CN106420776A - Rare ginsenoside compound containing rare ginsenoside Rk1 - Google Patents

Rare ginsenoside compound containing rare ginsenoside Rk1 Download PDF

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CN106420776A
CN106420776A CN201610615257.7A CN201610615257A CN106420776A CN 106420776 A CN106420776 A CN 106420776A CN 201610615257 A CN201610615257 A CN 201610615257A CN 106420776 A CN106420776 A CN 106420776A
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ginsenoside
acid
compositionss
group
tumor
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段志广
范代娣
马晓轩
黄蓉
范翠英
张婧婧
严建亚
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SHAANXI GIANT BIOGENE TECHNOLOGY Co Ltd
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SHAANXI GIANT BIOGENE TECHNOLOGY Co Ltd
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7028—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages
    • A61K31/7034—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin
    • A61K31/704—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin attached to a condensed carbocyclic ring system, e.g. sennosides, thiocolchicosides, escin, daunorubicin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/12—Carboxylic acids; Salts or anhydrides thereof

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  • Engineering & Computer Science (AREA)
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  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

The invention provides a rare ginsenoside compound containing rare ginsenoside Rk1. The rare ginsenoside compound contains ginsenoside Rk1 and edible C2-C6 organic dicarboxylic or tricarboxylic acid. Relative to 100 parts by weight of ginsenoside Rk1, the compound contains 0.5-5 parts by weight of edible C2-C6 organic dicarboxylic or tricarboxylic acid. The rare ginsenoside compound has remarkable anti-tumor activity and is efficient and low in toxicity.

Description

A kind of rare ginsenoside compositionss comprising rare ginsenoside Rk1
Technical field
The present invention relates to biomedicine field and in particular to comprise rare ginsenoside Rk1 have anti-tumor activity, The rare ginsenoside compositionss of high-efficiency low-toxicity.
Background technology
Cancer is the disease of the second largest threat mankind being only second to cerebrovascular disease.The number of the infected of China's cancer surpasses every year Cross 3,000,000 people, and the sickness rate of pulmonary carcinoma, breast carcinoma, the esophageal carcinoma increases year by year, wherein the sickness rate annual rate of growth of pulmonary carcinoma 26.8%, breast cancer incidence annual rate of growth 6.8%.Since 30 years, the mortality rate of breast carcinoma rises 96%, the death of pulmonary carcinoma Rate surges 465%, and the prevention and control of cancer work of China is very urgent and the situation is tense.
But, with regard to being such as how combined based on ginsenoside's one pack system, strengthen its antitumous effect, preparation is efficiently The antitumor drug of low toxicity, there is not yet any report.
Content of the invention
It is an object of the invention to provide based on a kind of Rk1 by rare ginsenoside, high-efficiency low-toxicity, have anti-swollen The rare ginsenoside compositionss of tumor effect.
Additionally, another object of the present invention is to providing above-mentioned rare ginsenoside compositionss in preparing antitumor drug Purposes.
The present inventor finds through further investigation, by by organic for rare ginsenoside Rk1 and edible C2-C6 binary The anti-tumor activity of rare ginsenoside compositionss or tricarboxylic acid is combined in specific proportions, can not only be significantly improved, And its toxicity can be significantly reduced, thus complete the present invention.
Present invention is as follows：
1. a kind of rare ginsenoside compositionss with anti-tumor activity, it comprises：
Ginsenoside Rk1 and the organic binary of edible C2-C6 or tricarboxylic acid；
Wherein, with respect to the described ginsenoside Rk1 of 100 weight portions, comprise the described edible of 0.05～5 weight portion The organic binary of C2-C6 or tricarboxylic acid.
2. the rare ginsenoside compositionss according to item 1, wherein, the organic binary of edible C2-C6 or ternary carboxylic Acid is selected from one or more of oxalic acid, malic acid, citric acid, lactic acid, succinic acid, adipic acid and a-ketoglutaric acid.
3. the rare ginsenoside compositionss according to item 1 or 2, wherein, with respect to the combination of described rare ginsenoside Thing 100 weight portion, the content of described ginsenoside Rk1 is more than 5 weight portions.
4. purposes in preparing antitumor drug for the rare ginsenoside compositionss any one of 1～3.
5. the purposes according to item 4, wherein, described antitumor drug is peroral dosage form or injection type.
6. the purposes according to any one of item 4 or 5, wherein, described tumor is pulmonary carcinoma, hepatocarcinoma and melanoma.
Invention effect
The rare ginsenoside compositionss based on rare ginsenoside Rk1 of the present invention have the anti-swollen of high-efficiency low-toxicity Tumor acts on.
The specific embodiment of invention
With reference to specific embodiment, the present invention will be described in detail.In the case of conflict free, this specification In scientific terminology there is the implication that those skilled in the art are generally understood that, if any conflict with the definition in this specification should be Accurate.
First, in an aspect, the present invention provides a kind of rare ginsenoside compositionss (this with anti-tumor activity The rare ginsenoside compositionss of invention), it comprises：
Ginsenoside Rk1 and the organic binary of edible C2-C6 or tricarboxylic acid；
Wherein, with respect to the described ginsenoside Rk1 of 100 weight portions, comprise the described edible of 0.05～5 weight portion The organic binary of C2-C6 or tricarboxylic acid.
In this manual, ginsenoside Rk1 refers to the compound described in following chemical formula 1.
【Chemical formula 1】
Above-mentioned ginsenoside Rk1 is known compound, can for example may be used using methods known in the art to prepare To prepare ginsenoside Rk1 by thermal cracking ginsenoside Rb1.
In this manual, the organic binary of edible C2-C6 or tricarboxylic acid specifically can include such as oxalic acid, Herba Marsileae Quadrifoliae Fruit acid, citric acid, lactic acid, succinic acid, adipic acid and a-ketoglutaric acid.
The inventors discovered that, by by organic for above-mentioned ginsenoside Rk1 and edible C2-C6 binary or tricarboxylic acid with Special ratios are combined, and can not only significantly improve the anti-tumor activity of rare ginsenoside compositionss, and can be notable Reduce its toxicity.
Specifically, in the rare ginsenoside compositionss of the present invention, with respect to the described ginsenoside of 100 weight portions Rk1, can for example comprise 0.05～5 weight portion, preferably 0.1～4 weight portion, more preferably 0.2～3 weight portion, more preferably 0.5～ The organic binary of described edible C2-C6 of 2 weight portions or tricarboxylic acid.
Have except comprising above-mentioned ginsenoside Rk1 and edible C2-C6 in the rare ginsenoside compositionss of the present invention Beyond machine binary or tricarboxylic acid, other compositions can also be comprised, as long as in the effect significantly not damaging the present invention.As Other compositions, can include other ginsenosides, other anti-tumor active ingredients, adjuvant etc..Preferably, the present invention's is rare In Panaxsaponin composition, with respect to described rare ginsenoside compositionss 100 weight portion, the content of described ginsenoside Rk1 More than 5 weight portions, more than preferably 10 weight portions, more than more preferably 20 weight portions, more than more preferably 30 weight portions.Described Radix Ginseng The content of saponin Rk1 can measure for example with HPLC method.
Adjuvant can also be comprised in the rare ginsenoside compositionss of the present invention.Rare ginsenoside group for the present invention Adjuvant in compound, is not particularly limited, for example, can be generally used for the adjuvant of medicine or health product using the art.
Secondly, in one aspect of the method, the present invention provides the rare ginsenoside compositionss of the invention described above anti-in preparation Purposes in tumour medicine.
Just it has been observed that the rare ginsenoside compositionss of the present invention have high-efficiency low-toxicity antitumor action.In " efficient " side Face, the antitumous effect of the rare ginsenoside compositionss of the present invention is substantially better than and is used alone ginsenoside Rk1；At " low toxicity " Aspect, the biological safety of the rare ginsenoside compositionss of the present invention can match in excellence or beauty even above sodium chloride.
Here, " antitumor " includes killing tumor cell, promotes apoptosis of tumor cells, suppression tumour growth, suppression tumor Shift, improve tumor prognosis or prevent tumor recurrence etc..These tumors are included for example：The cerebral tumor, incidence cancer, neck cancer, carcinoma of palate, Adenocarcinoma, oral cancer, salivary-gland carcinoma, Sublingual adenocarcinoma, carcinoma of parotid gland, tumor of nasal cavity, paranasal sinus cancer, larynx cancer, esophagus under upper carcinoma of palate, palate Cancer, pulmonary carcinoma, breast carcinoma, cancer of pancreas (inclusion pancreatic ductal carcinoma), gastric cancer, cancer of bile ducts, carcinoma of small intestine or duodenal carcinoma, colorectal cancer, bladder Cancer, renal carcinoma (inclusion renal cell carcinoma), hepatocarcinoma, carcinoma of prostate, uterus carcinoma (including cervical cancer, carcinoma of uterine body), ovarian cancer, first shape Adenocarcinoma, pharynx cancer, sarcoma, malignant lymphoma, leukemia, lymphoma, skin carcinoma and melanoma etc..
Antitumous effect can be by the pathological tissue diagnosis or swollen of the such as observed result of X-ray photograph, CT etc. and biopsy Value of tumor markers etc. confirms.
The dosage form of described antitumor drug is not particularly limited, for example, can be peroral dosage form or injection type.Described Peroral dosage form can be liquid dosage form or solid dosage formss.
When preparing solid preparation for oral administration, can in principal agent add excipient and depend on the needs binding agent, After disintegrating agent, lubricant, coloring agent, correctivess etc., conventionally make tablet, coated tablet, granule, granula subtilises, Powder, capsule etc..
As excipient, can using such as Lactose, corn starch, white sugar, glucose, Sorbitol, crystalline cellulose, two Silicon oxide etc.；As binding agent, such as polyvinyl alcohol, ethyl cellulose, methylcellulose, arabic gum, hydroxyl third can be used Base cellulose, HYDROXY PROPYL METHYLCELLULOSE etc.；As lubricant, such as magnesium stearate, Talcum, silicon dioxide etc. can be used； As coloring agent, can be using the coloring agent allowing interpolation in medicine；As correctivess, cocoa powder, Mentholum, fragrance can be used Acid, Oleum menthae, Borneolum Syntheticum, Cortex cinnamomi japonici powder.It is of course also possible to sugar-coat, gelatin clothing and other are coated on above-mentioned tablet, granule Necessary coat.
When preparing injection, pH adjusting agent, buffer agent, outstanding auxiliary agent, solubilizing agent, steady can be added as needed in principal agent Determine agent, isotonic agent, preservative etc., make vein, subcutaneous, intramuscular injection agent according still further to conventional method.At this time it is also possible to according to Need, make lyophilization thing using conventional method.
As outstanding auxiliary agent, such as methylcellulose, Tween 80, hydroxy ethyl cellulose, arabic gum, Radix astragali tree can be enumerated Rubber powder, sodium carboxymethyl cellulose, polyoxyethylene sorbitol mono laurate salt etc..
As solubilizing agent, such as polyoxyethylene hydrogenated castor oil, Tween 80, nicotiamide, polyoxyethylene can be enumerated Sugar alcohol mono laurate salt, Polyethylene Glycol, Castor Oil Fatty Acid ethyl ester etc..
In addition, as stabilizer, such as sodium sulfite, sodium metasulfite etc. can be enumerated；As preservative, can enumerate for example Methyl parahydroxybenzoate, ethylparaben, sorbic acid, phenol, cresol, chlorocresol etc..
The mechanism of action for described antitumor drug is not particularly limited, and can be suppression tumor cell proliferation, resist and swell Oncocyte transfer, promotion apoptosis of tumor cells, suppression tumor angiogenesis and/or the immunity improving body.
Additionally, in another aspect, the method that the present invention also provides the tumor in a kind for the treatment of target, it is included to described The step that object uses the rare ginsenoside compositionss of the present invention.
Here, described object can be mammal, for example, can be people, rat, rabbit, sheep, pig, cattle, cat, Canis familiaris L., monkey etc., It is preferably people.
The rare ginsenoside compositionss of the present invention, can be administered orally or parenteral administration.Amount of application is because of symptom degree, trouble Person's age, sex, body weight, sensitivity differences, application process, Dressing date, administration interval, the property of pharmaceutical preparation, effectively one-tenth Point species etc. and different, no particular restriction, but generally adult (body weight 60Kg) daily 1～3000mg, preferably 10～1000mg, more Preferably 100～500mg, above-mentioned amount of application generally can often 1～3 administration of bu.Preferably dosage is daily 300mg.
Embodiment
Example given below, is for the ease of understanding the present invention, and limits the right of the present invention never in any form The scope requiring.
Prepared by embodiment 1 ginsenoside's Rk1 capsule
Weigh ginsenoside Rk1 10kg, 0.2kg citric acid, add starch 68.5kg, mix, sieve, water-soluble with ethanol Liquid, as binding agent, makes suitable soft material, and 18 mesh sieves are pelletized, 60 DEG C of oven dryings 5 hours, and 16 mesh sieve granulate add 500g hard Fatty acid magnesium, mixes, prepared capsule.
Prepared by embodiment 2 ginsenoside's Rk1 tablet
Take ginsenoside Rk1 50kg, citric acid 1kg, be ground into fine powder, add Microcrystalline Cellulose 10kg, carboxymethyl starch Sodium 2kg, mix homogeneously, wet granulation, it is dried, plus Pulvis Talci 2kg, magnesium stearate 0.3kg, routinely tablet producing technology system processed Piece agent.
Prepared by embodiment 3 ginsenoside's Rk1 powder
Take ginsenoside Rk1 40kg and citric acid 0.8kg, be ground into fine powder, add magnesium stearate 0.3kg, mixing is all Even, it is distributed into powder.
The preparation of embodiment 4 ginsenoside's Rk1 injection
Take injection ginsenoside Rk1 1kg and pharmaceutical grade citric acid 5g, with the dissolving of 10L water for injection, filter, routinely Lyophilized technique fill becomes injectable powder.
The inhibitory action to tumor cell for the rare ginsenoside compositionss of embodiment 5 present invention
Design with reference to the open CN201510181848.3 embodiment 4 of Chinese patent, slightly change.
Laboratory animal：Kunming mouse, female, body weight 20g ± 2g, purchased from Xi'an Jiaotong University Medical College's laboratory animal The heart.
Cell：B16 melanoma cell (B16melanoma cell) and human liver cancer cell (HepG2) cell are from Shanghai hundred Match Bioisystech Co., Ltd obtains.
Culture medium：Cell culture cultivates (FBS with DMEM liquid；HyClone, Logan, UT, USA), culture fluid adds 10% Hyclone (FBS；HyClone, Logan, UT, USA), 0.03%L- L-Glutamine, 100U/L penicillin, 100mg/L strepto- Element, 5%Na2CO3Adjust pH to 6.8-7.0.
Sample：
Experimental group 1：Ginsenoside Rk1；
Experimental group 2：Ginsenoside Rk1：Citric acid=1:0.005 (weight ratio)；
Experimental group 3：Ginsenoside Rk1：Citric acid=1:0.02 (weight ratio)；
Experimental group 4：Ginsenoside Rk1：Citric acid=1:0.05 (weight ratio)；
Experimental group 5：Citric acid.
Compositionss are dissolved with 20 μ l dimethyl sulfoxide (DMSO), for configuring the DMEM cell culture medium of variable concentrations.Purple China fir alcohol (Paclitaxel) and cisplatin (Cisplatin) are purchased from Sigma Chemical company (St.Louis, MO).
The normal Kunming hamster kidney cell of original cuiture, B16 cell and HepG2 cell are with cell density for 1 × 104/ml It is inoculated in after cultivating 24 hours in 96 orifice plates, common DMEM culture medium is changed to containing final concentration of 0 μ g/ml, 25 μ g/ml, 50 μ The DMEM culture medium of g/ml, 75 μ g/ml, 100 μ g/ml heterogeneity, each concentration sets 3 holes, and uses MTT at 24 hours later Method detects the activity of cell, cell inhibitory activity inhibition concentration IC50(median inhibitory concentration) table Show.Inhibition concentration (IC50) it is drug level when 50% for cytoactive inhibiting rate, computational methods are
IC50=(ACell controls group-ATest sample group)/ACell controls group-ABlank group) × 100%.
Mtt assay：Detect the cytotoxicity of medicine according to the mtt assay that Mosmann sets up.Concrete grammar is：To sucking supernatant Cell hole in add 0.4mg/mL MTT, 0.1mL/ hole, 37 DEG C of 5%CO2Culture 4h, removes supernatant, and every hole adds 0.1mL diformazan Base sulfoxide (DMSO), is incubated 10min, measures absorbance under 570nm for the solution in microplate reader.
The half-inhibition concentration IC50 (μ g/mL) to tumor cell for the table 1
As shown in table 1, experimental group 1～4 all has inhibitory action to B16 and HepG2 cell to experimental result, and to two kinds of tumors The half-inhibition concentration IC of cell50All in below 25 μ g/mL.Individually citric acid group there is no that to tumor cell suppression is made With, but by with citric acid in combination, the inhibiting tumour cells activity of ginsenoside Rk1 significantly increases.And, all experimental grouies pair Normal mouse nephrocyte does not all have toxicity.
Additionally, the citric acid in experimental group is replaced with other organic carboxyl acids by us repeats above-mentioned experiment, find to work as reality When testing the citric acid in group and replacing with oxalic acid, malic acid, lactic acid, succinic acid, adipic acid and a-ketoglutaric acid, all can obtain phase As effect.Specifically, experimental group 1～4 all has inhibitory action, and half to two kinds of tumor cells to B16 and HepG2 cell Number inhibition concentration IC50 is all in below 25 μ g/mL.
Embodiment 6 ginsenoside Rk1 and organic acid composition extend the experiment of S180 survival time of mice
Design with reference to the open CN200910197807.8 embodiment 7 of Chinese patent, slightly change.
Materials and methods
Experiment material：Anhydrous citric acid (AR, >=99.5%), purchased from Shanghai Aladdin biochemical technology limited company； Ginsenoside Rk1 (purity >=98%), laboratory thermal cracking process is made by oneself；Take above-mentioned anhydrous citric acid and ginsenoside Rk1, It is formulated by embodiment 3 method, as with ginsenoside's Rk1 compositionss；Cyclophosphamide (CTX), 200mg/ bottle, Jiangsu perseverance is auspicious Medical limited company product.
Laboratory animal and cell line：Kunming mouse, female, body weight 20g ± 2g, real purchased from Xi'an Jiaotong University Medical College Test animal center.Sarcoma 180 ascit form (S180), purchased from Shanghai Bioscience Biotechnology Co., Ltd..
Method
Tumor kind preserves and passes on：Take oncocyte from abdominal cavity tumor-bearing mice is aseptic, after sterilized normal saline (NS) dilution no Bacterium operation is inoculated in normal adult mice abdominal cavity, passes for 1 generation within every 7 days.
Lotus knurl model production method：Put to death the S180 tumor-bearing mice that abdominal cavity is passed on 7 days, sterile working takes ascites.Sterilizing NS Dilution ascites adjustment oncocyte concentration is to 8 × 106Individual/mL, oncocyte mortality rate≤5%.By sterile working's requirement by oncocyte , in mouse peritoneal, 0.2mL/ is only for suspension inoculation.
Abdominal cavity carcinoma cell life cycle tests：90 mices, in addition to 15 are served only for Normal group, remaining equal abdominal cavity lotus Tumor, next day is randomly divided into 5 groups, every group 15.Packet includes abdominal cavity lotus knurl model group；CTX treatment group；Citric acid ginsenoside Rk1 compositionss are low, high dose group；Citric acid group；Ginsenoside's Rk1 group.Each group gastric infusion all from abdominal cavity lotus knurl next day, often It is once administered 0.1mL/10g every time.CTX position intraperitoneal injection, 50mg/kg, it is used in conjunction 7 days；Citric acid ginsenoside Rk1 Compositionss are low, high dose is respectively 250mg/kg, 1000mg/kg；Ginsenoside's Rk1 group is 1000mg/kg, citric acid group is 50mg/kg, with to dead first 1 day.Observe life cycle and ordinary circumstance.
Statistical procedures：Measurement data is represented with mean ± standard deviation (x ± s).Using one factor analysis of variance, two between group Two compare using q inspection.
Result
Citric acid ginsenoside's Rk1 compositionss high dose group can significantly extend S180 survival time of mice, and is better than Radix Ginseng soap Glycosides Rk1 group.Citric acid ginsenoside's Rk1 compositionss low dose group also have extend S180 survival time of mice trend, CTX group with Citric acid group, effect is inconspicuous.The results are shown in Table 2.
The impact (n=10, x ± s) to S180 survival time of mice for the table 2 citric acid ginsenoside's Rk1 compositionss
△ is compared with CTX group
Embodiment 7 ginsenoside Rk1 and organic acid composition are to S180 subcutaneous tumor-bearing mice inhibiting tumor assay
Design with reference to the open CN200910197807.8 embodiment 8 of Chinese patent, slightly change.
Materials and methods
Experiment material：Anhydrous citric acid (AR, >=99.5%), purchased from Shanghai Aladdin biochemical technology limited company； Ginsenoside Rk1 (purity >=95%), laboratory is made by oneself；Take above-mentioned citric acid and ginsenoside Rk1, join by embodiment 3 method System forms, as with ginsenoside's Rk1 compositionss；Cyclophosphamide (CTX), 200mg/ bottle, the permanent auspicious medicine limited public affairs of share in Jiangsu Department's product.
Laboratory animal and cell line：Kunming mouse, female, body weight 20g ± 2g, real purchased from Xi'an Jiaotong University Medical College Test animal center.Sarcoma 180 ascit form (S180), purchased from Shanghai Bioscience Biotechnology Co., Ltd..
Method
Tumor kind preserves and passes on：Take oncocyte from abdominal cavity tumor-bearing mice is aseptic, after sterilized normal saline (NS) dilution no Bacterium operation is inoculated in normal adult mice abdominal cavity, passes for 1 generation within every 7 days.
Lotus knurl model production method：Put to death the S180 tumor-bearing mice that abdominal cavity is passed on 7 days, sterile working takes ascites.Sterilizing NS Dilution ascites adjustment oncocyte concentration is to 8 × 106Individual/mL, oncocyte mortality rate≤5%.By sterile working's requirement by oncocyte , in mouse peritoneal, 0.2mL/ is only for suspension inoculation.
Laboratory observation to subcutaneous mice with tumor：120 mices, in addition to 15 are served only for Normal group, remaining all subcutaneous lotus Tumor, next day is randomly divided into 7 groups, every group 15.Packet includes subcutaneous lotus knurl model group；CTX treatment group；Compositionss group：Citric acid The basic, normal, high dosage group of ginsenoside's Rk1 compositionss, Protopanaxatriol's group；Citric acid group.Each group is all from abdominal cavity lotus knurl next day Gastric infusion, once a day, is administered 0.1mL/10g every time.CTX position intraperitoneal injection, 30mg/kg, it is used in conjunction 7 days；Citric acid (the basic, normal, high dosage of ginsenoside's Rk1 compositionss is respectively 250mg/kg, 500mg/kg, 1000mg/kg；Citric acid group is 30mg/kg, with to dead first 1 day, processing for the 12nd day after subcutaneous lotus knurl.Medication process observation ordinary circumstance.Each batch animal During process, first weigh, place after death takes tumor, thymus, spleen and weighs, so converse tumour inhibiting rate, thymus index, spleen refer to Number；Separately take right hind femur to do bone marrow nucleated cell (BMNC) to count.
Statistical procedures：Measurement data is represented with mean ± standard deviation (x ± s).Using one factor analysis of variance, two between group Two compare using q inspection.
Result
CTX group, the basic, normal, high dosage group of citric acid ginsenoside's Rk1 compositionss and ginsenoside's Rk1 group all can significantly be prolonged Long S180 mouse growth, the effect of citric acid group is inconspicuous.Wherein CTX group tumor-inhibiting action is notable；Citric acid ginsenoside Rk1 combines The tumor-inhibiting action of the basic, normal, high dosage group of thing and ginsenoside Rk1 is notable, and the effect of citric acid group is inconspicuous.Citric acid ginsenoside Rk1 compositionss more can promote the rise of thymus index, index and spleen index than ginsenoside Rk1 group.Caused by citric acid group is to lotus knurl The minimizing of bone marrow nucleated cell no significantly promotes rise effect.The results are shown in Table 3 and table 4.As can be seen here, ginsenoside Rk1 with The activity of edible organic dibasic acid or ternary acid composition is apparently higher than alone ginsenoside Rk1 or edible organic dibasic acid Or ternary acid.
The tumor-inhibiting action (n=10, x ± s) to subcutaneous tumor-bearing mice for the table 3 citric acid ginsenoside's Rk1 compositionss
* compare with matched group, △ is compared with CTX group.
The shadow to subcutaneous tumor-bearing mice immune organ and bonemarrow nucleated cells number for the table 4 citric acid ginsenoside's Rk1 compositionss Ring (n=10, x ± s)
* compare with matched group, △ is compared with CTX group.
The tumor suppression that embodiment 8 ginsenoside Rk1 and organic acid composition shift to mice B16-BL6z cell spontaneous lung Experiment
Design with reference to the open CN200910197807.8 embodiment 9 of Chinese patent, slightly change.
Materials and methods
Experiment material：Adipic acid (purity 99%), purchased from lark prestige Science and Technology Ltd.；Ginsenoside Rk1 (purity >= 95%), laboratory self-control；Take above-mentioned adipic acid and ginsenoside Rk1, be formulated by embodiment 4 method, as ginsenoside Rk1 compositionss；Paclitaxel, purchased from Guangzhou Ai Chun Pharmaceutical Technology Co., Ltd.
Laboratory animal and cell line：C57BL/6 mice, is provided by Chinese Academy of Sciences's Shanghai Experimental Animal Center.B16-BL6 Mouse melanin tumor cell high transfer strain, purchased from Shanghai Pharmaceutical Inst., Chinese Academy of Sciences.
Method
Lotus knurl model production method：By B16-BL6 cell 0.25% trypsinization good for growth conditions, it is centrifuged Collect cell, aseptic PBS washing, be configured to 1 × 10 with physiological saline solution7Individual/mL cell suspension.
Laboratory observation：120 mices, are divided into normal group；Lotus knurl matched group；Adipic acid treatment group；Paclitaxel treatment group；Oneself The basic, normal, high dosage group of diacid ginsenoside's Rk1 compositionss；Ginsenoside's Rk1 group, totally 8 groups, every group 15.Outside normal group, its Remaining every mouse hind leg palmula subcutaneous vaccination 50 μ L is (containing 5 × 105Individual oncocyte).Each group lumbar injection all from lotus knurl next day is given Medicine, 5 times a week, continuous 5 weeks, is administered 0.1mL/10g every time.Dose of paclitaxel is 10mg/kg；Adipic acid ginsenoside's Rk1 group The basic, normal, high dosage of compound is respectively 250mg/kg, 500mg/kg, 1000mg/kg；Ginsenoside Rk1 and the dosage of adipic acid group It is respectively 1000mg/kg, 10mg/kg.3 weeks after inoculation tumor liquid, as tumor body >=10mm3When, mice is anesthetized with ether, aseptic bar Suffering limb is excised under part.Animal is put to death, solution takes lung, weighs, and calculates paragonimus cyst after 2 weeks.Lung Bouins liquid is fixed, aobvious in dissecting Lung metastases tuberosity number is counted under micro mirror.Statistical procedures are carried out using Mann Withey U- inspection.
Experimental result
Paclitaxel and adipic acid ginsenoside's Rk1 compositionss are high, middle dosage is formed a team, and mice B16-BL6 cell spontaneous lung turns Shifting has the effect of significantly inhibiting, and adipic acid ginsenoside's Rk1 compositionss low dose group, ginsenoside's Rk1 group are to mouse cell certainly The property sent out Lung metastases have suppression trend, but there was no significant difference, the results are shown in Table 5.
The inhibitory action that table 5 adipic acid ginsenoside's Rk1 compositionss shift to mice B16-BL6 cell spontaneous lung
Embodiment 9 ginsenoside Rk1 and the acute toxicity testing of organic acid composition
Laboratory animal：Kunming mice 70, difference in Mice Body important guarantee group<20% (20～24g), male and female half and half, Ensure female do not produce, no pregnant.The feeding room to mice, cage tool, drinking bottle etc. is needed to carry out disinfection before raising.Mouse feeder is in side It is ensured that the drinking-water of abundance and food in the transparent mouse cage of shape.Raise 2～3 days before experiment, to adapt to experimental situation, and observe it Normal growth activity and health status.Before administration, fasting is processed -- and fasted overnight (can't help water).
Sample：
1：Rk1 and citric acid 1:0.02 weight ratio is made into compositionss
2：Sodium chloride
Experimentation：Mice is equally divided into 7 groups, 1 group as blank control group, 3 groups be sodium chloride administration group, 3 groups are Rk1 and citric acid composition administration group, carry out gastric infusion according to table 6 below dosage, count the animal dead number in 7 days, Result is as shown in table 6.
Table 6 ginsenoside Rk1 and the acute toxicity testing result of organic acid composition
Also, it should be noted can implement and the inconspicuous purport running counter to the present invention on the premise of, in this manual Combination as the partly described arbitrary technical characteristic of the composition of a certain technical scheme or technical characteristic equally can also be suitable for In other technical schemes；And, can implement and the inconspicuous purport running counter to the present invention on the premise of, as different technologies scheme The partly described technical characteristic of composition between can also be combined in any way, to constitute other technical schemes.This Invention be also contained in above-mentioned in the case of by technical scheme obtained from combination, and these technical schemes are equivalent to and are documented in this In description.
Describe the present invention above by specific embodiment and embodiment, but those skilled in the art should manage Solution, these are not intended to the scope of the present invention is defined, and the scope of the present invention should be determined by claims.
Industrial applicibility
In accordance with the invention it is possible to provide a kind of rare ginsenoside compositionss of high-efficiency low-toxicity.

Claims (6)

1. a kind of rare ginsenoside compositionss with anti-tumor activity, it comprises：
Ginsenoside Rk1 and the organic binary of edible C2-C6 or tricarboxylic acid；
Wherein, with respect to the described ginsenoside Rk1 of 100 weight portions, comprise the described edible C2- of 0.05～5 weight portion The organic binary of C6 or tricarboxylic acid.
2. rare ginsenoside compositionss according to claim 1, wherein, the organic binary of edible C2-C6 or ternary Carboxylic acid is selected from one or more of oxalic acid, malic acid, citric acid, lactic acid, succinic acid, adipic acid and a-ketoglutaric acid.
3. rare ginsenoside compositionss according to claim 1 and 2, wherein, with respect to described rare ginsenoside group Compound 100 weight portion, the content of described ginsenoside Rk1 is more than 5 weight portions.
4. purposes in preparing antitumor drug for the rare ginsenoside compositionss any one of claims 1 to 3.
5. purposes according to claim 4, wherein, described antitumor drug is peroral dosage form or injection type.
6. the purposes according to any one of claim 4 or 5, wherein, described tumor is pulmonary carcinoma, hepatocarcinoma and melanoma.
CN201610615257.7A 2016-07-29 2016-07-29 Rare ginsenoside compound containing rare ginsenoside Rk1 Pending CN106420776A (en)

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