CN1586491A - Medicinal composition containing salvianolic acid B, total ara-saponin and camphol and its preparation and use - Google Patents
Medicinal composition containing salvianolic acid B, total ara-saponin and camphol and its preparation and use Download PDFInfo
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- CN1586491A CN1586491A CN 200410071049 CN200410071049A CN1586491A CN 1586491 A CN1586491 A CN 1586491A CN 200410071049 CN200410071049 CN 200410071049 CN 200410071049 A CN200410071049 A CN 200410071049A CN 1586491 A CN1586491 A CN 1586491A
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- China
- Prior art keywords
- extract
- salviae miltiorrhizae
- acid
- radix salviae
- borneolum syntheticum
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- 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 47
- 238000002360 preparation method Methods 0.000 title claims abstract description 42
- 239000000203 mixture Substances 0.000 title claims abstract description 6
- SNKFFCBZYFGCQN-UHFFFAOYSA-N 2-[3-[3-[1-carboxy-2-(3,4-dihydroxyphenyl)ethoxy]carbonyl-2-(3,4-dihydroxyphenyl)-7-hydroxy-2,3-dihydro-1-benzofuran-4-yl]prop-2-enoyloxy]-3-(3,4-dihydroxyphenyl)propanoic acid Chemical compound C=1C=C(O)C=2OC(C=3C=C(O)C(O)=CC=3)C(C(=O)OC(CC=3C=C(O)C(O)=CC=3)C(O)=O)C=2C=1C=CC(=O)OC(C(=O)O)CC1=CC=C(O)C(O)=C1 SNKFFCBZYFGCQN-UHFFFAOYSA-N 0.000 title claims description 30
- SNKFFCBZYFGCQN-VWUOOIFGSA-N Lithospermic acid B Natural products C([C@H](C(=O)O)OC(=O)\C=C\C=1C=2[C@H](C(=O)O[C@H](CC=3C=C(O)C(O)=CC=3)C(O)=O)[C@H](OC=2C(O)=CC=1)C=1C=C(O)C(O)=CC=1)C1=CC=C(O)C(O)=C1 SNKFFCBZYFGCQN-VWUOOIFGSA-N 0.000 title claims description 30
- STCJJTBMWHMRCD-UHFFFAOYSA-N salvianolic acid B Natural products OC(=O)C(Cc1ccc(O)c(O)c1)OC(=O)C=Cc2cc(O)c(O)c3OC(C(C(=O)OC(Cc4ccc(O)c(O)c4)C(=O)O)c23)c5ccc(O)c(O)c5 STCJJTBMWHMRCD-UHFFFAOYSA-N 0.000 title claims description 30
- 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 114
- 239000000284 extract Substances 0.000 claims abstract description 96
- 235000003143 Panax notoginseng Nutrition 0.000 claims abstract description 58
- 241000180649 Panax notoginseng Species 0.000 claims abstract description 58
- 239000007924 injection Substances 0.000 claims abstract description 52
- 238000002347 injection Methods 0.000 claims abstract description 52
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 46
- 240000007164 Salvia officinalis Species 0.000 claims abstract description 40
- 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 21
- 239000011347 resin Substances 0.000 claims abstract description 11
- 229920005989 resin Polymers 0.000 claims abstract description 11
- 238000001556 precipitation Methods 0.000 claims abstract description 8
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- 239000000706 filtrate Substances 0.000 claims description 36
- 239000003814 drug Substances 0.000 claims description 29
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 24
- 238000000605 extraction Methods 0.000 claims description 23
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- 150000007965 phenolic acids Chemical class 0.000 claims description 15
- 238000003756 stirring Methods 0.000 claims description 15
- 235000017276 Salvia Nutrition 0.000 claims description 14
- 238000001035 drying Methods 0.000 claims description 13
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 10
- 238000000703 high-speed centrifugation Methods 0.000 claims description 10
- 238000004108 freeze drying Methods 0.000 claims description 8
- 239000012567 medical material Substances 0.000 claims description 8
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- 244000131316 Panax pseudoginseng Species 0.000 claims description 7
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- 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
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-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
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims description 4
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- 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
- 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
- 150000007524 organic acids Chemical class 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
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 2
- 229910000147 aluminium phosphate Inorganic materials 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
- 239000012362 glacial acetic acid Substances 0.000 claims description 2
- 239000008103 glucose Substances 0.000 claims description 2
- 150000007522 mineralic acids Chemical class 0.000 claims description 2
- 239000008194 pharmaceutical composition Substances 0.000 claims description 2
- 239000001267 polyvinylpyrrolidone Substances 0.000 claims description 2
- 229920000036 polyvinylpyrrolidone Polymers 0.000 claims description 2
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 claims description 2
- 239000001117 sulphuric acid Substances 0.000 claims description 2
- 235000011149 sulphuric acid Nutrition 0.000 claims description 2
- 239000003463 adsorbent Substances 0.000 claims 2
- YPJUIYBMJQCGJM-UHFFFAOYSA-N acetic acid;pentan-3-one Chemical compound CC(O)=O.CCC(=O)CC YPJUIYBMJQCGJM-UHFFFAOYSA-N 0.000 claims 1
- 229910052500 inorganic mineral Inorganic materials 0.000 claims 1
- 239000011707 mineral Substances 0.000 claims 1
- 150000001875 compounds Chemical class 0.000 abstract description 28
- 235000005412 red sage Nutrition 0.000 abstract description 26
- 230000000694 effects Effects 0.000 abstract description 10
- 238000003810 ethyl acetate extraction Methods 0.000 abstract description 9
- 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 abstract 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 abstract description 5
- 229930183842 salvianolic acid Natural products 0.000 abstract description 5
- 238000002137 ultrasound extraction Methods 0.000 abstract description 2
- 238000003809 water extraction Methods 0.000 abstract description 2
- 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
- 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
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- 238000000034 method Methods 0.000 description 29
- 239000008899 fufang danshen Substances 0.000 description 20
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 15
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- 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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Landscapes
- Medicines Containing Plant Substances (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
The medicinal composition of the present invention is compound freeze dried red sage powder for injection comprising red sage extract with salvianolic acid 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 ultrasonic extraction, ultrafiltering, ethyl acetate extraction and concentration; 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 salvianolic acid B, 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, has the cooperative compensating effect behind Radix Salviae Miltiorrhizae and the Radix Notoginseng compatibility; Salvianolic acid B that Radix Salviae Miltiorrhizae is contained and TANSHINONES all have the effect that resists myocardial ischemia, and [the compound red sage root formula mechanism of action is verified.Modern combination of Chinese and Western medicine magazine 2004,13 (8): 999]; What the Radix Salviae Miltiorrhizae pharmacological action was strong is its aqueous soluble active constituent, mainly is phenolic acid compound in the water soluble ingredient, and wherein content of danshinolic acid B is the highest, reaches more than 5%, and effect is the strongest [Zhang Qiwei etc. also.Salvianolic acid B in the high effective liquid chromatography for measuring Radix Salviae Miltiorrhizae.CHINA JOURNAL OF CHINESE MATERIA MEDICA, 2001,26 (12): 848].Therefore, the height of content of danshinolic acid B in the medicine directly affects the clinical therapeutic efficacy of preparation.
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.Patent CN01142288 and patent CN02117923 disclose the preparation method of total salvianolic acid in the Radix Salviae Miltiorrhizae respectively.But pressure differential self is very unstable, even for a long time 60-70 ℃ of heating, also can decompose rotten active other the more weak or invalid composition that is, pharmacological action is obviously reduced or forfeiture.Application number is that the patent of CN01142288 and CN02117923 all adopts the aqueous soluble active constituent in 60-100 ℃ the hot water extraction red rooted salvia, though that has noticed the salvianolic acid constituents is subjected to thermal instability for a long time, in extraction process, fundamentally do not take measures to remedy the defective and the deficiency of prior art.
Phenolic acids effective ingredient in the Radix Salviae Miltiorrhizae and tannin structural similarity, character is close.So application number is 02144600,03112650,03132383,90107488,98103032 the used method of removing the tannin in the Radix Salviae Miltiorrhizae extract of patent documentation can be very big to the phenolic acids loss of effective components, make its content reduce, can't reach the mass effect of expection.
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.
Ultrasound assisted extraction technique is to utilize ultrasound wave to produce judder, and is high-speed, intensive cavitation effect, and stirring action can destroy the cell of vegetable drug, make the solvent porous in crude drug cell, thereby the effective ingredient that quickens in the medical material is dissolved in the solvent.Ultrasonic technique extraction rate height, extraction time be short, it is low to extract temperature, is particularly suitable for the extraction for determination system of thermal unstable material.Rotate shave embrane method is suitable for concentrating, separating determination system of thermal unstable material.
Hyperfiltration technique is meant under the room temperature with certain pressure and flow, utilize asymmetric microcellular structure and semipermeable membrane separating medium, filter in the cross-flow mode, solvent and small-molecule substance are passed through, polymer substance and micropartical such as protein, water soluble polymer, antibacterial etc. are by the filter membrane detention, thereby reaching separation, purification, spissated new membrane isolation technics with fastest developing speed, can the isolated molecule amount be 1000～1000000 daltonian materials.Compare with traditional separation method, have separation process do not have phase transformation, separation efficiency height, need not to add chemical reagent pollution-free, need not to heat, energy consumption is low, mild condition is not destroyed composition, easy to operate, characteristics that flow process is short.In addition, ultrafilter membrane can also be used to removing the impurity such as tannin, protein and macromolecular saccharide in the injection, improves the clarity of injection etc.Utilize hyperfiltration technique to prepare injection, can also be used for effectively removing antibacterial and pyrogen.So the present invention adopts hyperfiltration technique in preparation process after, the quality of injection has obtained tangible improvement and raising.
Summary of the invention
The present invention improves the dosage form of FUFANG DANSHEN PIAN (see one one of " pharmacopeia " version in 2000, Chinese Pharmacopoeia Commission compiles), and 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 and preparation method thereof.The present invention adopts supersound extraction, ultrafiltration, and ethyl acetate extraction, the method that rotation knifing concentration technique combines is extracted the effective ingredient based on salvianolic acid B from Radix Salviae Miltiorrhizae; Adopt decoction and alcohol sedimentation technique, macroreticular resin absorbing method extracts from Radix Notoginseng 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) get the red rooted salvia decoction pieces, pulverize, add 6-10 water doubly, put into the supersound extraction jar, carry out supersound extract, time is 20-50 minute, frequency of oscillation is 20-100kHz, the control temperature is a room temperature, extracts 2-4 time, and merge extractive liquid, filters, the filtrate high speed centrifugation, the centrifugal liquid molecular cut off is 5000 ultrafilter membrane ultrafiltration, filtrate with the control temperature be 40 ℃ rotation knifing concentrating instrument to be concentrated into relative density be to be 1-3 with organic acid or inorganic acid for adjusting pH value behind the 1.10-1.15, with 0.5～3 times ethyl acetate extraction 3～9 times, merge ethyl acetate liquid, with the control temperature is that 40 ℃ rotation knifing concentrating instrument concentrates, and concentrates the extractum vacuum drying below 40 ℃ that obtains, and obtaining with the salvianolic acid B 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, and it is 1.15-1.16 that filtrate is concentrated into relative density for 50 ℃, adds ethanol and makes and contain the alcohol amount and reach 60%-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 macroporous adsorptive resins of having handled well, with the water elution of 4-6 times of column volume, the ethanol elution of the 50%-80% of reuse 6-8 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 5.0-6.8, fill, lyophilization, promptly.
In the preparation process of Radix Salviae Miltiorrhizae extract, be that 5000 ultrafilter membrane has been removed the bigger impurity of the molecular weight based on tannin in the Radix Salviae Miltiorrhizae with high speed centrifugation and molecular cut off, and the less phenolic acids effective ingredient of molecular weight pass through smoothly.Removing of tannin, patient's misery when having alleviated injection; With the effective ingredient in the lower boiling ethyl acetate extraction aqueous solution, not only the extraction efficiency height, the time spent is short, temperature is low, and the temperature that heats in the spissated process of ethyl acetate liquid of extraction is lower, cooperate rotation knifing concentration technique again, prevent that the salvianolic acid effective constituents is heated for a long time and decomposes.Preparation technology of the present invention carries out under lower temperature fully, can effectively keep effective ingredient.Salvianolic acid effective constituents absolute content and relative amount are all higher in the feasible extract that finally obtains.
Two, the Radix Salviae Miltiorrhizae extract of distinct methods preparation, salvianolic acid B, the content of total phenolic acid are relatively
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.Salvianolic acid B (Qianluchun Science and Technology Co., Ltd., Beijing's laboratory provides, and purity is 98.2%).
No. 1 Radix Salviae Miltiorrhizae extract, the 5kg red rooted salvia is by the method preparation of patent CN02117923.9; No. 2 Radix Salviae Miltiorrhizae extracts, the 5kg red rooted salvia is by the method preparation of patent CN01142288.2; No. 3 Radix Salviae Miltiorrhizae extracts, the 5kg red rooted salvia is by the preparation method preparation (Qianluchun Science and Technology Co., Ltd., Beijing's laboratory provides) of Radix Salviae Miltiorrhizae extract of the present invention;
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 (45: 55); Flow velocity: 1.0ml/min; Detect wavelength: 288nm.Number of theoretical plate should be not less than 3000 by salvianolic acid B peak compute.
3. reference substance solution prepares precision and takes by weighing salvianolic acid B 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, salvianolic acid B is the good linear relation in 0.5 μ g～6.0 μ g scopes as a result, regression equation is Y=1000843X-4989, r=0.9998.
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.
Radix Salviae Miltiorrhizae total phenolic acids is that the method in 01142288 the patent application document is measured with reference to application number.
The Radix Salviae Miltiorrhizae extract of table 1 distinct methods preparation relatively
Total phenolic content (%) extract weight (g) of numbering content of danshinolic acid B (%)
1 54.11 82.69 221.3
2 53.46 84.52 115.6
3 58.26 88.37 225.6
By above measurement result as can be seen, total phenolic content, content of danshinolic acid B in the Radix Salviae Miltiorrhizae extract of the present invention, extract yield illustrates that apparently higher than the content of other two kinds of Radix Salviae Miltiorrhizae extracts preparation technology of the present invention is more reasonable, science has more practical significance more.
Three, the tannin inspection in the Radix Salviae Miltiorrhizae extract of distinct methods preparation
1. No. 1 Radix Salviae Miltiorrhizae extract of sample preparation, the 500g red rooted salvia is by the method preparation of patent CN02144600; No. 2 Radix Salviae Miltiorrhizae extracts, the 500g red rooted salvia is by the method preparation of patent CN95115854; No. 3 Radix Salviae Miltiorrhizae extracts, the 500g red rooted salvia is by the preparation method preparation (Qianluchun Science and Technology Co., Ltd., Beijing's laboratory provides) of Radix Salviae Miltiorrhizae extract of the present invention;
2. it is an amount of that inspection method is got each Radix Salviae Miltiorrhizae extract, adds the water for injection dissolving and also be diluted to 200ml, and precision is measured each solution 1ml, according to list of references [Jiang Bo, etc.Contain Radix Salviae Miltiorrhizae Chinese medicine injection tannin and check new method.Chinese patent medicine, 2000,22 (3): 192] experimental technique carries out, and observes muddy or sedimentary situation.The results are shown in Table 2.
Tannin inspection in the Radix Salviae Miltiorrhizae extract of table 2 distinct methods preparation
The numbering phenomenon
1 +
2 +
3 -
Annotate: the no turbid phenomenon of-expression; + expression has turbid phenomenon;
By above check result as can be seen, the content of tannin in the Radix Salviae Miltiorrhizae extract of the present invention is starkly lower than the content of other two kinds of Radix Salviae Miltiorrhizae extracts, illustrate that preparation technology of the present invention 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 total phenolic acid, salvianolic acid B 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 total phenolic acid and salvianolic acid B 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
Total phenolic acid salvianolic acid B Radix Notoginseng total arasaponins
1 88.37 58.26 67.58
2 85.86 56.75 56.34
3 88.13 59.73 63.52
4 87.42 57.28 57.63
5 90.58 58.37 60.08
By above measurement result as can be seen, the salvianolic acid B weight percentage is greater than 55% greater than 85%, in the Radix Salviae Miltiorrhizae extract for total phenolic acid weight percentage 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 17.55 ± 2.64
FUFANG DANSHEN ZHUSHEYE group 10 27.48 ± 2.86
*
Compound red sage root freezing-dried powder injection group 10 32.22 ± 3.17 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 6.42 ± 0.88
FUFANG DANSHEN ZHUSHEYE group 10 11.76 ± 0.54
*
Compound red sage root freezing-dried powder injection group 10 13.84 ± 0.63 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 0.36 ± 0.14 0.25 ± 0.19 0.18 ± 0.024
FUFANG DANSHEN ZHUSHEYE group 10 0.24 ± 0.07
*0.16 ± 0.04
*0.086 ± 0.016
*
Compound red sage root freezing-dried powder injection group 10 0.18 ± 0.06 of the present invention
*# 0.10 ± 0.03
*# 0.053 ± 0.013
*#
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, pulverize, add 10 times water, put into the supersound extraction jar, carry out supersound extract, time is 50 minutes, frequency of oscillation is 100kHz, the control temperature is a room temperature, extracts 4 times, and merge extractive liquid, filters, filtrate 13000rpm is centrifugal, the centrifugal liquid molecular cut off is 5000 ultrafilter membrane ultrafiltration, filtrate with the control temperature be 40 ℃ rotation knifing concentrating instrument to be concentrated into relative density be that to regulate pH value with hydrochloric acid be 1 in 1.15 backs, with 3 times ethyl acetate extractions 9 times, merge ethyl acetate liquid, with the control temperature is that 40 ℃ rotation knifing concentrating instrument concentrates, and concentrates the extractum vacuum drying below 40 ℃ that obtains, and obtaining with the salvianolic acid B is the Radix Salviae Miltiorrhizae extract 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, and it is 1.15 that filtrate is concentrated into relative density for 50 ℃, adds ethanol and makes and contain the alcohol amount and reach 60%, 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, 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 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 5.0,500 bottles of fills, lyophilization, promptly.
The assay result is: total phenolic acid weight percentage is 88.37% in the Radix Salviae Miltiorrhizae extract, the salvianolic acid B weight percentage is 58.26% in the Radix Salviae Miltiorrhizae extract, and the Radix Notoginseng total arasaponins weight percentage is 67.58% in the Radix Notoginseng extract.
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, pulverize, add 6 times water, put into the supersound extraction jar, carry out supersound extract, time is 20 minutes, frequency of oscillation is 20kHz, the control temperature is a room temperature, extracts 2 times, and merge extractive liquid, filters, filtrate 12000rpm is centrifugal, the centrifugal liquid molecular cut off is 5000 ultrafilter membrane ultrafiltration, filtrate with the control temperature be 40 ℃ rotation knifing concentrating instrument to be concentrated into relative density be that to regulate pH value with sulphuric acid be 3 in 1.10 backs, with 0.5 times ethyl acetate extraction 3 times, merge ethyl acetate liquid, with the control temperature is that 40 ℃ rotation knifing concentrating instrument concentrates, and concentrates the extractum vacuum drying below 40 ℃ that obtains, and obtaining with the salvianolic acid B is the Radix Salviae Miltiorrhizae extract 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, and it is 1.16 that filtrate is concentrated into relative density for 50 ℃, adds ethanol and makes and contain 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 AB-8 type macroporous adsorptive resins of having handled well, earlier with the water elution of 6 times of column volumes, 50% 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 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 6.8,500 bottles of fills, lyophilization, promptly.
The assay result is: total phenolic acid weight percentage is 85.86% in the Radix Salviae Miltiorrhizae extract, the salvianolic acid B weight percentage is 56.75% in the Radix Salviae Miltiorrhizae extract, and the Radix Notoginseng total arasaponins weight percentage is 56.34% in the Radix Notoginseng extract.
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, pulverize, add 8 times water, put into the supersound extraction jar, carry out supersound extract, time is 40 minutes, frequency of oscillation is 50kHz, the control temperature is a room temperature, extracts 3 times, and merge extractive liquid, filters, filtrate 18000rpm is centrifugal, the centrifugal liquid molecular cut off is 5000 ultrafilter membrane ultrafiltration, filtrate with the control temperature be 40 ℃ rotation knifing concentrating instrument to be concentrated into relative density be that to regulate pH value with phosphoric acid be 2 in 1.13 backs, with 2 times ethyl acetate extractions 5 times, merge ethyl acetate liquid, with the control temperature is that 40 ℃ rotation knifing concentrating instrument concentrates, and concentrates the extractum vacuum drying below 40 ℃ that obtains, and obtaining with the salvianolic acid B is the Radix Salviae Miltiorrhizae extract of main component.
(3) getting the pseudo-ginseng decoction pieces pulverizes, decoct extraction 2 times with 8 times of water gagings, each 1 hour, merge extractive liquid, filters, and it is 1.15 that filtrate is concentrated into relative density for 50 ℃, adds ethanol and makes and contain 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 NKA type macroporous adsorptive resins of having handled well, earlier with the water elution of 5 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 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 6.0,500 bottles of fills, lyophilization, promptly.
The assay result is: total phenolic acid weight percentage is 88.13% in the Radix Salviae Miltiorrhizae extract, the salvianolic acid B weight percentage is 59.73% in the Radix Salviae Miltiorrhizae extract, and the Radix Notoginseng total arasaponins weight percentage is 63.52% in the Radix Notoginseng extract.
Embodiment 4
(1) prescription of crude drug is: Radix Salviae Miltiorrhizae 430g, Borneolum Syntheticum 9g, Radix Notoginseng 130g;
(2) get the red rooted salvia decoction pieces, pulverize, add 9 times water, put into the supersound extraction jar, carry out supersound extract, time is 30 minutes, frequency of oscillation is 40kHz, the control temperature is a room temperature, extracts 2 times, and merge extractive liquid, filters, filtrate 14000rpm is centrifugal, the centrifugal liquid molecular cut off is 5000 ultrafilter membrane ultrafiltration, filtrate with the control temperature be 40 ℃ rotation knifing concentrating instrument to be concentrated into relative density be that to regulate pH value with acetic acid be 3 in 1.12 backs, with 1 times ethyl acetate extraction 7 times, merge ethyl acetate liquid, with the control temperature is that 40 ℃ rotation knifing concentrating instrument concentrates, and concentrates the extractum vacuum drying below 40 ℃ that obtains, and obtaining with the salvianolic acid B is the Radix Salviae Miltiorrhizae extract of main component.
(3) getting the pseudo-ginseng decoction pieces pulverizes, decoct extraction 2 times with 10 times of water gagings, each 2 hours, merge extractive liquid, filters, and it is 1.16 that filtrate is concentrated into relative density for 50 ℃, adds ethanol and makes and contain the alcohol amount and reach 65%, 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 macroporous adsorptive resins of having handled well, earlier with the water elution of 4 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 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 5.5,500 bottles of fills, lyophilization, promptly.
The assay result is: total phenolic acid weight percentage is 87.42% in the Radix Salviae Miltiorrhizae extract, the salvianolic acid B weight percentage is 57.28% in the Radix Salviae Miltiorrhizae extract, and the Radix Notoginseng total arasaponins weight percentage is 57.63% in the Radix Notoginseng extract.
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, pulverize, add 7 times water, put into the supersound extraction jar, carry out supersound extract, time is 45 minutes, frequency of oscillation is 80kHz, the control temperature is a room temperature, extracts 3 times, and merge extractive liquid, filters, filtrate 16000rpm is centrifugal, the centrifugal liquid molecular cut off is 5000 ultrafilter membrane ultrafiltration, filtrate with the control temperature be 40 ℃ rotation knifing concentrating instrument to be concentrated into relative density be that to regulate pH value with glacial acetic acid be 2 in 1.14 backs, with 2.5 times ethyl acetate extractions 4 times, merge ethyl acetate liquid, with the control temperature is that 40 ℃ rotation knifing concentrating instrument concentrates, and concentrates the extractum vacuum drying below 40 ℃ that obtains, and obtaining with the salvianolic acid B is the Radix Salviae Miltiorrhizae extract of main component.
(3) getting the pseudo-ginseng decoction pieces pulverizes, decoct extraction 3 times with 9 times of water gagings, each 2 hours, merge extractive liquid, filters, and it is 1.16 that filtrate is concentrated into relative density for 50 ℃, adds ethanol and makes and contain the alcohol amount and reach 75%, 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 macroporous adsorptive resins of having handled well, earlier with the water elution of 5 times of column volumes, 65% 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 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 5.8,500 bottles of fills, lyophilization, promptly.
The assay result is: total phenolic acid weight percentage is 90.58% in the Radix Salviae Miltiorrhizae extract, the salvianolic acid B weight percentage is 58.37% in the Radix Salviae Miltiorrhizae extract, and the Radix Notoginseng total arasaponins weight percentage is 60.08% in the Radix Notoginseng extract.
Claims (7)
1, a kind of drug regimen group that contains salvianolic acid B, 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 total phenolic acid weight percentage is more than or equal to 85% in the Radix Salviae Miltiorrhizae extract, and the salvianolic acid B weight percentage is more than or equal to 55% 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 salvianolic acid B, 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) get the red rooted salvia decoction pieces, pulverize, add 6-10 water doubly, put into the supersound extraction jar, carry out supersound extract, time is 20-50 minute, frequency of oscillation is 20-100kHz, the control temperature is a room temperature, extracts 2-4 time, and merge extractive liquid, filters, the filtrate high speed centrifugation, the centrifugal liquid molecular cut off is 5000 ultrafilter membrane ultrafiltration, filtrate with the control temperature be 40 ℃ rotation knifing concentrating instrument to be concentrated into relative density be to be 1-3 with organic acid or inorganic acid for adjusting pH value behind the 1.10-1.15, with 0.5～3 times acetic acid ethyl ketone extraction 3～9 times, merge ethyl acetate liquid, with the control temperature is that 40 ℃ rotation knifing concentrating instrument concentrates, and concentrates the extractum vacuum drying below 40 ℃ that obtains, and obtaining with the salvianolic acid B 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, and it is 1.15-1.16 that filtrate is concentrated into relative density for 50 ℃, adds ethanol and makes and contain the alcohol amount and reach 60%-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 macroporous adsorptive resins of having handled well, with the water elution of 4-6 times of column volume, the ethanol elution of the 50%-80% of reuse 6-8 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 5.0-6.8, fill, lyophilization, promptly.
4, macroporous adsorbent resin according to claim 3 can be the macroporous adsorbent resin of nonpolar or low pole.
5, ultracentrifugal speed according to claim 3 is advisable with 12000-18000 rev/min.
6, mineral acid according to claim 3 and organic acid include but not limited to hydrochloric acid, sulphuric acid, phosphoric acid, acetic acid, glacial acetic acid.
7, freeze-dried excipient according to claim 3 is a kind of, two or more the mixture in mannitol, glucosan, polyvinylpyrrolidone, glucose, fructose, dextrorotation fructose and the lactose.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
| CN101085000B (en) * | 2006-06-08 | 2012-04-18 | 天津天士力之骄药业有限公司 | Compound red sage root freezing-dried powder injection containing salvianolic acid B and its preparation method |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN1242199A (en) * | 1998-07-17 | 2000-01-26 | 张家口市长城制药厂 | Process for producing powder injection of compound red sage root medicine |
| CN1349818A (en) * | 2001-10-24 | 2002-05-22 | 沈阳药科大学 | Effective part group in red sage mixture and its delayed release prepn. medicinal use and prepn process |
| CN1460517A (en) * | 2003-07-02 | 2003-12-10 | 北京博尔达生物技术开发有限公司 | Compound danshen oral disintegrant tablet and its preparation method |
| CN100372525C (en) * | 2004-06-01 | 2008-03-05 | 广东天之骄生命科技有限公司 | Frozen dry powder injection of composite salvia miltiorrhiza and its preparation |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
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| 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 |
| CN101085000B (en) * | 2006-06-08 | 2012-04-18 | 天津天士力之骄药业有限公司 | Compound red sage root freezing-dried powder injection containing salvianolic acid B and its preparation method |
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