CN1305485C - Injection danhong of radix salviae miltorrhizae and flos carthami, and its preparing method and quality control method - Google Patents
Injection danhong of radix salviae miltorrhizae and flos carthami, and its preparing method and quality control method Download PDFInfo
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- CN1305485C CN1305485C CN 200410000321 CN200410000321A CN1305485C CN 1305485 C CN1305485 C CN 1305485C CN 200410000321 CN200410000321 CN 200410000321 CN 200410000321 A CN200410000321 A CN 200410000321A CN 1305485 C CN1305485 C CN 1305485C
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- 239000007924 injection Substances 0.000 title claims abstract description 105
- 238000000034 method Methods 0.000 title claims abstract description 41
- 239000008522 danhong Substances 0.000 title claims description 99
- 241000628997 Flos Species 0.000 title claims description 92
- 238000003908 quality control method Methods 0.000 title description 2
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- 239000006228 supernatant Substances 0.000 claims description 70
- 238000004321 preservation Methods 0.000 claims description 57
- 239000000284 extract Substances 0.000 claims description 50
- 238000004108 freeze drying Methods 0.000 claims description 35
- 238000007598 dipping method Methods 0.000 claims description 32
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- WLYGSPLCNKYESI-RSUQVHIMSA-N Carthamin Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@H]1[C@@]1(O)C(O)=C(C(=O)\C=C\C=2C=CC(O)=CC=2)C(=O)C(\C=C\2C([C@](O)([C@H]3[C@@H]([C@@H](O)[C@H](O)[C@@H](CO)O3)O)C(O)=C(C(=O)\C=C\C=3C=CC(O)=CC=3)C/2=O)=O)=C1O WLYGSPLCNKYESI-RSUQVHIMSA-N 0.000 description 5
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- OIRDTQYFTABQOQ-KQYNXXCUSA-N adenosine Chemical compound C1=NC=2C(N)=NC=NC=2N1[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O OIRDTQYFTABQOQ-KQYNXXCUSA-N 0.000 description 2
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Abstract
The present invention discloses an injection of radices salviae miltiorrhizae and safflower, a preparing method and a content measuring method thereof. The preparing method of the present invention has the working procedures: radices salviae miltiorrhizae is extracted by adopting an ethanol reflux extracting method; the radices salviae miltiorrhizae which is processed with the ethanol reflux extracting method is decocted with water; decocting liquid is merged and filtered; safflower is extracted by being immersed in ethanol, and is filtered; radices salviae miltiorrhizae extracting liquid and safflower extracting liquid are uniformly mixed and prepared into the injection. The injection of radices salviae miltiorrhizae and safflower and the preparing method thereof of the present invention have the advantages of advanced and scientific preparing technology, complete effective ingredient extraction, controllable extracting technology quality, high quality standard of the preparation, good stability, high medicine concentration, and convenient transportation, storage and use.
Description
Technical field
The invention belongs to medicine field, relating to a kind of is Danhong for injection of raw material and preparation method thereof, content assaying method with vegetable crude drug Radix Salviae Miltiorrhizae and Flos Carthami.
Background technology
Present existing DANHONG ZHUSHEYE is to be raw material by the Radix Salviae Miltiorrhizae and Flos Carthami, carry out the aqueous injection for preparing after the extracts active ingredients, though be the Chinese medicine emergent treatment medicine that truly has curative effect clinically, be used for the treatment of cardiovascular diseasies such as coronary heart disease, angina pectoris, myocardial infarction, ischemic encephalopathy, cerebral thrombosis and pulmonary heart disease, also can be used for treating the thoracic obstruction due to the blood stasis obturation and apoplexy etc.But there is the extraction process imperfection in existing DANHONG ZHUSHEYE, and extracts active ingredients is incomplete, and the control of product quality difficulty is big, and the poor stability of preparation quality standard low and imperfection, particularly DANHONG ZHUSHEYE, stores also all inconvenience etc. at transportation.For example: in the related preparation method of the preparation technology (WS-11220 (ZD-1220)-2002) of existing DANHONG ZHUSHEYE and Chinese patent CN 1418678A (a kind of pharmaceutical composition for the treatment of cardiovascular and cerebrovascular disease and preparation method thereof), do not have monitoring and extract the method for terminal point, the medicinal component of Flos Carthami is extracted incomplete; The content measuring standard of Flos Carthami is comprehensive inadequately; It is water insoluble that injection water-soluble flavone glycoside composition decomposes the aglycon that generates; Adding sodium chloride for injection adjusting etc. is oozed, and according to document (Cao Yimin etc., Flos Carthami injection and five kinds of injection compatibility stability are investigated, the Guangdong pharmacy, 2002,12 (4): 31-32) report: Flos Carthami injection and sodium chloride injection compatibility, particle diameter all increases severely greater than the microgranule of 2 μ m and 5 μ m, and the negative effect of microgranule can not be ignored; Existing DANHONG ZHUSHEYE adopts technique for extracting mixed, and composition is too complicated, and intermediate control difficulty is big; DANHONG ZHUSHEYE stability is also relatively poor, and after the long term storage, color can deepen, and produces precipitation.Document (Shen Qingliang etc., the best process for refining of orthogonal design research Radix Salviae Miltiorrhizae Flos Carthami injection, fashionable pharmaceutical journal, 2001,15 (1)) the best process for refining of described Radix Salviae Miltiorrhizae Flos Carthami injection exists significantly not enough, the one, only with the amount of one of the composition of Radix Salviae Miltiorrhizae protocatechualdehyde as unique judge index, and do not consider other main component, particularly the contained medicinal component of Flos Carthami such as adenosine and Flos Carthami flavochrome etc.; The 2nd, the extraction process that adopts be the Radix Salviae Miltiorrhizae Flos Carthami the two mix earlier, water extract-alcohol precipitation again, the Radix Salviae Miltiorrhizae and Flos Carthami also only has water to put forward component, does not also have the method for monitoring extraction terminal point, the control of product quality difficulty is big; At last, the transportation of Radix Salviae Miltiorrhizae Injection, store very inconvenient.Just because of above-mentioned shortcoming, the present invention has carried out further research and improvement to extraction process.
Summary of the invention
The object of the present invention is to provide a kind of Danhong for injection effective ingredient mixed liquor and method of quality control thereof, another purpose of the present invention is to provide the method for mixed liquor being made freeze-dried powder.
The present invention seeks to be achieved through the following technical solutions:
1, Radix Salviae Miltiorrhizae adopts 20～50 times of alcohol reflux 3～4 times earlier, and each 2～3 hours, extract terminal point with thin layer chromatography control, get effective component in red sage extracting solution A; The Radix Salviae Miltiorrhizae that alcohol reflux is crossed boils 2～3 times with 10～20 times decocting again, and each 40～80 minutes, collecting decoction filtered; Carry out ethanol precipitation twice after filtrate concentrates, make for the first time to contain the alcohol amount and reach 75%, make for the second time to contain the alcohol amount and reach 85%, behind each precipitate with ethanol all cold preservation place, get supernatant then and filter, filtrate and said extracted liquid A merging, cold preservation; Get supernatant and filter, after filtrate was concentrated into the thick paste shape, aqueous precipitation was handled, and spends the night, and got supernatant then and filtered, and promptly got the medicinal component extracting solution of Radix Salviae Miltiorrhizae B, used for dosing.
2, Flos Carthami adopts 20～50 times of Diluted Alcohol dippings to extract earlier 2～3 times, and each 3.0 hours, cold preservation was got supernatant and filtered, and filtrate concentrates the back water precipitating, gets supernatant again and filters, and promptly gets safflower effective ingredients extracting solution C; The Flos Carthami that alcohol dipping was extracted is got with 20～50 times of water temperature lixiviates again, filters, and adding ethanol carried out ethanol precipitation twice after filtrate was concentrated into the thick paste shape; Make for the first time to contain the alcohol amount and reach 80%, make for the second time to contain the alcohol amount and reach 85%, filter, merging filtrate reclaims ethanol and also is concentrated into the thick paste shape, adds water then, stirs evenly, and cold preservation filters, and promptly gets the medicinal component extracting solution of Flos Carthami D; Safflower effective ingredients extracting solution C and D are merged, filter, promptly get the medicinal component extracting solution of Flos Carthami E.
3, with above-mentioned gained extracting solution B and E mixing, promptly get the extracts active ingredients liquid of the used vegetable crude drug of Danhong for injection, in extracts active ingredients liquid, add excipient 0.05～0.5 gram by every milliliter, stir, dissolving filters, and it is an amount of to add the injection water, re-adjustment pH value to 4～9 promptly get Danhong for injection effective ingredient mixed liquor; Every milliliter of Danhong for injection contains and is equivalent to primary dose Radix Salviae Miltiorrhizae 0.75～3.0g, Flos Carthami 0.25～1.0g;
The effective ingredient mixed liquor of above-mentioned Danhong for injection is pressed every bottle of 2ml, 5ml, after the specification packing of 10ml or 20ml, do not seal and put into and freeze drying box size corresponding metal dish, freeze drying box is carried out sterilization treatment, and the temperature of its shelf is reduced to-25 ℃～-50 ℃, the metal dish that preparation will be housed is put into freeze drying box rapidly, keeps 1～6 hour, then freeze drying box is carried out application of vacuum, making the vacuum in the case is 0.2～0.5Pa, again shelf is heated up, and be strict controlled in below the eutectic point-2 ℃, kept 10～24 hours, be warming up to 40 ℃ at last, and kept 1～5 hour, formulation temperature is overlapped with shelf temperature, put into aseptic filtering gas, the water content of control preparation is sealed rapidly and is got final product 1～5%.
Selectable optimum physical condition is in the freezing dry process: at first shelf is cooled to-30 ℃, kept 3 hours, making the vacuum in the freeze drying box then is 0.2Pa, shelf is heated up and be strict controlled in-2 ℃, kept 18 hours, with shelf be warming up to 40 ℃ put into aseptic gas after, control preparation water content be 2%.
Assay
The content assaying method of protocatechualdehyde and danshensu:
1, chromatographic condition and system property test on probation: with octadecylsilane chemically bonded silica is filler; With the cruel acid of water-methanol-ice (94: 6: 0.6) is mobile phase; The detection wavelength is 280nm.Number of theoretical plate is pressed danshensu and is calculated, and should be not less than 5000.
2, the preparation of reference substance solution: close protocatechualdehyde, each 30mg of danshensu reference substance that is dried to constant weight at 100～110 ℃ that take by weighing, put in the 50ml measuring bottle, add mobile phase to scale, shake up.Precision is measured 1ml, puts in the 10ml measuring bottle, adds mobile phase to scale, shakes up, and promptly gets (containing protocatechualdehyde, each 0.06mg of danshensu among every 1ml).
3, algoscopy: precision is measured Danhong for injection 5ml of the present invention, puts in the 25ml measuring bottle, adds mobile phase to scale, shakes up.Precision is measured 10 μ l and is injected chromatograph of liquid, the record chromatogram; Other gets reference substance solution, measures with method, presses external standard method with calculated by peak area, promptly.
The every 1ml of Danhong for injection of the present invention contains Radix Salviae Miltiorrhizae extract with protocatechualdehyde (C
7H
6O
3) and danshensu (C
9H
10O
5) the total amount meter, should be no less than 0.6mg.
The content of total flavone assay method:
1, the preparation of reference substance solution: precision takes by weighing the control substance of Rutin 30mg that is dried to constant weight at 100-110 ℃, puts in the 100ml measuring bottle, and it is an amount of to add 50% methanol, and jolting makes dissolving and is diluted to scale, shakes up, and promptly gets (containing anhydrous rutin 0.3mg among every 1ml).
2, the preparation of standard curve: precision is measured reference substance solution 0.5ml, 1.0ml, 2.0ml, 3.0ml, 4.0ml, 5.0ml, put respectively in the 10ml measuring bottle, respectively add 40-60% methanol to 5ml, add 5% sodium nitrite solution 0.3ml, shake up, placed 4-8 minute, add 10% aluminum nitrate solution 0.3ml, shake up, placed 5-8 minute, hydro-oxidation sodium test solution 4ml, add 50% methanol again to scale, shaking up, is blank with corresponding solution, according to spectrophotography (an appendix V of Chinese Pharmacopoeia version in 2000 B), measure trap at 500nm wavelength place, with the trap is vertical coordinate, and concentration is abscissa, the drawing standard curve.
3, algoscopy: precision is measured Danhong for injection 5ml of the present invention, puts in the 100ml measuring bottle, and thin up is to scale, shake up, precision is measured 1ml, puts in the 10ml measuring bottle, add 40-60% methanol to scale, shake up, as blank, precision is measured 1ml in addition, puts in the 10ml measuring bottle method under the sighting target directrix curve preparation, from " adding 50% methanol " to 5ml, measure trap immediately in accordance with the law, read the weight that is equivalent to rutin the need testing solution from standard curve, calculate, promptly.
The every 1ml of Danhong for injection of the present invention contains total flavones with rutin (C
27H
30O
16) meter, should be no less than 6.0mg.
The content assaying method of flavochrome:
1, the preparation of reference substance solution: precision takes by weighing the flavochrome reference substance 100mg that is dried to constant weight at 105 ℃, puts in the 100ml measuring bottle, and it is an amount of to add 60-80% methanol, and jolting makes dissolving and is diluted to scale, shakes up, and promptly gets (containing flavochrome 1.0mg among every 1ml).
2, the preparation of standard curve: precision is measured reference substance solution 1.5ml, 3.0ml, 4.5ml, 6.0ml, 7.5ml, 9ml, 10.5ml, put respectively in the 50ml measuring bottle, respectively add 70% methanol to scale, shaking up, is blank with corresponding solution, according to spectrophotography (an appendix V of Chinese Pharmacopoeia version in 2000 B), measure trap at 403nm wavelength place, with the trap is vertical coordinate, and concentration is abscissa, the drawing standard curve.
3, algoscopy: precision is measured Danhong for injection 2ml of the present invention, puts in the 100ml measuring bottle, and thin up is to scale, shake up, precision is measured 1ml, puts in the 10ml measuring bottle, add 70% methanol to scale, shake up, as blank, precision is measured 1ml in addition, puts in the 10ml measuring bottle, adds 70% methanol to scale, measure trap immediately in accordance with the law, read the weight that is equivalent to flavochrome the need testing solution from standard curve, calculate, promptly.
Danhong for injection of the present invention contains flavochrome should be not less than 25%.
The preparation method of Danhong for injection of the present invention provides a kind of extraction process more advanced, science, and extracts active ingredients is more complete, and extraction process is quality controllable, preparation quality standard is higher, and good stability, the drug level height is convenient to Danhong for injection that transports, stores and use and preparation method thereof.
Experimental example 1: the screening of Radix Salviae Miltiorrhizae and safflower effective ingredients extraction process
Extraction process (1) alcohol reflux extracts effective component in red sage in conjunction with decoction alcohol precipitation method separately: claim Radix Salviae Miltiorrhizae 0.75kg, adopt 20 times of alcohol reflux 3 times, and each 2.5 hours, extract terminal point with thin layer chromatography control, get effective component in red sage extracting solution A; The Radix Salviae Miltiorrhizae that alcohol reflux is crossed boils three times with 20 times decocting respectively again, each 60 minutes, collecting decoction, filter, carry out ethanol precipitation twice after filtrate concentrates, make for the first time to contain the alcohol amount and reach 75%, make for the second time to contain the alcohol amount and reach 85%, all cold preservation placements behind each precipitate with ethanol, get supernatant then and filter, filtrate and said extracted liquid A merge, cold preservation, getting supernatant filters, after filtrate is concentrated into the thick paste shape, add water to the 450ml precipitation process, spend the night, get supernatant then and filter, promptly get the medicinal component extracting solution of Radix Salviae Miltiorrhizae B.(2) alcohol dipping is extracted bound water warm macerating extraction method and is extracted safflower effective ingredients: take by weighing Flos Carthami 0.25kg, adopt 20 times of Diluted Alcohol dippings to extract each 3.0 hours 2 times earlier, cold preservation is got supernatant and is filtered, and filtrate concentrates the back water precipitating, get supernatant again and filter, promptly get safflower effective ingredients extracting solution C; The Flos Carthami that alcohol dipping was extracted is got with 20 times of water temperature lixiviates again, filters, and adding ethanol carried out ethanol precipitation twice after filtrate was concentrated into the thick paste shape, make for the first time and contain the alcohol amount and reach 80%, make for the second time to contain the alcohol amount and reach 85%, filter merging filtrate, reclaim ethanol and be concentrated into the thick paste shape, add water then, stir evenly, cold preservation, filter, promptly get the medicinal component extracting solution of Flos Carthami D; Safflower effective ingredients extracting solution C and D are merged, add water to 450ml, filter, promptly get the medicinal component extracting solution of Flos Carthami E.(3) Radix Salviae Miltiorrhizae and safflower effective ingredients extract the preparation of mixed liquor: Radix Salviae Miltiorrhizae and Flos Carthami medicinal component extracting solution B and E mix homogeneously with above-mentioned gained, add water to 1000ml then, and promptly get the extracts active ingredients liquid of the used vegetable crude drug of Danhong for injection.
Technique for extracting mixed: the alcohol leaching water extraction extracts Radix Salviae Miltiorrhizae and safflower effective ingredients mixed liquor: according to DANHONG ZHUSHEYE (WS
3-B-3267-98) described preparation method prepares Radix Salviae Miltiorrhizae and safflower effective ingredients mixed liquor.Specific practice is: take by weighing Radix Salviae Miltiorrhizae 0.75kg, with Diluted Alcohol warm macerating secondary, each 60 minutes, filter filtrate for later use; Medicinal residues add water temperature and soak secondary with after Flos Carthami mixes, and each 60 minutes, filter, merging filtrate is concentrated into relative density and is 1.15 clear paste, adds water to 1000ml then, and cold preservation filters, promptly.
Every processing repeats 3 times, experimental result (seeing Table 1) shows: calculate with protocatechualdehyde and danshensu, total flavones and Carthamus yellow, the independent extraction process of Radix Salviae Miltiorrhizae and Flos Carthami, promptly adopt alcohol reflux to extract effective component in red sage earlier in conjunction with water decoction-alcohol sedimentation, adopt Diluted Alcohol dipping bound water warm macerating to extract the effective ingredient of Flos Carthami again, at last the two is mixed, the amount of this independent extraction process gained protocatechualdehyde and danshensu, total flavones and Carthamus yellow is all apparently higher than the amount of technique for extracting mixed gained.
Table 1 extraction process is to the influence of protocatechualdehyde and danshensu, total flavones and Carthamus yellow amount
| Independent extraction process | Technique for extracting mixed | |
| Protocatechualdehyde and danshensu (mg/ml) total flavones (mg/ml) Carthamus yellow (%) | 0.99 7.1 32.5％ | 0.61 5.4 14.3％ |
Experimental example 2: the selection of excipient
In the medicinal component extracting solution of above-mentioned independent extraction process gained, add different types of excipient, make the appearance results of lyophilized injectable powder, see Table 2 through lyophilization.
The influence of the different excipient of table 2
| Dextran | Glucose | Mannitol | Gelatin hydrolysate | Sucrose | Lactose | Appearance index |
| 0.05 | 0.05 0.05 0.05 | 0.05 0.05 0.05 | 0.05 | 0.05 0.05 0.05 | 0.05 | Better general best general atrophy is relatively poor better relatively poor general |
Every processing repeats 3 times, and table 2 shows that selecting mannitol for use is best excipient.
Experimental example 3: Danhong for injection of the present invention has raising than the quality standard of original DANHONG ZHUSHEYE, and its " assay " is down to such as table 3:
The comparison of table 3 " assay " method and index
| Method | Index | |
| DANHONG ZHUSHEYE | HPLC method spectrophotography | Protocatechualdehyde and danshensu are no less than the 0.5mg/ml total flavones and are no less than 5.0mg/ml |
| Danhong for injection | HPLC method spectrophotography spectrophotography | Protocatechualdehyde and danshensu are no less than the 0.6mg/ml total flavones and are no less than the 6.0mg/ml Carthamus yellow and are not less than 25% |
Danhong for injection of the present invention " assay " method is as follows:
(1) content assaying method of protocatechualdehyde and danshensu
Chromatographic condition and system try out the property test: with octadecylsilane chemically bonded silica is filler; With the cruel acid of water-methanol-ice (94: 6: 0.6) is mobile phase; The detection wavelength is 280nm.Number of theoretical plate is pressed danshensu and is calculated, and should be not less than 5000.
The preparation of reference substance solution: precision takes by weighing protocatechualdehyde, each 30mg of danshensu reference substance that is dried to constant weight at 105 ℃, puts in the 50ml measuring bottle, adds mobile phase to scale, shakes up.Precision is measured 1ml, puts in the 10ml measuring bottle, adds mobile phase to scale, shakes up, and promptly gets (containing protocatechualdehyde, each 0.06mg of danshensu among every 1ml).
Algoscopy: precision is measured Danhong for injection 5ml of the present invention, puts in the 25ml measuring bottle, adds mobile phase to scale, shakes up.Precision is measured 10 μ l and is injected chromatograph of liquid, the record chromatogram; Other gets reference substance solution, measures with method, presses external standard method with calculated by peak area, promptly.
The every 1ml of Danhong for injection of the present invention contains Radix Salviae Miltiorrhizae extract with protocatechualdehyde (C
7H
6O
3) and danshensu (C
9H
10O
5) the total amount meter, should be no less than 0.6mg.
(2) content of total flavone assay method
The preparation of reference substance solution: precision takes by weighing the control substance of Rutin 30mg that is dried to constant weight at 105 ℃, puts in the 100ml measuring bottle, and it is an amount of to add 50% methanol, and jolting makes dissolving and is diluted to scale, shakes up, and promptly gets (containing anhydrous rutin 0.3mg among every 1ml).
The preparation of standard curve: precision is measured reference substance solution 0.5ml, 1.0ml, 2.0ml, 3.0ml, 4.0ml, 5.0ml, put respectively in the 10ml measuring bottle, respectively add 50% methanol to 5ml, add 5% sodium nitrite solution 0.3ml, shake up, placed 6 minutes, add 10% aluminum nitrate solution 0.3ml, shake up, placed 6 minutes, hydro-oxidation sodium test solution 4ml, add 50% methanol again to scale, shaking up, is blank with corresponding solution, according to spectrophotography (an appendix V of Chinese Pharmacopoeia version in 2000 B), measure trap at 500nm wavelength place, with the trap is vertical coordinate, and concentration is abscissa, the drawing standard curve.
Algoscopy: precision is measured Danhong for injection 5ml of the present invention, puts in the 100ml measuring bottle, and thin up is to scale, shake up, precision is measured 1ml, puts in the 10ml measuring bottle, add 50% methanol to scale, shake up, as blank, precision is measured 1ml in addition, puts in the 10ml measuring bottle method under the sighting target directrix curve preparation, from " adding 50% methanol " to 5ml, measure trap immediately in accordance with the law, read the weight that is equivalent to rutin the need testing solution from standard curve, calculate, promptly.
The every 1ml of Danhong for injection of the present invention contains total flavones with rutin (C
27H
30O
16) meter, should be no less than 6.0mg.
(3) content assaying method of flavochrome
The preparation of reference substance solution: precision takes by weighing the flavochrome reference substance 100mg that is dried to constant weight at 105 ℃, puts in the 100ml measuring bottle, and it is an amount of to add 70% methanol, and jolting makes dissolving and is diluted to scale, shakes up, and promptly gets (containing flavochrome 1.0mg among every 1ml).
The preparation of standard curve: precision is measured reference substance solution 1.5ml, 3.0ml, 4.5ml, 6.0ml, 7.5ml, 9ml, 10.5ml, put respectively in the 50ml measuring bottle, respectively add 70% methanol to scale, shaking up, is blank with corresponding solution, according to spectrophotography (an appendix V of Chinese Pharmacopoeia version in 2000 B), measure trap at 403nm wavelength place, with the trap is vertical coordinate, and concentration is abscissa, the drawing standard curve.
Algoscopy: precision is measured Danhong for injection 2ml of the present invention, puts in the 100ml measuring bottle, and thin up is to scale, shake up, precision is measured 1ml, puts in the 10ml measuring bottle, add 70% methanol to scale, shake up, as blank, precision is measured 1ml in addition, puts in the 10ml measuring bottle, adds 70% methanol to scale, measure trap immediately in accordance with the law, read the weight that is equivalent to flavochrome the need testing solution from standard curve, calculate, promptly.
Danhong for injection of the present invention contains flavochrome should be not less than 25%.
Experimental example 4: the comparison of Danhong for injection and DANHONG ZHUSHEYE stability
Place 37 ℃ of climatic chambers to deposit together Danhong for injection of the present invention and corresponding DANHONG ZHUSHEYE.Timing sampling is checked (DANHONG ZHUSHEYE every day check clarity), and 3 totally months, inspection item was as follows:
Visual examination: DANHONG ZHUSHEYE: whether the overview color deepens;
Danhong for injection: whether be out of shape atrophy, whether color deepens;
Clarity test: DANHONG ZHUSHEYE: whether lamp inspection has precipitate to separate out;
Danhong for injection: getting one bottle and add the 5ml distilled water, observe dissolution time, is instant in 20 seconds, and it is qualified to be considered as.Whether lamp inspection has precipitate to separate out.
The medicinal liquid pH value is checked: DANHONG ZHUSHEYE: measure the medicinal liquid pH value with 25 type pH meters;
Danhong for injection: get one bottle add the 5ml dissolved in distilled water after, measure the medicinal liquid pH value with 25 type pH meters.
The assay of main component protocatechualdehyde and danshensu
Measure the protocatechualdehyde of DANHONG ZHUSHEYE and Danhong for injection and the content of danshensu as stated above respectively.
Table 4 result shows that DANHONG ZHUSHEYE is very unstable, and accelerated test promptly precipitated in 60 days, and the content of pH value and protocatechualdehyde and danshensu all obviously descends.
Place 37 ℃ to investigate 3 months continuously Danhong for injection, experimental result sees Table 5.The content of the outward appearance of Danhong for injection, color and luster, water solublity, pH value and protocatechualdehyde and danshensu has no significant change, steady quality, and every batch of moisture determination in addition is all below 2%.The result represents that Danhong for injection has good stability, and is better than DANHONG ZHUSHEYE.
37 ℃ of accelerated test results of table 4 DANHONG ZHUSHEYE
| Time (my god) | ||||||
| 0 | 10 | 20 | 40 | 60 | ||
| 01 batch | Color and luster pH value clarity protocatechualdehyde and danshensu (mg/ml) | Reddish brown 6.31 clear and bright 0.67 | Reddish brown 6.24 clear and bright 0.62 | Reddish brown 6.15 clear and bright 0.61 | Reddish brown 5.82 obvious opalescences 0.59 | Reddish brown 5.76 precipitations 0.57 |
| 02 batch | Color and luster pH value clarity protocatechualdehyde and danshensu (mg/ml) | Reddish brown 6.35 clear and bright 0.63 | Reddish brown 6.32 clear and bright 0.58 | Reddish brown 6.31 clear and bright 0.55 | Reddish brown 6.22 obvious opalescences 0.54 | Reddish brown 6.12 precipitations 0.53 |
| 03 batch | Color and luster pH value clarity protocatechualdehyde and danshensu (mg/ml) | Reddish brown 6.83 clear and bright 0.59 | Reddish brown 6.78 clear and bright 0.55 | Reddish brown 6.64 clear and bright 0.52 | Reddish brown 6.29 precipitations 0.48 | Undetermined undetermined undetermined undetermined |
37 ℃ of accelerated test experimental results of table 5 Danhong for injection
| Time (moon) | |||||
| 0 | 1 | 2 | 3 | ||
| 01 batch | Color and luster pH value water solublity protocatechualdehyde and danshensu (mg/ml) | Yellowish 6.40 instant 0.99 | Yellowish 6.39 instant 0.99 | Yellowish 6.35 instant 0.97 | Yellowish 6.31 instant 0.95 |
| 02 batch | Color and luster pH value water solublity protocatechualdehyde and danshensu (mg/ml) | Yellowish 6.13 instant 0.89 | Yellowish 6.09 instant 0.89 | Yellowish 6.09 instant 0.86 | Yellowish 6.01 instant 0.84 |
| 03 batch | Color and luster pH value water solublity protocatechualdehyde and danshensu (mg/ml) | Yellowish 6.43 instant 0.87 | Yellowish 6.39 instant 0.85 | Yellowish 6.37 instant 0.83 | Yellowish 6.35 instant 0.82 |
Embodiment 1: the preparation of Danhong for injection mixed liquor
Prescription is formed:
Radix Salviae Miltiorrhizae 7.5kg
Flos Carthami 2.5kg
Mannitol 1kg
Water for injection is an amount of
Make 10000ml
Preparation method: 1, Radix Salviae Miltiorrhizae is through choosing, clean, dry, be ground into acinous, take by weighing and be ground into 25 times of alcohol reflux of granuliform Radix Salviae Miltiorrhizae 7.5kg elder generation's employing 3 times, each 2.5 hours, extract terminal point with thin layer chromatography control, get effective component in red sage extracting solution A; The Radix Salviae Miltiorrhizae that alcohol reflux is crossed boils three times with 20 times decocting again, each 60 minutes, collecting decoction, filter, filtrate is carried out ethanol precipitation twice after concentrating, and makes for the first time to contain the alcohol amount and reach 75%, make for the second time and contain the alcohol amount and reach 85%, all cold preservation placements behind each precipitate with ethanol are got supernatant then and are filtered, and filtrate and said extracted liquid A merge, cold preservation, get supernatant and filter, filtrate adds water to 4500ml after being concentrated into the thick paste shape, spend the night, get supernatant then and filter, promptly get the medicinal component extracting solution of Radix Salviae Miltiorrhizae B, use for dosing.
2, Flos Carthami adopts 50 times of Diluted Alcohol dippings to extract earlier 2 times through selection, and each 3.0 hours, cold preservation was got supernatant and filtered, and filtrate concentrates the back water precipitating, gets supernatant again and filters, and promptly gets safflower effective ingredients extracting solution C; The Flos Carthami that alcohol dipping was extracted is got with 40 times of water temperature lixiviates again, filters, and adding ethanol carried out ethanol precipitation twice after filtrate was concentrated into the thick paste shape, make for the first time and contain the alcohol amount and reach 80%, make for the second time to contain the alcohol amount and reach 85%, filter merging filtrate, reclaim ethanol and be concentrated into the thick paste shape, add water then, stir evenly, cold preservation, filter, promptly get the medicinal component extracting solution of Flos Carthami D; Safflower effective ingredients extracting solution C and D are merged, add water for injection, filter, promptly get the medicinal component extracting solution of Flos Carthami E, use for dosing to 4500ml.
3, with the medicinal component extracting solution B and the E mix homogeneously of above-mentioned gained, promptly get the extracts active ingredients liquid of the used vegetable crude drug of Danhong for injection, in extracts active ingredients liquid, add mannitol 1000 grams, stir, dissolving filters, and adds the injection water to 10000ml, re-adjustment pH value to 6.5 promptly gets the effective ingredient mixed liquor of Danhong for injection.
Embodiment 2: the preparation of Danhong for injection mixed liquor
Prescription is formed:
Radix Salviae Miltiorrhizae 27kg
Flos Carthami 3kg
Mannitol 1kg
Water for injection is an amount of
Make 10000ml
Preparation method: 1, Radix Salviae Miltiorrhizae is through choosing, clean, dry, be ground into acinous, take by weighing and be ground into 25 times of alcohol reflux of granuliform Radix Salviae Miltiorrhizae 27kg elder generation's employing 3 times, each 2.5 hours, extract terminal point with thin layer chromatography control, get effective component in red sage extracting solution A; The Radix Salviae Miltiorrhizae that alcohol reflux is crossed boils three times with 20 times decocting again, each 60 minutes, collecting decoction, filter, filtrate is carried out ethanol precipitation twice after concentrating, and makes for the first time to contain the alcohol amount and reach 75%, make for the second time and contain the alcohol amount and reach 85%, all cold preservation placements behind each precipitate with ethanol are got supernatant then and are filtered, and filtrate and said extracted liquid A merge, cold preservation, get supernatant and filter, filtrate adds water to 4500ml after being concentrated into the thick paste shape, spend the night, get supernatant then and filter, promptly get the medicinal component extracting solution of Radix Salviae Miltiorrhizae B, use for dosing.
2, Flos Carthami adopts 50 times of Diluted Alcohol dippings to extract earlier 2 times through selection, and each 3.0 hours, cold preservation was got supernatant and filtered, and filtrate concentrates the back water precipitating, gets supernatant again and filters, and promptly gets safflower effective ingredients extracting solution C; The Flos Carthami that alcohol dipping was extracted is got with 40 times of water temperature lixiviates again, filters, and adding ethanol carried out ethanol precipitation twice after filtrate was concentrated into the thick paste shape, make for the first time and contain the alcohol amount and reach 80%, make for the second time to contain the alcohol amount and reach 85%, filter merging filtrate, reclaim ethanol and be concentrated into the thick paste shape, add water then, stir evenly, cold preservation, filter, promptly get the medicinal component extracting solution of Flos Carthami D; Safflower effective ingredients extracting solution C and D are merged, add water for injection, filter, promptly get the medicinal component extracting solution of Flos Carthami E, use for dosing to 4500ml.
3, with the medicinal component extracting solution B and the E mix homogeneously of above-mentioned gained, promptly get the extracts active ingredients liquid of the used vegetable crude drug of Danhong for injection, in extracts active ingredients liquid, add mannitol 1000 grams, stir, dissolving filters, and adds the injection water to 10000ml, re-adjustment pH value to 6.5 promptly gets the effective ingredient mixed liquor of Danhong for injection.
Embodiment 3: the preparation of Danhong freeze dried powder injection
Prescription is formed:
Radix Salviae Miltiorrhizae 10kg
Flos Carthami 4kg
Mannitol 0.5kg
Glucose 0.5kg
Water for injection is an amount of
Make 10000ml
Preparation method: 1, Radix Salviae Miltiorrhizae is through choosing, clean, dry, be ground into acinous, take by weighing and be ground into granuliform Radix Salviae Miltiorrhizae 10kg, adopt 30 times of alcohol reflux 3 times earlier, each 2.5 hours, extract terminal point with thin layer chromatography control, get effective component in red sage extracting solution A; The Radix Salviae Miltiorrhizae that alcohol reflux is crossed boils three times with 20 times decocting again, each 60 minutes, collecting decoction, filter, filtrate is carried out ethanol precipitation twice after concentrating, and makes for the first time to contain the alcohol amount and reach 75%, make for the second time and contain the alcohol amount and reach 85%, all cold preservation placements behind each precipitate with ethanol are got supernatant then and are filtered, and filtrate and said extracted liquid A merge, cold preservation, get supernatant and filter, filtrate adds water to 4500ml after being concentrated into the thick paste shape, spend the night, get supernatant then and filter, promptly get the medicinal component extracting solution of Radix Salviae Miltiorrhizae B, use for dosing.
2, Flos Carthami takes by weighing the Flos Carthami 4kg that chose through selection, adopts 50 times of Diluted Alcohol dippings to extract earlier 2 times, and each 3.0 hours, cold preservation was got supernatant and filtered, and filtrate concentrates the back water precipitating, gets supernatant again and filters, and promptly gets safflower effective ingredients extracting solution C; The Flos Carthami that alcohol dipping was extracted is got with 40 times of water temperature lixiviates again, filters, and adding ethanol carried out ethanol precipitation twice after filtrate was concentrated into the thick paste shape, make for the first time and contain the alcohol amount and reach 80%, make for the second time to contain the alcohol amount and reach 85%, filter merging filtrate, reclaim ethanol and be concentrated into the thick paste shape, add water then, stir evenly, cold preservation, filter, promptly get the medicinal component extracting solution of Flos Carthami D; Safflower effective ingredients extracting solution C and D are merged, add water for injection, filter, promptly get the medicinal component extracting solution of Flos Carthami E, use for dosing to 4500ml.
3, with the medicinal component extracting solution B and the E mix homogeneously of above-mentioned gained, promptly get the extracts active ingredients liquid of the used vegetable crude drug of Danhong for injection, in extracts active ingredients liquid, add mannitol 0.5kg, glucose 0.5kg stirs, dissolving, filter, and adding the injection water to 10000ml, re-adjustment pH value to 6.5 promptly gets the effective ingredient mixed liquor of the used vegetable crude drug of Danhong for injection lyophilizing.
Lyophilization: with the effective ingredient mixed liquor of the used vegetable crude drug of above-mentioned Danhong for injection lyophilizing by every bottle of 10ml packing after, do not seal and put into and freeze drying box size corresponding metal dish, freeze drying box is carried out sterilization treatment, and the temperature of its shelf is reduced to-30 ℃, the metal dish that preparation will be housed is put into freeze drying box rapidly, kept 3 hours, then freeze drying box is carried out application of vacuum, making the vacuum in the case is 0.2Pa, again shelf is heated up, and be strict controlled in below the eutectic point-2 ℃, kept 20 hours, be warming up to 40 ℃ at last, and the maintenance certain hour, formulation temperature is overlapped with shelf temperature, put into aseptic filtering gas, the water content of control preparation is sealed rapidly and is got final product 2%.
Embodiment 4: the preparation of Danhong freeze dried powder injection
Prescription is formed:
Radix Salviae Miltiorrhizae 15kg
Flos Carthami 6kg
Mannitol 0.8kg
Glucose 0.8kg
Water for injection is an amount of
Make 10000ml
Preparation method: 1, Radix Salviae Miltiorrhizae is through choosing, clean, dry, be ground into acinous, take by weighing and be ground into granuliform Radix Salviae Miltiorrhizae 15kg, adopt 35 times of alcohol reflux 3 times earlier, each 2.5 hours, extract terminal point with thin layer chromatography control, get effective component in red sage extracting solution A; The Radix Salviae Miltiorrhizae that alcohol reflux is crossed boils three times with 20 times decocting again, each 60 minutes, collecting decoction, filter, filtrate is carried out ethanol precipitation twice after concentrating, and makes for the first time to contain the alcohol amount and reach 75%, make for the second time and contain the alcohol amount and reach 80%, all cold preservation placements behind each precipitate with ethanol are got supernatant then and are filtered, and filtrate and said extracted liquid A merge, cold preservation, get supernatant and filter, filtrate adds water to 4500ml after being concentrated into the thick paste shape, spend the night, get supernatant then and filter, promptly get the medicinal component extracting solution of Radix Salviae Miltiorrhizae B, use for dosing.
2, Flos Carthami takes by weighing the Flos Carthami 6kg that chose through selection, adopts 40 times of Diluted Alcohol dippings to extract earlier 2 times, and each 3.0 hours, cold preservation was got supernatant and filtered, and filtrate concentrates the back water precipitating, gets supernatant again and filters, and promptly gets safflower effective ingredients extracting solution C; The Flos Carthami that alcohol dipping was extracted is got with 30 times of water temperature lixiviates again, filters, and adding ethanol carried out ethanol precipitation twice after filtrate was concentrated into the thick paste shape, make for the first time and contain the alcohol amount and reach 80%, make for the second time to contain the alcohol amount and reach 85%, filter merging filtrate, reclaim ethanol and be concentrated into the thick paste shape, add water then, stir evenly, cold preservation, filter, promptly get the medicinal component extracting solution of Flos Carthami D; Safflower effective ingredients extracting solution C and D are merged, add water for injection, filter, promptly get the medicinal component extracting solution of Flos Carthami E, use for dosing to 4500ml.
3, with the medicinal component extracting solution B and the E mix homogeneously of above-mentioned gained, promptly get the extracts active ingredients liquid of the used vegetable crude drug of Danhong for injection, in extracts active ingredients liquid, add mannitol 0.8kg, glucose 0.8kg stirs, dissolving, filter, and adding the injection water to 10000ml, re-adjustment pH value to 6.0 promptly gets the effective ingredient mixed liquor of the used vegetable crude drug of Danhong for injection lyophilizing.
Lyophilization: with the effective ingredient mixed liquor of the used vegetable crude drug of above-mentioned Danhong for injection lyophilizing by every bottle of 10ml packing after, do not seal and put into and freeze drying box size corresponding metal dish, freeze drying box is carried out sterilization treatment, and the temperature of its shelf is reduced to-35 ℃, the metal dish that preparation will be housed is put into freeze drying box rapidly, kept 3 hours, then freeze drying box is carried out application of vacuum, making the vacuum in the case is 0.2Pa, again shelf is heated up, and be strict controlled in below the eutectic point-2 ℃, kept 17 hours, be warming up to 35 ℃ at last, and the maintenance certain hour, formulation temperature is overlapped with shelf temperature, put into aseptic filtering gas, the water content of control preparation is sealed rapidly and is got final product 2%.
Embodiment 5: the preparation of Danhong freeze dried powder injection
Prescription is formed:
Radix Salviae Miltiorrhizae 30kg
Flos Carthami 10kg
Mannitol 2.5kg
Glucose 2.5kg
Water for injection is an amount of
Make 10000ml
Preparation method: 1, Radix Salviae Miltiorrhizae is through choosing, clean, dry, be ground into acinous, take by weighing and be ground into granuliform Radix Salviae Miltiorrhizae 30kg, adopt 50 times of alcohol reflux 3 times earlier, each 2.5 hours, extract terminal point with thin layer chromatography control, get effective component in red sage extracting solution A; The Radix Salviae Miltiorrhizae that alcohol reflux is crossed boils three times with 20 times decocting again, each 60 minutes, collecting decoction, filter, filtrate is carried out ethanol precipitation twice after concentrating, and makes for the first time to contain the alcohol amount and reach 75%, make for the second time and contain the alcohol amount and reach 85%, all cold preservation placements behind each precipitate with ethanol are got supernatant then and are filtered, and filtrate and said extracted liquid A merge, cold preservation, get supernatant and filter, filtrate adds water to 4500ml after being concentrated into the thick paste shape, spend the night, get supernatant then and filter, promptly get the medicinal component extracting solution of Radix Salviae Miltiorrhizae B, use for dosing.
2, Flos Carthami takes by weighing the Flos Carthami 10kg that chose through selection, adopts 50 times of Diluted Alcohol dippings to extract earlier 2 times, and each 3.0 hours, cold preservation was got supernatant and filtered, and filtrate concentrates the back water precipitating, gets supernatant again and filters, and promptly gets safflower effective ingredients extracting solution C; The Flos Carthami that alcohol dipping was extracted is got with 40 times of water temperature lixiviates again, filters, and adding ethanol carried out ethanol precipitation twice after filtrate was concentrated into the thick paste shape, make for the first time and contain the alcohol amount and reach 75%, make for the second time to contain the alcohol amount and reach 85%, filter merging filtrate, reclaim ethanol and be concentrated into the thick paste shape, add water then, stir evenly, cold preservation, filter, promptly get the medicinal component extracting solution of Flos Carthami D; Safflower effective ingredients extracting solution C and D are merged, add water for injection, filter, promptly get the medicinal component extracting solution of Flos Carthami E, use for dosing to 4500ml.
3, with the medicinal component extracting solution B and the E mix homogeneously of above-mentioned gained, promptly get the extracts active ingredients liquid of the used vegetable crude drug of Danhong for injection, in extracts active ingredients liquid, add each 2.5kg of manna alcohol and glucose, stir, dissolving filters, and adds the injection water to 10000ml, re-adjustment pH value to 6.5 promptly gets the effective ingredient mixed liquor of the used vegetable crude drug of Danhong for injection lyophilizing.
Lyophilization: with the effective ingredient mixed liquor of the used vegetable crude drug of above-mentioned Danhong for injection lyophilizing by every bottle of 10ml packing after, do not seal and put into and freeze drying box size corresponding metal dish, freeze drying box is carried out sterilization treatment, and the temperature of its shelf is reduced to-40 ℃, the metal dish that preparation will be housed is put into freeze drying box rapidly, kept 2 hours, then freeze drying box is carried out application of vacuum, making the vacuum in the case is 0.2Pa, again shelf is heated up, and be strict controlled in below the eutectic point-2 ℃, kept 18 hours, be warming up to 35 ℃ at last, and the maintenance certain hour, formulation temperature is overlapped with shelf temperature, put into aseptic filtering gas, the water content of control preparation is sealed rapidly and is got final product 2%.
Embodiment 5
Prescription is formed:
Radix Salviae Miltiorrhizae 20kg
Flos Carthami 8kg
Mannitol 0.5kg
Glucose 0.5kg
Water for injection is an amount of
Make 10000ml
Preparation method: 1, Radix Salviae Miltiorrhizae is through choosing, clean, dry, be ground into acinous, take by weighing and be ground into granuliform Radix Salviae Miltiorrhizae 20kg, adopt 35 times of alcohol reflux 3 times earlier, each 2.5 hours, extract terminal point with thin layer chromatography control, get effective component in red sage extracting solution A; The Radix Salviae Miltiorrhizae that alcohol reflux is crossed boils three times with 20 times decocting again, each 60 minutes, collecting decoction, filter, filtrate is carried out ethanol precipitation twice after concentrating, and makes for the first time to contain the alcohol amount and reach 75%, make for the second time and contain the alcohol amount and reach 80%, all cold preservation placements behind each precipitate with ethanol are got supernatant then and are filtered, and filtrate and said extracted liquid A merge, cold preservation, get supernatant and filter, filtrate adds water to 4500ml after being concentrated into the thick paste shape, spend the night, get supernatant then and filter, promptly get the medicinal component extracting solution of Radix Salviae Miltiorrhizae B, use for dosing.
2, Flos Carthami takes by weighing the Flos Carthami 8kg that chose through selection, adopts 40 times of Diluted Alcohol dippings to extract earlier 2 times, and each 3.0 hours, cold preservation was got supernatant and filtered, and filtrate concentrates the back water precipitating, gets supernatant again and filters, and promptly gets safflower effective ingredients extracting solution C; The Flos Carthami that alcohol dipping was extracted is got with 40 times of water temperature lixiviates again, filters, and adding ethanol carried out ethanol precipitation twice after filtrate was concentrated into the thick paste shape, make for the first time and contain the alcohol amount and reach 80%, make for the second time to contain the alcohol amount and reach 85%, filter merging filtrate, reclaim ethanol and be concentrated into the thick paste shape, add water then, stir evenly, cold preservation, filter, promptly get the medicinal component extracting solution of Flos Carthami D; Safflower effective ingredients extracting solution C and D are merged, add water for injection, filter, promptly get the medicinal component extracting solution of Flos Carthami E, use for dosing to 4500ml.
3, with the medicinal component extracting solution B and the E mix homogeneously of above-mentioned gained, promptly get the extracts active ingredients liquid of the used vegetable crude drug of Danhong for injection, in extracts active ingredients liquid, add mannitol 0.5kg, glucose 0.5kg stirs, dissolving, filter, and adding the injection water to 10000ml, re-adjustment pH value to 6.5 promptly gets the effective ingredient mixed liquor of the used vegetable crude drug of Danhong for injection lyophilizing.
Lyophilization: with the effective ingredient mixed liquor of the used vegetable crude drug of above-mentioned Danhong for injection lyophilizing by every bottle of 10ml packing after, do not seal and put into and freeze drying box size corresponding metal dish, freeze drying box is carried out sterilization treatment, and the temperature of its shelf is reduced to-30 ℃, the metal dish that preparation will be housed is put into freeze drying box rapidly, kept 3 hours, then freeze drying box is carried out application of vacuum, making the vacuum in the case is 0.2Pa, again shelf is heated up, and be strict controlled in below the eutectic point-2 ℃, kept 20 hours, be warming up to 40 ℃ at last, and the maintenance certain hour, formulation temperature is overlapped with shelf temperature, put into aseptic filtering gas, the water content of control preparation is sealed rapidly and is got final product 2%.
Embodiment 6
Prescription is formed:
Radix Salviae Miltiorrhizae 15kg
Flos Carthami 7.5kg
Mannitol 0.8kg
Glucose 0.8kg
Water for injection is an amount of
Make 10000ml
Preparation method: 1, Radix Salviae Miltiorrhizae is through choosing, clean, dry, be ground into acinous, take by weighing and be ground into granuliform Radix Salviae Miltiorrhizae 15kg, adopt 30 times of alcohol reflux 3 times earlier, each 2.5 hours, extract terminal point with thin layer chromatography control, get effective component in red sage extracting solution A; The Radix Salviae Miltiorrhizae that alcohol reflux is crossed boils three times with 20 times decocting again, each 60 minutes, collecting decoction, filter, filtrate is carried out ethanol precipitation twice after concentrating, and makes for the first time to contain the alcohol amount and reach 75%, make for the second time and contain the alcohol amount and reach 85%, all cold preservation placements behind each precipitate with ethanol are got supernatant then and are filtered, and filtrate and said extracted liquid A merge, cold preservation, get supernatant and filter, filtrate adds water to 4500ml after being concentrated into the thick paste shape, spend the night, get supernatant then and filter, promptly get the medicinal component extracting solution of Radix Salviae Miltiorrhizae B, use for dosing.
2, Flos Carthami takes by weighing the Flos Carthami 7.5kg that chose through selection, adopts 50 times of Diluted Alcohol dippings to extract earlier 2 times, and each 3.0 hours, cold preservation was got supernatant and filtered, and filtrate concentrates the back water precipitating, gets supernatant again and filters, and promptly gets safflower effective ingredients extracting solution C; The Flos Carthami that alcohol dipping was extracted is got with 40 times of water temperature lixiviates again, filters, and adding ethanol carried out ethanol precipitation twice after filtrate was concentrated into the thick paste shape, make for the first time and contain the alcohol amount and reach 80%, make for the second time to contain the alcohol amount and reach 85%, filter merging filtrate, reclaim ethanol and be concentrated into the thick paste shape, add water then, stir evenly, cold preservation, filter, promptly get the medicinal component extracting solution of Flos Carthami D; Safflower effective ingredients extracting solution C and D are merged, add water for injection, filter, promptly get the medicinal component extracting solution of Flos Carthami E, use for dosing to 4500ml.
3, with the medicinal component extracting solution B and the E mix homogeneously of above-mentioned gained, promptly get the extracts active ingredients liquid of the used vegetable crude drug of Danhong for injection, in extracts active ingredients liquid, add mannitol 0.8kg, glucose 0.8kg stirs, dissolving, filter, and adding the injection water to 10000ml, re-adjustment pH value to 6.5 promptly gets the effective ingredient mixed liquor of the used vegetable crude drug of Danhong for injection lyophilizing.
Lyophilization: with the effective ingredient mixed liquor of the used vegetable crude drug of above-mentioned Danhong for injection lyophilizing by every bottle of 10ml packing after, do not seal and put into and freeze drying box size corresponding metal dish, freeze drying box is carried out sterilization treatment, and the temperature of its shelf is reduced to-30 ℃, the metal dish that preparation will be housed is put into freeze drying box rapidly, kept 3 hours, then freeze drying box is carried out application of vacuum, making the vacuum in the case is 0.2Pa, again shelf is heated up, and be strict controlled in below the eutectic point-2 ℃, kept 20 hours, be warming up to 40 ℃ at last, and the maintenance certain hour, formulation temperature is overlapped with shelf temperature, put into aseptic filtering gas, the water content of control preparation is sealed rapidly and is got final product 2%.
Claims (9)
1, a kind of Danhong for injection effective ingredient mixed liquor, mixed liquor contain for every milliliter and are equivalent to primary dose Radix Salviae Miltiorrhizae 0.75～3.0g, Flos Carthami 0.25～1.0g, it is characterized in that this Danhong for injection mixed liquor made by following method:
The medicinal component of Radix Salviae Miltiorrhizae adopts alcohol reflux to boil the extraction that combines with decocting; The medicinal component of Flos Carthami adopts the Diluted Alcohol dipping to soak the extraction that combines with water temperature; The extraction process step is:
Radix Salviae Miltiorrhizae powder is broken into acinous, adopts 20～50 times of alcohol reflux 3～4 times earlier, and each 2～3 hours, extract terminal point with thin layer chromatography control, get effective component in red sage extracting solution A; The Radix Salviae Miltiorrhizae that alcohol reflux is crossed boils 2～3 times with 10～20 times decocting again, and each 40～80 minutes, collecting decoction filtered; Carry out ethanol precipitation twice after filtrate concentrates, make for the first time to contain the alcohol amount and reach 75%, make for the second time to contain the alcohol amount and reach 85%, behind each precipitate with ethanol all cold preservation place, get supernatant then and filter, filtrate and said extracted liquid A merging, cold preservation; Get supernatant and filter, after filtrate was concentrated into the thick paste shape, aqueous precipitation was handled, and spends the night, and got supernatant then and filtered, and promptly got the medicinal component extracting solution of Radix Salviae Miltiorrhizae B, used for dosing;
Flos Carthami adopts 20～50 times of Diluted Alcohol dippings to extract earlier 2～3 times through selection, and each 3.0 hours, cold preservation was got supernatant and filtered, and filtrate concentrates the back water precipitating, gets supernatant again and filters, and promptly gets safflower effective ingredients extracting solution C; The Flos Carthami that alcohol dipping was extracted is got with 20～50 times of water temperature lixiviates again, filters, and adding ethanol carried out ethanol precipitation twice after filtrate was concentrated into the thick paste shape; Make for the first time to contain the alcohol amount and reach 80%, make for the second time to contain the alcohol amount and reach 85%, filter, merging filtrate reclaims ethanol and also is concentrated into the thick paste shape, adds water then, stirs evenly, and cold preservation filters, and promptly gets the medicinal component extracting solution of Flos Carthami D; Safflower effective ingredients extracting solution C and D are merged, filter, promptly get the medicinal component extracting solution of Flos Carthami E;
With above-mentioned gained extracting solution B and E mixing, promptly get the extracts active ingredients liquid of the used vegetable crude drug of Danhong for injection, in extracts active ingredients liquid, add excipient 0.05～0.5 gram by every milliliter, stir, dissolving filters, and it is an amount of to add the injection water, re-adjustment pH value to 4～9 promptly get Danhong for injection effective ingredient mixed liquor.
2, Danhong for injection effective ingredient mixed liquor according to claim 1 is characterized in that this mixed liquor made by following method:
Radix Salviae Miltiorrhizae powder is broken into acinous, adopts 25 times of alcohol reflux 3 times earlier, and each 2.5 hours, extract terminal point with thin layer chromatography control, get effective component in red sage extracting solution A; The Radix Salviae Miltiorrhizae that alcohol reflux is crossed boils three times with 20 times decocting again, each 60 minutes, collecting decoction, filter, filtrate is carried out ethanol precipitation twice after concentrating, and makes for the first time to contain the alcohol amount and reach 75%, make for the second time and contain the alcohol amount and reach 85%, all cold preservation placements behind each precipitate with ethanol are got supernatant then and are filtered, and filtrate and said extracted liquid A merge, cold preservation, get supernatant and filter, after filtrate was concentrated into the thick paste shape, aqueous precipitation was handled, spend the night, get supernatant then and filter, promptly get the medicinal component extracting solution of Radix Salviae Miltiorrhizae B, use for dosing;
Flos Carthami adopts 50 times of Diluted Alcohol dippings to extract earlier 2 times through selection, and each 3.0 hours, cold preservation was got supernatant and filtered, and filtrate concentrates the back water precipitating, gets supernatant again and filters, and promptly gets safflower effective ingredients extracting solution C; The Flos Carthami that alcohol dipping was extracted is got with 40 times of water temperature lixiviates again, filters, and adding ethanol carried out ethanol precipitation twice after filtrate was concentrated into the thick paste shape, make for the first time and contain the alcohol amount and reach 80%, make for the second time to contain the alcohol amount and reach 85%, filter merging filtrate, reclaim ethanol and be concentrated into the thick paste shape, add water then, stir evenly, cold preservation, filter, promptly get the medicinal component extracting solution of Flos Carthami D; Safflower effective ingredients extracting solution C and D are merged, filter, promptly get the medicinal component extracting solution of Flos Carthami E;
Medicinal component extracting solution B and E mix homogeneously with above-mentioned gained, promptly get the extracts active ingredients liquid of the used vegetable crude drug of Danhong for injection, in extracts active ingredients liquid, add excipient 0.05 gram by every milliliter, stir, dissolving filters, and it is an amount of to add the injection water, re-adjustment pH value to 6.5 promptly gets the effective ingredient mixed liquor of Danhong for injection.
3, the effective ingredient mixed liquor of Danhong for injection as claimed in claim 1 or 2, it is characterized in that the excipient that adds in the mixed liquor preparation method is mannitol, dextran or glucose: mannitol is 1: 1 mixture.
4, the freeze-dried powder of making as Danhong for injection effective ingredient mixed liquor as described in the claim 1,2 or 3 is characterized in that this freeze-dried powder made by following method:
With mixed liquor by after every bottle of quantitative packing, do not seal the metal dish of putting into freeze drying box, and the temperature of its shelf is reduced to-25 ℃～-50 ℃, the metal dish that preparation will be housed is put into freeze drying box rapidly, kept 1～6 hour, then freeze drying box is carried out application of vacuum, making the vacuum in the case is 0.2～0.5Pa, shelf is heated up again, and be strict controlled in below the eutectic point-2 ℃, kept 10～24 hours, and be warming up to 40 ℃ at last, and keep certain hour, formulation temperature is overlapped with shelf temperature, put into aseptic filtering gas, the water content of control preparation is sealed rapidly 1～5%.
5, as freeze-dried powder as described in the claim 4, it is characterized in that the physical condition that freezing dry process is selected in this freeze-dried powder preparation method is: at first shelf is cooled to-30 ℃, kept 3 hours, make the vacuum 0.2Pa in the freeze drying box then, shelf is heated up and be strict controlled in-2 ℃, kept 18 hours, with shelf be warming up to 40 ℃ put into aseptic gas after, control preparation water content be 2%.
6, a kind of Danhong for injection effective ingredient mixed liquor is characterized in that this Danhong for injection mixed liquor made by following method:
Radix Salviae Miltiorrhizae 27kg
Flos Carthami 3kg
Mannitol 1kg
Water for injection is an amount of
Radix Salviae Miltiorrhizae is ground into 25 times of alcohol reflux of granuliform Radix Salviae Miltiorrhizae 27kg elder generation's employing 3 times through choosing, clean, dry, be ground into acinous, taking by weighing, and each 2.5 hours, extract terminal point with thin layer chromatography control, get effective component in red sage extracting solution A; The Radix Salviae Miltiorrhizae that alcohol reflux is crossed boils three times with 20 times decocting again, each 60 minutes, collecting decoction, filter, filtrate is carried out ethanol precipitation twice after concentrating, and makes for the first time to contain the alcohol amount and reach 75%, make for the second time and contain the alcohol amount and reach 85%, all cold preservation placements behind each precipitate with ethanol are got supernatant then and are filtered, and filtrate and said extracted liquid A merge, cold preservation, get supernatant and filter, filtrate adds water to 4500ml after being concentrated into the thick paste shape, spend the night, get supernatant then and filter, promptly get the medicinal component extracting solution of Radix Salviae Miltiorrhizae B, use for dosing;
Flos Carthami adopts 50 times of Diluted Alcohol dippings to extract earlier 2 times through selection, and each 3.0 hours, cold preservation was got supernatant and filtered, and filtrate concentrates the back water precipitating, gets supernatant again and filters, and promptly gets safflower effective ingredients extracting solution C; The Flos Carthami that alcohol dipping was extracted is got with 40 times of water temperature lixiviates again, filters, and adding ethanol carried out ethanol precipitation twice after filtrate was concentrated into the thick paste shape, make for the first time and contain the alcohol amount and reach 80%, make for the second time to contain the alcohol amount and reach 85%, filter merging filtrate, reclaim ethanol and be concentrated into the thick paste shape, add water then, stir evenly, cold preservation, filter, promptly get the medicinal component extracting solution of Flos Carthami D; Safflower effective ingredients extracting solution C and D are merged, add water for injection, filter, promptly get the medicinal component extracting solution of Flos Carthami E, use for dosing to 4500ml;
Medicinal component extracting solution B and E mix homogeneously with above-mentioned gained, promptly get the extracts active ingredients liquid of the used vegetable crude drug of Danhong for injection, in extracts active ingredients liquid, add mannitol 1000 grams, stir, dissolving filters, and adds the injection water to 10000ml, re-adjustment pH value to 6.5 promptly gets the effective ingredient mixed liquor of Danhong for injection.
7, a kind of preparation method of Danhong for injection effective ingredient mixed liquor, mixed liquor contain for every milliliter and are equivalent to primary dose Radix Salviae Miltiorrhizae 0.75～3.0g, Flos Carthami 0.25～1.0g, it is characterized in that this method is:
The medicinal component of Radix Salviae Miltiorrhizae adopts alcohol reflux to boil the extraction that combines with decocting; The medicinal component of Flos Carthami adopts the Diluted Alcohol dipping to soak the extraction that combines with water temperature; The extraction process step is:
Radix Salviae Miltiorrhizae powder is broken into acinous, adopts 20～50 times of alcohol reflux 3～4 times earlier, and each 2～3 hours, extract terminal point with thin layer chromatography control, get effective component in red sage extracting solution A; The Radix Salviae Miltiorrhizae that alcohol reflux is crossed boils 2～3 times with 10～20 times decocting again, and each 40～80 minutes, collecting decoction filtered; Carry out ethanol precipitation twice after filtrate concentrates, make for the first time to contain the alcohol amount and reach 75%, make for the second time to contain the alcohol amount and reach 85%, behind each precipitate with ethanol all cold preservation place, get supernatant then and filter, filtrate and said extracted liquid A merging, cold preservation; Get supernatant and filter, after filtrate was concentrated into the thick paste shape, aqueous precipitation was handled, and spends the night, and got supernatant then and filtered, and promptly got the medicinal component extracting solution of Radix Salviae Miltiorrhizae B, used for dosing;
Flos Carthami adopts 20～50 times of Diluted Alcohol dippings to extract earlier 2～3 times through selection, and each 3.0 hours, cold preservation was got supernatant and filtered, and filtrate concentrates the back water precipitating, gets supernatant again and filters, and promptly gets safflower effective ingredients extracting solution C; The Flos Carthami that alcohol dipping was extracted is got with 20～50 times of water temperature lixiviates again, filters, and adding ethanol carried out ethanol precipitation twice after filtrate was concentrated into the thick paste shape; Make for the first time to contain the alcohol amount and reach 80%, make for the second time to contain the alcohol amount and reach 85%, filter, merging filtrate reclaims ethanol and also is concentrated into the thick paste shape, adds water then, stirs evenly, and cold preservation filters, and promptly gets the medicinal component extracting solution of Flos Carthami D; Safflower effective ingredients extracting solution C and D are merged, filter, promptly get the medicinal component extracting solution of Flos Carthami E;
With above-mentioned gained extracting solution B and E mixing, promptly get the extracts active ingredients liquid of the used vegetable crude drug of Danhong for injection, in extracts active ingredients liquid, add excipient 0.05～0.5 gram by every milliliter, stir, dissolving filters, and it is an amount of to add the injection water, re-adjustment pH value to 4～9 promptly get Danhong for injection effective ingredient mixed liquor.
8, the preparation method of Danhong for injection effective ingredient mixed liquor according to claim 1, mixed liquor contains for every milliliter and is equivalent to primary dose Radix Salviae Miltiorrhizae 0.75～3.0g, Flos Carthami 0.25～1.0g, it is characterized in that this method is:
Radix Salviae Miltiorrhizae powder is broken into acinous, adopts 25 times of alcohol reflux 3 times earlier, and each 2.5 hours, extract terminal point with thin layer chromatography control, get effective component in red sage extracting solution A; The Radix Salviae Miltiorrhizae that alcohol reflux is crossed boils three times with 20 times decocting again, each 60 minutes, collecting decoction, filter, filtrate is carried out ethanol precipitation twice after concentrating, and makes for the first time to contain the alcohol amount and reach 75%, make for the second time and contain the alcohol amount and reach 85%, all cold preservation placements behind each precipitate with ethanol are got supernatant then and are filtered, and filtrate and said extracted liquid A merge, cold preservation, get supernatant and filter, after filtrate was concentrated into the thick paste shape, aqueous precipitation was handled, spend the night, get supernatant then and filter, promptly get the medicinal component extracting solution of Radix Salviae Miltiorrhizae B, use for dosing;
Flos Carthami adopts 50 times of Diluted Alcohol dippings to extract earlier 2 times through selection, and each 3.0 hours, cold preservation was got supernatant and filtered, and filtrate concentrates the back water precipitating, gets supernatant again and filters, and promptly gets safflower effective ingredients extracting solution C; The Flos Carthami that alcohol dipping was extracted is got with 40 times of water temperature lixiviates again, filters, and adding ethanol carried out ethanol precipitation twice after filtrate was concentrated into the thick paste shape, make for the first time and contain the alcohol amount and reach 80%, make for the second time to contain the alcohol amount and reach 85%, filter merging filtrate, reclaim ethanol and be concentrated into the thick paste shape, add water then, stir evenly, cold preservation, filter, promptly get the medicinal component extracting solution of Flos Carthami D; Safflower effective ingredients extracting solution C and D are merged, filter, promptly get the medicinal component extracting solution of Flos Carthami E;
Medicinal component extracting solution B and E mix homogeneously with above-mentioned gained, promptly get the extracts active ingredients liquid of the used vegetable crude drug of Danhong for injection, in extracts active ingredients liquid, add excipient 0.05 gram by every milliliter, stir, dissolving filters, and it is an amount of to add the injection water, re-adjustment pH value to 6.5 promptly gets the effective ingredient mixed liquor of Danhong for injection.
9, as the preparation method of the effective ingredient mixed liquor of Danhong for injection as described in claim 7 or 8,, it is characterized in that the excipient that adds in this method is mannitol, dextran or glucose: mannitol is 1: 1 mixture.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 200410000321 CN1305485C (en) | 2004-01-07 | 2004-01-07 | Injection danhong of radix salviae miltorrhizae and flos carthami, and its preparing method and quality control method |
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| CN 200410000321 CN1305485C (en) | 2004-01-07 | 2004-01-07 | Injection danhong of radix salviae miltorrhizae and flos carthami, and its preparing method and quality control method |
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| CN101002828B (en) * | 2007-01-10 | 2010-11-03 | 厦门国宇知识产权研究有限公司 | Method for preparing Danhong injection, and products thereof |
| CN102692462B (en) * | 2012-06-03 | 2014-01-08 | 浙江大学 | Danhong injection quality control method |
| CN104825540A (en) * | 2015-04-30 | 2015-08-12 | 上海交通大学医学院附属第九人民医院 | Composition used for treating acute attack of cluster headache |
| CN105920096B (en) * | 2016-06-12 | 2020-05-08 | 南京中医药大学 | Composition of red sage root and safflower, preparation method and application thereof |
| CN108671004A (en) * | 2018-08-01 | 2018-10-19 | 青海大学 | A kind of extracting method and its extract of improving eyesight preparation active ingredient |
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Address after: 044600 Fumin Road, Ruicheng, Shanxi, No. 43 Patentee after: SHANXI YABAO PHARMACEUTICAL Group Corp. Patentee after: SHANGHAI INSTITUTE OF MATERIA MEDICA, CHINESE ACADEMY OF SCIENCES Address before: 044600 Fumin Road, Ruicheng, Shanxi, No. 43 Patentee before: Shanxi Yabao Pharmaceutical Group Co.,Ltd. Patentee before: Shanghai Institute of Materia Medica, Chinese Academy of Sciences |
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