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CN102183659B - Method for detecting carbamazepine - Google Patents

Method for detecting carbamazepine Download PDF

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CN102183659B
CN102183659B CN201110049830.XA CN201110049830A CN102183659B CN 102183659 B CN102183659 B CN 102183659B CN 201110049830 A CN201110049830 A CN 201110049830A CN 102183659 B CN102183659 B CN 102183659B
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carbamazepine
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detecting
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CN102183659A (en
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虞留明
梁耀铭
李洪波
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Hangzhou Jinyu Medical Laboratory Co ltd
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Guangzhou Kingmed Diagnostics Central Co Ltd
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Priority to US13/069,192 priority patent/US8563713B2/en
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Abstract

本发明公开了一种卡马西平检测方法，包括以下步骤：将待测样本与抗卡马西平特异性抗体接触；根据待测样本中的物质与抗体的结合情况，判断样本中卡马西平的含量，其中抗卡马西平特异性抗体由卡马西平免疫原免疫动物得到。本发明的检测方法，特异性高，可以准确的确定待测样本中是否存在卡马西平，同样可以准确地确定卡马西平的含量。The invention discloses a carbamazepine detection method, comprising the following steps: contacting a sample to be tested with an anti-carbamazepine specific antibody; content, wherein the specific antibody against carbamazepine is obtained by immunizing animals with carbamazepine immunogen. The detection method of the present invention has high specificity, can accurately determine whether there is carbamazepine in the sample to be tested, and can also accurately determine the content of carbamazepine.

Description

A kind of method for detecting carbamazepine
Technical field
The present invention relates to a kind of detection method, particularly a kind of method for detecting carbamazepine.
Background technology
Carbamazepine (5 h-dibenzo[ b, f] azepine-5-carboxamide, 5H-dibenzo[b,f), its structural formula is suc as formula shown in (II).
Figure 201110049830X100002DEST_PATH_IMAGE002
Carbamazepine is a class anti-epileptic, the class of setting the mind at rest medicine, is mainly used in epilepsy, anxiety disorder and prosopalgic treatment.Carbamazepine has a lot of spinoffs, comprising: likely life-threatening allergic reaction; May cause skin and internal organs grievous injury to trigeminal neuralgia is poisonous.Therefore during treating, the blood substance level to patient is monitored extremely important.
Summary of the invention
The object of the present invention is to provide a kind of method for detecting carbamazepine.
The technical solution used in the present invention is:
A kind of method for detecting carbamazepine, comprises the following steps:
1) sample to be tested is contacted with anti-carbamazepine specific antibody;
2) according to the combination situation of the material in sample to be tested and antibody, the content of carbamazepine in judgement sample,
Wherein anti-carbamazepine specific antibody is obtained by carbamazepine immunogen immune animal, and the immunogenic structural formula of described carbamazepine is as shown in (I):
In formula, R is linking group, and carrier has immunogenicity.
Preferably, carrier is for having immunogenic protein.
R Wei – O-(CH 2) n-COO-, n is the integer between 1 to 20, R Xuan Wei – O-(CH 2) 4-COO-.
Step 2) the inspection-free determination method of use enzyme.The inspection-free determination method of enzyme is homogeneous EIA method or enzyme-linked immunosorbent assay method.
Sample to be tested is physiology sample, is preferably blood sample.
Detection method of the present invention, specificity is high, can determine accurately in sample to be tested whether have carbamazepine, can determine exactly equally the content of carbamazepine.
Brief description of the drawings
Fig. 1 is carbamazepine ELISA detection reaction curve;
Fig. 2 is carbamazepine homogeneous enzyme immunoassay response curve.
Embodiment
A kind of method for detecting carbamazepine, comprises the following steps:
1) sample to be tested is contacted with anti-carbamazepine specific antibody;
2) according to the combination situation of the material in sample to be tested and antibody, the content of carbamazepine in judgement sample,
Wherein anti-carbamazepine specific antibody is obtained by carbamazepine immunogen immune animal, and the immunogenic structural formula of described carbamazepine is as shown in (I):
In formula, R is linking group, and carrier has immunogenicity.
Preferably, carrier is for having immunogenic protein.Although other enough the large immunogenic material that possesses also can be used as carrier, select under normal circumstances protein as carrier.The most frequently used immunogenic carrier comprises haemocyanin, hemocyanin (KLH) and thyroglobulin.The selection of carrier is those skilled in the art's basic general knowledge.
R Wei – O-(CH 2) n-COO-, n is the integer between 1 to 20, R Xuan Wei – O-(CH 2) 4-COO-.
Below in conjunction with embodiment, further illustrate the present invention.
The carbamazepine derivative chemical constitution using in following examples is suc as formula shown in (III).
Figure 201110049830X100002DEST_PATH_IMAGE006
The synthetic route of this carbamazepine derivative is as follows:
Figure 201110049830X100002DEST_PATH_IMAGE008
Concrete synthesis step is as follows:
synthesizing of compound 2:
Figure DEST_PATH_IMAGE010
1) accurately take nitroso-the disulfonic acid potassium ((KSO of 2.5 g 3) 2nO, Fremy's salt (Fremy ' s salt), 9.32 mmol) and 1.8 g Na 2hPO 4(12.7 mmol), puts into beaker, adds 95ml distilled water to dissolve, and regulates pH to 7.22; Take 0.55g compound 1 (12.76 mmol) to 60ml acetone soln;
2) above-mentioned two kinds of solution are mixed, vigorous stirring, obtains purple solution;
3) above-mentioned purple solution is joined in acetone soln, continue to stir 10 minutes, filter, and be placed in refrigerator overnight;
4) solution spending the night is concentrated through argon gas Rotary Evaporators, extract with 500ml ether, after having extracted, organic phase solvent is evaporated;
5) evaporation residue being carried out to rapid column chromatography with bonded silica gel post purifies, eluant, eluent is hexane (Hexane) and the tetraethyl ammonium chloride(TEAC (Tetraethoxypropane that 4:1 ratio is mixed, TEAC) solution, finally by ether (Diethyl ether, Et 2o) the peony crystal powder shape material that recrystallization obtains is imido grpup quinone compounds 2(0.12g, 21%).
synthesizing of compound 3:
Figure DEST_PATH_IMAGE012
1) accurately take 1.2 g compound 2(5.8 mmol) be dissolved in 50ml CHCl 3solution, is placed in separating funnel;
2) take 2.5 sodium hydrosulfite (Na 2s 2o 4) (14.3 mmol) be dissolved in 20 ml water and make solution;
3) in above-mentioned separating funnel, add excessive Na 2s 2o 4solution, vibrates gently to the color of organic solution layer and becomes yellow from redness, and stratification;
4) by water CHCl 3carry out extract and separate, the organic phase obtaining is used Na again 2sO 4carry out absorbent drying, by the method for rotary distillation, solvent is evaporated.
5) through CHCl 3it is compound 3 (1.1g, 92%) that residue after extraction carries out the pistac crystal that recrystallization obtains.
synthesizing of compound 4:
Figure DEST_PATH_IMAGE014
1) accurately take compound 3 to the 10 ml CHCl of 1.1g 3in solution, then add the triethylamine (Triethylamine, TEA) of 1ml;
2) in this solution, add 2 g tert-butyl chloro-silicanes (tert-butylchlorodimethylsilane, TBDMSCl) (15.2 mmol), under room temperature, stir 3 days, then solvent is evaporated;
3) add water-soluble solution, with chloroform (CHCl 3) carry out extract and separate, the organic phase Na obtaining 2sO 4absorbent drying, evaporates solvent by the method for rotary distillation.
What can obtain 1.6g through said process slightly carries compound 4.
synthesizing of compound 5:
Figure DEST_PATH_IMAGE016
1) take the CHCl of compound 4 to 10 ml of 1.6 g 3in solution, then add 2 ml TMSOCN(4.95 mmol), under room temperature, stir 2 days, solvent is evaporated;
2) add water-soluble solution, use CHCl 3extraction, the organic phase obtaining is first washed with salt solution, then adds Na 2sO 4be dried, finally by the method for rotary distillation, solvent evaporated.
What finally obtain 1.6 g yellow through said process slightly carries compound 5.
synthesizing of compound 6:
Figure DEST_PATH_IMAGE018
1) take 1.6g compound 5(4.37 mmol) and 2 g tetrabutyl ammonium fluoride (Tetrabutylammonium fluoride, TBAF) (15.2 mmol) is in beaker, add 20 ml tetrahydrofuran (Tetrahydrofuran, THF) dissolve, under room temperature, stir after 4 hours, solvent is evaporated;
2) add distilled water to dissolve, with ethyl acrylate (ethyl acrylate, EA) extract and separate, the organic phase Na obtaining 2sO 4be dried, by rotary distillation, solvent evaporated;
3) crude extract is through chromatographic column (EA/PE(ethyl acrylate/tygon)=1:1) after purifying, obtain the compound 6 of 1.0g.(productive rate from compound 3 to compound 6 is 75%)
synthesizing of compound 7:
Figure DEST_PATH_IMAGE020
1) accurately take the compound 6(4.0 mmol of 1.0 g) join in the vinyl cyanide (Acrylonitrile, ACN) of 30 ml, in this solution, add 1.38 g K 2cO 3(10.0 mmol) and 1.16g compd A (the positive methyl valerate of 5-bromine) (6.0 mmol), stir and spend the night under room temperature;
2) solution is concentrated through vacuum filtration method, then uses ethyl acetate (Acetoacetate, EtOAc) extract and separate;
3) organic phase obtaining adds Na 2sO 4be dried, then through vacuumizing filtration;
4) slightly carry compound silica gel keys zygostyle and carry out flash chromatography and purify, eluant, eluent is EA and the PA solution E A/PE(ethyl acrylate/tygon that 1:3 ratio is mixed), finally obtain 1.1 g white solid compounds 7, productive rate is 76%.
Similarly, by change in compd A-CH 2-quantity, can obtain the analog of compound 7.
synthesizing of carbamazepine derivative:
Figure DEST_PATH_IMAGE022
1) take 1.1 g compound 7(3.0 mmol) to 20 ml tetrahydrofurans (Tetrahydrofuran, THF), dissolve;
2) take again 0.48 g containing the lithium hydroxide (LiOHH of water of crystallization 2o) (11.8mmol) to 10ml distilled water, dissolve;
3) above-mentioned two kinds of solution are mixed, stir after 6 hours at 50 DEG C, TLC shows that hydrolytic action completes;
4) this mixed solution is concentrated and is acidified to water layer pH value and equal 3, after filtration by Separation of Solid and Liquid;
5) white solid is obtained to 230mg carbamazepine derivative after methyl alcohol (Methanol, MeOH) recrystallization, productive rate is 48%.
Similarly, can obtain suc as formula the analog shown in (III) be only-CH of its difference 2the difference of-number.
Utilize Bruker Avance III plus 400 MHz to carry out NMR (Nuclear Magnetic Resonance) spectrum scanning to carbamazepine derivative, interior mark adopts TMS.Result is as follows: 1h NMR (DMSO-d6,400MHz): 12.04 (s, 1H), 7.37-7.45 (m, 3H), 7.29-7.35 (m, 2H), 5.53 (s, 1H), 3.98 (t, 2H, j=6.4 Hz), 2.28 (t, 2H, j=7.2 Hz), 1.63-1.75 (m, 4H).Be characterized by the carbamazepine derivative shown in formula (III).
Utilize Chromatography/Mass Spectrometry technology (LCMS) to carry out Analysis and Identification to the derivant obtaining, instrument is the series connection level Four bar mass spectrometer LC/MSD1200 series of Agilent company, and ion gun adopts positive ion or negative ionization pattern.Chromatographic column specification is: and Welchrom XB-C18 (50 × 4.6 mm, m), column temperature is 30 DEG C to 5 μ, and flow velocity is 1.5 mL/min, and mobile phase is that acetonitrile-water ratio is 5%-60%.
LCMS result shows: purity 99.2%; Retention time is 2.769 min; Molecular weight 352; Molion is: 353 (M+1).
bSA-carbamazepine derivative is immunogenic synthetic
Immunogene is by BSA and carbamazepine Tong Guo – O-(CH 2) 4-COO-group is formed by connecting, and concrete synthetic method is as follows:
1) bovine serum albumin(BSA) (Bovine Serum Albumin, BSA) (200 mg) is dissolved in to 50 ml 0.2 M, in the phosphate buffer of pH 8.5;
2) following chemicals is joined to stirring and dissolving in small beaker: carbamazepine derivative, 3.5 ml dimethylformamide (dimethylformamide that 200 mg are synthetic, DMF), 3.5 ml ethanol, 7.0 ml 10mM, the kaliumphosphate buffer of pH 5.0,200 mg 1-ethyl-3-(3-dimethylaminopropyl) carbodiimides, 50 mg N-hydroxy thiosuccinimide (N-hydroxysuccinimide, Sulfo-NHS), by these chemicals at room temperature stirring and dissolving react 30 min;
3) solution having dissolved is dropped in BSA solution, and stir and spend the night at 2～8 DEG C, obtain antigen; Synthetic antigen is carried out to purifying through dialysis, obtain carbamazepine immunogene.
the preparation of anti-carbamazepine specific antibody
Adopt conventional method Dispersal risk, roughly step is as follows:
Synthetic carbamazepine immunogene is diluted to 1.0 mg/ml with PBS, then mixes with Freund's complete adjuvant with the antigenic solution of 1.0 ml, rabbit is injected;
After 2～3 weeks, then rabbit is injected once with the identical antigenic solution of 1.0 ml and incomplete Freund's adjuvant, afterwards every surrounding once, totally twice, the antibody titer of acquisition is about 1:3000.
carbamazepine ELISA inspection
The antibody that employing makes carries out the ELISA inspection of carbamazepine.
This inspection is to utilize competitive immunization analytic approach to measure the carbamazepine content in liquid sample.
Carbamazepine in sample and the carbamazepine derivative of coupling (HRP-carbamazepine derivative enzyme conjugates) competition is in conjunction with being coated on the limited site on antibody in elisa plate.If be not almost with or without carbamazepine in liquid sample, the carbamazepine derivative of HRP enzyme coupling will be combined by the antibody in ELISA Plate.Contrary, if contain the carbamazepine of a large amount of or some in liquid sample, enzyme-carbamazepine derivative couplet will reduce and the combination of antibody so, thereby color signal is weakened.Therefore the carbamazepine content in absorbance and liquid sample that, inspection produces is inversely proportional to.Its dose-effect curve as shown in Figure 1.
the inspection of carbamazepine homogeneous enzyme immunoassay
The antibody that employing makes carry out carbamazepine EMIT(Enzyme Multiplied Immunoassay Technique, enzyme connection expands immunoassays) inspection.
This inspection is a kind of competitive reaction, and the carbamazepine of being combined with antibody in reaction system does not need to separate by solid phase with free carbamazepine.The ultimate principle of this inspection is, carbamazepine free in liquid sample is at war with to the binding site of specific antibody with the carbamazepine derivative being coupled on glucose-6-phosphate dehydrogenase (G6PD) (Glucose-6-Phosphate Dehydrogenase, G6PDH).The carbamazepine enzyme conjugates that the emulative replacement of carbamazepine in liquid sample is combined with antibody, and its binding site from antibody is discharged, thus make enzyme activity recovery.Therefore, in liquid sample, the content of carbamazepine is more, and free carbamazepine derivative-G6PDH enzyme conjugates is just more, thereby can obtain stronger signal.
The dose-effect curve that its homogeneous phase immunity inspection obtains as shown in Figure 2.
interfering effects of drug test
Choose 30 kinds of common compounds and medicine, adjusting its concentration is 10.0 μ g/ml, carries out interference test mensuration, and test findings is as shown in the table:
ID# Compound title Be equivalent to the concentration (μ g/ml) of carbamazepine
1 Acetylsalicylic acid < 0.1
2 Amytal < 0.1
3 Ampicillin < 0.1
4 Phenyl ethylamine < 0.1
5 Caffeine < 0.1
6 Bent < 0.1
7 Chlorpromazine < 0.1
8 Chlordiazepoxide < 0.1
9 D-crystal methamphetamine < 0.1
10 Fenoprofen < 0.1
11 Gemfibrozil < 0.1
12 Gentianic acid < 0.1
13 Dihydrocodeinone < 0.1
14 Brufen < 0.1
15 Imipramine < 0.1
16 (L)-ephedrine < 0.1
17 Lidocaine < 0.1
18 Naproxen < 0.1
19 Niacinamide < 0.1
20 Penicillin < 0.1
21 Phyenlephrinium < 0.1
22 Phenylpropanolamine < 0.1
23 Procainamide < 0.1
24 Procaine < 0.1
25 Quinindium < 0.1
26 The U.S. acid of assistant < 0.1
27 Ecgonine methyl ester < 0.1
28 Ecgonine < 0.1
29 Stable < 0.1
30 Cotinine < 0.1
By the method for carbamazepine ELISA inspection, above-claimed cpd is carried out to multiple hole mensuration, result is all negative.Visible, antibody of the present invention is anti-carbamazepine specific antibody.

Claims (7)

1. a method for detecting carbamazepine for non-diagnostic purpose, comprises the following steps:
1) sample to be tested is contacted with anti-carbamazepine specific antibody;
2) according to the combination situation of the material in sample to be tested and antibody, the content of carbamazepine in judgement sample,
Wherein anti-carbamazepine specific antibody is obtained by carbamazepine immunogen immune animal, and the immunogenic structural formula of described carbamazepine is as shown in (I):
Figure 201110049830X100001DEST_PATH_IMAGE002
In formula, R Wei – O-(CH 2) n-COO-, n is the integer between 1 to 20, carrier has immunogenicity.
2. the method for detecting carbamazepine of non-diagnostic purpose according to claim 1, is characterized in that: carrier is for having immunogenic protein.
3. the method for detecting carbamazepine of non-diagnostic purpose according to claim 1, is characterized in that: R Wei – O-(CH 2) 4-COO-.
4. the method for detecting carbamazepine of non-diagnostic purpose according to claim 1, is characterized in that: step 2) the inspection-free determination method of use enzyme.
5. the method for detecting carbamazepine of non-diagnostic purpose according to claim 4, is characterized in that: the inspection-free determination method of enzyme is homogeneous EIA method or enzyme-linked immunosorbent assay method.
6. the method for detecting carbamazepine of non-diagnostic purpose according to claim 1, is characterized in that: sample to be tested is physiology sample.
7. the method for detecting carbamazepine of non-diagnostic purpose according to claim 6, is characterized in that: physiology sample is blood sample.
CN201110049830.XA 2011-03-02 2011-03-02 Method for detecting carbamazepine Active CN102183659B (en)

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CN201110049830.XA CN102183659B (en) 2011-03-02 2011-03-02 Method for detecting carbamazepine
US13/069,181 US8569000B2 (en) 2011-03-02 2011-03-22 Immunoassays using antibodies specific to carbamazepine
US13/069,192 US8563713B2 (en) 2011-03-02 2011-03-22 Antibodies specific to carbamazepine

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Publication number Priority date Publication date Assignee Title
CN102507917A (en) * 2011-11-01 2012-06-20 四川金域医学检验中心有限公司 Valproic acid homogeneous-phase enzyme immunity rapid detection kit
CN102768284B (en) * 2012-08-01 2015-05-06 苏州博源医疗科技有限公司 Preparation method of immunodetection reagent of carbamazepine homogeneous enzyme
CN114671809A (en) * 2020-12-25 2022-06-28 苏州博源医疗科技有限公司 Oxcarbazepine derivative, immunogen, anti-oxcarbazepine specific antibody, preparation method and application thereof
CN113045643B (en) * 2021-03-10 2022-05-10 杭州隆基生物技术有限公司 Carbamazepine antigen and preparation method thereof

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4058511A (en) * 1976-01-12 1977-11-15 Syva Company Tegretol antigens and antibodies
CN1616433A (en) * 2004-09-20 2005-05-18 俞锋 Carbamazepine medicine and its preparing method
CN1767833A (en) * 2003-04-01 2006-05-03 诺瓦提斯公司 Use of carbamazepine derivatives for the treatment of agitation in dementia patients

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20060046273A1 (en) * 2004-08-27 2006-03-02 Lin-Zhi International Inc. Homogeneous enzyme immunoassay for oral fluid

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4058511A (en) * 1976-01-12 1977-11-15 Syva Company Tegretol antigens and antibodies
CN1767833A (en) * 2003-04-01 2006-05-03 诺瓦提斯公司 Use of carbamazepine derivatives for the treatment of agitation in dementia patients
CN1616433A (en) * 2004-09-20 2005-05-18 俞锋 Carbamazepine medicine and its preparing method

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