CN1854148B - Astragalus total heteroside extract and its production - Google Patents
Astragalus total heteroside extract and its production Download PDFInfo
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- CN1854148B CN1854148B CN2006100084939A CN200610008493A CN1854148B CN 1854148 B CN1854148 B CN 1854148B CN 2006100084939 A CN2006100084939 A CN 2006100084939A CN 200610008493 A CN200610008493 A CN 200610008493A CN 1854148 B CN1854148 B CN 1854148B
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Abstract
An astragalus root extract and its production are disclosed. The extract consists of astragaloside 80-100wt% and astragalmethyloside 6-50wt%. It is cheap, has no residual organic solvent and environmental pollution. It can be used to make preparation and treat mouse with viral myocarditis.
Description
Technical field
The present invention relates to Radix Astragali total glycosides extract, particularly, be to be the extract of raw material, and contain pharmaceutical composition of this extract and preparation method thereof, belong to pharmaceutical field with the medicinal material Radix Astragali.
Background technology
Contain active stronger triterpenoid saponin, flavonoid, polyose, amino acid and trace element in the Chinese medicine astragalus (Astragalus membranaceus (Fisch.) Bge.).Radix Astragali total saponins is the effective ingredient in Chinese extract that is obtained by Chinese medicine astragalus extraction separation total saponins, i.e. Radix Astragali total glycosides.This medicine has the cardiac stimulant function and can be used for treating heart failure; Especially the function that has strengthening vital QI to eliminate pathogenic factors, Yiqiyangyuan, nourishes heart and promote blood circulation is used for that the motive is deficient, the viral myocarditis of blood-vessel obstructive, that disease is seen is uncomfortable in chest, pareordia secret anguish, palpitaition, dizziness, breathe hard, weak, deep and weak pulse, thin puckery or knot be for the person.Wherein Cyclosiversioside F (astragaloside IV) is its main active ingredient.Pharmacological experiment shows that Cyclosiversioside F has anti-inflammatory, analgesia, sedative effect, and cAMP in the increase blood plasma and the effects such as content of Liver Regeneration DNA.
Other Cyclosiversioside F homologue has acetyl astragaloside I (Acetylastragaloside I, 1), astragaloside I (astragaloside I, 2), different astragaloside I (isoastragaloside I, 3), different astragaloside II (Isoastragaloside II, 4), astragaloside II (astragaloside II, 5); Astragaloside IV (astragaloside IV, 6), the structural formula document 1,2 that sees reference.Many research bibliographical informations: compound 1,2,3,4,5 ethanoyl may take place in basic solution shifts and the deacetylate effect, as compound 4 ethanoyl may take place and be converted into 5, also may be converted into 6 by deacetylate.
The preparation method of the open Radix Astragali total glycosides of patent CN1425674, for water is carried-the macroporous resin partition method, Radix Astragali total glycosides content is 80-98% in the Radix Astragali total glycosides extract of gained, Astragaloside content is 50-80%, in preparation process, with the alkaline aqueous solution decolouring, make the Cyclosiversioside F homologue partly change into Cyclosiversioside F; Patent CN1470241 discloses a kind of Cyclosiversioside F pharmaceutical composition, and the content of its Cyclosiversioside F is more than 50%, especially greater than 75%; The open Radix Astragali total glycosides extract of patent CN1444949 contains Radix Astragali total glycosides and reaches 85-90%, and total glycosides rate of transform adopts the saturated n-butanol extraction-macroporous resin separation-dissolve with methanol of alcohol extracting-macroporous resin separation-water liquid at 80%-85%, and silicon bath soil stirs.All adopted the buck processing in the above technology, made the Cyclosiversioside F homologue partly change into Cyclosiversioside F.
As everyone knows, Cyclosiversioside F is the index components of Radix Astragali saponin, but and must be that Astragaloside content is high more good more.Between a series of homologues that obtain in the plant synergy is often arranged, thus the effective pure compound in the plant generally do not used, and use the plant efficient part.Reach best effect thereby homologue is retained in the effective part extract of crude drug by a certain percentage at aspects such as drug effect and production costs, just seem extremely important.
Summary of the invention
Technical scheme of the present invention has provided a kind of new Radix Astragali saponin extract, and the present invention also provides this Radix Astragali saponin preparation method of extract, contained pharmaceutical composition of this Radix Astragali saponin extract and preparation method thereof.
The invention provides Radix Astragali total glycosides extract, wherein the weight percentage of Radix Astragali total glycosides accounts for the 80-100% of general extractive, and the percentage composition of Cyclosiversioside F accounts for the 6-50% of general extractive.
Further, the weight percentage of Radix Astragali total glycosides accounts for the 80-90% of general extractive, and wherein the percentage composition of Cyclosiversioside F accounts for the 15-50% of general extractive.
Further, the weight percentage of Radix Astragali total glycosides accounts for the 80-90% of general extractive, and wherein the percentage composition of Cyclosiversioside F accounts for the 20-50% of general extractive.
Above-mentioned Radix Astragali total glycosides extract, it is to be raw material with the medicinal material Radix Astragali, as follows preparation:
A, with Chinese medicine astragalus, boiling or 10-80% ethanol percolation merge decoction liquor or percolate, concentrating under reduced pressure, Radix Astragali concentrated solution;
Carry out alcohol precipitation, static after b, the extracting solution cooling, filter to get filtrate a step preparation, filtrate by adsorption resin column, discard effluent liquid, wash with water to effluent liquid to colourless, discard water lotion;
C, with the adsorption resin column after the washing of b step with one or more wash-outs in methyl alcohol, ethanol, acetone, aqueous methanol or the aqueous acetone, collect elutriant, concentrate;
D, the concentrated solution of c step is added alcohol precipitation, filter, collect filtrate; Concentrate drying promptly gets Radix Astragali total glycosides extract.
Further, it is to be raw material with the medicinal material Radix Astragali, as follows preparation:
A. with Chinese medicine astragalus, boiling or 10-80% ethanol percolation merge decoction liquor or percolate, and concentrating under reduced pressure gets Radix Astragali concentrated solution;
B, the concentrated solution of a step is added ethanol reach 50%-80%, leave standstill 0 ℃ of-5 ℃ of refrigeration to containing the alcohol amount, 24～36 hours, filter, filtrate is concentrated into every milliliter and is equivalent to 0.5-1.0 gram crude drug, and refrigeration is left standstill, and 24～36 hours, filters; Get filtrate by macroporous adsorptive resins, be washed to closely colourless;
C, use the Diluted Alcohol wash-out, collect elutriant, filter, reclaim ethanol and also be concentrated into and do not have the alcohol flavor, refrigeration is left standstill, and filters;
D, the concentrated solution of c step is added ethanol reach 70%-90% to containing the alcohol amount, refrigeration is left standstill, and filters, and reclaims ethanol, boils, and filters, and promptly gets Radix Astragali total glycosides extract.
Wherein, the used macroporous resin of c step is nonpolar or/and the low-pole macroporous adsorbent resin, model is the macroporous adsorbent resin that resin can be selected HPD100, HPD300, D101, HPD100A, HPD700, LD140 and other types for use, or the macroporous adsorbent resin of above different model mixes by a certain percentage.
Wherein, the elutriant described in the c step is a 50-98% ethanol.
The present invention also provides the method for this Radix Astragali total glycosides extract, and it comprises the steps:
Get the recipe quantity Radix Astragali, add 10 times of amounts of water and decoct three times, each 1 hour, merge decoction liquor, filter, filtrate decompression is concentrated into every 1ml and is equivalent to crude drug in whole 1-2g, reaches 60% with 95% ethanol sedimentation to containing the alcohol amount, and refrigeration was left standstill 24 hours, filter, get filtrate recycling ethanol, refrigeration was left standstill 24 hours, filtered.Get filtrate and pass through HPD
100Post is washed to closely colourlessly, uses 75% ethanol elution, collects elutriant, filters, and reclaims ethanol and also is concentrated into 10g crude drug/ml, and refrigeration was left standstill 24 hours, filtered; Add 95% ethanol and reach 85% to containing the alcohol amount, refrigeration was left standstill 24 hours, filtered; Reclaim ethanol, boiled 30 minutes, (the 12.5g crude drug/ml), sealing, refrigeration filtered promptly more than 24 hours to add water to specified amount.
The present invention also provides a kind of pharmaceutical composition, and it is to contain by treatment significant quantity Radix Astragali total glycosides extract to be activeconstituents, to add the preparation that acceptable accessories or complementary composition are prepared from.
Wherein, described preparation is pill, powder, tablet, capsule, granule, injection.
The present invention also provides the application of this pharmaceutical composition in preparing treatment or prevention viral myocarditis, heart failure drugs.
The weight percentage of Radix Astragali total glycosides accounts for the 80-100% of extract in the extract of the present invention, and wherein Cyclosiversioside F accounts for 650% of Radix Astragali total glycosides.The fundamental technology route of this technology is carried-alcohol precipitation-macroporous adsorptive resins absorption-alcohol precipitating method for this extracting method adopts water.As evaluation index, buck of no use is handled in whole technological process, has kept astragaloside homologen in the Chinese medicine astragalus to greatest extent with Astragaloside content.Total glycosides content height, purity height, solvability be greater than Cyclosiversioside F, and have clearer and more definite quality control index, especially can prepare the high Radix Astragali injection of content, need not add any solubility promoter and thinner.This method have compared with prior art that cost is low, organic solvent-free is residual and production process in non-environmental-pollution, Cyclosiversioside F homologue solvability has synergistic function greater than Cyclosiversioside F in the Radix Astragali total glycosides in the treatment of viral myocarditis mouse.
Obviously, according to foregoing of the present invention,,, can also make modification, replacement or the change of other various ways not breaking away under the above-mentioned basic fundamental thought of the present invention prerequisite according to the ordinary skill knowledge and the customary means of this area.
The embodiment of form is described in further detail foregoing of the present invention again by the following examples.But this should be interpreted as that the scope of the above-mentioned theme of the present invention only limits to following example.All technology that realizes based on foregoing of the present invention all belong to scope of the present invention.
Description of drawings
Fig. 1 Radix Astragali total glycosides and injection liquid thin-layer chromatography contrast synoptic diagram, wherein, a, Radix Astragali total glycosides thin-layer chromatography; B, injection liquid thin-layer chromatography; C, acetyl astragaloside I thin-layer chromatography; D, astragaloside I thin-layer chromatography; E, different astragaloside I thin-layer chromatography; F, different astragaloside II thin-layer chromatography; G, astragaloside II thin-layer chromatography; H, Astragaloside IV thin-layer chromatography; I, Milkvetch Root thin-layer chromatography; J, Astragaloside IV homologue thin-layer chromatography.
Embodiment
Embodiment 1 Radix Astragali total glycosides extracting method of the present invention
Milkvetch Root meets relevant regulations under first 249 pages of Radix Astragali item of Chinese Pharmacopoeia version in 2000, and Cyclosiversioside F detects according to high performance liquid chromatography in the Milkvetch Root, and Milkvetch Root contains Cyclosiversioside F (C
41H
68O
14) must not be less than 0.06%.
Get recipe quantity Radix Astragali medicine materical crude slice (2-4mm sheet, produce in the Inner Mongol), add 8 times of amounts of water and decoct three times, each 1.5 hours, merge decoction liquor, filter, filtrate decompression concentrates (temperature: 70 ℃; Vacuum tightness :-0.08Mpa) extremely every 1ml is equivalent to crude drug in whole 2g, reaches 80% with 95% ethanol sedimentation to containing the alcohol amount, and refrigeration was left standstill 48 hours, filtered, and got filtrate recycling ethanol, refrigerated and left standstill 24 hours, filtered.Get the logical HPD100A of filtrate, be washed to closely colourlessly, use 95% wash-out, collect elutriant, filter, reclaim ethanol and also be concentrated into 10g crude drug/ml, refrigeration was left standstill 24 hours, filtration; Add 95% ethanol and reach 90% to containing the alcohol amount, refrigeration was left standstill 24 hours, filtered; Reclaim ethanol, boiled 30 minutes, (the 12.5g crude drug/ml), sealing, refrigeration filtered more than 24 hours, and check promptly gets Radix Astragali total glycosides extract 1 to add water to specified amount.
Embodiment 2 Radix Astragali total glycosides extracting method of the present invention
Get recipe quantity Radix Astragali medicine materical crude slice (2-4mm sheet, is produced from Shaanxi Province), add 12 times of amounts of water and decoct twice, each 2 hours, merge decoction liquor, filter, filtrate decompression concentrates (temperature: 70 ℃; Vacuum tightness :-0.08Mpa) extremely every 1ml is equivalent to crude drug in whole 2g, reaches 90% with 95% ethanol sedimentation to containing the alcohol amount, and refrigeration was left standstill 48 hours, filtered, and got filtrate recycling ethanol, refrigerated and left standstill 24 hours, filtered.Get the logical HPD700 of filtrate, be washed to closely colourlessly, use 80% wash-out, collect elutriant, filter, reclaim ethanol and also be concentrated into 10g crude drug/ml, refrigeration was left standstill 24 hours, filtration; Add 95% ethanol and reach 80% to containing the alcohol amount, refrigeration was left standstill 24 hours, filtered; Reclaim ethanol, boiled 30 minutes, (the 12.5g crude drug/ml), sealing, refrigeration filtered more than 24 hours, and check promptly gets Radix Astragali total glycosides extract 2 to add water to specified amount.
Embodiment 3 Radix Astragali total glycosides extracting method of the present invention
Get recipe quantity Radix Astragali medicine materical crude slice (2-4mm sheet, is produced from the Shanxi Province), add 8 times of amounts of water and decoct twice, each 1.5 hours, merge decoction liquor, filter, filtrate decompression concentrates (temperature: 70 ℃; Vacuum tightness :-0.08Mpa) extremely every 1ml is equivalent to crude drug in whole 2g, reaches 85% with 95% ethanol sedimentation to containing the alcohol amount, and refrigeration was left standstill 48 hours, filtered, and got filtrate recycling ethanol, refrigerated and left standstill 24 hours, filtered.Get the logical LD140 of filtrate, be washed to closely colourlessly, use 75% wash-out, collect elutriant, filter, reclaim ethanol and also be concentrated into 10g crude drug/ml, refrigeration was left standstill 24 hours, filtration; Add 95% ethanol and reach 85% to containing the alcohol amount, refrigeration was left standstill 36 hours, filtered; Reclaim ethanol, boiled 30 minutes, (the 12.5g crude drug/ml), sealing, refrigeration filtered more than 24 hours, and check promptly gets Radix Astragali total glycosides extract 3 to add water to specified amount.
Embodiment 4 Radix Astragali total glycosides extracting method of the present invention
Get recipe quantity Radix Astragali medicine materical crude slice (2-4mm sheet, the Gansu south of Gansu Province produces), add 10 times of amounts of water and decoct three times, each 1 hour, merge decoction liquor, filter, filtrate decompression concentrates (temperature: 70 ℃; Vacuum tightness :-0.08Mpa) extremely every 1ml is equivalent to crude drug in whole 2g, reaches 60% with 95% ethanol sedimentation to containing the alcohol amount, and refrigeration was left standstill 24 hours, filtered, and got filtrate recycling ethanol, refrigerated and left standstill 24 hours, filtered.Get the logical HPD100 of filtrate, be washed to closely colourlessly, use 80% wash-out, collect elutriant, filter, reclaim ethanol and also be concentrated into 10g crude drug/ml, refrigeration was left standstill 24 hours, filtration; Add 95% ethanol and reach 85% to containing the alcohol amount, refrigeration was left standstill 24 hours, filtered; Reclaim ethanol, boiled 30 minutes, (the 12.5g crude drug/ml), sealing, refrigeration filtered more than 24 hours, and check promptly gets Radix Astragali total glycosides extract 4 to add water to specified amount.
Embodiment 5 Radix Astragali total glycosides extracting method of the present invention
Get recipe quantity Radix Astragali medicine materical crude slice (2-4mm sheet, the Gansu south of Gansu Province produces), add 10 times of amounts of water and decoct three times, each 1 hour, merge decoction liquor, filter, filtrate decompression concentrates (temperature: 70 ℃; Vacuum tightness :-0.08Mpa) extremely every 1ml is equivalent to crude drug in whole 2g, reaches 60% with 95% ethanol sedimentation to containing the alcohol amount, and refrigeration was left standstill 24 hours, filtered, and got filtrate recycling ethanol, refrigerated and left standstill 24 hours, filtered.Get filtrate by the HPD300 post, be washed to closely colourlessly, use 75% ethanol elution, collect elutriant, filter, reclaim ethanol and also be concentrated into 10g crude drug/ml, refrigeration was left standstill 24 hours, filtration; Add 95% ethanol and reach 85% to containing the alcohol amount, refrigeration was left standstill 24 hours, filtered; Reclaim ethanol, boiled 30 minutes, (the 12.5g crude drug/ml), sealing, refrigeration filtered more than 24 hours, and check promptly gets Radix Astragali total glycosides extract 5 to add water to specified amount.
Embodiment 6 Radix Astragali total glycosides extracting method of the present invention:
Get recipe quantity Radix Astragali medicine materical crude slice (2-4mm sheet, the Gansu south of Gansu Province produces), add 10 times of amounts of water and decoct three times, each 1 hour, merge decoction liquor, filter, filtrate decompression concentrates (temperature: 70 ℃; Vacuum tightness :-0.08Mpa) extremely every 1ml is equivalent to crude drug in whole 2g, reaches 60% with 95% ethanol sedimentation to containing the alcohol amount, and refrigeration was left standstill 24 hours, filtered, and got filtrate recycling ethanol, refrigerated and left standstill 24 hours, filtered.Get filtrate by post D101, be washed to closely colourlessly, use 75% ethanol elution, collect elutriant, filter, reclaim ethanol and also be concentrated into 10g crude drug/ml, refrigeration was left standstill 24 hours, filtration; Add 95% ethanol and reach 85% to containing the alcohol amount, refrigeration was left standstill 24 hours, filtered; Reclaim ethanol, boiled 30 minutes, (the 12.5g crude drug/ml), sealing, refrigeration filtered more than 24 hours, and check promptly gets Radix Astragali total glycosides extract 6 to add water to specified amount.
The mensuration of Radix Astragali total glycosides, Cyclosiversioside F in embodiment 7 Radix Astragali total glycosides extracts of the present invention:
Cyclosiversioside F adopts evaporative light scattering detection HPLC method to detect in the Radix Astragali total glycosides extract.Radix Astragali total glycosides adopts ultraviolet spectrophotometry to detect, and Vanillin-ethanol is during as developer.
The content (mg/ml) of Radix Astragali total glycosides, Cyclosiversioside F in table 1 Radix Astragali total glycosides extract of the present invention
| Radix Astragali total glycosides extract | Solid content | Radix Astragali total glycosides content | Astragaloside content |
| Radix Astragali total glycosides extract 1 | 40.0 | 37.2 | 16.4 |
| Radix Astragali total glycosides extract 2 | 38.9 | 37.3 | 13.6 |
| Radix Astragali total glycosides extract 3 | 42.3 | 37.6 | 4.0 |
| Radix Astragali total glycosides extract 4 | 47.0 | 38.4 | 9.75 |
| Radix Astragali total glycosides extract 5 | 37.4 | 31.6 | 9.17 |
| Radix Astragali total glycosides extract 6 | 43.8 | 36.2 | 8.68 |
Adopt the different parameter of described Radix Astragali total glycosides preparation method, can obtain different products, wherein the weight percentage of Radix Astragali total glycosides accounts for the 80-100% of general extractive, and the percentage composition of Cyclosiversioside F accounts for the 6-50% of general extractive.
Preparation of Cyclosiversioside F and homologue thereof and evaluation in embodiment 8 Radix Astragali total glycosidess of the present invention
Press the Radix Astragali total glycosides 2500ml of embodiment 2 method gained, use ethyl acetate (2000ml * 4), propyl carbinol (2000ml * 4) to extract successively, get acetic acid ethyl ester extract 39g, n-butyl alcohol extract 62g.Ethyl acetate is partly carried out silica gel column chromatography, and (Φ 85mm, 1100g), (30: 1-2: 1) gradient elution, every bottle graft is received the 500ml eluent to chloroform-methanol, amounts to 130 parts.Fr.56-61 separates out compound 1 (70mg), and fr.97-100 separates out compound 4 (230mg).Fr.2-5 merges into A (2.3g) and carries out silica gel column chromatography (Φ 35mm, 110g), sherwood oil-acetone (5: 1-3: 1) gradient elution, every 100ml eluent receives one bottle, Fr.26-56 merges into B (6g) and carries out the reverse column chromatography of ODS (Φ 40mm, 200g), methanol-water (30-70%) gradient elution, every 100ml eluent receives one bottle, wherein fr.B38-49 merges into BE (1.2g), and (Φ 35mm 60g) carries out purifying to silica gel column chromatography, chloroform-methanol (15: 1) wash-out, Fr.66-81 merge into C (5.5g) carry out the reverse column chromatography of ODS (Φ 40m, 200g), methanol-water (40-90%) gradient elution, every 100ml eluent receives one bottle, wherein fr.C26-29 merges into CA (2.2g), and (Φ 40mm 110g) carries out purifying to silica gel column chromatography, chloroform-methanol (11: 1) wash-out obtains compound 2 (1.21g) from fr.CA9-23.Fr.82-88 merges into D (5.1g) and carries out the reverse column chromatography of ODS (Φ 40mm, 200g), methanol-water (40-90%) gradient elution, every 100ml eluent receives one bottle, and fr.D30-40 merges into DA (2.9g), silica gel column chromatography (Ф 45mm, 150g) carry out purifying, chloroform-methanol (11: 1) wash-out obtains compound 3 (0.95g) from fr.DA16-28
Propyl carbinol is partly carried out silica gel column chromatography, and (Φ 85mm, 1250g), (12: 1-1: 1) gradient elution, every bottle graft is received the 500ml eluent to chloroform-methanol, amounts to 145 parts.Fr.32-35 separates out compound 5 (8mg), and fr.41-46 separates out compound 8 (100mg), and fr.54-72 separates out compound 14 (3.38g), and fr.79-95 separates out compound 5 (1.40g), and fr.106-120 separates out compound 6 (2.13g).
Acetyl astragaloside I (1), white powder (MeOH);
1H and
13C NMR data (solvent: pyridine-d5)
Identical with reference 1,2; ESIMS m/z 933.9[M+Na]
+, 1843.7[2M+Na]
+
Astragaloside I (2), white powder (MeOH);
1H and
13C NMR data (solvent: pyridine-d5) identical with reference 1,2; ESIMS m/z 891.8[M+Na]
+, 1759.6[2M+Na]
+
Different astragaloside I (3), white powder (MeOH);
1H and
13C NMR data (solvent: pyridine-d5) with reference 1,2 identical ESIMS m/z 891.9[M+Na]
+, 1759.8[2M+Na]
+
Different astragaloside II (4), white powder (MeOH);
1H and
13C NMR data (solvent: pyridine-d5) identical with reference 1,2; ESIMS m/z 849.7[M+Na]
+, 1675.6[2M+Na]
+
Astragaloside II (5), white powder (MeOH);
1H and
13C NMR data (solvent: pyridine-d5) identical with reference 1,2; ESIMS m/z 849.6[M+Na]
+
Astragaloside IV (6), white powder (MeOH); Mp 282-283 ℃; ESIMS m/z 807.7[M+Na]
+, 1592.6[2M+Na]
+
The fusing point instrument is a Beckman numeral fusing point instrument; Mass spectrograph is Finnigan LCQ
DECANuclear magnetic resonance spectrometer is BrukerAM-400, and TMS is as interior mark.Column chromatography used silica gel (200-300 order) is produced by Haiyang Chemical Plant, Qingdao, oppositely material ODS (Cosmosil 75C
18-OPN) produce by Nacalai tesque company.
The preparation of embodiment 9 injection liquids
Injection liquid is formed:
Radix Astragali total glycosides 50g
SODIUM PHOSPHATE, MONOBASIC 0.45g
Sodium-chlor 9g (making 1000ml altogether)
Get Radix Astragali total glycosides, sodium-chlor and SODIUM PHOSPHATE, MONOBASIC, add the injection water, add the 0.1%-0.2% gac to 200-800ml, boil 30 minutes after, filter, add the injection water, transfer pH to 7.2-8.2, ultrafiltration with saturated sodium hydroxide solution to 1000ml, embedding, sterilization, check, promptly.
Be used for the treatment of myocarditis, heart failure, intravenous drip, every day, 100ml or followed the doctor's advice.Every contains Radix Astragali total glycosides in Cyclosiversioside F, must not be less than 90.0mg.Cyclosiversioside F must not be less than 20.0mg.
Table 2 Radix Astragali total glycosides injection liquid of the present invention quality investigation result
| Period of storage | Proterties | Differentiate | Clarity | The pH value | Aseptic | Pyrogen | Haemolysis | Pungency | Astragaloside IV content (mg/ml) |
| 0 month | Light yellow clear liquid | + | ∨ | 6.68 | ∨ | ∨ | ∨ | ∨ | 0.3014 |
| January | Light yellow clear liquid | + | ∨ | 6.65 | ∨ | ∨ | ∨ | ∨ | 0.3015 |
| February | Light yellow clear liquid | + | ∨ | 6.66 | ∨ | ∨ | ∨ | ∨ | 0.3021 |
| March | Light yellow clear liquid | + | ∨ | 6.63 | ∨ | ∨ | ∨ | ∨ | 0.3034 |
| June | Light yellow clear liquid | + | ∨ | 6.62 | ∨ | ∨ | ∨ | ∨ | 0.3046 |
| 24 months | Light yellow clear liquid | + | ∨ | 6.60 | ∨ | ∨ | ∨ | ∨ | 0.3052 |
+-be positive reaction, ∨-expression is up to specification
Conclusion: adopt Radix Astragali total glycosides extract of the present invention to prepare injection liquid, can reach the specification of quality of preparation equally not using solubility promoter and helping under the situation of thinner, and also more reliable in security.Skilled in the art will recognize that, in some special preparation, the use of auxiliary material can make preparation stabilization on the one hand, and quality reaches requirement, may cause side effects such as allergy but then again, therefore, when adopting Radix Astragali total glycosides extract of the present invention to prepare injection,, can not use some necessary auxiliary materials because of the special property of itself, eliminate potential safety hazard, reached beyond thought beneficial effect.
Embodiment 10 crude drugs, Radix Astragali total glycosides and the contrast of injection liquid thin-layer chromatography
Prepare trial-product by crude drug, Radix Astragali total glycosides and finished product trial-product preparation method respectively.Get evaporate to dryness in an amount of trial-product water-bath, residue adds methyl alcohol 0.5ml makes dissolving, as need testing solution.Other gets compound 1,2,3,4,5,6 reference substances of embodiment 3 gained, adds methyl alcohol and makes the solution that every 1ml contains 1mg, in contrast product solution.The used thin layer plate of TLC is GF254 (Qingdao Marine Chemical Co.) and RP-18 254 (Merck), and expanding body is CHCl
3-MeOH (5: 1), spray is with 10% ethanol solution of sulfuric acid, and it is clear to dry by the fire to the spot colour developing at 105 ℃, and the result shows three's collection of illustrative plates basically identical, sees accompanying drawing 1, illustrates that Radix Astragali total glycosides, injection liquid technology have kept astragaloside homologen in the Chinese medicine astragalus to greatest extent.The solubleness of Cyclosiversioside F homologue in water is far longer than Cyclosiversioside F, and the solubleness in water greatly in pharmacy advantage be conspicuous.
The preparation of embodiment 11 medicament composition capsule agent of the present invention
The composition of every capsules:
Radix Astragali total glycosides (embodiment 2 makes) 100g
Starch 80g (making 1000 altogether)
Get according to the above ratio, starch, mixing, encapsulated.Every dress 180mg.
Every contains Radix Astragali total glycosides in Cyclosiversioside F, is no less than 80.0mg.
Embodiment 12: the preparation of tablet
Tablet is formed:
Radix Astragali total glycosides (embodiment 2 makes) 100g
HPMC?
LV100 30g
Lactose 70g
Magnesium Stearate 1g (making 1000 altogether)
With Radix Astragali total glycosides, HPMC, lactose mixing, be tackiness agent system wet granular with 75% ethanol, cross 22 mesh sieves, 50 ℃ of dry 3h, the whole grain of 22 mesh sieves adds Magnesium Stearate mixing compressing tablet, every heavy 0.15g.
Every contains Radix Astragali total glycosides in Cyclosiversioside F, must not be less than 80.0mg.
Below by pharmacodynamics test proof beneficial effect of the present invention:
Test example 1 Radix Astragali total glycosides causes the therapeutic action and the action intensity of cat acute heart failure to vetanarcol:
2～4kg animal cat (Beijing tonneau animal rearing factory provides body weight, the male and female dual-purpose) is divided into normal control group, positive drug group (cedilanid), Radix Astragali total glycosides extract 1 heavy dose of group, middle dosage and low dose, 5 groups altogether, 7～8 every group.3% vetanarcol (Beijing chemical reagents corporation, lot number 020402, be mixed with physiological saline) abdominal injection 30mg/kg anesthesia, the jugular vein intubate is used for constant infusion 3% vetanarcol, and femoral venous catheter is used for constant infusion and is subjected to the reagent thing, connect that electrocardiogram(ECG (ECG) limb is led, trachea cannula, connection breathing apparatus, respiratory rate is 26 times/min, and Tidal volume is 29～70ml, opens chest, left ventricular cannulation connects pressure transducer.ECG, left ventricular pressure (LVP) and left ventricular pressure differential (LVdp/dt) through Rm6240C bio signal acquisition processing system continuous recording in computer.Every numerical value of stablizing 30 minutes behind the animal surgery is as the arm's length basis value.
With the maximum climbing speed (LVdp/dt of left ventricular pressure
Max) as the cardiac contractility index, behind vein constant infusion 3% vetanarcol, LVdp/dt
MaxDescend gradually, when dropping to 26.6～66.5kPa (200～500mmHg), 5min does not have the tendency of rising, be considered as forming acute heart failure, vein constant infusion 0.2ml/min is subjected to the reagent thing then, blank group instillation physiological saline, positive drug group instillation Purpurea glycoside C injection liquid (cedilanid, Shanghai Xudong Hipu Medicine Co., Ltd, lot number 010901, face with preceding be diluted to desired concn with stroke-physiological saline solution) 0.1mg/ml, Radix Astragali total glycosides extract 1 heavy dose of 12.5g medicinal material/ml, middle dosage 1g medicinal material/ml, low dose of 0.5g medicinal material/ml.
After 3% vetanarcol constant speed intravenous injection causes the cat heart failure, three concentration of constant speed intravenous injection Radix Astragali total glycosides (12.5g crude drug/ml, 1g crude drug/ml, the 0.5g crude drug/ml), cedilanid 0.1mg/ml and physiological saline control group, the maximum rising difference of LVSP and LVdp/dtmax sees Table 3.
The quiet influence of annotating front and back of table 3 Radix Astragali total glycosides constant speed to heart failure cat LVdp/dtmax and the maximum rising difference of LVSP
Annotate: with physiological saline control group ratio
*P＜0.05.
As seen from Table 3, cause the cat acute heart failure with 3% vetanarcol, Radix Astragali total glycosides concentration 0.5g medicinal material/ml constant speed injection 0.2ml/min, the ascensional range of the maximum climbing speed of left ventricular pressure peak value (LVSP) and left ventricular pressure (LVdp/dtmax) is higher than physiological saline control group (P＜0.05), and the significant prolongation animals survived time (P＜0.01).Radix Astragali general glycoside 1g crude drug/ml concentration constant speed injection 0.2ml/min, the amplitude that heart failure cat LVSP and LVdp/dtmax rise and physiological saline control group are than no marked difference (P＞0.05), but the significant prolongation animals survived time (P＜0.01).Radix Astragali general glycoside 12.5g crude drug/ml does not all have obvious influence (P＞0.05) to LVSP, LVdp/dtmax and animals survived time.
Test example 2 Radix Astragali total glycosides interior therapeutic mouse CV B
3The myocarditis test
Mouse CV B
3The foundation of myocarditis model
BALB/C mice (in 6 ages in week, body weight 16-18g/ is only provided the animal conformity certification by West China Center of Medical Sciences management of laboratory animal center: No. the 75th, the real kinoplaszm pipe in (1996) river) 10 every group, and totally three groups.Adopt 10 respectively
-2/ ml, 10
-4/ ml and 10
-6The CV B of three concentration of/ml
3Virus liquid injects mouse peritoneal, and 0.2ml/.Heart rate, survival condition and the myocardial pathology of observing mouse on the 7th day detect, and determine injection CV B
3ID
50Be 10
-4/ ml virus liquid 0.2ml can cause typical mouse viral myocarditis.
Radix Astragali total glycosides treatment mouse CV B
3The myocarditis test
Being divided into is six experimental group: (1) normal control group, 10, do not do any processing; (2) infection group and viral infection group, 20, the abdominal cavity injects CV B
310
-4/ ml 0.2ml, not medication; (3) Radix Astragali total glycosides extract 4:20 only injects CV B
30.2ml behind the 2h, with 0.63g medicinal material/ml Radix Astragali total glycosides, 0.1ml/10g body weight; (4) Radix Astragali total glycosides extract 5:20 only injects CV B
30.2ml behind the 2h, with 1.25g medicinal material/ml Radix Astragali total glycosides, 0.1ml/10g body weight; (5) Radix Astragali total glycosides extract 6:20 only injects CV B
30.2ml behind the 2h, with 2.5g medicinal material/ml Radix Astragali total glycosides, 0.1ml/10g body weight; (6) medicine control group, injects CV B by 10
30.2ml behind the 2h, inject virazole 0.1g/kg, once a day.
At the 8th day, get mouse orbit blood, separation of serum is for detecting serum paraoxonase creatine phosphate kinase (CK), lactic acid desaminase (LDH) and virucidin.After putting to death mouse, weigh, it is dirty to core.
The Radix Astragali total glycosides of iv various dose is to CV B continuously
3The influence of myocarditis mouse heart weight and heart surface pathology the results are shown in Table 4.
Table 4 Radix Astragali total glycosides is to the influence of myocarditis mouse heart weight and heart surface pathology (X ± S)
Annotate: compare with model group,
*P＜0.05,
*P＜0.01.
As seen from Table 4, normal control group mouse and model group mouse heart weight, there were significant differences for coefficient ratio (p＜0.01), model group mouse weight loss, and the normal group body weight is weightening finish, there were significant differences for both, and no blutpunkte, surface, shows that mouse viral myocarditis model is reliable.Continuously iv Radix Astragali total glycosides 6.3,12.5,25g (crude drug)/kg.d7 days, the cardiac weight of three kinds of dosage Radix Astragali total glycosides mouse, coefficient, blutpunkte, blood spots all have obvious inhibition than model group as a result, body weight is also significantly increased (p＜0.01) than model group, show that Radix Astragali total glycosides is to CV B
3Causing the mouse viral myocarditis has remarkable restraining effect, and showing has good protective action to mouse heart.The power of provide protection and iv dosage have tangible dose-dependently.
The Radix Astragali total glycosides of iv various dose is to CV B continuously
3The influence of myocarditis mice serum CK and LDH enzymic activity the results are shown in Table 5.
Table 5 Radix Astragali total glycosides is to CK in the myocarditis mice serum, the LDH enzymic activity (influence of X ± SD)
Annotate: compare with model group,
*P＜0.05,
*P＜0.01.
As seen from Table 5, the CK and the LDH of model group all significantly raise than normal group, and p is all less than 0.01.Show CV B
3Myocarditis can cause that CK, LDH significantly raise, and CK, LDH of each group of Radix Astragali total glycosides all have remarkable reduction than model group, shows that continuous iv Radix Astragali total glycosides can stop CK, LDH due to the myocarditis virus to raise.
The Radix Astragali total glycosides of iv various dose is to CV B continuously
3CV among myocarditis mice serum neutralizing antibody and the myocardial cell
3The influence of titre the results are shown in Table 6.
Table 6 Radix Astragali total glycosides is to mice serum neutralizing antibody and CV B
3The influence of titre
Annotate: compare with model group, when neutralizing antibody or titre difference reach 4 times, show diagnostic significance, i.e. p＜0.01.
As seen from Table 6, all do not find neutralizing antibody and CV B in the serum of normal group
3Virus, and the neutralizing antibody of model group and titre were respectively 1: 32,1: 16, showed CV
3Virus causes CV B among the neutralizing antibody of myocarditis mouse and the myocardial cell
3Raise, the middle and high dosage group of Radix Astragali total glycosides in and antibody suppress equal highly significant (p＜0.01), the Radix Astragali total glycosides of three kinds of dosage is to myocardium CV B
3Titre suppresses equal highly significant.Show neutralizing antibody and the myocardial cell CV B of Radix Astragali total glycosides to the myocarditis mouse
3Good regulating effect is arranged.
The Radix Astragali total glycosides of iv various dose is to mouse CV B continuously
3The influence of myocarditis cardiac muscle pathological tissue integration the results are shown in Table 7.
Table 7 Radix Astragali total glycosides is to the influence of mouse cardiac muscle pathological tissue integration
Annotate: compare with model group,
*P＜0.05,
*P＜0.01.
As known from Table 7, continuous iv Radix Astragali total glycosides 6.3,12.5,25g (medicinal material)/kg.d are to CV B
3Myocarditis mouse pathology integration (inflammatory infiltration and necrosis) has significant inhibition, shows that Radix Astragali total glycosides has good protective action to the pathology damage that myocarditis causes mouse.
Can reduce serum paraoxonase creatine phosphate kinase, lactic acid desaminase level and neutralizing antibody with Radix Astragali total glycosides treatment mouse coxsackie myocarditis, reduce myocardial cell's virus titer, alleviate the damage of virus the myocardial cell.Show that Radix Astragali total glycosides has lethal effect to Coxsackie virus, the myocardial cell is had the better protecting effect.
In vivo test shows: to infecting CV B
3The Radix Astragali total glycosides 6.3,12.5 of viral myocarditis BALB/C mice iv various dose, 25g (crude drug)/kg.d, continuous 7 days, CV B among the serum CK of myocarditis mouse, LDH, neutralizing antibody, heart coefficient, the myocardial cell as a result
3Titre and inflammatory infiltration area degree of necrosis, with model group than p all less than 0.01, show that Radix Astragali total glycosides has anti-preferably CV B
3Due to the viral myocarditis effect.
Test example 3 toxicology tests
The medium lethal dose that tail vein injection gives the mouse Radix Astragali total glycosides is 184.2g (crude drug)/kg.Radix Astragali total glycosides rat long term toxicity test shows: in 7 weeks of administration, low dose group increases RBC number, content of hemoglobin and the pcv of rat, blood sugar significantly increases, and all the other hematologies of each administration group, biochemical indexes are no abnormal.Do not find macroscopic pathological change when dissecting animal, organ coefficient is normal.
The dog long term toxicity test shows: the symptom of scratching where it itches significant emesis appears and in middle and high dosage treated animal of administration initial stage, and the symptom of scratching where it itches is very fast disappearance after administration, and symptoms of emesis no longer appears in the most of animal in two week backs.Except that high, middle dosage cause that blood sugar reduces, blood parameters be there is no obvious influence.
Radix Astragali total glycosides of the present invention as can be seen treats that the effective dose of viral myocarditis mouse is 0.077,0.038,0.019g/kg.d from last data, and reference 3 report Cyclosiversioside Fs were treated effective dose 0.5g/kg days of mouse core myositis mouse, and 0.056g/kg days, treatment mouse core myositis was invalid in 0.17g/kg days.The effective dose of Cyclosiversioside F treatment mouse core myositis is greater than Radix Astragali total glycosides as can be seen.The Cyclosiversioside F homologue has synergistic function the viral myocarditis mouse of treatment in the proof Radix Astragali total glycosides.
Above-mentioned pharmacodynamics test explanation, adopt the Radix Astragali total glycosides of the inventive method preparation, kept the Cyclosiversioside F homologue, the performance synergistic function, this Radix Astragali total glycosides can be prepared into pharmaceutically various preparations commonly used, especially during injection, need not add any solubility promoter and thinner, be the clinical new selection approach that Radix Astragali total glycosides is provided.
Reference:
1.Isao?Kitagawa?et?al.Saponin?and?Sapogenol.Chem.Pharm.Bull.1983，31(2)，689-697.
2.Isao?Kitagawa?et?al.Saponin?and?Sapogenol.Chem.Pharm.Bull.1983，31(2)，698-708.
3, Chinese Journal of New Drugs and Clinical Remedies 2003,22 (9): 515-519.
Claims (7)
1. Radix Astragali total glycosides extract is characterized in that:
The weight percentage of Radix Astragali total glycosides accounts for the 80-100% of extract, and wherein the percentage composition of Cyclosiversioside F accounts for the 6-50% of general extractive; The preparation method of described Radix Astragali total glycosides extract comprises the steps:
A. with Chinese medicine astragalus, boiling merges decoction liquor, and concentrating under reduced pressure gets Radix Astragali concentrated solution;
B, the concentrated solution of a step is added ethanol reach 50%-80%, leave standstill 0 ℃ of-5 ℃ of refrigeration to containing the alcohol amount, 24～36 hours, filter, filtrate is concentrated into every milliliter and is equivalent to 0.5-1.0 gram crude drug, and refrigeration is left standstill, and 24～36 hours, filters; Get filtrate by macroporous adsorptive resins, be washed to closely colourless;
C, use the 50%-98% ethanol elution, collect elutriant, filter, reclaim ethanol and also be concentrated into and do not have the alcohol flavor, refrigeration is left standstill, and filters;
D, the concentrated solution of c step is added ethanol reach 70%-90% to containing the alcohol amount, refrigeration is left standstill, and filters, and reclaims ethanol, boils, and filters, and collects filtrate; Concentrate drying promptly gets Radix Astragali total glycosides extract.
2. according to the described Radix Astragali total glycosides extract of claim 1, the used macroporous adsorbent resin of preparation method b step that it is characterized in that Radix Astragali total glycosides extract is nonpolar or/and the low-pole macroporous adsorbent resin, and the resin model is a kind of or its mixing among HPD100, HPD300, D101, HPD100A, HPD700, the LD140.
3. a drug combination preparation is characterized in that the Radix Astragali total glycosides extract by claim 1 or 2 described treatment significant quantities is that activeconstituents and acceptable accessories are prepared from.
4. drug combination preparation according to claim 3 is characterized in that: described preparation is pill, powder, tablet, capsule, granule, injection.
5. the purposes of the described drug combination preparation of claim 3 in preparation treatment and prevention viral myocarditis, heart failure drugs.
6. the preparation method of Radix Astragali total glycosides extract is characterized in that this method comprises the steps:
A. with Chinese medicine astragalus, boiling merges decoction liquor, and concentrating under reduced pressure gets Radix Astragali concentrated solution;
B, the concentrated solution of a step is added ethanol reach 50%-80%, leave standstill 0 ℃ of-5 ℃ of refrigeration to containing the alcohol amount, 24～36 hours, filter, filtrate is concentrated into every milliliter and is equivalent to 0.5-1.0 gram crude drug, and refrigeration is left standstill, and 24～36 hours, filters; Get filtrate by macroporous adsorptive resins, be washed to closely colourless;
C, use the 50%-98% ethanol elution, collect elutriant, filter, reclaim ethanol and also be concentrated into and do not have the alcohol flavor, refrigeration is left standstill, and filters;
D, the concentrated solution of c step is added ethanol reach 70%-90% to containing the alcohol amount, refrigeration is left standstill, and filters, and reclaims ethanol, boils, and filters, and collects filtrate; Concentrate drying promptly gets Radix Astragali total glycosides extract; Wherein the weight percentage of Radix Astragali total glycosides accounts for the 80-100% of extract, and the percentage composition of Cyclosiversioside F accounts for the 6-41% of general extractive;
7. according to the described Radix Astragali total glycosides extract preparation method of claim 6, it is characterized in that the used macroporous adsorbent resin of b step is nonpolar or/and the low-pole macroporous adsorbent resin, the resin model is a kind of or its mixing among HPD100, HPD300, D101, HPD100A, HPD700, the LD140.
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| CN1470241A (en) * | 2002-07-22 | 2004-01-28 | 江苏正大天晴药业股份有限公司 | Astragalus root methyl-glycoside composition and preparation method |
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| CN1470241A (en) * | 2002-07-22 | 2004-01-28 | 江苏正大天晴药业股份有限公司 | Astragalus root methyl-glycoside composition and preparation method |
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