CN100482266C - Medical composite prepared by sarcandra and oldenlandia - Google Patents
Medical composite prepared by sarcandra and oldenlandia Download PDFInfo
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Abstract
本发明属于医药技术领域，公开了一种药物组合物及其制备方法，以及含有该药物组合物的制剂，该药物组合物主要由肿节风和白花蛇舌草制成，其重量比为：1∶0.01～10；也可由肿节风提取物和白花蛇舌草提取物制成，其重量比为：1∶0.004～4。该药物组合物可以制成任何一种临床上或药学上可接受的剂型。该药物组合物具有抗肿瘤作用，可用于胃癌、食管癌、直肠癌、恶性淋巴瘤、肺癌、肝癌、子宫颈癌、卵巢癌、膀胱癌等恶性肿瘤。The invention belongs to the technical field of medicine, and discloses a pharmaceutical composition and a preparation method thereof, as well as a preparation containing the pharmaceutical composition. The pharmaceutical composition is mainly made of sarcocarpus and Hedyotis diffusa, and its weight ratio is: 1:0.01-10; it can also be made from the extract of sarcocarpus and the extract of Hedyotis diffusa, the weight ratio is: 1:0.004-4. The pharmaceutical composition can be made into any clinically or pharmaceutically acceptable dosage form. The pharmaceutical composition has antitumor effect and can be used for gastric cancer, esophageal cancer, rectal cancer, malignant lymphoma, lung cancer, liver cancer, cervical cancer, ovarian cancer, bladder cancer and other malignant tumors.
Description
[technical field]
The present invention relates to a kind of pharmaceutical composition that is mainly used in the treatment tumor, be specifically related to a kind of pharmaceutical composition of mainly making and preparation method thereof, belong to medical technical field by Herba Sarcandrae or its extract and Herba Hedyotidis Diffusae or its extract.
[background technology]
Global New Development cases of cancer in 2000 is about 1,000 ten thousand, and is dead 6,200,000, existing ill example 2,200 ten thousand.Cancer is becoming the new century mankind's first killer.Since the seventies, China's cancer morbidity and mortality rate are in rising trend always, to the nineties 20 in the period of, cancer mortality rises 29.42%, ageadjusted mortality rate rises 11.56%.Pathogenesis of cancer number in 2000 is about 180～2,000,000, and is dead 140～1,500,000, and in the town dweller, cancer has accounted for the first place of the cause of the death.Modern medicine mainly is that operative treatment cooperates radiotherapy, chemotherapy to treatment for cancer at present.Though operation can be removed primary lesion, can not fundamentally stop the regeneration and the breeding of cancerous cell, and this root of cancer return and transfer in the future just; Put, though chemotherapy can be killed cancerous cell, but simultaneously a large amount of normal tissue cells is suffered damage, bring out gastrointestinal reaction, bone marrow depression and Liver and kidney, impairment of cardiac function, make patient's health weak more, be difficult to accept further treatment: and the traditional Chinese medical herbal treatment cancer more has long history, repeatedly practise through ancient Chinese medicine doctor, grope with great concentration, oneself has formed the theoretical system of self uniqueness, and in the clinical development in thousands of years, formed own uniqueness some the treatment rules, as strengthening vital QI to eliminate pathogenic factors, heat-clearing and toxic substances removing, rules such as blood circulation promoting and blood stasis dispelling, particularly pass through numerous traditional Chinese medical science in recent years, combination of Chinese and Western medicine worker's continuous effort, courageously practice, also oneself confirms that the Chinese medicine cancer has anti-cancer and inhibiting tumor, the human body immunity improving function, reduce the chemicotherapy toxicity, regulate the body equilibrium between yin and yang, treatment for cancer has been played medicine to be subtracted or the effect that As the medicine took effect, the symptoms lessened to sick, improve the outstanding role of band cancer survival rate and life quality, the particularly rehabilitation of Chinese medicine after to cancer operation, and the efficacy enhancing and toxicity reducing aspect of chemicotherapy brought into play important effect, be subjected to patient's welcome deeply.
Herba Sarcandrae belongs to the dry herb of Chloranthaceae Herba Pileae Scriptae platymiscium Herba Pileae Scriptae Sarcandra glabra (Thunb.) Nakai, have another name called Herba Pileae Scriptae, Herba Pileae Scriptae, successively row, Herba Pileae Scriptae, Peristrophe bivalvis (L.) Merr., drive GUFENG, synthetism lotus, be evergreen undershrub, be distributed in China south of the River one band.Its bitter in the mouth, suffering, property is flat, and GUIXIN, Liver Channel have clearing away heat and cooling blood, the effect of the speckle removing of invigorating blood circulation.Malignant tumor such as cancer of pancreas, hepatocarcinoma, gastric cancer, esophageal carcinoma, rectal cancer, leukemia, lymph tumor there is significant effect.Coumarins in the Herba Sarcandrae, organic acid are the main effective ingredient of its antineoplastic.
Herba Hedyotidis Diffusae Oldenlandia diffusa (Willd) the Roxb beginning is stated from " Guangxi Chinese medicinal herbal ", is the whole herb with root of Maguireothamnus speciosus Herba Hedyotidis Diffusae.Its leaf seemingly tang is opened and is spent in vain, so name.Another name Herba Hedyotidis Diffusae, short foot are spent Chinese Lobelia, the livings pearl grass of order order, Herba Hedyotidis Diffusae etc. in vain, are distributed widely on the south the Yangtze river basin reaches ground, its bitter in the mouth, sweet such as main product Fujian, Guangdong, Guangxi, cold in nature, go into the heart, liver, spleen three warps, heat-clearing and toxic substances removing is arranged, blood circulation promoting and blood stasis dispelling, effects such as anti-inflammatory analgetic.Modern pharmacological research shows that Herba Hedyotidis Diffusae has effects such as anti-inflammation, heat-clearing and toxic substances removing, blood circulation promoting and blood stasis dispelling, relieving stranguria by diuresis and antitumor, can be used for treating gastric cancer, the esophageal carcinoma, rectal cancer, malignant lymphoma, pulmonary carcinoma, hepatocarcinoma, cervical cancer, ovarian cancer, bladder cancer etc., clinical practice is extensive.Triterpene mixed acid in the Herba Hedyotidis Diffusae, Coumarins and polysaccharide are anticancer effective ingredient.
At present, utilize the interaction of Herba Sarcandrae and Herba Hedyotidis Diffusae, composition of prescription, preparation is used for the medicine of anti-tumor aspect, does not appear in the newspapers as yet.
[summary of the invention]
The purpose of this invention is to provide a kind of new pharmaceutical composition with antitumor action, it is mainly made by Herba Sarcandrae and Herba Hedyotidis Diffusae, its weight ratio is: Herba Sarcandrae: Herba Hedyotidis Diffusae 1: 0.01～10, be preferably Herba Sarcandrae: Herba Hedyotidis Diffusae 1: 0.02～6, optimum is a Herba Sarcandrae: Herba Hedyotidis Diffusae 1: 0.13.
Preparation of drug combination method of the present invention is: Herba Sarcandrae and Herba Hedyotidis Diffusae with The suitable solvent respectively or mix through extracting processing and obtain its extract, total extract is made various preparations with the pharmaceutic adjuvant hybrid process again.The suitable solvent is meant solvent pharmaceutically commonly used, preferred water or ethanol, and extracting method can extract with pharmaceutically conventional method, as infusion process, percolation, decocting method, reflux extraction, continuous extraction etc.
Herba Sarcandrae in the aforementioned pharmaceutical compositions can be carried acid precipitation, alcohol extraction, water extract-alcohol precipitation or water by water and put forward multiple modes such as post and prepare, and the present invention has carried out preferably the extraction process of Herba Sarcandrae, and step is as follows:
Get Herba Sarcandrae, decoct with water secondary, each 2 hours, add 10 times of amounts of water, collecting decoction filters at every turn, it is 1.33 (70 ℃) that filtrate is concentrated into relative density, adds the ethanol precipitation secondary, makes for the first time that to contain the alcohol amount be 70%, containing for the second time the alcohol amount is 80%, and each cold preservation 48 hours filters, filtrate recycling ethanol also is concentrated into every 1ml and contains crude drug 10g, adds the egg protein solution of an amount of new preparation, stirs, make precipitation, cold preservation 48 hours filters, filtrate is boiled, and excessive egg protein is solidified, and filters, filtrate adds ethanol, makes that to contain amount of alcohol be 75%, places precipitation, filter, filtrate recycling ethanol is not distinguished the flavor of to there being alcohol, spray drying, promptly.
Herba Sarcandrae extract yield by this prepared is 1～5%, and isofraxidin content is not less than 0.1%, and fumaric acid content is not less than 0.02%.
Herba Sarcandrae in the aforementioned pharmaceutical compositions can also extract preparation by the following method, but this should be interpreted as that the Herba Sarcandrae in the aforementioned pharmaceutical compositions only limits to extract preparation by above-mentioned or following technology:
Technology one: get Herba Sarcandrae, decoct with water three times, each 1 hour, amount of water is 10 times of amounts first time, and two, three times is 8,8 times of amounts, collecting decoction, filter, filtrate adds ethanol precipitation 2 times, makes that to contain the alcohol amount be 70% for the first time, containing for the second time the alcohol amount is 80%, each cold preservation 48 hours filters, and filtrate recycling ethanol also is concentrated into the thick paste shape, spray drying, promptly.
The Herba Sarcandrae extract yield that makes by this technology is 4～7%, and isofraxidin content is not less than 0.05%, and fumaric acid content is not less than 0.012%.
Technology two: get Herba Sarcandrae, decoct with water three times, each 1 hour, amount of water was 10 times of amounts first time, and two, three times is 8,8 times of amounts, and collecting decoction filters, and filtrate is concentrated into the thick paste shape, drying under reduced pressure below 85 ℃, promptly.
The Herba Sarcandrae extract yield that makes by this technology is 6～8%, and isofraxidin content is not less than 0.04%, and fumaric acid content is not less than 0.01%.
The preferred extraction and preparation technique of Herba Hedyotidis Diffusae in the aforementioned pharmaceutical compositions is specific as follows:
Get Herba Hedyotidis Diffusae, be ground into coarse powder,, make solvent with 80% ethanol according to the percolation under fluid extract of 2005 editions pharmacopeia and the extractum item, flooded 24 hours, percolation slowly, the liquid of filtering are evaporated to does not have the alcohol flavor, and thin up becomes every 1ml to be equivalent to the amount of 1g crude drug, cold preservation, left standstill 12 hours, and filtered, filtrate adds ethanol and carries out three subgradient precipitate with ethanol, make for the first time the alcohol amount 60% that contains, make for the second time to contain alcohol amount 70%, make the alcohol amount 80% that contains for the third time, each all cold preservation 24 hours, filter, filtrate decompression is concentrated into relative density 1.10～1.15, spray drying, promptly.
Herba Hedyotidis Diffusae extract yield by this prepared is 0.5～1.5%, presses dry product and calculates, and contains total flavones with rutin (C
27H
30O
16) meter, should be not less than 50%.
Herba Hedyotidis Diffusae in the aforementioned pharmaceutical compositions also can be extracted preparation by the following method, but this should be interpreted as that the Herba Hedyotidis Diffusae in the aforementioned pharmaceutical compositions only limits to above-mentioned or following technology extraction preparation:
Technology one: get Herba Hedyotidis Diffusae, be ground into coarse powder, according to the percolation under 2005 editions fluid extracts of pharmacopeia and the extractum item, make solvent with 75% ethanol, flooded 12 hours, percolation slowly, the liquid of filtering are evaporated to does not have the alcohol flavor, thin up becomes every 1ml to be equivalent to the amount of 1g crude drug, cold preservation was left standstill 12 hours, filtered, filtrate is added on the polyamide of having handled well, earlier with the water of 2～3 times of column volumes towards post, reuse 10% ethanol discards cleaning mixture towards post, use 80% ethanol elution of 3～4 times of column volumes at last, collect eluent.Eluent is evaporated to relative density 1.10～1.15, spray drying, promptly.
The Herba Hedyotidis Diffusae extract yield that makes by this technology is 0.5～1.5%, contains total flavones with rutin (C
27H
30O
16) meter, be not less than 45%.
Technology two: get Herba Hedyotidis Diffusae, be ground into coarse powder, 80% alcohol reflux secondary, each 2 hours, filter, filtrate decompression is concentrated into does not have the alcohol flavor, thin up becomes every 1ml to be equivalent to the amount of 1g crude drug, and cold preservation was left standstill 12 hours, filter, filtrate adds ethanol and carries out two subgradient precipitate with ethanol, makes the alcohol amount 60% that contains for the first time, make for the second time the alcohol amount 80% that contains, each all cold preservation 12 hours filters, filtrate decompression is concentrated into relative density 1.10～1.15, spray drying, promptly.
The Herba Hedyotidis Diffusae extract yield that makes by this technology is 0.5～1.5%, contains total flavones with rutin (C
27H
30O
16) meter, be not less than 40%.
Pharmaceutical composition of the present invention also can be made up of Herba Sarcandrae extract and Herba Hedyotidis Diffusae extract, calculate with respect to the yield of medical material according to extract that (the Herba Sarcandrae extract yield is 1～5%, the Herba Hedyotidis Diffusae extract yield is 0.5～1.5%) weight proportion of Herba Sarcandrae extract and Herba Hedyotidis Diffusae extract is: 1: 0.004～4, be preferably 1: 0.01～0.5, optimum is 1: 0.04～0.2.
In the aforementioned pharmaceutical compositions, the main effective ingredient of Herba Sarcandrae extract is organic acid and Coumarins, assay is an index with isofraxidin and fumaric acid, wherein contains isofraxidin and preferably is not less than 0.1%, contains fumaric acid and preferably is not less than 0.02%; The main effective ingredient of Herba Hedyotidis Diffusae extract is a flavonoid, and content is with rutin (C
27H
30O
16) meter, preferably be not less than 50%.
The consumption of each component is groped to sum up to draw through the inventor in a large number in the pharmaceutical composition of the present invention, and the consumption of each component all has better curative effect in above-mentioned weight range.Above-mentioned composition as if being unit with the gram, can be made the preparation of 100～10000 consumptions.As tablet, can make 100～10000,1～10 of each consumption, every day 1～5 time.As injection, can make 100～10000,1～10 of each consumption, every day 1～3 time.More than forming when producing and can increase or reduce according to corresponding proportion, can be raw material with the kilogram as large-scale production, or is unit with the ton, and small-scale production can be unit with the gram also, and weight can increase or reduce, but each form between weight proportion constant.Above ratio obtains through science screening, and for especial patient, the ratio of can corresponding adjustment forming increases or reduce being no more than 100%.
Pharmaceutical composition of the present invention is to S
180Solid tumor growth and lotus SRS-82 sarcoma mice had remarkable tumor-inhibiting action, growth has remarkable tumor-inhibiting action to rat liver cancer (HePA) solid tumor, but the life of significant prolongation ehrlich carcinoma (EAC) mice, to cyclophosphamide, 5 fluorouracil and
60Co radiotherapy and chemotherapy all have remarkable potentiation, can be used for the treatment and the auxiliary treatment of malignant tumor such as gastric cancer, the esophageal carcinoma, rectal cancer, malignant lymphoma, pulmonary carcinoma, hepatocarcinoma, cervical cancer, ovarian cancer, bladder cancer.
Pharmaceutical composition of the present invention can be mixed and made into clinically any or pharmaceutically acceptable dosage form with one or more pharmaceutically acceptable carriers, preferred oral preparation or injection are applied to the patient who needs this treatment in the mode of oral or parenteral.
When being used for oral administration, can be made into conventional solid preparation, as tablet, capsule, pill, granule etc.; Also can be made into oral liquid, as oral solution, oral suspensions, syrup etc.Tablet means disk shape or the special-shaped flaky solid preparation that medicine and the auxiliary materials and mixing compacting that suits form, based on oral ordinary tablet, other has buccal tablet, Sublingual tablet, mouth paster, chewable tablet, dispersible tablet, fuse, effervescent tablet, slow releasing tablet, controlled release tablet and enteric coatel tablets etc.Capsule means medicine or is added with the adjuvant filling in Capsules or be sealed in solid preparation in the soft capsule material, according to its dissolving and release characteristics, can be divided into hard capsule (being commonly referred to as capsule), soft capsule (soft gelatin capsule), slow releasing capsule, controlled release capsule and enteric coated capsule etc.Pill means medicine and suitable adjuvant uniform mixing, and the spherical or near-spherical solid preparation so that proper method is made comprises drop pill, sugar pill, piller etc.Granule means that medicine and suitable adjuvant make the dried particles shape preparation with certain particle size, can be divided into soluble particles (being commonly referred to as granule), mix suspension grain, effervescent granule, enteric coated particles, slow-releasing granules and controlled release granule etc.Oral solution means that medicine dissolution makes for oral supernatant liquid preparation in suitable solvent.Oral suspensions means the slightly solubility solid drugs, is dispersed in the liquid medium, makes for oral suspension body preparation, also comprises dry suspension or dense suspension.Syrup means the dense aqueous sucrose solution that contains medicine.
When making oral formulations, can add suitable filler, binding agent, disintegrating agent, lubricant etc.Filler commonly used comprises starch, Icing Sugar, calcium phosphate, calcium sulfate two water things, dextrin, microcrystalline Cellulose, lactose, pregelatinized Starch, mannitol etc.; Typical binders comprises sodium carboxymethyl cellulose, PVP-K30, hydroxypropyl cellulose, starch slurry, methylcellulose, ethyl cellulose, hypromellose, gelling starch etc.; Disintegrating agent commonly used comprises dried starch, polyvinylpolypyrrolidone, cross-linking sodium carboxymethyl cellulose, carboxymethyl starch sodium, low-substituted hydroxypropyl cellulose etc.; Conventional lubricants comprises magnesium stearate, Pulvis Talci, sodium lauryl sulphate, micropowder silica gel etc.
When being used for parenteral, can be made into injection.Injection means the intravital solution of confession injection, emulsion or the suspension that medicine is made and supplies to face with preceding preparation or be diluted to solution or the sterile preparation of the powder of suspension or concentrated solution that injection can be divided into injection, injectable sterile powder and concentrated solution for injection.Injection means that the confession that medicine is made is injected into sterile solution type injection, emulsion-type injection or the suspension type injection of using in the body, can be used for intramuscular injection, intravenous injection, intravenous drip etc.; Its specification has 1ml, 2ml, 5ml, 10ml, 20ml, 50ml, 100ml, 200ml, 250ml, 500ml etc., and wherein large volume (generally the being not less than 100ml) injection of using for intravenous drip also claims venous transfusion.Injectable sterile powder means that confession that medicine is made is faced with the suitable sterile solution of preceding usefulness and is mixed with settled solution or the evenly sterilized powder or the aseptic block of suspension, available suitable solvent for injection preparation back injection, also available venous transfusion preparation posterior vein instils; Sterilized powder makes with solvent crystallization, spray drying method or freeze-drying etc.Concentrated solution for injection means that confession that medicine is made faces the aseptic concentrated solution of using for intravenous drip with preceding dilution.
When making injection, optional use solvent or non-aqueous solvent can add suitable additives according to the character of medicine.The most frequently used aqueous solvent is a water for injection, also available 0.9% sodium chloride solution or other suitable aqueous solutions; Non-aqueous solvent commonly used is a vegetable oil, is mainly the injection soybean oil, and other also have the aqueous solution of ethanol, propylene glycol, Polyethylene Glycol etc.Additives commonly used comprise osmotic pressure regulator, pH value regulator, solubilizing agent, filler, antioxidant, antibacterial, emulsifying agent, suspending agent etc.Osmotic pressure regulator commonly used comprises sodium chloride, glucose, potassium chloride, magnesium chloride, calcium chloride, sorbitol etc., preferred sodium chloride or glucose; PH value regulator commonly used comprises acetic acid-sodium acetate, lactic acid, citric acid-sodium citrate, sodium bicarbonate-sodium carbonate etc.; Solubilizing agent commonly used comprises polyoxyethylene sorbitan monoleate, propylene glycol, lecithin, polyoxyethylene castor oil etc.; Filler commonly used comprises lactose, mannitol, sorbitol, dextran etc.; Antioxidant commonly used has sodium sulfite, sodium sulfite, sodium pyrosulfite etc.; Antibacterial commonly used is phenol, cresol, chlorobutanol etc.Injection container commonly used has glass ampule, vial, plastic ampoule, plastic bottle etc.
The invention has the beneficial effects as follows:
(1) the invention provides a kind of new pharmaceutical composition, satisfied clinical needs with good resistance function of tumor.
Studies have shown that by pharmacological experiment first that (2) pharmaceutical composition of the present invention is compared with Herba Sarcandrae or Herba Hedyotidis Diffusae with single, to S
180Solid tumor growth and lotus SRS-82 sarcoma mice had remarkable tumor-inhibiting action, growth has remarkable tumor-inhibiting action to rat liver cancer (HePA) solid tumor, but the life of significant prolongation ehrlich carcinoma (EAC) mice, to cyclophosphamide, 5 fluorouracil and
60Co radiotherapy and chemotherapy all have remarkable potentiation, and the curative effect of its best proportioning and positive control drug KANGLAITE ZHUSHEYE, the therapeutic equivalence of cyclophosphamide, toxicity are little, and this is that those of ordinary skills institute is beyond thought.
(3) the present invention has drawn the best proportioning of the performance antitumor curative effect of Herba Sarcandrae and Herba Hedyotidis Diffusae by pharmacodynamic experiment.
(4) in preparation of pharmaceutical compositions of the present invention, extract the Herba Sarcandrae extract and the Herba Hedyotidis Diffusae extract active constituent content height that make, make medicine purity higher, impurity is few, and safety is higher, and drug quality is more uniform and stable.
(5) confirm drug combination injection safety and stability of the present invention by specific safety test and stability experiment.
(6) Herba Sarcandrae and Herba Hedyotidis Diffusae drug combination are synergism, and dosage reduces relatively, are with a wide range of applications.
Below routine by experiment beneficial effect of further setting forth medicine of the present invention, these experimental examples comprise the pharmacodynamic experiment of pharmaceutical composition of the present invention.Herba Sarcandrae extract used in the following experimental example all makes with reference to embodiment 1; Herba Hedyotidis Diffusae extract all makes with reference to embodiment 2.
Experimental example 1 pharmaceutical composition of the present invention is to the tumor-inhibiting action of lotus SRS-82 sarcoma mice
Laboratory animal: ICR kind mice, body weight 18～25g, male and female half and half.
Tumor kind: mice SRS-82 cell strain
Test sample:
Positive controls: KANGLAITE ZHUSHEYE, Zhejiang Kanglaite Pharmaceutical Co., Ltd;
Herba Sarcandrae extract group: Herba Sarcandrae extract injection, self-control;
Herba Hedyotidis Diffusae extract group: Herba Hedyotidis Diffusae extract injection, self-control;
Pharmaceutical composition group of the present invention: composite injection, self-control, different proportionings.
Experimental technique: get 210 of ICR kind mices, be divided into 21 groups at random, every group 10, be respectively the blank group, positive controls, the Herba Sarcandrae extract group, the Herba Hedyotidis Diffusae extract group, the different proportioning groups of pharmaceutical composition of the present invention: Herba Sarcandrae extract+Herba Hedyotidis Diffusae extract, 200mg+10mg, 200mg+30mg, 200mg+60mg, 200mg+130mg, 300mg+10mg, 300mg+20mg, 300mg+30mg, 300mg+60mg, 300mg+130mg, 300mg+150mg, 400mg+10mg, 400mg+30mg, 400mg+130mg, 1000mg+10mg, 1000mg+20mg, 1000mg+60mg, 1000mg+130mg.
Tumor inoculation: with behind the SRS-82 cell inoculation kunming mice of cultivating the 8th day, extract the about 15ml of ascites in 4 mouse peritoneals respectively, being diluted to cell number with normal saline is 1.0 * 10
7Behind/the ml (30ml altogether), every mice left side groin subcutaneous injection 0.2ml (2.0 * 10
6/ only).
Administering mode and time: every mouse peritoneal injection (ip) administration (each extract group dosage: 140mg/kg), KANGLAITE ZHUSHEYE is not diluted direct ip administration (dosage: 10ml/kg), beginning administration in the 2nd day behind inoculated tumour, 1 time/day, totally 10 days.
Tumour inhibiting rate: in postvaccinal the 12nd day, take off cervical vertebra execution and respectively organize mice, peel off tumor mass, take by weighing tumor weight, and calculate tumour inhibiting rate as follows:
Tumour inhibiting rate=(model group average tumor weight-administration group average tumor weight)/model group average tumor weight * 100%.
Table 1 present composition is to the tumour inhibiting rate of lotus SRS-82 sarcoma mice (X ± SD) relatively
Annotate: compare with the blank group,
*P＜0.05,
*P＜0.01; Compare with the Herba Sarcandrae group,
#P＜0.05,
##P＜0.01; Compare with the Herba Hedyotidis Diffusae group,
△P＜0.05,
△ △＜0.01.
Experimental result and conclusion: experimental result sees Table 1.
Compare with the blank group, each administration group has obvious inhibitory action (p＜0.05 to lotus SRS-82 tumor mouse tumor, p＜0.01), pharmaceutical composition wherein of the present invention (Herba Sarcandrae extract: Herba Hedyotidis Diffusae extract=1: 0.01～0.5) compare with Herba Sarcandrae extract group or Herba Hedyotidis Diffusae extract group with single by group, its curative effect all is better than single with Herba Sarcandrae extract group and Herba Hedyotidis Diffusae extract group (p＜0.05, p＜0.01), and close with positive control medicine KANGLAITE ZHUSHEYE curative effect, prompting Herba Sarcandrae and Herba Hedyotidis Diffusae two medicine compatibilities have synergistic function.Wherein with Herba Sarcandrae extract: Herba Hedyotidis Diffusae extract=1: 0.07 proportioning group curative effect is (p＜0.01) significantly, and curative effect and KANGLAITE ZHUSHEYE are suitable, point out it in the optimal proportion scope.
Experimental example 2 pharmaceutical composition drug combinations of the present invention are to S
180
The influence of solid tumor growth
Animal subject: ICR kind mice, body weight 18～22g, male.
Tumor kind: S
180Tumor liquid.
Test sample: blank group: 0.9% normal saline solution, self-control;
Positive controls: cyclophosphamide sheet, Nantong Jinghua Pharmacy Co. Ltd;
Herba Sarcandrae group: Herba Sarcandrae tablet, self-control;
Herba Hedyotidis Diffusae group: Herba Hedyotidis Diffusae tablet, self-control;
Pharmaceutical composition group of the present invention: pharmaceutical composition tablet of the present invention, self-control.
Experimental technique: get 210 of ICR kind mices, be divided into 21 groups at random, every group 10, be respectively the blank group, positive controls, Herba Sarcandrae group, Herba Hedyotidis Diffusae group, the different proportioning groups of pharmaceutical composition of the present invention: (Herba Sarcandrae+Herba Hedyotidis Diffusae, 50g+1g, 50g+2g, 50g+15g, 50g+30g, 50g+60g, 20g+1g, 20g+2g, 20g+15g, 20g+30g, 20g+60g, 15g+1g, 15g+2g, 15g+15g, 15g+30g, 15g+60g, 10g+2g, 10g+60g).Each administration group is with normal saline and is mixed with gastric infusion behind the suspension.
Get the ICR mice, all subcutaneous vaccination S
180Tumor liquid (2 * 10
7/ ml) 0.2ml/, weigh next day.Gastric infusion, dosage sees Table 2, and be administered once every day, and totally 10 days, drug withdrawal was weighed next day, put to death mice and peeled off the subcutaneous tumors piece, claimed tumor heavy, and calculated tumour inhibiting rate.
Table 2 pharmaceutical composition of the present invention is to S
180The influence of solid tumor growth (X ± SD)
Annotate:
*P＜0.05,
*P＜0.01 is compared with the blank group;
#P＜0.05 is compared with the Herba Sarcandrae group;
△＜0.05, compare with the Herba Hedyotidis Diffusae group.
Experimental result and conclusion: experimental result sees Table 2.
Each administration group all has obvious suppression S
180Tumor growth effect (p＜0.05, p＜0.01).(Herba Sarcandrae: Herba Hedyotidis Diffusae=1: 0.02～6) effect all obviously is better than singly with Herba Sarcandrae or Herba Hedyotidis Diffusae (p＜0.05) pharmaceutical composition group wherein of the present invention, and tumour inhibiting rate is 60.74%～68.60%.Proof Herba Sarcandrae and Herba Hedyotidis Diffusae compatibility have the effect of good restraining tumor growth, and relevant with the proportioning of compositions, and wherein with Herba Sarcandrae: Herba Hedyotidis Diffusae=effect in 1: 0.13 is best, points out it may be best proportioning.
Experimental example 3 pharmaceutical compositions of the present invention are to the influence of rat liver cancer (HePA) growth
Laboratory animal: ICR kind mice, body weight 18～25g, male and female half and half.
Test sample:
Blank group: 0.9% normal saline solution, self-control;
Positive controls: Cyclophosphamide for injection, Hengrui Medicine Co., Ltd., Jiangsu Prov.;
Herba Sarcandrae group: ZHONGJIEFENG ZHUSHEYE, self-control;
Herba Hedyotidis Diffusae group: BAIHUASHESHECAO ZHUSHEYE, self-control;
Pharmaceutical composition group of the present invention: medicine composition injection of the present invention (Herba Sarcandrae+Herba Hedyotidis Diffusae=15g+2g), self-control.
Preparation method is referring to embodiment 3.
Experimental technique: get the equal subcutaneous vaccination hepatocarcinoma of mice (HePA) tumor liquid (2 * 10
7/ ml) 0.2ml/, grouping next day is respectively blank group, positive controls, Herba Sarcandrae group, Herba Hedyotidis Diffusae group, the high, medium and low dosage group of pharmaceutical composition of the present invention, weighs.Inoculation tumor mice begins intraperitoneal injection next day, and be administered once every day, and totally 10 days, drug withdrawal was weighed next day, put to death mice and also peeled off the subcutaneous tumors piece, claimed tumor heavy, and calculated tumour inhibiting rate.
Table 3 pharmaceutical composition of the present invention is to the influence of rat liver cancer (HePA) solid tumor growth
Annotate: compare with the blank group,
*P＜0.05,
*P＜0.01; Compare with the Herba Sarcandrae group,
#P＜0.05,
##P＜0.01; Compare with the Herba Hedyotidis Diffusae group,
△＜0.05,
△ △0.01.
Experimental result and conclusion: experimental result sees Table 3.
Result in the table 3 shows, compares with the blank group, and Herba Sarcandrae, Herba Hedyotidis Diffusae, pharmaceutical composition of the present invention, cyclophosphamide are all to rat liver cancer (HePA) tumor growth (p＜0.05, p＜0.01).Wherein the compositions curative effect is better than single use Herba Sarcandrae and Herba Hedyotidis Diffusae, and the high dose group curative effect is close with positive control medicine cyclophosphamide curative effect, and Herba Sarcandrae and Herba Hedyotidis Diffusae are share in prompting, and synergistic function is arranged, and relevant with dosage, and the high dose effect is more excellent.
Experimental example 4 pharmaceutical compositions of the present invention are to the influence of ehrlich carcinoma (EAC) mice increase in life span
Laboratory animal: ICR kind mice, body weight 18～25g, male and female half and half.
Test sample:
Blank group: 0.9% normal saline solution, self-control;
Positive controls: Cyclophosphamide for injection, Hengrui Medicine Co., Ltd., Jiangsu Prov.;
Herba Sarcandrae group: ZHONGJIEFENG ZHUSHEYE, self-control;
Herba Hedyotidis Diffusae group: BAIHUASHESHECAO ZHUSHEYE, self-control;
Pharmaceutical composition group of the present invention: medicine composition injection of the present invention (Herba Sarcandrae extract+Herba Hedyotidis Diffusae extract=300mg+20mg), self-control.
Preparation method is referring to embodiment 3.
Experimental technique: aseptic extraction EAC ascites, with 1: 2 times of dilution of normal saline, every Mus abdominal cavity inoculation 0.2ml, grouping after 24 hours is respectively blank group, positive controls, Herba Sarcandrae group, Herba Hedyotidis Diffusae group, pharmaceutical composition various dose group of the present invention, weigh and administration, inoculation tumor mice begins intraperitoneal injection next day, and be administered once every day, totally 10 days, after this observe the death time of mice, the result represents with average survival natural law and increase in life span.
Table 4 pharmaceutical composition of the present invention is to the influence of EAC ehrlich ascites carcinoma mice increase in life span
Annotate: compare with the blank group,
*P＜0.05,
*P＜0.01; Compare with the Herba Sarcandrae group,
#P＜0.05,
##P＜0.01; Compare with the Herba Hedyotidis Diffusae group,
△＜0.05,
△ △0.01.
Experimental result and conclusion: experimental result sees Table 4.
Result in the table 4 shows, compares with the blank group, and Herba Sarcandrae, Herba Hedyotidis Diffusae, pharmaceutical composition of the present invention, cyclophosphamide all can prolong the time-to-live (p＜0.05, p＜0.01) of mice EAC ehrlich carcinoma mice.Wherein the compositions curative effect is better than single use Herba Sarcandrae and Herba Hedyotidis Diffusae, and the high dose group curative effect is close with positive control medicine cyclophosphamide curative effect, and Herba Sarcandrae and Herba Hedyotidis Diffusae are share in prompting, and synergistic function is arranged.
The potentiation that experimental example 5 pharmaceutical compositions of the present invention and fluorouracil (Fu) share
Laboratory animal: ICR kind mice, body weight 18～25g, male and female half and half.
Test sample:
Blank group: 0.9% normal saline solution, self-control;
Fluorouracil group: Fluorouracil Injection, Zizhu Pharmaceutical Co., Ltd., Beijing;
Fu+ Herba Sarcandrae group: ZHONGJIEFENG ZHUSHEYE, self-control, every 1ml is equivalent to Chinese medicinal material of sarcandra glaber 5g;
Fu+ Herba Hedyotidis Diffusae group: BAIHUASHESHECAO ZHUSHEYE, self-control, every 1ml is equivalent to Herba Hedyotidis Diffusae medical material 1g;
Fu+ pharmaceutical composition group of the present invention: Fu+ medicine composition injection of the present invention, self-control, every 5ml contains Herba Sarcandrae extract+Herba Hedyotidis Diffusae extract: 300mg+20mg (being equivalent to Herba Sarcandrae 15g, Herba Hedyotidis Diffusae 2g).
Experimental technique: mouse hypodermic inoculation S
180Tumor liquid (2 * 10
7/ ml) 0.2ml/, next day, grouping was divided into 7 groups, and 10 every group, be respectively blank group, Fu+ Herba Sarcandrae group, Fu+ Herba Hedyotidis Diffusae group, the high, medium and low dosage group of Fu+ pharmaceutical composition of the present invention, 5-fluorouracil group (5-Fu), weigh.Except that the blank group, all the other respectively organize equal lumbar injection 5-fluorouracil (5-Fu) 60mg/kg.Inoculation tumor mice begins intraperitoneal injection next day, is administered once every day totally 10 days.Drug withdrawal is weighed next day, puts to death mice and peels off the subcutaneous tumors piece, claims tumor heavy, calculates tumour inhibiting rate and potentiation rate.
Table 5 pharmaceutical composition of the present invention and the anti-S of fluorouracil
180The potentiation of tumor
Annotate: compare with the Fu group,
*P＜0.05,
*P＜0.01; Compare with 5-Fu+ Herba Sarcandrae group,
#P＜0.05,
##P＜0.01; Compare with 5-Fu+ Herba Hedyotidis Diffusae group,
△＜0.05,
△ △0.01.
Experimental result and conclusion: experimental result sees Table 5.
Result in the table 5 shows, compare with the blank group, Herba Sarcandrae, Herba Hedyotidis Diffusae, pharmaceutical composition of the present invention all have synergistic function (p＜0.05 with fluorouracil, p＜0.01), wherein the compositions potentiation is better than single with Herba Sarcandrae and Herba Hedyotidis Diffusae, high dose group potentiation the strongest (p＜0.01).
Experimental example 6 pharmaceutical compositions of the present invention are to the potentiation of radiotherapy
Laboratory animal: ICR kind mice, body weight 18～25g, male and female half and half.
Test sample:
Blank group: 0.9% normal saline solution, self-control;
60Co+ Herba Sarcandrae group: ZHONGJIEFENG ZHUSHEYE, self-control, every 1ml is equivalent to Chinese medicinal material of sarcandra glaber 5g;
60Co+ Herba Hedyotidis Diffusae group: BAIHUASHESHECAO ZHUSHEYE, self-control, every 1ml is equivalent to Herba Hedyotidis Diffusae medical material 1g;
60Co+ pharmaceutical composition group of the present invention:
60Co+ medicine composition injection of the present invention, self-control, every 5ml contains Herba Sarcandrae extract+Herba Hedyotidis Diffusae extract: 300mg+20mg (being equivalent to Herba Sarcandrae 15g, Herba Hedyotidis Diffusae 2g).
Experimental technique: get mice, all subcutaneous vaccination S
180Tumor liquid (2 * 10
7/ ml) 0.2ml/ only, next day, grouping was divided into 7 groups, 10 every group, be respectively the blank group,
60Co+ Herba Sarcandrae group,
60Co+ Herba Hedyotidis Diffusae group,
60The high, medium and low dosage group of Co+ pharmaceutical composition of the present invention,
60The Co group is weighed.Except that the blank group, all the other each groups are the 3rd, the 6th day usefulness after inoculation all
60Co total irradiation, exposure dose are 0.05Gy.Inoculation tumor mice begins intraperitoneal injection next day, and be administered once every day, and administration is 10 days altogether, and drug withdrawal is weighed next day, puts to death animal.Peel off the subcutaneous tumors piece, claim tumor heavy, calculate tumour inhibiting rate and potentiation rate.
Table 6 pharmaceutical composition of the present invention is to the potentiation of radiotherapy
Annotate: with
60Co organizes relatively,
*P＜0.05,
*P＜0.01; With
60Co+ Herba Sarcandrae group compares,
#P＜0.05,
##P＜0.01; With
60Co+ Herba Hedyotidis Diffusae group compares,
△＜0.05,
△ △P＜0.01.
Experimental result and conclusion: experimental result sees Table 6.
Result in the table 6 shows, with the blank group relatively, Herba Sarcandrae, Herba Hedyotidis Diffusae, pharmaceutical composition of the present invention all with
60Co radiotherapy has synergistic function (p＜0.05, p＜0.01), and wherein the compositions potentiation is better than single with Herba Sarcandrae and Herba Hedyotidis Diffusae, high dose group potentiation the strongest (p＜0.01).
Experimental example 7 pharmaceutical compositions of the present invention are to the potentiation of chemotherapy and the effect of attenuation
Animal subject: healthy mice, 70, body weight 20～25g, the male and female dual-purpose is divided into 7 groups at random, 10 every group.Test sample:
Blank group: 0.9% normal saline solution, self-control;
Positive controls: cyclophosphamide (CTX) tablet, Nantong Jinghua Pharmacy Co. Ltd;
CTX+ Herba Sarcandrae group: CTX+ Herba Sarcandrae tablet, self-control;
CTX+ Herba Hedyotidis Diffusae group: CTX+ Herba Hedyotidis Diffusae tablet, self-control;
CTX+ pharmaceutical composition group of the present invention: the CTX+ composition tablet (Herba Sarcandrae+Herba Hedyotidis Diffusae=15g+2g): be divided into high, medium and low three dosage groups, self-control.
Preparation method is referring to embodiment 7.
Each administration group is with normal saline and is mixed with gastric infusion behind the suspension.
Tumor strain: rat liver cancer H
22
Experimental technique: every mice left fore oxter subcutaneous vaccination H
22Tumor strain cell suspension (suspension concentration 0.3g/ml, inoculum concentration 0.01ml/g).The inoculation next day, the mice random packet is weighed in, gastric infusion, dosage sees Table 7, the next day 1 time, continuous 10 days.Weigh in every day, observes the mice with tumor body weight change, 24h eye socket blood sampling after the last administration, counting peripheral leukocytes (WBC) number; Put to death immediately, peel off the subcutaneous tumors piece, take by weighing the tumor body weight, calculate tumour inhibiting rate and potentiation rate
[potentiation rate=(the average tumor of average tumor weight-chemotherapy of chemotherapy group and composition capsule therapeutic alliance group is heavy)/average tumor of chemotherapy group heavy * 100%]; Anatomical isolation thymus, spleen and target organ are weighed and are calculated organ index.
Table 7 pharmaceutical composition of the present invention is to the potentiation of chemotherapy and the effect of attenuation (X ± SD)
Annotate:
*P＜0.05,
*Compare with the blank group in p＜0.01;
#P＜0.05,
##Compare with positive controls in p＜0.01,
﹠amp;Compare with Herba Sarcandrae in p＜0.05;
$Compare with the Herba Hedyotidis Diffusae group in p＜0.05.
Experimental result and conclusion: the results are shown in Table 7.
(1) potentiation of chemotherapy:
1. compare with the blank group, the independent medication of cyclophosphamide has significant inhibitory effect (p＜0.05) to rat liver cancer H22;
2. compare with the independent medication of cyclophosphamide, cyclophosphamide and Herba Sarcandrae or cyclophosphamide and Herba Hedyotidis Diffusae drug combination are to rat liver cancer H
22Significant inhibitory effect (p＜0.05) is arranged;
3. compare with the independent medication of cyclophosphamide, cyclophosphamide with in, low dosage composition capsule drug combination is to rat liver cancer H
22Inhibitory action significantly strengthen (p＜0.05), cyclophosphamide and high dose composition capsule drug combination are to rat liver cancer H
22Inhibitory action extremely significantly strengthen (p＜0.01).
4. compare with independent Herba Sarcandrae or Herba Hedyotidis Diffusae drug combination with cyclophosphamide, cyclophosphamide and high, medium and low dosage composition capsule drug combination significantly strengthen (p＜0.05) to the inhibitory action of rat liver cancer H22.
(2) to the Attenuation of chemotherapy:
1. compare with the blank group, the independent medication of cyclophosphamide all significantly reduces (p＜0.05) to peripheral leukocytes number, the spleen index of mice.
2. compare with the independent medication of cyclophosphamide, cyclophosphamide and Herba Sarcandrae or cyclophosphamide and Herba Hedyotidis Diffusae drug combination all significantly reduce (p＜0.05) to peripheral leukocytes number, the spleen index of mice.
3. compare with the independent medication of cyclophosphamide, cyclophosphamide with in, low dosage composition capsule drug combination all significantly reduces (p＜0.05) to the peripheral leukocytes number of mice, spleen index, cyclophosphamide and high dose composition capsule drug combination are to peripheral leukocytes number, all extremely significantly reductions (p＜0.01) of spleen index of mice.
4. compare with independent Herba Sarcandrae or Herba Hedyotidis Diffusae drug combination with cyclophosphamide, cyclophosphamide and high, medium and low dosage composition capsule drug combination all significantly reduce (p＜0.05) to peripheral leukocytes number, the spleen index of mice.
Above-mentioned experimental result shows, pharmaceutical composition of the present invention can significantly strengthen the curative effect of cyclophosphamide in chemotherapy, and reduce the toxicity of cyclophosphamide, potentiation and the Attenuation of prompting compositions in chemotherapy, Herba Sarcandrae and Herba Hedyotidis Diffusae drug combination have synergistic function in addition, and relevant with dosage, effect is better during high dose.
Experimental example 8 pharmaceutical composition aqueous injection specific safety of the present invention experiments
1, anaphylaxis experiment
Laboratory animal: Cavia porcellus, 18, body weight 280～310g, the male and female dual-purpose is divided at random for three groups of reagent group, negative control and positive controls, 6 of every big groups.
Test sample:
Medicine composition injection of the present invention: self-control, every 5ml contains Herba Sarcandrae extract+Herba Hedyotidis Diffusae extract 300mg+20mg (being equivalent to Herba Sarcandrae 15g, Herba Hedyotidis Diffusae 2g); Get 1 of medicine composition injection of the present invention during use and be dissolved in the 100ml0.9% sodium chloride injection, be made into test liquid.
Negative control: sodium chloride injection, Shandong Huaxin Pharmaceutical Co., Ltd..
Positive control drug: 5% ovalbumin normal saline solution (self-control).
Dosage: priming dose 0.5ml/ only; The sensitization number of times: the next day lumbar injection 1 time, continuous 3 times; Challenge dose 1ml/, intravenous injection.
Experimental technique: the above-mentioned medicinal liquid 0.5ml of lumbar injection next day of giving Cavia porcellus respectively by above-mentioned grouping, inject three times altogether.Then every big group Cavia porcellus is divided into two groups, 3 of every groups again.The first group Cavia porcellus after first time sensitization 14 days, second group carried out antigen in 14 days and attacks every above-mentioned medicinal liquid 1ml of the equal intravenous injection of Cavia porcellus after first time sensitization.Observe and write down the performance of attacking Cavia porcellus in the 15min of back.
Experimental result and conclusion: all do not find anaphylaxis for reagent group and negative control medicine group Cavia porcellus, and the ovalbumin group produces anaphylaxis and dead.Show that medicine composition injection of the present invention does not have obvious sensitization.
2, hemolytic experiment
Laboratory animal: male rabbit, 1, body weight 2.5kg.
Test sample: medicine composition injection of the present invention (self-control, every 5ml contains Herba Sarcandrae extract+Herba Hedyotidis Diffusae extract 300mg+20mg), get 1 of composite injection during use and be dissolved in the 100ml0.9% sodium chloride injection, be made into test liquid.
Experimental technique: it is standby to prepare 2% erythrocyte normal saline suspension.Get 7 of clean tube, number and be arranged on the test tube rack, according to the form below operation in tandem, incubation in the rearmounted 37 ℃ of water-baths of mixing, the result of observed and recorded 15min, 30min, 45min, 1h, 2h, 3h.
Experimental result and conclusion: each pipe of test sample 0.1～0.5ml haemolysis and hemagglutination all do not occur at 15min, 30min, 45min, 1h, 2h, 3h.Show that medicine composition injection of the present invention does not have obvious hemolytic.
3, blood vessel irritation experiment
Laboratory animal: rabbit, body weight 2.1～2.3kg, male and female dual-purpose.
Test sample:
Medicine composition injection of the present invention (self-control, every 5ml contains Herba Sarcandrae extract+Herba Hedyotidis Diffusae extract 300mg+20mg) is got 1 of composite injection and is dissolved in the 100ml0.9% sodium chloride injection during use, be made into test liquid.
Contrast medicine: sodium chloride injection, Shandong Huaxin Pharmaceutical Co., Ltd..
Dosage: quiet dosage of rabbit is 100ml/kg.
Experimental technique: get 6 of healthy rabbits, be divided at random for reagent group and 0.9% sodium chloride injection matched group, 3 every group, dosage is 20ml/kg.Rabbit is put in the fixed case before the administration, instils respectively for reagent and 0.9% sodium chloride injection by above-mentioned grouping in auricular vein, drip speed and be 1ml/min (20/min), the 24h injection site has or not hyperemia, edema, hemorrhage, downright bad after the observation administration.Successive administration 3 days, 24h does pathological examination getting the rabbit ear 10% formalin fixed away from the entad end of injection site 1cm after the last administration.
Experimental result and conclusion: perusal and pathologic finding show that administration group and matched group do not have significant difference, and the blood vessel of agents area and surrounding tissue there is no hyperemia, edema, hemorrhage, downright bad, and pathologic finding is no abnormal.Show that quiet of medicine composition injection vein of the present invention is to the blood vessel nonirritant.
Experimental example 9 medicine composition injection stability experiments of the present invention
Sample: medicine composition injection of the present invention: self-control, every 5ml contains Herba Sarcandrae extract+Herba Hedyotidis Diffusae extract 300mg+20mg (being equivalent to Herba Sarcandrae 15g, Herba Hedyotidis Diffusae 2g).
Investigation project: character, pH value, clarity, related substance, sign content; And at accelerated tests 6 months and the aseptic and pyrogen test of long-term experiment end of term increase.
1, influence factor's experiment
The strong illumination experiment: get test sample, putting illumination is interior the placement 10 days of lighting box of 4500Lx.
High temperature experiment: get test sample, place respectively under 40 ℃, the 60 ℃ conditions and placed 10 days.
Low temperature test: get test sample, in 4 ℃ of refrigerators, placed 10 days.
Above-mentioned experiment was respectively at the 5th, 10 day sampling and measuring.Relatively test every index after the character, and with result and comparison in 0 day.
The result: placed 10 days under the illumination 4500Lx condition, except that related substance slightly raise, all other indexs had no significant change.Placed 10 days under 60 ℃ of conditions of high temperature, outward appearance becomes faint yellow clear liquid, indicates content and descends, and related substance slightly raises.Placed 10 days under 40 ℃ of high temperature, 4 ℃ of conditions of low temperature, every index does not have significant change.
2, accelerated tests
Method: put under the condition of 40 ℃ ± 2 ℃ of temperature, relative humidity 75% ± 5% and placed 6 months.Respectively at taking a sample 1st month, 2 months, 3 months, 6 the end of month, relatively after the outward appearance, test every index at experimental session, with result and comparison in 0 month; And at 6 aseptic and pyrogen tests of increase at the end of month.
Result: placed 6 months under the condition of 40 ℃ ± 2 ℃ of temperature, relative humidity 75% ± 5%, removing related substance slightly increases, and outside sign content slightly descended, all other indexs had no significant change, at 6 the end of month of accelerated tests, pyrogen, sterility test are all up to specification.
3, long-term experiment
Method: put under the condition of 25 ℃ ± 2 ℃ of temperature, relative humidity 60% ± 10% and placed 18 months.Respectively at 3rd month, 6 months, 9 months, 12 months, 18 months, relatively after the outward appearance, test every index, with result and comparison in 0 month; And at 18 aseptic and pyrogen tests of increase at the end of month.
The result: placed under the condition of 25 ℃ ± 2 ℃ of temperature, relative humidity 60% ± 10% 18 months, every index has no significant change, and at 18 the end of month of long-term experiment, pyrogen, sterility test are all up to specification.
Conclusion: reached a conclusion by above-mentioned investigation result, in every experiment, medicine composition injection of the present invention is more stable.
[specific embodiment]
The specific embodiment of form is described in further detail foregoing of the present invention by the following examples.But this should be interpreted as that the scope of the above-mentioned theme of the present invention only limits to following embodiment.All technology that realizes based on foregoing of the present invention all belong to scope of the present invention.The adjuvant of each dosage form can be replaced with acceptable accessories in following examples, perhaps reduces, increases.
The preparation of embodiment 1 Herba Sarcandrae extract
Preparation method:
Get Herba Sarcandrae, decoct with water secondary, each 2 hours, add 10 times of amounts of water, collecting decoction filters at every turn, it is 1.33 (70 ℃) that filtrate is concentrated into relative density, adds the ethanol precipitation secondary, makes for the first time that to contain the alcohol amount be 70%, containing for the second time the alcohol amount is 80%, and each cold preservation 48 hours filters, filtrate recycling ethanol also is concentrated into every 1ml and contains crude drug 10g, adds the egg protein solution of an amount of new preparation, stirs, make precipitation, cold preservation 48 hours filters, filtrate is boiled, and excessive egg protein is solidified, and filters, filtrate adds ethanol, make that to contain amount of alcohol be 75%, place precipitation, filter, filtrate recycling ethanol is not to there being the alcohol flavor, and spray drying promptly gets Herba Sarcandrae extract.
Prepare 4 batches altogether, every crowd of 50kg, yield and assay see Table 8.
Differentiate:
(1) get this product 50mg, put in the test tube, add zinc powder and reach 1 of 0.1% ammonium chloride solution on a small quantity, low baking temperature is heated to dried.With the filter paper of the benzole soln moistening of 5% paradime thylaminobenzaldehyde-20% trichloroacetic acid, continue the low baking temperature heating on the test tube flap, filter paper shows pink or purple.
(2) get this product 50mg, add ethanol 0.5ml, put slight fever in the water-bath, stir, a little is put on filter paper to get supernatant, and drying is observed down at ultra-violet lamp (365nm), shows the light blue green fluorescence.With ammonia smoked after, the displaing yellow speckle, fluorescence strengthens.
The isofraxidin assay:
High performance liquid chromatography
Chromatographic condition and system suitability test: with octadecylsilane chemically bonded silica is filler; Acetonitrile-0.1% phosphoric acid solution (20: 80) is a mobile phase; The detection wavelength is 344nm.Number of theoretical plate calculates by the isofraxidin peak should be not less than 2000.
The preparation of reference substance solution: dry 24 hours the isofraxidin reference substance of phosphorus pentoxide of learning from else's experience is an amount of, and accurate the title decides, and adds methanol and makes the solution that every 1ml contains 4 μ g, promptly.
The preparation of need testing solution: get Herba Sarcandrae extract 50mg, the accurate title, decide, and the accurate methanol 25ml that adds claims to decide weight, supersound process (power 300W, frequency 25kHz) 40 minutes claims to decide weight again, supplies with methanol to subtract weight loss, shake up, filter, get subsequent filtrate, promptly.
Algoscopy: accurate respectively reference substance solution and each 20 μ l of need testing solution of drawing, inject chromatograph of liquid, measure, promptly.
The fumaric acid assay:
According to high performance liquid chromatography (appendix VID of 2005 editions pharmacopeia).
The system suitability test: with octadecylsilane chemically bonded silica is filler, and 0.16mol/L potassium dihydrogen phosphate (regulating pH value with phosphoric acid is 2.80) is mobile phase, and the detection wavelength is 210nm; Number of theoretical plate is pressed fumaric acid and is calculated, and should be not less than 5000.
The preparation of reference substance solution: precision takes by weighing the fumaric acid reference substance 10mg that is dried to constant weight through 105 ℃, put in the 25ml measuring bottle, with water dissolution and be diluted to scale, shake up, the accurate 2ml that draws puts in the 100ml measuring bottle, is diluted with water to scale, shake up, promptly get (containing fumaric acid 8 μ g among every 1ml).
The preparation of need testing solution: precision takes by weighing this product 50mg, puts in the 25ml measuring bottle, and thin up shakes up to scale, promptly.
Algoscopy: accurate reference substance solution and each 5～10 μ l of need testing solution of drawing, inject chromatograph of liquid, measure, promptly.
4 batches of Herba Sarcandrae extract yield of table 8 and assay
Used Herba Sarcandrae extract in following examples is in the present embodiment and prepares.
The preparation of embodiment 2 Herba Hedyotidis Diffusae extracts
Preparation method:
Get Herba Hedyotidis Diffusae, be ground into coarse powder,, make solvent with 80% ethanol according to the percolation under fluid extract of 2005 editions pharmacopeia and the extractum item, flooded 24 hours, percolation slowly, the liquid of filtering are evaporated to does not have the alcohol flavor, and thin up becomes every 1ml to be equivalent to the amount of 1g crude drug, cold preservation, left standstill 12 hours, and filtered, filtrate adds ethanol and carries out three subgradient precipitate with ethanol, make for the first time the alcohol amount 60% that contains, make for the second time to contain alcohol amount 70%, make the alcohol amount 80% that contains for the third time, each all cold preservation 24 hours, filter, filtrate decompression is concentrated into relative density 1.10～1.15, spray drying, promptly.
Prepare 4 batches altogether, every crowd of 10kg, yield and assay see Table 9.
Assay:
The preparation of reference substance solution: precision takes by weighing at the control substance of Rutin 10mg of 120 ℃ of drying under reduced pressure to constant weight, puts in the 50ml measuring bottle, adds an amount of 70% ethanol, put that slight fever makes dissolving in the water-bath, put coldly, add 70% ethanol to scale, shake up, promptly get (containing anhydrous rutin 0.2mg among every 1ml).
The preparation of standard curve: precision is measured reference substance solution 0.0,1.0,2.0,3.0,4.0,5.0 and 6.0ml, put respectively in the 25ml measuring bottle, respectively add 70% ethanol to 6ml, add 5% sodium nitrite solution 1ml, shake up, placed 6 minutes, add 10% aluminum nitrate solution 1ml, shake up, placed 6 minutes, hydro-oxidation sodium test solution 10ml adds ethanol again to scale, shake up, placed 15 minutes, and, measured trap at the wavelength place of 507nm according to spectrophotography (appendix VA of 2005 editions pharmacopeia), with the trap is that vertical coordinate, concentration are abscissa, the drawing standard song.
Algoscopy: it is an amount of that precision is measured this product, is added on the polyamide column (50 orders, the 2g that have handled well, internal diameter 12～15mm, wet method dress post) on, use the 50ml water elution, discard eluent, use 70% ethanol elution, collect the about 25ml of eluent, put in the 25ml measuring bottle, add 70% ethanol dilution, shake up to scale, precision is measured 5ml respectively, puts first, in two 25ml measuring bottles of second, add 5% sodium nitrite solution 1ml in the first bottle, shake up, placed 6 minutes, add 10% aluminum nitrate solution 1ml, shake up, placed 6 minutes, in first, each hydro-oxidation sodium test solution 10ml in two bottles of the second adds ethanol dilution again to scale, shake up, placing 15 minutes, according to spectrophotography (appendix VA of 2005 editions pharmacopeia), is blank with the second bottle, wavelength place at 507nm measures trap, read the amount of rutin the need testing solution from standard curve, calculate, promptly.
The yield of 4 batches of extracts and assay data see the following form.
4 batches of Herba Hedyotidis Diffusae extract yield of table 9 and assay
Used Herba Hedyotidis Diffusae extract in following examples is in the present embodiment and prepares.
The preparation of embodiment 3 pharmaceutical composition aqueous injection of the present invention
Prescription one:
Prescription two:
Prescription three:
Preparation technology:
1) carries and handle the previous day such as pipeline that dosing uses and container etc., face with the fresh water for injection flushing of preceding reuse.
2) get the water for injection of dosing amount 80%, add the dissolving of Tween-80 agitating heating, add the Herba Sarcandrae extract and the Herba Hedyotidis Diffusae extract of recipe quantity then, the heated and stirred dissolving fully.
3) benefit adds to the full amount of water for injection.
4) needle-use activated carbon of adding dosing amount 0.1%, heated and stirred 15 minutes.
5) through sand filtration rod filtering decarbonization.Measure the also pH value of regulator solution.
6) through the microporous filter membrane fine straining of 0.45 μ m.
7) clarity of inspection solution, the semi-finished product chemical examination.
8) with the solution sealing by fusing in glass ampule.
9) 100 ℃ of flowing steam sterilizations are 30 minutes.
10) while hot sample being put into 0.01% methylene blue solution hunts leak.
11) lamp inspection, finished product is examined entirely, the packing warehouse-in.
The preparation of embodiment 4 pharmaceutical composition injectable powder of the present invention
Prescription one:
Prescription two:
Prescription three:
Prescription four:
Preparation technology:
1) vessel of at first dosing being used and antibiotic glass bottle, plug etc. carry out aseptic process.
2) take by weighing supplementary material according to recipe quantity.
3) get the sterile water for injection of dosing amount 80%, add the dissolving of Tween-80 agitating heating, then Herba Sarcandrae extract and Herba Hedyotidis Diffusae extract are added the heated and stirred dissolving fully.Add the dissolving of mannitol heated and stirred more fully, add sterile water for injection to full dose.
4) needle-use activated carbon of adding dosing amount 0.1%, heated and stirred 15 minutes.
5) through sand filtration rod filtering decarbonization.Measure the also pH value of regulator solution.
6) through the microporous filter membrane fine straining of 0.22 μ m.
7) clarity of inspection solution, the semi-finished product chemical examination.
8) be sub-packed in the antibiotic glass bottle half tamponade.Sample is put into the freeze dryer lyophilization.Pre-freeze-45 ℃ 5 hours, low-temperature vacuum drying-45 ℃～0 ℃ 20 hours was warming up to 25 ℃ of vacuum dryings 3 hours then.
9) lyophilizing finishes, and lid is rolled in tamponade.
10) finished product is examined entirely, the packing warehouse-in.
The preparation of embodiment 5 pharmaceutical composition sodium chloride transfusions of the present invention
Prescription one:
Prescription two:
Prescription three:
Preparation technology:
1) handles the previous day such as pipeline that dosing uses and container etc., face with the fresh water for injection flushing of preceding reuse.
2) water for injection of getting dosing amount 20% adds the dissolving of Tween-80 agitating heating, then Herba Sarcandrae extract and Herba Hedyotidis Diffusae extract is added the heated and stirred dissolving fully.Sodium chloride is complete with the water for injection dissolving of dosing amount 40%.
3) merge two solution, benefit adds to the full amount of water for injection.
4) needle-use activated carbon of adding dosing amount 0.1%, heated and stirred 15 minutes.
5) through sand filtration rod filtering decarbonization.Measure the also pH value of regulator solution.
6) through the microporous filter membrane fine straining of 0.45 μ m.
7) clarity of inspection solution, the semi-finished product chemical examination.
8) fill is in the infusion bottle of 100ml.
9) 115 ℃ of pressure sterilizings are 30 minutes.
10) lamp inspection, finished product is examined entirely, the packing warehouse-in.
The preparation of embodiment 6 pharmaceutical composition glucose infusion liquids of the present invention
Prescription one:
Prescription two:
Prescription three:
Preparation technology:
1) carries and handle the previous day such as pipeline that dosing uses and container etc., face with the fresh water for injection flushing of preceding reuse.
2) water for injection of getting dosing amount 20% adds the dissolving of Tween-80 agitating heating, then Herba Sarcandrae extract and Herba Hedyotidis Diffusae extract is added the heated and stirred dissolving fully.Glucose is complete with the water for injection dissolving of dosing amount 40%.
3) merge two solution, benefit adds to the full amount of water for injection.
4) needle-use activated carbon of adding dosing amount 0.1%, heated and stirred 15 minutes.
5) through sand filtration rod filtering decarbonization.Measure the also pH value of regulator solution.
6) through the microporous filter membrane fine straining of 0.45 μ m.
7) clarity of inspection solution, the semi-finished product chemical examination.
8) fill is in the infusion bottle of 100ml.
9) 115 ℃ of pressure sterilizings are 30 minutes.
10) lamp inspection, finished product is examined entirely, the packing warehouse-in.
The preparation of embodiment 7 pharmaceutical composition tablets of the present invention
Prescription one:
Prescription two:
Preparation technology:
Herba Sarcandrae in the raw material and Herba Hedyotidis Diffusae are made extract with reference to the preparation method among the embodiment 1,2.
1) it is standby Herba Sarcandrae extract and Herba Hedyotidis Diffusae extract to be pulverized 100 mesh sieves.
2) take by weighing supplementary material according to recipe quantity.
3) hypromellose 2% the aqueous solution made soluble in water is standby.
4) with Herba Sarcandrae extract, Herba Hedyotidis Diffusae extract, starch, microcrystalline Cellulose mix homogeneously, adding 2%HPMC aqueous solution is an amount of, stirs, and makes suitable soft material.
5) cross 20 mesh sieve system granules.
6) granule is dried under 60 ℃ condition.
7) dry good granule adds magnesium stearate and carboxymethylstach sodium, crosses 18 mesh sieve granulate, mix homogeneously.
8) sampling, the semi-finished product chemical examination.
9) the sheet weight sheet of determining according to chemical examination.
10) finished product is examined entirely, the packing warehouse-in.
The preparation of embodiment 8 medicament composition capsule agent of the present invention
Prescription one:
Prescription two:
Prescription three:
Preparation technology:
1) it is standby Herba Sarcandrae extract and Herba Hedyotidis Diffusae extract to be pulverized 100 mesh sieves.
2) take by weighing supplementary material according to recipe quantity.
3) hypromellose 2% the aqueous solution made soluble in water is standby.
4) with Herba Sarcandrae extract, Herba Hedyotidis Diffusae extract, starch, microcrystalline Cellulose mix homogeneously, adding 2%HPMC aqueous solution is an amount of, stirs, and makes suitable soft material.
5) cross 20 mesh sieve system granules.
6) granule is dried under 60 ℃ condition.
7) dry good granule adds magnesium stearate, crosses 18 mesh sieve granulate, mix homogeneously.
8) sampling, the semi-finished product chemical examination.
9) loading amount of determining according to chemical examination incapsulates.
10) finished product is examined entirely, the packing warehouse-in.
The preparation of embodiment 9 medicament composition granule agent of the present invention
Prescription one:
Prescription two:
Prescription three:
Preparation technology:
1) it is standby sucrose to be pulverized 100 mesh sieves.It is standby that Herba Sarcandrae extract and Herba Hedyotidis Diffusae extract were pulverized 100 mesh sieves.
2) take by weighing supplementary material according to recipe quantity.
3) the method mix homogeneously that Herba Sarcandrae extract, Herba Hedyotidis Diffusae extract and Icing Sugar are progressively increased with equivalent, adding 2%HPMC50% alcoholic solution is an amount of, stirs, and makes suitable soft material,
4) cross 20 mesh sieve system granules.
5) granule is dried under 60 ℃ condition.
6) dried granule is crossed 18 mesh sieve granulate.
7) sampling, the content of principal agent is determined loading amount in the semi-finished product chemical examination granule.
8) packing, finished product is examined entirely, the packing warehouse-in.
The preparation of embodiment 10 medicinal composition soft capsule agent of the present invention
Prescription one:
Prescription two:
Prescription three:
Preparation technology:
Herba Sarcandrae extract and Herba Hedyotidis Diffusae extract pulverize separately are crossed 100 mesh sieves, standby.With the soybean oil of recipe quantity and soybean phospholipid, Cera Flava heating and melting, mixing is put coldly, adds Herba Sarcandrae extract and Herba Hedyotidis Diffusae extract and grinds well, and is pressed into soft capsule and gets final product.
The preparation of embodiment 11 medicament composition dropping pills agent of the present invention
Prescription one:
Prescription two:
Prescription three:
Preparation technology:
With polyethylene glycol 6000 heating and melting in water-bath, treat to add after whole fusions Herba Sarcandrae extract and Herba Hedyotidis Diffusae extract, stirring and dissolving, 60 mesh sieves filter, and keep 60 ℃ to splash in the liquid paraffin that is chilled to below 10 ℃ and make ball.
The preparation of embodiment 12 drug composition oral liquid agent of the present invention
Prescription one:
Prescription two:
Preparation technology:
Herba Sarcandrae in the raw material and Herba Hedyotidis Diffusae are made extract with reference to the preparation method among the embodiment 1,2.
1) earlier Herba Sarcandrae extract and Herba Hedyotidis Diffusae extract are added in the water of dosing amount 60%, the heated and stirred dissolving fully.
2) sodium benzoate and cyclamate is complete with the water dissolution of dosing amount 20%.
3) merge above-mentioned two solution, mend and add water to full dose.
4) filtering with microporous membrane of mistake 0.8 μ m.
5) semi-finished product chemical examination.
6) fill.Finished product is examined entirely, the packing warehouse-in.
Claims (9)
1, a kind of pharmaceutical composition for the treatment of tumor is characterized in that this pharmaceutical composition made by Herba Sarcandrae and Herba Hedyotidis Diffusae, and the weight proportion of the two is: 1: 0.01～10.
2, pharmaceutical composition according to claim 1 is characterized in that, the weight proportion of Herba Sarcandrae and Herba Hedyotidis Diffusae is: 1:0.02～6.
3, pharmaceutical composition according to claim 2 is characterized in that, the weight proportion of Herba Sarcandrae and Herba Hedyotidis Diffusae is: 1:0.13.
4, according to the described preparation of drug combination method of the arbitrary claim of claim 1～3, it is characterized in that, described Herba Sarcandrae and Herba Hedyotidis Diffusae can be with The suitable solvent respectively or mix through extracting processing and obtain its extract, total extract is made any preparation with the pharmaceutic adjuvant hybrid process again, and the main effective ingredient of gained total extract is organic acid, Coumarins and flavonoid.
5, pharmaceutical composition according to claim 1, it is characterized in that, this medicine can also be made by Herba Sarcandrae extract and Herba Hedyotidis Diffusae extract, the main effective ingredient of described Herba Sarcandrae extract is organic acid and Coumarins, contain isofraxidin and be not less than 0.1%, contain fumaric acid and be not less than 0.02%, the main effective ingredient of described Herba Hedyotidis Diffusae extract is the Herba Hedyotidis Diffusae total flavones, content is not less than 50%, and the weight proportion of Herba Sarcandrae extract and Herba Hedyotidis Diffusae extract is: 1: 0.004～4.
6, pharmaceutical composition according to claim 5 is characterized in that, the weight proportion of Herba Sarcandrae extract and Herba Hedyotidis Diffusae extract is 1: 0.01～0.5.
7, pharmaceutical composition according to claim 6 is characterized in that, the weight proportion of Herba Sarcandrae extract and Herba Hedyotidis Diffusae extract is 1: 0.04～0.2.
According to claim 1～3, the described pharmaceutical composition of 5～7 arbitrary claim, it is characterized in that 8, this pharmaceutical composition can combine with arbitrary acceptable accessories and make clinically any or pharmaceutically acceptable dosage form.
9, pharmaceutical composition according to claim 8 is characterized in that, clinically described or pharmaceutically acceptable dosage form is oral formulations or injection.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 200610142637 CN100482266C (en) | 2005-10-26 | 2006-10-25 | Medical composite prepared by sarcandra and oldenlandia |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN200510104347 | 2005-10-26 | ||
| CN200510104347.1 | 2005-10-26 | ||
| CN 200610142637 CN100482266C (en) | 2005-10-26 | 2006-10-25 | Medical composite prepared by sarcandra and oldenlandia |
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| CN100482266C true CN100482266C (en) | 2009-04-29 |
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| CN106267029A (en) * | 2016-10-12 | 2017-01-04 | 南宁多灵生物科技有限公司 | A kind of Chinese medicine composition treating ovarian cancer |
| CN106309749A (en) * | 2016-10-12 | 2017-01-11 | 南宁多灵生物科技有限公司 | Traditional Chinese medicine for treating cervical cancer |
| CN106421386A (en) * | 2016-10-13 | 2017-02-22 | 南宁多灵生物科技有限公司 | Traditional Chinese medicine for curing esophagus cancer |
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| Title |
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