CN1247223C - Greater celandine extract and its preparation method and application - Google Patents
Greater celandine extract and its preparation method and application Download PDFInfo
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- CN1247223C CN1247223C CN 03101200 CN03101200A CN1247223C CN 1247223 C CN1247223 C CN 1247223C CN 03101200 CN03101200 CN 03101200 CN 03101200 A CN03101200 A CN 03101200A CN 1247223 C CN1247223 C CN 1247223C
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Abstract
The present invention discloses a greater celandine extract. The greater celandine extract contains the active ingredients of the proportion by weight: 0.5 to 10 wt% of chelidonine, 0.1 to 8 wt% of protopine and 0.6 to 200 wt% of total alkaloid of greater celandine. The present invention also discloses a preparation method of the greater celandine extract. The greater celandine extract of the present invention is applied to the treatment of patients with cancer and cancer pain, and has antitumoral effect, analgesic effect and outstanding curative effect.
Description
Technical field
The present invention relates to a kind of preparation method with Herba Chelidonii extract of anticancer analgesic effect.
Background technology
Cancer is a kind of pilosity on the our times, is difficult to the disease of capturing again.Existing therapy such as operation, chemotherapy, radiotherapy all can not be effected a radical cure.Though the medicine of present various treatment tumor, cancer all has certain effect, but Western medicine mostly has certain toxic and side effects, side effect such as heating, gastrointestinal reaction, alopecia, acroanesthesia, lung toxic reaction are just arranged as Bleomycin A5, cisplatin also has the untoward reaction of aspects such as gastrointestinal, hemogram, kidney, has influenced Cancerous disease is treated smoothly.Use the anticancer need of Chinese medicine to be used and to produce better therapeutic effect with Western medicine.
Cancerous pain is a general worldwide problem, and violent pain can appear in about 70% patient with advanced cancer.Effectively the main contents that patient's pain is treatment of cancer are alleviated or alleviated to pain management especially for patients with advanced cancer.At present, cancer pain still belongs to a kind of disease that is difficult to conquer.Three rescue by stages are recommended to use to the treatment of cancerous pain by World Health Organization (WHO).Mild pain uses the non-opium analgesic, as: acetaminophen, aspirin and ibuprofen, naproxen, piroxicam etc.; Moderate pain then uses weak opium kind analgesics, as: codeine, paracetamol ﹠ codeine, or add nonopioid analgesic and auxiliary medicaments etc.; Severe pain then adopts strong opiates medicine, as: morphine, Dilauid, methadone etc.These strong opiates medicines can make the patient solve temporary transient misery, and spirit is suitably had a rest, and easily produce side effect such as cumulative toxicity and dependency but use continuously.If improper use, the management of mistake more can endanger health of human body and social stability.In recent years, the abuse of this quasi drugs and dependent generation obviously increase, and the serious social problem that brings therefrom becomes increasingly conspicuous, make the clinical practice of this quasi drugs be subjected to strict restriction, cause many cancer pain patients well not treated yet so far, to the processing of cancer pain remain doctors and the stubborn problem of facing.Still do not have at present existing antitumaous effect clinically, again the very little medicine of analgesic activity and untoward reaction arranged.
Summary of the invention
Order of the present invention is to provide a kind of preparation method with Herba Chelidonii extract of anticancer analgesic effect, and this method technical process is simple, and product yield is big.
Herba Chelidonii [Chelidonium majus L.] is the herb of bloodroot Herba Chelidonii.There is distribution in most of area, the whole nation.Have the function of removing toxic substances and promoting subsidence of swelling, analgesia cough-relieving, be mainly used in diseases such as stomachache, stomachache, chronic tracheitis, pertussis, jaundice, hepatitis, edema.Fitochemical studies result shows: herb contains multiple alkaloid, as Chelidonine, protopine, Sanguinarine, coptisine, chelerythrine, berberine etc.
A kind of preparation method provided by the invention with Herba Chelidonii extract of anticancer analgesic effect, form by following steps:
(1) be raw material with the plant Herba Chelidonii, add 75% alcohol reflux, merge extractive liquid, filters;
(2) with above-mentioned filtrate recycling ethanol, to be concentrated into relative density be 1.05～1.25 clear paste;
(3) with above-mentioned clear paste with 0.5～1.5mol/L phosphoric acid solution adjust pH to 1.5～4.5, in 5～10 ℃ of cold preservations more than 10 hours, filter, filtrate is with 5～40% sodium hydroxide solution adjust pHs to 11, extract 2～8 times with equal amounts of chloroform, combined chloroform liquid reclaims chloroform, the residue vacuum drying gets Herba Chelidonii extract.
The Herba Chelidonii extract of the inventive method preparation, the composition of its contained active component and ratio (weight) are: Chelidonine 0.5～10, protopine 0.1～8, total alkaloid from chelidouium majus 0.6～200.
The Herba Chelidonii extract of the inventive method preparation is applied in treatment cancer and cancerous pain aspect, can be mixed with medicament with one or more pharmaceutically acceptable carriers (adjuvant).
Above-mentioned pharmaceutically acceptable carrier is meant the pharmaceutical carrier or the adjuvant of pharmaceutical field routine, for example: diluent, excipient and water etc., filler such as starch, dextrin, mannitol, sucrose, lactose, microcrystalline Cellulose etc.; Binding agent such as cellulose derivative, alginate, gelatin and polyvinylpyrrolidone; Wetting agent such as glycerol; Disintegrating agent such as methyl starch sodium, hyprolose, agar, calcium carbonate and sodium bicarbonate; Absorption enhancer such as quaternary ammonium compound; Surfactant such as hexadecanol, Tweens, sodium lauryl sulphate; Absorption carrier such as Kaolin and soap clay; Lubricant such as Pulvis Talci, calcium stearate and magnesium, micropowder silica gel and Polyethylene Glycol etc.
Above-mentioned medicament can be applied to cancer and cancerous pain patient by the mode of oral, rectum or parenteral.Be used for when oral, can be made into conventional solid preparation such as tablet, capsule, powder, granule etc., make liquid preparation such as water or oil-suspending agent, other liquid preparation such as syrup, mixture, elixir etc.; When being used for parenteral, can be made into solution, powder pin, water or the oiliness suspending agent etc. of injection.The preferred form of the present invention is powder pin, injection and tablet, capsule.
Herba Chelidonii extract of the present invention is applied to treat cancer and cancerous pain patient, not only has antitumaous effect, and also has analgesic activity, determined curative effect.
The present invention is further illustrated below by embodiment and Pharmacodynamic test of active extract.
The preparation of embodiment 1 Herba Chelidonii extract
Get Herba Chelidonii 3500g, be cut into the 0.5cm section, add 75% ethanol of 10 times of amounts, heating and refluxing extraction 4 times each 1.5 hours, merges alcohol extract, decompression recycling ethanol and to be concentrated into relative density be 1.12 is with 1mol/L phosphoric acid solution adjust pH to 3.5, in 5 ℃ of cold preservations 72 hours, filter, filtrate is extracted 5 times with equal amounts of chloroform with 30% sodium hydroxide solution adjust pH to 11, combined chloroform liquid, reclaim chloroform, the residue vacuum drying, promptly.
The preparation of embodiment 2 Herba Chelidonii extract injectable powder
Embodiment 1 Herba Chelidonii extract 8 grams
Mannitol 25 grams
Get embodiment 1 Herba Chelidonii extract, put in the appropriate vessel, add the about 800ml of injection water, with 1.2mol/L phosphoric acid solution adjust pH to 3.2, filter, filtrate adds mannitol and stirs, add the injection water again to 1000ml, mixing, with the filtering with microporous membrane of 0.22um, filtrate is under aseptic condition, fill is in cillin bottle, part is the fourth rubber stopper beyond the Great Wall, sabot, lyophilization.Lyophilizing finishes back tamponade, gland promptly.
The preparation of embodiment 3 Herba Chelidonii extract injection
Embodiment 1 Herba Chelidonii extract 14g
Tween 80 10ml
Sodium chloride 3.5g
Benzyl alcohol 8ml
Water for injection adds to 1000ml.
Get embodiment 1 Herba Chelidonii extract, add injection water 800ml, stir and make dissolving, use 1mol/L phosphoric acid solution adjust pH to 3.5., filter, filtrate adds tween 80, benzyl alcohol, sodium chloride, and mixing filters with microporous filter membrane, add water for injection to 1000ml, embedding, sterilization, promptly.
The preparation of embodiment 4 Herba Chelidonii extract capsules
Embodiment 1 Herba Chelidonii extract 25g
Dextrin 200g
Starch 100g
Sodium carboxymethyl cellulose 15g
Magnesium stearate 10g
Get embodiment 1 Herba Chelidonii extract, dextrin, starch, sodium carboxymethyl cellulose, magnesium stearate mix homogeneously, cross 80 mesh sieves,,, irritate in capsule, promptly with 60 mesh sieve granulate with dry granulation mechanism grain.
Above embodiment is only for the present invention is further illustrated, and scope of the present invention is not subjected to the limitation of illustrated embodiment.
The present invention is to provide a kind of novel have natural drug---Herba Chelidonii extract and medicament thereof anticancer and the analgesia dual function, for proving its anticancer analgesic effect and safety, the inventor uses the Herba Chelidonii extract and the injection thereof that prepare by the method that provides in the foregoing description to carry out toxicity and pharmacodynamics test, and result of study is as follows:
One, animal acute toxicity test
Herba Chelidonii extract observed for 1 week by different dosage injection mice or rat.The activity of animal reduces after the administration, and is prostrate few moving, occur before the high dose group animal dead dyspnea, cyanosis, tic, etc. symptom.The LD50 of ip in mice, iv is 156.7mg/kg and 39.4mg/kg, and the LD50 of rat ip is 117.6mg/kg.
Two, Herba Chelidonii extract injection analgesic test
Mice is placed on 55 ± 1 ℃ the hot plate, licks the metapedes time as normal pain threshold with mice.The replication secondary, averaging is normal pain threshold (pain threshold before the administration), the screening pain threshold is used for experiment by the mice in 5-30s.Select 60 of qualified mices, random packet.Intramuscular injection various dose Herba Chelidonii extract injection (be divided into 10,20,40mg/kg totally 3 dosage groups), etc. molten amount normal saline (blank group), tramadol injection 50mg/kg (positive controls), each group is by the corresponding dosage administration then.Each group all after administration 15,60,120,240min measures pain threshold respectively once.Mice stops 60s when still not licking metapedes on hot plate, then take out mice immediately, in case soup is hindered, its pain threshold calculates with 60s.Calculate the threshold of pain and improve percentage rate.Herba Chelidonii extract injection analgesic activity 15min onset after administration as a result, analgesic activity reaches the peak behind the 2h, and analgesic activity is still arranged behind the 4h.Compare with tramadol, though Herba Chelidonii analgesia intensity than tramadol a little less than, analgesia duration is longer than tramadol.
Three, the anticancer test of Herba Chelidonii extract injection (hereinafter to be referred as SQC)
1 cell culture and preparation
Behind conventional method recovery gastric cancer SGC7901 cell, with the DMEM culture medium culturing that contains 10% hyclone, condition of culture is 5%CO
2, 37 ℃.Changed liquid 1 time in per 2 days, and when cell grows into 80% coverage rate, went down to posterity with 0.25% trypsinization.Mice S180 sarcoma cell, the mice SRS-82 cell RPMI-1640 culture medium suspension culture that contains 10% hyclone, condition of culture is 5%CO
2, 37 ℃, changed a culture fluid in per 2 days.The stomach cancer cell culture fluid that grows to logarithmic (log) phase is discarded, the about 2-5min of trypsinization with 3ml 0.25% preheating (carries out under microscopic examination, begin to become circle up to cellular morphology, disappearance adhering to each other), discard Digestive system, add the DMEM culture fluid 10ml that contains 10%FCS, with hair suction pipe piping and druming bottle wall collecting cell, and piping and druming repeatedly, disperse the back to move in the centrifuge tube of 10ml up to cell, the centrifugal 5min of 1000r/min abandons supernatant, add 6ml culture fluid suspension cell again, centrifugal collecting cell again behind the counting cells, with the centrifugal 3min washing of the normal saline 1000r/min that is preheated to 37 ℃ 1 time, the reuse normal saline is suspension cell again, each solencyte is collected together, adjusted cell number 1.0 * 10
7/ ml, subcutaneous vaccination nude mice immediately.
Murine sarcoma cell and ascites tumor cells in vitro are cultured to logarithmic growth after date collecting cell, use the normal saline of preheating to wash 2 times, are suspended in again in the normal saline, transfer cell number 1.0 * 10
7/ ml, every intraperitoneal mouse inoculation 0.2ml cultivated after 8 days, extracted the about 5ml of ascites in the ascites tumor mouse peritoneal, and being diluted to cell number with normal saline is 1.0 * 10
7/ ml is used for the subcutaneous or abdominal cavity inoculation of groin of mice.
2.SQC inhibition test to the tumor bearing nude mice solid tumor
40 of nude mices are divided into dosage group (3.0mg/kg) among model group (normal saline), SQC high dose group (9.0mg/kg), the SQC, SQC low dose group (1.0mg/kg), 5-Fu and organize (5.0mg/kg), every group of 8 animals.It is 1.0 * 10 that the stomach cancer cell SGC7901 that cultivates is diluted to cell number with normal saline
7/ ml, every mice left side groin subcutaneous injection 0.2ml (2.0 * 10
6/ only).Injection group nude mice abdominal cavity drug administration by injection 0.2ml, the beginning administration in the 2nd day behind inoculated tumour, 1 time/day, totally 10 days.In postvaccinal the 12nd day, disconnected neck was put to death and is respectively organized mice, peels off tumor mass, takes by weighing tumor weight, and calculates tumour inhibiting rate as follows:
Tumour inhibiting rate=(tumor weight of model group tumor weight-this group)/model group tumor weight * 100%
Result of the test shows that SQC has the obvious suppression effect to lotus people SGC7901 gastric cancer nude mice, and the 9mg/kg suppression ratio is 74.4%, low dose group 1.0mg/kg tumour inhibiting rate is 27.6%, sees Table 1.
Table 1 SQC is to the inhibitory action of people SGC7901 gastric cancer
| Group | Dosage (mg/kg) | Average tumor weight (g) | Tumour inhibiting rate (%) |
| Model | - | 1.45±0.34 | - |
| 5-Fu | 5.0 | 0.47±0.17 | 67.6 |
| SQC | 1.0 | 1.05±0.40 | 27.6 |
| SQC | 3.0 | 0.64±0.21 | 55.9 |
| SQC | 9.0 | 0.35±0.11 | 75.9 |
3 SQC are to the inhibition test of lotus SRS-82 sarcoma kunming mice tumor
It is the same that mice is divided into group, 20 of every group of mices.Behind the SRS-82 sarcoma cell inoculation kunming mice of cultivating the 8th day, in the ascites tumor mouse peritoneal, extract the about 5ml of ascites, being diluted to cell number with normal saline is 1.0 * 10
7/ ml, every mice left side groin subcutaneous injection 0.2ml (2.0 * 10
6/ only).Intraperitoneal injection, all beginning of the 2nd day behind inoculated tumour administrations, 1/ day, totally 10 days.In postvaccinal the 12nd day, disconnected neck was put to death and is respectively organized mice, peels off tumor mass, takes by weighing tumor weight, and calculates tumour inhibiting rate as follows:
Tumour inhibiting rate=(tumor weight of model group tumor weight-this group)/model group tumor weight * 100%
SQC is to the tangible tumor-inhibiting action that shows of lotus SRS-82 tumor mice, and high, medium and low three dosage group tumour inhibiting rates are respectively 19.7%, 40.9%, 61.4%, and positive control medicine 5-Fu also shows obvious antineoplastic, and tumour inhibiting rate 48.0% sees Table 2.
Table 2 Herba Chelidonii injection is to the inhibitory action of lotus SRS-82 sarcoma mouse tumor
| Group | Dosage (mg/kg) | Average tumor heavy (g) | Cancer suppressing ratio (%) |
| Model | - | 1.27±0.65 | - |
| 5-Fu | 5.0 | 0.66±0.33 | 48.0 |
| SQC | 1.0 | 1.02±0.41 | 19.7 |
| SQC | 3.0 | 0.75±0.32 | 40.9 |
| SQC | 9.0 | 0.49±0.25 | 61.4 |
4 SQC are to the inhibition test of lotus tumor kunming mice ascites tumor
It is the same that mice is divided into group, 20 of every group of mices.Behind the S180 cell inoculation kunming mice of cultivating the 8th day, in S180 ascites tumor mouse peritoneal, extract the about 7ml of ascites, being diluted to cell number with normal saline is 1.0 * 10
7/ ml, every mouse peritoneal injection 0.2ml (2.0 * 10
6/ only).High and low dose group mice is oral administration 0.3ml respectively, the beginning administration in the 2nd day behind inoculated tumour, 1/ day, totally 10 days.Write down dead mice quantity every day, and calculate mice prolonged survival period ratio as follows:
Mice prolonged survival period rate=(this group mice mean survival time-model group mice mean survival time)/model group mean survival time * 100%
Result of the test shows that SQC presents tangible prolongation effect to the S180 ascites tumor mice time-to-live, and the rate elongation of high, medium and low three dosage group mices is respectively 71.7%, 47.8%, 22.8%, and positive drug group 5-Fu increase in life span is 57.6%, sees Table 3.
Table 3 SQC is to the influence of mice time-to-live of S180 ascites tumor
| Group | Dosage (mg/kg) | Time-to-live (my god) | Prolonged survival period (%) |
| Model | - | 9.2±2.3 | - |
| 5-Fu | 5.0 | 14.5±3.6 | 57.6 |
| SQC | 1.0 | 11.3±2.7 | 22.8 |
| SQC | 3.0 | 13.6±3.9 | 47.8 |
| SQC | 9.0 | 15.8±3.1 | 71.7 |
Claims (1)
1, a kind of preparation method with Herba Chelidonii extract of anticancer analgesic effect is characterized in that being made up of following steps:
(1) be raw material with the plant Herba Chelidonii, add 75% alcohol reflux, merge extractive liquid, filters;
(2) with above-mentioned filtrate recycling ethanol, to be concentrated into relative density be 1.05～1.25 clear paste;
(3) with above-mentioned clear paste with 0.5～1.5mol/L phosphoric acid solution adjust pH to 1.5～4.5, in 5～10 ℃ of cold preservations more than 10 hours, filter, filtrate is with 5～40% sodium hydroxide solution adjust pHs to 11, extract 2～8 times with equal amounts of chloroform, combined chloroform liquid reclaims chloroform, the residue vacuum drying gets Herba Chelidonii extract.
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| CN 03101200 CN1247223C (en) | 2002-09-13 | 2003-01-21 | Greater celandine extract and its preparation method and application |
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Families Citing this family (5)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN101541339B (en) * | 2006-08-02 | 2011-10-19 | 郑日香 | A percutaneous intratumoral injection composition for treating thyroma |
| CN101402637B (en) * | 2008-11-17 | 2011-08-03 | 曾建国 | Process for producing protopine total alkaloids extract |
| CN103059037B (en) * | 2012-12-13 | 2016-05-25 | 大兴安岭林格贝寒带生物科技股份有限公司 | A kind of method of Chelidonine in enriching and purifying greater celandine |
| CN104800294B (en) * | 2015-04-28 | 2017-11-07 | 陕西中医学院 | The extracting method of anti-tumor Chinese medicine extract and application |
| CN106008432A (en) * | 2016-06-12 | 2016-10-12 | 王伟明 | Method for preparing celandine acid salt from arenga pinnata fruits |
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