusion:

Levofloxacin tablets, classified as BCS Class Ⅰ, demonstrated that the altered excipients in the formulation did not impact on the API’s permeability, confirming bioequivalence between the reference and generic formulations. The bioequivalence exemption study based on PAMPA can be utilized for permeability studies of raw materials, excipient screening and optimization, and prediction of formulation bioequivalence, effectively reducing drug development costs and time. This study provides reference data for pharmaceutical companies applying for bioequivalence exemptions.

bioequivalence  /  biowaiver  /  levofloxacin  /  solubility  /  permeability  /  parallel artificial membrane permeability assay  /  permeation rate  /  cumulative permeation
王文丽, 张小燕, 王小晶, 庾莉菊, 张晓明, 孙莺. 左氧氟沙星片辅料变更后的生物等效性豁免研究*. 药物分析杂志, 2024 , 44 (7) : 1212 -1221 . DOI: 10.16155/j.0254-1793.2024-0089
Wen-li WANG, Xiao-yan ZHANG, Xiao-jing WANG, Li-ju YU, Xiao-ming ZHANG, Ying SUN. Study on bioequivalence exemption for levofloxacin tablets post-excipient modification[J]. Chinese Journal of Pharmaceutical Analysis, 2024 , 44 (7) : 1212 -1221 . DOI: 10.16155/j.0254-1793.2024-0089
正文
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生物等效性豁免(biowaiver)是指在特定条件下，药品监管机构允许药品在没有进行体内生物等效性(bioequivalence)研究的情况下，通过基于体外数据的推理来证明其生物等效性的做法，是药品监管领域的关键创新。传统的生物等效性验证依赖于人体临床试验，为降低实验成本，加快上市周期，相关领域学者一直在探究一种可能的替代方案。自1995年Admidon等[1]提出了生物药剂学分类(BCS)后，随着科学认知的不断深入，基于BCS的人体生物等效性豁免的概念逐渐被FDA、WHO和EMA等越来越多的权威机构接受，国家药品监督管理局、美国FDA与国际人用药品注册技术协调会(ICH)均发布了相关指导原则。
因此，在药物的临床试验审批、新药上市审批、仿制药申请以及上市后的变更时，若想要申请生物等效性豁免，需向评审机构提交药物的BCS、辅料对有效成分的渗透吸收无干扰等方面充分可靠的数据[2]。体外渗透作为研究关键，测定方法主要分为细胞模型、动物肠模型和人体药物动力学试验等[3]，近年来，平行人工膜渗透试验(parallel artificial membrane permeability assay，PAMPA)因其高通量性，良好的重现性，低成本，短周期以及多参数研究的能力，被广泛应用于药物的被动转运研究中，Avdeef的团队通过一系列研究证实了PAMPA与细胞模型以及人体小肠灌流法所得到的结果之间存在正相关性，表明它们在某种程度上可相互替代[4-5]。
左氧氟沙星(levofloxacin)是一种广谱抗菌药物[6]，对大多数需氧革兰氏阳性菌和革兰氏阴性菌具有活性，片剂在口服给药后，药物迅速且广泛地渗透到身体组织和体液中[7]，主要应用于泌尿系统、呼吸系统和皮肤软组织[8-10]等多种感染的治疗。在国产仿制制剂申请辅料变更后，根据评审单位提出的发补要求及已了解的资料，比较仿制制剂与参比制剂的辅料种类、型号和用量等处方差异，从原料、辅料到制剂的各个阶段进行体外渗透行为考察，探讨在变更辅料后是否满足生物等效性豁免的条件。
本研究采用μFluxTM测试系统测定原料的渗透性(Pe)，结合溶解度实验进一步探讨左氧氟沙星的BCS，并通过原料与原辅料混合后原料的表观渗透性(Papp)对比，以及参比和仿制制剂粉末中原料的Papp对比，以评估差异性辅料对原料渗透行为的影响。采用Macro FluxTM测试系统建立了基于体外溶出-渗透速率测试的模型，测定仿制制剂与参比制剂的渗透速率(JFlux)和终点时的药物累计渗透量(AMT)，通过计算几何均值的90%置信区间预测2种制剂的生物等效性，为左氧氟沙星片在辅料变更后的生物等效性豁免申请提供必要的技术支持和数据依据。
1　仪器与试药
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1.1　仪器
μFluxTM型药物渗透性测定系统(Pion Inc公司)；Macro FluxTM型药物溶出度与渗透速率测试系统(Pion Inc公司)；PB-10型pH计与MU205DU型十万分之一电子分析天平(Mettler Toledo公司)；Vision Elite8型溶出仪(Hanson公司)；1260型高效液相色谱仪(Agilent公司)；CSTHZ-81水浴恒温振荡器(金坛区金城致杰实验仪器厂)。
1.2　药品与对照品
左氧氟沙星片参比制剂(第一三共制药有限公司，批号BT066G1，规格0.5 g)；左氧氟沙星片仿制制剂(企业提供，批号B158B11902D，规格0.5 g)；左氧氟沙星对照品(批号130455-202108，含量97.1%，中国食品药品检定研究院)；左氧氟沙星原料(批号DK21-1811082-111)和辅料硬脂富马酸钠(批号1907)均由企业提供。
1.3　试剂
胃肠道模拟脂质体溶液(Pion Inc公司，批号520616)；受体室缓冲液(Accepter Sink Buffer，ASB，Pion Inc公司，批号110139)；Original SIF Powder(北京牛牛基因有限公司)；冰醋酸、二水合磷酸二氢钠、氯化钠与氢氧化钠均为分析纯；实验用水为纯化水。
2　方法与结果
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2.1　溶解度的测定
为评估左氧氟沙星的溶解性，采用了经典的摇瓶法来测定其在不同pH条件下的溶解度。称取过量的左氧氟沙星放置于锥形瓶中，并分别加入不同pH的溶液(pH 1.0的盐酸溶液和pH 3.0、4.0、5.0、6.0、6.8的磷酸盐缓冲溶液[11])50 mL制成过饱和溶液，置(37±0.5) ℃水浴振荡6 h，取出后滤过，参照《中华人民共和国药典》采用高效液相色谱法[12]，用十八烷基硅烷键合硅胶为填充剂，以醋酸铵高氯酸钠溶液（取醋酸铵4.0 g和高氯酸钠7.0 g，加水1 300 mL使溶解，用磷酸调节pH至2.2）-乙腈(85∶15)为流动相，在294 nm波长下测定原料的溶解度。结果如表1所示，左氧氟沙星的溶解度随着pH增大而减小，这可能与在酸性溶液中更容易产生溶剂化效应有关，在pH 5.0时溶解度不再明显降低，在pH 1.0的介质中溶解度最高，为62.7 mg·mL-1，pH 6.8时最低，为16.4 mg·mL-1，具有pH依赖性，3次重复试验的RSD均<2.0%，方法具有良好的重复性。
2.2　渗透行为研究
2.2.1　供体室介质(肠模拟溶液)的配制
pH 5.0的饱腹肠模拟液：称取氯化钠11.87 g，氢氧化钠4.04 g，冰醋酸8.65 g，加纯化水至1 L，用0.1 mol·L-1氢氧化钠溶液或冰醋酸调节pH至5.0，临用时加入Original SIF Powder 11.20 g，超声(功率300 W，频率30 kHz，下同)2 h，静置30 min后使用。
pH 6.5的空腹肠模拟液：称取氯化钠6.19 g，氢氧化钠0.42 g，二水合磷酸二氢钠4.47 g，加纯化水至1 L，用0.1 mol·L-1氢氧化钠溶液或磷酸调节pH至6.5，临用时加入Original SIF Powder 0.39 g，超声2 h，静置30 min后使用。
pH 7.4的磷酸盐缓冲液：取磷酸二氢钾6.8 g，加0.1 mol·L-1氢氧化钠溶液395 mL，用水稀释至1 L，即得。
2.2.2　对照品储备液的配制
分别称取左氧氟沙星对照品300、20 mg，精密称定，置于不同的10 mL量瓶中，用二甲基亚砜溶解并稀释至刻度，摇匀，配制成每1 mL含有30、2 mg的溶液，分别作为供体室和受体室对照品储备液。
2.2.3　标准曲线的测定
供体室标准曲线的测定：将紫外光纤探头(光程为2 mm)放入100 mL的不同的肠模拟溶液中，每加入1次350 μL的供体室对照品储备液，采集1次数据，测得质量浓度为100、200、300、400、500 μg·mL-1的左氧氟沙星标准溶液的紫外光谱图，用AuPROTM型软件二阶导数法校正后，选择波长为364~382 nm，以选定波长范围内曲线与横坐标围成的面积Y为纵坐标，以质量浓度X为横坐标进行线性回归，结果见表2。
受体室标准曲线的测定：将紫外光纤探头(μFlux光程为20 mm，Macro Flux光程为10 mm)放入50 mL的Accepter Sink Buffer中，每加入1次20 μL的受体室对照品储备液，采集1次数据，测得质量浓度为0.8、1.6、2.4、3.2、4.0 μg·mL-1的左氧氟沙星标准溶液的紫外光谱图，二阶导数法校正后，选择波长为304~322 nm，进行线性回归，结果见表2。供体室和受体室标曲的回归方程的相关系数均>0.99，供体室和受体室药物在选择的波长范围内吸收度的二阶导数和质量浓度呈良好的线性关系。
2.2.4　μFlux和Macro Flux测试系统
μFlux和Macro Flux测定装置如图1、2所示，均由供体室和受体室相连组成，供体室代表胃肠道环境，受体室代表血液环境，中间以仿生膜(涂有胃肠道模拟脂质体溶液)隔离，两室分别放入紫外光纤探头，随着检测时间的增加，供体室的药物逐渐通过仿生膜渗透至受体室中，药物浓度变化通过原位光纤DAD检测器实时检测，即可得到药物的溶解(溶出)曲线和渗透曲线，数据使用AuPROTM型软件(Pion Inc公司)采集并处理。
2种设备的核心技术均为人工仿生膜，是在聚偏氟乙烯等疏水材质制成的多微孔滤片(孔径0.22~0.45 μm)上涂抹了不同成分的磷脂溶液，模拟体内的渗透屏障，通过调整磷脂的组成和比例，PAMPA能够作为胃肠道(GIT-PAMPA)、血脑屏障(BBB-PAMPA)和皮肤吸收(SKIN-PAMPA)等的体外模型，以满足不同的实验需求[14]。2种设备的主要区别在于供体室不同，μFlux的供体室与受体室等体积，一般用于原料和辅料等微量粉末样品JFlux和Papp测定，更适合早期的、高通量的实验，而Macro Flux是以溶出杯作为供体室，实现药物溶出释放和渗透吸收同时监测，测定制剂的JFlux和AMT，可更好地模拟体内条件，综合考察制剂处方、工艺和存储等其他影响因素带来的渗透差异。总体来说，μFlux和MacroFlux结合使用，可实现从原辅料的初步考察筛选到制剂的体内外相关性的较为全面的研究。
2.2.5　渗透性的测定
对仿制制剂与参比制剂的处方进行对比分析，发现仿制制剂新增了辅料硬脂富马酸钠，并且其他辅料的种类、型号和用量均有差异，采用μFluxTM渗透性测试系统测定以下供试品中原料的Papp(原料为Pe)：a.左氧氟沙星原料；b.原料与处方量50倍的硬脂富马酸钠混合物(以下称混合物)；c.参比制剂研细粉末；d.仿制制剂研细粉末，采用IBM SPSS statistics 22版执行双侧t检验，分别对供试品a和b以及c和d的Pe(Papp)进行统计学分析，评估试验组间差异是否显著，考察硬脂富马酸钠及处方中其他辅料变更对原料渗透吸收的影响。
称取供试品(约含左氧氟沙星8 mg)置供体室，在供体室中精密加入肠模拟液16 mL，在受体室中精密加入Accepter Sink Buffer 16 mL，水浴循环温度为(37±0.5) ℃，转子速度200 r·min-1，采样频率30 s，采集时间180 min，采集波长与“2.2.3”项中标准曲线测定的波长一致，连续采集供体室和受体室中药物的吸收光谱，计算各采集点时两室溶液中药物的浓度，得到该药物的溶解和渗透曲线。以受体室50~120 min渗透曲线的斜率代入式①计算出渗透速率，进而通过式②得到左氧氟沙星的Pe以及原辅料混合物和制剂粉末中原料的Papp。
式中JFlux为渗透速率，即药物在单位时间通过单位膜面积的量(μg·mL-1·cm-2)；为单位时间内受体室中药物浓度的变化速率，即渗透曲线的斜率(μg·mL-1·min-1)；V为受体室中缓冲液体积；A为人工膜面积(μFlux的A为1.54 cm2，Macro Flux的A为3.88 cm2)。
式中Pe(Papp)为渗透性或表观渗透性(cm·s-1)；Ct为计算时间段内受体室中药物的平均浓度(μg·cm-3)。
2.2.6　评估辅料对原料的影响
μFluxTM测得原料的溶解和渗透典型曲线如图3所示，供体室中的药物迅速溶解达到最大浓度，受体室中药物浓度随时间增加，曲线表现出线性增长趋势，说明在测定时间范围内，药物在仿生膜的渗透速率保持相对恒定。
盐酸左氧氟沙星是两性化合物，在25 ℃下的解离常数(pKa)分别为6.2和8.2[15]，在pH 5.0的饱腹小肠模拟液、pH 6.5的空腹小肠模拟液和pH 7.4的磷酸缓冲液中的渗透曲线比较见图4，Pe分别为2.92×10-6、1.01×10-5和1.07×10-5 cm·s-1，随着供体室溶液的pH升高，Pe逐渐增大，表现出一定的pH依赖性，由于pH增大时药物分子更多地以非离子化形式存在，从而引起渗透性的增加。
原料以及混合物、参比制剂和仿制制剂粉末中原料的渗透性结果见表3、4，所有结果均为6次重复试验结果的平均值，RSD在10%以内。对原料和混合物以及仿制和参比制剂粉末的渗透性结果分别进行双侧t检验分析，P均>0.05，说明在考察的3种介质中渗透性均无显著差异，证明了新增辅料硬脂富马酸钠和仿制制剂中变更的其他辅料均不影响原料的渗透行为，具体渗透性比较和t检验结果详见图5。
2.2.7　 JFlux和AMT的测定
采用Macro FluxTM药物溶出度与渗透速率测定系统，照溶出度与释放度测定法2020年版《中华人民共和国药典》四部通则0931第二法，分别取参比制剂和仿制制剂1片置溶出杯中，以pH 5.0的饱腹小肠模拟液、pH 6.5的空腹小肠模拟液1 000 mL为溶出介质，桨转速为75 r·min-1；精密量取ASB缓冲液12 mL，置于受体室中，微搅拌棒的转速为450 r·min-1，采集频率与测定波长均与“2.2.5”项中一致。根据50~120 min渗透曲线的斜率按式①得到JFlux，按以下式③计算180 min终点时的AMT，再根据式④计算2种制剂JFlux和AMT几何均值90%置信区间，预测制剂的生物等效性。
式中AMT为终点时的药物累计渗透量(μg)；Cend为受体室终点时的药物浓度(μg·mL-1)；V为受体室中缓冲液体积。
式中AG为仿制制剂JFlux或AMT的平均值；AR为参比制剂JFlux或AMT的平均值；SG为仿制制剂JFlux或AMT的标准偏差；n为样本重复次数(本次试验n=6)；C为换算系数，与重复次数具有相关性，n=6时，C=2.015。
2.2.8　预测制剂的生物等效性
在pH 5.0和pH 6.5介质中测定的仿制制剂和参比制剂的溶出-渗透曲线如图6、7所示，参比制剂的溶出和渗透速度略慢于仿制制剂，溶出度在15 min内都达到了85%以上，说明2种制剂均属于“非常快速溶出”，溶出曲线相似；计算的JFlux和AMT见表5，结果显示，仿制制剂与参比制剂渗透速率无明显差异，在pH 5.0和pH 6.5介质中，JFlux的几何均值比值分别为106.2%和102.5%，90%置信区间为103.1%~109.4%和99.2%~105.82%，AMT的几何均值比值分别为102.3%和106.2%，90%置信区间为100.7%~103.9%和103.1%~109.4%，均在80%~125%范围内，预测受试制剂与参比制剂生物等效。
3　讨论
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3.1　溶解性和渗透性
左氧氟沙星单次给药的最高剂量为750 mg，由测定结果可知，在pH 1.0~pH 6.8的介质中溶解度为16.4~62.7 mg·mL-1，各介质溶解750 mg原料所需的体积为12~46 mL，均<250 mL，符合指导原则中对BCS高溶解性的定义[16-17]。而WHO收录的左氧氟沙星溶解性数据为30~300 mg·mL-1[18]，原料和溶剂的不同以及其他影响因素均会引起溶解性差异，因此不能使用简单的试验或仅提供文献来源的数据支持高溶解性，需提供试验资料以及试验内容的详细信息。
而体外测定渗透性高低的判定方式目前没有明确统一的规定，一般有2种，一是渗透性>1×10-6 cm·s-1，即为高渗透[16]，以此为依据，比较本研究中测定的Pe可认为左氧氟沙星为高渗；二是与NMPA指导原则附录A中推荐的渗透性模型药物对比，通常选择高渗透的美托洛尔进行比较，与此前课题组测得美托洛尔的渗透性(pH 5.0、pH 6.5和pH 7.4依次为5.87×10-6、5.33×10-5和1.34×10-4 cm·s-1)[20]比较，左氧氟沙星为低渗，然而仅依赖单一阈值进行比较可能无法全面准确地评估药物的渗透性，制定统一且具有特异性的测定方法和评定标准是尤为重要的。
生物等效性豁免指导原则指出，BCSⅠ类和Ⅲ类药物在满足一定的条件时，可申请生物等效性豁免[17]。根据上述溶解性和渗透性的研究结果，左氧氟沙星被归类为BCSⅠ类或Ⅲ类，此外，美国FDA和WHO将其归为Ⅰ类，美国国家儿童健康与人类发展研究所(NICHD)将其归为Ⅲ类[16,21]，因其口服吸收迅速，生物利用度达到99%以上，大多数研究中均归为Ⅰ类[22-24]。因此，本仿制制剂在辅料变更后可尝试向监管机构申报生物等效性豁免。
3.2　辅料对原料的干扰
在本研究中，通过2组对比试验，证明了即便仿制制剂处方中辅料的种类、型号和用量等发生部分变化，也不会造成原料渗透性的显著变化，这2组对比试验有效地证实了仿制制剂处方变更的合理性。PAMPA在处方筛选研究中扮演了关键角色，可探究任意单一或多种辅料与原药混合的情况，以便有针对性地评估辅料对原料的潜在干扰，方法具有灵活性和高效性，不仅节约了成本和时间，同时还提供了一个更加安全和直观的评估策略，从而为药物研发和优化提供了重要的技术支持。
3.3　预测制剂的生物等效性
在NMPA指导原则[25]中，接受生物等效的标准为体内药动学关键参数血药达峰时间(Cmax)和血药浓度-时间曲线下的面积(AUC)几何均值比值的90%置信区间数值应不低于80.00%，且不超过125.00%。文献报道[26-27]PAMPA中的关键参数渗透速率(JFlux)和Cmax呈正相关，而药物在终点时的累计渗透量(AMT)也可用于表征AUC，因此，在PAMPA中，计算JFlux和AMT的几何均值比值的90%置信区间，可用于预测制剂的体外生物等效性。
制剂的溶出-渗透曲线研究中，参比制剂的溶出和渗透速度均略慢于仿制制剂，2种制剂均属于非常快速溶出(溶出度在15 min内达到85%以上)，溶出曲线相似，不同介质中仿制制剂和参比制剂的JFlux和AMT几何均值比值的90%的置信区间，均在80%~125%范围之内，初步预测了2种制剂生物等效。
3.4　PAMPA的局限性
在应用PAMPA评估药物渗透行为时，需谨慎考虑其局限性。首先，因其主要模拟被动转运机制，无法充分反应主动运输机制，但在此领域资深的专家Li和Sugano等撰写的综述性文献中指出，被动扩散是大多数药物的主要吸收途径，在某些情况下是唯一途径[28-29]，所以PAMPA依然具有比较广泛的适用性；其次，磷脂膜的组成差异可导致同一药物在不同PAMPA系统中得到不同的渗透数据，体现了实验设计中磷脂来源和组成的重要性；此外，实验过程中观察到的渗透滞后现象及渗透速率的非恒定性，提示在不同时间段内计算得到的渗透速率可能存在变异，这为药物渗透性的准确评估增加了复杂度，需选择合理的测定波长和计算时间段；最后，PAMPA模型无法全面模拟体内环境的复杂性，如pH梯度、食物效应或代谢因素，这可能会导致体外数据与实际生物等效性评估之间的偏差。因此，虽然PAMPA为药物研发提供了一种高效的渗透性评估工具，若要对药物吸收和渗透性进一步全面理解，应与其他生物学模型和实验数据相结合。
4　结论
收起
综上所述，左氧氟沙星片为BCS Ⅰ类，处方研究证明新增辅料和其他变更辅料均不影响原料的渗透吸收，搭建的溶出-渗透模型表明溶出曲线相似，验证了仿制制剂与参比制剂之间的生物等效性，满足了NMPA指导原则中对于溶解性、渗透性、处方组成和溶出度等关键属性的要求，支持了在辅料变更后基于体外数据申请生物等效性豁免的可行性，降低了药物开发的成本和时间，避免不必要的人体试验风险，消除了受试者变异性的影响，可加快安全、有效药品的上市流程，同时也为制药企业在申请生物等效性豁免时提供参考。
基金
收起
  • * 国家药品监督管理局药品监管科学体系建设重点项目(RS2024H001)
  • 甘肃省药品科研项目(2023GSMPA071)
  • 甘肃省药品科研项目(2021GSMPA001)
文献
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2024年第44卷第7期
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doi: 10.16155/j.0254-1793.2024-0089
  • 接收时间：2024-02-06
  • 首发时间：2026-03-13
  • 出版时间：2024-07-31
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  • 收稿日期：2024-02-06
基金
* 国家药品监督管理局药品监管科学体系建设重点项目(RS2024H001)
甘肃省药品科研项目(2023GSMPA071)
甘肃省药品科研项目(2021GSMPA001)
作者信息
    1.甘肃省药品检验研究院，兰州 730070
    2.中国食品药品检定研究院，北京 102629

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鹅膏菌科Amanitaceae 2 11 5.26 鹅膏菌属 Amanita 10 4.78
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