CN106236757A - A kind of rare ginsenoside compositions comprising rare Protopanaxatriol PPT - Google Patents
A kind of rare ginsenoside compositions comprising rare Protopanaxatriol PPT Download PDFInfo
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- CN106236757A CN106236757A CN201610601092.8A CN201610601092A CN106236757A CN 106236757 A CN106236757 A CN 106236757A CN 201610601092 A CN201610601092 A CN 201610601092A CN 106236757 A CN106236757 A CN 106236757A
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
- A61K31/575—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of three or more carbon atoms, e.g. cholane, cholestane, ergosterol, sitosterol
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- A—HUMAN NECESSITIES
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/194—Carboxylic acids, e.g. valproic acid having two or more carboxyl groups, e.g. succinic, maleic or phthalic acid
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Abstract
The present invention provides one to comprise the rare ginsenoside compositions of rare Protopanaxatriol (PPT).This rare ginsenoside compositions comprises Protopanaxatriol (PPT) and the edible organic binary of C2 C6 or tricarboxylic acid；Wherein, relative to the described Protopanaxatriol (PPT) of 100 weight portions, the described edible organic binary of C2 C6 or the tricarboxylic acid of 0.05～5 weight portions are comprised.This rare ginsenoside compositions has significant anti-tumor activity, and high-efficiency low-toxicity.
Description
Technical field
The present invention relates to biomedicine field, the antitumor that has being specifically related to comprise rare Protopanaxatriol (PPT) is lived
Property, the rare ginsenoside compositions of high-efficiency low-toxicity.
Background technology
Cancer is the sick kind 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, it being combined about based on the most how ginsenoside's one pack system, strengthen its antitumous effect, preparation is efficiently
The antitumor drug of low toxicity, there is not yet any report.
Summary of the invention
It is an object of the invention to provide a kind of based on rare Protopanaxatriol (PPT), high-efficiency low-toxicity, have
The rare ginsenoside compositions of antitumor action.
Additionally, another object of the present invention is to provide above-mentioned rare ginsenoside compositions in preparing antitumor drug
Purposes.
The present inventor finds through further investigation, by by organic with edible C2-C6 for rare Protopanaxatriol (PPT)
Binary or tricarboxylic acid are combined in specific proportions, and the antitumor that can not only significantly improve rare ginsenoside compositions is lived
Property, and its toxicity can be significantly reduced, thus complete the present invention.
That is, the present invention is as follows.
1. having a rare ginsenoside compositions for anti-tumor activity, it comprises:
Protopanaxatriol (PPT) and the organic binary of edible C2-C6 or tricarboxylic acid；
Wherein, relative to the described Protopanaxatriol (PPT) of 100 weight portions, the described edible of 0.05～5 weight portions is comprised
The organic binary of C2-C6 or tricarboxylic acid.
2. according to the rare ginsenoside compositions described in item 1, wherein, the organic binary of edible C2-C6 or ternary carboxylic
Acid is one or more in oxalic acid, malic acid, citric acid, lactic acid, succinic acid, adipic acid and a-ketoglutaric acid.
3. according to the rare ginsenoside compositions described in item 1 or 2, wherein, combine relative to described rare ginsenoside
Thing 100 weight portion, the content of described Protopanaxatriol (PPT) is more than 5 weight portions.
4. the purposes in preparing antitumor drug of the rare ginsenoside compositions according to any one of 1～3.
5. according to the purposes described in item 6, wherein, described antitumor drug is peroral dosage form or injection type.
6. according to the purposes according to any one of item 4 or 5, wherein, described tumor is pulmonary carcinoma, hepatocarcinoma or melanoma.
Invention effect
The rare ginsenoside compositions based on rare Protopanaxatriol (PPT) of the present invention has high-efficiency low-toxicity
Antitumor action.
The detailed description of the invention of invention
Below in conjunction with detailed description of the invention, 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 should be with the definition in this specification
Accurate.
First, in an aspect, the present invention provides a kind of rare ginsenoside compositions (this with anti-tumor activity
The rare ginsenoside compositions of invention), it comprises:
Protopanaxatriol (PPT), and the organic binary of edible C2-C6 or tricarboxylic acid；
Wherein, relative to the described Protopanaxatriol (PPT) of 100 weight portions, the described edible of 0.05～5 weight portions is comprised
The organic binary of C2-C6 or tricarboxylic acid.
In this manual, Protopanaxatriol (PPT) refers to the compound described in following chemical formula 1.
[chemical formula 1]
Above-mentioned Protopanaxatriol (PPT) is known compound, methods known in the art can be used to prepare, example
As Protopanaxatriol (PPT) can be prepared by enzymolysis ginsenoside Re.
In this manual, the organic binary of edible C2-C6 or tricarboxylic acid specifically can list 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 above-mentioned Protopanaxatriol (PPT) and the organic binary of edible C2-C6 or ternary carboxylic
Acid is combined with special ratios, can not only significantly improve the anti-tumor activity of rare ginsenoside compositions, and can
Significantly reduce its toxicity.
Specifically, in the rare ginsenoside compositions of the present invention, relative to the described Protopanaxatriol of 100 weight portions
(PPT), can such as comprise 0.05～5 weight portions, preferably 0.1～4 weight portions, more preferably 0.2～3 weight portions, more preferably 0.5
～2 weight portion the organic binary of described edible C2-C6 or tricarboxylic acid.
Except comprising above-mentioned Protopanaxatriol (PPT) and edible C2-in the rare ginsenoside compositions of the present invention
Beyond the organic binary of C6 or tricarboxylic acid, it is also possible to comprise other compositions, as long as in the effect significantly damaging the present invention.
As other compositions, other ginsenosides, other anti-tumor active ingredient, adjuvants etc. can be listed.Preferably, the present invention
In rare ginsenoside compositions, relative to described rare ginsenoside compositions 100 weight portion, described Protopanaxatriol
(PPT) content is more than 5 weight portions, more than preferably 10 weight portions, more than more preferably 20 weight portions, more preferably 30 weight portions with
On.The content of described Protopanaxatriol (PPT) can measure for example with HPLC method.
For the adjuvant in the rare ginsenoside compositions of the present invention, it is not particularly limited, such as, can use this skill
Art field is generally used for the adjuvant of medicine or health product.
Secondly, in one aspect of the method, the present invention provides the rare ginsenoside compositions of the invention described above to resist in preparation
Purposes in tumour medicine.
Just it has been observed that the rare ginsenoside compositions of the present invention has high-efficiency low-toxicity antitumor action.In " efficiently " side
Face, the antitumous effect of the rare ginsenoside compositions of the present invention is substantially better than and is used alone Protopanaxatriol (PPT)；?
" low toxicity " aspect, the biological safety of the rare ginsenoside compositions of the present invention can match in excellence or beauty even above sodium chloride.
Here, " antitumor " includes killing tumor cell, promoting apoptosis of tumor cells, suppression tumor growth, suppression tumor
Shift, suppress blood capillary proliferation, improve tumor prognosis or prevent tumor recurrence etc..These tumors include such as: the cerebral tumor, head
Adenocarcinoma, oral cancer, salivary-gland carcinoma, Sublingual adenocarcinoma, carcinoma of parotid gland, tumor of nasal cavity, secondary nose under cervical region cancer, neck cancer, carcinoma of palate, upper carcinoma of palate, palate
Chamber cancer, larynx cancer, esophageal carcinoma, pulmonary carcinoma, breast carcinoma, cancer of pancreas (including pancreatic ductal carcinoma), gastric cancer, cancer of bile ducts, carcinoma of small intestine or 12 refer to
Intestinal cancer, colorectal cancer, bladder cancer, renal carcinoma (including renal cell carcinoma), hepatocarcinoma, carcinoma of prostate, uterus carcinoma (include cervical cancer, uterus
Body cancer), ovarian cancer, thyroid carcinoma, pharynx cancer, sarcoma, malignant lymphoma, leukemia, lymphoma, skin carcinoma and melanoma
Deng.
Antitumous effect can be diagnosed by the pathological tissue of the observed result of such as X-ray photograph, CT etc. and biopsy or swollen
The values of tumor markers etc. confirm.
The dosage form of described antitumor drug is not particularly limited, such as, can be peroral dosage form or injection type.Described
Peroral dosage form can be liquid dosage form, it is also possible to be solid dosage forms.
When preparing solid preparation for oral administration, can add in principal agent excipient and the binding agent depended on the needs,
After disintegrating agent, lubricant, coloring agent, correctives etc., conventionally make tablet, coated tablet, granule, granula subtilis,
Powder, capsule etc..
As excipient, can use 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, the coloring agent allowing to add in medicine can be used；As correctives, cocoa powder, Mentholum, fragrance can be used
Acid, Oleum menthae, Borneolum Syntheticum, Cortex cinnamomi japonici powder.It is of course also possible on above-mentioned tablet, granule be coated with sugar-coat, gelatin clothing and other
Necessary coat.
When preparing injection, pH adjusting agent, buffer agent, outstanding auxiliary agent, solubilizing agent, steady can be added as required 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, utilize conventional method to make lyophilization thing.
As outstanding auxiliary agent, such as methylcellulose, Tween 80, hydroxy ethyl cellulose, arabic gum, hyalomitome can be enumerated
Acid sodium, 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..
It addition, as stabilizer, such as sodium sulfite, sodium metasulfite etc. can be enumerated；As preservative, can enumerate such as
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 of raising body.
Additionally, in another aspect, the present invention also provides for the method for the tumor in a kind for the treatment of target, and it includes to described
Object uses the step of the rare ginsenoside compositions of the present invention.
Here, described object can be mammal, such as, can be people, rat, rabbit, sheep, pig, cattle, cat, Canis familiaris L., monkey etc.,
It is preferably people.
The rare ginsenoside compositions of the present invention, can be administered orally or parenteral use.Amount of application is because of symptom degree, patient
Age, sex, body weight, sensitivity differences, application process, Dressing date, administration interval, the character of pharmaceutical preparation, effective ingredient
Kind etc. and different, without particular restriction, but generally adult (body weight 60Kg) every day 1～3000mg, preferably 10～1000mg, more excellent
Selecting 100～500mg, above-mentioned amount of application generally can every bu 1～use for 3 times.Preferably dosage is about 300mg every day.
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 required.
Embodiment 1 ginsenoside's glue PPT capsule
Tablet (10000, PPT content: 50mg/ grain) is made according to following proportioning
Technical process is as follows: by load weighted corn starch, Protopanaxatriol (PPT), citric acid, carboxymethyl cellulose
Element sodium, microcrystalline Cellulose, Pulvis Talci are poured in high-speed mixing granulating machine successively, and operator are according to equipment regulation and post
Rule of operation operates, rotating speed 550rpm, stirs 10min, is allowed to mix homogeneously, is subsequently adding appropriate 90% ethanol, continues
5min is to mix homogeneously in stirring, pelletizes and i.e. obtains wet granular.Granule is poured in container then uniform spreading in dish, thickness 3-5cm,
Putting on truck, each truck is piled, and pushes in heated-air circulation oven, by equipment regulation and dry post operation code,
Temperature is controlled in the range of 50 DEG C～55 DEG C, open steam drainage valve, the condensed water in first venting jet chimney, then close
Closing, open gas outlet valve, open inlet valve, open blower fan, heating i.e. starts, and records temperature simultaneously, when temperature rises to 50 DEG C, and note
Time, it is dried 3h, closes admission valve and blower fan, cooling.The material moisture pelletized controls at 0.5-1.0%.Then
With full-automatic capsule filling machine fill, use 0# capsule, content 400mg/ grain, Protopanaxatriol (PPT) content:
50mg/ grain.
Embodiment 2 Protopanaxatriol (PPT) tablet
Tablet (10000, PPT content: 50mg/ sheet) is made according to following proportioning
Technical process is as follows: by load weighted pregelatinized Starch, Protopanaxatriol (PPT), malic acid, stearic acid
Magnesium, cross-linked pvp, sodium carboxymethyl cellulose and microcrystalline Cellulose are poured in high-speed mixing granulating machine successively, and operator are according to setting
Standby rule of operation and post operation code operate, and rotating speed 450rpm stirs 10min, is allowed to mix homogeneously, is subsequently adding suitable
Measuring 85% ethanol, continuation stirring 5min, to mix homogeneously, pelletizes and i.e. obtains wet granular.Granule is poured in container then uniform spreading exist
In dish, thickness 3-5cm, to put on truck, each truck is piled, and pushes in heated-air circulation oven, by equipment regulation and dry
Dry post operation code, controls in the range of 45 DEG C～50 DEG C by temperature, opens steam drainage valve, in first venting jet chimney
Condensed water, is then shut off, and opens gas outlet valve, opens inlet valve, opens blower fan, and heating i.e. starts, and records temperature simultaneously, works as temperature
When rising to 45 DEG C, beginning of clocking, it is dried 32h, closes admission valve and blower fan, cooling.The material moisture pelletized controls
3%～4%.The most again with full-automatic tablet machine entrance pressure sheet, every net weight 500mg, Protopanaxatriol (PPT) content 50mg/ sheet.
Embodiment 3 Protopanaxatriol (PPT) drop pill
Tablet (10000 balls, PPT content: 5mg/ ball) is made according to following proportioning
Technical process is as follows: keep operation room room temperature 18 DEG C～25 DEG C, relative humidity 20%～40%.Melting material cylinder temperature
Spending 145 DEG C-150 DEG C, after PEG-4000 melts as supernatant liquid, pour Protopanaxatriol (PPT), oxalic acid into, stirring is to entirely
Portion dissolves, and blowing enters accumulator.Accumulator temperature 100 DEG C-110 DEG C, keeps internal fluid temperature 90 DEG C-100 DEG C, and blowing enters to drip
Material cylinder.Tear drop cylinder temperature 100 DEG C-110 DEG C, cooling oil temperature 5 DEG C-10 DEG C, drop pill, board controls ball weight 22-24mg.The element oozed
After ball removing oil, sieve ball, after censorship, prepare coating.Coating operations room temperature 18 DEG C～25 DEG C, relative humidity 20%～40%.By bright
Glue adds purification decocting in water with 1: 5 ratio and dissolves to whole, and mannose adds purification decocting in water with 2.5: 1 ratios and dissolves to whole, and the two mixes
Carbohydrate gum liquid and the magnesium stearate closed are coating material, in efficient atresia seed-coating machine, element ball are wrapped 10-12 layer sugar-coat, finally
With Cera Flava polishing, pick out after sieve ball ball shape uniformly, without adhesion, get product without the pill crushed.Every ball net weight about 25mg, former
Panaxatriol (PPT) content 5mg/ ball.
Embodiment 4 Protopanaxatriol (PPT) spray
Spray (200 bottles, 50mL/ bottle, PPT content 250mg/ bottle) is made according to following proportioning
Technical process is as follows: by adding medical-grade absolute ethanol in reactor, be subsequently adding Protopanaxatriol
(PPT), adipic acid, Borneolum Syntheticum and menthol, chuck is heated to 50 DEG C, rotating speed 100rpm, and closed reactor dissolves 10min.
Finally add ethyl acetate and ethyl n-butyrate. maintains temperature and rotating speed constant, stop stirring after continuing stirring 15min, be cooled to
With binary filling machine inflated with nitrogen fill after room temperature.Net content 20mL/ bottle, Protopanaxatriol (PPT) content 250mg/ bottle.
Embodiment 5 Protopanaxatriol (PPT) ointment
Ointment (1000 pipes, 10g/ manages, and PPT content 100mg/ manages) is made according to following proportioning
Technical process is as follows: by being initially charged glycerol and pentanediol in vacuum emulsification tank, be warming up to 80 DEG C, speed of agitator
For 100rpm, then it is sequentially added into methyl hydroxybenzoate, octadecanol, liquid paraffin and vaseline, adjustment of rotational speed to 300rpm, stirring
After 10min, being cooled to 50 DEG C, after adding Protopanaxatriol (PPT), citric acid continuation stirring 15min, evacuation adjustment of rotational speed is extremely
2500rpm stirring 10min i.e. completes emulsifying, is cooled to room temperature and gets final product fill.Net content 10g/ is managed, and Protopanaxatriol (PPT) contains
Amount 100mg/ pipe.
Embodiment 6 Protopanaxatriol (PPT) powder
Take Protopanaxatriol (PPT) 40kg and citric acid 0.8kg, be ground into fine powder, add magnesium stearate 0.3kg, mixing
Uniformly, it is distributed into powder.
Embodiment 7 Protopanaxatriol (PPT) injection
Take injection Protopanaxatriol (PPT) 1kg and injection malic acid 5g, dissolve with 10L water for injection, filter, press
Conventional lyophilizing technique fill becomes injectable powder.
Embodiment 8PPT and organic acid compositions extend the experiment of S180 survival time of mice
With reference to the open CN104814972A embodiment 7 of Chinese patent, slightly change.
Experiment material: anhydrous citric acid (AR, >=99.5%), purchased from Shanghai Aladdin biochemical technology limited company；
Protopanaxatriol's (PPT) (purity >=95%), laboratory hydrolysis technique is made by oneself；Take above-mentioned anhydrous citric acid and Protopanaxatriol
(PPT), formulated by embodiment 6 method, it is and Protopanaxatriol (PPT) compositions；Cyclophosphamide (CTX), 200mg/
Bottle, Hengrui Medicine Co., Ltd., Jiangsu Prov.'s product.
Laboratory animal and cell line: Kunming mouse, female, body weight 18 ± 2g, real purchased from Xi'an Jiaotong University Medical College
Test animal center.Sarcoma 180 ascit form (S180), purchased from Shanghai Pharmaceutical Inst., Chinese Academy of Sciences.
Method
Tumor kind preserves and passes on: nothing after the aseptic oncocyte that takes of abdominal cavity tumor-bearing mice, sterilized normal saline (NS) dilution
Bacterium operation is inoculated in normal adult mice abdominal cavity, within every 7 days, passes for 1 generation.
Lotus tumor model production method: putting to death the S180 tumor-bearing mice that abdominal cavity is passed on 7 days, sterile working takes ascites.Sterilizing NS
Dilution ascites adjusts oncocyte concentration to 8 × 106Individual/mL, oncocyte mortality rate < 5%.By sterile working's requirement, oncocyte is hanged
Liquid is inoculated in mouse peritoneal, and 0.2mL/ is only.
Abdominal cavity carcinoma cell experiment life cycle: 60 mices, in addition to 10 are served only for Normal group, remaining equal abdominal cavity lotus
Tumor, is randomly divided into 5 groups next day, often group 10.Packet includes abdominal cavity lotus tumor model group；CTX treatment group；Citric acid Protopanaxatriol
(PPT) compositions is low, high dose group；Citric acid group；Protopanaxatriol (PPT) group.Each group all plays gavage in abdominal cavity lotus tumor next day
It is administered, once a day, is administered 0.1mL/10g every time.CTX position intraperitoneal injection, 50mg/kg, it is used in conjunction 7 days；Citric acid protoplast
Ginseng triol (PPT) compositions is low, high dose is respectively 250mg/kg, 1000mg/kg；Protopanaxatriol (PPT) group is 1000mg/
Kg, citric acid group are 50mg/kg, with to dead first 1 day.Observe life cycle and ordinary circumstance.
Statistical procedures: measurement data represents with mean ± standard deviation (x ± s).Use one factor analysis of variance, between group two
Two compare employing q inspection.
Result
Citric acid Protopanaxatriol (PPT) compositions high dose group can significantly extend S180 survival time of mice, and is better than former
Panaxatriol (PPT) group.Citric acid Protopanaxatriol (PPT) compositions low dose group also has prolongation S180 survival time of mice
Trend, CTX group and citric acid group effect are inconspicuous.The results are shown in Table 1.
The impact (n=10, x ± s) on S180 survival time of mice of table 1 citric acid Protopanaxatriol (PPT) compositions
△ with CTX group compares
Embodiment 9 ginsenoside and organic acid compositions tumor-bearing mice subcutaneous to S180 inhibiting tumor assay
With reference to the open CN104814972A embodiment 8 of Chinese patent, slightly change.
Experiment material: anhydrous citric acid (AR, >=99.5%), purchased from Shanghai Aladdin biochemical technology limited company；
Protopanaxatriol's (PPT) (purity >=95%), laboratory biological conversion process is made by oneself；Take above-mentioned citric acid and Protopanaxatriol
(PPT), formulated by example 6 method, it is and Protopanaxatriol (PPT) compositions；Cyclophosphamide (CTX), 200mg/ bottle,
Hengrui Medicine Co., Ltd., Jiangsu Prov.'s product.
Laboratory animal and cell line: Kunming mouse, female, body weight is purchased from Xi'an Jiaotong University Medical College's laboratory animal
The heart.Sarcoma 180 ascit form (S180), purchased from Shanghai Pharmaceutical Inst., Chinese Academy of Sciences.
Method
Tumor kind preserves and passes on: nothing after the aseptic oncocyte that takes of abdominal cavity tumor-bearing mice, sterilized normal saline (NS) dilution
Bacterium operation is inoculated in normal adult mice abdominal cavity, within every 7 days, passes for 1 generation.
Lotus tumor model production method: putting to death the S180 tumor-bearing mice that abdominal cavity is passed on 7 days, sterile working takes ascites.Sterilizing NS
Dilution ascites adjusts oncocyte concentration to 8 × 106/mL, oncocyte mortality rate < 5%.By sterile working's requirement, oncocyte is hanged
Liquid is inoculated in mouse peritoneal, and 0.2mL/ is only.
Laboratory observation to subcutaneous mice with tumor: 80 mices, in addition to 10 are served only for Normal group, remaining the most subcutaneous lotus
Tumor, is randomly divided into 7 groups next day, often group 10.Packet includes subcutaneous lotus tumor model group；CTX treatment group；Compositions group: citric acid
Protopanaxatriol (PPT) compositions basic, normal, high dosage group, Protopanaxatriol's group；Citric acid group.Each group is all in abdominal cavity lotus tumor time
Day plays 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；Lemon
(the basic, normal, high dosage of Protopanaxatriol (PPT) compositions is respectively 250mg/kg, 500mg/kg, 1000mg/kg in lemon acid；Fructus Citri Limoniae
Acid group is 4mg/kg, with to dead first 1 day, within the 12nd day after subcutaneous lotus tumor, processes.Medication process observation ordinary circumstance.Each batch
When animal processes, first weighing, place after death takes tumor, thymus, spleen and weighs, and then converses tumour inhibiting rate, thymus index, spleen
Index；Separately take right hind femur and do bone marrow nucleated cell (BMNC) counting.
Statistical procedures: measurement data represents with mean ± standard deviation (x ± s).Use one factor analysis of variance, between group two
Two compare employing q inspection.
Result
CTX group, citric acid Protopanaxatriol (PPT) compositions basic, normal, high dosage group and Protopanaxatriol's group (PPT) are equal
Can significantly extend S180 mouse growth, citric acid group effect is inconspicuous.Wherein CTX group tumor-inhibiting action is notable；Citric acid protoplast joins
The tumor-inhibiting action of triol (PPT) compositions low dose group, middle and high dosage group and Protopanaxatriol's group is notable, citric acid group effect
Inconspicuous.Than Protopanaxatriol (PPT) group, citric acid Protopanaxatriol (PPT) compositions more can promote that thymus index, spleen refer to
The rise of number.Citric acid group promotes rise effect to the minimizing of the bone marrow nucleated cell caused by lotus tumor without obvious.The results are shown in Table 2
With table 3.As can be seen here, the activity of Protopanaxatriol (PPT) and organic acid compositions is apparently higher than alone Protopanaxatriol (PPT)
Or organic acid.
The table 2 citric acid PPT compositions tumor-inhibiting action (n=10, x ± s) to subcutaneous tumor-bearing mice
* comparing with matched group, △ with CTX group compares.
Table 3 citric acid PPT compositions on the impact of subcutaneous tumor-bearing mice immune organ and bonemarrow nucleated cells number (n=10,
x±s)
* comparing with matched group, △ with CTX group compares.
The tumor suppression that mice B16-BL6z cell spontaneous lung is shifted by embodiment 10 ginsenoside and organic acid compositions is real
Test
Experiment material: DL-malic acid (purity 99%), purchased from lark prestige Science and Technology Ltd.；Protopanaxatriol (PPT)
(purity >=95%), laboratory hydrolysis technique is made by oneself；Take above-mentioned malic acid and Protopanaxatriol (PPT), join by embodiment 7 method
System forms, and is and Protopanaxatriol (PPT) compositions；Paclitaxel, purchased from Guangzhou Ai Chun Pharmaceutical Technology Co., Ltd.
Laboratory animal and cell line: C57BL/6 mice, purchased from Xi'an Jiaotong University Medical College's Experimental Animal Center.B16-
The transfer strain of BL6 mouse melanin tumor cell height, purchased from Shanghai Pharmaceutical Inst., Chinese Academy of Sciences.
Method
Lotus tumor model production method: by B16-BL6 cell 0.25% trypsinization good for growth conditions, centrifugal
Collecting cell, aseptic PBS washs, and is configured to 1 × 10 with physiological saline solution7Individual/mL cell suspension.
Laboratory observation: 120 mices, is divided into normal group；Lotus tumor matched group；Malic acid treatment group；Paclitaxel treatment group；Herba Marsileae Quadrifoliae
Fruit acid Protopanaxatriol (PPT) compositions basic, normal, high dosage group；Protopanaxatriol (PPT) group, totally 8 groups, often group 15.Normally
Outside group, remaining every mouse hind leg palmula subcutaneous vaccination 50 μ L is (containing 5 × 105Individual oncocyte).Each group all plays abdomen in lotus tumor next day
Chamber drug administration by injection, 5 times a week, continuous 5 weeks, is administered 0.1mL/10g every time.Dose of paclitaxel is 10mg/kg；Malic acid protoplast joins
The basic, normal, high dosage of triol (PPT) compositions is respectively 250mg/kg, 500mg/kg, 1000mg/kg；Protopanaxatriol (PPT)
It is respectively 1000mg/kg, 10mg/kg with the dosage of malic acid group.Inoculation tumor liquid after 3 weeks, when tumor body > 10mm3Time, mice is used
Etherization, excises suffering limb under aseptic condition.Putting to death animal after 2 weeks, solution takes lung, weighs, and calculates paragonimus cyst.By lung Bouins
Liquid-solid fixed, under anatomic microscope, count Lung metastases tuberosity number.Mann Withey U-inspection is used to carry out statistical procedures.
Experimental result
Paclitaxel and malic acid Protopanaxatriol (PPT) compositions dosage high, middle mice B16-BL6 cell of forming a team is spontaneous
Lung metastases has the effect of significantly inhibiting, malic acid Protopanaxatriol (PPT) compositions low dose group, malic acid Protopanaxatriol
(PPT) compositions has suppression trend to the transfer of mouse cell spontaneous lung, but there was no significant difference, and the results are shown in Table 4.
The inhibitory action that mice B16-BL6 cell spontaneous lung is shifted by table 4 malic acid Protopanaxatriol (PPT) compositions
Embodiment 11 Protopanaxatriol (PPT) and the acute toxicity testing of organic acid compositions
Laboratory animal: cleaning rank kunming mice 56, difference in Mice Body important guarantee group < 20% (20g～24g),
Male and female half and half, it is ensured that female do not produce, without pregnant.The feeding room to mice, cage tool, drinking bottle etc. is needed to carry out disinfection before raising.Little
Mus is raised in square transparent mouse cage, it is ensured that sufficient drinking-water and food.2d～3d is raised, to adapt to experimental ring before experiment
Border, and observe its normal growth activity and health status.Before being administered, fasting processes--and fasted overnight (can't help water).
Sample:
1:PPT and malic acid 1:0.02 weight ratio are made into compositions
2: sodium chloride
Experimentation: mice is equally divided into 7 groups, 1 group as blank group, 3 groups is sodium chloride administration group, and 3 groups are
PPT and malic acid compositions administration group, carry out gastric infusion according to following table one dosage, add up the animal dead number of eight days,
Result is as shown in the table.
Also, it should be noted can implement and on the premise of the inconspicuous purport running counter to the present invention, in this manual
Combination as the arbitrary technical characteristic described by the composition part of a certain technical scheme or technical characteristic can also be suitable for equally
In other technical scheme；Further, can implement and on the premise of the inconspicuous purport running counter to the present invention, as different technologies scheme
The technical characteristic described by composition part between can also be combined in any way, constitute other technical scheme.This
Invention be also contained in above-mentioned in the case of by combination the technical scheme that obtains, and these technical schemes are equivalent to be documented in
In description.
Describe the present invention above by detailed description of the invention and embodiment, but those skilled in the art should manage
Solving, these are not intended to be defined the scope of the present invention, and the scope of the present invention should be determined by claims.
Industrial applicibility
In accordance with the invention it is possible to provide the rare ginsenoside compositions of a kind of high-efficiency low-toxicity.
Claims (6)
1. having a rare ginsenoside compositions for anti-tumor activity, it comprises:
Protopanaxatriol (PPT) and the organic binary of edible C2-C6 or tricarboxylic acid；
Wherein, relative to the described Protopanaxatriol (PPT) of 100 weight portions, the described edible of 0.05～5 weight portions is comprised
The organic binary of C2-C6 or tricarboxylic acid.
Rare ginsenoside compositions the most according to claim 1, wherein, the organic binary of edible C2-C6 or ternary
Carboxylic acid is one or more in oxalic acid, malic acid, citric acid, lactic acid, succinic acid, adipic acid and a-ketoglutaric acid.
Rare ginsenoside compositions the most according to claim 1 and 2, wherein, relative to described rare ginsenoside group
Compound 100 weight portion, the content of described Protopanaxatriol (PPT) is more than 5 weight portions.
4. the purposes in preparing antitumor drug of the rare ginsenoside compositions according to any one of claims 1 to 3.
Purposes the most according to claim 6, wherein, described antitumor drug is peroral dosage form or injection type.
6. according to the purposes according to any one of claim 4 or 5, wherein, described tumor is pulmonary carcinoma.
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| CN110958873A (en) * | 2017-05-19 | 2020-04-03 | 株式会社爱茉莉太平洋 | Skin whitening composition containing protopanaxatriol |
| WO2021197372A1 (en) * | 2020-03-31 | 2021-10-07 | 陕西巨子生物技术有限公司 | Anti-tumor composition containing rare ginsenosides rk2, ck, and ppt |
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN110958873A (en) * | 2017-05-19 | 2020-04-03 | 株式会社爱茉莉太平洋 | Skin whitening composition containing protopanaxatriol |
| CN110958873B (en) * | 2017-05-19 | 2023-06-09 | 株式会社爱茉莉太平洋 | Composition for skin whitening containing protopanaxatriol |
| WO2021197372A1 (en) * | 2020-03-31 | 2021-10-07 | 陕西巨子生物技术有限公司 | Anti-tumor composition containing rare ginsenosides rk2, ck, and ppt |
| AU2021246790B2 (en) * | 2020-03-31 | 2024-05-02 | Shaanxi Giant Biotechnology Co., Ltd | Anti-tumor composition containing rare ginsenosides Rk2, CK, and PPT |
| AU2021246790B9 (en) * | 2020-03-31 | 2024-05-30 | Shaanxi Giant Biotechnology Co., Ltd | Anti-tumor composition containing rare ginsenosides Rk2, CK, and PPT |
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