CN1669578A - Injection for treating cardiovascular and cerebrovascular diseases and process for preparing same - Google Patents
Injection for treating cardiovascular and cerebrovascular diseases and process for preparing same Download PDFInfo
- Publication number
- CN1669578A CN1669578A CN 200410083967 CN200410083967A CN1669578A CN 1669578 A CN1669578 A CN 1669578A CN 200410083967 CN200410083967 CN 200410083967 CN 200410083967 A CN200410083967 A CN 200410083967A CN 1669578 A CN1669578 A CN 1669578A
- Authority
- CN
- China
- Prior art keywords
- injection
- folium crataegi
- crataegi extract
- preparation
- extract
- 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.)
- Pending
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- 239000007924 injection Substances 0.000 title claims abstract description 42
- 238000002347 injection Methods 0.000 title claims abstract description 42
- 208000024172 Cardiovascular disease Diseases 0.000 title description 9
- 208000026106 cerebrovascular disease Diseases 0.000 title description 8
- 230000002526 effect on cardiovascular system Effects 0.000 title description 8
- 238000004519 manufacturing process Methods 0.000 title 1
- 238000002360 preparation method Methods 0.000 claims abstract description 33
- 239000000843 powder Substances 0.000 claims abstract description 25
- 230000000694 effects Effects 0.000 claims abstract description 8
- 238000001802 infusion Methods 0.000 claims abstract description 5
- 206010002383 Angina Pectoris Diseases 0.000 claims abstract 2
- 208000029078 coronary artery disease Diseases 0.000 claims abstract 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 34
- 239000008215 water for injection Substances 0.000 claims description 16
- JMFSHKGXVSAJFY-UHFFFAOYSA-N Saponaretin Natural products OCC(O)C1OC(Oc2c(O)cc(O)c3C(=O)C=C(Oc23)c4ccc(O)cc4)C(O)C1O JMFSHKGXVSAJFY-UHFFFAOYSA-N 0.000 claims description 15
- MOZJVOCOKZLBQB-UHFFFAOYSA-N Vitexin Natural products OCC1OC(Oc2c(O)c(O)cc3C(=O)C=C(Oc23)c4ccc(O)cc4)C(O)C(O)C1O MOZJVOCOKZLBQB-UHFFFAOYSA-N 0.000 claims description 15
- PZKISQRTNNHUGF-UHFFFAOYSA-N vitexine Natural products OC1C(O)C(O)C(CO)OC1OC1=C(O)C=C(O)C2=C1OC(C=1C=CC(O)=CC=1)=CC2=O PZKISQRTNNHUGF-UHFFFAOYSA-N 0.000 claims description 15
- 238000001914 filtration Methods 0.000 claims description 13
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 claims description 12
- 239000003708 ampul Substances 0.000 claims description 11
- 238000003556 assay Methods 0.000 claims description 10
- 239000012982 microporous membrane Substances 0.000 claims description 10
- GEHJYWRUCIMESM-UHFFFAOYSA-L sodium sulfite Chemical compound [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 claims description 10
- -1 vitexin glycoside Chemical class 0.000 claims description 10
- 238000012856 packing Methods 0.000 claims description 9
- SHZGCJCMOBCMKK-UHFFFAOYSA-N D-mannomethylose Natural products CC1OC(O)C(O)C(O)C1O SHZGCJCMOBCMKK-UHFFFAOYSA-N 0.000 claims description 8
- SGEWCQFRYRRZDC-VPRICQMDSA-N vitexin Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@H]1C1=C(O)C=C(O)C2=C1OC(C=1C=CC(O)=CC=1)=CC2=O SGEWCQFRYRRZDC-VPRICQMDSA-N 0.000 claims description 8
- 229930182470 glycoside Natural products 0.000 claims description 7
- 238000007789 sealing Methods 0.000 claims description 7
- OVSQVDMCBVZWGM-SJWGPRHPSA-N Hyperin Natural products O[C@H]1[C@H](O)[C@@H](O)[C@@H](CO)O[C@H]1OC1=C(C=2C=C(O)C(O)=CC=2)OC2=CC(O)=CC(O)=C2C1=O OVSQVDMCBVZWGM-SJWGPRHPSA-N 0.000 claims description 6
- FVQOMEDMFUMIMO-UHFFFAOYSA-N Hyperosid Natural products OC1C(O)C(O)C(CO)OC1OC1C(=O)C2=C(O)C=C(O)C=C2OC1C1=CC=C(O)C(O)=C1 FVQOMEDMFUMIMO-UHFFFAOYSA-N 0.000 claims description 6
- 235000005687 corn oil Nutrition 0.000 claims description 6
- 239000003978 infusion fluid Substances 0.000 claims description 6
- OVSQVDMCBVZWGM-DTGCRPNFSA-N quercetin 3-O-beta-D-galactopyranoside Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1OC1=C(C=2C=C(O)C(O)=CC=2)OC2=CC(O)=CC(O)=C2C1=O OVSQVDMCBVZWGM-DTGCRPNFSA-N 0.000 claims description 6
- BBFYUPYFXSSMNV-UHFFFAOYSA-N quercetin-7-o-galactoside Natural products OC1C(O)C(O)C(CO)OC1OC1=CC(O)=C2C(=O)C(O)=C(C=3C=C(O)C(O)=CC=3)OC2=C1 BBFYUPYFXSSMNV-UHFFFAOYSA-N 0.000 claims description 6
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 5
- 229910052799 carbon Inorganic materials 0.000 claims description 5
- 238000005516 engineering process Methods 0.000 claims description 5
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 5
- 235000010265 sodium sulphite Nutrition 0.000 claims description 5
- JGSARLDLIJGVTE-UHFFFAOYSA-N 3,3-dimethyl-7-oxo-6-[(2-phenylacetyl)amino]-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid Chemical compound O=C1N2C(C(O)=O)C(C)(C)SC2C1NC(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-UHFFFAOYSA-N 0.000 claims description 4
- 239000002671 adjuvant Substances 0.000 claims description 4
- 239000000463 material Substances 0.000 claims description 4
- IIZPXYDJLKNOIY-JXPKJXOSSA-N 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCC\C=C/C\C=C/C\C=C/C\C=C/CCCCC IIZPXYDJLKNOIY-JXPKJXOSSA-N 0.000 claims description 3
- 230000001804 emulsifying effect Effects 0.000 claims description 3
- 238000004108 freeze drying Methods 0.000 claims description 3
- 239000000787 lecithin Substances 0.000 claims description 3
- 229940067606 lecithin Drugs 0.000 claims description 3
- 235000010445 lecithin Nutrition 0.000 claims description 3
- 235000012424 soybean oil Nutrition 0.000 claims description 3
- 239000003549 soybean oil Substances 0.000 claims description 3
- 238000001694 spray drying Methods 0.000 claims description 3
- XFZJEEAOWLFHDH-UHFFFAOYSA-N (2R,2'R,3R,3'R,4R)-3,3',4',5,7-Pentahydroxyflavan(48)-3,3',4',5,7-pentahydroxyflavan Natural products C=12OC(C=3C=C(O)C(O)=CC=3)C(O)CC2=C(O)C=C(O)C=1C(C1=C(O)C=C(O)C=C1O1)C(O)C1C1=CC=C(O)C(O)=C1 XFZJEEAOWLFHDH-UHFFFAOYSA-N 0.000 claims description 2
- 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 2
- 229930195725 Mannitol Natural products 0.000 claims description 2
- CWEZAWNPTYBADX-UHFFFAOYSA-N Procyanidin Natural products OC1C(OC2C(O)C(Oc3c2c(O)cc(O)c3C4C(O)C(Oc5cc(O)cc(O)c45)c6ccc(O)c(O)c6)c7ccc(O)c(O)c7)c8c(O)cc(O)cc8OC1c9ccc(O)c(O)c9 CWEZAWNPTYBADX-UHFFFAOYSA-N 0.000 claims description 2
- MOJZMWJRUKIQGL-FWCKPOPSSA-N Procyanidin C2 Natural products O[C@@H]1[C@@H](c2cc(O)c(O)cc2)Oc2c([C@H]3[C@H](O)[C@@H](c4cc(O)c(O)cc4)Oc4c3c(O)cc(O)c4)c(O)cc(O)c2[C@@H]1c1c(O)cc(O)c2c1O[C@@H]([C@H](O)C2)c1cc(O)c(O)cc1 MOJZMWJRUKIQGL-FWCKPOPSSA-N 0.000 claims description 2
- 239000002552 dosage form Substances 0.000 claims description 2
- 238000004945 emulsification Methods 0.000 claims description 2
- 239000004615 ingredient Substances 0.000 claims description 2
- 239000000594 mannitol Substances 0.000 claims description 2
- 235000010355 mannitol Nutrition 0.000 claims description 2
- HGVVOUNEGQIPMS-UHFFFAOYSA-N procyanidin Chemical compound O1C2=CC(O)=CC(O)=C2C(O)C(O)C1(C=1C=C(O)C(O)=CC=1)OC1CC2=C(O)C=C(O)C=C2OC1C1=CC=C(O)C(O)=C1 HGVVOUNEGQIPMS-UHFFFAOYSA-N 0.000 claims description 2
- 229920002414 procyanidin Polymers 0.000 claims description 2
- 238000001291 vacuum drying Methods 0.000 claims description 2
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 claims 2
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 claims 2
- 239000012528 membrane Substances 0.000 claims 2
- 238000000108 ultra-filtration Methods 0.000 claims 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 claims 1
- ZZZCUOFIHGPKAK-UHFFFAOYSA-N D-erythro-ascorbic acid Natural products OCC1OC(=O)C(O)=C1O ZZZCUOFIHGPKAK-UHFFFAOYSA-N 0.000 claims 1
- 229920001503 Glucan Polymers 0.000 claims 1
- 239000004471 Glycine Substances 0.000 claims 1
- SQUHHTBVTRBESD-UHFFFAOYSA-N Hexa-Ac-myo-Inositol Natural products CC(=O)OC1C(OC(C)=O)C(OC(C)=O)C(OC(C)=O)C(OC(C)=O)C1OC(C)=O SQUHHTBVTRBESD-UHFFFAOYSA-N 0.000 claims 1
- 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 1
- 239000004952 Polyamide Substances 0.000 claims 1
- 229930003268 Vitamin C Natural products 0.000 claims 1
- 239000003963 antioxidant agent Substances 0.000 claims 1
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- 235000006708 antioxidants Nutrition 0.000 claims 1
- 238000004440 column chromatography Methods 0.000 claims 1
- CDAISMWEOUEBRE-GPIVLXJGSA-N inositol Chemical compound O[C@H]1[C@H](O)[C@@H](O)[C@H](O)[C@H](O)[C@@H]1O CDAISMWEOUEBRE-GPIVLXJGSA-N 0.000 claims 1
- 229960000367 inositol Drugs 0.000 claims 1
- 239000008101 lactose Substances 0.000 claims 1
- 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 1
- 239000008176 lyophilized powder Substances 0.000 claims 1
- 229920002647 polyamide Polymers 0.000 claims 1
- CDAISMWEOUEBRE-UHFFFAOYSA-N scyllo-inosotol Natural products OC1C(O)C(O)C(O)C(O)C1O CDAISMWEOUEBRE-UHFFFAOYSA-N 0.000 claims 1
- HRZFUMHJMZEROT-UHFFFAOYSA-L sodium disulfite Chemical compound [Na+].[Na+].[O-]S(=O)S([O-])(=O)=O HRZFUMHJMZEROT-UHFFFAOYSA-L 0.000 claims 1
- 235000010262 sodium metabisulphite Nutrition 0.000 claims 1
- AKHNMLFCWUSKQB-UHFFFAOYSA-L sodium thiosulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=S AKHNMLFCWUSKQB-UHFFFAOYSA-L 0.000 claims 1
- 235000019345 sodium thiosulphate Nutrition 0.000 claims 1
- 235000019154 vitamin C Nutrition 0.000 claims 1
- 239000011718 vitamin C Substances 0.000 claims 1
- 239000003814 drug Substances 0.000 abstract description 12
- 239000007788 liquid Substances 0.000 abstract description 3
- 229940079593 drug Drugs 0.000 abstract description 2
- 201000006474 Brain Ischemia Diseases 0.000 abstract 1
- 206010008120 Cerebral ischaemia Diseases 0.000 abstract 1
- 206010008118 cerebral infarction Diseases 0.000 abstract 1
- 239000012530 fluid Substances 0.000 abstract 1
- 229940028435 intralipid Drugs 0.000 abstract 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 49
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- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical class CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 8
- FOGVNFMUZXDMTR-UHFFFAOYSA-N [Mg].Cl Chemical compound [Mg].Cl FOGVNFMUZXDMTR-UHFFFAOYSA-N 0.000 description 8
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- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 5
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- KJCVRFUGPWSIIH-UHFFFAOYSA-N 1-naphthol Chemical compound C1=CC=C2C(O)=CC=CC2=C1 KJCVRFUGPWSIIH-UHFFFAOYSA-N 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 4
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- DLYUQMMRRRQYAE-UHFFFAOYSA-N tetraphosphorus decaoxide Chemical compound O1P(O2)(=O)OP3(=O)OP1(=O)OP2(=O)O3 DLYUQMMRRRQYAE-UHFFFAOYSA-N 0.000 description 4
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- QGMRQYFBGABWDR-UHFFFAOYSA-M Pentobarbital sodium Chemical compound [Na+].CCCC(C)C1(CC)C(=O)NC(=O)[N-]C1=O QGMRQYFBGABWDR-UHFFFAOYSA-M 0.000 description 2
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- YTJSFYQNRXLOIC-UHFFFAOYSA-N octadecylsilane Chemical compound CCCCCCCCCCCCCCCCCC[SiH3] YTJSFYQNRXLOIC-UHFFFAOYSA-N 0.000 description 2
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Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses a haw leaf extract injection having substantial curative effect for treating coronary disease, angina pectoris and cerebral ischemia, and its preparation, wherein the dosages types include liquid drug injection, powder injection, freeze-dried powder injection, fluid infusion and intralipid.
Description
Technical field
The invention belongs to medical technical field, being specifically related to a kind of is main component with the Folium Crataegi extract, injection of treatment cardiovascular and cerebrovascular disease and preparation method thereof.
Background technology
Contain abundant flavonoids in the Folium Crataegi, main component has vitexin rhamnopyranoside, vitexin glycoside, hyperin etc., has pharmacologically active widely, be mainly: increase coronary flow, anti-myocardial ischemia, arrhythmia, vasodilator is removed local congestion state.Be mainly used in diseases such as depressed blood stasis, chest distress, cardiovascular and cerebrovascular disease, coronary insufficiency clinically.
Listing at present with the Folium Crataegi extract be that the pharmaceutical preparation of functional component treatment cardiovascular and cerebrovascular disease has the Yixintong sheet, the capsule of feeling at ease, multiple heart sheet etc., the performance of oral formulations curative effect is slow, and cardiovascular and cerebrovascular disease belongs to clinical acute disease, rapid onset, need first aid medicine, injection is best dosage form.Because Folium Crataegi extract is made aqueous injection certain degree of difficulty is arranged on technology, so never relevant product comes out.We finally succeed in developing through having researched and solved an a series of difficult problem.Effect experiment proof Folium Crataegi extract injection has blood circulation promoting and blood stasis dispelling, the easypro network of regulating the flow of vital energy, and the function of the logical heart arteries and veins of a surname can increase coronary flow, dilating coronary blood vessel, and the treatment cardiovascular and cerebrovascular disease is had significant curative effect.Experimental result shows: the PH scope is an optimum PH value range at 6.0-7.5 in the injection, and compares more than the PH7.5, and not only the preparation color is more shallow, and active component is more stable.
Retrieve the disclosed patent of relevant Folium Crataegi such as: 02116789.3 1 kinds of macroporous adsorbent resins extract the method for Folium Crataegi total flavoness, 98107298.4 the extracting method of a Folium Crataegi total flavones, 91111834.9 there is Folium Crataegi to extract the method for total flavones, 03102024.0 a Folium Crataegi injection and a 03120841.X who is used for the treatment of cardiovascular disease is the preparation that main functional component is made by Folium Crataegi extract for one kind, its lixiviate solvent all adopts Diluted Alcohol, because the different solubility of extract in aqueous solution that different solvents extract, we are that preparation technology among the 03120841.X " a kind of is the preparation that main functional component is made by Folium Crataegi extract " contrasts with technology of the present invention and application number, the dissolubility of Folium Crataegi extract in water and the color and luster of aqueous solution (concentration is 10mg/ml) (concerning Chinese medicine, these two indexs are one of leading indicators of judging quality of the pharmaceutical preparations height) that different process obtains have been compared.
Comparative result is as follows:
| Extracting method | Dissolubility (mg/ml) | Color and luster |
| Extracting method of the present invention | ????1200 | Pale yellow |
| 03120841.X method | ????30 | Dark red |
The extract that obtains with method of the present invention has the following advantages: dissolubility has improved 40 times, and the lighter color good stability meets the requirement of injection raw material.
Summary of the invention
The object of the present invention is to provide a kind of good stability, quality height, injection Folium Crataegi extract pin preparation evident in efficacy and preparation method thereof, use Folium Crataegi extract pin preparation that this method makes the effect of Acute Myocardial Ischemia in Rats protection and treatment myocardial infarction all is better than existing Folium Crataegi preparation.The present invention relates to a kind of Folium Crataegi extract injection of cardiovascular and cerebrovascular disease being had significant curative effect and preparation method thereof that has.Wherein the component of effective ingredient Folium Crataegi extract consists of: the content of vitexin rhamnopyranoside is 20-53%, and vitexin glycoside content is 8-25%, and the content of hyperin is 0.01-2%, and total procyanidin content is 3-20%.Wherein injection comprises aqueous injection, injectable powder, lyophilized injectable powder, infusion solution and lipomul.
Preparation Folium Crataegi extract aqueous injection, with Folium Crataegi extract, be dissolved in an amount of water for injection, add the injection water soluble adjuvant of metering, the active carbon that adds 0.1-0.5% is removed thermal source, regulate PH to 6.0-7.5, behind filtering with microporous membrane, replenish water for injection to ormal weight, fill is in ampoule bottle or in the infusion bottle, sealing by fusing/roll lid, through after the assay was approved, packing promptly.Per ampoule Folium Crataegi extract content is 3.0-50.0mg/ml; Folium Crataegi extract content is 0.5-10.0mg/ml in the infusion solution, and specification is 50ml, 100ml, 150ml and 200ml.
Preparation Folium Crataegi extract injectable powder, Folium Crataegi extract is dissolved in an amount of water for injection, add the pharmaceutic adjuvant of metering, the active carbon that adds 0.1-0.5% is removed thermal source, and regulating PH is that 6.0-7.5 is behind filtering with microporous membrane, vacuum or spray drying, aseptic subpackaged in cillin bottle, every bottle contains Folium Crataegi extract 10-200mg, rolls lid, through after the assay was approved, packing promptly.
Preparation Folium Crataegi extract lyophilized injectable powder, Folium Crataegi extract is dissolved in an amount of water for injection, add the pharmaceutic adjuvant of metering, the active carbon that adds 0.1-0.5% is removed thermal source, and adjusting PH is 6.0-7.5, behind filtering with microporous membrane, be sub-packed in the ampoule, per ampoule contains Folium Crataegi extract 10-200mg, sealing by fusing after lyophilization, after the assay was approved, packing promptly.
Preparation Folium Crataegi extract infusion solution, above-mentioned Folium Crataegi extract is dissolved in the proper amount of water for injection, the pharmaceutic adjuvant that adds metering, regulate PH to 6.0-7.5, behind filtering with microporous membrane, replenish water for injection to ormal weight, fill is in the 100ml infusion bottle, per ampoule contains Folium Crataegi extract 10-100mg sealing by fusing/roll lid, and through after the assay was approved, packing promptly.
Preparation Folium Crataegi extract lipomul is dissolved in above-mentioned Folium Crataegi extract in an amount of rare glycerol, adds the injection soybean oil and the injection lecithin of metering, and emulsifying both got repeatedly in high pressure homogenizer.
The preparation method of Folium Crataegi extract of the present invention is as follows:
Preparation method one: get Folium Crataegi, add the water temperature lixiviate and get three times, each 1-3 hour, filter, merging filtrate, concentrating under reduced pressure, being concentrated into relative density is 1.10～1.20 (60 ℃), adds ethanol and reaches 60-85% to containing the alcohol amount, cold preservation 12-24 hour, draw supernatant, lower floor filters, and filtrate and supernatant merge, decompression recycling ethanol, go up polyamide resin column behind the thin up, use the distilled water eluting, begin reception when hydrochloric acid-magnesium powder reaction is arranged, and use ethanol elution simultaneously instead, collect ethanol elution,, reclaim ethanol to hydrochloric acid-magnesium powder reaction negative.Being evaporated to does not have the alcohol flavor, when thin up to relative density is 1.10～1.12 (60 ℃), puts coldly, puts in the separatory funnel, with water saturated n-butyl alcohol equimultiple extraction three times, merges, and reclaims n-butyl alcohol to dried, promptly gets extract of the present invention.
Preparation method two: will be evaporated to nothing alcohol flavor by the separating obtained ethanol elution of polyamide resin column in the method one, when thin up to relative density is 1.05～1.08 (60 ℃), pass through macroporous adsorptive resins, it is negative earlier to be washed till the alpha-Naphthol strong sulfuric acid response with distilled water, use ethanol elution instead, collect ethanol elution, to hydrochloric acid-magnesium powder reaction negative, be evaporated to both do extract of the present invention.
The specific embodiment
1. prepare Folium Crataegi extract (method one)
Get Folium Crataegi 200g, add 12 times of water gaging warm macerating (60 ℃) and extract three times, each 2.0 hours, filter, merging filtrate, concentrating under reduced pressure water, being concentrated into relative density is 1.10～1.20 (60 ℃), adds ethanol and reaches 75% to containing the alcohol amount, cold preservation 24 hours, draw supernatant, lower floor filters, and filtrate and supernatant merge, add water to 600ml, last polyamide resin column is used the distilled water eluting, begins to receive when the reaction of hydrochloric acid-magnesium powder is arranged, and use 40% ethanol elution simultaneously instead, collect ethanol elution,, reclaim ethanol to hydrochloric acid-magnesium powder reaction negative.When being evaporated to relative density and being 1.10～1.12 (60 ℃), put coldly, put in the separatory funnel,, merge, reclaim n-butyl alcohol, promptly get extract 3.5g of the present invention to doing with water saturated n-butyl alcohol equimultiple extraction three times.
2. prepare Folium Crataegi extract (method two)
Get Folium Crataegi 200g, add 12 times of water gaging warm macerating (60 ℃) and extract three times, each 2.5 hours, filter, merging filtrate, concentrating under reduced pressure, being concentrated into relative density is 1.10～1.20 (60 ℃), adds ethanol and reaches 70% to containing the alcohol amount, cold preservation 24 hours, draw supernatant, lower floor filters, and filtrate and supernatant merge, add water to 800ml, last polyamide resin column is used the distilled water eluting, begins to receive when the reaction of hydrochloric acid-magnesium powder is arranged, and use 40% ethanol elution simultaneously instead, collect ethanol elution, to hydrochloric acid-magnesium powder reaction negative, when being evaporated to relative density and being 1.10～1.12 (60 ℃), put cold, when thin up to relative density was 1.05～1.08 (60 ℃), by macroporous adsorptive resins, it was negative to be washed till no alpha-Naphthol strong sulfuric acid response with distilled water earlier, use 40% ethanol elution instead, collect ethanol elution, to hydrochloric acid-magnesium powder reaction negative, ethanol elution be evaporated to both do extract of the present invention.
3. prepare the Folium Crataegi extract aqueous injection.
With above-mentioned Folium Crataegi extract 2kg, be dissolved in the 100L water for injection, be made into 20mg/ml, regulate PH to 6.0-7.5, add sodium sulfite 10g.Behind filtering with microporous membrane, replenish water for injection to ormal weight, fill is in the 5ml ampoule bottle, and sealing by fusing/roll lid through after the assay was approved, is packed promptly.
4. prepare the Folium Crataegi extract infusion solution
With above-mentioned Folium Crataegi extract 2kg, be dissolved in the 2000L water for injection, be made into 1mg/ml, regulate PH to 6.0-7.5, add sodium sulfite 10g, behind filtering with microporous membrane, replenish water for injection to ormal weight, fill is in the 100ml infusion bottle, sealing by fusing/roll lid, through after the assay was approved, packing promptly.
5. prepare the Folium Crataegi extract injectable powder
Above-mentioned Folium Crataegi extract 2kg is dissolved in an amount of 100L water for injection, add sodium sulfite 10g, adjusting PH is 6.0-7.5, behind filtering with microporous membrane, spray drying gets the Folium Crataegi extract aseptic powder, and is aseptic subpackaged in cillin bottle, make every bottle and contain two specifications of Folium Crataegi extract aseptic powder 50mg, 100mg, roll lid, through after the assay was approved, packing promptly.
6. prepare the Folium Crataegi extract lyophilized injectable powder
Above-mentioned Folium Crataegi extract 2kg is dissolved in an amount of 100L water for injection, add mannitol 100g, adjusting PH is 6.0-7.5, behind filtering with microporous membrane, aseptic subpackaged in cillin bottle, make every bottle and contain two specifications of Folium Crataegi extract aseptic powder 50mg, 100mg, after the lyophilization, roll lid, through after the assay was approved, packing promptly.
7. prepare the Folium Crataegi extract lipomul
Above-mentioned Folium Crataegi extract 2kg is dissolved in (glycerol content is 12%) in the rare glycerol of 876kg, and emulsifying has been both repeatedly in the high pressure dispersing emulsification machine to add injection soybean oil 100kg, injection lecithin 12kg.
The relevant pharmacodynamic experiment of Folium Crataegi extract injection of the present invention:
Experiment one, Folium Crataegi extract are to the influence of dog coronary flow
Experiment material
1. laboratory animal: 36 of healthy adult dogs, male and female dual-purpose, body weight 17.50 ± 1.77kg.
2. experiment medicine: the injectable powder that above-mentioned Folium Crataegi extract is made, 50mg/ props up, 0.9% sodium chloride injection.
Experiment is divided into 4 groups of (1) blank groups, normal saline 1ml/kg; (2) Folium Crataegi extract 10mg/kg dosage group; (3) Folium Crataegi extract 15mg/kg dosage group; (4) Folium Crataegi extract 20mg/kg dosage group.N=12 before each administration group 60min, n=6 behind the 90min.
The experiment medicine is mixed with same volume (50ml) with normal saline, and the computer micro-injection pump feeds reagent with the speed of 5ml/min through femoral vein.
Experimental technique
Laboratory animal pentobarbital sodium (30mg/kg) intravenous anesthesia, tracheal intubation connects the phrenoton.Execute left side the 4th intercostal thoracotomy, expose heart, cut off pericardium, make the pericardium bed, separate LCA and aortic root, place the electromagnetic flowmeter probe, measure coronary flow.Operation finishes, treat that observed index is stable after, value before the record medicine feeds institute's reagent thing.And in behind the medicine at once, behind the medicine 10,30,60,90min writes down and measure the influence of each administration group to dog coronary flow (ml/100gmin-1).Every observation index and derivation parameter are carried out statistical procedures, carry out administration with the measured values of different observing times before and after self relatively, its change percentage rate organize between relatively, judge its significance with the t check.
Table 1: each administration group is to the influence of dog coronary flow (ml/100gmin-1) (X ± SD)
| Group | Dosage/kg | Before the ischemia (normal value) | (value before the medicine) rate of change (%) behind the ischemia | Behind the medicine at once | Minute (min) | |||
| ??10 | ????30 | ??60 | ??90 | |||||
| Normal saline | ? ??1ml | ????89.2±54. ? ????7 | ? ??110.1±56.8 | ??99.4 ??±61.9 | ??89.3 ??±53. ??5 | ????90.9 ????±55. ????1 | ??91.7 ??±57. ??8 | ??92.6 ??±52. ??0 |
| Folium Crataegi extract | ??16mg | ????78.8±33. ? ????1 | ? ??81.5±30.5 | ??103.1 ??±34.2 | ??105.8 ??±39. ??9 | ????109.3 ????±46. ????6 | ??118.1 ??±40. ??6 | ??131.0 ??±42. ??1 |
| Folium Crataegi extract | ? ??8mg | ????80.5±31. ? ????2 | ? ??91.2±41.1 | ??100.8 ??±53.8 | ??102.8 ??±50. ??7 | ????104.1 ????±43. ????3 | ??109.0 ??±57. ??7 | ??117.7 ??±50. ??8 |
| Folium Crataegi extract | ? ??4mg | ????90.5±46. ? ????1 | ? ??93.7±50.7 | ??98.3 ??±50.7 | ??100.3 ??±57. ??1 | ????103.9 ????±57. ????2 | ??105 ??±58. ??1 | ??109.2 ??±61. ??6 |
Experimental result shows that Folium Crataegi extract can obviously increase coronary flow, and dilating coronary blood vessel reduces coronary resistance, improves the blood supply oxygen supply of cardiac muscle, and can reduce total peripheral resistance, cardiovascular system is played adjust and the improvement effect.
Experiment two. Folium Crataegi extract is to the influence of myocardial infarction due to the ischemia-reperfusion
Experiment material
1. laboratory animal: 32 of Wistar kind rats, male, body weight 250～270g.
2. experiment medicine: the injectable powder that above-mentioned Folium Crataegi extract is made, 50mg/ props up, 0.9% sodium chloride injection.
Experimental technique
Animal is divided into 4 groups at random: model group (normal saline), Folium Crataegi extract 20,15,10mg/kg group.Medicine is diluted to desired concn with normal saline, and the administration volume is 3ml/kg, and route of administration is a vein.
Animal faces upward the position and fixes with pentobarbital sodium intraperitoneal anesthesia (45mg/kg), and electrocardiograph leads with standard I I and monitors the animal electrocardiogram; Tracheostomize inserts tracheal intubation, connects respirator practice artificial respiration (32 times/minute, breathed ratio 1: 3); Open breast, disconnected 3 ~ 5 ribs are opened pericardium, expose heart, in left anterior descending coronary artery root threading (No. 0 stitching thread), are equipped with ligation and use; Separate left femoral vein, be equipped with administrable; Stablize 10min behind the threading, recessed pipe of plastics and blood vessel is arranged side by side, and ligation (no ST section and T ripple changer eliminate) feeds and is subjected to the reagent thing; Behind the 40min, cut off ligature, make anterior descending branch realize perfusion again along groove; Sew up thoracic wall, recover autonomous respiration.
After the reperfusion injury 2 hours, abdominal aortic blood is measured Serum LDH, CK, SOD, MDA content; 5 of the following crosscuts of heart ligature, N-BT dyeing adopts multi-media color pathology picture and text analytical systems (MPIAS-500) fixedly to get image distance from measuring normal myocardium and infarcted myocardium area, observes the myocardial infarction degree; The result carries out statistical procedures (t check).
Experimental result sees Table 2
Table 2. Folium Crataegi extract is to the influence of myocardial infarction degree
| Grouping | Dosage/kg | Number of animals | Normal myocardium area mm2 | Infarcted myocardium area mm2 | Infarct weight g | Infarct accounts for ventricle % | Infarct accounts for heart % |
| Model group | ????8 | ?333.2±42.3 | ?102.7±13.1 | ?0.259±0.032 | ?31.7±4.3 | ?25.3±4.7 | |
| Folium Crataegi extract | 24mg | ????8 | ?323.2±16.0 | ?69.8±16.99 | ?0.171±0.022 | ?18.5±5.0 | ?16.5±4.2 |
| Folium Crataegi extract | 12mg | ????8 | ?339.6±24.2 | ?73.9±16.0 | ?0.189±0.031 | ?22.7±4.1 | ?19.2±3.3 |
| Folium Crataegi extract | 6mg | ????8 | ?347.5±26.3 | ?75.4±12.1 | ?0.210±0.021 | ?23.6±4.7 | ?21.2±2.3 |
Compare P＜0.05, P＜0.01. with model group
Experimental result confirms that Folium Crataegi extract 20mg/kg, 15mg/ml and 10mg/kg group infarct size reduce infarct
Account for ventricle and heart percentage ratio and reduce, significant difference (P＜0.01) is relatively arranged with model group; The 20mg/kg group also can obviously alleviate infarct weight, with model group significant difference (P＜0.01) is arranged relatively.
The optimum PH value range screening experiment result of injection of the present invention:
Investigate relatively both stability, condition: 40 ℃ of temperature, relative humidity 75% with the accelerated stability experimental technique, three months time, every other month sampling Detection once, optimum PH value range is 6.0-7.5, the color is too dark for injection, is unfavorable for the inspection of orange lightness.The results are shown in following table:
| ??PH | 0 month | 1 month | 2 months | 3 months |
| ??6.0 | Yellow, clear and bright | Yellow, clear and bright | Yellow, clear and bright | Yellow, a small amount of muddy |
| ??7.0 | Deep yellow, clear and bright | Deep yellow, clear and bright | Deep yellow, clear and bright | Deep yellow, clear and bright |
| ??7.5 | Light brown, clear and bright | Light brown, clear and bright | Light brown, clear and bright | Light brown, clear and bright |
| ??8.0 | Dark brown red, clear and bright | Dark brown red, clear and bright | Dark brown red, clear and bright | Dark brown red, clear and bright |
The assay method of extractive content among the present invention:
One, hyperin (detecting) with efficient liquid-phase chromatography method
1, chromatographic condition
With the octadecylsilane chemically bonded silica is filler; With oxolane-methanol-acetonitrile-0.5% glacial acetic acid aqueous solution (19.4: 1: 1: 78.6) be mobile phase; The detection wavelength is 363nm, and column temperature is 25 ℃, and flow velocity is 1ml/min, and number of theoretical plate calculates by the hyperin peak and is not less than 3000.
2, reference substance solution preparation
It is that the hyperin reference substance of desiccant drying under reduced pressure 24h is an amount of that precision takes by weighing with the phosphorus pentoxide, adds 50% ethanol and makes the solution that contains 0.02mg among every 1ml, promptly.
3, the preparation of need testing solution
Take the Folium Crataegi extract 10mg among the present invention, put in the 50ml measuring bottle, with the dissolving of 50% Diluted Alcohol, filtration both gets.
4, algoscopy
Draw each 10 μ l of reference substance and test sample respectively, inject chromatograph of liquid promptly.
Two, vitexin rhamnopyranoside and vitexin glycoside (detecting) with efficient liquid-phase chromatography method
1, chromatographic condition
With the octadecylsilane chemically bonded silica is filler; With oxolane-isopropyl alcohol-0.5% glacial acetic acid aqueous solution (10: 2.0: 88) is mobile phase; The detection wavelength is 340nm, and column temperature is 25 ℃, and flow velocity is 1ml/min, and number of theoretical plate calculates by vitexin rhamnopyranoside and is not less than 2000.
2, reference substance solution preparation
It is that vitexin rhamnopyranoside and the vitexin glycoside reference substance of desiccant drying under reduced pressure 24h is an amount of that precision takes by weighing with the phosphorus pentoxide, adds 50% ethanol and makes the solution that contains 0.02mg among every 1ml, promptly.
3, the preparation of need testing solution
Take the Folium Crataegi extract 10mg among the present invention, put in the 50ml measuring bottle, with the dissolving of 50% Diluted Alcohol, filtration both gets.
4, algoscopy
Draw each 10 μ l of reference substance and test sample respectively, inject chromatograph of liquid promptly.
Three, the mensuration of anthocyanidin content (detecting) with the UV Absorption method
1, the preparation of reference substance
Getting the anthocyanidin reference substance, to be made into the stock solution of 100ug/ml standby.
2, the preparation of standard curve
The accurate anthocyanidin stock solution 0,1,2,3,4,5 of drawing, 6ml places the 10ml measuring bottle respectively, and it is rare to scale to add water, shakes up, and measures trap, drawing standard curve at ultraviolet-visible spectrophotometer 280nm place.
3, the preparation of need testing solution
Take the Folium Crataegi extract 10mg among the present invention, put in the 50ml measuring bottle, with the dissolving of 50% Diluted Alcohol, filtration both gets.
4, algoscopy
In the instrument ultraviolet-visible spectrophotometer, the 280nm place measures light absorption with need testing solution, calculates the anthocyanidin content of need testing solution from standard curve.
Remarks: the chemical name of vitexin rhamnopyranoside and vitexin glycoside among the present invention:
Vitexin rhamnopyranoside is: 5,7, and 4`-trihydroxyflavone-8-C-β-D-glucosyl group (1 → 2)-β-D-rhamnoside
The vitexin glycoside is: 5,7, and 4`-trihydroxyflavone-8-C-β-D-glucosyl group (1 → 4)-β-D-glycoside
Claims (9)
1, a kind of have the Folium Crataegi extract injection of significant curative effect to coronary heart disease, angina pectoris, it is characterized in that the percentage by weight of the effective ingredient of said preparation consists of:
Vitexin rhamnopyranoside 20-53%, vitexin glycoside 8-25%, hyperin 0.01-2%, total procyanidin 3-20%.
2, Folium Crataegi extract injection according to claim 1 is characterized in that the preparation technology of Folium Crataegi extract comprises that hot water lixiviate, polyamide column chromatography separate two steps.
3, Folium Crataegi extract injection according to claim 1, the dosage form of this injection comprises aqueous injection, injectable powder, lyophilized injectable powder, infusion solution and lipomul.
4, Folium Crataegi extract injection according to claim 1, wherein the preparation method of aqueous injection is: with Folium Crataegi extract, be dissolved in an amount of water for injection, add the injection water soluble adjuvant, the active carbon that adds 0.1-0.5% is removed thermal source, regulate PH to 6.0-7.5, behind filtering with microporous membrane, replenish water for injection to ormal weight, fill is in ampoule bottle or in the infusion bottle, sealing by fusing/roll lid, through after the assay was approved, to pack promptly, the content of Folium Crataegi extract is 3.0-50.0mg/ml in the injection, infusion solution contains Folium Crataegi extract 0.5-10.0mg/ml, and specification is 50ml, 100ml, 150ml and 200ml.
5, Folium Crataegi extract injection according to claim 1, wherein the preparation method of injectable powder is: Folium Crataegi extract is dissolved in an amount of water for injection, add proper quantity of medicinal auxiliary material, the active carbon that adds 0.1-0.5% is removed thermal source, and adjusting PH is 6.0-7.5, after the microporous filter membrane ultrafiltration, vacuum or spray drying, aseptic subpackaged in cillin bottle, every bottle contains Folium Crataegi extract 10-200mg, roll lid, packing promptly;
6, Folium Crataegi extract injection according to claim 1, wherein the preparation method of lyophilized injectable powder is: Folium Crataegi extract is dissolved in an amount of water for injection, add proper quantity of medicinal auxiliary material, adjusting PH is 6.0-7.5, behind filtering with microporous membrane, be sub-packed in the ampoule, Folium Crataegi extract content is 10-200mg in the per ampoule, sealing by fusing after lyophilization, packing promptly.
7, Folium Crataegi extract lipomul according to claim 1, wherein the preparation method of lipomul is: Folium Crataegi extract is dissolved in an amount of rare glycerol, the injection soybean oil and the injection lecithin that add metering, in the high pressure dispersing emulsification machine repeatedly emulsifying after the microporous filter membrane ultrafiltration, be sub-packed in the ampoule, Folium Crataegi extract content is that 10-50mg both got in the per ampoule.
8, according to claim 4 or 5 described Folium Crataegi extract injections, pharmaceutic adjuvant wherein is meant antioxidant, comprises in the following adjuvant one or both: sodium sulfite, sodium sulfite, sodium pyrosulfite, sodium thiosulfate, vitamin C.
9, Folium Crataegi extract injection according to claim 6, pharmaceutic adjuvant wherein is meant the lyophilized powder proppant, comprises in the following adjuvant one or both: lactose, mannitol, inositol, glucosan, glycine.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EA022379B1 (en) * | 2007-12-22 | 2015-12-30 | Виваселле Био, Инк. | Method of treating hypovolemia, ischaemia and haemorrhagic shock in mammals |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EA022379B1 (en) * | 2007-12-22 | 2015-12-30 | Виваселле Био, Инк. | Method of treating hypovolemia, ischaemia and haemorrhagic shock in mammals |
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