CN108872446A - The rich quantitative detecting method for Buddhist nun's medicament residue of card in a kind of meat products - Google Patents
The rich quantitative detecting method for Buddhist nun's medicament residue of card in a kind of meat products Download PDFInfo
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- CN108872446A CN108872446A CN201811009671.9A CN201811009671A CN108872446A CN 108872446 A CN108872446 A CN 108872446A CN 201811009671 A CN201811009671 A CN 201811009671A CN 108872446 A CN108872446 A CN 108872446A
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- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
- G01N30/02—Column chromatography
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Abstract
The present invention provides a kind of rich quantitative detecting methods for Buddhist nun's medicament residue of card in meat products, including：Sample preparation；Sample extraction；Sample purification；Liquid Chromatography-Tandem Mass Spectrometry analysis detection；Liquid chromatography-tandem mass spectrometry detection is obtained the rich peak area substitution following formula for replacing Buddhist nun of card to calculate, blocks the rich measured value for Buddhist nun in prepare liquid to obtain；
Description
Technical field
Present invention relates particularly to block the rich quantitative detecting method for Buddhist nun's medicament residue in a kind of meat products.
Background technique
Meat products because its demand is big, full of nutrition and the features such as easy to digest due to welcome by each age stratum.
However, the growth and breeding for various spoilage organisms, pathogenic bacteria provides base since its moisture content is high, required nutriment is abundant
Matter causes meat products to be easy by various microbial contaminations.Listeria monocytogenes
(Listeriamonocytogenes, LM) abbreviation Listeria monocytogenes are a kind of important infecting both domestic animals and human pathogens, divide extensively
It being distributed in nature, Listeria monocytogenes can still be grown at 4 DEG C, the main infection morbidity for causing people by meat cream and its product,
Caused No. second fatal Diet_induced obesity disease is infected as Salmonella is only second to.China's food origin disease monitoring net
Data in recent years show, China's pollution different degrees of by Listeria monocytogenes in raw meat, cold cuts, aquatic products etc..
Antibiotic is wide and practical applied to the treatment of various infectious diseases at present, for controlling for Listeria infection
Treating drug is mostly that extracellular antibiotic, these antibiotic such as penicillins, cephalosporins, sulfalene uh azoles cannot be introduced into the cell
Sterilize and be present in the problems such as intracellular bacterium can escape the immune defense and removing of body make individual infection LM after
Lead to higher disease incidence and dies of illness.In recent years, multinomial research confirms, c-Met inhibitor card is rich can specific inhibition LM for Buddhist nun
Into cell, there is efficient blocking effect to Liszt's thallus (LM) infection in animal body, novel anti-intracellular infection medicine will be used as
Object promotes listing.
Card is rich to be known as N- [4- [(6,7- dimethoxy-4 '-quinolyl) oxygen for Buddhist nun (Cabozantinib) Chinese chemical name
Base] phenyl]-N '-(4- fluorophenyl)-l, 1- cyclopropane diformamide, the entitled N- of English language Chemical [4- [(6,7-dimethoxy-
4-quinolinyl) oxy] phenyl]-N '-(4-fluorophenyl)-l, 1-cyclopr opane-dicarboxamide,
It is a kind of oral novel multiple receptor tyrosine kinases inhibitor, in 2012 Nian Huo Food and Drug Adminstration of the US (FDA) approvals
City is used for the treatment of metastatic medullary thyroid carcinoma.Cell and zoopery, which have proven to card, to be won can adjust Met letter for Buddhist nun extremely
Number access, to inhibit the proliferation of tumour cell.Medullary carcinoma of thyroid gland can be treated with before for Buddhist nun by proving that card is rich through clinical research
Column gland cancer, and there are safe-dosaging limits.Card is rich to replace Buddhist nun as a kind of targeted drug, and side effect is more obvious, and stomach occurs
The probability that bowel perforation and fistula are formed is 3% and 1%, has 3% probability serious hemoptysis or hemorrhage of gastrointestinal tract occur, sometimes
Lead to life danger, in addition have and will appear common adverse reaction greater than 25% probability, such as diarrhea, stomatitis, skin injury
Deng.
Once the listing of such drug high-volume is contaminated for treating Listeria body-sensing in animal body, will not in animal matrix
It is evitable to generate certain medicament residue.It is well known that targeting medicine disadvantage be exactly administration time extension, drug resistance with
, hinder continuing to use for targeting medicine.And if people's long-term consumption contains the remaining meat products of targeted drug, in addition to
, in vivo once generating drug resistance, the therapeutic effect for suffering from cancer disease can be will seriously affect with outside certain toxic side effect.
Therefore studying and formulate the rich quantitative detecting method for Buddhist nun's medicament residue of card in meat products has important reality meaning
Justice.Currently, having no the rich related patents or document report for Buddhist nun's detection of card both at home and abroad.In addition, via ISO, ASTM, GB, SN etc.
Standard, which is looked into, newly has no that relevant criterion is reported.Therefore it is rich for Buddhist nun's medicament residue to be badly in need of developing card in a kind of accurately and rapidly meat products
Quantitative measurement technology.
Summary of the invention
The technical problem to be solved in the present invention is to provide the rich quantitative detection for Buddhist nun's medicament residue of card in a kind of meat products
Method.
The invention is realized in this way：The rich quantitative detecting method for Buddhist nun's medicament residue of card in a kind of meat products, including with
Lower step：
(1) sample preparation：Representative sample is taken, is sufficiently smashed to pieces, is mixed well with tissue mashing machine, acquisition prepares sample, so
It is packed into clean container sealing afterwards, -18 DEG C or less freezen protectives are spare；
(2) sample extraction：2g sample is weighed in sample from preparing, is accurate to 0.01g, 15mL ethyl acetate is added, and vortex is mixed
Even 2min, then 4000r/min is centrifuged 5min, takes supernatant, and residue continues to repeat to extract with 15mL ethyl acetate, merges and extract
Liquid, 40 DEG C of water-bath rotary evaporated to dryness；
(3) sample purification：0.1mol/L hydrochloric acid 3mL is added in the sample of extraction, vortex mixes 1min, lysate is collected,
Undissolved residue adds 0.1mol/L hydrochloric acid 3mL, and vortex mixes 1min, merges lysate；In lysate be added 3mL just oneself
Alkane, vortex mix 1min, and then 4000r/min is centrifuged 5min, discards n-hexane layer, add 3mL n-hexane, repeat above-mentioned step
Suddenly, reserve liquid is obtained；
MCX solid-phase extraction column is successively balanced with 3mL methanol and 0.1mol/L hydrochloric acid 2mL using preceding, and reserve liquid is added, with
The flow velocity of 1.0mL/min all passes through solid-phase extraction column, then uses 0.1mol/L hydrochloric acid 1mL, methanol 1mL, -2% ammonia of methanol respectively
Water (10+90, v/v) 1mL elution, discards leacheate, is finally eluted with -5% ammonium hydroxide of 5mL methanol (60+40, v/v), collects elution
Liquid is dried with nitrogen under 40 DEG C of water-baths, and the substance that drying is obtained 30% acetonitrile solution of 1mL dissolves, and 0.2 μm excessively organic
Filter membrane obtains prepare liquid；
(4) analysis detection is carried out using ultra performance liquid chromatography-tandem mass spectrometry, is blocked with obtaining measured object in prepare liquid
The rich response for Buddhist nun chooses the corresponding standard working solution of response according to the response condition of measured object in prepare liquid and carries out chromatography
Analysis, standard working solution are equipped with comprising five concentration gradients including zero point, and are blocked in standard working solution and prepare liquid rich for Buddhist nun
Response should all be in instrument linear response range, and blank control is set simultaneously；
The condition of the ultra performance liquid chromatography-tandem mass spectrum is：
A. ultra performance liquid chromatography:
Chromatographic column：Thermo Syncronnic C18 column, 50mm × 2.1mm, 1.7 μm；Flow velocity：0.3mL/min；Sample introduction
Amount：10μL；Column temperature：30℃；Gradient elution program is as follows：
B. Mass Spectrometry Conditions：
Ion source：Electron spray ESI, cation；Scanning mode：Multiple-reaction monitoring MRM；Atomization gas, curtain gas, auxiliary heating
Gas, collision gas are high pure nitrogen；Monitoring ion pair, quota ion pair go to cluster voltage, collision gas energy, collision cell outlet
Voltage is as follows：
(5) by ultra performance liquid chromatography-tandem mass spectrum detect the rich peak area for Buddhist nun of card obtained substitute into following formula (1) into
Row calculates, and blocks the rich measured value for Buddhist nun in prepare liquid to obtain；
Wherein：
Block in X-sample rich for Buddhist nun's residual content, mg/kg；
Block the rich peak area for Buddhist nun in A-prepare liquid；
Block the rich peak area for Buddhist nun in As-standard working solution；
Block in c-standard working solution rich for Buddhist nun's concentration, mg/L；
The final constant volume of V-prepare liquid, mL；
M-sample quality, g.
The advantage of the invention is that：China has been filled up to block in meat products on the rich quantitative measurement technology for Buddhist nun's medicament residue
Blank, and have the advantages that easily operated and detection accuracy is high.
Specific embodiment
The rich quantitative detecting method for Buddhist nun's medicament residue of card, includes the following steps in a kind of meat products：
(1) sample preparation：Representative sample is taken, is sufficiently smashed to pieces, is mixed well with tissue mashing machine, it is close to be packed into clean container
Envelope, -18 DEG C or less freezen protectives are spare；
(2) sample extraction：About 2g sample (being accurate to 0.01g) is weighed in sample in 50mL tool plug centrifuge tube from preparing, and is added
Enter 15mL ethyl acetate, whirling motion 2min, 4000r/min are centrifuged 5min, and supernatant is transferred in 100mL chicken heart bottle, and residue is used
15mL repeats to extract once in ethyl acetate, merges extracting solution twice, 40 DEG C of water-bath rotary evaporated to dryness；
(3) sample purification：0.1mol/L hydrochloric acid 3mL, whirling motion 1min are added in chicken heart bottle, abundant dissolved residue is transferred to
In 15mL centrifuge tube, then 0.1mol/L hydrochloric acid 3mL is added into chicken heart bottle, whirling motion 1min is transferred in same centrifuge tube.Centrifugation
3mL n-hexane is added in pipe, whirling motion 1min, 4000r/min centrifugation 5min discards n-hexane layer, then 3mL is added in centrifuge tube
N-hexane, repetition degreasing is primary, eliminates n-hexane layer, spare；
It takes MCX solid-phase extraction column on solid-phase extraction device, is successively balanced, added with 3mL methanol and 0.1mol/L hydrochloric acid 2mL
Enter reserve liquid, solid-phase extraction column passed through all with the flow velocity of 1.0mL/min, then respectively with 0.1mol/L hydrochloric acid 1mL, methanol 1mL,
- 2% ammonium hydroxide of methanol (10+90, v/v) 1mL elution, discards leacheate, is finally washed with -5% ammonium hydroxide of 5mL methanol (60+40, v/v)
It is de-, eluent is collected, is dried with nitrogen under 40 DEG C of water-baths, is dissolved with 30% acetonitrile solution 1mL, 0.2 μm of organic filter membrane is crossed, to
It surveys；
(4) analysis detection is carried out using ultra performance liquid chromatography-tandem mass spectrometry, is blocked with obtaining measured object in prepare liquid
The rich response for Buddhist nun chooses the corresponding standard working solution of response according to the response condition of measured object in prepare liquid and carries out chromatography
Analysis, standard working solution are equipped with comprising five concentration gradients including zero point, and are blocked in standard working solution and prepare liquid rich for Buddhist nun
Response should all be in instrument linear response range, and blank control is set simultaneously；
The condition of the ultra performance liquid chromatography-tandem mass spectrum is：
A. ultra performance liquid chromatography:
Chromatographic column：Thermo Syncronnic C18 column, 50mm × 2.1mm, 1.7 μm；Flow velocity：0.3mL/min；Sample introduction
Amount：10μL；Column temperature：30℃；Gradient elution program is as follows：
B. Mass Spectrometry Conditions：
Ion source：Electron spray ESI, cation；Scanning mode：Multiple-reaction monitoring MRM；Atomization gas, curtain gas, auxiliary heating
Gas, collision gas are high pure nitrogen；Monitoring ion pair, quota ion pair go to cluster voltage, collision gas energy, collision cell outlet
Voltage is as follows：
(5) by ultra performance liquid chromatography-tandem mass spectrum detect the rich peak area for Buddhist nun of card obtained substitute into following formula (1) into
Row calculates, and blocks the rich measured value for Buddhist nun in prepare liquid to obtain；
Wherein：
Block in X-sample rich for Buddhist nun's residual content, mg/kg；
Block the rich peak area for Buddhist nun in A-prepare liquid；
Block the rich peak area for Buddhist nun in As-standard working solution；
Block in c-standard working solution rich for Buddhist nun's concentration, mg/L；
The final constant volume of V-prepare liquid, mL；
M-sample quality, g.
Embodiment 1：Sample to be tested --- pork
1.1 sample preparation：Representative sample is taken, is sufficiently smashed to pieces, is mixed well with tissue mashing machine, test is divided into two parts,
It is packed into clean container and seals and carry out mark, -18 DEG C or less freezen protectives, as sample.Sample preparation procedure must be prevented from trying
Sample is contaminated or occurs the variation of residuals content, saves under room temperature.
The test of 1.2 backgrounds：The examination in 2g (being accurate to 0.01g) 1.1 is respectively weighed into six 50mL tool plug centrifuge tubes
Sample is then successively operated according to step in the specific embodiment of the invention (2), step (3) and step (4), is finally calculated
Resulting each actual measured value and average value are as shown in table 1, which is background values.
Block the rich background values determination data for Buddhist nun in 1 pork of table
1.3 verifyings one：It is rich for Buddhist nun to add 5 μ g/kg cards
The sample in 2g (being accurate to 0.01g) 1.1, which is respectively weighed, into six 50mL tool plug centrifuge tubes (is specifically shown in Table 2
In sample weighting amount), then added into each centrifuge tube 0.1mg/L card it is rich replace Buddhist nun's standard solution 0.1mL, then successively according to
Step (2), step (3) and step (4) operate in the present invention, finally calculate resulting each actual measured value and are listed in Table 2 below.
The rich related data for Buddhist nun of card of 5 μ g/kg is added in 2 pork of table
1.4 verifyings two：It is rich for Buddhist nun to add 50 μ g/kg cards
The sample in 2g (being accurate to 0.01g) 1.1, which is respectively weighed, into six 50mL tool plug centrifuge tubes (is specifically shown in Table 3
In sample weighting amount), then added into each centrifuge tube 1mg/L card it is rich replace Buddhist nun's standard solution 0.1mL, then successively according to this
Step (2), step (3) and step (4) are operated in invention, and will finally be calculated resulting each actual measured value and be listed in table 3
In.
The rich related data for Buddhist nun of card of 50 μ g/kg is added in 3 pork of table
Embodiment 2：Sample to be tested --- chicken
2.1 sample preparation：Representative sample is taken, is sufficiently smashed to pieces, is mixed well with tissue mashing machine, test is divided into two parts,
It is packed into clean container and seals and carry out mark, -18 DEG C or less freezen protectives, as sample.Sample preparation procedure must be prevented from trying
Sample is contaminated or occurs the variation of residuals content, saves under room temperature.
The test of 2.2 backgrounds：The examination in 2g (being accurate to 0.01g) 2.1 is respectively weighed into six 50mL tool plug centrifuge tubes
Sample is then successively operated according to step in the specific embodiment of the invention (2), step (3) and step (4), is finally calculated
Resulting each actual measured value and average value are as shown in table 4, which is background values.
Block the rich background values determination data for Buddhist nun in 4 chicken of table
2.3 verifyings one：It is rich for Buddhist nun to add 5 μ g/kg cards
The sample in 2g (being accurate to 0.01g) 2.1, which is respectively weighed, into six 50mL tool plug centrifuge tubes (is specifically shown in Table 5
In sample weighting amount), then added into each centrifuge tube 0.1mg/L card it is rich replace Buddhist nun's standard solution 0.1mL, then successively according to
Step (2), step (3) and step (4) operate in the present invention, finally calculate resulting each actual measured value and are listed in Table 5 below.
The rich related data for Buddhist nun of card of 5 μ g/kg is added in 5 chicken of table
2.4 verifyings two：It is rich for Buddhist nun to add 50 μ g/kg cards
The sample in 2g (being accurate to 0.01g) 2.1, which is respectively weighed, into six 50mL tool plug centrifuge tubes (is specifically shown in Table 6
In sample weighting amount), then added into each centrifuge tube 1mg/L card it is rich replace Buddhist nun's standard solution 0.1mL, then successively according to this
Step (2), step (3) and step (4) are operated in invention, and will finally be calculated resulting each actual measured value and be listed in table 6
In.
The rich related data for Buddhist nun of card of 50 μ g/kg is added in 6 chicken of table
By above-mentioned experimental result it is found that being measured when the present invention is won applied to card in detection meat products for Buddhist nun's drug residue
Lower bound is：5 μ g/kg, rate of recovery 77.4-96.4%, it is good in 5~100 μ g/L range internal standard curve linear relationships, it is related
Coefficient r is greater than 0.999.
It can determine whether out that detection method of the invention not only may be used from the size of the rate of recovery and RSD in respective verification result
Row, and accuracy is high.
Although specific embodiments of the present invention have been described above, those familiar with the art should be managed
Solution, we are merely exemplary described specific embodiment, rather than for the restriction to the scope of the present invention, it is familiar with this
The technical staff in field should be covered of the invention according to modification and variation equivalent made by spirit of the invention
In scope of the claimed protection.
Claims (1)
1. blocking the rich quantitative detecting method for Buddhist nun's medicament residue in a kind of meat products, it is characterised in that：Include the following steps：
(1) sample preparation：Representative sample is taken, is sufficiently smashed to pieces, is mixed well with tissue mashing machine, acquisition prepares sample, then fills
Enter clean container sealing, -18 DEG C or less freezen protectives are spare；
(2) sample extraction：2g sample is weighed in sample from preparing, is accurate to 0.01g, 15mL ethyl acetate is added, and vortex mixes
2min, then 4000r/min is centrifuged 5min, takes supernatant, and residue continues to repeat to extract with 15mL ethyl acetate, merges and extract
Liquid, 40 DEG C of water-bath rotary evaporated to dryness；
(3) sample purification：0.1mol/L hydrochloric acid 3mL is added in the sample of extraction, vortex mixes 1min, collects lysate, not molten
The residue of solution adds 0.1mol/L hydrochloric acid 3mL, and vortex mixes 1min, merges lysate；3mL n-hexane is added in lysate,
Vortex mixes 1min, and then 4000r/min is centrifuged 5min, discards n-hexane layer, adds 3mL n-hexane, repeat the above steps,
Obtain reserve liquid；
MCX solid-phase extraction column is successively balanced with 3mL methanol and 0.1mol/L hydrochloric acid 2mL using preceding, reserve liquid is added, with 1.0mL/
The flow velocity of min all passes through solid-phase extraction column, then uses 0.1mol/L hydrochloric acid 1mL, methanol 1mL, -2% ammonium hydroxide 10+ of methanol respectively
90, v/v 1mL elution, discards leacheate, finally with -5% ammonium hydroxide 60+40, the v/v elution of 5mL methanol, eluent is collected, in 40
It is dried with nitrogen under DEG C water-bath, the substance that drying is obtained 30% acetonitrile solution of 1mL dissolves, and crosses 0.2 μm of organic filter membrane, obtains
To prepare liquid；
(4) analysis detection is carried out using ultra performance liquid chromatography-tandem mass spectrometry, blocks rich replace to obtain measured object in prepare liquid
The response of Buddhist nun chooses the corresponding standard working solution of response according to the response condition of measured object in prepare liquid and carries out chromatography point
Analysis, standard working solution are equipped with comprising five concentration gradients including zero point, and are blocked in standard working solution and prepare liquid rich for Buddhist nun's
Response should all be in instrument linear response range, and blank control is arranged simultaneously；
The condition of the ultra performance liquid chromatography-tandem mass spectrum is：
A. ultra performance liquid chromatography:
Chromatographic column：Thermo Syncronnic C18 column, 50mm × 2.1mm, 1.7 μm；Flow velocity：0.3mL/min；Sample volume：10
μL；Column temperature：30℃；Gradient elution program is as follows：
B. Mass Spectrometry Conditions：
Ion source：Electron spray ESI, cation；Scanning mode：Multiple-reaction monitoring MRM；Atomization gas, curtain gas, auxiliary heating gas,
Collision gas is high pure nitrogen；Monitoring ion pair, quota ion pair remove cluster voltage, collision gas energy, collision cell exit potential
It is as follows：
(5) ultra performance liquid chromatography-tandem mass spectrum rich peak area substitution following formula (1) for replacing Buddhist nun of card obtained is detected to count
It calculates, blocks the rich measured value for Buddhist nun in prepare liquid to obtain；
Wherein：
Block in X-sample rich for Buddhist nun's residual content, mg/kg；
Block the rich peak area for Buddhist nun in A-prepare liquid；
Block the rich peak area for Buddhist nun in As-standard working solution；
Block in c-standard working solution rich for Buddhist nun's concentration, mg/L；
The final constant volume of V-prepare liquid, mL；
M-sample quality, g.
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| CN201811009671.9A CN108872446B (en) | 2018-08-31 | 2018-08-31 | Quantitative detection method for cabozantinib drug residue in meat product |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201811009671.9A CN108872446B (en) | 2018-08-31 | 2018-08-31 | Quantitative detection method for cabozantinib drug residue in meat product |
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| CN108872446B CN108872446B (en) | 2021-02-05 |
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103664778A (en) * | 2013-11-27 | 2014-03-26 | 苏州摩尔医药有限公司 | Synthesis method of antineoplastic drug cabozant inib |
| WO2014145693A1 (en) * | 2013-03-15 | 2014-09-18 | Exelixis, Inc. | Metabolites of n-[3-fluoro-4-({ 6-(methyloxy)-7-[(3-morpholin-4-ylpropyl)oxy]quinolin-4-yl}oxy)phenyl]-n'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide |
-
2018
- 2018-08-31 CN CN201811009671.9A patent/CN108872446B/en active Active
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2014145693A1 (en) * | 2013-03-15 | 2014-09-18 | Exelixis, Inc. | Metabolites of n-[3-fluoro-4-({ 6-(methyloxy)-7-[(3-morpholin-4-ylpropyl)oxy]quinolin-4-yl}oxy)phenyl]-n'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide |
| CN103664778A (en) * | 2013-11-27 | 2014-03-26 | 苏州摩尔医药有限公司 | Synthesis method of antineoplastic drug cabozant inib |
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| CHENG CUI ET AL.: "An UPLC–MS/MS method to determine CT-707 and its twometabolites in plasma of ALK-positive advanced non-small cell lungcancer patients", 《JOURNAL OF PHARMACEUTICAL AND BIOMEDICAL ANALYSIS》 * |
| CHUNYONG WU ET AL.: "Degradation kinetics study of cabozantinib by a novelstability-indicating LC method and identification of its majordegradation products by LC/TOF-MS and LC–MS/MS", 《JOURNAL OF PHARMACEUTICAL AND BIOMEDICAL ANALYSIS》 * |
| QINGHONG SU ET AL.: "An LC-MS/MS method for the quantitation of cabozantinib in ratplasma: Application to a pharmacokinetic study", 《JOURNAL OF CHROMATOGRAPHY B》 * |
| WEIJIAN YE ET AL.: "Determination and pharmacokinetics of engeletin in rat plasma by ultrahigh", 《JOURNAL OF CHROMATOGRAPHY B》 * |
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| 金鑫 等: "LC-MS/MS法检测卡博替尼降解产物", 《江西中医药大学学报》 * |
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