CN103463104A - Medicinal composition and its application - Google Patents
Medicinal composition and its application Download PDFInfo
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- CN103463104A CN103463104A CN2013103474857A CN201310347485A CN103463104A CN 103463104 A CN103463104 A CN 103463104A CN 2013103474857 A CN2013103474857 A CN 2013103474857A CN 201310347485 A CN201310347485 A CN 201310347485A CN 103463104 A CN103463104 A CN 103463104A
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Abstract
The invention relates to a medicinal composition. The medicinal composition is characterized in that the medicinal composition contains tanshinone IIA and/or its derivatives, and andrographolide and/or its derivatives. The medicinal composition has substantial synergetic effects in the treatment of the stomach cancer, the breast cancer, the liver cancer and the like, and can improve medicinal curative effects, reduce the dosage and reduce side effects.
Description
Technical field
The present invention relates to a kind of pharmaceutical composition and the application in the medicine of preparation treatment pulmonary carcinoma, cancer of pancreas, colon cancer, hepatocarcinoma, carcinoma of prostate, renal carcinoma, gastric cancer, cerebroma, sarcoma, ovarian cancer or breast carcinoma thereof.
Background technology
Malignant tumor is one of principal disease of current harm humans health.A research report of World Health Organization (WHO) shows, 20 years from now on, new tumor patient number will be increased to 1,500 ten thousand by current annual 1000 ten thousand.The annual number because of malignant tumor death also will increase to 1,000 ten thousand by 6,000,000.According to the health ministry statistics, the nineties in 20th century, China's tumor incidence rose to 1,27/,100,000, and China increases tumor patient 160-170 ten thousand newly every year in recent years, and Estimate of Total Number is in 4,500,000 left and right.
The antitumor drug gone on the market at present is more, and as alkylating agent medicine, antimetabolite, antitumor antibiotics, immunomodulator etc., but most drug is larger due to toxicity, and patient does not tolerate.A large amount of clinical practices prove, malignant tumor can be effectively treated in the traditional Chinese medical science or the combination of Chinese and Western medicine, simplifies the toxic and side effects of chemicotherapy simultaneously.Use the modern medicine means to find the effectively growth of inhibition tumor cell of some bioactive natural products, the effect of cell death inducing is arranged.Use at present numerous antibiotic and antitumor drug or be directed to natural product, or obtaining through structure of modification.Therefore safe bioactive natural product applies to clinically with the treatment cancer, have broad prospects, and is also the new direction of current therapeutic field of tumor development.
Ether or ethanol extraction that TANSHINONES (Tanshinone) is the Radix Salviae Miltiorrhizae root, be the main effective ingredient of Radix Salviae Miltiorrhizae, be divided into the compositions such as Tanshinone I, tanshinone IIA, Tanshinone II B, cryptotanshinone, iso tanshinone I, iso tanshinone IIA, different cryptotanshinone, hydroxyl tanshinone ⅡA by chemical constitution.Tanshinone IIA (TanshinoneIIA wherein, Tan IIA) be the main component of total tanshinone, there is the natural anti-oxidation effect, the clinical cardiovascular pharmacological action shows atherosclerosis, dwindle myocardial infarction area, reduce myocardial oxygen consumption, thrombosis and platelet aggregation are had to inhibitory action, be mainly used at present the treatment of cardiovascular disease and seat skin ulcer.Research in recent years also finds that tanshinone IIA has propagation to kinds of tumor cells and suppresses and cytotoxicity.Flow cytometer detection display tanshinone IIA processed group apoptotic index is apparently higher than matched group.To the research discovery of the anti-rat liver cancer H22 of tanshinone IIA, tanshinone IIA has obvious inhibitory action to rat liver cancer.
Andrographolide system extracts the diterpene ginkgolide obtained in acanthaceous plant Herba Andrographis (Andrographis paniculata (Burm.f) Nees), is one of main effective ingredient of Chinese medicine Herba Andrographis.Modern study shows, andrographolide has the several functions such as antiphlogistic antibacterial, viral infection resisting, anti-cardiovascular disease, antitumor, immunostimulation, hepatic cholagogic.At anti-tumor aspect, andrographolide and derivant thereof have obvious inhibitory action to kinds cancer, have report to show that its anti-breast carcinoma effect is similar to paclitaxel, the similar what Cis of anti-prostate cancer effect platinum, but toxicity is much lower.
But up to the present, about combining in antitumor, use tanshinone IIA and andrographolide and the two synergism in antitumor have not been reported.
Summary of the invention
The object of the present invention is to provide a kind of highly active antineoplastic pharmaceutical compositions and the application in the medicine of all kinds of cancers of preparation treatment thereof.
Pharmaceutical composition of the present invention contains tanshinone IIA and/or its derivant and andrographolide and/or its derivant, preferably contains tanshinone IIA and andrographolide.When using derivant, the preferred sodium tanshinon IIA silate injection of tanshinone II A derivative, the preferred andrographolide sodium bisulfate of andrographolidume derivative, deoxyandrographolide, neoandrographolide, andrographolide anhydrates, but derivant is not limited to this, can also be its pharmaceutically useful salt, hydrate or other derivant.
The structural formula of tanshinone IIA and andrographolide is respectively suc as formula shown in I, II.
I tanshinone IIA II andrographolide
The mol ratio of tanshinone IIA and/or its derivant and andrographolide and/or its derivant is preferably 50:1-1:50, more preferably 10:1-1:10.
Pharmaceutical composition of the present invention can be used for treating all kinds of tumors, and described tumor includes but not limited to pulmonary carcinoma, cancer of pancreas, colon cancer, hepatocarcinoma, carcinoma of prostate, renal carcinoma, gastric cancer, cerebroma, sarcoma, ovarian cancer or breast carcinoma.
Pharmaceutical composition of the present invention can adopt the method for this area routine to make the preparation that is suitable for gastrointestinal administration or parenteral administration, preferably this pharmaceutical composition is made to the preparation of gastrointestinal administration, its dosage form can be conventional tablet, capsule, controlled release or slow releasing preparation.
Tanshinone IIA in pharmaceutical composition of the present invention and/or its derivant can directly be mixed and make preparation with andrographolide and/or its derivant; Or mix and make respectively preparation with corresponding adjuvant, and then pack or combine according to the mode of this area routine respectively; Or, after adjuvant mixes respectively and accordingly, remix and make preparation.The adjuvant that preparation is used can adopt the adjuvant of this area routine, but take, discord pharmaceutical composition of the present invention reacts or the curative effect that do not affect pharmaceutical composition of the present invention is prerequisite.
According to the difference of dosage form and preparation specification, the content of pharmaceutical composition of the present invention in preparation can be adjusted between 1-99wt%, preferably 10-90wt%.In addition, the dosage of pharmaceutical composition of the present invention can suitably change according to the dosage form of administration object, route of administration or medicine, but take, guarantees that this pharmaceutical composition can reach effective blood drug level as prerequisite in mammalian body.
Pharmaceutical composition of the present invention has significant collaborative effectiveness in treatment gastric cancer, breast carcinoma, hepatocarcinoma etc., has improved the curative effect of medicine, has reduced dosage, has reduced the generation of side effect.
The accompanying drawing explanation
Fig. 1 be show two prescriptions with and the figure of variable concentrations to the MCF-7 cell inhibitory effect while share.
Fig. 2 be show two prescriptions with and the figure of variable concentrations to the SMMC7721 cell inhibitory effect while share.
Fig. 3 be show two prescriptions with and the figure of variable concentrations to the BGC823 cell inhibitory effect while share.
In each figure, Andro means andrographolide, and Tan IIA means tanshinone ⅡA.
The specific embodiment
Below in conjunction with embodiment, the invention will be further elaborated, but the present invention is not limited to this, in the situation that do not break away from thought of the present invention and aim, any variation that technical scheme of the present invention is done all should fall in the claims in the present invention book limited range.
Embodiment
Cell: the BGC823(human stomach cancer cell line), the strain of MCF-7(human breast cancer cell), the SMMC-7721(human hepatoma cell strain) be this laboratory and preserve.
Medicine: accurate weighing tanshinone IIA and andrographolide (all purchased from Shifang City open-birth plant material company limited), with dimethyl sulfoxide, dissolve respectively, being made into tanshinone IIA concentration is 10mmol, the stock solution that andrographolide concentration is 200mmol, preserve under-20 ℃, during use, by fresh culture medium, be diluted to suitable concentration.
MTT detects cell proliferation: cell in the DMEM high glucose medium containing 10% hyclone, 100kU/L penicillin, 100mg/L streptomycin, 37 ℃, 5%CO
2condition under cultivate.Cell, with after trypsinization, is counted with blood cell counting plate.Be inoculated in 96 porocyte culture plates (5000/hole of cell inoculum concentration is selected according to cell size and the speed of growth) by every hole 100 μ l volumes, overnight incubation makes cell attachment.The testing sample that adds the variable concentrations gradient is established blank, 5%CO simultaneously
2, 37 ℃ hatch 48 hours.The MTT of preparation 5mg/ml, every hole adds 20 μ l, hatches 4h for 37 ℃.Culture medium in 96 orifice bores is sucked, and then every hole adds 200 μ l dimethyl sulfoxide.Detect extinction (OD) value at 570nm wavelength place by microplate reader.
The calculating of Combination index (CI):
(1) determine the relational expression between dosage (D) and cell survival rate (fu)
Suppression ratio (fa)=1-survival rate (fu)
According to middle efficacious prescriptions formula: fa/fu=(D/Dm)
m, take the logarithm in both sides,
log（fa/fu）=m?logD-m?log?Dm，
If b=m, a=-m logDm, Y=log(fa/fu), X=logD,
Dosage and cell survival rate relational expression are that Y=bX+a(Dm is middle effect dosage).
Can record by experiment certain medicine cell survival rate corresponding to different dosing dosage when individually dosed.Dosage and the above-mentioned Equation for Calculating of cell survival rate data substitution are gone out to Y and X.These group data are carried out to linear fit, calculate corresponding b value, a value, obtain corresponding to the dosage of this medicine and the equation Y=bX+a of suppression ratio relation.
(2) calculate Combination index (CI)
A in aforesaid equation, b value are tried to achieve middle effect dosage (Dm) and m value.
Efficacious prescriptions formula D=Dm (fa/fu) in utilization
1/m, the independent theoretical dosage (D that uses two kinds of medicines while calculating the depression effect that reaches two kinds of drug combinations
single 1, D
single 2).
Calculate Combination index (CI): CI=D by following formula
close 1/ D
single 1+ D
close 2/ D
single 2
(D
close 1and D
close 2be two medicines every kind of medicine dosage separately in compositions while share, for testing the dosage of actual use.）
Embodiment 1
The combination Synergistic of the andrographolide of different proportion and tanshinone ⅡA promotes the experimental result of MCF-7 cell death to see Fig. 1 and table 1.
Table 1 liang prescription with and MCF-7 cell survival rate while share variable concentrations
From the result of Fig. 1 and table 1, can find out, andrographolide and tanshinone ⅡA show obvious synergism simultaneously while acting on MCF-7.When independent use 100 μ M andrographolide or 25 μ M tanshinone ⅡA, the survival rate of cell is about 60%-70%, and both while using simultaneously the survival rate of cell drop to 21.0%; When independent use 200 μ M andrographolide or 50 μ M tanshinone ⅡA, the survival rate of cell is 50% left and right, and both while using simultaneously the survival rate of cell drop to 15.6%.
Drug combination has 3 kinds of results: cooperative effect, antagonistic effect and additive effect.The general Combination index CI that adopts judges concrete effect, and CI value<1 thinks to have cooperative effect, and CI value=1 thinks to have additive effect, the CI value > 1 think to there is antagonistic effect, CI value<0.7 thinks to have significant cooperative effect.From the above results, can find out, during the administration simultaneously of andrographolide and tanshinone ⅡA, the CI value can reach between 0.2-0.4 under doses and proportioning, and the lethal effect that visible andrographolide and tanshinone ⅡA share the MCF-7 cell has synergism preferably.
Below, with table 1 data instance, the computational methods of share index (CI) are described.
Calculate corresponding Y value and X value according to the cell survival rate under andrographolide different dosing dosage, result is as shown in table 2.
Cell survival Relation Parameters under table 2 andrographolide different dosing dosage is calculated
Y, X value are carried out to linear fit and obtain equation Y=1.2256X-2.7842, b=1.2256, a=-2.7842, m=b=0.8055, Dm=10
(a/b)=186.84 μ M.
Deriving thus the theoretical dosage of andrographolide and the relational expression of cell survival rate is:
D
single 1=Dm (fa/fu)
1/m=186.84[(1-fu)/fu)]
1/0.8055
In like manner can obtain the theoretical dosage of tanshinone ⅡA and the relational expression of cell survival rate is:
D
single 2=Dm (fa/fu)
1/m=64.92[(1-fu)/fu)]
1/0.5746
Take and organize 2 as example, cell survival rate fu when 25 μ M andrographolide and 6.25 μ M tanshinone ⅡAs share is 53.6% ± 6.0, D
close 1=25 μ M, D
close 2=6.25 μ M.
By in the relational expression of the above-mentioned theory dosage of fu=53.6 difference substitution andrographolide and tanshinone ⅡA and cell survival rate, can obtain
D
single 1=186.84[(1-fu)/fu)]
1/0.8055=156.21 μ M
D
single 2=64.92[(1-fu)/fu)]
1/0.5746=50.51 μ M
The computing formula of substitution Combination index (CI), can obtain
CI=D
close 1/ D
single 1+ D
close 2/ D
single 2=25/156.21+6.25/50.51=0.28
Embodiment 2
The experimental result that the combination Synergistic of the andrographolide of different proportion and tanshinone ⅡA promotes the SMMC7721 cell death is in Table 3 and Fig. 2.
Table 3 liang prescription with and SMMC7721 cell survival rate while share variable concentrations
From the result of table 3 and Fig. 2, can find out, andrographolide and tanshinone ⅡA show obvious synergism simultaneously while acting on SMMC7721.When independent use 100 μ M andrographolide or 25 μ M tanshinone ⅡA, the survival rate of cell is respectively 71.4% and 85.0%, and both while using simultaneously the survival rate of cell drop to 41.7%; When independent use 200 μ M andrographolide or 50 μ M tanshinone ⅡA, the survival rate of cell is respectively 49.5% and 83.5%, and both while using simultaneously the survival rate of cell drop to 17.6%.In addition, from the CI value, can find out, the lethal effect that andrographolide and tanshinone ⅡA share the SMMC7721 cell has synergism preferably.
Embodiment 3
The experimental result that the combination Synergistic of the andrographolide of different proportion and tanshinone ⅡA promotes the BGC823 cell death is in Table 4 and Fig. 3.
Table 4 liang prescription with and BGC823 cell survival rate while share variable concentrations
From table 4 and Fig. 3, can find out, andrographolide and tanshinone ⅡA show obvious synergism simultaneously while acting on the BGC823 cell.When independent use 200 μ M andrographolide or 50 μ M tanshinone ⅡA, the survival rate of cell is respectively 58.7% and 73.7%, and both while using simultaneously the survival rate of cell drop to 20.2%.When independent use 100 μ M andrographolide or 25 μ M tanshinone ⅡA, the survival rate of cell is respectively 76.2% and 84.8%, and both while using simultaneously the survival rate of cell drop to 39.1%.In addition, from the CI value, can find out, the lethal effect that andrographolide and tanshinone ⅡA share the BGC823 cell has synergism preferably.
Claims (5)
1. a pharmaceutical composition, is characterized in that, described pharmaceutical composition contains tanshinone IIA and/or its derivant and andrographolide and/or its derivant.
2. pharmaceutical composition according to claim 1, it is characterized in that, described tanshinone II A derivative is sodium tanshinon IIA silate injection, and described andrographolidume derivative is andrographolide sodium bisulfate, deoxyandrographolide, neoandrographolide, andrographolide anhydrates.
3. pharmaceutical composition according to claim 1 and 2, is characterized in that, the mol ratio of described tanshinone IIA and/or its derivant and andrographolide and/or its derivant is 50:1-1:50.
4. pharmaceutical composition according to claim 3, is characterized in that, the mol ratio of described tanshinone IIA and/or its derivant and andrographolide and/or its derivant is 10:1-1:10.
5. the application of the described pharmaceutical composition of any one in the medicine of preparation treatment pulmonary carcinoma, cancer of pancreas, colon cancer, hepatocarcinoma, carcinoma of prostate, renal carcinoma, gastric cancer, cerebroma, sarcoma, ovarian cancer or breast carcinoma in claim 1-4.
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| CN113045637A (en) * | 2021-03-30 | 2021-06-29 | 兰州大学 | Anticancer medicine, its preparation method and key protein |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101342254A (en) * | 2007-07-11 | 2009-01-14 | 中国中医科学院中药研究所 | Combination of traditional Chinese medicine extract for preventing and treating atherosis, hyperlipemia, and preparation thereof |
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Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101342254A (en) * | 2007-07-11 | 2009-01-14 | 中国中医科学院中药研究所 | Combination of traditional Chinese medicine extract for preventing and treating atherosis, hyperlipemia, and preparation thereof |
Non-Patent Citations (1)
| Title |
|---|
| 漫步云端: "丹参酮与穿心莲复合制剂的免疫药理学试验研究", 《HTTP://BLOG.SINA.COM.CN/S/BLOG_65C9B18001012ZGC.HTML》, 7 June 2012 (2012-06-07), pages 1 - 7 * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113045637A (en) * | 2021-03-30 | 2021-06-29 | 兰州大学 | Anticancer medicine, its preparation method and key protein |
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Application publication date: 20131225 |