CN101618015A - Microemulsion composition containing Silibinin complex - Google Patents
Microemulsion composition containing Silibinin complex Download PDFInfo
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- CN101618015A CN101618015A CN200810116086A CN200810116086A CN101618015A CN 101618015 A CN101618015 A CN 101618015A CN 200810116086 A CN200810116086 A CN 200810116086A CN 200810116086 A CN200810116086 A CN 200810116086A CN 101618015 A CN101618015 A CN 101618015A
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Abstract
The invention relates to a microemulsion composition. The composition comprises Silibinin compound used as an active component, emulsifying agent, auxiliary emulsifying agent and oil. The microemulsion composition can further increase Silibinin solubility and bioavailability.
Description
Technical field
The present invention relates to a kind of microemulsion composition containing Silibinin complex.
Background technology
Liver is the metabolism organ that body weight for humans is wanted, and a lot of important physical activities all will lean on the operate as normal of liver to carry out smoothly.Several factors all can exert an influence to liver, such as overworked, bad dietary habit (the excessive picked-up of high protein, higher fatty acid and high confectionery thing), excessively smoking is drunk, infectious disease and virus attack all can produce harm to liver.Therefore, hepatopathy becomes one of very high disease of sickness rate, also is one of disease of healing of refractory.
It is reported that hepatic injury is with to produce too much free radical relevant, therefore, the free radical resisting activity becomes one of leading indicator of treatment hepatic injury.In numerous free radical resisting natural products, silymarin is a few one of widely used medicine clinically, and clinical practice for many years proved its determined curative effect, and toxicity is extremely low.
Herba Silybi mariani Silybum ma-rianum (L.) Gaeren is a feverfew, is used as medicine with achene.Originate in southern Europe and north African, 1972 by Germany's introducing NORTHWEST CHINA, North China's cultivation.Silymarin (silymarin) means flavanolignan's constituents that the class flavanonol that extracts and phenyl propanoid derivative condensation form from the seed of Herba Silybi mariani.The content that is used at present the silymarin total flavones lignanoid of preparation in the world is about 80%, wherein mainly contain silibinin (Silybin), dehydro-silibinin (dehydrosi-Silybin), silybinomer (Silybinomer), Herba Silybi mariani Roripa (Silychristin), silidianin (Silydianin) etc., above composition is referred to as silymarin at present.Topmost composition is silibinin and isomers Isosilybin thereof in the silymarin, and silibinin is dissolved in acetone, ethyl acetate, methanol, ethanol, is slightly soluble in chloroform, and is water insoluble.Silibinin has pharmacological characteristics more widely, and there is the multiple mechanism of action in its therapeutical effect to hepatopathy, has found that it has following effect in the resisting alcoholic hepatic injury: 1. remove oxygen-derived free radicals and prevent cytotoxicity; 2. protect cell membrane; 3. promote the hepatocyte reparative regeneration; 4. fibrosis; 5. immunoregulation effect.Be widely used in antioxidation clinically and remove free radical, treat diseases such as chronic alcoholic liver poisoning and various acute, chronic hepatitis liver cirrhosis, treat hyperlipemia, control ischemic cardio cerebrovascular diseases, anti-platelet aggregation, prevent and treat diabetes and complication etc.In addition, it is also having certain effect aspect tuberculosis, the health and beauty.
Silibinin is a clinical practice natural activity chemical compound widely, and constantly has new effect to be found, and has no side effect simultaneously.
Silibinin is the maximum main active of the content in the silymarin, have clear and definite structure, for the higher one-component of purity can, lost the assosting effect of other isomer, make it have the dissolubility lower than silymarin, oral absorption is poorer.
Micro emulsion composition, perhaps self-emulsifying composition, be the solution of the transparent and homogeneous that forms by oil phase, emulsifying agent, coemulsifier (also comprising water in the micro emulsion composition), under temperature (being generally 37 ℃) and the temperate condition, form the microemulsion microgranule of particle diameter below 1 μ m in vivo by gastric peristalsis.Medicine is present in these tiny microemulsion microgranules, is distributed in whole gastrointestinal tract fast, and medicine distributes between oil/water is biphase, the stripping that the huge specific surface area of dependence fine particles improves insoluble drug greatly, thus improve bioavailability of medicament.
(it is warm that article sees Zhao for details for Zhao Nuan etc., Luan Libiao, " pharmacokinetics of silibinin-phosphatide complexes and pharmacodynamic study progress ", the pharmacy progress, 2006,30 (7), 295-9) point out chromocor compounds such as the silibinin reason of absorption difference in vivo, may be that its molecular structure is complicated, be difficult to absorb, and they again can not active absorption by simple diffusion; Secondly, the compatibility of flavone molecule and oils and fats and other lipophilic substances is poor, has limited its ability by intestinal epithelial cell lipid adventitia greatly.Behind this flavonoid molecule forming composite, then be easy to enter the lipophilic environment, enter cell, finally arrive blood plasma by the hydrophilic environment of enterocyte film.
Adopt microemulsified or self-emulsifying microemulsion technology to make the microemulsion concentrated solution of microemulsion solution or self-microemulsion, oral back can form microemulsion rapidly in gastrointestinal tract, significantly improve the dissolution of silibinin, thereby improve its bioavailability.Why the reason with phosphatide complexes is the dissolution characteristics that is in silibinin, its solvability in polarity and non-polar solven is all relatively poor, ready-made phosphatide complexes has oily preferably solvability, the dissolubility that can improve in oil phase makes it reach the dosage of clinical administration, in addition, complex is made the distribution that micro emulsion composition can improve complex, help the dispersity of complex in gastrointestinal tract more, help more entering the body circulation, thereby reach the effect of further raising bioavailability by small intestine epithelium.
Summary of the invention
The invention provides a kind of silibinin phosphatide complexes micro emulsion composition.
The invention provides a kind of oral and emulsifying composition drug administration by injection of being used for, it comprises silibinin complex, emulsifying agent, co-emulsifier, and the microemulsion that constitutes of other adjuvant
The oil that adopts among the present invention, be the oil compatible with coemulsifier,, comprise to form stable microemulsion with described emulsifying agent: MCT Oil (as Miglyol 812N), medium-chain fatty acid list-, two-or the ester of list/two-glyceride, fatty acid unit price alkanol, as C
8～C
20Fatty acid and C
2-
3The ester of monovalent alcohol (as isopropyl myristate, Ethyl linoleate, ethyl oleate), crude vegetal or animal oil (as Semen Maydis oil, Oleum Glycines, olive oil), carbohydrate (as Squalene and squalane), other forms of fatty acid (as oleic acid and linoleic acid or wherein several mixture), and their mixture.The preferred oleic acid of the present invention, linoleic acid, Miglyol 812N, Ethyl linoleate or ethyl oleate and their mixture.
The emulsifying agent that the present invention uses is generally the agent of HLB value higher surface activity, comprise: the acidifying natural or hydrogenated vegetable oil (polyoxyethylene castor oil Cremophor EL) of polyoxyethylene glycol, polyoxyethylene sorbitan fatty acid ester (as Tween), polyoxyethylene fatty acid ester such as Myrj 45 (Myrij), polyox-yethylene-polyoxypropylene block copolymer (Poloxamer), polyoxyethylene aliphatic alcohol ether (Brij), dioctyl sodium sulphosuccinate, sodium lauryl sulphate, cholic acid or its salt, the phospholipid or derivatives thereof, propylene glycol list or di fatty acid ester, as the propylene glycol dicaprylate, propylene glycol is sad-capric acid diester (Miglyol 840), the transesterification product of crude vegetal triglyceride and poly alkylene glycol (Labrafil M), the glycerol list, two or list/two acid esters, as glycerol list and two caprylic/capric esters (Imwitor), fatty acid esters of sorbitan (as Span), the sterol or derivatives thereof, as cholesterol, plant sterol (Pytosterol) and their mixture, preferred polyoxyethylene castor oil or Tweens and their mixture among the present invention.
The coemulsifier that the present invention uses has ethanol, propylene glycol, Polyethylene Glycol (molecular weight 200～600), propylene carbonate, TC (transcutol), tetrahydrofurfuryl alcohol polyglycol ether (Glycofurol), Isosorbide dimethyl ether or their mixture.Wherein preferred Polyethylene Glycol, ethanol or Isosorbide dimethyl ether and their mixture.
According to the present invention, silibinin in the composition of micro emulsion composition: oil: emulsifying agent: the weight ratio of coemulsifier is 1: 1-5: 15-20: 5-15.
In addition, also comprise in the micro emulsion composition of the present invention to learn in the oral administration acceptable additive, as aromatic, stabilizing agent and antiseptic.
Stabilizing agent used in the present invention is the one or more combination in sodium sulfite, sodium pyrosulfite, sodium isoascorbate, vitamin E, sodium L-ascorbate-2-phosphate, propyl gallate, butylated hydroxyarisol (BHA), the di-tert-butyl hydroxy-methylbenzene (BHT), stabilizing agent is 0.01%～2% in the bulking value concentration of microemulsion, is preferably 0.01%～1%.
Can with adjuvant preparation of compositions be become injection, oral liquid and soft capsule etc. with pharmaceutically useful additive according to any conventional method in the medicament.For example, add an amount of water for injection, antiseptic, aromatic, can be made into oral liquid; Or add antiseptic and be filled in the soft capsule shell, can be made into soft capsule.
In order to reach purpose of the present invention, the present invention has carried out granularmetric analysis and pharmacokinetics test behind dissolution determination, the microemulsified.
As mentioned above, the present composition can improve the dissolubility of silibinin compositions, further improves bioavailability, reduces individual variation, improves the curative effect of medicine.
Description of drawings
Fig. 1 is silibinin phosphatide complexes self-emulsification soft capsules and commercially available product dissolution curve
Fig. 2 silibinin self-emulsification soft capsules particle size distribution figure after the emulsifying in simulated gastric fluid
Fig. 3 is silibinin phosphatide complexes self-emulsification soft capsules and commercially available product pharmacokinetics test blood drug level-time graph
Following examples are used to further describe the present invention, but limit the scope of the present invention anything but.
The specific embodiment
Silibinin phosphatide complexes 53mg
Cremophor?EL35 350mg
Imwitor392 200mg
Ethanol 150mg
PEG400 150mg
Ethyl linoleate 50mg
Sodium benzoate 20mg
Sodium sulfite 5mg
Oral liquid adds water to 10ml
Silibinin phosphatide complexes 53g
Cremophor?EL35 500mg
Phosphatidase 12 00mg
Glycofurol 150mg
PEG400 150mg
Oleic acid 80mg
Propylparaben 0.3mg
BHA 0.2mg
BHT 0.1mg
Soft capsule
Silibinin phosphatide complexes 53mg
IMWITOR?375 400mg
pytosterol 150mg
Isosorbide dimethyl ether 100mg
PEG600 200mg
Miglyol 35mg
Butoben 0.1mg
Sodium L-ascorbate-2-phosphate 0.2mg
Soft capsule
Embodiment 4
Silibinin phosphatide complexes 53mg
Cremophor?EL35 600mg
poloxamer?188 100mg
Transcutol 100mg
PEG300 200mg
Miglyol?812N 50mg
Ethyl hydroxybenzoate 0.5mg
Propyl gallate 1mg
Soft capsule
Silibinin phosphatide complexes 53mg
Cremophor?EL35 300mg
Fabaceous lecithin 350mg
Sodium deoxycholate 50mg
Isosorbide dimethyl ether 150mg
PEG400 150mg
Miglyol812N 100mg
Propylparaben 0.33mg
VE 0.55mg
Soft capsule
Silibinin phosphatide complexes 53mg
CremophorEL?35 450mg
Myrij?35 250mg
Propylene glycol 150mg
Glycerol formal 150mg
Semen Maydis oil 50mg
Sodium sorbate 10mg
Sodium erythorbate (water solublity) 50mg
Oral liquid (moisture) adds water to 10ml
Silibinin phosphatide complexes 80mg
Tween?80 500mg
Brij?35 50mg
Isobutyl carbonate propyl ester 100mg
Glycerol formal 200mg
Linoleic acid 100mg
Ethyl hydroxybenzoate 0.5mg
Sodium L-ascorbate-2-phosphate 0.2mg
Soft capsule
Silibinin phosphatide complexes 80mg
Tween?80 500mg
Imwitor375 50mg
Propylene glycol 100mg
Ethanol 100mg
Miglyol?812N 50mg
Propylparaben 0.25mg
Propyl gallate 0.8mg
Oral liquid
Silibinin phosphatide complexes 80mg
Tween?80 450mg
Fabaceous lecithin 200mg
Isosorbide dimethyl ether 250mg
Glycerol formal 200mg
Ethyl linoleate 80mg
Chlorobutanol 50mg
Sodium pyrosulfite 10mg
Oral liquid (moisture) adds water to 10ml
Silibinin phosphatide complexes 80mg
Tween?80 400mg
Labrafil 150mg
Transcutol 150mg
Ethanol 200mg
Ethyl oleate 50mg
Butoben 0.1mg
BHA 0.2mg
BHT 0.1mg
Oral liquid
Embodiment 11
Silibinin phosphatide complexes 80mg
Miglyol?812N 100mg
Ethanol 300mg
CremophorEL?35 600mg
Water for injection is an amount of
Injection
More than the preparation technology of all embodiment be: silibinin phosphatide complexes, oil, coemulsifier and the solvent of getting recipe quantity, heating, the control temperature is no more than 70 ℃, stir, after reducing to room temperature, add emulsifying agent and other additive in prescription ratio separately again, behind the mixing, make injection, oral concentrated solution respectively or on the soft capsule filling machine fill make oral soft capsule.
Test example 1. dissolution contrast tests
By Fig. 1 result as can be known, very fast stripping after embodiment 2 disintegrates, with commercially available product mutually intrisinc rate of dissolution obviously improve.
The granularmetric analysis behind the microemulsified in gastric juice of test example 2.
By Fig. 2 result as can be known, the self-emulsification soft capsules that embodiment 2 makes can form monodispersed little oil droplet in gastric juice, and mean diameter is about＜50nm.Result of the test illustrates that soft capsule content that this embodiment makes is easy to form the microemulsion drop rapidly in vivo the environment.
Test example 3. pharmacokinetics contrast tests
With the rat is that animal is used in development test, carries out gastric infusion (n=3) with embodiment 2 and commercially available product respectively, and dosage is 200mg/kg, and respectively at the different time blood sample collection, sampling time point is 0.25h 0.5h, 0.75h, 1h, 1.5h, 2h, 3h, 4h, 6h, 8h, 12h.Every rat is got blood with eye socket, separate and obtain serum, adding the concussion of internal standard substance and buffer vortex extracts, add mobile phase dissolving standardize solution behind the evaporate to dryness, sample introduction is analyzed, and assay method is the HPLC method, presses internal standard method with the peak area ratio calculating concentration, measure and calculate the blood drug level of different time points after above-mentioned two kinds of preparation administrations respectively, the results are shown in Figure 3.
By Fig. 3 result as can be known, with embodiment 2 administrations, compare with commercially available product, obviously improved and reach peak concentration, the AUC value also has significance to improve, and the two peak time is more close.
Invention has been described though utilized above-mentioned specific embodiment, it should be understood that those skilled in the art can also carry out various improvement or change, and in their scope of the invention that also should in as claim, limit.
Claims (9)
1. one kind is used for oral and micro emulsion composition drug administration by injection, and it comprises as the phosphatide complexes of the silibinin of active component, emulsifying agent, coemulsifier and oil, and acceptable other additive of pharmacy.
2. oral microemulsion compositions as claimed in claim 1, silibinin complex wherein: oil: emulsifying agent: the weight ratio of coemulsifier is 1: 1-5: 15-20: 5-15.
3. micro emulsion composition as claimed in claim 1, the effective dose that it is characterized in that silibinin are 0.2%～10% (W/V).
4. micro emulsion composition as claimed in claim 1, it is characterized in that described emulsifying agent is lecithin or soybean phospholipid and derivant thereof, polyox-yethylene-polyoxypropylene block copolymer, Polyethylene Glycol-fatty acid ester, the polyoxyethylene fatty acid ester class, the polyoxyethylene sorbitan fatty acid ester class, the polyoxyethylene aliphatic alcohol ether class, alkyl succinate, alkyl sulfate, polyethyleneglycol glyceride, the propylene glycol list-or two-fatty acid ester, glyceryl monoacetate, diglyceride or glycerol list/two acid esters, the crude vegetal triglyceride, cholic acid or its esters, polyoxyethylene castor oil and derivant thereof, sterol or derivatives thereof, and their mixture.
5. micro emulsion composition as claimed in claim 1 is characterized in that described coemulsifier is ethanol, propylene glycol, Polyethylene Glycol (molecular weight 200～600), propylene carbonate, TC, Isosorbide dimethyl ether or its mixture.
6. micro emulsion composition as claimed in claim 1, it is characterized in that described oil be MCT Oil, medium-chain fatty acid list-, two-or unit price alkanol ester, crude vegetal or animal oil, Squalene, squalane, oleic acid, linoleic acid or the wherein several mixture of list/two-glyceride, fatty acid.
7. micro emulsion composition as claimed in claim 1 is characterized in that described other additives comprise stabilizing agent, antiseptic, solvent, aromatic.
Micro emulsion composition as claimed in claim 1, it is characterized in that described stabilizing agent is the one or more combination in sodium sulfite, sodium pyrosulfite, sodium isoascorbate, vitamin E, sodium L-ascorbate-2-phosphate, propyl gallate, butylated hydroxyarisol (BHA), the di-tert-butyl hydroxy-methylbenzene (BHT), the bulking value concentration of stabilizing agent in microemulsion is 0.01%～2%.
8. micro emulsion composition as claimed in claim 1 is characterized in that described antiseptic is the mixture of chlorobutanol, benzoic acid or its esters, sorbic acid or its esters, oxybenzene Arrcostab or several Arrcostabs.
9. micro emulsion composition as claimed in claim 1 is characterized in that described solvent is glycerol, propylene glycol, Polyethylene Glycol, water or wherein several mixture.
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| CN200810116086A CN101618015A (en) | 2008-07-03 | 2008-07-03 | Microemulsion composition containing Silibinin complex |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102309441A (en) * | 2010-07-09 | 2012-01-11 | 天津天士力制药股份有限公司 | Silymarin medicinal composition wrapper and preparation method thereof |
| CN102872164A (en) * | 2012-08-30 | 2013-01-16 | 江苏大学 | Micro-emulsion preparation prepared from sterol in unsaponifiable flammulina velutipes extracts and preparation method of micro-emulsion preparation |
| CN107594534A (en) * | 2017-10-20 | 2018-01-19 | 广州润虹医药科技股份有限公司 | A kind of compound nutrient liquor with effects of losing weight and lowering blood sugar and blood lipid and preparation method thereof |
-
2008
- 2008-07-03 CN CN200810116086A patent/CN101618015A/en active Pending
Cited By (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102309441A (en) * | 2010-07-09 | 2012-01-11 | 天津天士力制药股份有限公司 | Silymarin medicinal composition wrapper and preparation method thereof |
| WO2012003804A1 (en) * | 2010-07-09 | 2012-01-12 | 天津天士力制药股份有限公司 | Pharmaceutical composition of silybin and preparation method thereof |
| CN102958510A (en) * | 2010-07-09 | 2013-03-06 | 天士力制药集团股份有限公司 | Pharmaceutical composition of silybin and preparation method thereof |
| CN102309441B (en) * | 2010-07-09 | 2015-07-22 | 天士力制药集团股份有限公司 | Silymarin medicinal composition wrapper and preparation method thereof |
| CN102958510B (en) * | 2010-07-09 | 2015-09-09 | 天士力制药集团股份有限公司 | A kind of Silymarin medicinal composition wrapper and preparation method thereof |
| CN102872164A (en) * | 2012-08-30 | 2013-01-16 | 江苏大学 | Micro-emulsion preparation prepared from sterol in unsaponifiable flammulina velutipes extracts and preparation method of micro-emulsion preparation |
| CN107594534A (en) * | 2017-10-20 | 2018-01-19 | 广州润虹医药科技股份有限公司 | A kind of compound nutrient liquor with effects of losing weight and lowering blood sugar and blood lipid and preparation method thereof |
| CN107594534B (en) * | 2017-10-20 | 2020-09-15 | 广州润虹医药科技股份有限公司 | Compound nutrient solution with functions of losing weight, reducing blood sugar and reducing blood fat and preparation method thereof |
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Application publication date: 20100106 |