CN1586492A - Medicinal composition containing danshensu, total ara-saponin and camphol and its preparation and use - Google Patents
Medicinal composition containing danshensu, total ara-saponin and camphol and its preparation and use Download PDFInfo
- Publication number
- CN1586492A CN1586492A CN 200410071050 CN200410071050A CN1586492A CN 1586492 A CN1586492 A CN 1586492A CN 200410071050 CN200410071050 CN 200410071050 CN 200410071050 A CN200410071050 A CN 200410071050A CN 1586492 A CN1586492 A CN 1586492A
- Authority
- CN
- China
- Prior art keywords
- filtrate
- danshensu
- borneolum syntheticum
- radix notoginseng
- salviae miltiorrhizae
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- PAFLSMZLRSPALU-QMMMGPOBSA-N Danshensu Natural products OC(=O)[C@@H](O)CC1=CC=C(O)C(O)=C1 PAFLSMZLRSPALU-QMMMGPOBSA-N 0.000 title claims abstract description 54
- PAFLSMZLRSPALU-UHFFFAOYSA-N Salvianic acid A Natural products OC(=O)C(O)CC1=CC=C(O)C(O)=C1 PAFLSMZLRSPALU-UHFFFAOYSA-N 0.000 title claims abstract description 54
- 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 title claims abstract description 53
- DTGKSKDOIYIVQL-WEDXCCLWSA-N (+)-borneol Chemical compound C1C[C@@]2(C)[C@@H](O)C[C@@H]1C2(C)C DTGKSKDOIYIVQL-WEDXCCLWSA-N 0.000 title claims abstract description 48
- 238000002360 preparation method Methods 0.000 title claims abstract description 44
- 239000000203 mixture Substances 0.000 title claims abstract description 5
- DTGKSKDOIYIVQL-UHFFFAOYSA-N dl-isoborneol Natural products C1CC2(C)C(O)CC1C2(C)C DTGKSKDOIYIVQL-UHFFFAOYSA-N 0.000 title abstract 3
- 239000001397 quillaja saponaria molina bark Substances 0.000 title 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims abstract description 150
- 239000000284 extract Substances 0.000 claims abstract description 59
- 235000003143 Panax notoginseng Nutrition 0.000 claims abstract description 53
- 241000180649 Panax notoginseng Species 0.000 claims abstract description 53
- 239000007924 injection Substances 0.000 claims abstract description 52
- 238000002347 injection Methods 0.000 claims abstract description 52
- 240000007164 Salvia officinalis Species 0.000 claims abstract description 41
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 39
- ODLHGICHYURWBS-LKONHMLTSA-N trappsol cyclo Chemical compound CC(O)COC[C@H]([C@H]([C@@H]([C@H]1O)O)O[C@H]2O[C@@H]([C@@H](O[C@H]3O[C@H](COCC(C)O)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](COCC(C)O)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](COCC(C)O)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](COCC(C)O)[C@H]([C@@H]([C@H]3O)O)O3)[C@H](O)[C@H]2O)COCC(O)C)O[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@@H]3O[C@@H]1COCC(C)O ODLHGICHYURWBS-LKONHMLTSA-N 0.000 claims abstract description 30
- 239000000843 powder Substances 0.000 claims abstract description 25
- 239000011347 resin Substances 0.000 claims abstract description 12
- 229920005989 resin Polymers 0.000 claims abstract description 12
- 238000003810 ethyl acetate extraction Methods 0.000 claims abstract description 9
- 238000001556 precipitation Methods 0.000 claims abstract description 9
- 239000003513 alkali Substances 0.000 claims abstract 2
- 239000000706 filtrate Substances 0.000 claims description 50
- 239000007788 liquid Substances 0.000 claims description 44
- 239000003814 drug Substances 0.000 claims description 35
- 239000000243 solution Substances 0.000 claims description 22
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 21
- 238000001035 drying Methods 0.000 claims description 21
- 238000010828 elution Methods 0.000 claims description 21
- 238000001914 filtration Methods 0.000 claims description 21
- 239000012047 saturated solution Substances 0.000 claims description 21
- 229940079593 drug Drugs 0.000 claims description 18
- 239000000796 flavoring agent Substances 0.000 claims description 17
- 235000019634 flavors Nutrition 0.000 claims description 17
- -1 hydroxypropyl Chemical group 0.000 claims description 16
- 238000000108 ultra-filtration Methods 0.000 claims description 15
- 239000012528 membrane Substances 0.000 claims description 14
- 238000004321 preservation Methods 0.000 claims description 14
- 238000003756 stirring Methods 0.000 claims description 14
- 238000000703 high-speed centrifugation Methods 0.000 claims description 13
- 235000017276 Salvia Nutrition 0.000 claims description 11
- HEMHJVSKTPXQMS-UHFFFAOYSA-M sodium hydroxide Inorganic materials [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 11
- 238000000605 extraction Methods 0.000 claims description 10
- 230000000274 adsorptive effect Effects 0.000 claims description 8
- 239000012567 medical material Substances 0.000 claims description 8
- 239000006228 supernatant Substances 0.000 claims description 8
- 244000131316 Panax pseudoginseng Species 0.000 claims description 7
- 235000003181 Panax pseudoginseng Nutrition 0.000 claims description 7
- 239000012141 concentrate Substances 0.000 claims description 7
- 238000010979 pH adjustment Methods 0.000 claims description 7
- 229930091371 Fructose Natural products 0.000 claims description 4
- 239000005715 Fructose Substances 0.000 claims description 4
- RFSUNEUAIZKAJO-ARQDHWQXSA-N Fructose Chemical compound OC[C@H]1O[C@](O)(CO)[C@@H](O)[C@@H]1O RFSUNEUAIZKAJO-ARQDHWQXSA-N 0.000 claims description 4
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 claims description 4
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 4
- 239000008101 lactose Substances 0.000 claims description 4
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 4
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 claims description 3
- 229920001503 Glucan Polymers 0.000 claims description 3
- 229930195725 Mannitol Natural products 0.000 claims description 3
- 239000003463 adsorbent Substances 0.000 claims description 3
- TWNIBLMWSKIRAT-VFUOTHLCSA-N levoglucosan Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@H]2CO[C@@H]1O2 TWNIBLMWSKIRAT-VFUOTHLCSA-N 0.000 claims description 3
- 239000000594 mannitol Substances 0.000 claims description 3
- 235000010355 mannitol Nutrition 0.000 claims description 3
- 239000008194 pharmaceutical composition Substances 0.000 claims description 3
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 claims description 2
- 239000007864 aqueous solution Substances 0.000 claims description 2
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 claims description 2
- 239000008103 glucose Substances 0.000 claims description 2
- 150000007522 mineralic acids Chemical class 0.000 claims description 2
- 150000007524 organic acids Chemical class 0.000 claims description 2
- 239000001267 polyvinylpyrrolidone Substances 0.000 claims description 2
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 claims description 2
- 229920000036 polyvinylpyrrolidone Polymers 0.000 claims description 2
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 claims 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims 2
- 229910000019 calcium carbonate Inorganic materials 0.000 claims 1
- AXCZMVOFGPJBDE-UHFFFAOYSA-L calcium dihydroxide Chemical compound [OH-].[OH-].[Ca+2] AXCZMVOFGPJBDE-UHFFFAOYSA-L 0.000 claims 1
- 239000000920 calcium hydroxide Substances 0.000 claims 1
- 229910001861 calcium hydroxide Inorganic materials 0.000 claims 1
- 150000007529 inorganic bases Chemical class 0.000 claims 1
- 229910000027 potassium carbonate Inorganic materials 0.000 claims 1
- 229910000029 sodium carbonate Inorganic materials 0.000 claims 1
- 150000001875 compounds Chemical class 0.000 abstract description 33
- 235000005412 red sage Nutrition 0.000 abstract description 30
- 230000000694 effects Effects 0.000 abstract description 9
- 230000007062 hydrolysis Effects 0.000 abstract description 6
- 238000006460 hydrolysis reaction Methods 0.000 abstract description 6
- REPVLJRCJUVQFA-UHFFFAOYSA-N (-)-isopinocampheol Natural products C1C(O)C(C)C2C(C)(C)C1C2 REPVLJRCJUVQFA-UHFFFAOYSA-N 0.000 abstract 2
- 229940116229 borneol Drugs 0.000 abstract 2
- CKDOCTFBFTVPSN-UHFFFAOYSA-N borneol Natural products C1CC2(C)C(C)CC1C2(C)C CKDOCTFBFTVPSN-UHFFFAOYSA-N 0.000 abstract 2
- 238000003809 water extraction Methods 0.000 abstract 2
- 230000000747 cardiac effect Effects 0.000 abstract 1
- 230000002490 cerebral effect Effects 0.000 abstract 1
- 229940112950 sage extract Drugs 0.000 abstract 1
- 238000001179 sorption measurement Methods 0.000 abstract 1
- 208000019553 vascular disease Diseases 0.000 abstract 1
- 239000008899 fufang danshen Substances 0.000 description 24
- 238000000034 method Methods 0.000 description 19
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 15
- 238000012360 testing method Methods 0.000 description 13
- 241001465754 Metazoa Species 0.000 description 9
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 8
- 238000005516 engineering process Methods 0.000 description 8
- 238000004108 freeze drying Methods 0.000 description 8
- 241000699666 Mus <mouse, genus> Species 0.000 description 6
- 241000699670 Mus sp. Species 0.000 description 6
- 239000012535 impurity Substances 0.000 description 6
- 230000004083 survival effect Effects 0.000 description 6
- YMGFTDKNIWPMGF-QHCPKHFHSA-N Salvianolic acid A Natural products OC(=O)[C@H](Cc1ccc(O)c(O)c1)OC(=O)C=Cc2ccc(O)c(O)c2C=Cc3ccc(O)c(O)c3 YMGFTDKNIWPMGF-QHCPKHFHSA-N 0.000 description 5
- YMGFTDKNIWPMGF-UCPJVGPRSA-N Salvianolic acid A Chemical compound C([C@H](C(=O)O)OC(=O)\C=C\C=1C(=C(O)C(O)=CC=1)\C=C\C=1C=C(O)C(O)=CC=1)C1=CC=C(O)C(O)=C1 YMGFTDKNIWPMGF-UCPJVGPRSA-N 0.000 description 5
- 230000009471 action Effects 0.000 description 5
- 238000006243 chemical reaction Methods 0.000 description 5
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- 239000004615 ingredient Substances 0.000 description 5
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- 230000001105 regulatory effect Effects 0.000 description 5
- 229930183842 salvianolic acid Natural products 0.000 description 5
- QAIPRVGONGVQAS-DUXPYHPUSA-N trans-caffeic acid Chemical compound OC(=O)\C=C\C1=CC=C(O)C(O)=C1 QAIPRVGONGVQAS-DUXPYHPUSA-N 0.000 description 5
- JLTCWSBVQSZVLT-CDIPANDDSA-N (2s)-n-[(2s)-6-amino-1-[(2-amino-2-oxoethyl)amino]-1-oxohexan-2-yl]-1-[(4r,7s,10s,13s,16s,19r)-19-amino-7-(2-amino-2-oxoethyl)-10-(3-amino-3-oxopropyl)-13-benzyl-16-[(4-hydroxyphenyl)methyl]-6,9,12,15,18-pentaoxo-1,2-dithia-5,8,11,14,17-pentazacycloicosan Chemical compound NCCCC[C@@H](C(=O)NCC(N)=O)NC(=O)[C@@H]1CCCN1C(=O)[C@H]1NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CC=2C=CC=CC=2)NC(=O)[C@H](CC=2C=CC(O)=CC=2)NC(=O)[C@@H](N)CSSC1.C([C@H]1C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CSSC[C@@H](C(N[C@@H](CC=2C=CC(O)=CC=2)C(=O)N1)=O)N)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCCN=C(N)N)C(=O)NCC(N)=O)C1=CC=CC=C1 JLTCWSBVQSZVLT-CDIPANDDSA-N 0.000 description 4
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- ACEAELOMUCBPJP-UHFFFAOYSA-N (E)-3,4,5-trihydroxycinnamic acid Natural products OC(=O)C=CC1=CC(O)=C(O)C(O)=C1 ACEAELOMUCBPJP-UHFFFAOYSA-N 0.000 description 2
- DOUMFZQKYFQNTF-WUTVXBCWSA-N (R)-rosmarinic acid Chemical compound C([C@H](C(=O)O)OC(=O)\C=C\C=1C=C(O)C(O)=CC=1)C1=CC=C(O)C(O)=C1 DOUMFZQKYFQNTF-WUTVXBCWSA-N 0.000 description 2
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 2
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- JOYRKODLDBILNP-UHFFFAOYSA-N Ethyl urethane Chemical compound CCOC(N)=O JOYRKODLDBILNP-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- 238000012449 Kunming mouse Methods 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
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- QAIPRVGONGVQAS-UHFFFAOYSA-N cis-caffeic acid Natural products OC(=O)C=CC1=CC=C(O)C(O)=C1 QAIPRVGONGVQAS-UHFFFAOYSA-N 0.000 description 2
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- WTPPRJKFRFIQKT-UHFFFAOYSA-N 1,6-dimethyl-8,9-dihydronaphtho[1,2-g][1]benzofuran-10,11-dione;1-methyl-6-methylidene-8,9-dihydro-7h-naphtho[1,2-g][1]benzofuran-10,11-dione Chemical compound O=C1C(=O)C2=C3CCCC(=C)C3=CC=C2C2=C1C(C)=CO2.O=C1C(=O)C2=C3CCC=C(C)C3=CC=C2C2=C1C(C)=CO2 WTPPRJKFRFIQKT-UHFFFAOYSA-N 0.000 description 1
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- 241000700157 Rattus norvegicus Species 0.000 description 1
- 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 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical group [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
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- 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 description 1
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Landscapes
- Medicines Containing Plant Substances (AREA)
Abstract
The medicinal composition of the present invention is compound freeze dried red sage powder for injection comprising red sage extract with danshensu as main component, notoginseng extract with arasaponin as main component, hydroxypropyl beta-cyclodextrin clathrate of borneol and medicinal supplementary material. The preparation process includes extracting red sage component via water extraction, ultrafiltering, alkali hydrolysis and ethyl acetate extraction; extracting notoginseng component via water extraction, alcohol precipitation and macro resin adsorption; clathrating borneol to raise its water solubility; and other steps. The present invention is used in preventing and treating cardiac and cerebral vascular diseases and has obvious curative effect.
Description
Affiliated technical field
The invention belongs to technical field of traditional Chinese medicine pharmacy, be specifically related to a kind of drug regimen group and preparation and application that contains danshensu, Radix Notoginseng total arasaponins and Borneolum Syntheticum.We are referred to as compound red sage root freezing-dried powder injection again this pharmaceutical composition.
Background technology
Coronary heart disease, angina pectoris are commonly encountered diseases, frequently-occurring disease clinically, in recent years, raising along with people's living standard, the incidence of coronary heart disease age shifts to an earlier date to some extent, add the aging of population structure, its sickness rate is the trend that rises year by year, and the medicine of exploitation treatment cardiovascular and cerebrovascular disease gradually becomes the focus of research.Increasing clinical report shows that Chinese medicine is having a good application prospect aspect treatment coronary heart disease, the angina pectoris, and particularly the few side effects of Chinese medicine is subjected to liking of people day by day.By the compound red sage root preparation that Radix Salviae Miltiorrhizae, Radix Notoginseng and Borneolum Syntheticum are formed, be mainly used in the treatment of cardiovascular disease aspect clinically, have effect preferably, fine always as FUFANG DANSHEN DIWAN sales volume on market.Up-to-date bibliographical information: Zhang uncle's the Confucian or feudal ethical codes by the Tianjin College of Traditional Chinese Medicine president and award " effective substance of compound red sage root formula and the study on mechanism " of the heading the list of signers, confirmed compound red sage root formula multicomponent, many target treatments cardiovascular diseases science.Research worker is used for reference the analytical method of Western medicine when keeping the former side's compatibility of Chinese medicine characteristics, carried out systematic study from aspects such as the compatibility proportioning of this prescription, mechanism of action, effective substances.The final confirmation: compound red sage root formula not only has function of resisting myocardial ischemia, and enhancing ischemic preconditioning effect is arranged, and mechanism of action may be coronary artery dilator and the release that activates the endogenous protection material; The action target spot of Radix Salviae Miltiorrhizae lays particular emphasis on blood vessel, and the action target spot of Radix Notoginseng lays particular emphasis on cardiac muscle, and [the compound red sage root formula mechanism of action is verified to have the cooperative compensating effect behind Radix Salviae Miltiorrhizae and the Radix Notoginseng compatibility.Modern combination of Chinese and Western medicine magazine 2004,13 (8): 999].
The compound red sage root preparation of being made up of Radix Salviae Miltiorrhizae, Radix Notoginseng, Borneolum Syntheticum three flavor medicines has multiple dosage form clinically, but is only limited to oral formulations [patent documentation CN02158104.5].For the patent of compound red sage root preparation, more to its solid dosage forms report, patent CN01136155.7 and patent CN02158104.5 disclose solid dosage forms of this compound preparation and preparation method thereof respectively; Patent CN01133333.2 then discloses slow release and the controlled release form and the preparation method of this compound preparation; Patent CN02157383, CN02157377, CN02157379, CN02157380, CN02157382 then disclose the whole solid dosage forms that comprises compound Salviae Miltiorrhizae.Application number is the report that FUFANG DANSHEN ZHUSHEYE is arranged in the patent documentation of CN98103032, CN02133724, CN02144600, CN031112650, but raw material is made up of Radix Salviae Miltiorrhizae and Lignum Dalbergiae Odoriferae two flavor medicines.The ejection preparation of being made by Radix Notoginseng or Radix Salviae Miltiorrhizae single medicinal material effective site has more report.Patent CN99106223 discloses the injection of being made by Radix Notoginseng total arasaponins.
The aqueous soluble active constituent pharmacological action of Radix Salviae Miltiorrhizae is strong, comprising danshensu and multiple liposoluble ingredient.Danshensu is caffeinic hydrolyzate 3,4 dihydroxy phenyl lactic acid, rosmarinic acid is that caffeic acid and danshensu esterification condensation form, prolithospermic acid is by dimolecular caffeic acid condensation, it further with a part or the further condensation of bimolecular danshensu, form alkannic acid and alkannic acid second, also all contain the unit of danshensu in other the oligomerization caffeic acid compounds structure.These salvianolic acid constituents extract, very unstable in the process of purification, under heating condition just easily hydrolysis become danshensu [Chen Yan, etc.Different Extraction Method is measured the comparative study of content of Danshensu in the red rooted salvia.The Jiangsu Chinese medicine, 2003,24 (6): 55].In the preparation technology of existing Radix Salviae Miltiorrhizae, in order to prevent that salvianolic acid from hydrolysis taking place in leaching process, adopted for example supersound extraction, rotation to scrape technologies such as membrance concentration, polyamide remove impurity, macroporous adsorbent resin remove impurity, lyophilization, in preparation, also must add some stabilizing agents, prevent from storage, transportation, hydrolysis to take place.These measures make that not only the preparation process of medicine is very loaded down with trivial details, cause loss of active ingredients, and the production cycle are long, and investment is big, medicine cost height.The medicine of making is that index is carried out assay with the salvianolic acid, also has certain difficulty; With salvianolic acid content is index, and a small amount of hydrolysis of its composition just can make the salvianolic acid constituents in the medicine descend, and makes medicament contg defective.So existing FUFANG DANSHEN ZHUSHEYE is that the content with danshensu is index.But the result that content of Danshensu is measured can not reflect the height of content of Danshensu initial in the medicine really, thereby whether qualified medicine is can't judge, thereby brings difficulty for clinically the bigger patient's of individual variation accurate medication.Dosage is crossed conference and is caused that patient's untoward reaction increases the too small desired therapeutic effect that do not reach again of dosage.Shi Yili etc. and Zhang Jianhua etc. be by having carried out assay to the danshensu in 8 FUFANG DANSHEN ZHUSHEYE of the different lot numbers of commercially available different manufacturers and same producer, the content of Danshensu between results sample have highly significant difference [Shi Yili, etc.The quality examination research of FUFANG DANSHEN ZHUSHEYE.Chinese Pharmaceutical Journal, 2002,37 (4): 300; Zhang Jianhua, etc.The Radix Salviae Miltiorrhizae active ingredient is investigated in the FUFANG DANSHEN ZHUSHEYE.The Zhejiang College Of Traditional Chinese Medicine journal, 2001,25 (4): 64].There are so big difference in different manufacturers and same producer with the content of danshensu in the compound Danshen root injection of identical production method preparation, explanation is except the reason of the content difference of medical material own, and the instability of preparation ingredient is the significant maximum effect factor of content difference.Therefore, preparation quality Radix Salviae Miltiorrhizae extract controlled, determined curative effect is extremely important.
When adopting aqueous extraction-alcohol precipitation technology to remove impurity in the Radix Salviae Miltiorrhizae extract, it is very important that concentration of ethanol does not play the person for content of effective yet.Concentration of alcohol is little, does not reach the effect of precipitate with ethanol; But along with the increase of concentration of alcohol, in the extracting solution content of danshensu obviously reduce [Li Shuli, etc.The different concentration ethanol precipitation is to the research of danshensu response rate influence.Basic unit's Chinese medicine impurity, 1995,9 (1): 21].Application number is the patent application document of CN02144600, CN02133724, CN90107488, in the preparation technology of Radix Salviae Miltiorrhizae extract, in order to remove many impurity as far as possible, all adopt the technology of the ethanol precipitation remove impurity of high concentration, this can cause very big loss to the content of danshensu.
Borneolum Syntheticum is a liposoluble constituent, and the dissolubility in injection is less, also brings difficulty to being prepared into ejection preparation.
In patent retrieval, do not see Radix Salviae Miltiorrhizae is arranged, the report of the injection, particularly lyophilized injectable powder of Radix Notoginseng, Borneolum Syntheticum three flavor medicine prescriptions.It is rapid that lyophilized injectable powder has an onset, stablely is convenient to advantages such as transportation, storage, more suitable for the Radix Salviae Miltiorrhizae extract that stability is bad.Therefore, further develop particularly its freeze-dried powder dosage form of compound red sage root preparation, will have vast market prospect.
Summary of the invention
The present invention (sees one one of " pharmacopeia " version in 2000 to FUFANG DANSHEN PIAN, Chinese Pharmacopoeia Commission compiles) dosage form improve, purpose is to provide that a kind of onset is rapid, dosage form is advanced, the injection use compound red sage root freezing-dried powder injection of preparation stabilization, quality controllable, drug safety and preparation method thereof.The present invention adopts water to carry, and the method for basic hydrolysis, ethyl acetate extraction is extracted the effective ingredient based on danshensu from Radix Salviae Miltiorrhizae; Adopt the method for decoction and alcohol sedimentation technique, mistake macroporous adsorptive resins from Radix Notoginseng, to extract and purification Radix Notoginseng total arasaponins effective constituents; (HP-β-CD) Borneolum Syntheticum in the prescription is carried out enclose has solved it and dissolved difficult problem in the injection aqueous solution, has improved the quality and the clinical efficacy of preparation to utilize hydroxypropyl.Also adopt ultrafiltration in the preparation method of the present invention, guaranteed that the clarity of injection and pyrogen are qualified, the quality of injection and curative effect are significantly improved.
The present invention is achieved through the following technical solutions:
One, process recipes
(1) prescription of crude drug is: Radix Salviae Miltiorrhizae 400-500 weight portion, Borneolum Syntheticum 6-10 weight portion, Radix Notoginseng 120-160 weight portion;
(2) getting the red rooted salvia decoction pieces pulverizes, adding the decocting that 6-10 doubly measures boils 2-4 time, each 1-3 hour, merge extractive liquid, filters, filtrate is put cold, high speed centrifugation (15000rpm), centrifugal liquid molecular cut off are 5000 ultrafilter membrane ultrafiltration, and filtrate adds lye pH adjustment value 9-11, boiled 0.5-3 hour, put cold, 24 hours after-filtration of cold preservation (4 ℃), filtrate is 2-3 with organic acid or inorganic acid for adjusting pH value, with 0.5～3 times ethyl acetate extraction 3～9 times, merge ethyl acetate liquid, the concentrating under reduced pressure drying, obtaining with the danshensu is the Radix Salviae Miltiorrhizae extract of main component.
(3) getting the pseudo-ginseng decoction pieces pulverizes, decoct extraction 1-3 time with 6-12 times of water gaging, each 1-2 hour, merge extractive liquid, filters, it is 1.15-1.16 that filtrate is concentrated into relative density for 50 ℃, add ethanol and make and contain alcohol amount and reach 60%-70%, leave standstill after-filtration, filtrate adds ethanol to be made and contains the alcohol amount and reach 70%-85%, leave standstill after-filtration, filtrate is concentrated into does not have alcohol flavor, thin up (solution: medical material is 1: 1), high speed centrifugation, supernatant is crossed the macroporous adsorptive resins of having handled well, with the water elution of 3-6 times of column volume, the ethanol elution of the 40%-80% of reuse 5-8 times column volume is collected ethanol elution and is recycled to nothing alcohol flavor earlier, concentrate, drying is pulverized, and obtaining with the arasaponin is the Radix Notoginseng extract of main component.
(4) Borneolum Syntheticum becomes nearly saturated solution standby with anhydrous alcohol solution; Other gets HP-β-CD and adds the injection water and make saturated solution, and Borneolum Syntheticum ethanol liquid slowly is added drop-wise in HP-β-CD saturated solution, does not stop to stir.After adding, 50 ℃ are continued to stir 3 hours again, and cold preservation is spent the night, and filters, and the precipitation cold drying gets Borneolum Syntheticum HP-beta-CD inclusion.
(4) get above-mentioned Radix Salviae Miltiorrhizae extract, Radix Notoginseng extract and add the dissolving of injection water, filter, filtrate is 5000 ultrafilter membrane ultrafiltration with molecular cut off, ultrafiltrate mixes with Borneolum Syntheticum HP-β-CD liquid, adds the lyophilizing excipient, adds the injection water to ormal weight, regulate pH value to 7.0-8.5, fill, lyophilization, promptly.
Two, the content of danshensu compares in the Radix Salviae Miltiorrhizae extract of distinct methods preparation
1. instrument and reagent high performance liquid chromatograph comprise LC-10ATvp type solvent delivery pump, SPD-10ATvp type UV, visible light detector (day island proper Tianjin company); N2000 chromatographic work station (Zhejiang University's intelligent information Graduate School of Engineering); KQ3200 type ultrasonic washing instrument (Kunshan Ultrasonic Instruments Co., Ltd.), TGL-16G high speed tabletop centrifuge (Anting Scientific Instrument Factory, Shanghai).Chromatographically pure methanol (the effective company of Beijing chemical reagent); Water is tri-distilled water (self-control); Other reagent is analytical pure.Danshensu reference substance (Nat'l Pharmaceutical ﹠ Biological Products Control Institute).
No. 1 Radix Salviae Miltiorrhizae extract, the 100g red rooted salvia is by the method preparation of patent CN95115854; No. 2 Radix Salviae Miltiorrhizae extracts, the 100g red rooted salvia is by the method preparation of patent CN98103032; No. 3 Radix Salviae Miltiorrhizae extracts, the 100g red rooted salvia is by the preparation method preparation of Radix Salviae Miltiorrhizae extract of the present invention; Three duplicate samples provide by Qianluchun Science and Technology Co., Ltd., Beijing's laboratory.
2. chromatographic column tested in chromatographic condition and system suitability: the C of Di Ma company
18Post (5 μ m, 150mm * 4.6mm, I.D); Mobile phase: methanol-5% acetic acid (25: 75); Flow velocity: 1.0ml/min; Detect wavelength: 280nm.Number of theoretical plate should be not less than 3000 by danshensu peak compute.
3. reference substance solution prepares precision and takes by weighing danshensu reference substance 5.0mg, inserts in the 10ml measuring bottle, adds methanol, ultrasonicly makes dissolving, adds methanol again to scale, shakes up, promptly.
4. standard curve preparation difference precision is drawn above-mentioned reference substance solution 1 μ l, 2 μ l, 4 μ l, 6 μ l, 8 μ l, 10 μ l, 12 μ l, sample introduction is measured under the said determination condition, danshensu is the good linear relation in 0.5 μ g～6.0 μ g scopes as a result, regression equation is Y=9726483X+3989, r=0.9997.
5. the about 10mg of each Radix Salviae Miltiorrhizae extract decided in the accurate title of the preparation of need testing solution, put in the tool plug conical flask, the accurate methanol 10ml that adds claims to decide weight, supersound process 30min, put coldly, claim again to decide weight, supply the weight that subtracts mistake with methanol, shake up, filter, get subsequent filtrate centrifugal (12000rpm) 10min, supernatant is as need testing solution.
6. accurate each the 10 μ l of need testing solution that draw of algoscopy inject chromatograph of liquid, measure peak area, calculate content with standard curve.The results are shown in Table 1.
Content of Danshensu relatively in the Radix Salviae Miltiorrhizae extract of table 1 distinct methods preparation
Sample number into spectrum content of Danshensu (%)
1 4.46
2 6.72
3 28.57
By above measurement result as can be seen, the content of the effective ingredient danshensu in the Radix Salviae Miltiorrhizae extract of the present invention apparently higher than the content of other two kinds of Radix Salviae Miltiorrhizae extracts, illustrates that preparation technology of the present invention is more reasonable, and science has more practical significance more.
Three, the study on the stability of the Radix Salviae Miltiorrhizae extract of distinct methods preparation
Get the Radix Salviae Miltiorrhizae extract of distinct methods preparation,, be settled to equal-volume with the water for injection dissolving.Placed 2 days at 80 ℃ waters bath with thermostatic control (temperature difference ± 1 ℃) internal heating.After time arrived, sampling immediately rapidly with the ice-water bath cooling, was measured the content of danshensu according to said method.The results are shown in Table 2.
The study on the stability of the Radix Salviae Miltiorrhizae extract of table 2 distinct methods preparation
Content of Danshensu (mg/ml)
Sample number into spectrum
0 day 2 days
1 4.46 6.46
2 6.72 8.82
3 28.57 28.62
By above check result as can be seen, the stable content of the danshensu in the solution of Radix Salviae Miltiorrhizae extract of the present invention, and the content of the danshensu of the Radix Salviae Miltiorrhizae extract of other method preparation significantly increases.Illustrate that preparation technology of the present invention has made effective ingredient be essentially danshensu in the process of preparation, thereby be easier to quality control, be easier to clinical application.Illustrate that this preparation method is more reasonable, science has more practical significance more, meets the requirement of ejection preparation fully.
Four, the assay of Radix Notoginseng total arasaponins in danshensu and the Radix Notoginseng extract in the Radix Salviae Miltiorrhizae extract of the present invention
The five batches of Radix Salviae Miltiorrhizae extracts and Radix Notoginseng extract are provided by the Qianluchun Science and Technology Co., Ltd., Beijing.The content assaying method of danshensu is measured according to the method described above; The content assaying method of Radix Notoginseng total arasaponins according to list of references [Wei Fengling, etc.The Radix Notoginseng total arasaponins extraction process is preferred.CHINA JOURNAL OF CHINESE MATERIA MEDICA, 2000,25 (12): 722] the content of the total saponins in radix notoginseng assay method in is measured; The results are shown in Table 3
Component content measurement result in five batches of extracts of table 3
Content (w/w, %)
Lot number
The danshensu Radix Notoginseng total arasaponins
1 28.57 67.58
2 26.75 56.34
3 29.73 63.52
4 27.28 57.63
5 30.37 60.08
By above measurement result as can be seen, the danshensu weight percentage is greater than 25% in the Radix Salviae Miltiorrhizae extract of the present invention, and the Radix Notoginseng total arasaponins weight percentage is greater than 55% in the Radix Notoginseng extract.
Five, pharmacology embodiment
1. the influence of anoxia in mice endurance is tested
Experimental technique: get 30 of healthy Kunming mouses, body weight 20～24g.Be divided into matched group at random, FUFANG DANSHEN ZHUSHEYE group, freeze drying powder injection of compound red sange root group of the present invention.Every group 10, male and female half and half, sub-cage rearing.With the conversion of people's conventional therapy dosage is the dosage of mice.The conversion formula is: tested animal is tried out the body surface area ratio of the body surface area ratio/known animal of dosage=known animals administer amount * tested animal.Control group administered physiological saline, 1 time/d, continuous 7d.1h after the last administration, it is the 150ml port grinding bottle that mice is placed volume respectively, in put the 15g sodica calx, its time-to-live of airtight observation.The results are shown in Table 4.
The influence of table 4 pair mice normobaric hypoxia (X ± SD)
Group Mus number (only) mean survival time (min)
Matched group 10 16.44 ± 2.57
FUFANG DANSHEN ZHUSHEYE group 10 26.85 ± 2.25
*
Compound red sage root freezing-dried powder injection group 10 30.94 ± 3.245 of the present invention
*#
Annotate: compare with matched group:
*P＜0.001;
Compare with the FUFANG DANSHEN ZHUSHEYE group: #P＜0.05
FUFANG DANSHEN ZHUSHEYE, compound red sage root freezing-dried powder injection of the present invention all can improve mice normobaric hypoxia endurance, and mean survival time is than matched group significant prolongation (P＜0.01); Compound red sage root freezing-dried powder injection of the present invention is compared with FUFANG DANSHEN ZHUSHEYE, mean survival time also variant (P＜0.05).Illustrate: the effect of compound red sage root freezing-dried powder injection is better than FUFANG DANSHEN ZHUSHEYE.
2. to the anoxybiotic protective effect experiment of mouse cardiac muscle
Experimental technique: get 30 of healthy Kunming mouses, body weight 18～22g is divided into 3 groups at random, matched group, FUFANG DANSHEN ZHUSHEYE group, compound red sage root freezing-dried powder injection group of the present invention.Every group of male and female half and half, sub-cage rearing.With the conversion of people's conventional therapy dosage is the dosage of mice.The conversion formula is: tested animal is tried out the body surface area ratio of the body surface area ratio/known animal of dosage=known animals administer amount * tested animal.Control group administered physiological saline, medication: 1 time/d, continuous 6d.1h is with urethane 1.2g/kg intraperitoneal injection of anesthesia after the last administration, and back fixation is separated trachea, with the bulldog clamp folder pipe of holding one's breath, observes electrocardio with electrocardiogram equipment, and writes down the little mousetrap with stopwatch and hold one's breath time of Guan Houzhi electrocardio disappearance.The results are shown in Table 5.
The anoxybiotic influence of table 5 pair mouse cardiac muscle (X ± SD)
Group Mus number (only) mean survival time (min)
Matched group 10 5.83 ± 0.64
FUFANG DANSHEN ZHUSHEYE group 10 10.52 ± 0.87*
Compound red sage root freezing-dried powder injection group 10 12.14 ± 0.74*# of the present invention
Annotate: compare with matched group:
*P＜0.001;
Compare with the FUFANG DANSHEN ZHUSHEYE group: #P＜0.05
FUFANG DANSHEN ZHUSHEYE, compound red sage root freezing-dried powder injection of the present invention all can shield to the mouse cardiac muscle anoxia, and mean survival time is than matched group significant prolongation (P＜0.01); Compound red sage root freezing-dried powder injection of the present invention is compared with FUFANG DANSHEN ZHUSHEYE, mean survival time also variant (P＜0.05).Illustrate: the pharmacological action of compound red sage root freezing-dried powder injection of the present invention is better than FUFANG DANSHEN ZHUSHEYE.
3. to the influence of rat ischemia ECG T wave due to the pituitrin
Get 30 of body weight 250～300g Wistar rats, male and female half and half are divided into 3 groups at random, and 10 every group, continuous ip. administration 7d.Each treated animal is behind last administration 30min, and lumbar injection 25% urethane 0.4ml/100g anaesthetizes, and it is fixing to lie on the back, normal voltage 1mv=15mm, chart drive speed 50mm/s, record II lead electrocardiogram.Sublingual vein injection of pituitrin 0.75u/kg has injected in 5s.Electrocardiogram of every 30s record.In the rat intravenous injection pituitrin 1min, great majority show as decreased heart rate, and the T wave height is alarmmed, and the ST section such as raises at variation.Observe the variation that medication front and back 30s, 1min and 50min go up T ripple propagation respectively.The results are shown in Table 6.
The influence of rat ischemia ECG T wave due to the table 6 pair pituitrin.
Mus is counted T ripple increment (mV)
Group
(only) 30s 1min 5min
Normal saline group 10 0.37 ± 0.17 0.26 ± 0.15 0.19 ± 0.031
FUFANG DANSHEN ZHUSHEYE group 10 0.25 ± 0.07
*0.17 ± 0.06
*0.092 ± 0.014
*Compound red sage root freezing-dried powder injection group 10 0.21 ± 0.06 of the present invention
*# 0.13 ± 0.04
*# 0.063 ± 0.018
*#
Annotate: compare with matched group:
*P＜0.01;
Compare with the FUFANG DANSHEN ZHUSHEYE group: #P＜0.05
T ripple propagation (P＜0.01) when compound red sage root freezing-dried powder injection of the present invention and FUFANG DANSHEN ZHUSHEYE all can significantly reduce 30s, 1min and 5min; Compound red sage root freezing-dried powder injection of the present invention is compared with FUFANG DANSHEN ZHUSHEYE, the degree of reduction also variant (P＜0.05).Illustrate: the pharmacological action of compound red sage root freezing-dried powder injection of the present invention is better than FUFANG DANSHEN ZHUSHEYE.
Six, preparation embodiment
Embodiment 1
(1) prescription of crude drug is: Radix Salviae Miltiorrhizae 500g, Borneolum Syntheticum 10g, Radix Notoginseng 160g;
(2) get the red rooted salvia decoction pieces and pulverize, the decocting that adds 10 times of amounts boils 4 times, and each 3 hours, merge extractive liquid, filtered, and filtrate is put cold, and high speed centrifugation (15000rpm), centrifugal liquid molecular cut off are 5000 ultrafilter membrane ultrafiltration, and filtrate adds Na (OH)
2The lye pH adjustment value is 9, boiled 3 hours, put cold, 24 hours after-filtration of cold preservation (4 ℃), it is 1 that filtrate is regulated pH value with hydrochloric acid, with 3 times ethyl acetate extractions 9 times, and merging ethyl acetate liquid, the concentrating under reduced pressure drying, obtaining with the danshensu is the Radix Salviae Miltiorrhizae extract (the danshensu weight percentage is 28.57% after testing) of main component.
(3) getting the pseudo-ginseng decoction pieces pulverizes, decoct extraction 3 times with 12 times of water gagings, each 2 hours, merge extractive liquid, filters, it is 1.15 that filtrate is concentrated into relative density for 50 ℃, add ethanol and make and contain alcohol amount and reach 60%, leave standstill after-filtration, filtrate adds ethanol to be made and contains the alcohol amount and reach 70%, leave standstill after-filtration, filtrate is concentrated into does not have alcohol flavor, thin up (solution: medical material is 1: 1), high speed centrifugation, supernatant is crossed the D101 type macroporous adsorptive resins of having handled well, earlier with the water elution of 3 times of column volumes, 80% ethanol elution of 8 times of column volumes of reuse is collected ethanol elution and is recycled to and does not have alcohol and distinguish the flavor of, concentrate, drying is pulverized, and obtaining with the arasaponin is the Radix Notoginseng extract (the Radix Notoginseng total arasaponins weight percentage is 67.58% after testing) of main component.
(4) Borneolum Syntheticum becomes nearly saturated solution standby with anhydrous alcohol solution; Other gets HP-β-CD and adds the injection water and make saturated solution, and Borneolum Syntheticum ethanol liquid slowly is added drop-wise in HP-β-CD saturated solution, does not stop to stir.After adding, 50 ℃ are continued to stir 3 hours again, and cold preservation is spent the night, and filters, and the precipitation cold drying gets Borneolum Syntheticum HP-beta-CD inclusion.
(5) get above-mentioned Radix Salviae Miltiorrhizae extract, Radix Notoginseng extract and add the dissolving of injection water, filter, filtrate is 5000 ultrafilter membrane ultrafiltration with molecular cut off, ultrafiltrate mixes with Borneolum Syntheticum HP-β-CD liquid, adds mannitol, adds the injection water to 1000ml, regulate pH value to 8.5, fill, lyophilization promptly gets 500 bottles of compound red sage root freezing-dried powder injections.
Embodiment 2
(1) prescription of crude drug is: Radix Salviae Miltiorrhizae 400g, Borneolum Syntheticum 6g, Radix Notoginseng 120g;
(2) get the red rooted salvia decoction pieces and pulverize, the decocting that adds 6 times of amounts boils 2 times, and each 1 hour, merge extractive liquid, filtered, and filtrate is put cold, and high speed centrifugation (15000rpm), centrifugal liquid molecular cut off are 5000 ultrafilter membrane ultrafiltration, and filtrate adds NaCO
3Lye pH adjustment value 11, boiled 0.5 hour, put cold, 24 hours after-filtration of cold preservation (4 ℃), it is 3 that filtrate is regulated pH value with sulphuric acid, with 0.5 times ethyl acetate extraction 3 times, and merging ethyl acetate liquid, the concentrating under reduced pressure drying, obtaining with the danshensu is the Radix Salviae Miltiorrhizae extract (the danshensu weight percentage is 26.75% after testing) of main component.
(3) getting the pseudo-ginseng decoction pieces pulverizes, decoct extraction 1 time with 6 times of water gagings, each 1 hour, merge extractive liquid, filters, it is 1.16 that filtrate is concentrated into relative density for 50 ℃, add ethanol and make and contain alcohol amount and reach 70%, leave standstill after-filtration, filtrate adds ethanol to be made and contains the alcohol amount and reach 85%, leave standstill after-filtration, filtrate is concentrated into does not have alcohol flavor, thin up (solution: medical material is 1: 1), high speed centrifugation, supernatant is crossed the AB-8 type macroporous adsorptive resins of having handled well, earlier with the water elution of 6 times of column volumes, 40% ethanol elution of 5 times of column volumes of reuse is collected ethanol elution and is recycled to and does not have alcohol and distinguish the flavor of, concentrate, drying is pulverized, and obtaining with the arasaponin is the Radix Notoginseng extract (the Radix Notoginseng total arasaponins weight percentage is 56.34% after testing) of main component.
(4) Borneolum Syntheticum becomes nearly saturated solution standby with anhydrous alcohol solution; Other gets HP-β-CD and adds the injection water and make saturated solution, and Borneolum Syntheticum ethanol liquid slowly is added drop-wise in HP-β-CD saturated solution, does not stop to stir.After adding, 50 ℃ are continued to stir 3 hours again, and cold preservation is spent the night, and filters, and the precipitation cold drying gets Borneolum Syntheticum HP-beta-CD inclusion.
(5) get above-mentioned Radix Salviae Miltiorrhizae extract, Radix Notoginseng extract and add the dissolving of injection water, filter, filtrate is 5000 ultrafilter membrane ultrafiltration with molecular cut off, ultrafiltrate mixes with Borneolum Syntheticum HP-β-CD liquid, adds lactose and glucosan, adds the injection water to 1000ml, regulate pH value to 7.0, fill, lyophilization promptly gets 500 bottles of compound red sage root freezing-dried powder injections.
Embodiment 3
(1) prescription of crude drug is: Radix Salviae Miltiorrhizae 450g, Borneolum Syntheticum 8g, Radix Notoginseng 141g;
(2) get the red rooted salvia decoction pieces and pulverize, the decocting that adds 8 times of amounts boils 3 times, and each 2 hours, merge extractive liquid, filtered, and filtrate is put cold, and high speed centrifugation (15000rpm), centrifugal liquid molecular cut off are 5000 ultrafilter membrane ultrafiltration, and filtrate adds Ca (OH)
2The lye pH adjustment value is 10, boiled 2 hours, put cold, 24 hours after-filtration of cold preservation (4 ℃), it is 2 that filtrate is regulated pH value with phosphoric acid, with 1.5 times ethyl acetate extractions 7 times, and merging ethyl acetate liquid, the concentrating under reduced pressure drying, obtaining with the danshensu is the Radix Salviae Miltiorrhizae extract (the danshensu weight percentage is 29.73% after testing) of main component.
(3) getting the pseudo-ginseng decoction pieces pulverizes, decoct extraction 2 times with 8 times of water gagings, each 2 hours, merge extractive liquid, filters, it is 1.15 that filtrate is concentrated into relative density for 50 ℃, add ethanol and make and contain alcohol amount and reach 65%, leave standstill after-filtration, filtrate adds ethanol to be made and contains the alcohol amount and reach 80%, leave standstill after-filtration, filtrate is concentrated into does not have alcohol flavor, thin up (solution: medical material is 1: 1), high speed centrifugation, supernatant is crossed the D101 type macroporous adsorptive resins of having handled well, earlier with the water elution of 4 times of column volumes, 70% ethanol elution of 6 times of column volumes of reuse is collected ethanol elution and is recycled to and does not have alcohol and distinguish the flavor of, concentrate, drying is pulverized, and obtaining with the arasaponin is the Radix Notoginseng extract (the Radix Notoginseng total arasaponins weight percentage is 63.52% after testing) of main component.
(4) Borneolum Syntheticum becomes nearly saturated solution standby with anhydrous alcohol solution; Other gets HP-β-CD and adds the injection water and make saturated solution, and Borneolum Syntheticum ethanol liquid slowly is added drop-wise in HP-β-CD saturated solution, does not stop to stir.After adding, 50 ℃ are continued to stir 3 hours again, and cold preservation is spent the night, and filters, and the precipitation cold drying gets Borneolum Syntheticum HP-beta-CD inclusion.
(5) get above-mentioned Radix Salviae Miltiorrhizae extract, Radix Notoginseng extract and add the dissolving of injection water, filter, filtrate is 5000 ultrafilter membrane ultrafiltration with molecular cut off, ultrafiltrate mixes with Borneolum Syntheticum HP-β-CD liquid, adds polyvinylpyrrolidone and glucose and fructose, adds the injection water to 1000ml, regulate pH value to 7.5, fill, lyophilization promptly gets 500 bottles of compound red sage root freezing-dried powder injections.
Embodiment 4
(1) prescription of crude drug is: Radix Salviae Miltiorrhizae 430g, Borneolum Syntheticum 9g, Radix Notoginseng 130g;
(2) getting the red rooted salvia decoction pieces pulverizes, the decocting that adds 9 times of amounts boils 3 times, each 3 hours, merge extractive liquid, filters, filtrate is put cold, high speed centrifugation (15000rpm), centrifugal liquid molecular cut off are 5000 ultrafilter membrane ultrafiltration, and it is 10 that filtrate adds KOH lye pH adjustment value, boiled 1 hour, put cold, 24 hours after-filtration of cold preservation (4 ℃), it is 1 that filtrate is regulated pH value with acetic acid, with 2.5 times ethyl acetate extractions 4 times, merge ethyl acetate liquid, the concentrating under reduced pressure drying, obtaining with the danshensu is the Radix Salviae Miltiorrhizae extract (the danshensu weight percentage is 27.28% after testing) of main component.
(3) getting the pseudo-ginseng decoction pieces pulverizes, decoct extraction 3 times with 10 times of water gagings, each 1 hour, merge extractive liquid, filters, it is 1.15 that filtrate is concentrated into relative density for 50 ℃, add ethanol and make and contain alcohol amount and reach 68%, leave standstill after-filtration, filtrate adds ethanol to be made and contains the alcohol amount and reach 73%, leave standstill after-filtration, filtrate is concentrated into does not have alcohol flavor, thin up (solution: medical material is 1: 1), high speed centrifugation, supernatant is crossed the AB-8 type macroporous adsorptive resins of having handled well, earlier with the water elution of 5 times of column volumes, 50% ethanol elution of 5 times of column volumes of reuse is collected ethanol elution and is recycled to and does not have alcohol and distinguish the flavor of, concentrate, drying is pulverized, and obtaining with the arasaponin is the Radix Notoginseng extract (the Radix Notoginseng total arasaponins weight percentage is 57.63% after testing) of main component.
(4) Borneolum Syntheticum becomes nearly saturated solution standby with anhydrous alcohol solution; Other gets HP-β-CD and adds the injection water and make saturated solution, and Borneolum Syntheticum ethanol liquid slowly is added drop-wise in HP-β-CD saturated solution, does not stop to stir.After adding, 50 ℃ are continued to stir 3 hours again, and cold preservation is spent the night, and filters, and the precipitation cold drying gets Borneolum Syntheticum HP-beta-CD inclusion.
(5) get above-mentioned Radix Salviae Miltiorrhizae extract, Radix Notoginseng extract and add the dissolving of injection water, filter, filtrate is 5000 ultrafilter membrane ultrafiltration with molecular cut off, ultrafiltrate mixes with Borneolum Syntheticum HP-β-CD liquid, adds lactose and dextrorotation fructose and glucosan, adds the injection water to 1000ml, regulate pH value to 8.0, fill, lyophilization, promptly.
Embodiment 5
(1) prescription of crude drug is: Radix Salviae Miltiorrhizae 480g, Borneolum Syntheticum 7g, Radix Notoginseng 150g;
(2) get the red rooted salvia decoction pieces and pulverize, the decocting that adds 7 times of amounts boils 2 times, and each 2 hours, merge extractive liquid, filtered, and filtrate is put cold, and high speed centrifugation (15000rpm), centrifugal liquid molecular cut off are 5000 ultrafilter membrane ultrafiltration, and filtrate adds CaCO
3And KCO
3The lye pH adjustment value is 9, boiled 2.5 hours, put cold, 24 hours after-filtration of cold preservation (4 ℃), it is 2 that filtrate is regulated pH value with glacial acetic acid, with 1 times ethyl acetate extraction 6 times, and merging ethyl acetate liquid, the concentrating under reduced pressure drying, obtaining with the danshensu is the Radix Salviae Miltiorrhizae extract (the danshensu weight percentage is 30.37% after testing) of main component.
(3) getting the pseudo-ginseng decoction pieces pulverizes, decoct extraction 2 times with 9 times of water gagings, each 2 hours, merge extractive liquid, filters, it is 1.16 that filtrate is concentrated into relative density for 50 ℃, add ethanol and make and contain alcohol amount and reach 63%, leave standstill after-filtration, filtrate adds ethanol to be made and contains the alcohol amount and reach 77%, leave standstill after-filtration, filtrate is concentrated into does not have alcohol flavor, thin up (solution: medical material is 1: 1), high speed centrifugation, supernatant is crossed the NKA type macroporous adsorptive resins of having handled well, earlier with the water elution of 5 times of column volumes, 60% ethanol elution of 7 times of column volumes of reuse is collected ethanol elution and is recycled to and does not have alcohol and distinguish the flavor of, concentrate, drying is pulverized, and obtaining with the arasaponin is the Radix Notoginseng extract (the Radix Notoginseng total arasaponins weight percentage is 60.08% after testing) of main component.
(4) Borneolum Syntheticum becomes nearly saturated solution standby with anhydrous alcohol solution; Other gets HP-β-CD and adds the injection water and make saturated solution, and Borneolum Syntheticum ethanol liquid slowly is added drop-wise in HP-β-CD saturated solution, does not stop to stir.After adding, 50 ℃ are continued to stir 3 hours again, and cold preservation is spent the night, and filters, and the precipitation cold drying gets Borneolum Syntheticum HP-beta-CD inclusion.
(5) get above-mentioned Radix Salviae Miltiorrhizae extract, Radix Notoginseng extract and add the dissolving of injection water, filter, filtrate is 5000 ultrafilter membrane ultrafiltration with molecular cut off, ultrafiltrate mixes with Borneolum Syntheticum HP-β-CD liquid, adds mannitol and lactose, adds the injection water to 1000ml, regulate pH value to 7.2, fill, lyophilization promptly gets 500 bottles of compound red sage root freezing-dried powder injections.
Claims (6)
1, a kind of drug regimen group that contains danshensu, Radix Notoginseng total arasaponins and Borneolum Syntheticum is characterized in that it is that hydroxypropyl clathrate and pharmaceutic adjuvant by Radix Salviae Miltiorrhizae extract, Radix Notoginseng extract and Borneolum Syntheticum is prepared from; Its feature is that also the danshensu weight percentage is more than or equal to 25% in the Radix Salviae Miltiorrhizae extract, and the Radix Notoginseng total arasaponins weight percentage is more than or equal to 55% in the Radix Notoginseng extract.
2, pharmaceutical composition according to claim 1 is a lyophilized injectable powder.
3, a kind of preparation method that contains the drug regimen group of danshensu, Radix Notoginseng total arasaponins and Borneolum Syntheticum, its feature may further comprise the steps:
(1) prescription of crude drug is: Radix Salviae Miltiorrhizae 400-500 weight portion, Borneolum Syntheticum 6-10 weight portion, Radix Notoginseng 120-160 weight portion;
(2) getting the red rooted salvia decoction pieces pulverizes, adding the decocting that 6-10 doubly measures boils 2-4 time, each 1-3 hour, merge extractive liquid, filters, filtrate is put cold, with 15000 rev/mins centrifugal, the centrifugal liquid molecular cut off is 5000 ultrafilter membrane ultrafiltration, filtrate adds lye pH adjustment value 9-11, boiled 0.5-3 hour, put cold, 24 hours after-filtration of cold preservation (4 ℃), filtrate is 2-3 with organic acid or inorganic acid for adjusting pH value, with 0.5～3 times ethyl acetate extraction 3～9 times, merge ethyl acetate liquid, the concentrating under reduced pressure drying, obtaining with the danshensu is the Radix Salviae Miltiorrhizae extract of main component.
(3) getting the pseudo-ginseng decoction pieces pulverizes, decoct extraction 1-3 time with 6-12 times of water gaging, each 1-2 hour, merge extractive liquid, filters, it is 1.15-1.16 that filtrate is concentrated into relative density for 50 ℃, add ethanol and make and contain alcohol amount and reach 60%-70%, leave standstill after-filtration, filtrate adds ethanol to be made and contains the alcohol amount and reach 70%-85%, leave standstill after-filtration, filtrate is concentrated into does not have alcohol flavor, thin up (solution: medical material is 1: 1), high speed centrifugation, supernatant is crossed the macroporous adsorptive resins of having handled well, with the water elution of 3-6 times of column volume, the ethanol elution of the 40%-80% of reuse 5-8 times column volume is collected ethanol elution and is recycled to nothing alcohol flavor earlier, concentrate, drying is pulverized, and obtaining with the arasaponin is the Radix Notoginseng extract of main component.
(4) Borneolum Syntheticum becomes nearly saturated solution standby with anhydrous alcohol solution; Other gets HP-β-CD and adds the injection water and make saturated solution, and Borneolum Syntheticum ethanol liquid slowly is added drop-wise in HP-β-CD saturated solution, does not stop to stir.After adding, 50 ℃ are continued to stir 3 hours again, and cold preservation is spent the night, and filters, and goes precipitation, gets Borneolum Syntheticum HP-beta-CD inclusion.
(5) get above-mentioned Radix Salviae Miltiorrhizae extract, Radix Notoginseng extract and add the dissolving of injection water, filter, filtrate is 5000 ultrafilter membrane ultrafiltration with molecular cut off, ultrafiltrate mixes with Borneolum Syntheticum HP-β-CD liquid, adds the lyophilizing excipient, adds the injection water to ormal weight, regulate pH value to 7.0-8.5, cool-drying is frozen in fill, promptly.
4, alkali liquor according to claim 3 is the aqueous solution of inorganic bases such as sodium hydroxide, sodium carbonate, calcium hydroxide, calcium carbonate, potassium hydroxide, potassium carbonate.
5, macroporous adsorbent resin according to claim 3 can be the macroporous adsorbent resin of nonpolar or low pole.
6, freeze-dried excipient according to claim 3 is a kind of, two or more the mixture in mannitol, glucosan, glucose, fructose, dextrorotation fructose, polyvinylpyrrolidone and the lactose.
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| CN1919247B (en) * | 2005-08-24 | 2011-02-16 | 天津天士力制药股份有限公司 | Chinese medicine for treating cardiovascular and cerebrovascular disease |
| CN101084998B (en) * | 2006-06-08 | 2011-10-26 | 天津天士力之骄药业有限公司 | Compound red sage root freezing-dried powder injection |
| CN101085001B (en) * | 2006-06-08 | 2011-11-30 | 天津天士力之骄药业有限公司 | Compound red sage root freezing-dried powder injection containing tanshinol and its preparation method |
| CN101085002B (en) * | 2006-06-08 | 2012-02-01 | 天津天士力之骄药业有限公司 | Compound red sage root freezing-dried powder injection containing borneol and its preparation method |
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| CN101084997B (en) * | 2006-06-08 | 2012-06-06 | 天津天士力之骄药业有限公司 | Traditional Chinese medicine freezing-dried powder injection for treating cardiovascular and cerebrovascular diseases and its preparing method |
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| CN104547026A (en) * | 2013-10-23 | 2015-04-29 | 天津天士力现代中药资源有限公司 | Preparation method and application of salvia miltiorrhiza leave and panax pseudo-ginseng extract |
| CN104547026B (en) * | 2013-10-23 | 2020-08-11 | 天津天士力现代中药资源有限公司 | Preparation method and application of salvia miltiorrhiza leave pseudo-ginseng extract |
| CN106748149A (en) * | 2016-12-23 | 2017-05-31 | 庆阳敦博科技发展有限公司 | A kind of walnut nutritious fertilizer and preparation method thereof |
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