CN105769891B - Low polarity rare ginsenoside mixture and application thereof - Google Patents
Low polarity rare ginsenoside mixture and application thereof Download PDFInfo
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Abstract
The invention belongs to field of medicaments, be related to a kind of low polarity rare ginsenoside mixture Rk2/Rh3 prepare for treat and/or pre- preventing tumor and/or the drug of cancer in purposes；And its prepare for immunological regulation, improve microcirculation, improve quality of life health products in purposes.Invention further provides the compositions and application thereof for including low polarity rare ginsenoside mixture Rk2/Rh3.Low polarity rare ginsenoside mixture Rk2/Rh3 in the present invention has the antitumor validity of height of wide spectrum, its activity and validity are superior to monomer Rk2, Rh3 of existing Ginsenosides antitumor medicine/health products Rg3, Rh2 and the mixture currently on the market, it can be made for treating and/or preventing the drug of various cancers and/or tumour, and for immunological regulation and/or improves microcirculation and/or improve the health products of quality of life, focus on the application has broad application prospects in the treatment of malignant tumour.
Description
Technical field
The present invention relates to field of medicaments, and in particular to a kind of low polarity rare ginsenoside mixture and application thereof.
Background technology
Cancer is to torture the second-biggest-in-the-world disease of human life, and the death rate is only second to cardiovascular and cerebrovascular disease, is that the mankind are dead
One of main factor died.Organize cancer mechanism of the official International Cancer Research Center (IARC) of subordinate negative by World Health Organization
The latest edition of duty《World's cancer report》Swift and violent proliferation situation will be presented in prediction, global cases of cancer, by 2012 14,000,000
People, fast 19,000,000 people for increasing to 2025,24,000,000 people were up to by 2035 year by year.Report also shows that the whole world was new in 2012
Increasing cases of cancer has nearly half to appear in Asia, and wherein most ranks first in China, the newly-increased cases of cancer height of China.2012
Newly-increased 3,070,000 cancer patients of China simultaneously cause about 2,200,000 people death , Fen Do to account for the 21.9% and 26.8% of global total amount.WHO
Data be slightly below China statistics.2012 annual datas of national tumour Register publication show that China is annual newly-increased
Cases of cancer about 3,500,000, it is therefore dead that there are about 2,500,000 people.
There are mainly three types of patterns for the common method for the treatment of of cancer now：Operation, radiotherapy and drug therapy, and which is selected and is controlled
Treatment method then depends on position, grade malignancy, development degree and the patient body state of tumour.In Three models, operation
Therapy, the invasion of Chang Yinwei cancer cells spreads to adjacent tissue or far-end transfer and effect is limited；The therapy of radiotherapy, then
It is limited to injure caused by other internal normal structures；The therapy of drug, it is pernicious for late period dispersivity and metastatic
Tumour is most basic therapy.In past decades, though the chemotherapy for being conceived to direct killing tumour cell has significantly
Development and progress becomes the backbone of tumor pharmacother, but this treatment mode is poor to the slow solid tumor effect of proliferation, drug
Selectivity is small, toxicity is more and serious defect becomes the important limiting factor in clinical treatment.After operation, radiation and chemotherapy
The 4th kind of pattern later is the biological therapy of tumour, mainly passes through the effect of tumor host defense mechanism or biological agent
The biologically of body itself is adjusted, to suppressing or eliminating tumour；Although biological therapy without too big toxic side effect,
Since technology requires tight, complex process, price is high, and numerous cancer patients and family members are difficult to bear, influence it and controlled in cancer
It popularizes in treatment field.
Since there are the research and development of above-mentioned various limitations, natural antitumor drug to achieve more and more concerns.It is natural anti-
Cancer drug either in inhibition or killing tumor cell, adjustment body's immunity, improvement symptom and feature and mitigates chemicotherapy
In toxic side effect, or in the conditioning after being ill of tumour, all have important function.As a result, natural plants new treatment will become after
The 5th kind of pattern after operation, radiotherapy, chemotherapy and biotherapy.
Araliaceae (araliaceae) Panax (Panax) plant, such as ginseng (P.ginseng), American Ginseng
(P.quenquefolinus), Radix Notoginseng (P.notoginseng), panax japonicus (P.uaponicus), cucurbitaceae genus gynostemma
Gynostemma pentaphylla (Gynostemma oentaphyllum Thrunb Mak) etc. is the rare traditional medicinal plant of China, main
Active ingredient is dammarane type four-ring triterpenoid ginseng saponin series compound.Have now been found that the prototype ginseng in Araliaceae
Saponin(e has more than 60 kinds, R1, Ral, Ra2, Rb1, Rb2, Rb3, Rc, Rd, Re, Rf, Rg1, Rg2, Rh1, F etc. is named as, all by glucoside
Member and sugar composition, are generally dissolved easily in water, curative effect includes mainly：Immunoloregulation function, adjusts digestion machine at improving micro_circulation effect
Can, enhance memory and learning ability, anti-aging, tranquilizing the mind etc., but apparent antitumor activity is not shown.
Low polarity rare ginsenoside content in former panax species is little, exists only in wild ginseng or red ginseng, black
In ginseng and the ginseng and Radix Notoginseng product of processings such as ripe Radix Notoginseng, it is also only ten thousand/it is several, and it is insoluble in water, usually only it is dissolved in ethyl alcohol
Or in the low polar organic solvents such as ethyl acetate, it is referred to as low polarity rare ginsenoside, includes mainly：Rg3、Rh2、Rk1、
Rg5, Rk2, Rh3, Rk3, Rh4 etc..Modern pharmacology research shows that low polarity rare ginsenoside has stronger antitumor work
Property, growth of cancer cells can be inhibited, induce cancer cell-apoptosis, selective depression tumor cell invasion and transfer, and make cancer cell
Before induction is reversed into non-cancerous cells etc. again, therefore low polarity rare ginsenoside has high medical value and application
Scape.
Tung et al. (Chem.Pharm.Bull.58 (8) 1111-1115 (2010)) once reported the rare ginseng of too low polarity
Saponin(e Rk2 or low polarity rare ginsenoside Rh3 have relatively strong in acute human progranulocyte leukemia HL-60 cell lines
Active anticancer；Currently, also there is low polarity rare ginsenoside to be listed as the main component in anticancer drugs or health products,
Such as low polarity rare ginsenoside-Rg3 (" Shenyi capsule ") and low polarity rare ginsenoside-Rh2 (" modern good fortune capsule ").So
And existing low polarity rare ginsenoside monomer, such as above-mentioned several ginsenosides its wide spectrum active anticancer and have
Effect property aspect does not embody absolute advantage yet.
Invention content
The technical problem to be solved in the present invention is to provide a kind of rare people of low polarity of the high anticancer validity with wide spectrum
Join saponin mixture Rk2/Rh3, the present invention provides the purposes of the low polarity rare ginsenoside mixture Rk2/Rh3, originally
Invention further provide include low polarity rare ginsenoside mixture Rk2/Rh3 composition and application thereof.
Low polarity rare ginsenoside mixture Rk2/Rh3 of the present invention is by having the following structure formula
Low polarity rare ginsenoside monomer Rk2 and have following structural
Low polarity rare ginsenoside monomer Rh3 mix, Rk2 and Rh3 belong to isomerism in chemical constitution
Body.
The weight ratio of the low polarity ginsenoside monomer Rk2 and low polarity ginsenoside Rh 3 are 1~9:9~1, preferably
It is 1~5：5~1, further preferably 1~3：3~1.We have found in an experiment：The combination of two kinds of isomers is in drug effect
On produce synergistic effect.
The low polarity rare ginsenoside mixture Rk2/Rh3 a use on the way, show preparation for treating
And/or the purposes in pre- preventing tumor and/or the drug of cancer.
Wherein the tumour and/or cancer is selected from：
Malignant tumour, including but not limited to carcinoma of urinary bladder, breast cancer, colon cancer, kidney, liver cancer, lung cancer (including cellule lung
Cancer, non-small cell lung cancer), head and neck cancer, the cancer of the esophagus, gallbladder cancer, oophoroma, cancer of pancreas, gastric cancer, cervix cancer, thyroid cancer,
Prostate cancer and cutaneum carcinoma (including squamous cell carcinoma)；
It is the hematopoetic tumor of lymphatic system, including but not limited to leukaemia, acute lymphoblastic leukemia, acute thin at lymph
Born of the same parents' leukaemia, B- cell lymphoms, T- cell lymphoms, Huo Qijin lymph cancers, non-Huo Qijin lymph cancers, hairy cell lymphom,
Mantle cell lymphoma, myeloma and Burkett ' sShi lymph cancers；
The hematopoetic tumor of marrow system, including but not limited to acute and chronic myelocytic leukemia, myeloproliferative disorder
Syndrome and promyelocytic leukemia；
The tumour of the interstitial origin cause of formation, including but not limited to fibrosarcoma and rhabdomyosarcoma；
The tumour of maincenter and peripheral nervous system, including but not limited to astrocytoma, at fibroneuroma, neuroglia
Tumor and neurinoma；And
Other tumours, including but not limited to melanoma, seminoma, teratocarcinoma, osteosarcoma, exophytic pigment neck tumor,
Thyroid gland filters capsule cancer and Kaposi's sarcoma.
Another of the low polarity rare ginsenoside mixture Rk2/Rh3 is used on the way, shows preparation for exempting from
Epidemic disease adjust, improve microcirculation, improve quality of life health products in purposes.
The present invention also provides a kind of compositions, including the low polarity rare ginsenoside mixture Rk2/Rh3.
The composition is preferably pharmaceutical preparation, and it includes treatment and/or the low rare ginsengs of polarity of prevention effective dose
Saponin mixture Rk2/Rh3 and optional pharmaceutically acceptable diluent, carrier, excipient, auxiliary material or medium.
The dosage form of the pharmaceutical preparation is any one of peroral dosage form, injection type or Topical application forms.
The peroral dosage form includes but not limited to tablet, pulvis, suspension, emulsion, capsule, granule, sugar coated tablet, medicine
Ball, liquid, spirit, syrup or limonada.
The injection type includes but not limited to aqua, suspension or solution.
The Topical application forms include but not limited to ointment, solid, suspension, aqua, spirit, pulvis, paste, bolt
Agent, aerosol, opoultice, liniment, lotion, enema or emulsion.
One use of the composition on the way, shows preparation for treating and/or the medicine of pre- preventing tumor and/or cancer
Purposes in object.
Wherein the tumour and/or cancer is selected from：
Malignant tumour, including but not limited to carcinoma of urinary bladder, breast cancer, colon cancer, kidney, liver cancer, lung cancer (including cellule lung
Cancer, non-small cell lung cancer), head and neck cancer, the cancer of the esophagus, gallbladder cancer, oophoroma, cancer of pancreas, gastric cancer, cervix cancer, thyroid cancer,
Prostate cancer and cutaneum carcinoma (including squamous cell carcinoma)；
It is the hematopoetic tumor of lymphatic system, including but not limited to leukaemia, acute lymphoblastic leukemia, acute thin at lymph
Born of the same parents' leukaemia, B- cell lymphoms, T- cell lymphoms, Huo Qijin lymph cancers, non-Huo Qijin lymph cancers, hairy cell lymphom,
Mantle cell lymphoma, myeloma and Burkett ' sShi lymph cancers；
The hematopoetic tumor of marrow system, including but not limited to acute and chronic myelocytic leukemia, myeloproliferative disorder
Syndrome and promyelocytic leukemia；
The tumour of the interstitial origin cause of formation, including but not limited to fibrosarcoma and rhabdomyosarcoma；
The tumour of maincenter and peripheral nervous system, including but not limited to astrocytoma, at fibroneuroma, neuroglia
Tumor and neurinoma；And
Other tumours, including but not limited to melanoma, seminoma, teratocarcinoma, osteosarcoma, exophytic pigment neck tumor,
Thyroid gland filters capsule cancer and Kaposi's sarcoma.
The composition is health products, and it includes treatment and/or the low polarity rare ginsenosides of prevention effective dose
Acceptable carrier in mixture Rk2/Rh3 and optional health products.
Another of the composition on the way, show preparation for immunological regulation and/or improve microcirculation and/or
Improve the purposes in the health products of quality of life.
Terminology used in the present invention have it is defined below, unless otherwise described：
The term as used herein " low polarity ", refer to for general ginsenosides, Rg3, Rh2 of content rareness,
Rk2, Rh3 etc. are insoluble in water, are only dissolve in low polar organic solvent.
The term as used herein " composition " mean include comprising specified amount each specified ingredient product, and directly or
Any product generated indirectly from the combination of each specified ingredient of specified amount.The Topical application forms include ointment, solid, hang
Turbid, aqua, spirit, pulvis, paste, suppository, aerosol, opoultice, liniment, lotion, enema or emulsion..Sterile
Under the conditions of by reactive compound and pharmaceutically acceptable carrier and any desired preservative, buffer or propellants.Eye
It is also considered within the scope of the present invention with preparation, eye ointment, powder and solution.
When for above-mentioned treatment or other treatment, a kind of the compounds of this invention for the treatment of and/or prevention effective dose can be with
It applies, or is applied by pharmaceutically acceptable salt, ester or prodrug forms (in the case of in the form of there are these) in a pure form.Or
Person, the compound can be with the pharmaceutical compositions containing the purpose compound Yu one or more pharmaceutically acceptable excipient
Administration.The compounds of this invention of word " treatment and/or prevention effective dose " refer to the reasonable effect suitable for any therapeutic treatment/
Hazard ratio treats the compound of the sufficient amount of obstacle.It is to be understood that total consumption per day of the compounds of this invention and composition must be by
Attending physician makes decision in reliable medical judgment scope.For any specific patient, specific treatment and/or prevention
Effective dose level must be depending on many factors, and the factor includes the severity of treated obstacle and the obstacle；Institute
The activity of the particular compound of use；Used concrete composition；Age of patient, weight, general health, gender and
Diet；Administration time, administration route and the excretion rate of used particular compound；Duration for the treatment of；With used tool
Body compound combination uses or drug used at the same time；And similar factor well known to medical field.For example, the way of this field
It is that the dosage of compound gradually increases dosage, until obtaining since less than obtaining required therapeutic effect and desired level
Required effect.
The present invention also provides comprising optionally with the acceptable diluent of one or more non-toxic pharmaceuticals, carrier, excipient,
The pharmaceutical preparation of auxiliary material or medium the compounds of this invention formulated together.The pharmaceutical preparation can especially particular formulation at
Solid or liquid form is for oral administration, for parental injection or for rectally.
The pharmaceutical composition of the present invention can by oral, rectum, parenteral, pond, in intravaginal, peritonaeum, part is (as logical
Cross powder, ointment or drops), buccal give the mankind and other mammals, or as oral spray or nasal spray
Agent is given.Terms used herein " parenteral " refer to including in intravenous, intramuscular, intraperitoneal, breastbone, subcutaneous and intra-articular injection
With the administering mode of infusion.
On the other hand, the present invention provides the pharmaceutical composition for including present component and physiologically tolerable diluent.
The present invention includes one or more above compounds, with one or more nontoxic physiologically tolerable or acceptable diluents,
Carrier, auxiliary material or medium (they are referred to as diluent herein) are configured to composition together, for parental injection, intranasal
Transmission, in solid or liquid form oral medication, rectum or local administration etc..
The composition for being suitable for parental injection may include physiologically acceptable sterile, aqueous or non-aqueous liquor, dispersion
Agent, suspension or emulsion, and the sterile powders for being reconstructed into Sterile injectable solution or dispersant.It is suitable aqueous or non-aqueous
Carrier, diluent, solvent or medium example include water, ethyl alcohol, polyalcohol (propylene glycol, polyethylene glycol, glycerine etc.), plant
Oily (such as olive oil), injectable organic ester such as ethyl oleate and their suitable mixture.
These compositions can also contain auxiliary material, such as preservative, wetting agent, emulsifier and dispersant.Pass through various antibacteriums
Agent and antifungal agent, such as parabens, anesin, phenol, sorbic acid etc., it can be ensured that prevent the effect of microorganism.
It is also expected to including isotonic agent, such as carbohydrate, sodium chloride etc..By using can postpone absorb substance, such as aluminum monostearate and
Gelatin, the extension that can reach injectable drug form absorb.
Suspending agent, such as ethoxylation i-octadecanol, polyoxyethylene mountain can also be contained in suspension in addition to the active compound
Pears alcohol and polyoxyethylene sorbitan esters, microcrystalline cellulose, inclined aluminium hydroxide, bentonite, agar and bassora gum or this
The mixture etc. of a little substances.
In some cases, to extend the effect of drug, it is expected that slowing down the absorption for subcutaneously or intramuscularly injecting drug.This can lead to
It crosses and is realized using the liquid suspension of the crystal of poorly water-soluble or amorphous substance.In this way, the infiltration rate of drug depends on
Its solution rate, and solution rate may depend on crystal size and crystal form.Alternatively, the delay of the medicament forms of parenteral
Absorption is realized by the way that the drug to be dissolved in or be suspended in oily medium.
Injectable depot formulations form can be by biodegradable polymer such as polylactide-polyglycolide
(polylactide-polyglycolide) microcapsule matrix of drug is formed in prepare.Can according to drug and polymer it
Than the property with used specific polymer, drug releasing rate is controlled.The reality of other biological degradable polymer
Example includes polyorthoester class (poly (orthoesters)) and polyanhydrides (poly (anhydrides)).Injectable depot formulations
Also can by by drug be embedded in can be compatible with bodily tissue liposome or micro emulsion in prepare.
Injectable formulation can for example by with bacteria filter filtering or pass through mix aseptic solid composite form bactericidal agent
It sterilizes, the solid composite can be dissolved or dispersed in sterile water or other sterile injectable mediums before use.
Solid dosage forms for oral administration includes capsule, tablet, pill, powder and granule.In such solid dosage forms
In, reactive compound can be at least one inert pharmaceutically acceptable excipient or carrier such as sodium citrate or Dicalcium Phosphate
And/or following material mixing：A) filler or incremental agent such as starch, lactose, sucrose, glucose, mannitol and silicic acid；B) it glues
Mixture such as carboxymethyl cellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose and gum arabic；C) moisturizer is for example sweet
Oil；D) disintegrant such as agar, calcium carbonate, potato or tapioca, alginic acid, certain silicates and sodium carbonate；E) solution hinders
Stagnant dose such as paraffin；F) absorbsion accelerator such as quaternary ammonium compound；G) wetting agent such as cetanol and glyceryl monostearate；H) adsorbent
Such as kaolin and bentonite and i) lubricant such as talcum powder, calcium stearate, magnesium stearate, solid polyethylene glycol, dodecyl
The mixture of sodium sulphate and they.In the case of capsule, tablet and pill, it also may include buffer in the dosage form.
The solid composite of similar type is using excipient such as lactose and high molecular weight polyethylene glycol, it is also possible to make soft
Filler in capsule and hard capsule.
Tablet, dragee (dragees), capsule, pill and granule solid dosage forms can be with coating and shell material such as
Other clothing materials are prepared together well known to enteric coating material and field of medicine preparations.These solid dosage forms can optionally contain opacifier, and
It, which is formed, can also make it only or preferentially at some position of enteron aisle optionally with delayed mode discharge active component.It can use
The example of embedding composition include polymer substance and wax class.If be suitble to, reactive compound also can with it is one or more on
It states excipient and is made into microencapsulated form.
Liquid dosage form for oral administration includes pharmaceutically acceptable emulsion, solution, suspension, syrup and elixir.
Liquid dosage form is removed also contains inert diluent commonly used in the art, such as water or other solvents containing active ingredient beyond the region of objective existence, increases
Solvent and emulsifier such as ethyl alcohol, isopropanol, ethyl carbonate, ethyl acetate, benzylalcohol, Ergol, propylene glycol, 1,3- fourths two
Alcohol, dimethylformamide, oils (especially cottonseed oil, peanut oil, corn oil, embryo oil, olive oil, castor oil and sesame
Oil), the aliphatic acid of glycerine, tetrahydrofurfuryl alcohol (tetrahydrofurfuryl alcohol), polyethylene glycol and sorbitan
Ester and their mixture.Orally administered composition also may include auxiliary material in addition to comprising inert diluent, such as wetting agent, emulsification and outstanding
Floating agent, sweetener, corrigent and flavouring agent.
It is preferably suppository for the composition of rectum or vagina administration.Suppository can by by the compounds of this invention with it is suitable non-
Irritation excipient or carrier such as cocoa butter, polyethylene glycol or suppository wax mix to prepare, they are solid at room temperature, but
It is then under body temperature liquid, therefore can be melted in rectal cavity or vaginal canal and release reactive compound.
The compounds of this invention can also liposomal form administration.As it is known in the art, liposome usually use phosphatide or its
He is made lipid material.Liposome is formed by the single-layer or multi-layer aquation liquid crystal being scattered in water-bearing media.It is any being capable of shape
At liposome it is nontoxic, be physiologically subjected to and metabolizable lipid can be used.The present composition of liposomal form removes
Outside containing the compounds of this invention, it can also contain stabilizer, preservative, excipient etc..Preferred lipid is natural and synthesis phosphorus
Fat and phosphatidyl choline (lecithin), they can be used individually or together.The method for forming liposome is well known in the art.
The prodrug that the term as used herein " pharmaceutically acceptable prodrug " represents the compounds of this invention, in reliable medicine
It is suitable for being contacted with the tissue of the mankind and lower animal without there is excessive toxicity, stimulation, allergic reaction in determination range
Deng matching with rational effect/Hazard ratio and effective to its intended purpose, also represent the compounds of this invention in the conceived case
Zwitterionic form.The prodrug of the present invention can for example be rapidly converted into the parent of above formula in vivo by hydrolyzing in blood
Compound.
The present invention low polarity rare ginsenoside mixture Rk2/Rh3 have inhibit human tumor cells (17 kinds surveyed it is swollen
Oncocyte) and cell proliferation of human umbilical vein antitumor activity, the experiment proved that because mixture synergistic effect make its wide spectrum
High anti-cancer activity and validity are better than low polarity rare ginsenoside monomer Rg3, Rh2, Rk2 and Rh3, can be made for controlling
The drug of various cancers and/or tumour is treated and/or prevented, and for immunological regulation and/or improves microcirculation and/or improves life
The health products of quality are ordered, focus on the application has broad application prospects in the treatment of malignant tumour.
Specific implementation mode
Unless specifically indicated, term used herein has the general sense in fields of the present invention.
Below with reference to specific embodiment, the present invention will be described, it should be noted that these embodiments are only explanation
Property, and be not considered as limiting the invention.Particular technique or condition are not specified in embodiment, according in the art
Technology or condition described in document are carried out according to product description.Reagents or instruments used without specified manufacturer,
Being can be with conventional products that are commercially available.
1 low polarity rare ginsenoside mixture Rk2/Rh3 of embodiment and preparation method thereof
A kind of low polarity rare ginsenoside mixture Rk2/Rh3 is present embodiments provided, by having the following structure formula
's
Low polarity rare ginsenoside monomer Rk2 and have following structural
Low polarity rare ginsenoside monomer Rh3 with weight ratio 1:3 ratio mixes.
Specific preparation method is as follows：
The low polarity rare ginsenoside monomer Rk2 of 2.59mg are weighed (to buy from the Shanghai bio tech ltd Yuan Ye, production
Product number be YY91303) and the low polarity rare ginsenoside monomer Rh3 of 7.76mg (from the Shanghai bio tech ltd Yuan Ye
Purchase, product identification YY90242), it is uniformly mixed to get to low polarity rare ginsenoside mixture Rk2/Rh3.
2 low polarity rare ginsenoside mixture Rk2/Rh3 of embodiment and preparation method thereof
The present embodiment and embodiment 1 difference lies in, be weigh 8.63mg low polarity rare ginsenoside monomer Rk2 and
The low polarity rare ginsenoside monomer Rh3 of 1.73mg is with weight ratio 5:1 ratio is uniformly mixed, and obtains the low rare ginseng of polarity
Saponin mixture Rk2/Rh3.
3 low polarity rare ginsenoside mixture Rk2/Rh3 of embodiment and preparation method thereof
The present embodiment and embodiment 1 difference lies in, be weigh 1.04mg low polarity rare ginsenoside monomer Rk2 and
The low polarity rare ginsenoside monomer Rh3 of 9.32mg is with weight ratio 1:9 are uniformly mixed, and it is mixed to obtain low polarity rare ginsenoside
Close object Rk2/Rh3.
The application of 4 low polarity rare ginsenoside mixture Rk2/Rh3 of embodiment
Test classification：
The low polarity rare ginsenoside mixture Rk2/Rh3 of different mixing proportion inhibits multiclass tumor cell proliferation in vitro
Experiment
Laboratory sample：
Testing drug：The low polarity rare ginsenoside mixture Rk2/Rh3 that embodiment 1,2,3 is prepared.
Control drug：Low polarity rare ginsenoside monomer Rg3 (is bought, quotient from the Shanghai bio tech ltd Yuan Ye
Product article No. is B21059)；Low polarity rare ginsenoside monomer Rh2 (it is bought from the Shanghai bio tech ltd Yuan Ye,
YY91267)；Low polarity rare ginsenoside monomer Rk2 (is bought, product identification is from the Shanghai bio tech ltd Yuan Ye
YY91303)；Low polarity rare ginsenoside monomer Rh3 (is bought, product identification is from the Shanghai bio tech ltd Yuan Ye
YY90242)。
Experimental procedure：
With 18 kinds of cell lines (including 17 kinds of tumor cell lines and a kind of human umbilical vein endothelial cell line) for experiment cell
System, logarithmic growth phase cell (3x 104/ mL to 2.5x 105/ mL), it is seeded in 96 orifice plates with 100 μ L of every hole, each cell
It is 96 orifice plates；Then with 150 μM of high concentration to 2 μM of low concentration take 7 logarithmic decrease concentration (each concentration set two it is multiple
Hole), it is separately added into testing drug solution and control drug solution (testing drug solution or the preparation of control drug solution：It adopts respectively
0.5% DMSO solution is dissolved in testing drug or control drug) 500nL, after tested/control drug solution effects 72 hours
Afterwards, it uses (Promega；Cat.#G7573) luminescent cell viability examination method finds out every in each cell line
Each concentration of kind drug is the Proliferation Ability percentage of cell to this, and draws dose-effect relationship figure, finally according to curve in figure
Calculate IC50Inhibit percentage (E with highestmax), as shown in Table 1 and Table 2.
Table 1：The low polarity rare ginsenoside mixture Rk2/Rh3 and control drug Rg3, Rh2 of different mixing proportion,
Rk2 and Rh3 inhibits cell-proliferation activity testing result
Table 2：The low polarity rare ginsenoside mixture Rk2/Rh3 and control drug Rg3, Rh2 of different mixing proportion,
Rk2 and Rh3 inhibits cell Proliferation validation checking result
Note:The meaning for the term expression that table 1, table 2 and context occur is as follows：
Rk2/Rh3(1:3) represent the weight ratio of the Rk2 and Rh3 in low polarity rare ginsenoside mixture Rk2/Rh3 as
1：3, i.e., the low polarity rare ginsenoside mixture Rk2/Rh3 that embodiment 1 obtains.
Rk2/Rh3(5:1) represent the weight ratio of the Rk2 and Rh3 in low polarity rare ginsenoside mixture Rk2/Rh3 as
5：1, i.e., the low polarity rare ginsenoside mixture Rk2/Rh3 that embodiment 2 obtains.
Rk2/Rh3(1:9) represent the weight ratio of the Rk2 and Rh3 in low polarity rare ginsenoside mixture Rk2/Rh3 as
1：9, i.e., the low polarity rare ginsenoside mixture Rk2/Rh3 that embodiment 3 obtains.
Use SPSS Statistics software (suppliers：IBM corporation, software version:XL fit 21) it carries
For statistical analysis.Every group is detected in table 1 to table 2 with duplicate measurements analysis of variance (Re peated measure ANOVA)
Whether the difference between average value is presented statistically significant (P<0.05 or P<0.01), then subsequent with Bonferroni T t ests
Every class mean reason of discrepancies is further sought in calibrating.
Analysis result：
(1) table 1 is shown, when the low polarity rare ginsenoside mixture Rk2/Rh3 of different mixing proportion is in 18 cells
Average IC in system50Polarity rare ginsenoside monomer Rg3, Rh2, Rk2 and Rh3 low with control drug is in 18 cell lines respectively
In average IC50When comparing, low polarity rare ginsenoside mixture Rk2/Rh3 (5:1) pole low with all four control drugs
Statistically significant (P is presented in difference between property rare ginsenoside monomer Rg3, Rh2, Rk2 and Rh3<0.05 while P<0.01),
And itself and low polarity rare ginsenoside mixture Rk2/Rh3 (1:3) also there is notable difference (P between<0.05 while P<0.01)；
And low polarity rare ginsenoside mixture Rk2/Rh3 (1:3) with all four control drugs and other two kinds of ratios (5:1
With 1:9) mixture, which is compared, notable difference (P<0.05 while P<0.01)；Finally, low polarity rare ginsenoside mixing
Object Rk2/Rh3 (1:9) polarity rare ginsenoside monomer Rg3, Rh2, Rh3 low with control drug and the rare ginseng of low polarity
Saponin mixture Rk2/Rh3 (1:3) statistically significant (Rk2/Rh3 (1 is presented in difference:9) than Rg3, Rh2, Rk2/Rh3 (1:3)
P<0.05 while P<0.01；Rk2/Rh3(1:9) P than Rh3<0.05).In addition, removing the combination of Rk2 and Rh3 between control drug
Without significant difference (P>0.05) outside, remaining combination has notable difference (P<0.05 while P<0.01).
(2) table 2 is shown, when the low polarity rare ginsenoside mixture Rk2/Rh3 of different mixing proportion is in 18 cells
Average highest in system inhibits percentage polarity rare ginsenoside monomer Rg3, Rh2, Rk2 and Rh3 low with control drug respectively
When average highest in 18 cell line inhibits percentage comparisons, low polarity rare ginsenoside mixture Rk2/Rh3 (5:1)
Statistically significant (Rk2/Rh3 (5 is presented in difference between polarity rare ginsenoside monomer Rg3, Rk2 low with control drug:1) compare
The P of Rg3<0.05 while P<0.01；Rk2/Rh3(5:1) P than Rk2<0.05)；And low polarity rare ginsenoside mixture
Rk2/Rh3(1:3) it removes and low polarity rare ginsenoside mixture Rk2/Rh3 (5:1) outer (P of no significant difference between>0.05),
With remaining four kinds of control drug and low polarity rare ginsenoside mixture Rk2/Rh3 (1:9) the average highest between inhibits
Percentage has notable difference (Rk2/Rh3 (1:3) P than Rg3<0.05 while P<0.01；Rk2/Rh3(1:3) than Rh2, Rk2,
Rh3、Rk2/Rh3(1:9) P<0.05)；Finally, low polarity rare ginsenoside mixture Rk2/Rh3 (1:And control drug 9)
Low polarity rare ginsenoside monomer Rg3 and low polarity rare ginsenoside mixture Rk2/Rh3 (1:3) system is also presented in difference
Meter significantly (Rk2/Rh3 (1:9) P than Rg3<0.05 while P<0.01；Rk2/Rh3(1:9) than Rk2/Rh3 (1:3) P<
0.05).In addition, control drug low polarity rare ginsenoside monomer Rg3 has when being compared respectively with its excess-three kind control drug
Notable difference (P<0.05 while P<0.01)；Without significant difference (P between its excess-three kind control drug>0.05).
Conclusion：
(1) the low polarity rare ginsenoside mixture Rk2/Rh3 of different proportion is in all 18 kinds of surveyed cell lines
Inhibit cell-proliferation activity and validity it is different degrees of higher than similar low polarity rare ginsenoside monomer Rg3, Rh2 and should
Monomer Rk2, Rh3 of low polarity rare ginsenoside mixture show the low polarity rare ginsenoside list of two kinds of isomers
The combination of body Rk2, Rh3 produce synergistic effect in drug effect.
(2) in all tested cell systems, when in low polarity rare ginsenoside mixture Rk2/Rh3 Rk2 and Rh3 with
Weight ratio is 1:When 3 ratio mixing, activity is higher than other two kinds of mixed proportions (5:1 and 1:9), validity is higher than Rk2
With Rh3 with weight ratio for 1:The low polarity rare ginsenoside mixture Rk2/Rh3 of 9 ratio mixing, therefore low polarity is rare
The weight ratio of Rk2 and Rh3 in panaxsaponin mixture Rk2/Rh3 are 1:3 ratio is the rare people of low polarity surveyed at present
The optimal proportion that Rk2 in ginseng saponin mixture Rk2/Rh3 is mixed with Rh3.
(3) in all tested cell systems, low polarity rare ginsenoside mixture Rk2/Rh3 (1:3) in fibrosarcoma
In cell line there is highest to inhibit cell-proliferation activity (IC50=10.41 μM)；Cell-proliferation activity is inhibited to come the cell of next
System is Human umbilical vein endothelial cells (IC50=13.78 μM).
(4) low polarity rare ginsenoside mixture Rk2/Rh3 (1:3) percentage is inhibited to the highest of all tested cell systems
Rate (validity) all very close 100%, it means that it has extensive high anticancer validity.And the low pole of similar control drug
Property rare ginsenoside monomer Rg3 only have to a kind of cell line nearly 100% inhibiting rate；The low rare people of polarity of similar control drug
Though the validity of monomer Rk2, Rh3 of ginseng saponin monomer Rh2 polarity rare ginsenoside mixtures low with this are apparently higher than control
The low polarity rare ginsenoside monomer Rg3 of drug, but it is still below low polarity rare ginsenoside mixture Rk2/Rh3 (1:3)
Validity.
Claims (6)
1. a kind of low polarity rare ginsenoside mixture, which is characterized in that its by low polarity rare ginsenoside monomer Rk2 and
Low polarity rare ginsenoside monomer Rh3 is mixed, the low polarity rare ginsenoside monomer Rk2 and the rare people of low polarity
The weight ratio for joining saponin monomer Rh3 is 1:3.
2. low polarity rare ginsenoside mixture as described in claim 1, which is characterized in that the low rare ginseng of polarity
Saponin monomer Rk2 has the following structure formula：
The low polarity rare ginsenoside monomer Rh3 has the following structure formula：
3. low polarity rare ginsenoside mixture described in any one of claim 1-2 is being prepared for treating and/or pre-
Purposes in preventing tumor and/or the drug of cancer.
4. the low polarity rare ginsenoside mixture described in any one of claim 1-2 is preparing for immunological regulation, is changing
Purposes in the health products of kind microcirculation and/or raising quality of life.
5. a kind of composition, which is characterized in that including any one of the claim 1-2 low polarity rare ginsenoside mixing
Object.
6. composition according to claim 5, which is characterized in that the composition is pharmaceutical preparation, the pharmaceutical preparation
Including the low polarity rare ginsenoside mixture as described in any one of claim 1-2 and pharmaceutically acceptable carrier,
The dosage form of the pharmaceutical preparation is peroral dosage form, injection type or Topical application forms；
The peroral dosage form is tablet, pulvis, suspension, emulsion, capsule, granule, pill, spirit, syrup or lemonade
Agent；
The injection type includes aqua or suspension；
The Topical application forms include ointment, solid, suspension, aqua, spirit, paste, aerosol, opoultice, liniment,
Lotion, enema or emulsion, alternatively,
The composition is health products, and it includes the low polarity rare ginsenoside mixing as described in any one of claim 1-2
Acceptable carrier in object and health products.
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| CN106727638A (en) * | 2016-12-28 | 2017-05-31 | 吉林大学 | Application of the ginsenoside as heparanase inhibitors in anti-tumor medicine is prepared |
| CN108245525A (en) * | 2016-12-28 | 2018-07-06 | 吉林大学 | Ginsenoside inhibits application of the antagonist of albumen -2 in cancer in digestive system medicine is prepared as Protein Phosphatase 2A |
| CN107337704B (en) * | 2017-06-15 | 2019-05-31 | 吉林大学 | A kind of rare ginsenoside Rk2And Rh3Separation method |
| CN110237081A (en) * | 2018-03-08 | 2019-09-17 | 深圳以诺生物制药有限公司 | Low polarity rare ginsenoside mixture Δ (20-21) PPD/ Δ (20-22) PPD and application thereof |
| CN108578702B (en) * | 2018-05-24 | 2022-11-29 | 深圳以诺生物制药有限公司 | Mixture of rare ginsenoside and application thereof |
| KR101966117B1 (en) * | 2018-05-25 | 2019-04-05 | (주)녹십자웰빙 | Composition comprising extract of processed ginseng for stimulating of myogenesis |
| CN109432150A (en) * | 2018-12-27 | 2019-03-08 | 吉林明心堂生物科技有限公司 | A kind of processing method of ginseng tablet |
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| CN101695513A (en) * | 2009-10-28 | 2010-04-21 | 上海永神生物科技有限公司 | Composition with anti-tumor effect and application thereof |
| CN102352402A (en) * | 2011-07-29 | 2012-02-15 | 金凤燮 | Method for preparing red ginseng saponins Rg3 group and Rh2 group mixed saponins |
| CN102973623A (en) * | 2012-12-20 | 2013-03-20 | 刘淑莹 | Separation method of ginseng rare saponins in ginseng fibrils |
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| CN1465694A (en) * | 2002-06-20 | 2004-01-07 | 中国科学院大连化学物理研究所 | Aspergillus niger and method for preparing rare low polarity ginsenoside by alcoholysis of ginsenoside using same |
| CN101695513A (en) * | 2009-10-28 | 2010-04-21 | 上海永神生物科技有限公司 | Composition with anti-tumor effect and application thereof |
| CN102352402A (en) * | 2011-07-29 | 2012-02-15 | 金凤燮 | Method for preparing red ginseng saponins Rg3 group and Rh2 group mixed saponins |
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