CN104667284B - Oleanolic acid is used to modify application of the Emodin Liposome in medicine is prepared - Google Patents
Oleanolic acid is used to modify application of the Emodin Liposome in medicine is prepared Download PDFInfo
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- CN104667284B CN104667284B CN201510061160.1A CN201510061160A CN104667284B CN 104667284 B CN104667284 B CN 104667284B CN 201510061160 A CN201510061160 A CN 201510061160A CN 104667284 B CN104667284 B CN 104667284B
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- emodin
- liposome
- oleanolic acid
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Abstract
It is used for the application for modifying Emodin Liposome the invention provides oleanolic acid, oleanolic acid is additionally provided to be used to modify application of the Emodin Liposome in medicine is prepared, the medicine ordinance generally to be prepared by well known to a person skilled in the art processing method, wherein more preferably it is tablet, granule, oral liquid or capsule, Emodin Liposome is modified using oleanolic acid, recognition capability of the rheum emodin to target organ can be improved, or directly increase concentration of the rheum emodin in target organ, largely reduce drug toxicity, further improve the targeting of Emodin Liposome, strengthen therapeutic effect.
Description
Technical field
The invention belongs to pharmaceutical technology field, and in particular to oleanolic acid is preparing medicine for modifying Emodin Liposome
In application.
Background technology
Rheum emodin alias 9,10-Anthracenedione,1,3,8-thihydroxy-6-methyl, English name Emodin, chemical name：1'3'8- trihydroxy -6- tectoquinones, orange
The long acicular crystal of yellow (crystallization is orange that crystallization is yellow in methanol in acetone), 256 DEG C~257 DEG C of fusing point.With anthraquinone
Special reaction.Water is practically insoluble in, is dissolved in ethanol and aqueous slkali.Rheum emodin can be used as cathartic, though there is Purgative activity, due to body
Interior be easily oxidized is destroyed, and actually discharge function is very weak, and glycoside is such as combined into sugar, then can play discharge function.Rheum emodin -1-
O- β-D-Glucose glycosides and emodin -8-O-β-D-glucosule person are the glycosides that rheum emodin is combined with glucose, and the two is simply tied
The position of conjunction is different, while is present in rheum officinale.It is another to have the effect such as antibacterial, cough-relieving, antitumor, hypotensive.
Oleanolic acid is hepatopathy adjuvant, is clinically used for treating infectious acute icteric hepatitis, has obvious reduce
Glutamic-pyruvic transaminase and removing jaundice effect, improve viral and the symptom of chronic persistant hepatitis patient, sign and liver function；Also it can use
In psoriasis, rheumatic arthritis, nephritic dropsy, cirrhotic ascites, acute, chronic hepatitis, stranguria with turbid discharge of having a stomachache, metrorrhagia, traumatic injury,
The diseases such as carbuncle swells, soreness and weakness of waist and knees, fetal irritability.
Rheum emodin is fat-soluble, and bioavilability is low, and widely distributed in vivo after administration, lacks targeting.There is scholar
Rheum emodin is made magnetic nano liposome, lipid nanometer microvesicle is to improve the shortcomings that its bioavilability is low.But common
Study on targeting of liposome effect has to be reinforced, has document report guiding drug and target administration to have similitude, theory of traditional Chinese medical science thinks, tying-in
Medicine can change action direction or the position of other medicines, or its effect is stressed or is concentrated on specific direction and position.Application
People prepares oleanolic acid-Emodin Liposome using film-ultrasonic wave dispersion technique, and research oleanolic acid-Emodin Liposome is small
Pharmacokinetics in mouse body, experimental basis is provided to study its Tissue distribution, whether strengthen rheum emodin fat for research oleanolic acid
Plastid targeting is laid the groundwork.
The content of the invention
It is an object of the invention to improve the utilization rate of rheum emodin, strengthen the targeting in human body of rheum emodin, pass through
Emodin Liposome is modified using the active component oleanolic acid in Chinese medicine guiding drug as face finish material, so as to improve rheum officinale
The medicinal efficiency and targeting of element.
The present invention realizes especially by following technical scheme：
It is used for the application for modifying Emodin Liposome the invention provides oleanolic acid.
It is used to modify application of the Emodin Liposome in medicine is prepared present invention also offers oleanolic acid.
Medicine belonging to the present invention can be prepared into any pharmaceutically acceptable formulation according to processing needs, and it configures logical
Often to be prepared, i.e., mixed active component with liquid flux or solid carrier by well known to a person skilled in the art processing method,
It is prepared adding at least one surfactant, wherein being more preferably tablet, granule, oral liquid or capsule.
Medicine of the present invention can be used before use by user through dilution or directly.
Oleanolic acid of the present invention can be also administered simultaneously with rheum emodin, can improve identification of the rheum emodin to target organ
Ability, or directly increase rheum emodin in the concentration of target organ, drug toxicity is largely reduced, further improves rheum emodin lipid
The targeting of body, strengthen therapeutic effect.
Beneficial effects of the present invention are：Emodin Liposome is modified using oleanolic acid, research shows olive
Acid-Emodin Liposome can extend in mouse circulation time in vivo, reduce the utilization in rat kidney tissue scope, improving medicine
Efficiency and targeting.
Brief description of the drawings
Fig. 1 is Emodin Liposome group Drug-time curve of the embodiment of the present invention；
Fig. 2 is oleanolic acid of the embodiment of the present invention-Emodin Liposome group Drug-time curve.
Embodiment
With reference to embodiment, the present invention is described further, as described below, is only the preferable implementation to the present invention
Example, is not limited the present invention, any person skilled in the art is possibly also with the disclosure above
Technology contents be changed to the equivalent embodiment changed on an equal basis.It is every of the invention without departing from the present invention program content, foundation
Technical spirit any simple modification that following examples are made or equivalent variations, all fall within protection scope of the present invention.
Reference substance：Oleanolic acid reference substance (National Institute for Food and Drugs Control, lot number：110709-201206)；Rheum officinale
Plain reference substance (National Institute for Food and Drugs Control, lot number：110756-200110)；
Bulk drug：Oleanolic acid (Nanjing Ze Lang Pharmaceutical Technology Co., Ltd, lot number：ZL11225A, purity 98%)；Greatly
Flavine (West Asia reagent, lot number：1016837, purity 98%)；
Other materials：Cholesterol (Chengdu Ke Long chemical reagents factory, purity 99%)；Soybean lecithin (Chengdu section dragon
Chemical reagent factory, purity 99%)；
Animal：Male mouse of kunming 66,20~25g of body weight [Medical University Of Chongqing Experimental Animal Center card SCXK-
(Chongqing) 2007-0001].
Rheum emodin standard solution：Precision weighs rheum emodin standard items 10.0mg, is dissolved with methanol and is settled to 100ml appearances
In measuring bottle, it is 0.1mg/ml standard reserving solutions to be made into concentration, is stored in 4 DEG C, is diluted to a series of concentration before use.
Inner mark solution：Precision weighs internal standard 1,8- dihydroxy anthraquinone standard items 10.0mg, is dissolved and is settled to methanol
In 100ml volumetric flasks, it is 0.1mg/ml standard reserving solutions to be made into concentration, is stored in 4 DEG C, is diluted to concentration 4.0ug/ml before use.
PBS solution：Sodium dihydrogen phosphate 0.1g, dibastic sodium phosphate 0.78g, sodium chloride 4.10g accurately are weighed, is dissolved in 400ml steamings
Distilled water, salt acid for adjusting pH value to 6.7, distilled water is settled to 500ml.
The preparation of Emodin Liposome：Rheum emodin 20.0mg is weighed, lecithin 263.2mg, cholesterol 15.7mg, is dissolved in
In 20ml dichloromethane, mixed solution is contained in 250mL round-bottomed flasks, ultrasonic dissolution, the rotary evaporation under 40 DEG C of water-baths, burnt
Lipoids film is formed in bottle wall, adds 10mlPBS (pH=6.7) solution, is hydrated 2.5h, ultrasonic 20min, crosses 0.22um micropores
Filter membrane, prepare Emodin Liposome.
The preparation of oleanolic acid-Emodin Liposome：Weigh rheum emodin 10.0mg, oleanolic acid 10.0mg, lecithin
263.2mg, cholesterol 15.7mg, it is dissolved in 20ml dichloromethane, mixed solution is contained in 250ml round-bottomed flasks, ultrasound is molten
Solution, the rotary evaporation under 40 DEG C of water-baths, flask walls are interior to form lipoids film, adds 10ml PBS (pH=6.7) solution, hydration
2.5h, ultrasonic 20min, 0.22um miillpore filters are crossed, prepare oleanolic acid-Emodin Liposome.
The linear relationship of embodiment 1
6 parts of blank plasmas are taken, sequentially add a series of rheum emodin standard items and 4.0ug/ml inner mark solution 100ul, respectively
Be configured to 0.02,0.10,0.50,1.00,5.00,8.00ug/ml Standard plasma samples.
Add 100ul15% sulfuric acid, be vortexed and mix, (70 ± 2) DEG C heating water bath hydrolysis 30min.Cooling, add ether
2.0ml, vortex 5min, 4000r/min centrifugation 5min, draws ether layer, aqueous phase is extracted once again with 2.0ml ether with method, is closed
And ether solution, nitrogen drying, residue 100ul methanol dissolve twice.12000r/min centrifugations 10min takes supernatant.By chromatographic column：
Thermo Syncronis C18 (250mm × 4.6mm, 5um) post；Mobile phase:0.1% phosphate buffer solution:Methanol=15:85
(V/V)；Ultraviolet detection wavelength：254nm；Flow velocity：1.0ml/min；Column temperature：30℃；Sample introduction 20ul is determined.
With plasma sample concentration x (ug/ml) for abscissa, rheum emodin and internal standard chromatographic peak area ratio y are ordinate, are entered
Row linear regression, it is y=0.316x+0.0055r=0.9988 to obtain equation of linear regression, the results showed that rheum emodin 0.02~
There is good linear relation in 8.00ug/ml concentration ranges.0.02ug/ml is quantitatively limited to, detection is limited to 0.01ug/ml.
The pharmacokinetic of embodiment 2
60 healthy male mouse of kunming are taken, are randomly divided into a, two groups of b, a groups are Emodin Liposome group, and b groups are neat pier
Tartaric acid-Emodin Liposome group.After fasting 12h, by rheum emodin dosage 5mg/kg, a group tail vein injection Emodin Liposome, b
Group tail vein injection oleanolic acid-Emodin Liposome.Administration after time point 0.083h, 0.16h, 0.25h, 0.5h, 1h,
Every group of 3 mouse orbits of 2h, 4h, 6h, 12h, 24h take blood into the centrifuge tube added with heparin, and 10min is centrifuged in 4000r/min,
Supernatant blood plasma is taken, is preserved in -20 DEG C, it is stand-by.
Precision measures upper plasma 100ul and put in 5ml test tubes, addition 100ul internal standards 1,8- dihydroxy anthraquinones (4ug/ml),
Add 100ul15% sulfuric acid, be vortexed and mix, (70 ± 2) DEG C heating water bath hydrolysis 30min.Cooling, ether 2.0ml is added, be vortexed
5min, 4000r/min centrifuge 5min, draw ether layer, and aqueous phase is extracted once again with 2.0ml ether with method, merge ether twice
Liquid, nitrogen drying, the dissolving of residue 100ul methanol.12000r/min centrifugations 10min takes supernatant.By chromatographic column：Thermo
Syncronis C18 (250mm × 4.6mm, 5um) post；Mobile phase:0.1% phosphate buffer solution:Methanol=15:85(V/V)；
Ultraviolet detection wavelength：254nm；Flow velocity：1.0ml/min；Column temperature：30℃；Sample introduction 20ul is determined.Drug-time curve such as Fig. 1 and Fig. 2 institutes
Show.The softwares of Kinetica 2000 calculate pharmacokinetic parameters, and pharmacokinetic parameters the results are shown in Table 1.
The Emodin Liposome of table 1 and pharmacokinetic parameters (n=3) after oleanolic acid-Emodin Liposome administration
As shown in Table 1, the Cmax of Emodin Liposome and oleanolic acid-Emodin Liposome is respectively (1.99 ± 0.11)
Ug/ml and (2.02 ± 0.05) ug/ml；Vss is respectively (8671.08 ± 1247.31) ml/kg and (8188.13 ± 2548.07)
ml/kg；AUC0-t is respectively (4.62 ± 0.30) ugh/ml and (5.36 ± 1.15) ugh/ml；Clearance rate is (974.86
± 117.74) ml/hkg and (854.14 ± 170.13) ml/hkg.Year-on-year Emodin Liposome, oleanolic acid-rheum emodin
Liposome AUC0-t increases, and clearance rate reduces, and shows that oleanolic acid-Emodin Liposome can extend in mouse body-internal-circulation
Between；Vss is reduced simultaneously, is shown in rat kidney tissue be not as extensive as Emodin Liposome.
Claims (1)
1. oleanolic acid is used for the application for modifying Emodin Liposome, it is characterised in that oleanolic acid is used to modify rheum emodin fat
The method of plastid is：Rheum emodin 10.0mg is taken, oleanolic acid 10.0mg, lecithin 263.2mg, cholesterol 15.7mg, is dissolved in
In 20mL dichloromethane, mixed solution is contained in 250mL round-bottomed flasks, ultrasonic dissolution, the rotary evaporation under 40 DEG C of water-baths, burnt
Lipoids film is formed in bottle wall, adds 10mL pH=6.7 PBS solution, is hydrated 2.5h, ultrasonic 20min, cross 0.22 μm it is micro-
Hole filter membrane, prepare oleanolic acid-Emodin Liposome.
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Citations (6)
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| CN1857322A (en) * | 2006-03-28 | 2006-11-08 | 康成礼 | Antitumor animal medicine and its preparing method |
| CN1923178A (en) * | 2006-08-22 | 2007-03-07 | 河南大学 | Oleanolic acid liposome preparation, freeze dried powder injecta thereof and its preparation |
| CN101991538A (en) * | 2009-08-14 | 2011-03-30 | 浙江工业大学 | TPGS-containing liposome composition and application thereof |
| CN102151302A (en) * | 2010-02-11 | 2011-08-17 | 四川大学华西医院 | Rhubarb liposome for external use, and preparation method and application thereof |
| CN102895678A (en) * | 2012-09-18 | 2013-01-30 | 浙江大学 | Liver-targeted magnetic resonance imaging contrast agent based on oleanolic acid and preparation method thereof |
| CN104208071A (en) * | 2014-09-12 | 2014-12-17 | 重庆医科大学 | Norcantharidin oleanolic acid complex lipidosome and preparation method thereof |
-
2015
- 2015-02-06 CN CN201510061160.1A patent/CN104667284B/en not_active Expired - Fee Related
Patent Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1857322A (en) * | 2006-03-28 | 2006-11-08 | 康成礼 | Antitumor animal medicine and its preparing method |
| CN1923178A (en) * | 2006-08-22 | 2007-03-07 | 河南大学 | Oleanolic acid liposome preparation, freeze dried powder injecta thereof and its preparation |
| CN101991538A (en) * | 2009-08-14 | 2011-03-30 | 浙江工业大学 | TPGS-containing liposome composition and application thereof |
| CN102151302A (en) * | 2010-02-11 | 2011-08-17 | 四川大学华西医院 | Rhubarb liposome for external use, and preparation method and application thereof |
| CN102895678A (en) * | 2012-09-18 | 2013-01-30 | 浙江大学 | Liver-targeted magnetic resonance imaging contrast agent based on oleanolic acid and preparation method thereof |
| CN104208071A (en) * | 2014-09-12 | 2014-12-17 | 重庆医科大学 | Norcantharidin oleanolic acid complex lipidosome and preparation method thereof |
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