CN1535969A - Total alkaloid of xiatianwu (a Chinese medicinal material), its preparation method and application - Google Patents
Total alkaloid of xiatianwu (a Chinese medicinal material), its preparation method and application Download PDFInfo
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Abstract
The present invention relates to total alkaloid of Chinese medicinal material corydalis amabilis, its preparation method and application in medicine. Said total alkaloid mainly includes protopine 25-65%, tetrahydropalmatine 10-25%, bikukuling 5-10% and palmatine 10-20% and other alkaloid and extract 5-20%. Its preparation method includes the following steps: using corydalis amabilis as raw material, adding proper quantity of polar solvent, making diacolation extraction, collecting diacolate until there is not alkaloid reaction, combining diacolates, concentrating to obtain concentrate, making said concentrate pass through macroporous adsorption resin to make adsorption chromatography, using soda lye to make elution and remove impurity or using resin to adsorb impurity, using polar eluent to total alkaloid of corydalis amabilis, collecting eluent, recovering solvent, concentrating and crystallizing so as to obtain the invented product. Said invention also provides its application for preparing medicine.
Description
Technical field
The present invention relates to a kind of total alkaloids that from promoting flow of QI and blood, the Chinese medicine Rhizome of Decumbent Corydalis of removing obstruction in channels to relieve pain, prepares and preparation method thereof, the application of this total alkaloids in medicine.
Background technology
The do nothing summer dry tuber of bloodroot Hotseason grow Corydalis decumbens (Thunb) pers of Chinese medicine is a promoting flow of QI and blood commonly used, the medicine of removing obstruction in channels to relieve pain, can be used for stroke hemiplegia, injury from falling down, rheumatic arthritis, many disturbance of blood circulation treatment of diseases such as sciatica.Rhizome of Decumbent Corydalis is with decocting liquid or grind into powder and be used as medicine clinically.
At present both at home and abroad existing Rhizoma Corydalis Decumbentis tablet and Rhizoma corydalis decumbenti Injection production listing, Rhizoma Corydalis Decumbentis tablet be by the crude drug Rhizome of Decumbent Corydalis beat that powder mixes with its alcohol-extracted extract, granulation, compressing tablet form; Its injection liquid then be by the crude drug Rhizome of Decumbent Corydalis through aqueous extraction-alcohol precipitation technology, according to a conventional method through can, step such as seal and make.These preparations, technology are quite slightly poor, and inclusion is not really clear and definite, and inner quality is difficult to control.Through the retrieval of medicinal knowledge property right referral centre of magnificent section, still there are not total alkaloid of corydalis rhizome medicine or health-care preparation.
Summary of the invention
The technical problem to be solved in the present invention is, at above-mentioned the deficiencies in the prior art, mainly containing after effective constituent and pharmacological action further investigate to the Chinese medicine Rhizome of Decumbent Corydalis, in Rhizome of Decumbent Corydalis, isolate and mainly contain effective constituent through special process, it is total alkaloid of corydalis rhizome, and set up the preparation method who extracts described total alkaloids, the application of this total alkaloids in treatment relative disease medicine proposed.
One of technical scheme of the present invention is, proposing a kind of dry tuber with the bloodroot Hotseason grow is the total alkaloid of corydalis rhizome that raw material extracts, and the weight percent of this total alkaloids is formed and comprised:
Opium alkali: 25-65%,
Tetrahydropalmatine: 10-25%,
Bicuculline: 5-10%,
Prothionamide: 10-25%,
Other biological alkali and extract: 5-20%,
Its total alkaloid content detects with UV method or HPLC method and is no less than 80%.
Two of technical scheme of the present invention is, proposes a kind of method for preparing described total alkaloid of corydalis rhizome, the steps include:
(1) dry tuber with the bloodroot Hotseason grow is a raw material, add this crude drug in whole raw material weight 3-5 polar solvent doubly and soak after 12-36 hour, carry out diacolation with 5-20 polar solvent doubly again and extract extraction time 1-3 days, collect percolate to lifeless matter and react, merge percolate;
Described polar solvent is that concentration is one of phosphoric acid, hydrochloric acid, sulfuric acid, aqueous acetic acid of 2-3%, or weight percent concentration is ethanol or the methanol solution of 50-95%;
(2) percolate is converted to the 1-3 extracting solution doubly that it is described crude drug in whole raw material weight, and:
A, when used polar solvent is described ethanol or methanol solution, described diacolation is reclaimed solvent to there not being the alcohol flavor, gained medicinal extract concentration is the aqueous acid heating for dissolving of one of phosphoric acid, hydrochloric acid, sulfuric acid, aqueous acetic acid of 1-2%, filter, again with concentration be the NaoH of 5-20% or KoH solution adjust the filtrate pH value be 6-7 and constant volume its for 1-3 times of weightmeasurement ratio of described crude drug in whole raw material weight (promptly, for example when the crude drug in whole raw material weight was 1Kg, the concentrated solution volume was the 1-3 liter, and the back together);
B, when used polar solvent is described aqueous acid, with concentration be 5-20%NaoH or KoH solution to adjust the filtrate pH value be 6-7, concentrate and constant volume its be 1-3 times of weightmeasurement ratio of crude drug in whole raw material weight;
(3) above-mentioned gained extracting solution is carried out the macroporous resin adsorption chromatography, remove impurity with 1-3N NaoH eluant solution or with the absorption of chromatography carrier;
(4) with polarity elutriant wash-out total alkaloid of corydalis rhizome, collect elutriant, reclaim solvent and make 0.3-0.4 that elutriant is concentrated into the crude drug in whole raw material weight doubly;
Described polarity elutriant is that concentration is one of sulfuric acid, phosphoric acid, hydrochloric acid, acetum of 1-5%, or weight percent is 50-95% ethanol or methanol solution;
(5) be that 5-20%NaoH or KoH adjust the solution pH value to 9-12 with concentration, separate out precipitation, the leaching throw out, extremely neutral with the saturated common salt water washing precipitate, drying;
(6) with the dried neutral throw out of a kind of organic solvent dissolution in ethanol, methyl alcohol, acetone, the chloroform, filter, reclaiming solvent to filtrate is 3-8 times of weightmeasurement ratio of weight of precipitate, places crystallization, leaching, and crystallizing and drying promptly gets total alkaloid of corydalis rhizome.
Three of technical scheme of the present invention is, proposes second kind of method for preparing described total alkaloid of corydalis rhizome, the steps include:
(1) the dry stem piece with creamcups shape Hotseason grow is a raw material, add this crude drug in whole raw material weight 3-5 polar solvent doubly and soak after 12-36 hour, carry out diacolation with 5-20 polar solvent doubly again and extract extraction time 1-3 days, collect percolate to the lifeless matter alkali reaction, merge percolate;
Described polar solvent is meant that concentration is one of phosphoric acid, hydrochloric acid, sulfuric acid, aqueous acetic acid of 2-3%, or weight percent concentration is ethanol or the methanol solution of 50-95%;
(2) produce extracting solution:
A, when used polar solvent is described ethanol or methyl alcohol, percolate is reclaimed solvent to there not being the alcohol flavor, gained medicinal extract filters with 0.3-0.4 times of weightmeasurement ratio sour water heating for dissolving of crude drug in whole raw material weight, extracting solution;
Described sour water is meant that concentration is one of phosphoric acid, sulfuric acid, acetic acid, aqueous solution of hydrochloric acid of 1-2%;
B, when used polar solvent is described aqueous acid, described percolate is concentrated into 0.3-0.4 times of weightmeasurement ratio of crude drug in whole raw material weight, extracting solution;
(3) be that the pH value that 5-20%NaoH or KoH solution are adjusted extracting solution is 10-12 with concentration, add NaCl again and make into the saturated common salt aqueous solution, place precipitation, the leaching throw out, after draining again the sour water with throw out 10-20 times weight throw out is dissolved, filter, filtrate is that the pH value that 5-20%NaoH or KoH solution are adjusted extracting solution is 10-12 with concentration, adds Nacl again and makes into the saturated common salt aqueous solution, places precipitation, the leaching throw out, extremely neutral with the saturated common salt water washing precipitate;
Described sour water is meant that concentration is one of phosphoric acid, sulfuric acid, acetic acid, aqueous solution of hydrochloric acid of 5-10%;
(4) with the described neutral throw out of organic solvent dissolution of one of ethanol, methyl alcohol, acetone, chloroform, filter, reclaiming solvent to filtrate is 3-8 times of weightmeasurement ratio of weight of precipitate, places crystallization, leaching, and crystallizing and drying promptly gets total alkaloid of corydalis rhizome.
Four of technical scheme of the present invention is to propose the application of a kind of total alkaloid of corydalis rhizome in the medicine of damage disease due to preparation platelet activating factor and the free radical.
Five of technical scheme of the present invention is to propose the application of a kind of total alkaloid of corydalis rhizome in the medicine of treatment cerebrovascular disease, hypertension hemiplegia, poliomyelitis sequela, sciatica, rheumatic arthritis.
Below the present invention made further specify.
Learn that through the present invention's research total alkaloid of corydalis rhizome (Rhizoma corydalis decumbent totalalkaloids) is main effective constituent--the alkaloids with Rhizome of Decumbent Corydalis, is a compound bio alkali through the special process extraction separation.Its inclusion of this total alkaloids is relatively clearer and more definite, mainly contain protopine (Protopine), corydaline (Corydqline), Tetrahydropalmatine (Tetrahydropalmatine), palmatine (Palmatine), Bicuculline (Bicuculline), jateorhizine (Jatrorrhizine), dihydro palmatine, dihydro corydaline etc., total alkaloid content 〉=80%; Wherein main effective constituent protopine content is 25～65%, and Tetrahydropalmatine content is 10～25%, and Bicuculline content is 5～10%, and palmatine content is 10～25%, and other alkaloid and extract are 5～20%.The fingerprint image of this total alkaloid of corydalis rhizome meets shown in appended Fig. 1,2.
The present invention studies show that total alkaloid of corydalis rhizome has many-sided cardiovascular and cerebrovascular pharmacology and neural system pharmacological action.1. anticoagulant suppresses thrombosis; Obvious rising GAMP/CGMP ratio.2. have vasodilation, remarkable and persistent hypotensive effect; 3. has dilating coronary blood vessel, the effect of coronary blood flow increasing; 4. has significant analgesic activity; 5. have the excited spinal cord effect of Strychnine sample, help lend some impetus to the recovery that cerebrovascular accident causes the paralyzed limbs function.Can be used for the hypertension hemiplegia, poliomyelitis sequela, sciatica.Following drug effect is not appeared in the newspapers as yet:
(1) total alkaloid of corydalis rhizome suppresses the platelet aggregation effect that platelet activating factor is brought out
Animal: new zealand rabbit, body weight 2-3 kilogram, male and female have both, instrument: Chronolog type platelet aggregation instrument, platelet activating factor (PAF) is a Sigma company product, other reagent are homemade analytical pure, total alkaloid of corydalis rhizome makes for embodiment 1 method, (citric acid is received-citric acid-glucose solution: whole blood=anti-freezing in 1: 6) to get 10 milliliters of tame rabbit ear arteria comitans nervi mediani blood, 500 rev/mins centrifugal 5 minutes, get platelet rich plasma, 2000 rev/mins of separation got thrombocyte in 5 minutes, washed tears twice with the no calcium tyrode's solution of PH6.5, washed back 200 rev/mins at every turn and separated 5 minutes, abandon supernatant, add PH7.4 and contain 0.25% bovine serum albumin 50mM Tutofusin tris-tyrode's solution (TTBSA) adjustment PC to 2 * 10
8/ milliliter is rabbit washing platelet suspension (WRP).Get 018 milliliter of WRP, add 0.01 milliliter of total alkaloid of corydalis rhizome solution after 37 ℃ of (the mentioned temperature scale of this paper is ceslius scale) preheatings, write down curve of platelet aggregation with turbidimetry after adding 0.01 milliliter of platelet activating factor, the blank pipe replaces total alkaloid of corydalis rhizome solution with distilled water, compare with total alkaloid of corydalis rhizome pipe platelet aggregation rate and blank pipe platelet aggregation rate, calculate the anticoagulant rate.
The result
PAF concentration total alkaloid of corydalis rhizome concentration (mg/ml) anticoagulant rate (%)
2nM????????0.0??????????????????????????0.0
0.008????????????????????????32.9
0.016????????????????????????60.0
0.032????????????????????????79.4
The result shows that total alkaloid of corydalis rhizome suppresses the tangible dose-effect relationship of rabbit washing platelet gathering tool that platelet activating factor is brought out, and the total alkaloid of corydalis rhizome that other implementation methods make is identical with The above results trend according to this law experiment gained data.
(2) total alkaloid of corydalis rhizome suppresses the effect that thrombocyte that platelet activating factor brings out discharges serotonin (5-TH)
The WRP that above method makes, get 0.8 milliliter of WRP, add total alkaloid of corydalis rhizome (embodiment 1 method makes) solution, 37 ℃ of preheatings add 2000 rev/mins of 37 ℃ of reactions of 10 milliliters of platelet activating factors 4 minutes after 2 minutes centrifugal 10 minutes, get supernatant liquor and add the TTBS07 milliliter for 0.3 milliliter, it is centrifugal 20 minutes to add 3500 rev/mins of 0.3 milliliter of 100% Tricholroacetic Acids again, get 0.5 milliliter of supernatant liquor, add 2 milliliters of 0.05% o-phthalaldehyde(OPA)/HCI solution, 100 ℃ of heating in water bath 10 minutes, add after the water-cooled behind 2 milliliters of chloroform mixings 3500 rev/mins centrifugal 20 minutes, get 1 milliliter of supernatant and measure 5-TH fluorescence (EX360NM EM475NM) negative control pipe with distilled water replacement total alkaloid of corydalis rhizome solution, to replace the WRP pipe with concentration total alkaloid of corydalis rhizome TTBSA diluent is reagent blank, each reaction tubes measured value all deduct the reagent blank value record 5-TH fluorescent value F (EX360NM, EM475NM)
The result
PAF total alkaloid of corydalis rhizome concentration (mg/ml) F (EX360NM, EM475NM)
2NM????0????????????????????????????354.7
O.05?????????????????????????329.6
0.10?????????????????????????309.0
0.15?????????????????????????263.8
0.30?????????????????????????234.6
The result shows: total alkaloid of corydalis rhizome suppresses the tangible dose-effect relationship of 5-TH release tool that platelet activating factor causes, and the total alkaloid of corydalis rhizome that other embodiment method makes is identical with The above results trend according to this law gained data.
(3) effect of expansion of cerebral vascular and lower limb vascular.And can resist the cerebrovascular that norepinephrine causes and the Stress of lower limb vascular.
Method: cerebral circulation is tested with 24 of healthy male dogs, body weight 12.4 ± 1.5kg, intravenous injection vetanarcol 30mg/kg anesthesia, by general cerebral circulation experimental technique, measure arteria carotis communis blood pressure and ICAF amount (with the representative cerebral blood flow (CBF)), the volume of blood flow and the cerebral vascular resistance of calculating every 100g cerebral tissue.The lower limb circulation experiment is with 24 of healthy male dogs, body weight 11.6 ± 1.3kg (SD).Intravenous injection vetanarcol 30mg/kg anesthesia, measure femoral blood pressure and volume of blood flow (with representative lower extremity blood flow amount), calculate the lower limb vascular resistance with blood pressure divided by volume of blood flow.
Experimental data is represented with M ± SE.In all tables, except that special dated person,
*Compare P＜0.05 before the expression administration,
*P＜0.01,
* *P＜0.001.
The result
1. to the effect of anesthetized dog cerebral hemodynamic: the results are shown in Table 1
Table 1 Rhizoma corydalis decumbentis total alkaloids, Protopine intra-arterial injection are to the effect of the anesthetized dog cerebral hemodynamic (n=6 of x ± SD)
| Dosage mg/k g | Peak-to-average Δ peak-to-average Δ peak-to-average Δ after the injection before the injection after the injection before the injection after the injection before the blood pressure mmHg cerebral blood flow (CBF) ml/100g/min cerebral vascular resistance mmHg/ml/100g/min injection | |
| Physiological saline total alkali Protopine papaverine | - ? 1.0 ? 0..3 0.1 | 112.3???110.9????110.3???115.2???126.7???????113.7?????1.09??????0.96???????1.04 ±4.1???±6.9????±4.1???±24.9??±15.3??????±11.9????±0.10????±0.10?????±0.09 110.6???86.9?????103.6???93.3????162.1???????123.1?????1.21??????0.62???????0.88 ±4.4???±16.9 *?±5.7???±8.7???±12.68 ***?±8.4 ***?±0.06????±0.04 ***?±0.03 ***129.9???124.7????125.8???131.4???219.5???????166.2?????1.19??????0.69???????0.98 ±4.7???±5.9????±5.2???±25.2??±48.5 *????±38.3????±0.32???±0.21 *???±0.29 114.9???111.6????116.0???75.6????161.3???????125.6?????1.97??????1.03???????1.56 ±9.8???±9.4 *??±9.5???±14.9??±28.2 ***??±21.3 **?±0.46???±0.29 *???±0.51 * |
The result shows: injection total alkali, Protopine and Papaverine all make cerebral blood flow increase, and cerebral vascular resistance is lowered.Total alkali and Papaverine still make blood pressure drops.
2. to the effect of lower limb round-robin
Table 2 Rhizoma corydalis decumbentis total alkaloids, Protopine are to the dynamic (dynamical) effect of the anesthetized dog lower extremity blood flow amount (n=6 of X ± SD)
| Route of administration | Dosage ml/ kg | Peak-to-average Δ peak-to-average Δ peak-to-average Δ after the injection before the injection after the injection before the injection after the injection before the blood pressure mmHg lower extremity blood flow amount ml/min lower limb vascular resistance mmHg/ml/min injection | |
| The total alkali Protopine | The intravenous injection of intra arterial injection intravenous injection intra | 1 ? 5 ? 0.2 ? 2 | 112.3???80.4?????91.5??????46.0????93.2??????70.0?????3.19????1.12???????1.55 ±4.6???±10.7 *?±9.7 *??±9.3???±13.0 **?±12.6 *?±0.48??±0.13 ***?±0.08 *97.9????73.6?????83.7??????59.4????65.2??????55.4?????2.22????1.50???????2.18 ±8.0???±10.5 *?±10.3 *?±13.8??±14.9????±14.5???±0.43??±0.21?????±0.42 121.1???116.5????122.8?????33.6????77.1??????46.2?????3.39????1.72???????3.36 ±4.7???±5.7????±4.9?????±4.2???±12.5 *?±6.3 *??±0.52??±0.26 **??±0.44 125.0???116.4????123.9?????27.7????50.1??????33.6?????6.97????3.43???????5.12 ±3.5???±2.1 **?±3.5?????±7.6???±11.1 **?±6.9????±1.94??±1.05 *??±1.02 |
3 minutes mean value behind the Δ artery administration, behind the intravenously administrable 5 minutes
The result shows: Rhizoma corydalis decumbentis total alkaloids obviously descends blood pressure.
3. the influence that changes of the evaluation of cerebrovascular function using that norepinephrine is caused
The results are shown in Table 3, table 4.
The influence that the evaluation of cerebrovascular function using that table 3 Rhizoma corydalis decumbentis total alkaloids causes the norepinephrine changes (n=6 of X ± SD)
Blood pressure mmHg cerebral blood flow (CBF) ml/min cerebral blood flow resistance mmHg/ml/min
Administration preceding 122.1 ± 3.8 120.4 ± 17.2 1.08 ± 0.14
Go to first kidney 171.0 ± 2.8 108.3 ± 11.8 1.66 ± 0.18
Upper parathyrine
Total alkali 130.0 ± 6.1
*195.0 ± 19.9
*0.82 ± 0.09
*
The result shows: Rhizoma corydalis decumbentis total alkaloids increases cerebral blood flow (CBF), and cerebral vascular resistance is lowered, blood pressure drops.Show that total alkali can remove the cerebrovascular Stress that norepinephrine causes.
The influence that the lower limb vascular functional status that table 4 Rhizoma corydalis decumbentis total alkaloids causes the norepinephrine changes (n=6 of X ± SD)
Blood pressure mmHg lower extremity blood flow amount ml/min lower extremity blood flow resistance mmHg/ml/min
Administration preceding 109.0 ± 10.2 65.1 ± 18.0 1.81 ± 0.19
Go to first kidney 167.0 ± 12.0 85.6 ± 11.5 2.07 ± 0.21
Upper parathyrine
Total alkali 145.0 ± 7.6
*142.6 ± 5.0
*1.10 ± 0.05
*
The result shows: Rhizoma corydalis decumbentis total alkaloids can be removed the caused lower limb vascular Stress of norepinephrine.
(4) analgesic activity:
Select the Kunming mouse random packet of body weight 18-20 gram for use.1/2-1h after the administration, mouse knob body number of times such as table 5 in the every mouse abdominal injection 0.6% Glacial acetic acid 0.1ml/kg, 20min:
The analgesic activity of table 5 total alkaloid of corydalis rhizome (the mouse writhing method) (n=16 of X ± SD)
Group dosage is turned round body and is counted inhibiting rate P value
mg/Kg???????X±SD??????????％
Physiological saline--21.6 ± 10.6
Tetrahydropalmatine 0.05 4.7 ± 3.6 81.72% P＜0.01
Rhizoma corydalis decumbentis total alkaloids 0.05 7.2 ± 5.6 69.67% P＜0.01
0.1?????????5.1±5.7???????76.83％?????P＜0.01
0.15????????3.9±7.2???????89.76％?????P＜0.01
The result shows: Rhizoma corydalis decumbentis total alkaloids has significant analgesia role to mouse
(5) have the excited spinal cord effect of Strychnine sample, help lend some impetus to the recovery that cerebrovascular accident causes the paralyzed limbs function.
Total alkaloids of the present invention can be used for preparing the disturbance of blood circulation disease, the particularly pharmaceutical composition of hypertension hemiplegia, poliomyelitis sequela, sciatica of treatment tool platelet activating factor and radical damage.This composition contains activeconstituents total alkaloid of corydalis rhizome and pharmaceutically-acceptable excipients, carrier or thinner, is made into pharmaceutical preparation with ordinary method.
During the preparation said composition, total alkaloid of corydalis rhizome can be mixed or use carrier embedding, this carrier with carrier can be capsule or other loading forms.Carrier can be solid, semisolid or liquid substance, and it is as carrier, vehicle or the medium of total alkaloid of corydalis rhizome.Said composition can be various ways such as capsule, freeze-dried powder, infusion solutions, eye drop, gelifying agent, small-volume injection, sprays, tablet, suppository.
Variety carrier, vehicle or thinner can be used for this composition, as lactose, glucose, sucrose, sorbyl alcohol, carbomer, glycerine, N.F,USP MANNITOL, starch, polyoxyethylene glycol, gelatin etc.Also add lubricant, wetting agent, correctives, suspending agent, sanitas etc. in the said preparation.Any method preparation that composition of the present invention can use this area to adopt usually, to reach after patient's use, activeconstituents is brought into play the purpose of maximum drug effect.
But this pharmaceutical composition oral administration, intravenous injection, intramuscular injection is through skin or subcutaneous injection administration, per rectum administration etc.But single or multiple uses continuously, and the pharmaceutical composition using dosage then should generally should be controlled at 0.0005-0.05g total alkaloid of corydalis rhizome/kg body weight sky according to patient's particular case decision.
The present invention takes 1-5% acid extraction or 50-90% alkaline ethanol, methanol extraction.After the removal of impurity of absorption with macroporous adsorbent resin column chromatography elution method, make the higher total alkaloid of corydalis rhizome of a purity.These methods are not appeared in the newspapers as yet in the application that the Rhizome of Decumbent Corydalis composition extracts in the preparation process, they can remove impurity such as amino acid and carbohydrate, tannin effectively, obviously improve the purity of total alkaloid of corydalis rhizome, the total alkaloid of corydalis rhizome that method of the present invention prepares gained does not all have amino acid and free sugar and tannin reaction, adopts UV method and HPLC method to record its content 〉=80%; Its thin-layer chromatogram all as seen with reference substance protopine, Tetrahydropalmatine, palmatine, than the spot of withered alkali, five corresponding position clear-cuts of jateorhizine, point out total alkaloid of corydalis rhizome purity height of the present invention, and this method is easy and simple to handle, be easy to grasp, can be used as the total alkaloid of corydalis rhizome preparation method.
As known from the above, the invention provides total alkaloid of corydalis rhizome and preparation method thereof and the application of described total alkaloids in medicine, they have overcome the defective of prior art, and have realized the may command of total alkaloid of corydalis rhizome inner quality.
Description of drawings:
Fig. 1 and Fig. 2 are the fingerprint images that shows that total alkaloids effective ingredient of the present invention exists, and wherein Fig. 1 is the total alkaloid of corydalis rhizome thin-layer chromatogram, and Fig. 2 is a high performance liquid phase HPLC fingerprint image.In the drawings:
The 1---protopine, the 2---Bicuculline, the 3---Tetrahydropalmatine, the 4---total alkaloid of corydalis rhizome, the 5---palmatine,
The a---protopine, b---palmatine, c---Bicuculline, d---Tetrahydropalmatine.
Embodiment
Embodiment 1: a kind of total alkaloid of corydalis rhizome, its weight ratio ingredient comprise protopine 45%, tetrahydropalmatine 15%, prothionamide 20%, Bicuculline 5%, other biological alkali and extract 15%.
Example 2 (preparation method):
Get 1 kilogram of Rhizome of Decumbent Corydalis crude drug meal, add 3 kilograms of soaked overnight of phosphoric acid (hydrochloric acid or sulfuric acid or acetic acid) solution of 2%, the diafiltration tube of packing into, the above-mentioned solution diafiltration with 2% is collected percolate to alkaloid and is reacted till the reaction that is negative.Percolate is transferred about pH value to 6 with 10% sodium hydroxide, is concentrated into 0.4 gram crude drug/milliliter and gets final product.Use in order to separating.
Get concentrated solution, last column volume is 2000 milliliters macroporous adsorbent resin AB-8 (or D
201, D
3520, D
4020, D
101, H
103) to look shallow with the NaOH eluant solution of 1N, be washed till neutrality with distilled water again.Use the 50-95% ethanol elution again instead, collect elutriant to negative the getting final product of alkaloid reaction, elutriant reclaims ethanol to there not being alcohol, sodium hydroxide solution with 10% transfers to about 12, and add NaCI and make into the saturated common salt aqueous solution, place and make precipitation fully, collecting precipitation, the saturated common salt aqueous solution is washed till neutrality, and drying and crushing promptly gets the total alkaloid of corydalis rhizome crude product.
Get gained crude product 10g under the separate item, the alcohol reflux 3 times that at every turn adds 100ml95%, filter merging filtrate, reclaim solvent, place crystallization and promptly get total alkaloid of corydalis rhizome (Rhizoma corydalis decumbent totalalkaloids) elaboration to 50mI.Content is 86.3%
Embodiment 3 (preparation method):
Get 1 kilogram of Rhizome of Decumbent Corydalis crude drug meal, mix thoroughly with strong aqua, airing, the alcohol immersion that adds 3 kilogram 90% is spent the night, the diafiltration tube of packing into, ethanol percolation with 90% is collected percolate to alkaloid and is reacted till the reaction that is negative, and it is pure to not having to reclaim ethanol, medicinal extract is transferred PH 5 to 6 with 1% phosphoric acid (sulfuric acid or hydrochloric acid or acetic acid) solution, volume is about 3000 milliliters, and standing over night gets that supernatant liquor is standby to get final product.
Get said extracted solution, last column volume is 2000 milliliters macroporous adsorbent resin AB-8 (D
101Or D
201, D
3520, D
4020, H
103) to look shallow with 1% NaOH eluant solution, be washed till neutrality with distilled water again.Use the 50-95% ethanol elution again instead, collect elutriant to negative the getting final product of alkaloid reaction, elutriant reclaims ethanol to there not being alcohol, sodium hydroxide solution with 10% transfers to about 12, places to make precipitation fully, collecting precipitation, be washed to neutrality, drying and crushing promptly gets the total alkaloid of corydalis rhizome crude product.
Get gained crude product 10g under the separate item, add 50ml chloroform refluxing extraction 2 times at every turn, filter merging filtrate, reclaim solution to doing, use the 100ml dissolve with ethanol again, recovery solution is placed crystallization to 40ml and is promptly got the total alkaloid of corydalis rhizome elaboration.Content is 90.6%
Embodiment 4 (preparation method):
Getting on the extracting solution under said extracted method one, the binomial to column volume is the macroporous resin D of 2000ml
101(or D
201, D
3520, D
4020, AB-8, H
103) to look shallow with the NaOH eluant solution of 1N, be washed till neutrality with distilled water again.Using 2% sulfuric acid (or phosphoric acid or acetic acid) eluant solution to lifeless matter alkali reaction instead gets final product.Transfer PH to 7-8 with 20%NaOH, concentrate drying is pulverized and is promptly got the total alkaloid of corydalis rhizome crude product.
Get crude product 10g, add the 100ml methanol eddy at every turn and extract 3 times, filter merging filtrate, reclaim solution, place crystallization and promptly get the total alkaloid of corydalis rhizome elaboration.Content is 81%
Embodiment 5 (preparation method):
Get the extract under extracting method one, the binomial, go up to column volume be macroporous resin AB-8 (or the D of 2000ml
101, D
201, D
3520, D
4020, H
103) get final product with 2% sulfuric acid (or phosphoric acid or acetic acid) eluant solution to lifeless matter alkali reaction.Transfer PH to 7-8.5 with 15%NaOH solution, it is standby that the concentrate drying pulverizing promptly gets crude product.
Get gained crude product 10g under the separate item, add the alcohol reflux 3 times of 100ml95% at every turn, filter merging filtrate, reclaim solution, place crystallization and promptly get the total alkaloid of corydalis rhizome elaboration.Content is 82%
Embodiment 6 (preparation method):
Get 1 kilogram of Rhizome of Decumbent Corydalis crude drug meal, mix thoroughly with the 10ml strong aqua, airing, the ethanol or the methyl alcohol soaked overnight that add 3 kilogram 95%, the diafiltration tube of packing into, ethanol with 95% or methyl alcohol diafiltration, collect percolate to alkaloid and react till the reaction that is negative, it is pure to not having to reclaim solvent, and medicinal extract is transferred PH＜5 with phosphoric acid (sulfuric acid or hydrochloric acid or the acetic acid) solution of 1-2%, heating for dissolving, filter, filtrate is transferred PH to 12 with the NaOH solution of 5-20%, and adding NaCI makes into the saturated common salt aqueous solution, placement makes precipitation fully, leaching precipitation, after draining again the sour water with throw out 10-20 times weight throw out is dissolved filtration, filtrate is that the pH value that 5-20%NaoH or KoH solution are adjusted extracting solution is 10-12 with concentration, add Nacl again and make into the saturated common salt aqueous solution, place precipitation, the leaching throw out, saturated common salt is washed to neutrality, and is refining promptly with 85% ethanol repeatedly.Content is 80.2%
Embodiment 7 (preparation): total alkaloid of corydalis rhizome oral hard capsule agent
Total alkaloid of corydalis rhizome 5 grams
1000 hard capsule of packing into behind the said components mixing granulation promptly get the agent of total alkaloid of corydalis rhizome oral hard capsule
Embodiment 8 (preparation): total alkaloid of corydalis rhizome injection
Total alkaloid of corydalis rhizome 2g
Water for injection is an amount of
1000 milliliters of full doses
Getting 100 gram total alkaloid of corydalis rhizome adds 1%HCI and makes whole dissolvings, add 500 milliliters of waters for injection, transfer PH5-6 with 1%NaOH again, filter, add to 1000 milliliters according to a conventional method through can with an amount of water for injection, step such as seal and make the total alkaloid of corydalis rhizome injection.
Embodiment 9 (preparation): total alkaloid of corydalis rhizome glucose infusion solutions
Total alkaloid of corydalis rhizome 10g
Glucose is an amount of
Water for injection is an amount of
Get total alkaloid of corydalis rhizome 1 gram and add 1% phosphoric acid solution and make dissolving, transfer PH5-6 with 1%NaOH again, add an amount of glucose and water for injection after, according to a conventional method through can, step such as seal and produce and promptly get the total alkaloid of corydalis rhizome infusion solutions.
Embodiment 10 (preparation): total alkaloid of corydalis rhizome suppository
Total alkaloid of corydalis rhizome 5 grams
Semi-synthetic fatty acid glycerine fat is an amount of
Make 1000
Get the heating of semi-synthetic fatty acid glycerine fat and make and melt, suitably the cooling back adds 5 gram total alkaloid of corydalis rhizome mixings, the system bolt, and cooling promptly gets total alkaloid of corydalis rhizome suppository.
Embodiment 11 (preparation): total alkaloid of corydalis rhizome tablet
Total alkaloid of corydalis rhizome 5 grams
Starch 20 grams
Make 1000
Total alkaloid of corydalis rhizome, behind Magnesium Stearate and the starch mixing according to a conventional method through compressing tablet, dressing, technologies such as bottling promptly get the total alkaloid of corydalis rhizome tablet.
Embodiment 12 (preparation): total alkaloid of corydalis rhizome eye drop
Total alkaloid of corydalis rhizome 1 gram
Water for injection is an amount of
According to a conventional method through can, step such as seal and produce and promptly get the total alkaloid of corydalis rhizome eye drop after the total alkaloid of corydalis rhizome dissolving
Embodiment 13 (preparation): total alkaloid of corydalis rhizome gelifying agent
Total alkaloid of corydalis rhizome 10 grams
Carbopol 941 1.5 grams
10 milliliters of glycerine
15 milliliters of poly(oxyethylene glycol) 400
15 milliliters of ethanol
Distilled water is an amount of
Make 1000
Get carbomer 1.5 gram, add the less water swelling after, add trolamine, stir evenly standby.Other gets Rhizoma corydalis decumbentis total alkaloids 10 grams, adds glycerine, ethanol, poly(oxyethylene glycol) 400, dissolved substance, stirs evenly.Above-mentioned soup is slowly added in the above-mentioned matrix, and the limit edged stirs, and adding distil water to 100 gram continues to stir, and gets the agent of Rhizoma corydalis decumbentis total alkaloids clear gel.
Embodiment 14 (preparation): injection total alkaloid of corydalis rhizome
Total alkaloid of corydalis rhizome 2 grams
N.F,USP MANNITOL is an amount of
System claims 1000
Get total alkaloid of corydalis rhizome 2 gram and add 1%HCI solution and make dissolving, transfer PH5-6 with 1%NaOH again, add an amount of N.F,USP MANNITOL, the freeze-drying packing.
Embodiment 15 (preparation): total alkaloid of corydalis rhizome oral granular formulation
Total alkaloid of corydalis rhizome 5 grams
Dextrin 795 grams
Said components is mixed the back granulation, is distributed into 500 bags.Promptly get the total alkaloid of corydalis rhizome oral granular formulation
Embodiment 16 (preparation): total alkaloid of corydalis rhizome sprays
Total alkaloid of corydalis rhizome 5 grams
Ethanol 295 grams
Methyl chlorofluoride 700 grams
Total alkali is dissolved in the ethanol, filters, 100 bottles of packing, every bottle is pressed into difluoro bismethane 7 grams, promptly.
Claims (8)
1, a kind of dry tuber with the bloodroot Hotseason grow is the total alkaloid of corydalis rhizome that raw material extracts, and the weight fraction of this total alkaloids is formed and comprised:
Protopine: 25-60%,
Tetrahydropalmatine: 10-20%,
Bicuculline: 10-20%,
Prothionamide: 10-20%,
Other biological alkali and extract: 5-20%,
Its total alkaloid content detects with UV method or HPLC method and is no less than 80%.
2, a kind of method for preparing the described total alkaloid of corydalis rhizome of claim 1 the steps include:
(1) dry tuber with the bloodroot Hotseason grow is a raw material, add this crude drug in whole raw material weight 3-5 polar solvent doubly and soak after 12-36 hour, continue to carry out diacolation and extract extraction time 1-3 days with 5-20 polar solvent doubly, collect percolate to lifeless matter and react, merge percolate;
Described polar solvent is that concentration is one of phosphoric acid, hydrochloric acid, sulfuric acid, aqueous acetic acid of 2-3%, or weight percent concentration is ethanol or the methanol solution of 50-95%;
(2) percolate is converted to the 1-3 extracting solution doubly that it is described crude drug in whole raw material weight, and:
A, when used polar solvent is described ethanol or methanol solution, described diacolation is reclaimed solvent to there not being the alcohol flavor, gained medicinal extract concentration is the aqueous acid heating for dissolving of one of phosphoric acid, hydrochloric acid, sulfuric acid, aqueous acetic acid of 1-2%, filtering, is that NaoH or the KoH solution adjustment filtrate pH value of 5-20% is 1-3 times of weightmeasurement ratio of 6-7 and its described crude drug in whole raw material weight of constant volume with concentration again;
B, when used polar solvent is described aqueous acid, with concentration be 5-20%NaoH or KoH solution to adjust the filtrate pH value be 6-7, concentrate and constant volume its be 1-3 times of weightmeasurement ratio of crude drug in whole raw material weight;
(3) above-mentioned gained extracting solution is carried out the macroporous resin adsorption chromatography, with 1-3N NaoH eluant solution or with chromatography carrier absorption decon;
(4) with polarity elutriant wash-out total alkaloid of corydalis rhizome, collect elutriant, reclaim solvent and make 0.3-0.4 that elutriant is concentrated into the crude drug in whole raw material weight doubly;
Described polarity elutriant is that concentration is one of sulfuric acid, phosphoric acid, hydrochloric acid, acetum of 1-5%, or weight percent is 50-95% ethanol or methanol solution;
(5) be that 5-20%NaoH or KoH adjust the solution pH value to 9-12 with concentration, separate out precipitation, the leaching throw out, extremely neutral with the saturated common salt water washing precipitate, drying;
(6) with the dried neutral throw out of a kind of organic solvent dissolution in ethanol, methyl alcohol, acetone, the chloroform, filter, reclaiming solvent to filtrate is 3-8 times of weightmeasurement ratio of weight of precipitate, place crystallization, leaching, crystallizing and drying promptly gets the total biology total alkali of Rhizome of Decumbent Corydalis.
3, method according to claim 2 is characterized in that, described is 1 with the extracting solution of absorption with macroporous adsorbent resin chromatography and the volume ratio of big pore adsorption resin: 1-30.
4, method according to claim 2 is characterized in that, described macroporous adsorbent resin is AB-8, D
101, D
201, D
3520, D
4020, H
103In any.
5, a kind of method for preparing the described total alkaloid of corydalis rhizome of claim 1 the steps include:
(1) the dry stem piece with the creamcups Hotseason grow is a raw material, adding this crude drug in whole raw material weight 3-5 polar solvent doubly soaked after 12-36 hour, continuation is carried out the diacolation extraction with 5-20 polar solvent doubly, collects percolate to the lifeless matter alkali reaction, and merges percolate in extraction time 1-3 days;
Described polar solvent is meant that concentration is that one of the phosphoric acid, hydrochloric acid, sulfuric acid, aqueous acetic acid of 2-3% or weight percent concentration are ethanol or the methanol solution of 50-95%;
(2) produce extracting solution:
A, when used polar solvent is described ethanol or methyl alcohol, percolate is reclaimed solvent to there not being the alcohol flavor, gained medicinal extract filters with 0.3-0.4 times of weightmeasurement ratio sour water heating for dissolving of crude drug in whole raw material weight, extracting solution;
Described sour water is meant that concentration is one of phosphoric acid, sulfuric acid, acetic acid, aqueous solution of hydrochloric acid of 1-2%;
B, when used polar solvent is described aqueous acid, described percolate is concentrated into 0.3-0.4 times of weightmeasurement ratio of crude drug in whole raw material weight, extracting solution;
(3) be that the pH value that 5-20%NaoH or KoH solution are adjusted extracting solution is 10-12 with concentration, add Nacl again and make into the saturated common salt aqueous solution, place precipitation, the leaching throw out, with the saturated common salt water washing precipitate to neutral;
(4) with the described neutral throw out of organic solvent dissolution of one of ethanol, methyl alcohol, acetone, chloroform, filter, reclaiming solvent to filtrate is 3-8 times of weightmeasurement ratio of weight of precipitate, places crystallization, leaching, and crystallizing and drying promptly gets total alkaloid of corydalis rhizome.
6, the application of a kind of total alkaloid of corydalis rhizome in the medicine of damage disease due to preparation platelet activating factor and the free radical.
7, the application of a kind of total alkaloid of corydalis rhizome in the medicine of treatment cerebrovascular disease, hypertension hemiplegia, poliomyelitis sequela, sciatica, rheumatic arthritis.
8, the total alkaloid of corydalis rhizome of claim 1 is characterized in that, can make capsule, freeze-dried powder, granule, infusion solutions, eye drop, gelifying agent, small-volume injection, tablet, suppository etc.
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| CN100375746C (en) * | 2004-10-26 | 2008-03-19 | 江西天施康中药股份有限公司 | Process for preparing decumbent corydalis tuber total alkaloid and its preparation and quality detecting method |
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