CN103487517B - Determination method for theophylline in doxofylline injection preparation - Google Patents
Determination method for theophylline in doxofylline injection preparation Download PDFInfo
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- CN103487517B CN103487517B CN201310392241.0A CN201310392241A CN103487517B CN 103487517 B CN103487517 B CN 103487517B CN 201310392241 A CN201310392241 A CN 201310392241A CN 103487517 B CN103487517 B CN 103487517B
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- theophylline
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- ZFXYFBGIUFBOJW-UHFFFAOYSA-N theophylline Chemical compound O=C1N(C)C(=O)N(C)C2=C1NC=N2 ZFXYFBGIUFBOJW-UHFFFAOYSA-N 0.000 title claims abstract description 108
- 229960000278 theophylline Drugs 0.000 title claims abstract description 54
- 229960004483 doxofylline Drugs 0.000 title claims abstract description 36
- HWXIGFIVGWUZAO-UHFFFAOYSA-N doxofylline Chemical compound C1=2C(=O)N(C)C(=O)N(C)C=2N=CN1CC1OCCO1 HWXIGFIVGWUZAO-UHFFFAOYSA-N 0.000 title claims abstract description 36
- 238000002360 preparation method Methods 0.000 title claims abstract description 31
- 238000002347 injection Methods 0.000 title claims abstract description 14
- 239000007924 injection Substances 0.000 title claims abstract description 14
- 238000000034 method Methods 0.000 title abstract description 7
- 239000000243 solution Substances 0.000 claims abstract description 36
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical group CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims abstract description 12
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims abstract description 8
- 239000008351 acetate buffer Substances 0.000 claims abstract description 7
- 238000010828 elution Methods 0.000 claims abstract description 7
- 238000004128 high performance liquid chromatography Methods 0.000 claims abstract description 7
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims abstract description 6
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 claims abstract description 4
- 229960000583 acetic acid Drugs 0.000 claims abstract description 4
- 239000012362 glacial acetic acid Substances 0.000 claims abstract description 4
- 239000001632 sodium acetate Substances 0.000 claims abstract description 4
- 235000017281 sodium acetate Nutrition 0.000 claims abstract description 4
- 239000000945 filler Substances 0.000 claims abstract description 3
- YTJSFYQNRXLOIC-UHFFFAOYSA-N octadecylsilane Chemical compound CCCCCCCCCCCCCCCCCC[SiH3] YTJSFYQNRXLOIC-UHFFFAOYSA-N 0.000 claims abstract description 3
- 239000000377 silicon dioxide Substances 0.000 claims abstract description 3
- 238000012360 testing method Methods 0.000 claims description 39
- 239000007788 liquid Substances 0.000 claims description 19
- 238000003556 assay Methods 0.000 claims description 12
- 239000013558 reference substance Substances 0.000 claims description 9
- 238000007689 inspection Methods 0.000 claims description 3
- 238000004811 liquid chromatography Methods 0.000 claims description 3
- 239000000825 pharmaceutical preparation Substances 0.000 claims description 2
- 238000005464 sample preparation method Methods 0.000 claims description 2
- 239000007787 solid Substances 0.000 claims description 2
- 239000003814 drug Substances 0.000 abstract description 6
- 238000001514 detection method Methods 0.000 abstract description 5
- 239000012535 impurity Substances 0.000 abstract description 5
- 239000012085 test solution Substances 0.000 abstract description 4
- 238000010812 external standard method Methods 0.000 abstract description 2
- 230000014759 maintenance of location Effects 0.000 abstract description 2
- 239000000523 sample Substances 0.000 description 24
- 239000012071 phase Substances 0.000 description 13
- 239000000047 product Substances 0.000 description 10
- 229940079593 drug Drugs 0.000 description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 5
- 239000012467 final product Substances 0.000 description 4
- 238000011084 recovery Methods 0.000 description 4
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 238000010521 absorption reaction Methods 0.000 description 3
- 239000002253 acid Substances 0.000 description 3
- 239000003513 alkali Substances 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- 230000006378 damage Effects 0.000 description 2
- 238000009472 formulation Methods 0.000 description 2
- 238000005286 illumination Methods 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 230000003647 oxidation Effects 0.000 description 2
- 238000007254 oxidation reaction Methods 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 210000002460 smooth muscle Anatomy 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 239000012086 standard solution Substances 0.000 description 2
- PFWLFWPASULGAN-UHFFFAOYSA-N 7-methylxanthine Chemical compound N1C(=O)NC(=O)C2=C1N=CN2C PFWLFWPASULGAN-UHFFFAOYSA-N 0.000 description 1
- 235000007926 Craterellus fallax Nutrition 0.000 description 1
- 240000007175 Datura inoxia Species 0.000 description 1
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 1
- 241001597008 Nomeidae Species 0.000 description 1
- 102000004861 Phosphoric Diester Hydrolases Human genes 0.000 description 1
- 108090001050 Phosphoric Diester Hydrolases Proteins 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 208000006673 asthma Diseases 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 235000019636 bitter flavor Nutrition 0.000 description 1
- 210000000621 bronchi Anatomy 0.000 description 1
- 229940124630 bronchodilator Drugs 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 238000013461 design Methods 0.000 description 1
- 230000001066 destructive effect Effects 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- 238000003255 drug test Methods 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 230000000977 initiatory effect Effects 0.000 description 1
- 238000011835 investigation Methods 0.000 description 1
- 238000012417 linear regression Methods 0.000 description 1
- 239000007791 liquid phase Substances 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 230000009965 odorless effect Effects 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- 230000001590 oxidative effect Effects 0.000 description 1
- 239000003182 parenteral nutrition solution Substances 0.000 description 1
- 230000002040 relaxant effect Effects 0.000 description 1
- 239000012488 sample solution Substances 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 210000000329 smooth muscle myocyte Anatomy 0.000 description 1
- 230000001954 sterilising effect Effects 0.000 description 1
- 230000001629 suppression Effects 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
Abstract
The invention belongs to the field of medicine detection, and particularly relates to a determination method for theophylline in a doxofylline injection preparation. The invention aims to provide the determination method which performs determining by virtue of high performance liquid chromatography and can be used for authentication and content determination for theophylline in the doxofylline injection preparation, wherein the detection conditions are as follows: octadecylsilane chemically bonded silica is used as a filler; a mobile phase A is acetate buffer solution; a mobile phase B is acetonitrile, wherein the acetate buffer solution contains 0.005-0.1 mol/L of sodium acetate; the pH value is adjusted to 1.5-7.5 by glacial acetic acid; a mobile phase is prepared from the mobile phase A and the mobile phase B in a volume ratio of (70-95): (30-5); or the two mobile phases A and B are subjected to gradient elution; a detection wavelength is 265-275 nm; and the number of theoretical plates is not less than 5000 counted by the peaks of theophylline. If a chromatographic peak equal to the retention time of theophylline exists in the chromatogram of test solution, the content of theophylline in the test solution can be calculated by a peak area according to an external standard method, and theophylline impurity in the doxofylline injection preparation can be simply, rapidly and accurately determined.
Description
Technical field
The invention belongs to drug tests, be specifically related to the assay method of theophylline in doxofylline ejection preparation.
Background technology
Doxofylline (Doxofylline) is the derivant of methyl xanthine, is a kind of bronchodilator, can directly acts on bronchus, lax bronchial smooth muscle.By effects such as the phosphodiesterases in suppression smooth muscle cell, relaxing smooth muscle, thus reach the effect suppressing asthma.Compare with theophylline, have identical effect, but spinoff obviously to be lacked.
Doxofylline developed listing in 1980 by Italian company ABC.Through constantly researching and developing, the existing formulation compared with horn of plenty on Clinical practice: oral administration solution, tablet, capsule, granule, the large formulation such as small-capacity injection preparation, injection freeze-dried powder.
Doxofylline, chemical name is: 1,3-dimethyl-7-(1,3-dioxy cyclopentyl-2-base) methyl-3,7-dihydro-1H-purine-2,6-diketone.Molecular formula: C
11h
14n
4o
4; Molecular weight: 266.26.White, needle-shaped crystals or crystalline powder; Odorless, mildly bitter flavor.Easily molten in chloroform, slightly soluble in water, ethanol or acetone, almost insoluble in ether.This product stability is better, can tolerate pressure sterilizing, be applicable to making parenteral solution.
Theophylline is the synthesis initiation material of doxofylline, in the quality standard of existing doxofylline and preparation thereof, does not all control it.The present inventor, for providing the assay method of theophylline in a kind of detection level doxofylline ejection preparation, can be used for differentiating and assay.
Summary of the invention
Technical matters solved by the invention is to provide the assay method of theophylline in a kind of doxofylline ejection preparation.Assay method of the present invention adopts high performance liquid chromatography to measure, and can be used for differentiating and assay.
Testing conditions is as follows: take octadecylsilane chemically bonded silica as filling agent.
Mobile phase A: acetate buffer; Mobile phase B: acetonitrile; Wherein, acetate buffer is 0.01mol/L containing sodium acetate 0.005mol/L to 0.1mol/L(preferred concentration), be that 1.5 to 7.5(preferable ph is for 3.8 with glacial acetic acid adjust ph);
With mobile phase A: Mobile phase B is with following volume ratio 70 ~ 95:30 ~ 5 preparation mobile phase; Or above-mentioned two kinds of mobile phase A, B adopt following condition of gradient elution as mobile phase;
Survey wavelength is 265nm-275nm; Preferred 271nm.
Number of theoretical plate calculates by theophylline peak and is not less than 5000.
Sample preparation methods:
1) preparation of reference substance solution: it is appropriate that precision takes theophylline reference substance, adds mobile phase and dissolves and be diluted to every 1ml about containing the solution of theophylline 1 μ g, product solution in contrast;
2) preparation of need testing solution: get doxofylline ejection preparation as test sample: if doxofylline ejection preparation is liquid preparation, then directly get inspection product as need testing solution; If doxofylline ejection preparation is solid pharmaceutical preparation, the solution be mixed with containing doxofylline 10mg/ml is need testing solution.
Precision measures contrast solution and each 20 μ l of need testing solution, respectively injection liquid chromatography, record chromatogram.
If if any the chromatographic peak consistent with theophylline retention time in the chromatogram of need testing solution, by external standard method with calculated by peak area, Determination of Theophylline Concentration in test sample can be obtained, for the theophylline impurity in easy, quick, Accurate Determining doxofylline ejection preparation provides a kind of selection.
Accompanying drawing explanation
Fig. 1 adopts isorheic elution doxofylline liquid drugs injection theophylline to measure contrast liquid HPLC chromatogram.
Fig. 2 adopts isorheic elution doxofylline liquid drugs injection theophylline working sample liquid HPLC chromatogram.
Fig. 3 adopts gradient elution doxofylline liquid drugs injection theophylline to measure contrast liquid HPLC chromatogram.
Fig. 4 adopts gradient elution doxofylline liquid drugs injection theophylline working sample liquid HPLC chromatogram.
Embodiment
Below for the method for measuring of theophylline in doxofylline ejection preparation of the present invention is investigated
One, test liquid preparation
It is appropriate that theophylline reference substance test liquid gets theophylline reference substance, and dilute with water makes the solution containing 1.0 μ g/ml in every 1ml.
Sample test liquid gets doxofylline liquid drugs injection sample, and (producer: Chengdu Baiyu Pharmaceutical Technology Co., Ltd., lot number: 20101201) appropriate, as sample solution.
Two, the selection of chromatographic condition
Measure wavelength theophylline contrast liquid and all have larger absorption in 265nm to 275nm wavelength coverage, wherein there is absorption maximum at 271nm place.Therefore this mensuration can choose determined wavelength is 265nm-275nm; Preferred 271nm.
The selection of flow phase system:
Mobile phase A: acetate buffer (containing sodium acetate 0.01mol/L, glacial acetic acid regulates pH to be 3.8): Mobile phase B: acetonitrile.With A:B(90:10) be mobile phase, get above-mentioned contrast and sample test liquid sample introduction mensuration, see Fig. 1 and Fig. 2.Theophylline goes out peak at about 10min, but doxofylline appearance time is after 45min, and whole mensuration is consuming time oversize, is unfavorable for that production efficiency improves.
On this basis, design gradient elution program, by A:B(90:10) after wash-out 10min (now theophylline peak wash-out substantially), improve the ratio of organic phase B, enable doxofylline by quick wash-out, to wash-out, namely return original ratio, for carrying out lower pin preparation of determine.Elution program is as follows:
Get above-mentioned contrast and sample test liquid sample introduction mensuration, see Fig. 3 and Fig. 4.In sample test liquid collection of illustrative plates, visible doxofylline is at about 20min by wash-out, and whole system, at 35min, improves determination efficiency, is therefore preferably condition determination.
Three, methodological study
1, linearly investigate
Precision takes theophylline reference substance, becomes the reference substance solution of a series of concentration with solvent dilution.According to above-mentioned chromatographic condition, precision measures each 10 μ l injection liquid chromatographies of variable concentrations reference substance solution respectively, and sample introduction measures, and the results are shown in Table 1.
Table 1 linear relationship test findings table
| Numbering | 1 | 2 | 3 | 4 | 5 | 6 |
| Theophylline concentration (μ g/ml) | 2.044 | 1.022 | 0.409 | 0.307 | 0.204 | 0.051 |
| Theophylline peak area | 143153 | 70329 | 28585 | 21595 | 14477 | 3333 |
Respectively with theophylline concentration C for horizontal ordinate, peak area A is ordinate, carries out linear regression, and calculate regression equation and related coefficient, do linear relationship chart, result is as follows: doxofylline regression equation is: A=69897C-115.6, correlation coefficient r=0.9999.
Linear test result shows: in 0.051 ~ 2.044 μ g/ml concentration range, and theophylline detects in good linear relationship.
2, quantitative limit records that theophylline is minimum is quantitatively limited to 0.26ng.
3, precision test
Get theophylline contrast solution, accurate absorption 20 μ l, according to above-mentioned chromatographic condition, continuous 6 sample introductions are to investigate sample introduction precision:
Table 2 sample introduction Precision test result
| Numbering | 1 | 2 | 3 | 4 | 5 | 6 | RSD |
| Peak area | 76448 | 76184 | 78546 | 74766 | 76166 | 76381 | 1.59% |
4, repeatability
Get 20101201 batch samples as test solution, precision measures 20 μ l, continuous sample introduction 6 times, record chromatogram, and calculates Determination of Theophylline Concentration.
Table 3 replica test result
| Numbering | 1 | 2 | 3 | 4 | 5 | 6 | RSD |
| Peak area | 7396 | 7394 | 7440 | 7475 | 7460 | 7536 | 0.72% |
| Content (%) | 0.0010 | 0.0010 | 0.0011 | 0.0011 | 0.0011 | 0.0011 | 0.72% |
Result shows that assay method precision is good.
5, accuracy test
Get theophylline standard items appropriate, dilute with water is into about the standard solution of every 1ml containing 1.132 μ g/ml; Precision measures standard solution 0.3ml, 0.5ml, 0.7ml and 20101201 batch sample 5ml and is diluted with water to 10ml respectively, successively as the recovery 80% concentration test solution, 100% concentration need testing solution, 120% concentration need testing solution, the parallel preparation of each concentration 3 parts; Each precision draws 20 μ l, and according to above-mentioned chromatographic condition sample introduction, record chromatogram, calculates the recovery.
Computing formula: the amount of bringing in sample=add content in the volume × sample of sample
The recovery (%)=(measured amount-sample amount of bringing into)/addition × 100%
Table 4 theophylline average recovery experiment investigation result table
Test findings shows: the method is used for theophylline and detects, and accuracy is good.
6, destructive test
In order to investigate the specificity of the above-mentioned chromatographic system tentatively determined further, intending the sample feeding analysis after destroying with acid, alkali, oxidation, high temperature, high light, investigating the separation case of main peak and impurity peaks.
Acid destruction need testing solution respectively precision measures this product 1ml, adds 2mol/L hydrochloric acid solution 1ml, places 1h, to obtain final product.
Alkali destruction need testing solution respectively precision measures this product 1ml, adds 2.0mol/L sodium hydroxide solution 0.5ml, places 30min, to obtain final product.
Oxidative demage need testing solution respectively precision measures this product 1ml, adds 30% superoxol 1ml, to obtain final product.
High temperature need testing solution respectively precision measures this product 10ml, evaporate to dryness, adds mobile phase dissolved residue and is diluted to 10ml, shaking up, to obtain final product.
High light destroys need testing solution this product after placing 50h under 4500Lux illumination.
Separately with method water intaking, carry out blank test.
Precision measures each 20 μ l injecting chromatographs of above-mentioned solution, record chromatogram.
Under this chromatographic system condition, blank solvent peak does not disturb theophylline inspection, each related substance and being effectively separated between catabolite with theophylline peak, does not disturb detecting of theophylline.The chemical depletions such as acid, alkali, oxidation make theophylline obviously increase, and the physical condition such as high temperature, illumination is very little on theophylline impact.
7, durability is investigated
According to the chromatographic condition drafted, column temperature is changed, to investigate the impact of testing conditions change on testing result.Adopt different liquid-phase chromatographic columns and liquid chromatograph to detect, measurement result, all without significant difference, shows that this method is durable.
Conclusion: by above-mentioned test, determines that the detection method of special impurities theophylline in this product is suitable for.
8, adopt preferred theophylline assay method, measure each batch sample Determination of Theophylline Concentration, the results are shown in Table 5.
Table 5 examination and test of products result
To sum up, employing assay method of the present invention can measure the theophylline impurity in doxofylline ejection preparation easy, fast, accurately.
Claims (2)
1. the assay method of theophylline in doxofylline ejection preparation, is characterized in that, adopts high performance liquid chromatography to measure;
Chromatographic condition is as follows: take octadecylsilane chemically bonded silica as filling agent;
Mobile phase A: acetate buffer; Mobile phase B: acetonitrile;
Wherein, acetate buffer contains sodium acetate 0.01mol/L, with glacial acetic acid adjust ph for 3.8;
Above-mentioned two kinds of mobile phase A, B adopt following condition of gradient elution as mobile phase;
Determined wavelength is 265nm-275nm;
Number of theoretical plate calculates by theophylline peak and is not less than 5000;
Sample preparation methods:
1) preparation of reference substance solution: it is appropriate that precision takes theophylline reference substance, adds mobile phase and dissolves and be diluted to every 1ml about containing the solution of theophylline 1 μ g, product solution in contrast;
2) preparation of need testing solution: get doxofylline ejection preparation as test sample: if doxofylline ejection preparation is liquid preparation, then directly get inspection product as need testing solution; If doxofylline ejection preparation is solid pharmaceutical preparation, solution containing doxofylline 10mg/ml should be mixed with as need testing solution;
Precision measures contrast solution and each 20 μ l of need testing solution, respectively injection liquid chromatography, record chromatogram.
2. the assay method of theophylline in doxofylline ejection preparation according to claim 1, is characterized in that: determined wavelength is 271nm.
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| CN111228518A (en) * | 2020-02-19 | 2020-06-05 | 无锡艾德美特生物科技有限公司 | Probe substrate for in vivo detection of CYP1A activity and application thereof |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101569603A (en) * | 2008-06-24 | 2009-11-04 | 黑龙江福和华星制药集团股份有限公司 | Doxofylline-contained liquid injection, preparation method and quality control method thereof |
| CN101647776A (en) * | 2009-09-02 | 2010-02-17 | 吴光彦 | Doxofylline venous injection with small volume as well as preparation method and quality control method thereof |
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2013
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101569603A (en) * | 2008-06-24 | 2009-11-04 | 黑龙江福和华星制药集团股份有限公司 | Doxofylline-contained liquid injection, preparation method and quality control method thereof |
| CN101647776A (en) * | 2009-09-02 | 2010-02-17 | 吴光彦 | Doxofylline venous injection with small volume as well as preparation method and quality control method thereof |
Non-Patent Citations (4)
| Title |
|---|
| Development and Validation of Same RP-HPLC Method for Separate Estimation of Theophylline and Doxofylline in Tablet Dosage Forms;AMIT KUMAR DE et al.;《Journal of Current Pharmaceutical Research》;20121231;第9卷(第1期);55-58 * |
| 人血浆中茶碱和多索茶碱的HPLC法测定;刘奕芳 等;《中国医药工业杂志》;20101231;第41卷(第2期);131-133 * |
| 多索茶碱及其片剂的高效液相色谱分析;刘春胜 等;《药学学报》;19961231;第31卷(第2期);156-160 * |
| 注射用多索茶碱有关物质和含量的HPLC测定法;沙吉达 等;《中国药事》;20061231;第20卷(第10期);616-618 * |
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| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
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| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant | ||
| C56 | Change in the name or address of the patentee | ||
| CP03 | Change of name, title or address |
Address after: 611130 Chengdu Wenjiang District, Sichuan Province, Chengdu Straits science and Technology Industry Development Zone, Chengdu Bai Yu pharmaceutical Limited by Share Ltd Patentee after: CHENGDU BAIYU PHARMACEUTICAL Co.,Ltd. Address before: 611130, Chengdu District, Sichuan, Wenjiang province Chengdu science and Technology Industrial Development Park on both sides of the Taiwan Straits, No. 433 west section of Willow Road Patentee before: CHENGDU BAIYU TECHNOLOGY PHARMACY Co.,Ltd. |
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| PE01 | Entry into force of the registration of the contract for pledge of patent right | ||
| PE01 | Entry into force of the registration of the contract for pledge of patent right |
Denomination of invention: Determination of theophylline in doxofylline injection Effective date of registration: 20210513 Granted publication date: 20150715 Pledgee: Bank of China Limited Chengdu Development Zone West sub branch Pledgor: CHENGDU BAIYU PHARMACEUTICAL Co.,Ltd. Registration number: Y2021980003590 |
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| PC01 | Cancellation of the registration of the contract for pledge of patent right | ||
| PC01 | Cancellation of the registration of the contract for pledge of patent right |
Date of cancellation: 20220517 Granted publication date: 20150715 Pledgee: Bank of China Limited Chengdu Development Zone West sub branch Pledgor: CHENGDU BAIYU PHARMACEUTICAL Co.,Ltd. Registration number: Y2021980003590 |
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| TR01 | Transfer of patent right | ||
| TR01 | Transfer of patent right |
Effective date of registration: 20221123 Address after: 10/F, Building B7, Tianfu Life Science Park, No. 88, South Keyuan Road, Hi tech Zone, Chengdu, Sichuan 610000 Patentee after: Sichuan Hongming Bosi Pharmaceutical Co.,Ltd. Address before: 611130 Chengdu Baiyu Pharmaceutical Co., Ltd., Chengdu cross strait science and Technology Industrial Development Park, Wenjiang District, Chengdu City, Sichuan Province Patentee before: CHENGDU BAIYU PHARMACEUTICAL Co.,Ltd. |