CN1650856A - Sensitizing energistic agent of chemotherapy medicine for treating tumour - Google Patents
Sensitizing energistic agent of chemotherapy medicine for treating tumour Download PDFInfo
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Abstract
A sensitizing synergist of chemicotherapeutic medicine for treating tumor is a liposoluble epigallocatechol gallate (C22H35O11-Ro).
Description
Technical field
The present invention relates to a kind of sensitizing and potentiating agent for the treatment of the chemotherapeutics that tumor uses, particularly a kind of can being used in combination with existing antineoplastic chemotherapy medicine forms the sensitizing and potentiating agent that a class has the antitumor drug of high tumour inhibiting rate, is a kind of purposes invention of chemical compound.
Background technology
Drug resistance be people know a kind of in the common failure phenomenon of disease treatment process, but in the treatment neoplastic process, because the particularity of treatment target, also multidrug resistance occurs easily and cause the reduction of chemotherapy effect and the failure of treatment.
Multidrug resistance (multidrug resistance, be called for short MDR) be meant that the cancerous cell contact is a kind of and derive from natural antitumor drug and when developing immunity to drugs, multiple different with the mechanism of action of structure derived from natural antineoplastic agent deposits yields cross-resistance.Tumour patient tends to produce multidrug resistance through after the chemotherapy.Multidrug resistance is the main cause that causes the chemotherapy of tumors failure, also is that chemotherapy of tumors is badly in need of one of difficult problem that solves.The formation mechanism complexity of multidrug resistance.Tumor cell can cause the generation of MDR by different approaches, and simultaneously, can there be multiple drug-fast mechanism simultaneously in single tumor cell.Any or number of mechanisms synergy all can cause the generation of MDR.
The inversion agent of MDR and antitumor drug thing share, and will improve the curative effect of chemotherapeutics to the MDR tumor significantly.Experimental results show that: chemical compound lot or medicine have the effect of external reversion MDR, but because their toxic and side effects is very big, so all there is not clinical value.So as the medicine of the MDR reversal agents of clinical practice, still untapped so far success.Therefore, material or the effective MDR reverse material of seeking low toxicity, the difficult MDR of generation are chemotherapy of tumors field urgent problems, also are the directions of the common pursuit of vast drug research person.
Run into difficulty just because of the research of seeking low toxicity, effective MDR reversal agents, do not obtain substantial progress for a long time, make a part of scientist change thinking, start with, seek the sensitizing and potentiating agent of the chemotherapeutics that class treatment tumor uses from the another one angle.People expectation can not only improve the sensitivity of the tumor cell of tumor cell, particularly multidrug resistance to antitumor drug, and can significantly improve the tumor killing effect of antitumor drug in therapeutic process when this compounds and antitumor drug share.Thisly expected to have substantial progress.
Chinese patent application (CN1444935A) discloses a kind of water miscible " application of epigallocatechin gallate (EGCG) (being called for short water solublity EGCG) in antitumor drug " of extracting from Folium Camelliae sinensis, with its enhanced sensitivity and synergist as tumor chemotherapeutic drug, play " good MDR reverse effect ", what significantly improved existing antitumor drug presses down the tumor effect, is a kind of sensitizing and potentiating agent that is expected to enter the natural anti-tumor of clinical practice.But blemish in an otherwise perfect thing is: water miscible EGCG itself is very unstable, sees that light easily decomposes, and experimental results show that: under condition of culture, its stable existence time is less than one day; In addition, find water miscible EGCG, its membrane permeability is relatively poor, and in other words, it is difficult for entering in the born of the same parents by cell membrane, thereby has influenced the performance of its effect.Therefore, seek a kind of good stability, be easy to again enter in the tumor cell, and keep " good MDR reverse effect ", the sensitizing and potentiating agent of the antineoplastic chemotherapy medicine of using as the treatment tumor has become main direction of the present invention naturally.
Summary of the invention
The objective of the invention is to overcome the shortcoming of prior art, a kind of sensitizing and potentiating agent for the treatment of the chemotherapeutics that tumor uses is provided, it not only has good stability, the advantage that membrane permeability is good, and can produce good enhanced sensitivity and potentiation when using with existing antitumor drug compatibility, improve the tumor treatment effect significantly.
The inventor is by water miscible epigallocatechin gallate (EGCG) ((-)-epigallocatechin gallate to extracting from Folium Camelliae sinensis, abbreviation EGCG) finds behind the systematic study, this extract not only has the effect that suppresses tumor cell proliferation, simultaneously can improve the sensitivity of tumor cell to chemotherapeutics, suppressed the Drug resistance of tumor cell in other words, improved the anticancer function of chemotherapeutics chemotherapeutics.But regrettably: discover that there are two big shortcomings in water solublity EGCG: the first is stable poor, easily decomposes, and life period is short in vivo, and drug effect is difficult to lastingly; It two is that membrane permeability is poor, is difficult for being absorbed by cell entering in the cell, and its bioavailability is low in other words, and is difficult to gather at target spot and reaches effective function concentration, thereby has influenced the performance of its effect.For this reason, the inventor is on the basis of being engaged in water solublity EGCG research work for a long time, and design is carried out necessary structural transformation to water solublity EGCG, modifies by hydrocarbonylation, becomes fat-soluble EGCG, has good stability, the advantage that membrane permeability is good.Fortunately, find by literature search: becoming fat-soluble EGCG by water solublity EGCG hydrocarbonylation is a kind of sophisticated prior art, fat (oil) the dissolubility EGCG of its preparation gained is as a kind of antioxidant, be used in food fresh keeping and the skin protection cosmetics, but do not see the report that is useful on the antitumor drug aspect.Therefore the present invention systematically explore fat (oil) dissolubility EGCG as antitumor drug or with existing antitumor drug compatibility as the enhanced sensitivity of the chemotherapeutics of treatment tumor and the probability of synergist, still ground-breaking work has positive innovative significance.
The said a kind of sensitizing and potentiating agent for the treatment of the chemotherapeutics that tumor uses of the present invention is meant the fat-soluble epigallocatechin gallate (EGCG) chemical compound of a class, and its general molecular formula is C
22H
35O
11-R
0, it is to be formed by water solublity epigallocatechin gallate (EGCG) that extracts from Folium Camelliae sinensis ((-)-epigallocatechin gallate is called for short EGCG) and the hydrocarbonylation of food grade unsaturated fatty acid, is called for short fat-soluble EGCG.Preferred unsaturated fatty acid commonly used is a kind of in the linoleic acid, linolenic acid, arachidonic acid of food grade.
The said fat-soluble EGCG of the present invention is the chemical compound that a class has following general structure:
Its general molecular formula is: C
22H
35O
11-R
0, molecular weight is: 696.9～769;
C wherein
22H
35O
11-be water miscible EGCG parent (or claiming aqueous-favoring EGCG gene);
R
0-be C
15～C
18The unsaturated fatty acid carbonyl of (or claim lipophile) of fat (oil) dissolubility.
1. experimental results show that fat-soluble EGCG has the ability that suppresses the tumor cell survival
Experiment 1: the cell strain KB-3-1 tumor cell with drug susceptibility is an object, carries out the research of concentration and survival rate.According to classic methods: the culture fluid that will contain the fat-soluble EGCG of variable concentrations adds in 96 orifice plates that are connected in advance with cell concentration, continuous culture 72h in incubator, with the survival rate of mtt assay observation of cell, and the concentration IC50 value of fat-soluble EGCG when measuring the KB-3-1 cell and producing half and suppress.
Experimental result is as shown in table 1:
The fat-soluble EGCG of table 1 is to the influence of KB-3-1 cell survival
| Concentration μ g/ml | 0 | 10 | 30 | 50 | 100 | 120 |
| Survival rate % | 100% | 92% | 86% | 79% | 58% | 47% |
| Explanation | Concentration is meant the amount that contains fat-soluble EGCG in the culture fluid in the table; Concentration IC50=113.4 μ g/ml when half suppresses. | |||||
Experimental results show that fat-soluble EGCG has the energy for growth of the KB-3-1 cell that suppresses drug susceptibility, and dose-effect relationship is obvious.
Experiment 2: with multidrug resistance cell strain KB-A-1 tumor cell is the research that object carries out concentration and survival rate.
The culture fluid adding that will contain the fat-soluble EGCG of variable concentrations according to classic methods is connected in 96 orifice plates of same cell amount in advance, continuous culture 72h in incubator, with the survival rate of mtt assay observation of cell, and the fat-soluble EGCG concentration IC50 value when measure producing half and suppressing.
Experimental result is as shown in table 2:
The fat-soluble EGCG of table 2 is to the influence of KB-A-1 cell survival
| Concentration μ g/ml | 0 | 10 | 30 | 50 | 75 | 100 |
| Survival rate % | 100% | 98% | 92% | 70% | 51% | 34% |
| Explanation | Concentration is meant the amount that contains fat-soluble EGCG in the culture fluid in the table; IC50=75.7 μ g/ml. | |||||
Experimental results show that fat-soluble EGCG has the energy for growth of the KB-A-1 cell that suppresses multidrug resistance, and repressed degree is directly proportional with the concentration of fat-soluble EGCG, dose-effect relationship is obvious.
In addition, can further find out from testing 1 and 2 result, multidrug resistance cell strain KB-A-1 cell comes highly to the sensitivity of fat-soluble EGCG chemical compound than KB-3-1: because of fat-soluble EGCG is 75.7 μ g/ml to the IC50 value of KB-A-1 effect, and be 113.4 μ g/ml to the IC50 value of KB-3-1 effect, this has shown that not only fat-soluble EGCG has higher sensitivity to KB-A-1, and further may there be synergism in prompting and potentiation with other drug and time spent as fat-soluble EGCG, thereby the effect of raising medicine.
Why fat-soluble EGCG has the energy for growth of good inhibition cell, may be based on the good cause of the membrane permeability of fat-soluble EGCG, and it is easy to enter in the cell, occupied cell spaces, blocked culture fluid to the nutrient source that cell provides, caused the cellular atrophy apoptosis, survival rate descends.
2. experimental results show that fat-soluble EGCG chemical compound has potentiation to antitumor drug, thereby improved the effect of medicine in therapeutic process.
Concrete experimental conditions is:
(1) select for use multidrug resistance cell strain KB-A-1 as experimental subject;
(2) medicine that cooperates experiment to use is three kinds of anticarcinogen amycin (being called for short DOX), vincristine, mitomycin, because they are respectively the concentration IC50 of the half inhibition of multidrug resistance cell strain KB-A-1 cell: 5.01,4.25,4.14 μ g/ml, all in the microgram level, close effect is arranged, for relatively more convenient, so choose the representative that amycin (being called for short DOX) is made anticarcinogen among the present invention with style of writing;
(3) in order to show the potentiation of fat-soluble EGCG better, in order to reduce the influence of fat-soluble EGCG to the KB-A-1 cell survival rate as far as possible, choosing fat-soluble EGCG activity is 20 μ g/ml, far below the concentration of IC50 in the experiment.
Experiment 3: the influence that fat-soluble EGCG flows in the KB-A-1 cell amycin
The culture fluid that will contain the KB-A-1 cell density and be 1 * 104cells/ml is inoculated in 96 orifice plates, places incubator to cultivate 3 days, treats that cell attachment covers with the back grouping experiment.In order to observe fat-soluble EGCG the medicine amycin is flowed into the intracellular influence of KB-A-1, experiment is by (a) 5 μ g/ml amycin, two groups of parallel carrying out of (b) 20 μ g/mlEGCG+5 μ g/ml amycin, and respectively 0,2h, during 3h, culture fluid sucking-off in 96 orifice plates is changed to (a) respectively, and (b) medicine continues to cultivate.By the 4th hour, medicine is exhausted, wash 3 times with ice PBS earlier, the lysate (50% acetic acid+0.1N Hcl) that adds 200 μ l then, put into and take out after the incubator temperature is bathed 20min, measure light absorption value (OD value) with fluorescence microplate reader, what of intracellular amycin are the size of OD value reflected, the amount of amycin is determined the influence that EGCG flows into amycin in the observation of cell.
Experimental result is as shown in table 3:
The influence that the fat-soluble EGCG of table 3 flows into amycin in the KB-A-1 cell
| Continue incubation time | ??1(h) | ??2(h) | ??3(h) |
| (a) group medicine OD value | ??0.6980 | ??0.7286 | ??0.7929 |
| (b) group medicine OD value | ??0.7010 | ??0.7571 | ??0.8298 |
Experiment shows: when having (a) group medicine amycin outside the born of the same parents, amycin can permeate in born of the same parents along concentration difference, and in 1h, amycin has increased by 1.22 times in the born of the same parents.Along with the prolongation of time, the transfer of amycin tends to balance, and the amycin behind the 4h in the born of the same parents increases by 1.59 times.Under the situation that EGCG exists, amycin inflow velocity in cell speeds, and the also corresponding increase of amycin content during balance under experiment condition, can increase by 3.1 times with single amycin content of comparing in the born of the same parents during with amycin.
Test 4. fat-soluble EGCG to the effusive influence of amycin in the KB-A-1 cell
Because the KB-A-1 cell has certain ability that pumps to the amycin that enters in the born of the same parents, thereby have influence on the valid density of intracellular amycin, influence the tumour inhibiting rate of amycin, explore fat-soluble EGCG for this reason and suppress KB-A-1, positive meaning is also arranged entering the ability that pumps of the amycin in the born of the same parents.
The culture fluid that will contain the KB-A-1 cell density and be 1 * 104cells/ml is inoculated in 96 orifice plates, places incubator to cultivate 3 days, treats that cell attachment covers with the back grouping experiment.According to flowing out experimental requirements, culture fluid in elder generation's sucking-off 96 orifice plates adds amycin (5 μ g/ml), in incubator, continue to cultivate 4h, make the intracellular amycin of KB-A-1 reach equilibrated concentration, then with the amycin sucking-off, with the PBS washing several all over after add culture fluid (concentration of EGCG is 20 μ g/ml) or the normal culture fluid that contains EGCG respectively.0,1,2, take out sample during 4h, measure light absorption value with fluorescence microplate reader respectively, study EGCG to the effusive influence of amycin in the KB-A-1 cell by the amount of investigating intracellular amycin, concrete experimental result is shown in Table 4.
The fat-soluble EGCG of table 4 is to the effusive influence of amycin in the KB-A-1 cell
| Time (hour) | ??0(h) | ??1(h) | ??2(h) | ??4(h) |
| Normal culture fluid group OD value | ??0.137 | ??0.105 | ??0.096 | ??0.076 |
| Contain EGCG culture fluid group OD value | ??0.137 | ??0.108 | ??0.100 | ??0.079 |
By table 4 as seen: fat-soluble EGCG has certain inhibitory action to the outflow of the intracellular amycin of KB-A-1, though the dynamics of its inhibition is little, but see that from the molecule angle outflow inhibition of table 4 and table 3 flow into increase, this one-in-and-one-out has been enough to make the amount of amycin in cell to reach target spot concentration, thereby the performance amycin is killed the effect of KB-A-1 cell, so test 3,4 results have shown fat-soluble EGCG from a side potentiation.
3. experimental results show that fat-soluble EGCG and antitumor drug unite use, have the tumor killing effect that improves antitumor drug
Set up nude mice KB-A-1 cellular entities tumor model according to a conventional method, random packet is carried out inhibition test then.
Wherein: the 1st group is the blank group of only giving not dispenser of normal saline thing;
The 2nd group is the amycin medicine group of executing 5 μ g/ml;
The 3rd group for executing the fat-soluble EGCG medicine of 40mg/kg group;
The 4th group for executing the fat-soluble EGCG+5 μ of 20mg/kg g/ml amycin medicine group;
The 5th group for executing the fat-soluble EGCG+5 μ of 40mg/kg g/ml amycin medicine group.
Experimental result is as shown in table 5.
The tumour inhibiting rate of table 5 different pharmaceutical group
| Group | ????1 | ????2 | ????3 | ????4 | ????5 |
| Average tumor heavy (g) | ????1.617 | ????0.967 | ????0.874 | ????0.692 | ????0.403 |
| Tumour inhibiting rate (%) | ????0.00 | ????40.18 | ????45.93 | ????57.18 | ????75.06 |
From experimental result as can be seen:
(1) with the amycin be the existing antineoplastic agent of representative in the face of KB-A-1 cellular entities tumor, its average tumour inhibiting rate only is 40.18%.
(2) fat-soluble EGCG itself also has certain tumor killing effect, and in the face of KB-A-1 cellular entities tumor, its tumour inhibiting rate can reach 45.93%.
(3) fat-soluble EGCG and the coupling of antitumor drug amycin have better tumor killing effect, and the highest is the fat-soluble EGCG+5 μ of 40mg/kg g/ml amycin medicine group, and its tumour inhibiting rate is up to 75.06%.And drug combination group (the 4th, the 5th group) experimental result shows: fat-soluble EGCG has tangible dose-effect relationship.
In a word, suffice to show that from above-mentioned experimental result: 1. fat-soluble EGCG has certain tumor function that presses down, and it be not immediately clear although it presses down tumor mechanism, needs further to explore.2. fat-soluble EGCG and the medication combined use of existing antitumor (or anticancer) have the antitumor drug of raising tumor killing effect, and it should be indubitable as the sensitizing and potentiating agent of antitumor drug.3. from fat-soluble EGCG the KB-3-1 cell is had higher relatively half-inhibition concentration IC50=113.4 μ g/ml and judge that fat-soluble EGCG is the chemical compound of a class low toxicity.
The effect that is had further to illustrate fat-soluble EGCG of the present invention below in conjunction with embodiment.
The specific embodiment
Tumor killing effect when embodiment 1 fat-soluble EGCG and amycin compatibility use
Method is at first routinely set up nude mice KB-A-1 cellular entities tumor model, and random packet is carried out the inhibition test of embodiment 1 respectively then.
Be used in combination the actual conditions that carries out inhibition test with fat-soluble EGCG and antitumor drug amycin:
The 1st group is the blank group of only giving not dispenser of normal saline thing;
The 2nd group is the amycin medicine group of executing 5 μ g/ml;
The 3rd group for executing the fat-soluble EGCG medicine of 40mg/kg group;
The 4th group for executing the fat-soluble EGCG+5 μ of 20mg/kg g/ml amycin medicine group;
The 5th group for executing the fat-soluble EGCG+5 μ of 40mg/kg g/ml amycin medicine group.
Experimental result is as shown in the table:
Table is the tumour inhibiting rate of the different pharmaceutical group of embodiment 1
| Group | ??1 | ??2 | ??3 | ??4 | ??5 |
| Average tumor heavy (g) | ??1.618 | ??0.966 | ??0.872 | ??0.690 | ??0.401 |
| Tumour inhibiting rate (%) | ??0.00 | ??40.29 | ??46.10 | ??57.35 | ??75.21 |
By the 4th, the 5th group of experimental result contrast in embodiment 1 table as seen: when fat-soluble EGCG and amycin were used in combination, fat-soluble EGCG had tangible dose-effect relationship, for clinical use provides scientific basis.
The tumor killing effect that embodiment 2 fat-soluble EGCG and antitumor drug vincristine compatibility use.
Method is at first routinely set up nude mice KB-A-1 cellular entities tumor model, and random packet is carried out inhibition test respectively then.
Use with fat-soluble EGCG and vincristine compatibility and to carry out the inhibition test actual conditions:
Normal saline, the blank group of not dispenser thing are given in the 1st group of position;
The 2nd group is the vincristine medicine group of executing 4 μ g/ml;
The 3rd group for executing the fat-soluble EGCG medicine of 40mg/kg group;
The 4th group for executing the fat-soluble EGCG+4 μ of 20mg/kg g/ml vincristine medicine group;
The 5th group for executing the fat-soluble EGCG+4 μ of 40mg/kg g/ml vincristine medicine group.
Experimental result is listed in the table below.
Table is the tumour inhibiting rate of the different pharmaceutical group of embodiment 2
| Group | ??1 | ??2 | ??3 | ??4 | ??5 |
| Average tumor heavy (g) | ??1.619 | ??0.960 | ??0.872 | ??0.685 | ??0.398 |
| Tumour inhibiting rate (%) | ??0.00 | ??40.70 | ??46.13 | ??57.69 | ??75.41 |
Show by last table result:
Fat-soluble EGCG and vincristine compatibility use has good tumor-inhibiting action equally, and when using by fat-soluble EGCG40mg/kg+4 μ g/ml vincristine compatibility, its tumour inhibiting rate is up to more than 75%, and experiment shows that fat-soluble EGCG has tangible dose-effect relationship.
The tumor killing effect that embodiment 3 fat-soluble EGCG and antitumor drug mitomycin compatibility use.
Method is at first routinely set up nude mice KB-A-1 cellular entities tumor model, and random packet is carried out inhibition test respectively then.
Use with fat-soluble EGCG and antitumor drug mitomycin compatibility, carry out the actual conditions of inhibition test:
The 1st group is the blank group of only giving not dispenser of normal saline thing;
The 2nd group is the medicine group of executing 4 μ g/ml mitomycins;
The 3rd group for executing the fat-soluble EGCG medicine of 40mg/kg group;
The 4th group for executing the fat-soluble EGCG+4 μ of 20mg/kg g/ml mitomycin medicine group;
The 5th group for executing the fat-soluble EGCG+4 μ of 40mg/kg g/ml mitomycin medicine group.
Experimental result is listed as follows:
Table is the tumour inhibiting rate of the different pharmaceutical group of embodiment 3
| Group | ??1 | ??2 | ??3 | ??4 | ??5 |
| Average tumor heavy (g) | ??1.618 | ??0.968 | ??0.872 | ??0.688 | ??0.396 |
| Tumour inhibiting rate (%) | ??0.00 | ??40.17 | ??46.12 | ??57.48 | ??75.52 |
By the 4th, the 5th group of experimental result contrast among the embodiment 3 as seen:
When fat-soluble EGCG and the use of mitomycin compatibility, fat-soluble EGCG has tangible dose-effect relationship.When fat-soluble EGCG40mg/kg+4 μ g/ml mitomycin compatibility uses, can obtain the effect of the high tumour inhibiting rate more than 75%.
In a word, prove once more by embodiment 1～3, when fat-soluble EGCG uses as the enhanced sensitivity of antitumor drug in the multidrug resistance chemotherapy of tumors process and synergist, undoubtedly can produce good high tumor killing effect, improve the curative effect of existing antitumor drug significantly.In other words, fat-soluble EGCG has significant sensitization for tumor cell, suppress or reversed its Drug resistance, for existing antitumor drug, increased its curative effect, therefore the enhanced sensitivity and the synergist of the chemotherapeutics used as the treatment tumor of fat-soluble EGCG, have the significant tumor therapeutic effect that presses down, be expected to promote the progress of chemotherapeutics production technology.
Claims (3)
1. sensitizing and potentiating agent for the treatment of the chemotherapeutics that tumor uses, the sensitizing and potentiating agent of said chemotherapeutics is
The fat-soluble epigallocatechin gallate (EGCG) chemical compound of one class has following general structure:
General molecular formula is: C
22H
35O
11-R
0, molecular weight is: 696.9～769;
R wherein
0Be C
15～C
20The unsaturated fatty acid carbonyl.
2. sensitizing and potentiating agent as claimed in claim 1 is characterized in that wherein said R
0The unsaturated fatty acid that comes from a class food grade, preferred unsaturated fatty acid commonly used is a kind of in linoleic acid, linolenic acid, the arachidonic acid.
3. as claim 1,2 described sensitizing and potentiating agents, it is characterized in that it and arbitrary antineoplastic agent amycin, vincristine, when mitomycin is used, can heavy dose of input, its input amount is 20～40mg/kg.
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103565849A (en) * | 2013-04-11 | 2014-02-12 | 海南林恒制药有限公司 | Capsule containing spirulina and preparation method thereof |
| CN101932320B (en) * | 2008-02-01 | 2014-06-18 | 开发邦宏 | Membrane fusion inhibitor |
| US20150056194A1 (en) * | 2013-08-21 | 2015-02-26 | Georgia Regents Research Institute, Inc. | Modified green tea polyphenols and methods thereof for treating liver disease |
| US9801850B2 (en) | 2009-07-31 | 2017-10-31 | Osaka University | Antibacterial agent |
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2004
- 2004-12-10 CN CN 200410089355 patent/CN1650856A/en active Pending
Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101932320B (en) * | 2008-02-01 | 2014-06-18 | 开发邦宏 | Membrane fusion inhibitor |
| US8952055B2 (en) | 2008-02-01 | 2015-02-10 | Protectea, Ltd. | Membrane fusion inhibitor |
| US9901565B2 (en) | 2008-02-01 | 2018-02-27 | Protectea, Ltd. | Membrane fusion inhibitor |
| US9801850B2 (en) | 2009-07-31 | 2017-10-31 | Osaka University | Antibacterial agent |
| CN103565849A (en) * | 2013-04-11 | 2014-02-12 | 海南林恒制药有限公司 | Capsule containing spirulina and preparation method thereof |
| US20150056194A1 (en) * | 2013-08-21 | 2015-02-26 | Georgia Regents Research Institute, Inc. | Modified green tea polyphenols and methods thereof for treating liver disease |
| CN104510840A (en) * | 2013-08-21 | 2015-04-15 | 乔治亚摄政研究学院有限公司 | Modified green tea polyphenols and methods thereof for treating liver disease |
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