CN101569606A - Curcumol liposome and preparation method thereof - Google Patents
Curcumol liposome and preparation method thereof Download PDFInfo
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- CN101569606A CN101569606A CNA2009100119081A CN200910011908A CN101569606A CN 101569606 A CN101569606 A CN 101569606A CN A2009100119081 A CNA2009100119081 A CN A2009100119081A CN 200910011908 A CN200910011908 A CN 200910011908A CN 101569606 A CN101569606 A CN 101569606A
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- liposome
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- phospholipid
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Abstract
The invention belongs to the technical field of medicine, and provides curcumol liposome and a preparation method thereof. The curcumol liposome is liposome or precursor liposome prepared from curcumol, phospholipids, cholesterol and other auxiliary materials, wherein antioxidant, organic acids, alkali, sugar, buffer and other auxiliary materials can also be added. Phospholipids as membrane material can adopt the prior phospholipids products on the market, including naturally extracted phospholipids, semi-synthetic or fully synthetic phospholipids or mixture thereof, and the quantity ratio of phospholipids to pharmaceutical substances is between 1.5:1 and 50:1. The preparation method can adopt an ethanol injection method, a thin-film dispersion method, a reverse evaporation method, an extrusion method, a mechanical method and the like. The ratio of supporting agent to the phospholipids is between 0.001:1 and 100:1. The curcumol liposome can be used for preparing anti-tumor medicaments for treating gastric cancer, liver cancer, cervical cancer and the like, and has the advantages of good stability, high encapsulation efficiency, low cost and few toxic-side effects. The preparation method is easy in process.
Description
Technical field:
The invention belongs to medical technical field, relate to antitumor drug Curcumol liposome (comprising pro-liposome) and preparation method thereof.
Background technology:
Curcumenol (Curcumol) has another name called Rhizoma Curcumae Longae ring alcohol difficult to understand, curcumol, is the sesquiterpenoids that extracts from Rhizoma Curcumae volatile oil.Molecular formula is C
15H
24O
2, molecular weight 236.34.Its character is colourless acicular crystal, is soluble in ether, chloroform, is dissolved in ethanol, is slightly soluble in petroleum ether, and is water-soluble hardly, and fusing point is 147-142 ℃, but metacrystal is bar-shaped under heating condition, and the distillation phenomenon takes place.
Recent study shows, pharmacological action such as curcumenol has antitumor, antiearly pregnancy, antiviral, mutation, protects the liver, blood circulation promoting and blood stasis dispelling, and wherein curcumenol has attracted the sight of numerous researcheres in the effect of anti-tumor aspect.The earliest, curcumenol as Compound Zedoary Turmeric Oil Suppositories, protect one of main effective ingredient of FUKANGNING bolt and Oleum Curcumae gelatine microsphere, be used for oncotherapys such as cervical cancer clinically.
Along with further going deep into of research, and according to the literature (Liu Zhimin, Xu Lichun, Chinese basic unit medicine, 2005,12 (7): 938.), curcumenol is to murine sarcoma S37, and the suppression ratio of 75mg/Kg dosage is 53.47%-61.96%; During 75mg/Kg dosage, be 45.7%-77.13% to mouse cervical cancer U14 suppression ratio; To mice ehrlich carcinoma (EAC), during 75mg/Kg dosage, its suppression ratio is 65.8%-78.9%.Have the scholar to select for use 15 kinds of gynecological tumor cells to do the research that curcumenol suppresses gynecological tumor, the result shows that curcumenol has remarkable inhibitory action to kinds of tumor cells wherein, and to the growth unrestraint effect of normal person's mammary glandular cell Mcf12a, Mcf10a.
Curcumenol has broad prospects aspect clinical practice, but because it is water-soluble hardly, the dissolubility in water only be 0.3% (Deng Rong, Chen Jimin, Yao Chongshun, etc., Liaoning medicine and clinical, 2001,4 (1): 37.), do not reach the clinical administration requirement.So the preparation of curcumenol is the report of listing never.Listing is the volatility aromatic turmeric oil preparation now, and Oleum Curcumae is the traditional medicine volatile oil that is grouped into by tens kinds of one-tenth, and curative effect is sure, but composition is indeterminate, and children's's toxic and side effects takes place often in clinical practice, and hemolytic reaction takes place, and has caused the great attention of medical circle.
Liposome (liposome) is as a kind of comparatively widely pharmaceutical carrier of Recent study, and its main feature is to protect encapsulated medicine, increases medicine stability, changes medicine distribution behavior in vivo, and carrying medicaments is passive or initiatively be targeted to diseased region.Liposome is applied to clinical main advantage as the advanced drugs carrier and is embodied in: 1). strengthen the dissolubility of medicine; 2). reduce drug toxicity; 3). give drug targeting; 4). increase the slow releasing function of medicine; 5). improve protective effect to medicine; 6). by fusion medicine is sent in cytoplasm or the nucleus.
At present the liposome cancer therapy drug of external listing have PEG long circulating liposomes (Caelyx), long circulation Evacet (Doxil), conventional Evacet (Evacet, Myoect), daunorubicin liposome (DaunoXome) and cytosine arabinoside liposome (DepoCyt).Also have an appointment 30 kinds of liposome cancer therapy drugs just in the clinical trial or the listing that waits for ratification.
The water solublity of curcumenol is low, it is wrapped in the vesicle of liposome, and then with its increase-volume in water, increases the distribution of drug molecule at tumor locus simultaneously, reduces its toxic and side effects to other normal structures.Curcumenol is made the liposome administration, can improve stability of drug, the intensifier target tropism suitably delays drug release, has important reality and clinical meaning.
Summary of the invention:
The purpose of this invention is to provide a kind of good stability, envelop rate height, cost is low, toxic and side effects is little Curcumol liposome and pro-liposome and preparation method thereof, poor to improve the curcumenol oral absorption, the shortcoming that bioavailability is low.
The present invention is according to the characteristic of liposome, select for use the mixture of phospholipids of special ratios to prepare the liposome of packaging medicine curcumenol, also can add the stability that adjuvants such as cholesterol and antioxidant, organic acid, alkali, sugar, buffer agent increase Curcumol liposome or pro-liposome in the prescription.Described antioxidant can be vitamin E, ascorbic acid, butylated hydroxyarisol, cysteine, sodium pyrosulfite etc.; Organic acid can be citric acid, succinic acid, acetic acid, oxalic acid, Fructus Vitis viniferae acid, lactobionic acid, glucuronic acid or galacturonic acid etc.; Alkali can be calcium carbonate, sodium carbonate, sodium bicarbonate, potassium phosphate or sodium hydroxide etc.; Sugar can be lactose, maltose, sucrose, glucose, trehalose or soft plantation white sugar etc.; Buffer agent can be phosphate buffer, citrate buffer or carbonate buffer solution etc.; Also can add other adjuvants such as sorbitol, mannitol, sodium chloride, dextran, stevioside.
Described preparation method can adopt the whole bag of tricks of pro-liposome method, alcohol injection, film dispersion method, inverted evaporation method, extrusion molding, Mechanical Method preparation liposomees such as (comprise use homogenizer, dispersing emulsification machine, extrude the method that various plant equipment such as instrument, nanometer machine, refiner, high pressure microjet prepare liposome) and nanometer liposome.
The phospholipid of described preparation liposome, can adopt the commodity phospholipid that has now gone on the market, the phospholipid that comprises natural extract, semi-synthetic, complete synthesis phospholipid or its mixture comprise dipalmitoyl phosphatidyl choline, Phosphatidylserine, phosphatidylinositols, PHOSPHATIDYL ETHANOLAMINE, phosphatidyl glycerol, phosphatidylcholine, two myristic acid phosphatidyl glycerols, two lauric acid phosphatidyl glycerols, two palmitic acid phosphatidyl glycerols, distearyl acid phosphatidyl glycerol, two myristic acid phosphatidic acid, distearyl acid phosphatidic acid, two lauric acid phosphatidic acid, two palmitic acid phosphatidic acid, two oleic acid Phosphatidylserine or dilinoleic acid phosphatidylinositols etc.
The Curcumol liposome of making, its composition comprises: adjuvants such as curcumenol and phospholipid, cholesterol, antioxidant, organic acid, alkali, sugar, buffer agent.Wherein the mol ratio of phospholipid and curcumenol is 1.5: 1-50: 1, and the weight ratio of C/PL is 0.01: 1-10: 1.
The prescription that is equipped with liposome by the pro-liposome legal system is: adjuvants such as curcumenol, phospholipid, cholesterol, antioxidant, organic acid, alkali, sugar, buffer agent.The mol ratio of phospholipid and curcumenol is 1.5: 1-50: 1, and the weight ratio of C/PL is 0.01: 1-10: 1, the ratio of adjuvant total amount such as antioxidant, organic acid, alkali, sugar, buffer agent and phospholipid is 0.001: 1-100: 1.Wherein, antioxidant can be vitamin E, ascorbic acid, butylated hydroxyarisol, cysteine, sodium pyrosulfite etc.; Organic acid can be citric acid, succinic acid, acetic acid, oxalic acid, Fructus Vitis viniferae acid, lactobionic acid, glucuronic acid or galacturonic acid etc.; Alkali can be calcium carbonate, sodium carbonate, sodium bicarbonate, potassium phosphate or sodium hydroxide etc.; Sugar can be lactose, maltose, sucrose, glucose, trehalose or soft plantation white sugar etc.; Buffer agent can be phosphate buffer, sodium hyaluronate plus buffer, citrate buffer or carbonate buffer solution etc.; Also can add other adjuvants such as sorbitol, mannitol, sodium chloride, dextran, stevioside.
Can make dosage forms such as injection, freeze-dried powder, transfusion Liposomal formulation, nano liposome preparations with Curcumol liposome (or pro-liposome).
Advantage of the present invention is: improved the deficiency that the curcumenol water solublity is low, bioavailability is low, improved the stability of curcumenol, utilized phospholipid to make the film material, curcumenol has been made liposome light and heat, improve the curative effect of curcumenol, reduce toxic and side effects cancers such as hepatocarcinoma, gastric cancer.
The specific embodiment:
Embodiment 1:
Alcohol injection prepares Curcumol liposome
Take by weighing the 50mg curcumenol, 150mg phospholipid of natural soybean (purity is 94% phosphatidylcholine), the 20mg cholesterol, the 1mg vitamin E, use the 10mL anhydrous alcohol solution, behind the groove type ultrasonic 5min mix homogeneously, slowly be injected in the phosphate buffered solution of 10mLpH7.4, constant temperature high-speed stirred 10min, the above-mentioned solution that makes is placed the ground round-bottomed flask, in 35-45 ℃ of water bath with thermostatic control, remove ethanol at 50rpm and evaporation under reduced pressure, obtain solution and cross 0.22 μ m microporous filter membrane and carry out granulate 5 times with Rotary Evaporators, promptly get Curcumol liposome, recording envelop rate is 74.8%.
Embodiment 2:
Film dispersion method prepares Curcumol liposome
Take by weighing the 4mg curcumenol, the 200mg phosphatidylinositols, the 40mg cholesterol, the 1mg vitamin E dissolves with the 15mL chloroform, this solution is placed the ground round-bottomed flask, in 25-35 ℃ of water bath with thermostatic control, boil off chloroform at 50rpm and under reduced pressure with Rotary Evaporators, make drag formation one even lipid membrane again such as medicine and phospholipid, place and continue to remove organic solvent 4-12hr in the vacuum drying oven, phosphate buffered solution with 10mLpH7.4 adds in the above-mentioned round-bottomed flask again, rotation evaporation water lipid membrane under 40 ℃ of waters bath with thermostatic control, the whole aquations of thin film on the bottle wall come off and form the milky liposome turbid liquor, extrude homogenize and reduce particle diameter (0.22 μ m microporous filter membrane, 5 times) by extruding instrument, promptly get Curcumol liposome, recording envelop rate is 69.2%.
Embodiment 3:
Reverse phase evaporation prepares Curcumol liposome
Take by weighing the 267mg curcumenol, 400mg distearyl acid phosphatidyl glycerol, 50mg cholesterol, 1mg vitamin E dissolve with the 30mL absolute ether, this solution is placed the ground round-bottomed flask, and the phosphate buffered solution of adding 10mLpH7.4, groove type ultrasonic 5min, behind the mix homogeneously, in 25-35 ℃ of water bath with thermostatic control, boil off ether at 50rpm and under reduced pressure with Rotary Evaporators, and continuation reduction vaporization 5-10min, eliminate ether, normal pressure rotary evaporation 3hr promptly gets Curcumol liposome, and recording envelop rate is 44.6%.
Embodiment 4:
Decompression rotating thin film legal system is equipped with the curcumenol pro-liposome
Take by weighing 2g sorbitol and 50mg curcumenol, progressively increase behind the method mix homogeneously, place 1000mL ground eggplant-shape bottle with equivalent, with this eggplant-shape bottle on the Rotary Evaporators of improvement, preheating 30min in 35-45 ℃ of water bath with thermostatic control; Take by weighing 800mg soybean phospholipid (purity＞90% phosphatidylcholine), 100mg cholesterol, 2mg vitamin E and be dissolved in the 20mL dehydrated alcohol, this alcoholic solution is added in the eggplant-shape bottle rotary evaporation under vacuum condition in batches.All add the back at ethanol liquid and continue pressurization evaporation 30-40min, obtain white powder, with this powder take out place exsiccator to spend the night after, sieve (40 orders, 450 μ m) promptly get the curcumenol pro-liposome, recording envelop rate is 55.9%.
Embodiment 5:
Fluidized bed process prepares the curcumenol pro-liposome
Take by weighing 30g sorbitol and 200mg curcumenol, progressively increase behind the method mix homogeneously, place fluid bed with equivalent; Take by weighing 4g soybean phospholipid (purity＞90% phosphatidylcholine), 800mg cholesterol, 2mg vitamin E and be dissolved in the 100mL dehydrated alcohol, by fluid bed boiling one-step palletizing, sieve (40 orders, 450 μ m) promptly get the curcumenol pro-liposome.
Embodiment 6:
Spray drying method for preparation curcumenol pro-liposome
The liposome of alcohol injection, film dispersion method preparation, spray drying promptly gets the curcumenol pro-liposome.
Embodiment 7:
Prepare Curcumol liposome by pro-liposome
Get the pro-liposome 2g that embodiment 6 makes, add water 10mL jolting 10min aquation, promptly get Curcumol liposome, microscope amplifies 1000 times of observations can see liposome.
Embodiment 8:
Freeze-drying prepares the curcumenol pro-liposome
Take by weighing the 20mg curcumenol, 100mg phospholipid of natural soybean (purity is 94% phosphatidylcholine), the 20mg cholesterol, the 1mg vitamin E, use the 10mL anhydrous alcohol solution, behind the groove type ultrasonic 5min mix homogeneously, under high-speed stirred, slowly be injected in the phosphate buffered solution of 10mLpH7.4, constant temperature high-speed stirred 10min, the above-mentioned solution that makes is placed the ground round-bottomed flask, in 35-45 ℃ of water bath with thermostatic control, remove ethanol at 50rpm and evaporation under reduced pressure with Rotary Evaporators, obtaining solution crosses 0.22 μ m microporous filter membrane and carries out granulate 5 times, packing, 2mL in every cillin bottle, promptly got the curcumenol pro-liposome in 24 hours through lyophilization, recording envelop rate is 75.3%.
Embodiment 9:
The curcumenol equilbrium solubility is measured
Present embodiment illustrates especially that only in order to further specify the present invention the liposome dosage form among the present invention helps to improve the dissolubility of curcumenol, rather than restriction the present invention.
Take by weighing excessive curcumenol and place the 1.5mL centrifuge tube, add the 1mL distilled water, centrifuge tube is placed (25 ± 2) ℃ water-bath, every 5min jolting 30s, promote that medicine reaches dissolution equilibrium, observe dissolving situation, the centrifugal 5min of 4000rpm in the 30min, carry out the HPLC analysis after getting supernatant liquid filtering, measure the equilbrium solubility of curcumenol in water.Bibliographical information is arranged, and the dissolubility of curcumenol in water only is 0.3% (Deng Rong, Chen Jimin, Yao Chongshun, etc., Liaoning medicine and clinical, 2001,4 (1): 37.), record result and above-mentioned bibliographical information basically identical in this experiment: the equilbrium solubility of curcumenol is 0.26% (37 ℃).
After curcumenol made liposome, can regulate curcumenol concentration as required, in embodiment 1, make curcumenol concentration and be 0.50% liposome; Among the embodiment 3, make curcumenol concentration and be 2.67% liposome.The above results is all pointed out in curcumenol parcel and the liposome, can improve its dissolubility in water.
Embodiment 10:
The test of curcumenol preliminarily stabilised
This embodiment illustrates especially that only in order to further specify the present invention the liposome dosage form among the present invention helps to improve the stability of curcumenol to light and heat, rather than restriction the present invention.
With curcumenol aqueous solution and Curcumol liposome solution, place respectively under 4,25,40 ℃ of water-baths and illumination (4500Lx, (25 ± 2) ℃) condition, in placing back 0,1,3,5,7 and 10d sampling, filter, carry out HPLC and analyze, calculate curcumenol residue percentage rate (C/C
0, %).The results are shown in Table 1.
Table 1 curcumenol solution and Curcumol liposome stability test result
By table 1 result as seen, after curcumenol is wrapped in the liposome, isolated to a certain extent in the water and airborne oxygen and light, its degraded is obviously slowed down.After the preliminarily stabilised results suggest was made the liposome dosage form with curcumenol, stability improved.
Embodiment 11:
Pharmacokinetics and tissue distribution research in the body
Present embodiment illustrates especially that only in order to further specify the present invention the liposome dosage form among the present invention can change the interior behavior of body of curcumenol, rather than restriction the present invention.
Select healthy body weight in 78 of 18～22g mices (male and female half and half), be divided into 6 groups immediately, preceding 3 groups of endnotes are penetrated the curcumenol aqueous solution, the 3 groups of tail vein injection Curcumol liposomes in back.Tail vein injection administration: after administration 0,2,5,9,14,20,30,45,60,120,240,360 and 480min get blood, the heart, liver, spleen, lung, kidney, brain, blood is put in the heparin test tube, centrifugal 10min (4000rpm), separated plasma is put in the test tube, and respectively be organized in-20 ℃ of refrigerators lucifuge with all the other freezing to be measured.The results are shown in Table 2 and 3.
The result of calculation of table 2 pharmacokinetic parameters
According to formula targeting index T
e=AUC
0～∞(targeting)/∑ AUC
0～∞(non-targeting) calculating curcumenol solution and liposome see Table 3 to the targeting index of each organ of mice.(AUC wherein
0～∞Adopt trapezoidal method to calculate)
The exponential calculating of table 3 targeting
After curcumenol made Liposomal formulation, than its pharmaceutical solutions, t
1/2Extend to 2.09h by 0.34h, prolonged the circulation time of curcumenol in blood, its reason may be that Curcumol liposome is mostly by reticuloendothelial system (RES, as liver, spleen etc.) picked-up, be that liposome has the effect of passive target in liver,, can arrive parenchyma by hepatic sinusoid when its enough hour (this test is controlled at the Curcumol liposome particle diameter about 100nm), with its interaction, the extension body internal recycle time; AUC
0～∞Bring up to 28.11 μ mol.h/L by 4.84 μ molh/L, CL is reduced to 6.07Lh/kg by 35.15Lh/kg, as seen liposome can form warehouse in circulation and tissue, and slowly discharge medicine, reduce the clearance rate in the blood, the circulation time of prolong drug in blood, thus make the AUC of liposome dosage form
0～∞Increase, help improving its bioavailability.
With the targeting index is that measurement index is made its liver targeting index of liposome with medicine and increased to 1.03 by 0.48, liver targeting index has tangible liver targeting type greater than 1 explanation Curcumol liposome, the targeting index of other each tissues (removing brain) descends in various degree simultaneously, has reduced the side effect to other each tissues.
Claims (10)
1, Curcumol liposome is characterized in that: comprise curcumenol, phospholipid, cholesterol, antioxidant, phospholipid and curcumenol mol ratio are 1.5: 1-50: 1, and the weight ratio of C/PL is 0.01: 1-10: 1.
2, Curcumol liposome according to claim 1 is characterized in that: described Curcumol liposome comprises Curcumol liposome or pro-liposome.
3, Curcumol liposome according to claim 1 is characterized in that: described phospholipid is selected from natural phospholipid, semi-synthetic, complete synthesis phospholipid or its mixture.
4, Curcumol liposome according to claim 3 is characterized in that: described natural phospholipid comes from the natural phospholipid in Semen sojae atricolor, egg yolk, animal brain or the internal organs; Described semi-synthetic, complete synthesis phospholipid comprises dipalmitoyl phosphatidyl choline, Phosphatidylserine, phosphatidylinositols, PHOSPHATIDYL ETHANOLAMINE, phosphatidyl glycerol, phosphatidylcholine, two myristic acid phosphatidyl glycerols, two lauric acid phosphatidyl glycerols, two palmitic acid phosphatidyl glycerols, distearyl acid phosphatidyl glycerol, two myristic acid phosphatidic acid, distearyl acid phosphatidic acid, two lauric acid phosphatidic acid, two palmitic acid phosphatidic acid, two oleic acid Phosphatidylserine or dilinoleic acid phosphatidylinositols.
5, Curcumol liposome according to claim 1 is characterized in that: described antioxidant is selected from one or more in vitamin E, ascorbic acid, butylated hydroxyarisol, cysteine, the sodium pyrosulfite.
6, Curcumol liposome according to claim 1, it is characterized in that: can also add organic acid, alkali, sugar, buffer agent, sorbitol, mannitol, sodium chloride, dextran, stevioside, as above the ratio of adjuvant total amount and phospholipid is 0.001: 1-100: 1.
7, Curcumol liposome according to claim 6 is characterized in that: described organic acid is selected from one or more in citric acid, succinic acid, acetic acid, oxalic acid, Fructus Vitis viniferae acid, lactobionic acid, glucuronic acid or the galacturonic acid; Alkali is selected from one or more in calcium carbonate, sodium carbonate, sodium bicarbonate, potassium phosphate or the sodium hydroxide; Sugar is selected from one or more in lactose, maltose, sucrose, glucose, trehalose or the soft plantation white sugar; Buffer agent is selected from one or more in phosphate buffer, citrate buffer or the carbonate buffer solution.
8, according to any one described Curcumol liposome of claim 1-7, it is characterized in that: described liposome can combine dosage forms such as making injection, freeze-dried powder, transfusion with pharmaceutically acceptable carrier.
9, a kind of preparation method of Curcumol liposome as claimed in claim 1 is characterized in that: described preparation method comprises pro-liposome method, alcohol injection, film dispersion method, inverted evaporation method, extrusion molding, Mechanical Method; Mechanical Method comprise use homogenizer, dispersing emulsification machine, extrude instrument, method that nanometer machine, refiner, high pressure microjet prepare liposome.
10, the preparation method of Curcumol liposome according to claim 9, it is characterized in that: it is as follows to adopt the pro-liposome legal system to be equipped with the Curcumol liposome method: prepare pro-liposome earlier, precursor by preparation forms liposome before use, or pro-liposome is prepared into capsule, tablet, granule etc., the direct spontaneous formation liposome of chance water in digestive tract.
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN104473949A (en) * | 2014-11-11 | 2015-04-01 | 济南星懿医药技术有限公司 | Pharmaceutical composition used for treating liver cancer |
| CN104510749A (en) * | 2014-11-11 | 2015-04-15 | 济南星懿医药技术有限公司 | Pharmaceutical composition for treating liver cancer |
| CN104523704A (en) * | 2014-11-11 | 2015-04-22 | 济南星懿医药技术有限公司 | Pharmaceutical composition for treating liver cancer |
| CN106509869A (en) * | 2016-11-07 | 2017-03-22 | 北京国仁堂医药科技发展有限公司 | Application of phosphatidylcholine combined with sodium bicarbonate in preparations of liver protecting food, health-care products or drugs |
| CN108403639A (en) * | 2018-04-24 | 2018-08-17 | 广东医科大学 | A kind of sugar-modified Curcumol liposome of gala and preparation method thereof |
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104473949A (en) * | 2014-11-11 | 2015-04-01 | 济南星懿医药技术有限公司 | Pharmaceutical composition used for treating liver cancer |
| CN104510749A (en) * | 2014-11-11 | 2015-04-15 | 济南星懿医药技术有限公司 | Pharmaceutical composition for treating liver cancer |
| CN104523704A (en) * | 2014-11-11 | 2015-04-22 | 济南星懿医药技术有限公司 | Pharmaceutical composition for treating liver cancer |
| CN106509869A (en) * | 2016-11-07 | 2017-03-22 | 北京国仁堂医药科技发展有限公司 | Application of phosphatidylcholine combined with sodium bicarbonate in preparations of liver protecting food, health-care products or drugs |
| CN108403639A (en) * | 2018-04-24 | 2018-08-17 | 广东医科大学 | A kind of sugar-modified Curcumol liposome of gala and preparation method thereof |
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Application publication date: 20091104 |