CN103961353B - The pharmaceutical composition of baicalin and 10-hydroxycamptothecine and application thereof - Google Patents
The pharmaceutical composition of baicalin and 10-hydroxycamptothecine and application thereof Download PDFInfo
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- IKIIZLYTISPENI-ZFORQUDYSA-N baicalin Chemical group O1[C@H](C(O)=O)[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1OC(C(=C1O)O)=CC2=C1C(=O)C=C(C=1C=CC=CC=1)O2 IKIIZLYTISPENI-ZFORQUDYSA-N 0.000 title claims abstract description 60
- 229960003321 baicalin Drugs 0.000 title claims abstract description 60
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- HAWSQZCWOQZXHI-FQEVSTJZSA-N 10-Hydroxycamptothecin Chemical compound C1=C(O)C=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)[C@]5(O)CC)C4=NC2=C1 HAWSQZCWOQZXHI-FQEVSTJZSA-N 0.000 title claims abstract description 53
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The present invention relates to a kind of pharmaceutical composition, pharmaceutical composition described in it contains 10-hydroxycamptothecine and baicalin.Pharmaceutical composition of the present invention has significant synergistic effects in treatment gastric cancer, breast carcinoma, hepatocarcinoma etc., reduces dosage, improves the curative effect of medicine, decrease the generation of side effect.
Description
Technical field
The present invention relates to a kind of antineoplastic pharmaceutical compositions, be specifically related to the pharmaceutical composition of baicalin and 10-hydroxycamptothecine and preparing the application in the medicine for the treatment of pulmonary carcinoma, cancer of pancreas, colon cancer, hepatocarcinoma, carcinoma of prostate, renal carcinoma, gastric cancer, cerebroma, sarcoma, ovarian cancer or breast carcinoma.
Background technology
Cancer is one of principal disease threatening human health.According to World Health Organization, caused 7,600,000 people's death (accounting for 13% of all death tolls) cancer in 2008, and this death toll will continue to rise, expecting the year two thousand thirty will more than 1,310 ten thousand.And most of cancer mortality is caused by pulmonary carcinoma, gastric cancer, hepatocarcinoma, colon cancer and breast carcinoma.Means at present for treatment of cancer mainly contain three kinds, i.e. operation, radiation and chemotherapy, wherein again based on chemotherapy.But chemotherapy medicine used often again can the problem such as, cellular drug resistance strong because of poor solubility, toxic and side effects and restrict the application of itself.Therefore, how to make medicine reach the object of attenuation synergistic, then become the focus point for the treatment of of cancer.And a kind of the most effective method, utilize the low cytotoxic drug with it with cooperative effect to carry out drug combination exactly.
10-hydroxycamptothecine is that the hydrogen of the 10th carbon atom of camptothecine is optionally substituted by a hydroxyl group, and is the another kind of alkaloid extracted from Fructus seu radix camptothecae acuminatae (Fructus Camptothecae Acuminatae).It is a kind of cell cycle specific agents, mainly through acting on topoisomerase I to suppress DNA replication dna, thus antiproliferative effect.The anticancer spectrum of this medicine is wide, with other antitumor drug without cross resistance, has significant curative effect to the Several Kinds of Malignancy such as hepatocarcinoma, gastric cancer, is widely used in the chemotherapy regimen of tumor.But this medicine dissolves hardly in water, and take in process and often produce some toxic and side effects, the symptoms such as such as Nausea and vomiting, leukopenia, alopecia.In order to make up these defects, then other low cytotoxic drugs with it with cooperative effect can be utilized to carry out drug combination, thus make the reduction of its concentration used when reaching same drug effect slow down the side reaction produced because of it.
Baicalin is the effective ingredient extracted in Labiatae perennial herb Chinese medicinal plant Radix Scutellariae dry root, in crude drug, account for 5.41%, is one of main active component of Radix Scutellariae.Baicalin is the important monomer of baikal skullcap root, is that one has multiple bioactive natural flavone compounds.Modern pharmacological research shows: baicalin has antibacterial, the multiple efficacies such as antiviral, antitumor, inflammation-inhibiting react, protect the liver, function of gallbladder promoting, diuresis, and has good clinical value.In addition, the wide material sources of baicalin, toxicity is extremely low, and Radix Scutellariae is now applied to diet-therapy health-preserving.
Up to the present, have not been reported about conbined usage 10-hydroxycamptothecine in antitumor and baicalin and the two synergism in antitumor.
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 cancer of preparation treatment thereof.
Antineoplastic pharmaceutical compositions of the present invention contains 10-hydroxycamptothecine and baicalin.
The structural formula of 10-hydroxycamptothecine and baicalin is as shown in I, II.
The mol ratio of 10-hydroxycamptothecine and baicalin is preferably 0.05 ~ 2:1.
Antineoplastic pharmaceutical compositions of the present invention, in preferred situation, the valid density of described 10-hydroxycamptothecine and baicalin is respectively 0.5 ~ 25 μM and 5 ~ 20 μMs; In preferred situation, be then respectively 3 ~ 13 μMs and 6 ~ 16 μMs.
Antineoplastic pharmaceutical compositions of the present invention, in preferred situation, the retarder thinner of described 10-hydroxycamptothecine and baicalin is dimethyl sulfoxide or ethanol.
Antineoplastic pharmaceutical compositions of the present invention can be applicable to treat all kinds of tumor, 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.
The application of described antineoplastic pharmaceutical compositions, in preferred situation, described baicalin and 10-hydroxycamptothecine add simultaneously; In preferred situation, effect 30 ~ 50h after simultaneously adding.
Antineoplastic pharmaceutical compositions of the present invention can adopt the method for this area routine to make the preparation being suitable for gastrointestinal administration or parenteral administration, preferably this pharmaceutical composition is made the preparation of gastrointestinal administration, its dosage form can be conventional tablet, capsule, controlled release or slow releasing preparation.
10-hydroxycamptothecine in antineoplastic pharmaceutical compositions of the present invention and/or its derivant can directly mix with baicalin and/or its derivant makes preparation; Or make preparation respectively with corresponding adjuvant mixing respectively, and then pack according to the mode of this area routine or combine; Or after mixing with corresponding adjuvant respectively, remix and make preparation.The adjuvant that preparation uses can adopt the adjuvant of this area routine, but reacts by pharmaceutical composition of the present invention of getting along well or do not affect premised on the curative effect of pharmaceutical composition of the present invention.
According to the difference of dosage form and preparation specification, pharmaceutical composition of the present invention content in the formulation can adjust between 1-99wt%, preferred 10-90wt%.In addition, the dosage of pharmaceutical composition of the present invention suitably can change according to the dosage form of administration object, route of administration or medicine, but to ensure that this pharmaceutical composition can reach premised on effective blood drug level in mammalian body.
Pharmaceutical composition of the present invention has significant synergistic effects in treatment gastric cancer, breast carcinoma, hepatocarcinoma etc., improves the curative effect of medicine, reduces dosage, decrease the generation of side effect.
Accompanying drawing explanation
Fig. 1 is displaying two prescription used time variable concentrations to the figure of MCF7 cell inhibitory effect and fit equation; Wherein: A: baicalin is to MCF7 cell inhibitory effect figure; B: carry out the rectilinear that matching obtains according to the relation between the dosage of baicalin and MCF7 cell survival rate; C:10-hydroxy camptothecin is to MCF7 cell inhibitory effect figure; D: carry out the rectilinear that matching obtains according to the relation between the dosage of 10-hydroxycamptothecine and MCF7 cell survival rate;
Fig. 2 is displaying two medicine variable concentrations and different administration timing of drug figure to MCF7 cell inhibitory effect when share; Wherein: significance analysis often organizes only to add HCPT medicine for contrast, if P<0.05, is then significantly, is expressed as " * "; If P<0.01, be then extremely remarkable, be expressed as " * * ".
Fig. 3 is displaying two prescription used time variable concentrations to the figure of BGC823 cell inhibitory effect and fit equation; Wherein: A: baicalin is to BGC823 cell inhibitory effect figure; B: carry out the rectilinear that matching obtains according to the relation between the dosage of baicalin and BGC823 cell survival rate; C:10-hydroxy camptothecin is to BGC823 cell inhibitory effect figure; D: carry out the rectilinear that matching obtains according to the relation between the dosage of 10-hydroxycamptothecine and BGC823 cell survival rate;
Fig. 4 is displaying two medicine variable concentrations and different administration timing of drug figure to BGC823 cell inhibitory effect when share; Wherein: significance analysis often organizes only to add HCPT medicine for contrast, if P<0.05, is then significantly, is expressed as " * "; If P<0.01, be then extremely remarkable, be expressed as " * * ".
Fig. 5 is displaying two prescription used time variable concentrations to the figure of SMMC7721 cell inhibitory effect and fit equation; Wherein: A: baicalin is to SMMC7721 cell inhibitory effect figure; B: carry out the rectilinear that matching obtains according to the relation between the dosage of baicalin and SMMC7721 cell survival rate; C:10-hydroxy camptothecin is to SMMC7721 cell inhibitory effect figure; D: carry out the rectilinear that matching obtains according to the relation between the dosage of 10-hydroxycamptothecine and SMMC7721 cell survival rate;
Fig. 6 is displaying two medicine variable concentrations and different administration timing of drug figure to SMMC7721 cell inhibitory effect when share; Wherein: significance analysis often organizes only to add HCPT medicine for contrast, if P<0.05, is then significantly, is expressed as " * "; If P<0.01, be then extremely remarkable, be expressed as " * * ".
In each figure, BA represents baicalin, and HCPT represents 10-hydroxycamptothecine.
Detailed description of the invention
Below in conjunction with embodiment, the invention will be further elaborated, but the present invention is not limited to this, when not departing from thought of the present invention and aim, all should fall in claims of the present invention limited range any change that technical scheme of the present invention is done.
Biomaterial used in embodiment 1 ~ 3, medicine and experimental technique are as follows:
Cell: MCF-7 (Breast cancer lines), BGC823 (human stomach cancer cell line), SMMC-7721 (human hepatoma cell strain) can middlely from commercial channels obtain, such as Shanghai Inst. of Life Science, CAS cellular resources center.
Medicine: precise 10-hydroxycamptothecine (Dalian Mei Lun Bioisystech Co., Ltd) and baicalin (lark prestige Science and Technology Ltd.), dissolve respectively with dimethyl sulfoxide or ethanol, being made into 10-hydroxycamptothecine concentration is 100mmol/L, baicalin concentration is the stock solution of 200mmol/L, preserve at-20 DEG C, be diluted to suitable concentration cited in table 1 ~ 9 by fresh culture medium during use, the culture medium used in embodiment 1 ~ 3 is DMEM high glucose medium.
MTT detects cell proliferation: cell in containing 10% hyclone, 100kU/L penicillin, 100mg/L streptomycin DMEM high glucose medium in, 37 DEG C, 5%CO
2condition under cultivate.After cell trypsinization, count with blood cell counting plate.96 porocyte culture plates (cell inoculum concentration 8000-10000/hole, according to cell size and speed of growth selection) are inoculated in, 5%CO by every hole 100 μ l volume
2, cultivate 24h in 37 DEG C of incubators after add the testing sample of variable concentrations gradient, 5%CO
2, hatch 48 hours in 37 DEG C of incubators.Discard culture medium, wash once with PBS, then every hole adds the serum-free medium 100 μ L containing 0.5mg/mLMTT, 5%CO
2, hatch 4h in 37 DEG C of incubators.Culture medium in 96 orifice bores sucked, then every hole adds 100 μ l dimethyl sulfoxide.Detect by microplate reader, determined wavelength is 570nm, and reference wavelength is 630nm.
The calculating of Combination index (CI):
(1) relational expression between dosage (D) and cell survival rate (fu) is determined
Survival rate (fu)=
medicine group OD value/matched group OD value
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)＝mlogD-mlogDm，
If b=m, a=-mlogDm, Y=log (fa/fu), X=logD,
Then dosage and cell survival rate relational expression are Y=bX+a (Dm is middle effect dosage).
The cell survival rate that when can record certain drug given alone by experiment, different dosing dosage is corresponding.Dosage and cell survival rate data are substituted into above-mentioned Equation for Calculating and goes out Y and X.Linear fit is carried out to these group data, calculates corresponding b value, a value, namely obtain corresponding to the dosage of this medicine and the equation Y=bX+a of suppression ratio relation.
(2) Combination index (CI) is calculated
Middle effect dosage (Dm) and m value is tried to achieve by a, b value in aforesaid equation.
Efficacious prescriptions formula D=Dm (fa/fu) in utilization
1/m, when calculating the depression effect reaching two kinds of drug combinations, be used alone the theoretical dosage (D of two kinds of medicines
single 1, D
single 2).
By following formulae discovery Combination index (CI): CI=D
close 1/ D
single 1+ D
close 2/ D
single 2
(D
close 1and D
close 2be that two medicines often plant medicine dosage respective in the composition, for testing the dosage of actual use when share.)
Embodiment 1
(1) dilute baicalin respectively and 10-hydroxycamptothecine is the concentration of table 1 ~ 3 by the DMEM high glucose medium culture medium containing 10% hyclone, 100kU/L penicillin, 100mg/L streptomycin, during the baicalin of variable concentrations and 10-hydroxycamptothecine alone, Fig. 1 and table 1 and table 2 are shown in the experimental result of MCF7 inhibited proliferation.
The MCF7 cell survival Relation Parameters of table 1 baicalin under different dosing dosage calculates
The MCF7 cell survival Relation Parameters of table 210-hydroxy camptothecin under different dosing dosage calculates
Carry out calculation specifications for table 1, first show that baicalin acts on the survival rate of MCF7 cell, then carry out matching according to the relation between dosage and cell survival rate and obtain equation Y=4.96X-9.81, then b=4.96, a=-9.81, m=b=4.96, Dm=10
(-a/m)=102.39
The relational expression of the theoretical dosage and cell survival rate of deriving baicalin is thus:
D
single 1=Dm (fa/fu)
1/m=102.39 [(1-fu)/fu)]
1/4.96
The relational expression of the theoretical dosage and cell survival rate that in like manner can obtain 10-hydroxycamptothecine is: D
single 2=Dm (fa/fu)
1/m=4.54 [(1-fu)/fu)]
1/0.51
(2) the combination Synergistic of baicalin and 10-hydroxycamptothecine promotes that the experimental result of MCF7 cell death is in table 3 and Fig. 2.
Table 3 two kinds of medicines are alone with MCF7 cell survival rate during drug combination and CI value
A: represent and add 10-hydroxycamptothecine effect 24h again after first adding baicalin effect 24h
B: act on 48h after representing baicalin and 10-hydroxycamptothecine dosing simultaneously
C: represent and add baicalin effect 24h again after first adding 10-hydroxycamptothecine effect 24h
Drug combination has 3 kinds of results: cooperative effect, antagonistic effect and additive effect.General employing Combination index CI judges concrete effect, CI value <1 thinks to have cooperative effect, CI thinks value=1 to have additive effect, and CI value >1 thinks to have antagonistic effect, and CI value <0.7 thinks to have significant cooperative effect.As can be seen from the above results, when baicalin and 10-hydroxycamptothecine administration simultaneously, CI value can reach between 0.3-0.5 under doses and proportioning, and now, the lethal effect of Papillary to MCF7 cell has good synergism.If first with the effect adding 10-hydroxycamptothecine effect 24h after baicalin effect 24h again and then present antagonism, otherwise then synergism is also smaller, even also there will be antagonism.So, should both simultaneously administrations then curative effect is best.
To organize the calculating that 4b illustrates CI value in table 3:
6.25 μm of ol/L baicalins and 3.125 μm of ol/L10-hydroxy camptothecins share, and during dosing simultaneously, cell survival rate fu is 37.33% ± 2.94, then D
close 1=6.25 μMs, D
close 2=3.125 μMs.
Fu=37.33 is substituted into respectively in the above-mentioned theory dosage of baicalin and 10-hydroxycamptothecine and the relational expression of cell survival rate, can obtain
D
single 1=102.39 [(1-fu)/fu)]
1/4.96=113.46 μMs
D
single 2=4.54 [(1-fu)/fu)]
1/0.51=11.99 μMs
Substitute into the computing formula of Combination index (CI), can obtain
CI=D
close 1/ D
single 1+ D
close 2/ D
single 2=6.26/113.46+3.125/11.99=0.32
Embodiment 2
(1) dilute baicalin respectively and 10-hydroxycamptothecine is the concentration of table 4 ~ 6 with the DMEM high glucose medium containing 10% hyclone, 100kU/L penicillin, 100mg/L streptomycin, during the baicalin of variable concentrations and 10-hydroxycamptothecine alone, Fig. 3 and table 4 and table 5 are shown in the experimental result of BGC823 inhibited proliferation.
The BGC823 cell survival Relation Parameters of table 4 baicalin under different dosing dosage calculates
The BGC823 cell survival Relation Parameters of table 510-hydroxy camptothecin under different dosing dosage calculates
The relational expression of the theoretical dosage and cell survival rate of in like manner deriving baicalin is:
D
single 1=Dm (fa/fu)
1/m=159.04 [(1-fu)/fu)]
1/5.57
The theoretical dosage of 10-hydroxycamptothecine and the relational expression of cell survival rate are: D
single 2=Dm (fa/fu)
1/m=5.71 [(1-fu)/fu)]
1/0.55
(2) the combination Synergistic of baicalin and 10-hydroxycamptothecine promotes that the experimental result of BGC-823 cell death is in table 6 and Fig. 4.
Table 6 two kinds of medicines are alone with BGC-823 cell survival rate during drug combination and CI value
A: represent and add 10-hydroxycamptothecine effect 24h again after first adding baicalin effect 24h
B: act on 48h after representing baicalin and 10-hydroxycamptothecine dosing simultaneously
C: represent and add baicalin effect 24h again after first adding 10-hydroxycamptothecine effect 24h
Drug combination has 3 kinds of results: cooperative effect, antagonistic effect and additive effect.General employing Combination index CI judges concrete effect, CI value <1 thinks to have cooperative effect, CI thinks value=1 to have additive effect, and CI value >1 thinks to have antagonistic effect, and CI value <0.7 thinks to have significant cooperative effect.As can be seen from the above results, when baicalin and 10-hydroxycamptothecine administration simultaneously, CI value can reach between 0.3-0.5 under doses and proportioning, and now, the lethal effect of Papillary to BGC823 cell has good synergism.If first with the effect adding 10-hydroxycamptothecine effect 24h after baicalin effect 24h again and then present antagonism, otherwise then synergism is also smaller, even also there will be antagonism.So, should both simultaneously administrations then curative effect is best.
Embodiment 3
(1) dilute baicalin respectively and 10-hydroxycamptothecine is the concentration of table 7 ~ 9 with the DMEM high glucose medium containing 10% hyclone, 100kU/L penicillin, 100mg/L streptomycin, during the baicalin of variable concentrations and 10-hydroxycamptothecine alone, Fig. 5 and table 7 and table 8 are shown in the experimental result of SMMC7721 inhibited proliferation.
The SMMC7721 cell survival Relation Parameters of table 7 baicalin under different dosing dosage calculates
The SMMC7721 cell survival Relation Parameters of table 810-hydroxy camptothecin under different dosing dosage calculates
The relational expression of the theoretical dosage and cell survival rate of in like manner deriving baicalin is:
D
single 1=Dm (fa/fu)
1/m=107.37 [(1-fu)/fu)]
1/2.61
The theoretical dosage of 10-hydroxycamptothecine and the relational expression of cell survival rate are: D
single 2=Dm (fa/fu)
1/m=33.45 [(1-fu)/fu)]
1/0.38
(2) the combination Synergistic of baicalin and 10-hydroxycamptothecine promotes that the experimental result of SMMC7721 cell death is in table 9 and Fig. 6.
Table 9 two kinds of medicines are alone with SMMC7721 cell survival rate during drug combination and CI value
A: represent and add 10-hydroxycamptothecine effect 24h again after first adding baicalin effect 24h
B: act on 48h after representing baicalin and 10-hydroxycamptothecine dosing simultaneously
C: represent and add baicalin effect 24h again after first adding 10-hydroxycamptothecine effect 24h
Drug combination has 3 kinds of results: cooperative effect, antagonistic effect and additive effect.General employing Combination index CI judges concrete effect, and CI value <1 thinks to have cooperative effect, and CI thinks value=1 to have to be added imitates.
Claims (3)
1. an antineoplastic pharmaceutical compositions, is characterized in that, containing 10-hydroxycamptothecine and baicalin; The mol ratio of described 10-hydroxycamptothecine and baicalin is 0.05 ~ 2:1; The concentration of described 10-hydroxycamptothecine and baicalin is respectively 0.5 ~ 25 μM and 5 ~ 20 μMs; Described baicalin and 10-hydroxycamptothecine add rear effect 30 ~ 50h simultaneously.
2. antineoplastic pharmaceutical compositions according to claim 1, is characterized in that, the retarder thinner of described 10-hydroxycamptothecine and baicalin is dimethyl sulfoxide or ethanol.
3. the application of the antineoplastic pharmaceutical compositions in claim 1-2 described in 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.
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