CN102183659A - Method for detecting carbamazepine - Google Patents

Method for detecting carbamazepine Download PDF

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CN102183659A
CN102183659A CN201110049830XA CN201110049830A CN102183659A CN 102183659 A CN102183659 A CN 102183659A CN 201110049830X A CN201110049830X A CN 201110049830XA CN 201110049830 A CN201110049830 A CN 201110049830A CN 102183659 A CN102183659 A CN 102183659A
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carbamazepine
sample
detection method
antibody
enzyme
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CN102183659B (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 US13/069,181 priority patent/US8569000B2/en
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Abstract

The invention discloses a method for detecting carbamazepine. The method comprises the following steps of: contacting a sample to be detected and a carbamazepine specificity antibody; and determining the content of the carbamazepine in the sample according to combination of a substance in the sample to be detected and the antibody, wherein the carbamazepine specificity antibody is obtained from a carbamazepine immunogen immune animal. The detection method is high in specificity; and by the method, the carbamazepine and the content of the carbamazepine in the sample to be detected can be determined accurately.

Description

A kind of carbamazepine detection method
Technical field
The present invention relates to a kind of detection method, particularly a kind of carbamazepine detection method.
Background technology
Carbamazepine (5 H-dibenzo[ b, f] azepine-5-carboxamide, 5H-dibenzo [b, f] azatropylidene-5-formamide), 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: possible life-threatening allergic reaction; May cause skin and internal organs grievous injury to trigeminal neuralgia is poisonous.Therefore during treating, monitor extremely important to the patients'blood levels of drugs.
Summary of the invention
The object of the present invention is to provide a kind of carbamazepine detection method.
The technical solution used in the present invention is:
A kind of carbamazepine detection method may further comprise the steps:
1) sample to be tested is contacted with anti-carbamazepine specific antibody;
2) according to the combine situation of the material in the sample to be tested with antibody, the content of carbamazepine in the judgement sample,
Wherein anti-carbamazepine specific antibody is obtained by carbamazepine immunogen immune animal, and the immunogenic structural formula of described carbamazepine is shown in (I):
Figure 201110049830X100002DEST_PATH_IMAGE004
In the formula, R is a linking group, and carrier has immunogenicity.
Preferably, carrier is for having immunogenic protein.
R Wei – O-(CH 2) n-COO-, n are the integers between 1 to 20, R Xuan Wei – O-(CH 2) 4-COO-.
Step 2) uses the inspection-free determination method of enzyme.The inspection-free determination method of enzyme is homogeneous EIA method or enzyme-linked immunosorbent assay method.
Sample to be tested is the physiology sample, is preferably blood sample.
Detection method of the present invention, the specificity height can determine whether to exist in the sample to be tested carbamazepine accurately, can determine the content of carbamazepine equally exactly.
Description of drawings
Fig. 1 is a carbamazepine ELISA detection reaction curve;
Fig. 2 is a carbamazepine homogeneous enzyme immunoassay response curve.
Embodiment
A kind of carbamazepine detection method may further comprise the steps:
1) sample to be tested is contacted with anti-carbamazepine specific antibody;
2) according to the combine situation of the material in the sample to be tested with antibody, the content of carbamazepine in the judgement sample,
Wherein anti-carbamazepine specific antibody is obtained by carbamazepine immunogen immune animal, and the immunogenic structural formula of described carbamazepine is shown in (I):
Figure 12768DEST_PATH_IMAGE004
In the formula, R is a linking group, and carrier has immunogenicity.
Preferably, carrier is for having immunogenic protein.Though the immunogenic material that possesses that other are enough big also can be used as carrier, generally selects for use 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 a basic general knowledge.
R Wei – O-(CH 2) n-COO-, n are the integers between 1 to 20, R Xuan Wei – O-(CH 2) 4-COO-.
Below in conjunction with embodiment, further specify the present invention.
The carbamazepine derivative chemical constitution of 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:
1) accurately takes by weighing nitroso-the disulfonic acid potassium ((KSO of 2.5 g 3) 2NO, Fremy (Fremy ' s salt), 9.32 mmol) and 1.8 g Na 2HPO 4(12.7 mmol) puts into beaker, adds the dissolving of 95ml distilled water, regulates pH to 7.22; Take by weighing 0.55g compound 1 (12.76 mmol) to the 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 the acetone soln, continue to stir 10 minutes, filter, and place refrigerator overnight;
4) solution that will spend the night concentrates through the argon gas Rotary Evaporators, extracts with the 500ml ether, after having extracted, with the organic phase solvent evaporation;
5) evaporation residue is carried out the rapid column chromatography purifying with the bonded silica gel post, (Tetraethoxypropane, TEAC) solution is after ether (Diethyl ether, Et for hexane (Hexane) that eluant, eluent mixes for the 4:1 ratio and tetraethyl ammonium chloride(TEAC 2O) the peony crystal powder shape material that obtains of recrystallization is imido grpup quinone compounds 2(0.12g, 21%).
Synthesizing of compound 3:
Figure 201110049830X100002DEST_PATH_IMAGE012
1) accurately take by weighing 1.2 g compound 2(5.8 mmol) be dissolved in 50ml CHCl 3Solution is placed in the separating funnel;
2) take by weighing 2.5 sodium hydrosulfite (Na 2S 2O 4) (14.3 mmol) be dissolved in the 20 ml water and make solution;
3) in above-mentioned separating funnel, add excessive N a 2S 2O 4Solution, vibrating gently to the color of organic solution layer becomes yellow by redness, and standing demix;
4) with water CHCl 3Carry out extract and separate, the organic phase that obtains is used Na again 2SO 4Carry out absorbent drying, the method by rotary distillation is with solvent evaporation.
5) through CHCl 3It is compound 3 (1.1g, 92%) that residue after the extraction carries out the pistac crystal that recrystallization obtains.
Synthesizing of compound 4:
Figure 201110049830X100002DEST_PATH_IMAGE014
1) accurately takes by weighing compound 3 to the 10 ml CHCl of 1.1g 3In the solution, add again 1ml triethylamine (Triethylamine, TEA);
2) (tert-butylchlorodimethylsilane, TBDMSCl) (15.2 mmol) stirred 3 days under room temperature, again with solvent evaporation to add 2 g tert-butyl chloro-silicanes in this solution;
3) add water-soluble separating, with chloroform (CHCl 3) carry out extract and separate, the organic phase Na that obtains 2SO 4Absorbent drying, the method by rotary distillation is with solvent evaporation.
Slightly carry compound 4 through what said process can obtain 1.6g.
Synthesizing of compound 5:
Figure 201110049830X100002DEST_PATH_IMAGE016
1) takes by weighing the CHCl of compound 4 to 10 ml of 1.6 g 3In the solution, add 2 ml TMSOCN(4.95 mmol again), under room temperature, stirred 2 days, with solvent evaporation;
2) add water-soluble separating, use CHCl 3Extraction, the organic phase that obtains is washed with salt solution earlier, adds Na again 2SO 4Carry out drying, pass through the method for rotary distillation at last solvent evaporation.
Slightly carry compound 5 through what said process finally obtained 1.6 g yellow.
Synthesizing of compound 6:
Figure 201110049830X100002DEST_PATH_IMAGE018
1) take by weighing 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) dissolving, after stirring 4 hours under the room temperature, with solvent evaporation;
2) add dissolved in distilled water, with ethyl acrylate (ethyl acrylate, EA) extract and separate, the organic phase Na that obtains 2SO 4Carry out drying, by rotary distillation with solvent evaporation;
3) behind crude extract process chromatographic column (EA/PE(ethyl acrylate/tygon)=1:1) purifying, obtain the compound 6 of 1.0g.(6 productive rate is 75% from compound 3 to compound)
Synthesizing of compound 7:
Figure 201110049830X100002DEST_PATH_IMAGE020
1) accurately take by weighing the compound 6(4.0 mmol of 1.0 g) join 30 ml vinyl cyanide (Acrylonitrile, ACN) in, 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 under the room temperature and spend the night;
2) solution concentrates through the vacuum filtration method, uses ethyl acetate (Acetoacetate, EtOAc) extract and separate again;
3) organic phase that obtains adds Na 2SO 4Carry out drying, again through vacuumizing filtration;
4) slightly carry compound and carry out the flash chromatography purifying, EA and PA solution E A/PE(ethyl acrylate/tygon that eluant, eluent mixes for the 1:3 ratio with the silica gel keys zygostyle), obtain 1.1 g white solid compounds 7 at last, productive rate is 76%.
Similarly, by changing in the compd A-CH 2-quantity, can obtain the analog of compound 7.
Synthesizing of carbamazepine derivative:
Figure 201110049830X100002DEST_PATH_IMAGE022
1) take by weighing 1.1 g compound 7(3.0 mmol) to 20 ml tetrahydrofurans (Tetrahydrofuran, THF) middle dissolving;
2) take by weighing the lithium hydroxide (LiOHH that contains water of crystallization of 0.48 g again 2O) (11.8mmol) to 10ml distilled water, dissolve;
3) above-mentioned two kinds of solution are mixed, stirring is after 6 hours down in 50 ℃, and TLC demonstration hydrolytic action is finished;
4) this mixed solution is concentrated and is acidified to water layer pH value equal 3, after filtration with Separation of Solid and Liquid;
5) (Methanol MeOH) obtains the 230mg carbamazepine derivative behind the recrystallization, productive rate is 48% through methyl alcohol with white solid.
Similarly, can obtain suc as formula the analog shown in (III), its difference only is-CH 2The difference of-number.
Utilize Bruker Avance III plus 400 MHz that carbamazepine derivative is carried out NMR (Nuclear Magnetic Resonance) spectrum scanning, interior mark adopts TMS.The 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), and 1.63-1.75 (m, 4H).Be characterized by the carbamazepine derivative shown in the formula (III).
Utilize chromatogram/mass-spectrometric technique (LCMS) that the derivant that obtains is carried out Analysis and Identification, 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.The chromatographic column specification is: Welchrom XB-C18 (50 * 4.6 mm, 5 μ m), and column temperature is 30 ℃, and flow velocity is 1.5 mL/min, and moving phase is 5%-60% for the acetonitrile-water ratio.
LCMS result shows: purity 99.2%; Retention time is 2.769 min; Molecular weight 352; Molion is: 353 (M+1).
The 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) with bovine serum albumin(BSA) (Bovine Serum Albumin, BSA) (200 mg) is dissolved in 50 ml, 0.2 M, in the phosphate buffer of pH 8.5;
2) following chemicals is joined stirring and dissolving in the 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), with these chemicals at room temperature stirring and dissolving react 30 min;
3) will dissolve good drips of solution and add in the BSA solution, and under 2～8 ℃, stir and spend the night, obtain antigen; Synthetic good antigen is carried out purifying through dialysis, obtain the carbamazepine immunogene.
The preparation of anti-carbamazepine specific antibody
Adopt conventional method to prepare antibody, roughly step is as follows:
With PBS synthetic carbamazepine immunogene is diluted to 1.0 mg/ml, the antigenic solution with 1.0 ml mixes with Freund's complete adjuvant then, and rabbit is injected;
After 2～3 weeks, again to the rabbit injection once with the identical antigenic solution of 1.0 ml and incomplete Freund, afterwards every around once, totally twice, the antibody titer of acquisition is about 1:3000.
Carbamazepine ELISA check
The antibody that employing makes carries out the ELISA check of carbamazepine.
This check is to utilize the competitive immunization analytic approach to measure carbamazepine content in the liquid sample.
Carbamazepine in the sample combines with the carbamazepine derivative of coupling (HRP-carbamazepine derivative enzyme conjugates) competition and is coated on the limited site on the antibody in the elisa plate.If almost there is not or do not have carbamazepine in the liquid sample, the carbamazepine derivative of HRP enzyme coupling will with the antibodies in the ELISA Plate.Opposite, if contain the carbamazepine of a large amount of or some in the liquid sample, enzyme-carbamazepine derivative couplet will reduce and the combining of antibody so, thereby color signal is weakened.Therefore, the absorbance of check generation and the carbamazepine content in the liquid sample are inversely proportional to.Its dose-effect curve as shown in Figure 1.
The check of carbamazepine homogeneous enzyme immunoassay
The antibody that employing makes carry out carbamazepine EMIT(Enzyme Multiplied Immunoassay Technique, enzyme connection enlarges immunoassays) check.
This check is a kind of competitive reaction, does not need to separate by solid phase with the carbamazepine that dissociates with the carbamazepine of antibodies in the reaction system.The ultimate principle of this check is, (Glucose-6-Phosphate Dehydrogenase, G6PDH) carbamazepine derivative on is at war with to the binding site of specific antibody carbamazepine free in the liquid sample with being coupled at glucose-6-phosphate dehydrogenase (G6PD).The carbamazepine enzyme conjugates of emulative replacement of the carbamazepine in the liquid sample and antibodies, and its binding site from antibody is discharged, thus make enzyme recover active.Therefore, the content of carbamazepine is many more in the liquid sample, and free carbamazepine derivative-G6PDH enzyme conjugates is just many more, thereby can obtain stronger signal.
The dose-effect curve that its homogeneous phase immunity inspection obtains as shown in Figure 2.
The medicine interference test
Choose 30 kinds of common compounds and medicine, adjusting its concentration is 10.0 μ g/ml, carries out interference test and measures, and test findings is as shown in the table:
ID# The 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 The 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 The ecgonine methyl ester < 0.1
28 Ecgonine < 0.1
29 Stable < 0.1
30 Cotinine < 0.1
By the method for carbamazepine ELISA check above-claimed cpd is carried out multiple hole and measure, the result is all negative.As seen, antibody of the present invention is anti-carbamazepine specific antibody.

Claims (8)

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

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US13/069,192 US8563713B2 (en) 2011-03-02 2011-03-22 Antibodies specific to carbamazepine
US13/069,181 US8569000B2 (en) 2011-03-02 2011-03-22 Immunoassays using antibodies specific to carbamazepine

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Cited By (4)

* Cited by examiner, † Cited by third party
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
CN102768284A (en) * 2012-08-01 2012-11-07 苏州博源医疗科技有限公司 Immunodetection reagent of carbamazepine homogeneous enzyme and detection method thereof
CN113045643A (en) * 2021-03-10 2021-06-29 杭州隆基生物技术有限公司 Carbamazepine antigen and preparation method thereof
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

Citations (4)

* 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
US20060046273A1 (en) * 2004-08-27 2006-03-02 Lin-Zhi International Inc. Homogeneous enzyme immunoassay for oral fluid
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

Patent Citations (4)

* 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
US20060046273A1 (en) * 2004-08-27 2006-03-02 Lin-Zhi International Inc. Homogeneous enzyme immunoassay for oral fluid
CN1616433A (en) * 2004-09-20 2005-05-18 俞锋 Carbamazepine medicine and its preparing method

Cited By (5)

* Cited by examiner, † Cited by third party
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
CN102768284A (en) * 2012-08-01 2012-11-07 苏州博源医疗科技有限公司 Immunodetection reagent of carbamazepine homogeneous enzyme and detection method thereof
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
CN113045643A (en) * 2021-03-10 2021-06-29 杭州隆基生物技术有限公司 Carbamazepine antigen and preparation method thereof

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