CN1857348A - Water soluble Chinese angelica extract and its injection and their preparing process - Google Patents
Water soluble Chinese angelica extract and its injection and their preparing process Download PDFInfo
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- CN1857348A CN1857348A CN 200610041842 CN200610041842A CN1857348A CN 1857348 A CN1857348 A CN 1857348A CN 200610041842 CN200610041842 CN 200610041842 CN 200610041842 A CN200610041842 A CN 200610041842A CN 1857348 A CN1857348 A CN 1857348A
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Abstract
The present invention provides a kind of water soluble angelica extract and its injection and their preparation process. The water soluble angelica extract is prepared through water or ethanol reflux extracting angelica, water or ethanol precipitating, filtering, eliminating ethanol from the filtrate, purifying with macroporous adsorption resin, eluting first with distilled water and then with ethanol solution, collecting eluted liquid, decompression to eliminate ethanol from the eluted liquid and concentrating. The water soluble angelica extract together with clinical acceptable pH regulator, osmotic regulator, freeze drying excipient and water for injection is prepared into injection, freeze dried powder for injection and infusion solution. The water soluble angelica extract has ferulic acid content higher than 25% and raised medicinal effect.
Description
Technical field
The present invention relates to a kind of Chinese medicine extract and preparation thereof and preparation method, be specifically related to a kind of Radix Angelicae Sinensis water solubility extract and injection preparation and preparation technology.
Background technology
Dry root when being classified as umbelliferae angelica Angelica sinensis (Oliv.) Diels has blood circulation promoting and blood stasis dispelling, anti-inflammatory analgetic, the effect of expelling wind and cold.Have clinically widely and use.
Dosage forms such as Radix Angelicae Sinensis concentrated pill, Radix Angelicae Sinensis Tabellae are arranged in the market, and concentrated pill and tablet are oral through gastrointestinal absorption, go into blood at liver generation first pass effect post-absorption, and bioavailability is low, absorb slow.Be unfavorable for bringing into play speciality and the advantage of Radix Angelicae Sinensis aspect the treatment cardiovascular and cerebrovascular disease.
Radix Angelicae Sinensis injection is the sterile water solution that Chinese medicine angelica is obtained through refining through water, clinically is used for diseases such as coronary heart disease, cerebral infarction, cerebral arteriosclerosis, thromboangiitis obliterans, ischemic osteonecrosis, sudden deafness, rheumatoid arthritis.Studies show that the intravenous injection of Radix Angelicae Sinensis water preparation has expansion peripheral blood vessel, blood flow increasing, improves effects such as peripheral circulation and anticoagulant.Ferulic acid is that Radix Angelicae Sinensis water is put forward one of main active partly, and its biological activity is almost among the pharmacological effect of whole Radix Angelicae Sinensis.Ferulic acid is a kind of non-peptide-like endothelin receptor competitive antagonist, the heart, brain, lung, kidney and angiopathy there is significant curative effect, have and resist myocardial ischemia, antiplatelet aggregation, improve heart microvascular endothelial cell, myocardial cell hypoxia-bearing capability, alleviate the effect of inflammatory factor the infringement of endothelium, myocardial cell.
Chinese patent CN02115699.9 discloses the patent of a piece " intravenous injection of Chinese angelica root and preparation method thereof ", aqueous extraction-alcohol precipitation technology is adopted in the extraction of medical material, the extracting solution color is dark, and impurity content height (wherein content of ferulic acid is very low) directly influences safety, effectiveness and the stability of medicine.
Summary of the invention
The objective of the invention is to overcome the deficiencies in the prior art, a kind of steady quality, Radix Angelicae Sinensis water solubility extract that active constituent content is high are provided.
Another object of the present invention provides a kind of injection preparation of Radix Angelicae Sinensis water solubility extract---injection, lyophilized injectable powder and infusion solution.
A further object of the invention promptly provides the preparation technology of Radix Angelicae Sinensis water solubility extract injection preparation.
The extraction process of Radix Angelicae Sinensis water solubility extract of the present invention comprises following processing step:
1. the Radix Angelicae Sinensis medical material is measured the water of volumes or the alcohol reflux of any concentration with 5～15 times;
2. extracting solution is got water or ethanol precipitation with 1～5 times of amount volume, and reclaim the ethanol of removing in the filtrate;
3. with filtrate through purification with macroreticular resin;
4. earlier with distilled water flush away impurity, the ethanol of reuse 30%～95% is the eluting macroporous adsorbent resin respectively, collects eluent, and the ethanol in the eluent is removed in decompression, concentrate the Radix Angelicae Sinensis water solubility extract.
The extraction of step in 1. comprise repeatedly and decocting, methods such as hot reflux, percolation, ultrasonic, microwave.
Described macroporous adsorbent resin is any among HPD-100, HPD-300, D101, AB-8 or the LSA-30.
Radix Angelicae Sinensis water solubility extract of the present invention, wherein ferulaic acid content is greater than 25%.
A kind of injection preparation of Radix Angelicae Sinensis water solubility extract is that the Radix Angelicae Sinensis water solubility extract is combined with pharmaceutically agent of acceptable pH regulator or osmotic pressure regulator or excipient, is prepared into injection, lyophilized injectable powder or infusion solution.
A kind of preparation technology of Radix Angelicae Sinensis water solubility extract injection is that the water for injection that adds 1～10 times of amount in the Radix Angelicae Sinensis water solubility extract stirs, and cold preservation 24～72 hours is filtered; Add water for injection again, regulate pH value to 6.5～8.0 with the pH regulator agent, ultrafiltration membrance filter, embedding, at 100～115 ℃ of sterilization 30～60min, packing gets Radix Angelicae Sinensis injection.
A kind of preparation technology of Radix Angelicae Sinensis water solubility extract lyophilized injectable powder is that the water for injection that the Radix Angelicae Sinensis water solubility extract adds 1～10 times of amount is stirred, and cold preservation 24～72 hours is filtered; The excipient that adds Radix Angelicae Sinensis water solubility extract 1%～10% amount, stirring and dissolving; Add water for injection again, regulate pH value to 6.5～8.0 with the pH regulator agent, ultrafiltration membrance filter, filtering with microporous membrane, embedding, lyophilization gets Chinese angelica root freeze-dried powder injectron.
The lyophilizing of described medicinal liquid divides the multistage lyophilizing.In freeze-drying process, medicinal liquid kept 2～10 hours down freeze-drying curve temperature-fall period temperature low spot-30～-70 ℃, kept 1～10 hour down for 0～50 ℃ at the high point of temperature rise period temperature, adopted noble gas to fill during encapsulation, to guarantee being difficult for generation oxidation storage period, the storage time is long.
A kind of preparation technology of Radix Angelicae Sinensis water solubility extract infusion solution is that the water for injection that the Radix Angelicae Sinensis water solubility extract adds 1～10 times of amount is stirred, and regulates pH value to 6.5～8.0 with the pH regulator agent, cold preservation was placed 24～72 hours, filtration, embedding, sterilization gets the Radix Angelicae Sinensis reserve liquid behind the ultrafiltration membrance filter; Get the injection osmotic pressure regulator again and be dissolved in an amount of water for injection, add above-mentioned Radix Angelicae Sinensis reserve liquid, and add water for injection, regulate pH value to 6.5～8.0 with the pH regulator agent; Filtering with microporous membrane is to clear and bright, and embedding at 100～115 ℃ of pressure sterilizings, gets the Radix Angelicae Sinensis transfusion.
Described pH regulator agent is at least a in acceptable clinically sodium hydroxide, sodium bicarbonate, sodium dihydrogen phosphate or the sodium hydrogen phosphate.
Described excipient be for can accepting mannitol, glucose, lactose, sorbitol, sucrose, maltose, dextran clinically, at least a among PEG, the PVP.
Described osmotic pressure regulator is at least a in acceptable clinically glucose, sodium chloride, fructose, xylose, the mannitol.
Sample with prepared of the present invention carries out pharmacodynamic experiment, and the result is as follows:
1 test objective
Investigate Radix Angelicae Sinensis different process extract effectiveness with Acute Myocardial Ischemia in Rats and apoplexy model, from biological activity angle Selection technology preferably.
2 test materials
2.1 medicine and reagent
The DG injection: sample 1 is a brown liquid, and every milliliter is equivalent to crude drug 10g, lot number 050403.Sample 2 is a brown liquid, and every milliliter is equivalent to crude drug 5g, lot number 050428.Sample 3 is a brown liquid, and every milliliter is equivalent to crude drug 5g, lot number 050429.
Red tetrazolium (TTC), Shanghai chemical reagents corporation produces, lot number F990930.Being mixed with 2%TTC solution with phosphate buffer uses for cerebral tissue dyeing.
2.2 animal
The Wistar rat, sub-cage rearing, 5 in every cage, free diet, the receptacle temperature is controlled at 22 ± 2 ℃ by central air conditioner system, and humidity is 45 ± 15%, illumination 12h (6:00～18:00).
2.3 instrument
Cardimax FX-101B electrocardiograph, Japanese Qindao Feitian company product.
The COOLPIX955 digital camera, Japanese Nikon company product.
Pathological image is gathered and analytical system, BJ University of Aeronautics ﹠ Astronautics's image center product.
The RXL automatic clinical chemistry analyzer, E.I.Du Pont Company's product.
PK121R freezing centrifuge, Italian ALC company product.
The BP310S electronic balance, German Sartorius product.
PYX-DHS-300 type water isolation type electro-heating standing-temperature cultivator, Huangshi medical apparatus and instruments factory produces.
The WZ-5013 micro-injection pump, Zhejiang Medical University Medical Instrument Factory production.
3 test methods
3.1 influence to rat heart muscle ischemia model due to the ligation coronary artery
3.1.1 model preparation
40 of Wistar rats, male and female half and half.35% chloral hydrate (360mg/kg) intraperitoneal injection of anesthesia, after measuring normal II and leading electrocardiogram, left chest unhairing, clavicle median line and the 4th rib intersection point are the center, cut skin, flesh layer along the clavicle median line, and circular layer is made purse string suture, get lines crossed to be equipped with and prick, cut off the 4th rib, with annular hook heart is pulled out the thoracic cavity, about 1.5mm sentences silk thread ligation arteria coronaria left anterior descending branch No. 6/0 under left auricle, heart is put back to the thoracic cavity, extract air in the thoracic cavity out, and make the pocket ligation of flesh layer, skin suture.
3.1.2 test grouping and dosage regimen
15min measures II and leads electrocardiogram after the rat coronary artery ligation, measures the J point value of raising as ST section lift-off value.According to ST section rising degree random packet.The moulding animal is established 4 groups, and model control group gives normal saline, and 3 are tried the thing group and give three kinds of Radix Angelicae Sinensis injections, and dosage is 5g crude drug/kg, 10 every group.15min begins administration after the coronary artery ligation, single tail venoclysis 1 time, and the infusion time is 30min, the administration volume only is 2mL/.
3.1.3 to the Electrocardiographic influence of rat
Rat 35% chloral hydrate (360mg/kg) intraperitoneal injection of anesthesia is measured II and is led electrocardiogram, as normal value before the rat art; Measure II behind the ligation arteria coronaria left anterior descending branch 15min and lead electrocardiogram, as being worth before the rat postoperative medicine; After the beginning administration respectively at 5,15,30,45,60,90,120,180min measures II and leads electrocardiogram, measures the J point value of raising as ST section lift-off value.
3.1.4 influence to the serum biochemistry index
Animal returns puts cage and raises, abdominal aortic blood behind the 24h, and low-temperature centrifugation prepares serum, puts-20 ℃ of preservations, measures serum biochemistry indexs such as AST, LDH, CK-MB in 1 month with biochemistry analyzer.
3.1.5 influence to the rat heart muscle infarction size
Behind the rat extracting blood, take out heart, normal saline flushing is cut into slices heart along the long axis of heart direction, and thickness is 1.5mm, section is placed 1%TTC liquid dyeing 15min after, take out the heart section.Infarcted region is dyed and is white, and normal district behind digital image-forming, measures percentage that infarcted region account for left chamber by image analysis system for red.
3.2 influence to rat cerebral ischemia model due to blocking-up middle cerebral artery (MCAO)
3.2.1 model preparation
40 of male Wistar rats, male and female half and half, lumbar injection 35% chloral hydrate (350mg/kg) anesthesia, lateral position is fixed.Cut skin in external auditory meatus and eye corner of the eyes line mid point, separating muscle successively, expose zygomatic arch and aquamous part of temporal bone, the disconnected zygomatic arch of hinge is under operating microscope, in about 2mm place, the front lower place of zygomatic arch and the preceding junction of aquamous part of temporal bone, open 2mm diameter microcephalia window with dental burr, expose middle cerebral artery, a fritter filter paper is spread on the medium-sized artery place, the 50%FeCl of 10 μ l
3Drip on filter paper, behind the 30min filter paper is taken out, and clean up, 2～3 penicillin liquid (1.6 * 10 of local dropping with normal saline
5U/ml), in case wound infection, layer-by-layer suture steams again and raises.
3.2.2 test grouping and dosage regimen
Postoperative 2h carries out the scoring of behavior disorder degree, according to the evenly grouping of score value height.The moulding animal is established 4 groups, and model control group gives normal saline, and 3 are tried the thing group and give three kinds of Radix Angelicae Sinensis injections, and dosage is 5g crude drug/kg, and each treated animal number average is 10.2h begins administration behind the MCAO, single tail venoclysis 1 time, and the infusion time is 30min, the administration volume only is 2mL/.
3.2.3 behavior scoring
30min, 24h adopted blind method to carry out function of nervous system's extent of damage scoring according to the standards of grading of subordinate list 1 after animal was finished respectively at administration.Total points is 11 minutes.
Table 1 MCAO rat function of nervous system standards of grading
| Method | Performance | Scoring |
| When animal is tranquil, vertically carry tail | A is slightly interior to be received or abduction | 1 |
| Observe the reaction of offside forelimb | Obvious or the interior receipts of B abduction | 2 |
| Receive in the C, obviously unable | 3 | |
| The significantly interior receipts of D are motionless | 4 | |
| Open with the observation of hands tractive forelimb | The A distraction force weakens or the reduction of keenly feeling | 1 |
| Power changes; The folder forelimb is observed painful | The B distraction force weakens and the reduction of keenly feeling | 2 |
| Pain reflex | C tension force obviously descends, and pain disappears substantially | 3 |
| Animal places plane hand push shoulder | A descends to collateral resistance | 1 |
| Observe animal and turn to resistance to offside | B is thrust slightly, and animal promptly changes to offside | 2 |
| The power size | The C animal obviously changes to offside | 3 |
| The D animal rotation occurs and adds 1 fen | 4 |
3.2.4 infarction size is measured
In last scoring back broken end, get full brain, freezing rapidly, be cut into the 2mm slab along coronalplane, getting above-mentioned half brain sheet puts into the 2%TTC dye liquor at interval, and 37 ℃ of temperature of lucifuge are incubated 30min and dyeed, after 10% formalin is fixing, adopt COOLPIX955 digital camera imaging system that digitized video is stored in the computer, and, calculate the cerebral infarction scope with image analysis system v4.0 software measurement infarcted region and full brain area.
3.2.5 brain water content is measured
After second half brain sheet is weighed, place 50 ℃ of baking ovens roasting to constant weight, its dry weight of weighing is calculated brain water content.
4 result of the tests
4.1.1 the influence that the rat ECG ST section is raised
After the venoclysis of rat single gives three kinds of Radix Angelicae Sinensis injection 5g crude drug/kg, can suppress the ST section that coronary ligation causes in various degree raises, alleviate degree of myocardial ischemia, compare with the model contrast, lot number is a plurality of time periods of Radix Angelicae Sinensis injection behind ischemia of 050428 can obviously suppress rats with myocardial ischemia ST section to raise, and lot number is a little less than 050429,050403 the Radix Angelicae Sinensis injection effect.
Three kinds of Radix Angelicae Sinensis injections of table 2 to the influence of acute myocardial ischemia rat II lead electrocardiogram ST section (mV) (x ± s, n=10)
Three kinds of Radix Angelicae Sinensis injections of table 3 are to the influence of area, peak area under the rats with myocardial ischemia ECG ST section influence curve
| Group | Dosage (g/kg) | Area under curve (minmv) | Peak area (minmv) | Effect assessment |
| The model contrast | - | 1.16 | 0.54 | |
| 050428 | 5.0 | 0.64 | 0.33 | 1 |
| 050429 | 5.0 | 0.75 | 0.42 | 2 |
| 050403 | 5.0 | 0.81 | 0.44 | 3 |
4.1.3 influence to the rat heart muscle infarction size
The venoclysis of rat single can be dwindled myocardial infarct size after giving three kinds of Radix Angelicae Sinensis injection 5g crude drug/kg in various degree, compares with the model contrast, and the infarcted region area descends 34.5%, 22.3%, 10.1% respectively; Infarcted region/left chamber percent descend respectively 33.8% (P＜0.01), 44.6% (P＜0.001), 56.3% (P＜0.001).Also obviously dwindle myocardial infarct size after the FUFANG DANSHEN DIWAN 250mg/kg administration, the FUFANG DANSHEN PIAN of 210mg/kg is compared no difference of science of statistics with the 250mg/kg drop pill.
Three kinds of Radix Angelicae Sinensis injections of table 4 to the influence of acute myocardial ischemia rat heart muscle infarction size (x ± s, n=10)
| Group | Dosage (g/kg) | Infarcted region/left chamber (%) | Effect assessment |
| The model contrast | - | 23.8±6.1 | |
| 050428 | 50 | 15.6±6.6 * | 1 |
| 050429 | 50 | 18.5±5.7 | 2 |
| 050403 | 50 | 21.4±7.9 | 3 |
Annotate: compare with model control group:
*P＜0.05.
4.2 the influence of the rat local cerebral ischemia model that MCAO is caused
4.2.1 influence to the rat behavior obstacle
Behind the MCAO, obvious delayed ischemic neurological deficits appears in rat, the single venoclysis gives three kinds of Radix Angelicae Sinensis injection 5g crude drug/kg, and its behavior disorder is improved in various degree, and behavior scoring has reduced by 28.57%, 3.57%, 10.71% respectively than model control group behind the 24h.The above results shows, lot number is that 050428 Radix Angelicae Sinensis injection can obviously improve local cerebral ischemia rat delayed ischemic neurological deficits, and it is not obvious that lot number is respectively 050429,050403 Radix Angelicae Sinensis injection effect.
The influence of function of nervous system's scoring that the rat that three kinds of Radix Angelicae Sinensis injections of table 5 cause MCAO is impaired (x ± s, n=10)
| Group | Dosage (g/kg) | Before the administration | After the administration | Effect assessment | |
| 30min | 24h | ||||
| The model contrast | - | 7.1±1.2 | 6.9±1.4 | 5.6±1.2 ++ | |
| 050428 | 5.0 | 7.2±1.0 | 6.1±0.9 ++ | 4.0±1.6 *++ | 1 |
| 050429 | 5.0 | 7.2±0.9 | 6.7±1.2 | 5.4±0.8 ++ | 3 |
| 050403 | 5.0 | 7.1±1.0 | 6.7±0.9 | 5.0±1.7 ++ | 2 |
Annotate: 1 with model group relatively:
*P＜0.01,2 is relatively preceding with administration
++P＜0.01.
4.2.2 influence to the rat cerebral infarction scope
Model control group cerebral infarction scope is obvious.The single venoclysis gives three kinds of Radix Angelicae Sinensis injection 5g crude drug/kg, can dwindle rats with cerebral ischemia cerebral infarction scope in various degree, compares with model control group, has dwindled 47.9%, 9.92%, 19.01% respectively.The above results shows, lot number is that 050428 Radix Angelicae Sinensis injection can obviously dwindle rats with cerebral ischemia cerebral infarction scope, and it is not obvious that lot number is respectively 050429,050403 Radix Angelicae Sinensis injection effect.
Three kinds of Radix Angelicae Sinensis injections of table 6 to the influence of local rats with cerebral ischemia cerebral infarction scope (x ± s, n=10)
| Group | Dosage (g/kg) | Cerebral infarction scope (%) | Effect assessment |
| The model contrast | - | 12.1±7.0 | |
| 050428 | 5.0 | 6.3±3.3 * | 1 |
| 050429 | 5.0 | 10.9±5.1 | 3 |
| 050403 | 5.0 | 9.8±4.9 | 2 |
Annotate: compare with model group:
*P＜0.05.
4.2.3 influence to the rat brain water content
The model control group brain water content obviously increases, and cerebral edema is obvious.The single venoclysis gives three kinds of Radix Angelicae Sinensis injection 5g crude drug/kg, can alleviate cerebral edema in various degree, compares with model control group, and cerebral edema has reduced 1.41%, 0.90% ,-0.38% respectively.The above results shows, lot number is that 050428 Radix Angelicae Sinensis injection can obviously be alleviated cerebral edema, and it is not obvious that lot number is respectively 050429,050403 Radix Angelicae Sinensis injection effect.
Three kinds of Radix Angelicae Sinensis injections of table 7 to the influence of local rats with cerebral ischemia cerebral edema (x ± s, n=10)
| Group | Dosage (g/kg) | Brain water content (%) | Effect assessment |
| The model contrast | - | 78.0±0.9 | |
| 050428 | 5.0 | 76.9±1.1 * | 1 |
| 050429 | 5.0 | 77.3±0.8 | 2 |
| 050403 | 5.0 | 78.3±1.1 | 3 |
Annotate: compare with model group:
*P＜0.05.
4.3 three kinds of Radix Angelicae Sinensis injection drug effects comprehensively relatively see Table the 8:050428 optimum, 050429 takes second place, and 050403 is relatively poor.
Three kinds of Radix Angelicae Sinensis injection drug effects of table 8 comprehensively compare
| Medicine | The electrocardiogram area under curve | The electrocardiogram peak area | Myocardial infarct size | Function of nervous system's scoring | The cerebral infarction scope | Brain water content | Add up to |
| 050428 | 1 | 1 | 1 | 1 | 1 | 1 | 6 |
| 050429 | 2 | 2 | 2 | 3 | 3 | 2 | 14 |
| 050403 | 3 | 3 | 3 | 2 | 2 | 3 | 16 |
Comparison to the stripped platelet aggregation effect of rabbit
1. test objective
Investigate Radix Angelicae Sinensis different process extract to the maximum accumulative inhibitory action of platelet with the isolated rabbit platelet aggregation test, from biological activity angle Selection technology preferably.
2. test material
2.1 medicine and reagent
The DG injection: sample 1 is a brown liquid, and every milliliter is equivalent to crude drug 10g, lot number 050403.Sample 2 is a brown liquid, and every milliliter is equivalent to crude drug 5g, lot number 050428.Sample 3 is a brown liquid, and every milliliter is equivalent to crude drug 5g, lot number 050429.
Adenosine diphosphate (ADP) (ADP): Serva company product, lot number 01993.
2.2 animal
Large ear rabbit, male, body weight 2.5-3.0kg.
2.3 instrument
PK121R type centrifuge (Italian ALC International SRL product).
SPA-3 type PPP platelet aggregation instrument (Shanghai Kodak test instrunment factory).
3. test method and result
The blood-letting of rabbit carotid artery, 3.8% sodium citrate anticoagulant, whole blood is 9: 1 with the ratio of anticoagulant, the centrifugal 10min of 800rpm, preparation platelet rich plasma (PRP), the centrifugal 10min of 3000rpm prepares platelet poor plasma (PPP).Get given the test agent, add among the PRP, mixing, 37 ℃ of temperature are incubated 10min.With the PPP zeroing, PRP transfers 100%, is derivant (final concentration is 2 μ M) with ADP, measures platelet aggregation percent by turbidimetry with SPA-3 type PPP platelet aggregation instrument, calculates suppression ratio, returns the half-inhibition concentration (IC that asks each given the test agent by the logit method
50), the results are shown in Table 1,2.
The result shows, Radix Angelicae Sinensis injection can suppress the inductive platelet aggregation of ADP by concentration dependent, the inhibitory action intensity of 3 kinds of technologies is followed successively by sample 2 (050428)＞samples 3 (050429)＞samples 1 (050403), and wherein sample 2 is stronger approximately 2 times than sample 1 and sample 3.
The Radix Angelicae Sinensis injection of table 9 variable concentrations is to the rabbit platelet aggregation inhibition rate (x ± s) that exsomatizes
| Sample 1 (050403) | Sample 2 (050428) | Sample 3 (050429) | |||
| Concentration (mg/ml) | Suppression ratio (%) | Concentration (mg/ml) | Suppression ratio (%) | Concentration (mg/ml) | Suppression ratio (%) |
| 95.7 | 25.1±9.8 | 48.3 | 26.2±14.7 | 95.7 | 25.9±12.0 |
| 187.8 | 50.5±11.4 | 95.7 | 49.7±14.3 | 187.8 | 55.1±9.0 |
| 276.5 | 71.9±8.4 | 142.2 | 76.2±11.6 | 232.6 | 73.1±14.9 |
| 362.0 | 93.4±6.6 | 187.8 | 92.3±10.2 | 276.5 | 85.6±10.4 |
| 232.6 | 97.9±3.5 | 362.0 | 95.9±4.4 | ||
Three kinds of different process extracts of table 10 are to the comparison of the stripped anticoagulant effect of rabbit
| Tried thing | Experiment number | IC 50(mg/ml) |
| No. 1 test liquid (050403) | 8 | 162.3±24.5 |
| No. 2 test liquids (050428) | 8 | 78.6±13.0 |
| No. 3 test liquids (050429) | 7 | 149.6±17.2 |
The present invention compared with prior art has the following advantages:
1, Radix Angelicae Sinensis water solubility extract of the present invention adopts macroporous resin adsorption to extract, and impurity content is low, and the active constituent content height has improved drug effect.(employing high performance liquid chromatography) after measured, main effective ingredient content of ferulic acid is greater than 25% in the extract.
2, injection preparation of the present invention adopts the ultrafiltration degerming, has guaranteed the stability of medicine.
3, the segmentation lyophilizing is adopted in the lyophilizing of injectable powder of the present invention, adopts noble gas to fill during encapsulation, prevents oxidation, hydrolysis, the inactivation of effective ingredient in water effectively, can guarantee content and curative effect better.
4, preparation process thereof maturation of the present invention, constant product quality is convenient to suitability for industrialized production.
Description of drawings
Fig. 1 is the effect curves figure of three kinds of Radix Angelicae Sinensis injections of the present invention to the rat heart muscle ischemia
The specific embodiment
The preparation of embodiment 1, injection of the present invention
Get an amount of Radix Angelicae Sinensis pulverizing medicinal materials, cross 10 mesh sieves; The ethanol (concentration 60%) that adds 2 times of amounts of Radix Angelicae Sinensis medical material soaked 6 hours, moved in the percolator, with the speed percolation of 1.0mL/min, collected the 5 times amounts of percolate to medical material; The water that adds the percolate equal volume, cold preservation 24h filters, and the ethanol in the filtrate is removed in decompression (0.1MP, 60 ℃); Filtrate is carried out purification by HPD-100 type macroporous adsorptive resins, with the drip washing of 4BV distilled water, reuse 60% ethanol 4BV eluting is collected ethanol elution then earlier, decompression is removed ethanol (0.1MP, 60 ℃) and is concentrated into relative density is that 1.10～1.15 (80 ℃) get the Radix Angelicae Sinensis water solubility extract.
Add 1 times of volume water for injection of extract in the Radix Angelicae Sinensis water solubility extract, fully stir, cold preservation 24h filters, add water for injection again, regulate pH value to 6.5, ultrafiltration membrance filter (molecular cut off 6000), embedding at 100 ℃ of sterilization 60min, gets Radix Angelicae Sinensis injection.Every 2ml of specification.
The preparation of embodiment 2, injection of the present invention
Get an amount of Radix Angelicae Sinensis medical material, add 15 times of amounts of Radix Angelicae Sinensis medical material volume decocting and boil 2 times, each 2h filters, and filtrate merges, and concentrating under reduced pressure (0.1MP, 60 ℃) is to relative density 1.15～1.20 (80 ℃); The ethanol that adds 5 times of volumes of filtrate, standing over night filters, and decompression filtrate recycling ethanol is to there not being alcohol flavor (0.1MP, 60 ℃), by D101 type macroporous adsorptive resins purification, earlier with the drip washing of 5BV distilled water, reuse 95% ethanol 3BV eluting, collect ethanol elution, ethanol (0.1MP, 60 ℃) is removed in decompression, gets the Radix Angelicae Sinensis water solubility extract.
The water for injection that adds 5 times of volumes of extract in the Radix Angelicae Sinensis water solubility extract stirs, and cold preservation 48 hours is filtered; Add water for injection again, regulate pH value to 7.2, ultrafiltration membrance filter (molecular cut off 6000), embedding, at 110 ℃ of sterilization 45min, packing gets Radix Angelicae Sinensis injection.Every 2ml of specification.
The preparation of embodiment 3, injection of the present invention
Get an amount of Radix Angelicae Sinensis medical material, with ethanol (80% ethanol) reflux, extract, of 10 times of amounts of Radix Angelicae Sinensis medical material 3 times, extract 1.5h at every turn, merge medicinal liquid, decompression is removed ethanol (0.1MP, 60 ℃) and is concentrated into relative density 1.10～1.15 (80 ℃).The water that adds 3 times of volumes of medicinal liquid, cold preservation 24h, filter, filtrate is passed through AB-8 type macroporous adsorptive resins purification, with the drip washing of 4BV distilled water, reuse 30% ethanol 4BV eluting is collected ethanol elution earlier, decompression is removed ethanol (0.1MP, 60 ℃) and is concentrated into relative density 1.20～1.25 (80 ℃) and gets the Radix Angelicae Sinensis water solubility extract.
The water for injection that adds 2 times of volumes of extract in the Radix Angelicae Sinensis water solubility extract fully stirs, and cold preservation 72h filters, add water for injection again, regulate pH value to 8.0, ultrafiltration membrance filter (molecular cut off 6000), embedding, at 115 ℃ of sterilization 30min, packing gets Radix Angelicae Sinensis injection.Every 2ml of specification.
The preparation of embodiment 4, lyophilized injectable powder of the present invention
Get an amount of Radix Angelicae Sinensis pulverizing medicinal materials, cross 10 mesh sieves; The ethanol (concentration 60%) that adds 2 times of amounts of Radix Angelicae Sinensis medical material soaked 6 hours, moved in the percolator, with the speed percolation of 1.0mL/min, collected the 5 times amounts of percolate to medical material; The water that adds 3 times of volumes of percolate, cold preservation 24h filters, and the ethanol in the percolate is removed in decompression (0.1MP, 60 ℃); Filtrate is carried out purification by HPD-300 type macroporous adsorptive resins, with the drip washing of 4BV distilled water, reuse 60% ethanol 4BV eluting is collected ethanol elution then earlier, decompression is removed ethanol (0.1MP, 60 ℃) and is concentrated into relative density is that 1.10～1.15 (80 ℃) get the Radix Angelicae Sinensis water solubility extract.
The water for injection that adds 10 times of amounts in the Radix Angelicae Sinensis water solubility extract stirs, and cold preservation 24 hours is filtered; The mannitol that adds Radix Angelicae Sinensis water solubility extract 10% amount, stirring and dissolving; Add water for injection again, regulate pH value to 6.5, ultrafiltration membrance filter (molecular weight 6000 dams), filtering with microporous membrane, under aseptic condition, fill is in the 5mL bottle (every bottled 2mL) of sterilizing, lyophilization, Chinese angelica root freeze-dried powder injectron.
The preparation of embodiment 5, lyophilized injectable powder of the present invention
Get an amount of Radix Angelicae Sinensis medical material, add 10 times of amounts of Radix Angelicae Sinensis medical material volume decocting and boil 2 times, each 2h filters, and filtrate merges, and concentrating under reduced pressure (0.1MP, 60 ℃) is to relative density 1.15～1.20 (80 ℃).Add 2 times of volume of ethanol of filtrate, standing over night filters, and decompression filtrate recycling ethanol is to there not being alcohol flavor (0.1MP, 60 ℃), by LSA-30 type macroporous adsorptive resins purification, earlier with the drip washing of 5BV distilled water, reuse 95% ethanol 3BV eluting, collect ethanol elution, ethanol (0.1MP, 60 ℃) is removed in decompression, gets the Radix Angelicae Sinensis water solubility extract.
The water for injection that adds 5 times of amounts in the Radix Angelicae Sinensis water solubility extract stirs, and cold preservation 48 hours is filtered; The glucose that adds Radix Angelicae Sinensis water solubility extract 5% amount, stirring and dissolving; Add water for injection again, regulate pH value to 7.0, ultrafiltration membrance filter (molecular weight 6000 dams), filtering with microporous membrane, under aseptic condition, fill is in the 5mL bottle (every bottled 2mL) of sterilizing, lyophilization, Chinese angelica root freeze-dried powder injectron.
The preparation of embodiment 6, lyophilized injectable powder of the present invention
Get an amount of Radix Angelicae Sinensis medical material, with ethanol (80% ethanol) reflux, extract, of 5 times of amounts of Radix Angelicae Sinensis medical material 3 times,, whenever this extracts 1.5h, merges medicinal liquid, and decompression is removed ethanol (0.1MP, 60 ℃) and is concentrated into relative density 1.10～1.15 (80 ℃).The water that adds the medicinal liquid equal volume, cold preservation 24h, filter, filtrate is passed through AB-8 type macroporous adsorptive resins purification, with the drip washing of 4BV distilled water, reuse 50% ethanol 4BV eluting is collected ethanol elution earlier, decompression is removed ethanol (0.1MP, 60 ℃) and is concentrated into relative density 1.20～1.25 (80 ℃) and gets the Radix Angelicae Sinensis water solubility extract.
The water for injection that adds 1 times of amount in the Radix Angelicae Sinensis water solubility extract stirs, and cold preservation 72 hours is filtered; The sorbitol that adds Radix Angelicae Sinensis water solubility extract 1% amount, stirring and dissolving; Add water for injection again, regulate pH value to 8.5, ultrafiltration membrance filter (molecular weight 6000 dams), filtering with microporous membrane, under aseptic condition, fill is in the 5mL bottle (every bottled 2mL) of sterilizing, lyophilization, Chinese angelica root freeze-dried powder injectron.
The preparation of embodiment 7, infusion solution of the present invention
Get an amount of Radix Angelicae Sinensis pulverizing medicinal materials, cross 10 mesh sieves; The ethanol (concentration 60%) that adds 2 times of amounts of Radix Angelicae Sinensis medical material soaked 6 hours, moved in the percolator, with the speed percolation of 1.0mL/min, collect the 5 times amounts of percolate, add the water of 2 times of volumes of percolate, cold preservation 24h to medical material, filter, the ethanol in the percolate is removed in decompression (0.1MP, 60 ℃); Filtrate is carried out purification by HPD-100 type macroporous adsorptive resins, with the drip washing of 4BV distilled water, reuse 60% ethanol 4BV eluting is collected ethanol elution then earlier, decompression is removed ethanol (0.1MP, 60 ℃) and is concentrated into relative density is that 1.10～1.15 (80 ℃) get the Radix Angelicae Sinensis water solubility extract.
The water for injection that the Radix Angelicae Sinensis water solubility extract is added 2 times of volumes stirs, and regulates pH value to 8.0, and cold preservation was placed 72 hours, filtration, embedding, and 100 ℃ of flowing steam sterilization 1h placed 3～7 days, got the Radix Angelicae Sinensis reserve liquid behind the ultrafiltration membrance filter; Get the injection xylose and be dissolved in an amount of water for injection, add again in the above-mentioned Radix Angelicae Sinensis reserve liquid, and add water for injection, regulate pH value to 7.0; Filtering with microporous membrane is to clear and bright, and embedding at 100 ℃ of pressure sterilizings, gets Radix Angelicae Sinensis xylose injection.Specification is every bottle of 250ml.
The preparation of embodiment 8, infusion solution of the present invention
Get an amount of Radix Angelicae Sinensis medical material, add 10 times of amounts of Radix Angelicae Sinensis medical material volume decocting and boil 2 times, each 2h filters, and filtrate merges, and concentrating under reduced pressure (0.1MP, 60 ℃) is to relative density 1.15～1.20 (80 ℃).Add 3 times of volume of ethanol of filtrate, standing over night filters, and decompression filtrate recycling ethanol is to there not being alcohol flavor (0.1MP, 60 ℃), by D101 type macroporous adsorptive resins purification, earlier with the drip washing of 5BV distilled water, reuse 95% ethanol 3BV eluting, collect ethanol elution, ethanol (0.1MP, 60 ℃) is removed in decompression, gets the Radix Angelicae Sinensis water solubility extract.
Be that the water for injection that the Radix Angelicae Sinensis water solubility extract adds 2 times of volumes is stirred, regulate pH value to 8.0, cold preservation was placed 48 hours, filtered, embedding, and 100 ℃ of flowing steam sterilization 1h placed 3～7 days, must the Radix Angelicae Sinensis reserve liquid behind the ultrafiltration membrance filter; Get sodium chloride for injection and be dissolved in an amount of water for injection, add again in the above-mentioned Radix Angelicae Sinensis reserve liquid, and add water for injection, regulate pH value to 6.5; Micropore filter mould is filtered to clear and bright, and embedding at 110 ℃ of pressure sterilizings, gets the Radix Angelicae Sinensis sodium chloride injection.Specification is every bottle of 250ml.
The preparation of embodiment 9, infusion solution of the present invention
Get an amount of Radix Angelicae Sinensis medical material, with ethanol (80% ethanol) reflux, extract, of 5 times of amounts of Radix Angelicae Sinensis medical material 3 times, this extracts 1.5h, merges medicinal liquid, and decompression is removed ethanol (0.1MP, 60 ℃) and is concentrated into relative density 1.10～1.15 (80 ℃).The water that adds 5 times of volumes of medicinal liquid, cold preservation 24h, filter, filtrate is passed through AB-8 type macroporous adsorptive resins purification, with 4BV distilled water eluting, reuse 50% ethanol 4BV eluting is collected ethanol elution earlier, decompression is removed ethanol (0.1MP, 60 ℃) and is concentrated into relative density 1.20～1.25 (80 ℃) and gets the Radix Angelicae Sinensis water solubility extract.
Be that the water for injection that the Radix Angelicae Sinensis water solubility extract adds 1 times of volume is stirred, regulate pH value to 8.0, cold preservation was placed 24 hours, filtered, embedding, and 100 ℃ of flowing steam sterilization 1h placed 3～7 days, must the Radix Angelicae Sinensis reserve liquid behind the ultrafiltration membrance filter; Get glucose for injection and be dissolved in an amount of water for injection, add again in the above-mentioned Radix Angelicae Sinensis reserve liquid, and add water for injection, regulate pH value to 6.5; Filtering with microporous membrane is to clear and bright, and embedding at 115 ℃ of pressure sterilizings, gets the Radix Angelicae Sinensis glucose injection.Specification is every bottle of 250ml.
Claims (10)
1, a kind of Radix Angelicae Sinensis water solubility extract, it is characterized in that: wherein ferulaic acid content is greater than 25%.
2, a kind of extraction process of the water solubility extract of Radix Angelicae Sinensis according to claim 1 comprises following processing step:
1. the Radix Angelicae Sinensis medical material is measured the water of volumes or the alcohol reflux of any concentration with 5～15 times;
2. with water or the ethanol precipitation of extracting solution, and reclaim the ethanol remove in the filtrate with 1～5 times of amount volume;
3. with filtrate through purification with macroreticular resin;
4. earlier with distilled water flush away impurity, the ethanol of reuse 30%～95% is the eluting macroporous adsorbent resin respectively, collects eluent, and the ethanol in the eluent is removed in decompression, concentrate the Radix Angelicae Sinensis water solubility extract.
3, as the extraction process of Radix Angelicae Sinensis water solubility extract as described in the claim 2, it is characterized in that: described macroporous adsorbent resin is any among HPD-100, HPD-300, D101, AB-8 or the LSA-30.
4, a kind of injection preparation of Radix Angelicae Sinensis water solubility extract is that the Radix Angelicae Sinensis water solubility extract is combined with pharmaceutically agent of acceptable pH regulator or osmotic pressure regulator or excipient, is prepared into injection, lyophilized injectable powder or infusion solution.
5, a kind of preparation technology of Radix Angelicae Sinensis water solubility extract injection is that the water for injection that adds 1～10 times of amount in the Radix Angelicae Sinensis water solubility extract stirs, and cold preservation 24～72 hours is filtered; Add water for injection again, regulate pH value to 6.5～8.0 with the pH regulator agent, ultrafiltration membrance filter, embedding, packing gets Radix Angelicae Sinensis injection at 100～115 ℃ of sterilization 30～60min.
6, as the preparation technology of Radix Angelicae Sinensis water solubility extract infusion solution as described in the claim 5, it is characterized in that: at least a in acceptable sodium hydroxide, sodium bicarbonate, sodium dihydrogen phosphate or the sodium hydrogen phosphate clinically of described pH regulator agent.
7, a kind of preparation technology of Radix Angelicae Sinensis water solubility extract lyophilized injectable powder is that the water for injection that the Radix Angelicae Sinensis water solubility extract adds 1～10 times of amount is stirred, and cold preservation 24～72 hours is filtered; The excipient that adds Radix Angelicae Sinensis water solubility extract 1%～10% amount, stirring and dissolving; Add water for injection again, regulate pH value to 6.5～8.0 with the pH regulator agent, ultrafiltration membrance filter, filtering with microporous membrane, embedding, lyophilization gets Chinese angelica root freeze-dried powder injectron.
8, as the preparation technology of Radix Angelicae Sinensis water solubility extract lyophilized injectable powder as described in the claim 7, it is characterized in that: at least a in acceptable sodium hydroxide, sodium bicarbonate, sodium dihydrogen phosphate or the sodium hydrogen phosphate clinically of described pH regulator agent; Described excipient be for can accepting mannitol, glucose, lactose, sorbitol, sucrose, maltose, dextran clinically, at least a among PEG, the PVP.
9, a kind of preparation technology of Radix Angelicae Sinensis water solubility extract infusion solution, be that the water for injection that the Radix Angelicae Sinensis water solubility extract adds 1～10 times of amount is stirred, and regulate pH value to 6.5～8.0 with the pH regulator agent, cold preservation was placed 24～72 hours, filtration, embedding, sterilization, placement get the Radix Angelicae Sinensis reserve liquid behind the ultrafiltration membrance filter; Get the injection osmotic pressure regulator again and be dissolved in an amount of water for injection, add above-mentioned Radix Angelicae Sinensis reserve liquid, and add water for injection, regulate pH value to 6.5～8.0 with the pH regulator agent; Filtering with microporous membrane is to clear and bright, and embedding at 100～115 ℃ of pressure sterilizings, gets the Radix Angelicae Sinensis transfusion.
10, as the preparation technology of Radix Angelicae Sinensis water solubility extract infusion solution as described in the claim 9, it is characterized in that: at least a in acceptable sodium hydroxide, sodium bicarbonate, sodium dihydrogen phosphate or the sodium hydrogen phosphate clinically of described pH regulator agent; Described osmotic pressure regulator is at least a in acceptable clinically glucose, sodium chloride, fructose, xylose, the mannitol.
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| CN 200610041842 CN1857348A (en) | 2006-02-22 | 2006-02-22 | Water soluble Chinese angelica extract and its injection and their preparing process |
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101684430B (en) * | 2008-09-27 | 2012-02-01 | 湖北中烟工业有限责任公司 | Novel radix angelicae sinensis tobacco flavor and preparation method thereof |
| CN105535050A (en) * | 2016-01-26 | 2016-05-04 | 甘肃中医药大学 | Radix angelica sinensis antitumor medicine |
| CN107954856A (en) * | 2016-10-17 | 2018-04-24 | 天津工业大学 | A kind of extraction preparation method of forulic acid |
| CN109498664A (en) * | 2019-01-07 | 2019-03-22 | 四川省中医药科学院 | A kind of monoamine oxidase A, B inhibitor Chinese medicine composition |
-
2006
- 2006-02-22 CN CN 200610041842 patent/CN1857348A/en active Pending
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101684430B (en) * | 2008-09-27 | 2012-02-01 | 湖北中烟工业有限责任公司 | Novel radix angelicae sinensis tobacco flavor and preparation method thereof |
| CN105535050A (en) * | 2016-01-26 | 2016-05-04 | 甘肃中医药大学 | Radix angelica sinensis antitumor medicine |
| CN107954856A (en) * | 2016-10-17 | 2018-04-24 | 天津工业大学 | A kind of extraction preparation method of forulic acid |
| CN109498664A (en) * | 2019-01-07 | 2019-03-22 | 四川省中医药科学院 | A kind of monoamine oxidase A, B inhibitor Chinese medicine composition |
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