CN101143142A - Silybin supersaturated self-emulsion composition and preparation method thereof - Google Patents
Silybin supersaturated self-emulsion composition and preparation method thereof Download PDFInfo
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- CN101143142A CN101143142A CNA2007101433908A CN200710143390A CN101143142A CN 101143142 A CN101143142 A CN 101143142A CN A2007101433908 A CNA2007101433908 A CN A2007101433908A CN 200710143390 A CN200710143390 A CN 200710143390A CN 101143142 A CN101143142 A CN 101143142A
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Abstract
The invention discloses a supersaturated self-emulsion combination of silibinin and the preparation method of the combination. The invention can effectively improve the biological utilization degree of the silibinin and improve the curative effect of the drug with low cost and simple technology. The supersaturated self-emulsion combination of silibinin consists of the silibinin, an oil phase, an emulsification, a coemulsifier and a stabilizer. The weight percentages of the raw material and the complementary materials are 1 percent to 20 percent of the silibinin, 5 percent to 40 percent of the oil phase, 10 percent to 90 percent of the emulsification, 1 percent to 20 percent of the coemulsifier and 0.5 percent to 10 percent of the stabilizer. The preparation method is that the silibinin, the oil phase, the emulsification and the coemulsifier are heated and synchronously mixed under 20 to 100 DEG C to completely dissolve the silibinin, and the stabilizer is added to be mixed uniformly, and the combination can be obtained. The supersaturated self-emulsion of silibinin of the invention can spontaneously form a micro-emulsion with the nanometer grade granular size when meeting the body fluid after arriving at the inside of body by injecting or orally taking, which can obviously improve the drug solubility and increase the drug stability and improve the biological utilization degree of the drug.
Description
Technical field
The invention belongs to field of medicaments, be specifically related to a kind of silybin supersaturated self-emulsion composition and preparation method thereof.
Technical background
Silibinin (Silybin) is a kind of chromocor compound that extraction separation obtains in feverfew Herba Silybi mariani (the Silybum marianum L.Gaertn) fruit.Herba Silybi mariani, the another name Silybum marianum Gaertn for Compositae Silybum one, biennial herb plant, originates in southern Europe and north African.China introduced a fine variety pale reddish brown Herba Silybi mariani in 1972 from West Germany, now in Shaanxi, ground plantations such as Heilungkiang, Liaoning, Panjin, Beijing.Silibinin chemical name: 2a-[2,3-is trans-2,3-dihydro-3-(4-hydroxy 3-methoxybenzene base)-2-methylol-1,4-benzodioxane-6-yl]-2,3-dihydro-3 β, 5,7-trihydroxy-4H-1-.alpha.-5:6-benzopyran-4-ketone monohydrate.2α-[2，3-trans-2，3-dihydro-3-(4-hydroxy-3-methoxypheny1)-2-(hydroxymethyl)-1，4-benzodioxan-6-y1]-2，3-dihydro-3β，5，7-trihydroxy-4H-1-Benzopyran-4-one monohydrate
Chemical structural formula:
The silibinin molecular formula is: C
25H
22O
10H
2O, molecular weight is: 500.47.Silibinin can be stablized liver plasma membrane; protect hepatocellular enzyme system; remove the reactive oxygen free radical in the hepatocyte, thereby improve the detoxification ability of liver, avoid hepatocyte at long-term contact poison, take liver toxicity medicine, smoking, sustain damage under the situation such as drink.The checking of clinical practice for many years, silibinin is to acute, chronic hepatitis, liver cirrhosis, hepatic coma, liver poisoning disease, the hepatopathy that a variety of causes causes, steatosis, cholestasiss etc. have remarkable therapeutic effect, and can be used for preventing health care etc. before and after cholelithiasis formation, radiotherapy syndrome and the hepatobiliary surgery, have safety, reliable, non-evident effect and chemical sproof characteristics.The These characteristics of silibinin has caused the extensive attention of countries in the world, and domestic also have many reports to its chemical research and clinical practice.This natural drug of discovered in recent years not only has the effect of hepatic cholagogic, but also has effects such as tangible anti peroxidation of lipid, radioprotective, removing free radical and anti-gastric-ulcer, and has expanded and be applied to health care and fields such as beauty and make-up.In blood fat reducing, prevent atherosclerosis, prevention of brain ischemia, anti-platelet aggregation and antitumor and aspect the treatment of skin carcinoma, also demonstrate gratifying effect.China Patent No.: 200410069354.8 disclose the patent of invention that a kind of name is called " silibinin oral disintegration tablet and preparation technology thereof ", and it is the oral cavity disintegration tablet that a kind of silibinin and various adjuvant are made; China Patent No.: 200610109474.5 disclose the patent of invention that a kind of name is called " the Chinese medicine and western medicine Synergistic medicinal composition that contains silibinin ", and it is actual to be the mixture of a kind of silibinin and Chinese medicine extract such as the Radix Astragali, Radix Codonopsis; China Patent No. 200410036376.4 discloses the patent of invention that a kind of name is called " new medical use of silibinin or its salt ", it is the application in damage due to preparation treatment or the prevention bacterial infection about silibinin or its salt, and silibinin or the application of its salt in the medicine that strengthens the antibiotic curative effect.Above-mentioned patent all is a silibinin examples of applications in every respect.
Because silibinin is insoluble in water and common organic solvents, oral absorption is poor, and its bioavailability is lower, thereby has influenced its clinical efficacy.The domestic and international research worker's active development that begins the seventies in 20th century is developed its novel form, increases dissolubility speed and absorption characteristic, to improve bioavailability.As silibinin being made cyclodextrin clathrate, solid dispersion, drop pill, phosphatide complexes; Or be made into water-soluble compounds such as meglumine salt, two inclined to one side succinic acid sodium salts; Be made into microemulsion, nanoparticle, pro-liposome etc. in addition in addition.In addition, though the bibliographical information phosphatide complexes is remarkable to improving the bioavailability effect, easily oxidation of phospholipid itself may cause the preparation instability.Therefore, the pharmaceutical composition of a kind of novel silibinin of necessary exploitation improves the preparation stability and the bioavailability of oral silibinin.
Summary of the invention
The object of the present invention is to provide a kind of silybin supersaturated self-emulsion composition and preparation method thereof.Can disperse to form microemulsion after this supersaturated self-emulsion composition enters in the body, can improve bioavailability; This method reduces production costs in addition, and drug loading is big, and preparation technology is simple, advantages such as taking convenience.
Oral administration solid or liquid dosage form that self-emulsifying microemulsion drug delivery system (Self-Microemulsifying Drug Delivery System SMEDDS) is made up of medicine, oil phase, surfactant, cosurfactant.The topmost feature of this drug-supplying system is exactly under the body temperature condition, meet behind the body fluid can be under the impelling of gastrointestinal motility spontaneous formation oil-in-water emulsion.Thereby rely on tiny oil droplet specific surface area increase and significantly improve the dissolution of water-insoluble drug in gastrointestinal tract, increase bioavailability of medicament greatly, the Emulsion of Xing Chenging can reduce simultaneously stimulates gastrointestinal.
Compare with common breast or microemulsion, the SMEDDS physical property is more stable, is easy to preparation.Oral back forms meticulous microemulsion, so it is claimed again. for precursor concentrates breast.The preparation advantage of SMEDDS mainly contains: (1) is spontaneous formation microemulsion under the gastrointestinal tract condition; (2) slightly solubility or fat-soluble medicine had higher solubilising power; (3) can filtration sterilization, can be used as intravenous administration formulation; (4) higher physical stability; (5) be filled in hard capsule or the soft capsule, preparation technology is simple, produces greatly easily.
SMEDDS compares with capsule with traditional tablet, and gastric emptying speed is fast, but the medicine fast Absorption.For good self-emulsifying microemulsion system, can form the little emulsion droplet that includes dissolved substance when contacting with gastro-intestinal Fluid.Therefore, the medicine in the microemulsion emulsion droplet has bigger interfacial area and medicine can keep dissolved state in intestinal, thereby can disperse permeate through cell membranes better.
Silibinin is made the supersaturated self-emulsion drug-supplying system, be about to silibinin and suitable oil phase, surfactant and cosurfactant, stabilizing agent etc. and make solution, again this formulations prepared from solutions is become capsule, soft capsule, subcutaneous, intramuscular, lumbar injection liquid or percutaneous plaster, contact with body fluid after entering in the body after oral administration or the injection, automatically form microemulsion, medicine is absorbed well and brings into play curative effect, and have slow releasing function.The present invention is achieved by the following technical solutions:
Among the present invention, the component of silybin supersaturated self-emulsion composition and percentage by weight thereof are: silibinin 1～20%, oil phase 5～40%, emulsifying agent 10～90%, coemulsifier 1～20%, stabilizing agent 0.5～10%.
Described oil phase is following any one or multiple: soybean oil, Oleum Arachidis hypogaeae semen, safflower oil, olive oil, fish oil, egg oil, whale oil, butter, oleic acid, olein, glyceryl linoleate, ethyl oleate, middle chain saturated fatty acid triglyceride, decanoyl/octanoyl glycerides.
Described emulsifying agent is following any one or multiple: glyceryl monostearate, mono laurate double glyceride, sucrose monolaurate, lecithin, fabaceous lecithin, watermiscible vitamin E, arabic gum, tragakanta, agar, sodium alginate, cholesterol, casein etc.The self-emulsifying microemulsion drug-loading system is often selected hydrophilic non-ionic surfactant for use, because non-ionic surface active agent is lower than ionic surfactant toxicity, typical concentrations is 30%～60% (W/W), but application can cause gastrointestinal tract mucous infiltrative irreversible transformation repeatedly, if excessive concentration can act as a spur to gastrointestinal tract.Find in the process of the present invention, silibinin has the appearance that produces degradation phenomenon under related substance, the silibinin content when using with surfactant compatibilities such as polyoxyethylene sorbitan ester, polyoxyethylene castor oil, polyoxyethylene hydrogenated Oleum Ricini, measure the content of silibinin with HPLC and find that the content of silibinin descends rapidly along with the prolongation of compatibility time.These phenomenons show that silibinin and above-mentioned surfactant have the possibility of other related substanceses of generation that react, supposition is that oxidation reaction has taken place the polyoxyethylene groups in structural phenolic hydroxyl group of silibinin and the above-mentioned surfactant, but concrete reaction mechanism also needs further research.Based on above result of the test, decision abandons containing the nonionic surfactant of polyoxyethylene groups.
The present invention has disclosed the reaction between silibinin and the above-mentioned surfactant first, this point at home and abroad in document and the patent all less than report, for silibinin provides reference when selecting pharmaceutic adjuvant.
Described coemulsifier is following any one or multiple: ethanol, glycerol, propylene glycol, Polyethylene Glycol, propylene carbonate, ethylene glycol monomethyl ether, dimethyl Soquad etc.
Described stabilizing agent is following any one or multiple: polyvinylpyrrolidone (PVP), hypromellose (HPMC), Carboxymethyl cellulose sodium (CMC), starch and derivant, gelatin and derivant thereof, alginic acid and sodium salt thereof etc.
The preparation method of silibinin self-emulsion composition of the present invention, may further comprise the steps: silibinin, oil phase, emulsifying agent, coemulsifier are heated while stirring at 20 ℃～100 ℃, after making the silibinin dissolving, add stabilizing agent, mixing, make it become homogeneous, transparent solution, promptly get the silybin supersaturated self-emulsion compositions.
Silibinin self-emulsion composition provided by the invention has overcome the problem of aspects such as the fat-soluble medicine bioavailability is low, drug loading is low, is a kind of oral drugs very easily.Said preparation will become a kind of novel acute and chronic hepatitis of effective treatment and chronic persistent hepatitis, hepatitis interstitialis chronica, fatty liver, the medicine of aspects such as cholecystitis.Also lay a good foundation for the experimentation of silibinin and clinical practice.
The beneficial effect of silibinin self-emulsion composition preparation that the present invention is prepared and preparation method thereof shows following several respects:
1, silibinin self-emulsion composition of the present invention is not found problems such as the principal agent silibinin is separated out, structural change, degraded through 2 years stability test results, and stability is preferably arranged.
2, selected oil phase has good mobility, principal agent is had certain dissolubility and very easily emulsified characteristic in preparation of the present invention, easy in vivo degraded and absorbed.
3, selected emulsifying agent is a safety in preparation of the present invention, nontoxic, non-irritating nonionic surfactant, amphoteric ionic surfactant, natural surfactant, emulsifiability is good, find that by external emulsifying experiment back its emulsifying particle diameter is less, help absorbing the bioavailability height.
4, preparation is simple for silibinin self-emulsion composition of the present invention.
5, silibinin self-emulsion composition of the present invention does not have any harm to health, and production cost is low, and the automaticity height quantitatively accurately, is easy to disintegrate, stripping, and absorption of human body is fast.
Description of drawings
Fig. 1. silibinin reference substance HPLC collection of illustrative plates
Chromatographic condition chromatographic column Kromasic C18 5 μ 200 * 4.6mm
Mobile phase methanol-water-glacial acetic acid (48: 52: 5)
Survey wavelength 288nm
40 ℃ of column temperatures
Fig. 2. the HPLC figure of silybin supersaturated self-emulsion composition
Fig. 3. the impurity peaks HPLC collection of illustrative plates of silibinin and polyoxyethylene sorbate, polyoxyethylene castor oil, generation when the polyoxyethylene hydrogenated Oleum Ricini compatibility is used
Fig. 4. the emulsion particle diameter scattergram that the solution that particle size analyzer forms silibinin compositions self-emulsifying microemulsion carries out granulometry
Fig. 5. soft capsule that silybin supersaturated self-emulsion composition of the present invention is made and commercially available capsular silibinin blood drug level through the time curve
Specific embodiment
It is composed as follows to write out a prescription:
Silibinin 25g
VE succinic acid cetomacrogol 1000 ester 340g
1,2-propylene glycol 50g
MCT Oil 100g
PVP K30 4g
HPMC K100M 4g
The preparation method of the silybin supersaturated self-emulsion composition in the present embodiment is: silibinin, oil phase, emulsifying agent, coemulsifier are heated while stirring in 90 ℃ of water-baths, treat that silibinin all after the dissolving, adds stabilizing agent, mixing both.
Silibinin 45g
VE succinic acid Macrogol 2000 ester 340g
1,2-propylene glycol 50g
Decanoyl/octanoyl glycerides 100g
PVP K30 4g
HPMC K100M 4g
The preparation method of the silybin supersaturated self-emulsion composition in the present embodiment is: silibinin, oil phase, emulsifying agent, coemulsifier are heated while stirring in 70 ℃ of water-baths, treat that silibinin all after the dissolving, adds stabilizing agent, mixing both.
Silibinin 35g
Lecithin 230g
1,2-propylene glycol 40g
Decanoyl/octanoyl glycerides 75g
PVP K30 6g
The preparation method of the silybin supersaturated self-emulsion composition in the present embodiment is: silibinin, oil phase, emulsifying agent, coemulsifier are heated while stirring in 60 ℃ of water-baths, treat that silibinin all after the dissolving, adds stabilizing agent, mixing both.
Silibinin 20g
Fabaceous lecithin 160g
1,2-propylene glycol 30g
Middle chain saturated fatty acid triglyceride 45g
PVP K30 4g
The preparation method of the silybin supersaturated self-emulsion composition in the present embodiment is: silibinin, oil phase, emulsifying agent, coemulsifier are heated while stirring in 40 ℃ of water-baths, treat that silibinin all after the dissolving, adds stabilizing agent, mixing both.
Silibinin 35g
Glyceryl monostearate 300g
1,2-propylene glycol 50g
Decanoyl/octanoyl glycerides 100g
PVP K30 8g
The preparation method of the silybin supersaturated self-emulsion composition in the present embodiment is: silibinin, oil phase, emulsifying agent, coemulsifier are heated while stirring in 70 ℃ of water-baths, treat that silibinin all after the dissolving, adds stabilizing agent, mixing both.
Silibinin 45g
Mono laurate double glyceride 300g
1,2-propylene glycol 50g
Decanoyl/octanoyl glycerides 100g
HPMCK15M 8g
Silybin supersaturated self-emulsion preparation of compositions method in the present embodiment is: silibinin, oil phase, emulsifying agent, coemulsifier are heated while stirring in 80 ℃ of water-baths, treat that silibinin all after the dissolving, adds stabilizing agent, mixing both.
Silibinin 30g
Lecithin 500g
1,2-propylene glycol 50g
Middle chain saturated fatty acid triglyceride 100g
HPMCK15M 8g
The preparation method of the silybin supersaturated self-emulsion composition in the present embodiment is: silibinin, oil phase, emulsifying agent, coemulsifier are heated while stirring in 65 ℃ of water-baths, treat that silibinin all after the dissolving, adds stabilizing agent, mixing both.
Although described the present invention by specific embodiment, some modification or equivalence are obvious for the technical staff who is proficient in this field, and these variations are believed to comprise within the scope of the present invention.
Press specific embodiment 1 preparation silibinin self-emulsion composition.Breast grain particle diameter with Nicomp 370 type laser light scattering particle size analyzer working sample liquid.The results are shown in Table:
The measurement result of table 1 self-emulsifying microemulsion ability and particle diameter
| Medium | Water | 0.1mol /LHCl | PBS(pH＝6.8) |
| Particle diameter (nm) | 16.8 | 21.7 | 18.8 |
Press specific embodiment 1 preparation silibinin self-emulsion composition, and, make the silibinin self-microemulsion soft capsules the silibinin self-emulsion composition solution soft capsule of packing into.Carry out pharmacokinetic studies by following experimental technique.
Table 2 pharmacokinetics test specimen
| Test name | Reference | Test article | 1 | |
| Sample title specification content | Every of silibinin capsule contains silibinin 35mg commercial goods, and capsule 's content is the silibinin phosphatide complexes, filler etc. | Every component that contains silibinin 35mg following examples 1 of silibinin self-emulsifying microemulsion gastric solubleness soft capsule of the present invention, the capsule of making according to corresponding preparation technology | Every component that contains silibinin 35mg following examples 3 of silibinin self-emulsifying microemulsion enteric soft capsules of the present invention, the capsule of making according to corresponding preparation technology |
9.1 test method:
Get 6 of healthy qualified Beagle dogs, half and half, 10 monthly age of male and female, body weight 8 ± 0.5Kg, its liver of pretest inspection, renal function and electrocardiogram, the result is all normal.Dog is divided into two groups (3 every group) at random, and test group is taken 4 of silibinin self-emulsification soft capsules (being equivalent to silibinin 140mg), and matched group is taken 4 of commercially available hard capsules (being equivalent to silibinin 140mg).The intersection administration, the clean phase is a week.Experiment fasting the previous day 12h freely drinks water, unified feed behind the administration 4h.Get blank blood before the administration, after the administration respectively at the 0th, 0.5,1,1.5,2,3,4,5,7,9,12 and 24h get forelimb venous blood 5 mL, heparin (50 units/mL) anticoagulant.Centrifugal 10min under the 3000r/min condition immediately, separated plasma is preserved down in-20 ℃, and is to be analyzed.After getting blood at every turn and finishing dog is put in and is free state in the cage.
9.2 the assay method of silibinin in the blood sample:
The accurate blood plasma 1.0mL that draws places 7mL band plug round bottom centrifuge tube, adds 0.2mol/L phosphate buffer (pH=5.0) 0.5mL, 100 μ L β-Pu Taotanggansuanmei solution (enzymatic activity is equivalent to 30u), and vortex 30s cultivates 16h in 37 ℃ of water-baths.Add 49.8 μ g/ml betanaphthol solution, 50 μ L, 0.5mol/l ((pH=8.5) 2.0mL, vortex 30s add the extraction of 3.5mL acetic acid ethyl ester to borate buffer solution, vortex 1min, the centrifugal 10min of 3000r/min separates organic layer, places point end centrifuge tube, nitrogen dries up in 45 ℃ of water-baths, residue dissolves with mobile phase 100 μ L, and the centrifugal 10min of 4000r/min gets supernatant 50 μ L and enters high performance liquid chromatograph.Record chromatogram and peak area are according to blood drug level in the standard curve Equation for Calculating Beagle dog body.Do the blood plasma blank as stated above simultaneously.Measure the concentration of silibinin in the dog plasma with high-efficient liquid phase technique.Chromatographic condition: chromatographic column is Diamonsil C
18(200mm * 4.6mm, 5 μ m), mobile phase is methanol-water-glacial acetic acid (51: 49: 0.5 v/v/v), flow velocity is 1.0 ml/min.Ultraviolet detection wavelength 288nm.The result is in the scope concentration of 0.049～19.6 μ g/ml, and the silibinin peak area becomes good linear relationship with the ratio of interior mark betanaphthol peak area with its concentration.The recovery of extraction scope of silibinin is 87.1%～94.3% in the blood plasma, and silibinin quantitatively is limited to 0.049 μ g/ml in the plasma sample.
Measure the silibinin content in the blood plasma, and calculate relative bioavailability.
9.3 result of the test
Table 3 pharmacokinetics result of the test
| Reference/sample title | Reference | Test article | 1 | Test article 2 |
| t 1/2(k e)(h) Ke(h 1) T max(h) C max(μg/ml) AUC 0→12(μg·h/ml) AUC 0→∞(μg·h/ml) AUMC 0→12(μg·h 2/ml) AUMC 0→∞(μg·h 2/ml) MRT(h) MAT(h) | 1.8490 0.3748 2.0 0.347 1.867 1.912 6.3921 6.8276 3.3617 0.6473 | 2.1448 0.3231 1.5 1.043 4.1037 4.3764 18.9713 22.7846 3.9781 0.7833 | 2.83 0.2845 2.5 1.038 4.528 4.813 20.873 25.763 4.1023 0.846 |
Relative bioavailability:
Last table presentation of results: all more commercially available reference preparation height of blood drug level and bioavailability behind the soft capsule that the oral silibinin self-emulsifying composition makes.
Claims (12)
1. a silybin supersaturated self-emulsion composition is characterized in that, the component of self-emulsion composition and percentage by weight are:
Silibinin 1～20%
Oil phase 5～40%
Emulsifying agent 10～90%
Coemulsifier 1～20%
Stabilizing agent 0.5～10%
2. silybin supersaturated self-emulsion composition according to claim 1 is characterized in that: contain active constituents of medicine silibinin 5～100mg in every silybin supersaturated self-emulsion compositions, preferred 15～50mg in this scope.
3. silybin supersaturated self-emulsion composition according to claim 1 is characterized in that: described oil phase can be natural animal and vegetable oil, through the vegetable oil after structure of modification and the hydrolysis.
4. silybin supersaturated self-emulsion composition according to claim 3, it is characterized in that: described oil phase can be the medium long-chain fat acid glyceride of chain length between C8～C10, and employed oil phase can be selected from one of following or their combination: soybean oil, Oleum Arachidis hypogaeae semen, safflower oil, olive oil, fish oil, egg oil, whale oil, butter, oleic acid, olein, glyceryl linoleate, ethyl oleate, MCT Oil, decanoyl/octanoyl glycerides.
5. silybin supersaturated self-emulsion composition according to claim 1 is characterized in that: described emulsifying agent can be nonionic surfactant, amphoteric ionic surfactant, natural surfactant.
6. silybin supersaturated self-emulsion composition according to claim 5 is characterized in that: described emulsifying agent can be selected following one or more for use: glyceryl monostearate, mono laurate double glyceride, sucrose monolaurate, lecithin, fabaceous lecithin, watermiscible vitamin E, arabic gum, tragakanta, agar, sodium alginate, cholesterol, casein.
7. silybin supersaturated self-emulsion composition according to claim 1, it is characterized in that: the existing hydrophilic of described coemulsifier also has lipophile, and coemulsifier helps active component to form the solution of transparent and homogeneous and keeps the stability of solution in storage process.
8. silybin supersaturated self-emulsion composition according to claim 7 is characterized in that: described coemulsifier can be selected following one or more for use: ethanol, glycerol, propylene glycol, Polyethylene Glycol, propylene carbonate, ethylene glycol monomethyl ether, dimethyl Soquad etc.
9. silybin supersaturated self-emulsion composition according to claim 1 is characterized in that: described stabilizing agent is the polymer substance with viscosity.
10. silybin supersaturated self-emulsion composition according to claim 9 is characterized in that: described stabilizing agent is one or more in polyvinylpyrrolidone (PVP), hypromellose (HPMC), Carboxymethyl cellulose sodium (CMC), starch and derivant, gelatin and derivant thereof, alginic acid and the sodium salt thereof etc.
11. preparation method according to described each silybin supersaturated self-emulsion composition of claim 1-9, it is characterized in that: silibinin, oil phase, emulsifying agent, the coemulsifier of recipe quantity are heated while stirring at 20～100 ℃, after treating the silibinin dissolving, add stabilizing agent, mixing promptly.
12., it is characterized in that: make capsule, soft capsule, injection or percutaneous plaster according to described each silybin supersaturated self-emulsion composition of claim 1-9.
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Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102614239A (en) * | 2012-04-25 | 2012-08-01 | 晨光生物科技集团天津有限公司 | Silymarin compound nanoparticle and preparation method thereof |
| CN103655482B (en) * | 2012-09-19 | 2016-05-25 | 重庆医科大学 | Be used for self-emulsifying microemulsion ca alginate gel bead of medicine carrying and preparation method thereof |
| CN109223721A (en) * | 2018-09-28 | 2019-01-18 | 江苏天美健大自然生物工程有限公司 | Phosphatide milk thistle vitamin E composition and its preparation method and application |
| CN110123751A (en) * | 2018-06-14 | 2019-08-16 | 中国药科大学 | A kind of milk thistle class medicament nano cream dust composition and preparation method thereof |
| CN111714454A (en) * | 2020-07-22 | 2020-09-29 | 宿迁医美科技有限公司 | Perilla seed oil and silybum marianum seed oil compounded fat emulsion and preparation method thereof |
| CN111728209A (en) * | 2019-03-25 | 2020-10-02 | 株式会社爱茉莉太平洋 | Composition for enhancing bioavailability of silymarin |
-
2007
- 2007-08-23 CN CNA2007101433908A patent/CN101143142A/en active Pending
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102614239A (en) * | 2012-04-25 | 2012-08-01 | 晨光生物科技集团天津有限公司 | Silymarin compound nanoparticle and preparation method thereof |
| CN103655482B (en) * | 2012-09-19 | 2016-05-25 | 重庆医科大学 | Be used for self-emulsifying microemulsion ca alginate gel bead of medicine carrying and preparation method thereof |
| CN110123751A (en) * | 2018-06-14 | 2019-08-16 | 中国药科大学 | A kind of milk thistle class medicament nano cream dust composition and preparation method thereof |
| CN109223721A (en) * | 2018-09-28 | 2019-01-18 | 江苏天美健大自然生物工程有限公司 | Phosphatide milk thistle vitamin E composition and its preparation method and application |
| CN111728209A (en) * | 2019-03-25 | 2020-10-02 | 株式会社爱茉莉太平洋 | Composition for enhancing bioavailability of silymarin |
| CN111714454A (en) * | 2020-07-22 | 2020-09-29 | 宿迁医美科技有限公司 | Perilla seed oil and silybum marianum seed oil compounded fat emulsion and preparation method thereof |
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