CN103149310B - Fingerprint building method of Shenxiong glucose injection preparation - Google Patents
Fingerprint building method of Shenxiong glucose injection preparation Download PDFInfo
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- CN103149310B CN103149310B CN201310021486.2A CN201310021486A CN103149310B CN 103149310 B CN103149310 B CN 103149310B CN 201310021486 A CN201310021486 A CN 201310021486A CN 103149310 B CN103149310 B CN 103149310B
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- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Chemical compound OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 title claims abstract description 91
- 229940093181 glucose injection Drugs 0.000 title claims abstract description 90
- 238000002360 preparation method Methods 0.000 title claims abstract description 62
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- IBGBGRVKPALMCQ-UHFFFAOYSA-N 3,4-dihydroxybenzaldehyde Chemical compound OC1=CC=C(C=O)C=C1O IBGBGRVKPALMCQ-UHFFFAOYSA-N 0.000 claims description 36
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 30
- 239000013558 reference substance Substances 0.000 claims description 27
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- 238000009472 formulation Methods 0.000 claims description 21
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- ZZAFFYPNLYCDEP-HNNXBMFYSA-N Rosmarinsaeure Natural products OC(=O)[C@H](Cc1cccc(O)c1O)OC(=O)C=Cc2ccc(O)c(O)c2 ZZAFFYPNLYCDEP-HNNXBMFYSA-N 0.000 claims description 18
- RQKFOGXUTRDQPB-UHFFFAOYSA-N hydron;2,3,5,6-tetramethylpyrazine;chloride Chemical compound Cl.CC1=NC(C)=C(C)N=C1C RQKFOGXUTRDQPB-UHFFFAOYSA-N 0.000 claims description 18
- 229960003371 protocatechualdehyde Drugs 0.000 claims description 18
- DOUMFZQKYFQNTF-MRXNPFEDSA-N rosemarinic acid Natural products C([C@H](C(=O)O)OC(=O)C=CC=1C=C(O)C(O)=CC=1)C1=CC=C(O)C(O)=C1 DOUMFZQKYFQNTF-MRXNPFEDSA-N 0.000 claims description 18
- TVHVQJFBWRLYOD-UHFFFAOYSA-N rosmarinic acid Natural products OC(=O)C(Cc1ccc(O)c(O)c1)OC(=Cc2ccc(O)c(O)c2)C=O TVHVQJFBWRLYOD-UHFFFAOYSA-N 0.000 claims description 18
- KFCMFABBVSIHTB-WUTVXBCWSA-N Salvianolic acid D Chemical compound OC(=O)CC1=C(O)C(O)=CC=C1\C=C\C(=O)O[C@@H](C(O)=O)CC1=CC=C(O)C(O)=C1 KFCMFABBVSIHTB-WUTVXBCWSA-N 0.000 claims description 17
- UMPZKDHDIZUVTO-UHFFFAOYSA-N Salvianolic acid D Natural products Cc1ccc(C=CC(=O)OC(Cc2ccc(O)c(O)c2)C(=O)O)c(CC(=O)O)c1O UMPZKDHDIZUVTO-UHFFFAOYSA-N 0.000 claims description 17
- 238000010790 dilution Methods 0.000 claims description 11
- 239000012895 dilution Substances 0.000 claims description 11
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims description 10
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 8
- 229940090044 injection Drugs 0.000 claims description 7
- 238000005304 joining Methods 0.000 claims description 7
- 239000007788 liquid Substances 0.000 claims description 7
- ZMMKVDBZTXUHFO-DDWIOCJRSA-M sodium;(2r)-3-(3,4-dihydroxyphenyl)-2-hydroxypropanoate Chemical compound [Na+].[O-]C(=O)[C@H](O)CC1=CC=C(O)C(O)=C1 ZMMKVDBZTXUHFO-DDWIOCJRSA-M 0.000 claims description 7
- 238000002347 injection Methods 0.000 claims description 6
- 239000007924 injection Substances 0.000 claims description 6
- 229910019142 PO4 Inorganic materials 0.000 claims description 4
- 239000010452 phosphate Substances 0.000 claims description 4
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- 239000002994 raw material Substances 0.000 abstract description 29
- 238000003908 quality control method Methods 0.000 abstract description 19
- 238000005516 engineering process Methods 0.000 abstract description 10
- 238000001514 detection method Methods 0.000 abstract description 7
- FGDQGIKMWOAFIK-UHFFFAOYSA-N acetonitrile;phosphoric acid Chemical compound CC#N.OP(O)(O)=O FGDQGIKMWOAFIK-UHFFFAOYSA-N 0.000 abstract 1
- 230000014759 maintenance of location Effects 0.000 description 121
- 240000007164 Salvia officinalis Species 0.000 description 98
- 235000017276 Salvia Nutrition 0.000 description 52
- 238000004519 manufacturing process Methods 0.000 description 48
- 235000005412 red sage Nutrition 0.000 description 46
- 239000000543 intermediate Substances 0.000 description 24
- 239000000523 sample Substances 0.000 description 23
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- PAFLSMZLRSPALU-MRVPVSSYSA-N (2R)-3-(3,4-dihydroxyphenyl)lactic acid Chemical compound OC(=O)[C@H](O)CC1=CC=C(O)C(O)=C1 PAFLSMZLRSPALU-MRVPVSSYSA-N 0.000 description 16
- PAFLSMZLRSPALU-QMMMGPOBSA-N Danshensu Natural products OC(=O)[C@@H](O)CC1=CC=C(O)C(O)=C1 PAFLSMZLRSPALU-QMMMGPOBSA-N 0.000 description 16
- PAFLSMZLRSPALU-UHFFFAOYSA-N Salvianic acid A Natural products OC(=O)C(O)CC1=CC=C(O)C(O)=C1 PAFLSMZLRSPALU-UHFFFAOYSA-N 0.000 description 16
- 238000011160 research Methods 0.000 description 11
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- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
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- 206010059245 Angiopathy Diseases 0.000 description 1
- -1 Ligustrazine Hydrochlorides Chemical class 0.000 description 1
- PBCJIPOGFJYBJE-UHFFFAOYSA-N acetonitrile;hydrate Chemical compound O.CC#N PBCJIPOGFJYBJE-UHFFFAOYSA-N 0.000 description 1
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- GBMDVOWEEQVZKZ-UHFFFAOYSA-N methanol;hydrate Chemical compound O.OC GBMDVOWEEQVZKZ-UHFFFAOYSA-N 0.000 description 1
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- 208000010110 spontaneous platelet aggregation Diseases 0.000 description 1
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- FINHMKGKINIASC-UHFFFAOYSA-N tetramethyl-pyrazine Natural products CC1=NC(C)=C(C)N=C1C FINHMKGKINIASC-UHFFFAOYSA-N 0.000 description 1
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- Medicines Containing Plant Substances (AREA)
Abstract
The invention discloses a fingerprint building method and a quality control method of Shenxiong glucose injection raw material, a Shenxiong glucose injection midbody and Shenxiong glucose injection preparation. Fingerprint detection is conducted on the raw material, the midbody and the preparation of the raw material and the midbody under the condition of the same chromatograph. Octadecylsilane chemically bonded silica is used as chromatographic column filling agent, acetonitrile-phosphate aqueous solution is used as mobile phase, gradient elution is conducted, a test sample fingerprint and a contrasted fingerprint have good relevance, similarity is larger than 0.90, a fingerprint of the Shenxiong glucose injection raw material, a fingerprint of the Shenxiong glucose injection midbody and a fingerprint of the Shenxiong glucose injection preparation have good relevance, and each characteristic peak in the preparation fingerprint can be tracked in the raw material and the midbody. The fingerprint building method and the quality control method of the Shenxiong glucose injection raw material, the Shenxiong glucose injection midbody and the Shenxiong glucose injection preparation can be used for controlling conditions and quality of the preparation technology of Shenxiong glucose injection products and ensure stability of the preparation technology and the quality of the products. A fingerprint detecting method has the advantages of being simple and convenient to operate, accurate, reliable, and suitable for controlling the quality of Shenxiong glucose injection.
Description
Technical field
The present invention relates to traditional Chinese medicine fingerprint method for building up and method of quality control technical field, specifically, the present invention is fingerprint and the method for quality control of a seed ginseng rhizome of chuanxiong glucose injection raw material, intermediate and preparation thereof.
Background technology
Chinese medicine compound prescription complicated component, traditional quality control method that carries out using single component as index more and more can not adapt to the requirement that current traditional Chinese medicine quality controls.In modernization of Chinese medicine process, the traditional Chinese medicine fingerprint with globality and ambiguity two fundamental characteristics has become the effective means that present stage can reflect Chinese medicine inherent quality comparatively comprehensively.Ginseng rhizome of chuanxiong glucose injection is made up of the red sage root and Ligustrazine Hydrochloride compatibility, has platelet aggregation-against, coronary vasodilation, the clinical treatment for obliterated cerebral vascular disease and other ischemic angiopathy.The assay project of the ginseng existing quality standard of rhizome of chuanxiong glucose injection (WS-10001-(HD-1136)-2002) only carries out fixing quantity to danshensu and Ligustrazine Hydrochloride, is difficult to the Chemical Composition Characteristics comprehensively reflecting preparation.Along with the raising of China's pharmaceutical production quality control level with to injection safety, curative effect, the deepening continuously of the problem attention degree such as quality controllable, State Food and Drug Administration proposes in succession " national drug standards raising action plan " and " safety of Chinese medicine injection revalues work ", with General Promotion Drug's control level.Therefore, set up the fingerprint pattern quality control method of a seed ginseng rhizome of chuanxiong glucose injection raw material, intermediate and preparation thereof, the mass uniformity between preparation batch and stability can be ensured better, for the quality control of ginseng rhizome of chuanxiong glucose injection and comprehensive evaluation provide the reference frame of science.
Summary of the invention
An object of the present invention is the method for building up of the finger-print providing a seed ginseng rhizome of chuanxiong glucose injection raw material, is set up the finger-print of ginseng rhizome of chuanxiong glucose injection raw material by the method.
Two of object of the present invention is the method for quality control providing above-mentioned ginseng rhizome of chuanxiong glucose injection raw material.
Three of object of the present invention is the method for building up of the finger-print providing a seed ginseng rhizome of chuanxiong glucose injection intermediate, is set up the finger-print of ginseng rhizome of chuanxiong glucose injection intermediate by the method.
Four of object of the present invention is the method for quality control providing above-mentioned ginseng rhizome of chuanxiong glucose injection intermediate.
Five of object of the present invention is the method for building up of the finger-print providing a seed ginseng rhizome of chuanxiong glucose injection formulation, is set up the finger-print of ginseng rhizome of chuanxiong glucose injection formulation by the method.
Six of object of the present invention is the method for quality control providing above-mentioned ginseng rhizome of chuanxiong glucose injection formulation.
As the method for building up of the finger-print of the ginseng rhizome of chuanxiong glucose injection raw material of first aspect present invention, be made up of following steps:
1, the preparation of reference substance solution: precision takes Sodium Danshensu, protocatechualdehyde, salvianolic acid D, Rosmarinic acid, tanshin polyphenolic acid B, salviandic acid A in right amount, add methyl alcohol and dissolve, the reference substance solution that concentration is respectively 1mgmL-1 is made in dilution;
2, the preparation of need testing solution: at least one solvent got in red rooted salvia water, methyl alcohol or ethanol proposes, and constant volume obtains red rooted salvia need testing solution;
3, the mensuration of need testing solution: draw need testing solution injection high performance liquid chromatograph and measure, obtain the finger-print of red rooted salvia; The chromatographic condition that finger-print detects is: octadecylsilane chemically bonded silica is chromatographic column filling agent; Acetonitrile (A)-phosphate aqueous solution (B) carries out gradient elution for mobile phase; Determined wavelength is 200 ~ 300nm; Column temperature is 35 DEG C ~ 55 DEG C; Sample size is 5 ~ 15 μ L; Flow velocity is 0.5 ~ 1.0mLmin
-1;
4, the foundation of reference fingerprint: by measuring the finger-print of more than 10 batches red rooted salvias, determines its total fingerprint characteristic peak, and sets up red rooted salvia reference fingerprint through the matching of traditional Chinese medicine fingerprint similarity evaluation software.
In a preferred embodiment of the method for building up of the finger-print of above-mentioned ginseng rhizome of chuanxiong glucose injection raw material, the preparation process of described step 2 need testing solution is specific as follows: got 40 mesh sieve red rooted salvia powder 0.5g, accurately weighed, precision adds water 25ml, weighed weight, heating and refluxing extraction 2h, lets cool weighed weight again, supplies the weight of less loss with water, shake up, supernatant 0.45 μm of miillpore filter filters, and gets subsequent filtrate, obtains red rooted salvia need testing solution.
In a preferred embodiment of the method for building up of the finger-print of above-mentioned ginseng rhizome of chuanxiong glucose injection raw material, in the mensuration of described step 3 need testing solution, described mensuration is specially: DiamonsilC
18chromatographic column (4.6mm × 250mm, 5 μm); Mobile phase acetonitrile (A)-0.05% phosphoric acid (B), flow velocity 1mLmin
-1, gradient elution, 0 ~ 7min, A2% ~ 4%; 7 ~ 12min, A4% ~ 18%; 12 ~ 15min, A18% ~ 20%; 15 ~ 22min, A20% ~ 23%; 22 ~ 32min, A23% ~ 32%; 32 ~ 42min, A32% ~ 35%; 42 ~ 50min, A35% ~ 90%; 50 ~ 60min, A90%; Column temperature 40 DEG C, determined wavelength 230nm, sample size 10 μ L; Record 60min chromatogram, namely obtains required red rooted salvia finger-print.
In a preferred embodiment of the method for building up of the finger-print of above-mentioned ginseng rhizome of chuanxiong glucose injection raw material, in the mensuration of described step 3 need testing solution, in red rooted salvia finger-print, maximum with the peak area of No. 15 peak tanshin polyphenolic acid B, with the retention time of tanshin polyphenolic acid B for reference, calculate the relative retention time at each total peak: the relative retention time at No. 1 total peak is 0.097 ± 0.001min; The relative retention time at No. 2 total peak is 0.111 ± 0.001min; The relative retention time at No. 3 total peak is 0.123 ± 0.001min; The relative retention time at No. 4 total peak is 0.198 ± 0.002min; The relative retention time at No. 5 total peak is 0.234 ± 0.002min; The relative retention time at No. 6 total peak is 0.271 ± 0.003min; The relative retention time at No. 7 total peak is 0.472 ± 0.005min; The relative retention time at No. 8 total peak is 0.491 ± 0.005min; The relative retention time at No. 9 total peak is 0.662 ± 0.007min; The relative retention time at No. 10 total peak is 0.687 ± 0.007min; The relative retention time that o.11 has peak is 0.788 ± 0.008min; The relative retention time at No. 12 total peak is 0.813 ± 0.008min; The relative retention time at No. 13 total peak is 0.877 ± 0.009min; The relative retention time at No. 14 total peak is 0.914 ± 0.009min; The relative retention time at No. 15 total peak is 1min; The relative retention time at No. 16 total peak is 1.047 ± 0.01min; The relative retention time at No. 16 total peak is 1.076 ± 0.01min.
In a preferred embodiment of the method for building up of the finger-print of above-mentioned ginseng rhizome of chuanxiong glucose injection raw material, in the foundation of described step 4 reference fingerprint, in red rooted salvia finger-print, determine 17 characteristic peaks, wherein peak 5,7,13,14,15,17 is followed successively by danshensu, protocatechualdehyde, salvianolic acid D, Rosmarinic acid, tanshin polyphenolic acid B, salviandic acid A respectively.
In a preferred embodiment of the method for building up of the finger-print of above-mentioned ginseng rhizome of chuanxiong glucose injection raw material, in the foundation of described step 4 reference fingerprint, adopt " similarity evaluation (2004 editions) " of Chinese Pharmacopoeia Commission's establishment to process the data obtained and collection of illustrative plates and namely obtain reference fingerprint.
As the method for quality control of the ginseng rhizome of chuanxiong glucose injection raw material of second aspect present invention, be that the finger-print of red rooted salvia is compared with red rooted salvia reference fingerprint; Calculate similarity through traditional Chinese medicine fingerprint similarity evaluation software and should be less than 0.90.
As the method for building up of the intermediate finger-print of the ginseng rhizome of chuanxiong glucose injection of third aspect present invention, be made up of following steps:
1, the preparation of reference substance solution: precision takes Sodium Danshensu, protocatechualdehyde, salvianolic acid D, Rosmarinic acid, tanshin polyphenolic acid B, salviandic acid A in right amount, add methyl alcohol and dissolve, the reference substance solution that concentration is respectively 1mgmL-1 is made in dilution;
2, get red sage root semi-manufacture, with at least one solvent extraction in water, methyl alcohol or ethanol, constant volume, obtains need testing solution;
3, the mensuration of need testing solution: draw need testing solution injection high performance liquid chromatograph and measure, obtain the half-finished finger-print of the red sage root; The chromatographic condition that finger-print detects is: octadecylsilane chemically bonded silica is chromatographic column filling agent; Acetonitrile (A)-phosphate aqueous solution (B) carries out gradient elution for mobile phase; Determined wavelength is 200 ~ 300nm; Column temperature is 35 DEG C ~ 55 DEG C; Sample size is 5 ~ 15 μ L; Flow velocity is 0.5 ~ 1.0mLmin
-1;
4, the foundation of reference fingerprint: by more than the 10 batches half-finished determining fingerprint patterns of the red sage root, determine its total fingerprint characteristic peak, and set up red sage root semi-manufacture reference fingerprint through the matching of traditional Chinese medicine fingerprint similarity evaluation software.
In a preferred embodiment of the method for building up of the finger-print of above-mentioned ginseng rhizome of chuanxiong glucose injection intermediate, the preparation process of described step 2 need testing solution is specific as follows: get red sage root semi-manufacture 0.15g, accurately weighed, be dissolved in water dilution, be settled to 50mL, shake up, supernatant 0.45 μm of miillpore filter filters, get subsequent filtrate, obtain red sage root semi-manufacture need testing solution.
In a preferred embodiment of the method for building up of the finger-print of above-mentioned ginseng rhizome of chuanxiong glucose injection intermediate, in the mensuration of described step 3 need testing solution, described mensuration is specially DiamonsilC
18chromatographic column (4.6mm × 250mm, 5 μm); Mobile phase acetonitrile (A)-0.05% phosphoric acid (B), flow velocity 1mLmin
-1, gradient elution, 0 ~ 7min, A2% ~ 4%; 7 ~ 12min, A4% ~ 18%; 12 ~ 15min, A18% ~ 20%; 15 ~ 22min, A20% ~ 23%; 22 ~ 32min, A23% ~ 32%; 32 ~ 42min, A32% ~ 35%; 42 ~ 50min, A35% ~ 90%; 50 ~ 60min, A90%; Column temperature 40 DEG C, determined wavelength 230nm, sample size 10 μ L; Record 60min chromatogram, namely obtains required red sage root semi-manufacture finger-print.
In a preferred embodiment of the method for building up of the finger-print of above-mentioned ginseng rhizome of chuanxiong glucose injection raw material, in the mensuration of described step 3 need testing solution, in red sage root semi-manufacture finger-print, maximum with the peak area of No. 4 peak danshensus, with the retention time of danshensu for reference, calculate the relative retention time at each total peak: the relative retention time at No. 1 total peak is 0.371 ± 0.003min; The relative retention time at No. 2 total peak is 0.423 ± 0.004min; The relative retention time at No. 3 total peak is 0.455 ± 0.004min; The relative retention time at No. 4 total peak is 0.754 ± 0.007min; The relative retention time at No. 5 total peak is 1min; The relative retention time at No. 6 total peak is 1.340 ± 0.013min; The relative retention time at No. 7 total peak is 1.509 ± 0.015min; The relative retention time at No. 8 total peak is 1.759 ± 0.017min; The relative retention time at No. 9 total peak is 2.462 ± 0.025min; The relative retention time at No. 10 total peak is 2.583 ± 0.026min; The relative retention time that o.11 has peak is 3.033 ± 0.030min; The relative retention time at No. 12 total peak is 3.268 ± 0.033min; The relative retention time at No. 13 total peak is 3.404 ± 0.034min; The relative retention time at No. 14 total peak is 3.732 ± 0.037min; The relative retention time at No. 15 total peak is 3.791 ± 0.038min; The relative retention time at No. 16 total peak is 4.010 ± 0.040min.
In a preferred embodiment of the method for building up of the finger-print of above-mentioned ginseng rhizome of chuanxiong glucose injection intermediate, in the foundation of described step 4 reference fingerprint, in red sage root semi-manufacture finger-print, determine 16 characteristic peaks, wherein peak 5,7,11,13,15,16 is followed successively by danshensu, protocatechualdehyde, salvianolic acid D, Rosmarinic acid, tanshin polyphenolic acid B, salviandic acid A respectively.
In a preferred embodiment of the method for building up of the finger-print of above-mentioned ginseng rhizome of chuanxiong glucose injection intermediate, in the foundation of described step 4 reference fingerprint, adopt " similarity evaluation (2004 editions) " of Chinese Pharmacopoeia Commission's establishment to process the data obtained and collection of illustrative plates and namely obtain reference fingerprint.
As the Quality control of intermediates method of the ginseng rhizome of chuanxiong glucose injection of fourth aspect present invention, be compared with the half-finished reference fingerprint of the red sage root by half-finished for red sage root finger-print, calculating similarity through traditional Chinese medicine fingerprint similarity evaluation software should be less than 0.90.
As the fingerprint of the ginseng rhizome of chuanxiong glucose injection formulation of fifth aspect present invention, be made up of following steps:
1, the preparation of reference substance solution: precision takes Sodium Danshensu, Ligustrazine Hydrochloride, protocatechualdehyde, salvianolic acid D, Rosmarinic acid, tanshin polyphenolic acid B, salviandic acid A in right amount, add methyl alcohol and dissolve, the reference substance solution that concentration is respectively 1mgmL-1 is made in dilution;
2, the preparation of need testing solution: get ginseng rhizome of chuanxiong glucose injection formulation, with at least one solvent extraction in water, methyl alcohol or ethanol, constant volume, obtains need testing solution;
3, the mensuration of need testing solution: draw need testing solution injection high performance liquid chromatograph and measure, obtain the finger-print of joining rhizome of chuanxiong glucose injection formulation; The chromatographic condition that finger-print detects is: octadecylsilane chemically bonded silica is chromatographic column filling agent; Acetonitrile (A)-phosphate aqueous solution (B) carries out gradient elution for mobile phase; Determined wavelength is 200 ~ 300nm; Column temperature is 35 DEG C ~ 55 DEG C; Sample size is 5 ~ 15 μ L; Flow velocity is 0.5 ~ 1.0mLmin
-1;
4, the foundation of reference fingerprint: by joining rhizome of chuanxiong glucose injection raw material or its intermediate to more than 10 batches, or the mensuration of its preparation, determine its total fingerprint characteristic peak, and set up its reference fingerprint through the matching of traditional Chinese medicine fingerprint similarity evaluation software.
Join in a preferred embodiment of the fingerprint of rhizome of chuanxiong glucose injection formulation in the present invention, 40 mesh sieve red rooted salvia powder 0.5g were got in being prepared as of described step 2 need testing solution, and accurately weighed, precision adds water 25ml, weighed weight, heating and refluxing extraction 2h, lets cool weighed weight again, supplies the weight of less loss with water, shake up, supernatant 0.45 μm of miillpore filter filters, and gets subsequent filtrate, obtains red rooted salvia need testing solution; Get red sage root semi-manufacture 0.15g, accurately weighed, be dissolved in water dilution, is settled to 50mL, shakes up, and supernatant 0.45 μm of miillpore filter filters, and gets subsequent filtrate, obtains red sage root semi-manufacture need testing solution; Precision measures ginseng rhizome of chuanxiong glucose injection formulation 10mL, and thin up, is settled to 25mL, shakes up, and must join rhizome of chuanxiong glucose injection need testing solution.
In a preferred embodiment of the method for building up of the finger-print of above-mentioned ginseng rhizome of chuanxiong glucose injection formulation, in the mensuration of described step 3 need testing solution, described mensuration is specially DiamonsilC
18chromatographic column (4.6mm × 250mm, 5 μm); Mobile phase acetonitrile (A)-0.05% phosphoric acid (B), flow velocity 1mLmin
-1, gradient elution, 0 ~ 7min, A2% ~ 4%; 7 ~ 12min, A4% ~ 18%; 12 ~ 15min, A18% ~ 20%; 15 ~ 22min, A20% ~ 23%; 22 ~ 32min, A23% ~ 32%; 32 ~ 42min, A32% ~ 35%; 42 ~ 50min, A35% ~ 90%; 50 ~ 60min, A90%; Column temperature 40 DEG C, determined wavelength 230nm, sample size 10 μ L; Record 60min chromatogram, namely obtains required red sage root semi-manufacture finger-print.
In a preferred embodiment of the method for building up of the finger-print of above-mentioned ginseng rhizome of chuanxiong glucose injection formulation, the mensuration of described step 3 need testing solution, in red rooted salvia finger-print, maximum with the peak area of No. 15 peak tanshin polyphenolic acid Bs, with the retention time of tanshin polyphenolic acid B for reference, calculate the relative retention time at each total peak: the relative retention time at the 1st total peak is 0.097 ± 0.001min; The relative retention time at the 2nd total peak is 0.111 ± 0.001min; The relative retention time at the 3rd total peak is 0.123 ± 0.001min; The relative retention time at the 4th total peak is 0.198 ± 0.002min; The relative retention time at the 5th total peak is 0.234 ± 0.002min; The relative retention time at the 6th total peak is 0.271 ± 0.003min; The relative retention time at the 7th total peak is 0.472 ± 0.005min; The relative retention time at the 8th total peak is 0.491 ± 0.005min; The relative retention time at the 9th total peak is 0.662 ± 0.007min; The relative retention time at the 10th total peak is 0.687 ± 0.007min; The relative retention time at the 11st total peak is 0.788 ± 0.008min; The relative retention time at the 12nd total peak is 0.813 ± 0.008min; The relative retention time at the 13rd total peak is 0.877 ± 0.009min; The relative retention time at the 14th total peak is 0.914 ± 0.009min; The relative retention time at the 15th total peak is 1min; The relative retention time at the 16th total peak is 1.047 ± 0.01; The relative retention time at the 17th total peak is 1.076 ± 0.01min;
In red sage root semi-manufacture finger-print, maximum with the peak area of No. 4 peak danshensus, with the retention time of danshensu for reference, the relative retention time calculating each total peak is: the relative retention time at the 1st total peak is 0.371 ± 0.003min; The relative retention time at the 2nd total peak is 0.423 ± 0.004min; The relative retention time at the 3rd total peak is 0.455 ± 0.004min; The relative retention time at the 4th total peak is 0.754 ± 0.007min; The relative retention time at the 5th total peak is 1min; The relative retention time at the 6th total peak is 1.340 ± 0.013min; The relative retention time at the 7th total peak is 1.509 ± 0.015min; The relative retention time at the 8th total peak is 1.759 ± 0.017min; The relative retention time at the 9th total peak is 2.462 ± 0.025min; The relative retention time at the 10th total peak is 2.583 ± 0.026min; The relative retention time at the 11st total peak is 3.033 ± 0.030min; The relative retention time at the 12nd total peak is 3.268 ± 0.033min; The relative retention time at the 13rd total peak is 3.404 ± 0.034min; The relative retention time at the 14th total peak is 3.732 ± 0.037min; The relative retention time at the 15th total peak is 3.791 ± 0.038min; The relative retention time at the 16th total peak is 4.010 ± 0.040min; In ginseng rhizome of chuanxiong glucose injection finger-print, maximum with the peak area of No. 5 peak Ligustrazine Hydrochlorides, with the retention time of Ligustrazine Hydrochloride for reference, the relative retention time calculating each total peak is: the relative retention time at the 1st total peak is 0.302 ± 0.003min; The relative retention time at the 2nd total peak is 0.347 ± 0.003min; The relative retention time at the 3rd total peak is 0.618 ± 0.006min; The relative retention time at the 4th total peak is 0.822 ± 0.008min; The relative retention time at the 5th total peak is 1min; The relative retention time at the 6th total peak is 1.233 ± 0.012min; The relative retention time at the 7th total peak is 2.375 ± 0.023min; The relative retention time at the 8th total peak is 2.658 ± 0.026min; The relative retention time at the 9th total peak is 3.034 ± 0.030min; The relative retention time at the 9th total peak is 3.254 ± 0.032min.
In a preferred embodiment of the method for building up of the finger-print of above-mentioned ginseng rhizome of chuanxiong glucose injection formulation, the foundation of described step 4 reference fingerprint, in red rooted salvia finger-print, determine 17 characteristic peaks, wherein peak 5,7,13,14,15,17 is followed successively by danshensu, protocatechualdehyde, salvianolic acid D, Rosmarinic acid, tanshin polyphenolic acid B, salviandic acid A respectively; In red sage root semi-manufacture finger-print, determine 16 characteristic peaks, wherein peak 5,7,11,13,15,16 is followed successively by danshensu, protocatechualdehyde, salvianolic acid D, Rosmarinic acid, tanshin polyphenolic acid B, salviandic acid A respectively; In ginseng rhizome of chuanxiong glucose injection finger-print, determine 10 characteristic peaks, wherein peak 4,5,6,7,8,9,10 is followed successively by danshensu, Ligustrazine Hydrochloride, protocatechualdehyde, salvianolic acid D, Rosmarinic acid, tanshin polyphenolic acid B, salviandic acid A respectively.
In a preferred embodiment of the method for building up of the finger-print of above-mentioned ginseng rhizome of chuanxiong glucose injection formulation, in the foundation of described step 4 reference fingerprint, adopt " similarity evaluation (2004 editions) " of Chinese Pharmacopoeia Commission's establishment to process the data obtained and collection of illustrative plates and namely obtain reference fingerprint.
As the method for quality control of the ginseng rhizome of chuanxiong glucose injection formulation of sixth aspect present invention, be that the finger-print of ginseng rhizome of chuanxiong glucose injection formulation is compared with ginseng rhizome of chuanxiong glucose injection formulation reference fingerprint; Calculate similarity through traditional Chinese medicine fingerprint similarity evaluation software and should be less than 0.90; Compared by the finger-print of ginseng rhizome of chuanxiong glucose injection raw material, intermediate and preparation thereof, in preparation finger, each characteristic peak must be followed the trail of in raw material and intermediate finger-print, and chromatographic peak must not be had to lack.
The present invention is directed to the deficiency of existing ginseng rhizome of chuanxiong glucose injection quality standard, propose first to measure the finger-print of ginseng rhizome of chuanxiong glucose injection raw material, intermediate and preparation thereof, there is provided a kind of simple, reliable, reproducible, the traditional Chinese medicine fingerprint assay method of joining rhizome of chuanxiong glucose injection inherent quality can be controlled comprehensively.
Under present invention can be implemented in same chromatographic condition, the finger-print of ginseng rhizome of chuanxiong glucose injection raw material, intermediate and preparation thereof is detected, source and the ownership of each characteristic peak of finger-print are described by correlation research, can be used for joining rhizome of chuanxiong glucose injection production quality control and process regulation, guarantee the stability of preparation technology, ensure the mass uniformity between product batches and stability better, promote the quality control level of preparation.
Accompanying drawing explanation
Fig. 1 is mixing reference substance solution collection of illustrative plates.
Fig. 2 is red rooted salvia reference fingerprint.
Fig. 3 is 18 batches of red rooted salvia fingerprint similarity evaluation maps.
Fig. 4 is red sage root semi-manufacture reference fingerprints.
Fig. 5 is 13 batches of red sage root semi-manufacture fingerprint similarity evaluation maps.
Fig. 6 is ginseng rhizome of chuanxiong glucose injection reference fingerprint.
Fig. 7 is 18 batches of ginseng rhizome of chuanxiong glucose injection fingerprint similarity evaluation maps.
Fig. 8 is raw material (A) and intermediate (B) finger-print comparison diagram.
Fig. 9 is intermediate (A) and preparation (B) finger-print comparison diagram.
Embodiment
The fingerprint pattern quality control method of ginseng rhizome of chuanxiong glucose injection raw material of the present invention, intermediate and preparation thereof is through the preferred plan that a large amount of shaker tests obtains, and following experimental study is preferred process of the present invention:
One, chromatographic condition and system suitability
1, instrument and reagent
Supper-fast liquid chromatographic system (UFLC, Shimadzu comprise binary gradient pump, vacuum degassing machine, automatic sampler, column oven, diode array detector, Lcsolution workstation); AE240 100,000/electronic balance (plum Teller-Tuo benefit instrument Shanghai company limited); Ultrapure water machine (Sichuan Water Technology Development Co., Ltd.).Acetonitrile (German MERCK company) is chromatographically pure; Water is ultrapure water; It is pure that other reagent are analysis.Sodium Danshensu (lot number 110855200508), Ligustrazine Hydrochloride (lot number 110817-200305), protocatechualdehyde (lot number 110810-200705) reference substance is purchased from Nat'l Pharmaceutical & Biological Products Control Institute; Rosmarinic acid (lot number MUST-10120901), tanshin polyphenolic acid B (lot number MUST-11031401), salviandic acid A (lot number MUST-10012901) reference substance is purchased from Beijing Heng Yuanqitian Chemical Engineering Technology research institute; Red rooted salvia is adopted in Zhong Jiang red rooted salvia planting base, Sichuan Province, is identified by Guiyang Medical College pharmaceutical college medicinal plant and pharmacognosy teaching and research room associate professor Long Qingde; Red sage root semi-manufacture and ginseng rhizome of chuanxiong glucose injection (Guizhou Jingfeng Injection Co., Ltd. provides).
2, the selection of chromatographic condition
Test was once investigated different ratio flow phase system such as methanol-water, acetonitrile-water, acetonitrile-0.05% phosphoric acid, acetonitrile-0.5% acetic acid, compare through degree such as grade or gradient test, result shows, with acetonitrile-0.05% phosphoric acid for eluent gradient wash-out separating effect is better, the each chromatographic peak detected can reach baseline separation, shortens analysis time again.KromasilC18 (5.0mm × 200mm is have employed in experiment, 5 μm, Dalian Yi Lite), HypersilC18 (5.0mm × 250mm, 5 μm, Dalian Yi Lite), InersilC18 (4.6mm × 250mm, 5 μm, Japanese GLSciencesInc.) and DiamonsilC18 (5.0mm × 250mm, 5 μm, Di Ma company) chromatographic column, result is better with the separating effect of DiamonsilC18 chromatographic column, and fingerprint peaks type is basically identical, therefore have finally chosen DiamonsilC18 post.The finger-print determined wavelength of array diode detecting device to red rooted salvia, semi-manufacture and preparation is adopted to select, result shows that determined wavelength is when 230nm, the quantity of information of medicinal material, intermediate and preparation is comparatively large, can take into account the abundance of each composition chromatographic peak, degree of separation and baseline etc.By being optimized on the basis of investigation to instrument, mobile phase, determined wavelength, column temperature isochromatic spectrum condition, obtaining and can be applicable to join the identical chromatographic conditions that rhizome of chuanxiong glucose injection raw material, intermediate and preparation thereof carry out finger-print detection: DiamonsilC
18chromatographic column (4.6mm × 250mm, 5 μm); Mobile phase acetonitrile (A)-0.05% phosphoric acid (B), flow velocity 1mLmin
-1, gradient elution, 0 ~ 7min, A2% ~ 4%; 7 ~ 12min, A4% ~ 18%; 12 ~ 15min, A18% ~ 20%; 15 ~ 22min, A20% ~ 23%; 22 ~ 32min, A23% ~ 32%; 32 ~ 42min, A32% ~ 35%; 42 ~ 50min, A35% ~ 90%; 50 ~ 60min, A90%.Column temperature 40 DEG C, determined wavelength 230nm, sample size 10 μ L.
Two, the preparation of reference substance solution
Precision takes Sodium Danshensu, Ligustrazine Hydrochloride, protocatechualdehyde, salvianolic acid D, Rosmarinic acid, tanshin polyphenolic acid B, salviandic acid A in right amount, and add methyl alcohol and dissolve, the reference substance solution that concentration is respectively 1mgmL-1 is made in dilution.
Three, the preparation of need testing solution
1, the preparation of red rooted salvia need testing solution
Got 40 mesh sieve red rooted salvia powder (raw material) about 0.5g, accurately weighed, precision adds water 25ml, weighed weight, heating and refluxing extraction 2h, let cool again weighed weight, supply the weight of less loss with water, shake up, supernatant miillpore filter (0.45 μm) filters, get subsequent filtrate, obtain red rooted salvia need testing solution.
2, the preparation of red sage root semi-manufacture need testing solution
Get red sage root semi-manufacture (intermediate) about 0.15g, accurately weighed, be dissolved in water dilution, is settled to 50mL, shakes up, and supernatant miillpore filter (0.45 μm) filters, and gets subsequent filtrate, obtains red sage root semi-manufacture need testing solution.
3, the preparation of rhizome of chuanxiong glucose injection need testing solution is joined
Precision measures ginseng rhizome of chuanxiong glucose injection (preparation) 10mL, and thin up, is settled to 25mL, shakes up, and must join rhizome of chuanxiong glucose injection need testing solution.
Four, the survey and valuation of finger-print
1, the survey and valuation of red rooted salvia finger-print
From the testing result of 18 batches of red rooted salvia test sample finger-prints, wherein 1,2,3,4,5,6,7,8,9,10,12,13,14,15,16, No. 17 peak all occurs at identical relative retention time place in 18 batches of medicinal materials, its fingerprint peaks area sum accounts for total amount and is all greater than 90%, and thus demarcating these 17 chromatographic peaks is common characteristic peak.Pointed out 6 chromatographic peaks by reference substance Comparability test, wherein peak 5,7,13,14,15,17 is followed successively by danshensu, protocatechualdehyde, salvianolic acid D, Rosmarinic acid, tanshin polyphenolic acid B, salviandic acid A respectively.
In red rooted salvia finger-print, maximum with the peak area of No. 15 peak tanshin polyphenolic acid Bs, with the retention time of tanshin polyphenolic acid B for reference, calculate the relative retention time at each total peak for (unit is min): 1(0.097 ± 0.001); 2(0.111 ± 0.001); 3(0.123 ± 0.001); 4(0.198 ± 0.002); 5(0.234 ± 0.002); 6(0.271 ± 0.003); 7(0.472 ± 0.005); 8(0.491 ± 0.005); 9(0.662 ± 0.007); 10(0.687 ± 0.007); 11(0.788 ± 0.008); 12(0.813 ± 0.008); 13(0.877 ± 0.009); 14(0.914 ± 0.009); 15(1); 16(1.047 ± 0.01); 17(1.076 ± 0.01).
2, the survey and valuation of red sage root semi-manufacture finger-print
From the testing result of 13 batches of red sage root semi-manufacture finger-prints, wherein 1,2,3,4,5,6,7,8,9,10,12,13,14,15, No. 16 peak all occurs at identical relative retention time place in 13 batches of red sage root semi-manufacture, its fingerprint peaks area sum accounts for total amount and is all greater than 95%, thus demarcates these 16 chromatographic peaks for total fingerprint characteristic peak.Pointed out 7 chromatographic peaks by reference substance Comparability test, wherein peak 5,7,11,13,15,16 is followed successively by danshensu, protocatechualdehyde, salvianolic acid D, Rosmarinic acid, tanshin polyphenolic acid B, salviandic acid A respectively.
In red sage root semi-manufacture finger-print, maximum with the peak area of No. 4 peak danshensus, with the retention time of danshensu for reference, calculate the relative retention time at each total peak for (unit is min): 1(0.371 ± 0.003); 2(0.423 ± 0.004); 3(0.455 ± 0.004); 4(0.754 ± 0.007); 5(1); 6(1.340 ± 0.013); 7(1.509 ± 0.015); 8(1.759 ± 0.017); 9(2.462 ± 0.025); 10(2.583 ± 0.026); 11(3.033 ± 0.030); 12(3.268 ± 0.033); 13(3.404 ± 0.034); 14(3.732 ± 0.037); 15(3.791 ± 0.038); 16(4.010 ± 0.040).
3, the survey and valuation of rhizome of chuanxiong glucose injection finger-print is joined
From the testing result of 17 batches of test samples, wherein 1,2,3,4,5,6,7,8,9, No. 10 peak all occurs at identical relative retention time place in 17 batches of preparations, its fingerprint peaks area sum accounts for total amount and is all greater than 95%, thus demarcates these 10 chromatographic peaks for total fingerprint characteristic peak.Pointed out 7 chromatographic peaks by reference substance Comparability test, wherein peak 4,5,6,7,8,9,10 is followed successively by danshensu, Ligustrazine Hydrochloride, protocatechualdehyde, salvianolic acid D, Rosmarinic acid, tanshin polyphenolic acid B, salviandic acid A respectively.
4, rhizome of chuanxiong glucose injection raw material, intermediate and preparation finger correlation research is joined
Under identical chromatographic conditions, finger-print detection is carried out to red rooted salvia, red sage root semi-manufacture and preparation, result shows, in preparation finger, each characteristic peak derives from except the Ligustrazine Hydrochloride bulk drug in prescription except No. 5 peaks (Ligustrazine Hydrochloride), all the other characteristic peaks all derive from the red sage root in prescription, all can be followed the trail of in red rooted salvia and red sage root semi-manufacture, without chromatographic peak disappearance, preparation and medicinal material, semi-manufacture finger-print have good correlativity, in table 1.
Table 1 medicinal material, intermediate, preparation finger correlativity
Enumerate embodiment below and further describe the present invention, this embodiment does not only limit the present invention for illustration of the present invention.
Embodiment 1: red rooted salvia determining fingerprint pattern
(1) crude drug source
Red rooted salvia sample source in Sichuan, Shandong, Henan, the ground such as Shaanxi and Jiangsu, details, in table 1, are identified by Guiyang Medical College medicinal plant and pharmacognosy teaching and research room.
Table 118 batch red rooted salvia source and the place of production
(2) chromatographic condition
DiamonsilC18 chromatographic column (4.6mm × 250mm, 5 μm); Mobile phase acetonitrile (A)-0.05% phosphoric acid (B), flow velocity 1mLmin
-1, gradient elution, 0 ~ 7min, A2% ~ 4%; 7 ~ 12min, A4% ~ 18%; 12 ~ 15min, A18% ~ 20%; 15 ~ 22min, A20% ~ 23%; 22 ~ 32min, A23% ~ 32%; 32 ~ 42min, A32% ~ 35%; 42 ~ 50min, A35% ~ 90%; 50 ~ 60min, A90%.Column temperature 40 DEG C, determined wavelength 230nm, sample size 10 μ L, record 60min chromatogram.
(3) need testing solution preparation method investigates
Extraction solvent and extracting method are selected: red rooted salvia is mainly containing liposoluble constituent and the large class of water soluble ingredient two.Test once measured finger-print by red rooted salvia 70% methanol extract liquid direct injected, and the finger-print obtained by the method is complicated, and the component after 60min is mainly liposoluble constituent.Consider that ginseng rhizome of chuanxiong glucose injection liquid preparing process is extraction process by water, and show through UPLC-ESI-MS analysis, main containing danshinolic acid class water soluble compound in ginseng rhizome of chuanxiong glucose injection, therefore the preparation method of red rooted salvia need testing solution adopts the method identical with preparation process thereof " poach extracts ", extract obtained need testing solution using water as solvent refluxing.This simple and convenient extraction and favorable reproducibility, finger-print baseline is comparatively steady, and collection of illustrative plates is clear, and has good correlativity with ginseng rhizome of chuanxiong glucose injection semi-manufacture, preparation finger.
The investigation of reflux extracting time: take water as Extraction solvent, investigate different heating return time respectively to the impact of extracting result, result shows water refluxing extraction 2h, in finger-print, the unit mass peak area at each peak and each index components content totally tend towards stability, consider, extract return time and be decided to be 2h.The results are shown in Table 2.
The medicinal material assay result (unit: mgg of table 2 different extraction time
-1)
Comprehensive above-mentioned test findings, red rooted salvia need testing solution preparation method is for getting red rooted salvia powder (crossing 40 mesh sieves) about 0.5g, and accurately weighed, precision adds water 25ml, weighed weight, heating and refluxing extraction 2h, lets cool weighed weight again, supplies the weight of less loss with water, shake up, supernatant miillpore filter (0.45 μm) filters, and gets subsequent filtrate, to obtain final product.
(4) fingerprint spectrum method research
In red rooted salvia finger-print, maximum with the peak area of No. 15 peak tanshin polyphenolic acid Bs, with the retention time of tanshin polyphenolic acid B for reference, calculate relative retention time and the relative peak area at each total peak, and adopt " similarity evaluation (2004A) " of Chinese Pharmacopoeia Commission's recommendation to carry out similarity evaluation, carry out methodological study.
Precision test: get same test sample solution, continuous sample introduction 6 times, detects finger-print, result shows, the RSD of each total peak relative retention time is all less than 1%, and the RSD of relative peak area is all less than 3%, similarity is greater than 0.99, meets fingerprint pattern technology requirement.
Stability test: get same need testing solution respectively at 0,2,4,6,10,24h detects finger-print, compares the chromatogram recorded at different time.Result shows, the RSD of each total peak relative retention time is all less than 1%, and the RSD of relative peak area is all less than 3%, and similarity is greater than 0.99, shows that need testing solution has good stability in 24h.
Replica test: get with batch red rooted salvia sample, parallel preparation 6 parts of test sample solution, sample detection.The RSD of each total peak relative retention time is all less than 1%, and the RSD of relative peak area is all less than 3%, and similarity is greater than 0.99, shows that method repeatability is good.
(5) A+E of finger-print
Get reference substance and 18 batches of red rooted salvia samples, prepare reference substance and need testing solution, detect finger-print, the chromatogram of record 60min.
Pointing out of chromatographic peak: from the testing result of 18 batches of red rooted salvia test sample finger-prints, wherein 1,2,3,4,5,6,7,8,9,10,12,13,14,15,16, No. 17 peak all occurs at identical relative retention time place in 18 batches of medicinal materials, its fingerprint peaks area sum accounts for total amount and is all greater than 90%, and thus demarcating these 17 chromatographic peaks is common characteristic peak.Pointed out 6 chromatographic peaks by reference substance Comparability test, wherein peak 5,7,13,14,15,17 is followed successively by danshensu, protocatechualdehyde, salvianolic acid D, Rosmarinic acid, tanshin polyphenolic acid B, salviandic acid A respectively.
The relative retention time at total peak: with the retention time of No. 15 peak tanshin polyphenolic acid Bs for reference, calculates the relative retention time at each total peak for (unit is min): 1(0.097 ± 0.001); 2(0.111 ± 0.001); 3(0.123 ± 0.001); 4(0.198 ± 0.002); 5(0.234 ± 0.002); 6(0.271 ± 0.003); 7(0.472 ± 0.005); 8(0.491 ± 0.005); 9(0.662 ± 0.007); 10(0.687 ± 0.007); 11(0.788 ± 0.008); 12(0.813 ± 0.008); 13(0.877 ± 0.009); 14(0.914 ± 0.009); 15(1); 16(1.047 ± 0.01); 17(1.076 ± 0.01).
Fingerprint similarity is evaluated: adopt Chinese Pharmacopoeia Commission's " similarity evaluation (A version in 2004) " to carry out Similarity Measure to 18 batches of medicinal materials fingerprints in 5 main red sage root places of production such as Sichuan, Shandong, Henan, Shaanxi and Jiangsu.From similarity-rough set result, 18 batches of red rooted salvias and reference fingerprint (common pattern that 18 batches of red rooted salvias generate) similarity are all greater than 0.8,6 batches of red rooted salvia fingerprint similarities that wherein Sichuan Zhong Jiang produces all are greater than 0.9, illustrate that the red rooted salvia finger-print that Sichuan Zhong Jiang produces is comparatively stable.
Chinese Pharmacopoeia Commission's " similarity evaluation (A version in 2004) " is adopted to carry out Similarity Measure to 6 batches of red rooted salvia finger-prints that Sichuan Zhong Jiang produces.From similarity-rough set result, 6 batches of red rooted salvias and reference fingerprint (common pattern that 6 batches of red rooted salvias generate) similarity are all greater than 0.95, illustrate that the red rooted salvia quality conformance that Sichuan Zhong Jiang produces is better.
Embodiment 2: red sage root semi-manufacture determining fingerprint pattern
(1) chromatographic condition
DiamonsilC18 chromatographic column (4.6mm × 250mm, 5 μm); Mobile phase acetonitrile (A)-0.05% phosphoric acid (B), flow velocity 1mLmin
-1, gradient elution, 0 ~ 7min, A2% ~ 4%; 7 ~ 12min, A4% ~ 18%; 12 ~ 15min, A18% ~ 20%; 15 ~ 22min, A20% ~ 23%; 22 ~ 32min, A23% ~ 32%; 32 ~ 42min, A32% ~ 35%; 42 ~ 50min, A35% ~ 90%; 50 ~ 60min, A90%.Column temperature 40 DEG C, determined wavelength 230nm, sample size 10 μ L, record 60min chromatogram.
(2) preparation of need testing solution
Get red sage root semi-manufacture and be about 0.15g, accurately weighed, be dissolved in water dilution, is settled to 50mL, shakes up, and supernatant miillpore filter (0.45 μm) filters, and gets subsequent filtrate, obtains red sage root semi-manufacture need testing solution;
(3) fingerprint spectrum method research
In red sage root semi-manufacture finger-print, maximum with the peak area of No. 4 peak danshensus, with the retention time of danshensu for reference, calculate relative retention time and the relative peak area at each total peak, and adopt " similarity evaluation (2004A) " of Chinese Pharmacopoeia Commission's recommendation to carry out similarity evaluation, carry out methodological study.
Precision test: get same test sample solution, continuous sample introduction 6 times, detects finger-print, result shows, the RSD of each total peak relative retention time is all less than 1%, and the RSD of relative peak area is all less than 3%, similarity is greater than 0.99, meets fingerprint pattern technology requirement.
Stability test: get same need testing solution respectively at 0,2,4,6,10,24h detects finger-print, compares the chromatogram recorded at different time.Result shows, the RSD of each total peak relative retention time is all less than 1%, and the RSD of relative peak area is all less than 3%, and similarity is greater than 0.99, shows that need testing solution has good stability in 24h.
Replica test: get with batch red sage root semi-manufacture sample, parallel preparation 6 parts of test sample solution, sample detection.The RSD of each total peak relative retention time is all less than 1%, and the RSD of relative peak area is all less than 3%, and similarity is greater than 0.99, shows that method repeatability is good.
(4) A+E of finger-print
Get reference substance and 13 batches of red sage root semi-manufacture samples, prepare reference substance and need testing solution, detect finger-print, the chromatogram of record 60min.
Pointing out of chromatographic peak: from the testing result of 13 batches of red sage root semi-manufacture finger-prints, wherein 1,2,3,4,5,6,7,8,9,10,12,13,14,15, No. 16 peak all occurs at identical relative retention time place in 13 batches of red sage root semi-manufacture, its fingerprint peaks area sum accounts for total amount and is all greater than 95%, thus demarcates these 16 chromatographic peaks for total fingerprint characteristic peak.Pointed out 7 chromatographic peaks by reference substance Comparability test, wherein peak 5,7,11,13,15,16 is followed successively by danshensu, protocatechualdehyde, salvianolic acid D, Rosmarinic acid, tanshin polyphenolic acid B, salviandic acid A respectively.
The relative retention time at total peak: with the retention time of No. 4 peak danshensus for reference, calculates the relative retention time at each total peak for (unit is min): 1(0.371 ± 0.003); 2(0.423 ± 0.004); 3 (0.455 ± 0.004); 4(0.754 ± 0.007); 5(1); 6(1.340 ± 0.013); 7(1.509 ± 0.015); 8(1.759 ± 0.017); 9(2.462 ± 0.025); 10(2.583 ± 0.026); 11(3.033 ± 0.030); 12(3.268 ± 0.033); 13(3.404 ± 0.034); 14(3.732 ± 0.037); 15(3.791 ± 0.038); 16(4.010 ± 0.040).
Fingerprint similarity is evaluated: adopt Chinese Pharmacopoeia Commission's " similarity evaluation (A version in 2004) " to carry out Similarity Measure to 13 batches of red sage root semi-manufacture finger-prints.From similarity-rough set result, 13 batches of red sage root semi-manufacture and reference fingerprint (common pattern that 13 batches of semi-manufacture finger-prints generate) similarity are respectively 0.966,0.964,0.972,0.929,0.977,0.952,0.975,0.975,0.959,0.923,0.943,0.909,0.932, similarity is all greater than 0.9, and red sage root semi-manufacture finger-print is comparatively stable.
Embodiment 3: ginseng rhizome of chuanxiong glucose injection determining fingerprint pattern
(1) chromatographic condition
DiamonsilC18 chromatographic column (4.6mm × 250mm, 5 μm); Mobile phase acetonitrile (A)-0.05% phosphoric acid (B), flow velocity 1mLmin
-1, gradient elution, 0 ~ 7min, A2% ~ 4%; 7 ~ 12min, A4% ~ 18%; 12 ~ 15min, A18% ~ 20%; 15 ~ 22min, A20% ~ 23%; 22 ~ 32min, A23% ~ 32%; 32 ~ 42min, A32% ~ 35%; 42 ~ 50min, A35% ~ 90%; 50 ~ 60min, A90%.Column temperature 40 DEG C, determined wavelength 230nm, sample size 10 μ L, record 60min chromatogram.
(2) preparation of need testing solution
Need testing solution: precision measures ginseng rhizome of chuanxiong glucose injection 10mL, adds 5% glucose solution dilution, is settled to 25mL, shakes up.
Reference substance solution: precision takes Sodium Danshensu, Ligustrazine Hydrochloride, protocatechualdehyde, salvianolic acid D, Rosmarinic acid, tanshin polyphenolic acid B, salviandic acid A in right amount, add methyl alcohol and dissolve, dilution is made concentration and is respectively 1mgmL
-1reference substance solution.
(3) fingerprint spectrum method research
Be with reference to peak with Ligustrazine Hydrochloride (No. 5 peaks), calculate relative retention time and the relative peak area at each total peak, and adopt " similarity evaluation (2004A) " of Chinese Pharmacopoeia Commission's recommendation to carry out similarity evaluation, carry out methodological study.
Precision test: get same test sample solution, continuous sample introduction 6 times, detects finger-print, result shows, the RSD of each total peak relative retention time is all less than 1%, and the RSD of relative peak area is all less than 3%, similarity is greater than 0.99, meets fingerprint pattern technology requirement.
Stability test: get same need testing solution respectively at 0,2,4,6,10,24h detects finger-print, compares the chromatogram recorded at different time.Result shows, the RSD of each total peak relative retention time is all less than 1%, and the RSD of relative peak area is all less than 3%, and similarity is greater than 0.99, shows that need testing solution has good stability in 24h.
Replica test: get with batch ginseng rhizome of chuanxiong glucose injection sample, by the parallel preparation of method 6 parts of test sample solution under " 2.2.1 " item, sample detection.The RSD of each total peak relative retention time is all less than 1%, and the RSD of relative peak area is all less than 3%, and similarity is greater than 0.99, shows that method repeatability is good.
(4) A+E of finger-print
Get reference substance and 17 batches of ginseng rhizome of chuanxiong glucose injection samples, prepare reference substance and need testing solution, detect finger-print, the chromatogram of record 60min.
Pointing out of chromatographic peak: by comparing different batches ginseng rhizome of chuanxiong glucose injection sample chromatogram figure, wherein 1 ~ No. 10 peak all occurs at identical relative retention time place in 17 batches of preparations, its fingerprint peaks area sum accounts for total amount and is all greater than 95%, thus demarcates these 10 chromatographic peaks for total fingerprint peaks.By contrasting with reference substance retention time and ultraviolet spectrum, determine that 4,5,6,7,8,9, No. 10 peaks are followed successively by danshensu, Ligustrazine Hydrochloride, protocatechualdehyde, salvianolic acid D, Rosmarinic acid, tanshin polyphenolic acid B, salviandic acid A respectively.
The relative retention time at total peak: with the retention time of Ligustrazine Hydrochloride chromatographic peak (No. 5 peaks) for 1, calculate the relative retention time at 17 batches of ginseng each total peaks of rhizome of chuanxiong glucose injection test sample solution, as a result the average relative retention time at 1 ~ No. 10 peak be respectively 0.302,0.347,0.618,0.822,1.000,1.233,2.357,2.658,3.034 and 3.254, RSD(%) be respectively 0.911,0.883,0.926,0.788,0.000,0.700,0.754,0.673,0.658,0.653.
The relative peak area at total peak: with the peak area of Ligustrazine Hydrochloride chromatographic peak (No. 5 peaks) for 1, calculate the relative peak area at 17 batches of ginseng each total peaks of rhizome of chuanxiong glucose injection test sample solution, as a result the average relative peak area at 1 ~ No. 10 peak be respectively 0.098,0.033,0.008,0.207,1.000,0.027,0.013,0.044,0.034 and 0.017, RSD(%) be respectively 2.150,2.843,2.547,2.548,0.000,2.977,2.198,2.189,2.345 and 2.800.
Fingerprint similarity is evaluated: adopt " similarity evaluation (2004A version) " software, and the common pattern finger-print generated with 17 batches of preparation averages is contrast, and the common pattern collection of illustrative plates similarity of each batch of preparation finger and its gained is respectively 0.997,0.989,0.995,0.993,0.995,0.999,0.992,0.997,0.991,0.993,0.987,0.997,0.989,0.987,0.999,0.983,0.998, result display is all more than 0.98.
(5) finger-print correlation research
Under identical chromatographic conditions, finger-print detection is carried out to red rooted salvia, red sage root semi-manufacture and preparation, result shows, in preparation finger, each characteristic peak derives from except the Ligustrazine Hydrochloride bulk drug in prescription except No. 5 peaks (Ligustrazine Hydrochloride), all the other characteristic peaks all derive from the red sage root in prescription, all can be followed the trail of in red rooted salvia and red sage root semi-manufacture, without chromatographic peak disappearance, preparation and medicinal material, semi-manufacture finger-print have good correlativity.
(6) brief summary
This research establishes the finger-print of ginseng rhizome of chuanxiong glucose injection, confirm 7 characteristic peaks wherein, and can realize detecting red rooted salvia and red sage root semi-manufacture finger-print under same chromatographic condition, source and the ownership at each total peak of finger-print are tentatively described by correlation research, can be used for joining rhizome of chuanxiong glucose injection production quality control and process regulation, guarantee the stability of preparation technology.
Claims (1)
1. join the fingerprint of rhizome of chuanxiong glucose injection formulation, it is characterized in that, be made up of following steps:
(1), the preparation of reference substance solution: precision takes Sodium Danshensu, Ligustrazine Hydrochloride, protocatechualdehyde, salvianolic acid D, Rosmarinic acid, tanshin polyphenolic acid B, salviandic acid A in right amount, and add methyl alcohol and dissolve, dilution is made concentration and is respectively 1mgmL
-1reference substance solution;
(2), the preparation of need testing solution: get ginseng rhizome of chuanxiong glucose injection formulation, with at least one solvent extraction in water, methyl alcohol or ethanol, constant volume, obtains need testing solution;
(3), the mensuration of need testing solution: draw need testing solution injection high performance liquid chromatograph and measure, obtain the finger-print of joining rhizome of chuanxiong glucose injection formulation; The chromatographic condition that finger-print detects is: octadecylsilane chemically bonded silica is chromatographic column filling agent; Acetonitrile (A)-phosphate aqueous solution (B) carries out gradient elution for mobile phase; Determined wavelength is 200 ~ 300nm; Column temperature is 35 DEG C ~ 55 DEG C; Sample size is 5 ~ 15 μ L; Flow velocity is 0.5 ~ 1.0mLmin
-1;
(4), the foundation of reference fingerprint: by joining the mensuration of rhizome of chuanxiong glucose injection formulation to more than 10 batches, determine its total fingerprint characteristic peak, and set up its reference fingerprint through the matching of traditional Chinese medicine fingerprint similarity evaluation software;
In the mensuration of described step (3) need testing solution, described mensuration is specially DiamonsilC18 chromatographic column; Mobile phase acetonitrile (A)-0.05% phosphoric acid (B), gradient elution, 0 ~ 7min, acetonitrile (A) 2% ~ 4%; 7 ~ 12min, acetonitrile (A) 4% ~ 18%; 12 ~ 15min, acetonitrile (A) 18% ~ 20%; 15 ~ 22min, acetonitrile (A) 20% ~ 23%; 22 ~ 32min, acetonitrile (A) 23% ~ 32%; 32 ~ 42min, acetonitrile (A) 32% ~ 35%; 42 ~ 50min, acetonitrile (A) 35% ~ 90%; 50 ~ 60min, acetonitrile (A) 90%; Record 60min chromatogram, namely obtains the finger-print of required ginseng rhizome of chuanxiong glucose injection formulation.
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Denomination of invention: Method for establishing fingerprint spectra of Shenxiong glucose injection preparations Effective date of registration: 20231122 Granted publication date: 20150520 Pledgee: Qingdao Qishun Investment Management Co.,Ltd. Pledgor: GUIZHOU JINGFENG INJECTION Co.,Ltd. Registration number: Y2023980066820 |