CN107233310A - A kind of moleplant seed fat oil cholate mixed micelle of the element containing moleplant seed and its preparation method and application - Google Patents

A kind of moleplant seed fat oil cholate mixed micelle of the element containing moleplant seed and its preparation method and application Download PDF

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CN107233310A
CN107233310A CN201710644356.2A CN201710644356A CN107233310A CN 107233310 A CN107233310 A CN 107233310A CN 201710644356 A CN201710644356 A CN 201710644356A CN 107233310 A CN107233310 A CN 107233310A
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moleplant seed
fat oil
moleplant
solution
cholate
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CN107233310B (en
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张超
郭菲
王英姿
林桂涛
高慧慧
杨立梅
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Shandong University of Traditional Chinese Medicine
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    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/28—Steroids, e.g. cholesterol, bile acids or glycyrrhetinic acid
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    • A61K47/44—Oils, fats or waxes according to two or more groups of A61K47/02-A61K47/42; Natural or modified natural oils, fats or waxes, e.g. castor oil, polyethoxylated castor oil, montan wax, lignite, shellac, rosin, beeswax or lanolin

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Abstract

The invention provides a kind of moleplant seed fat oil cholate mixed micelle of the element containing moleplant seed, including moleplant seed element, moleplant seed fat oil and dexycholate, the mass ratio of the moleplant seed element, moleplant seed fat oil and dexycholate is 13:20‑200:8‑16；Prepared using following methods：Moleplant seed element, moleplant seed fat oil, dexycholate are dissolved in appropriate solvent respectively；Moleplant seed element solution is mixed with the fatty oil solution of moleplant seed, and adipose membrane is made in desolventizing；Ultrasound after deoxycholate solution is mixed with adipose membrane, centrifugation takes supernatant liquid filtering, and filtrate is the moleplant seed fat oil cholate mixed micelle solution of the element containing moleplant seed, and freeze-drying produces the moleplant seed fat oil cholate mixed micelle preparation of the element containing moleplant seed.The present invention solves the plain poorly water-soluble of moleplant seed, and gastrointestinal absorption effect is undesirable, prevents the problems such as potential activity is from giving full play to, available for preparing antineoplastic.

Description

A kind of moleplant seed fat oil-cholate mixed micelle of element containing moleplant seed and its preparation side Method and application
Technical field
The present invention relates to moleplant seed fat oil-cholate mixed micelle and preparation method thereof of a kind of element containing moleplant seed and should With belonging to antineoplastic preparing technical field.
Background technology
Lathyrol ester type compound, also known as moleplant seed element, with rushing down, the pharmacology such as antitumor, anti-leukocythemia makees With modern study confirms such compound mainly by the CDCC to cancer cell or increase multidrug resistant cells to normal The sensitiveness of antineoplastic is advised to play antitumor action.
CDCC of the moleplant seed element to cancer cell：Zhang Jianye etc.（Zhang JY, Liang YJ, Chen HB, et al. Structure identification of Euphorbia factor L3 and its induction of apoptosis through the mitochondrial pathway[J]. Molecules, 2011, 16(4):3222- 3231）Moleplant seed element L is detected with mtt assay1To the IC of typeⅡ pneumocyte50For 51.34 ± 3.28 μM；Moleplant seed element L3 To the IC of typeⅡ pneumocyte, human colon carcinoma LoVo cells and MCF-7 Human Breast Cancer Cells50Respectively 34.04 ± 3.99, 41.67 ± 3.02 and 45.28 ± 2.56 μM.Lu J etc.（Lu J, Li G, Huang J, et al. Lathyrane-type diterpenoids from the seeds of Euphorbia lathyris[J]. Phytochemistry, 2014, 104(8):79-88）Research shows moleplant seed element L2MCF-7 Human Breast Cancer Cells show cytotoxicity（IC50=12.4-23.1 µM）, also have certain toxic action to rat glioma C6 cells.
Moleplant seed element artitumor multi-medicine-resistant effect：Jiao W etc.（Jiao W, Dong W, Li Z, et al. Lathyrane diterpenes from Euphorbia lathyris as modulators of multidrug resistance and their crystal structures[J]. Bioorg Med Chem,2009, 17(13): 4786-4792）Research finds the drug resistance reversal fold and positive control reversal index of moleplant seed element（RF=2.95）Compare, a thousand pieces of gold Sub- element L2（RF=12.84）>Moleplant seed element L8（RF=8.03）>Moleplant seed element L3（RF=6.57）>Moleplant seed element L1（RF=4.40）. Zhang Jianye etc.（Zhang JY, Zhang C, Chen HB, et al. Assignments of 1H and 13C NMR Signals of Euphorbia factor L1 and investigation of its anticancer activity in vitro[J]. J Med Plant Res, 2010,4(4):335-338. Zhang JY, Mi YJ, Chen SP, et al. Euphorbia factor L1 reverses ABCB1-mediated multidrug resistance involving interaction with ABCB1 independent of ABCB1 down regualtion[J]. J Cell Biochem, 2011,112(4):1076- 1083）It was found that moleplant seed element L1Multidrug resistance KBv200 can be dramatically increased With sensitiveness of the MCF-7/ADR cells to conventional anticancer drugs vincristine and adriamycin, and moleplant seed element L is confirmed1Can be dense Spend the reverse ABCB1 of dependence（P- glycoprotein）The tumor multi-medicine drug-resistant of mediation, most reversal indexes are up to 25 times.Choi JS Deng（Choi JS, Kang NS, Min YK, et al. Euphorbiasteroid reverses P-glycoprotein mediated multi-drug resistance in human sarcoma cell line MES-SA/Dx5 [J]. Phytother Res, 2010,24(7): 1042- 1046）Confirm moleplant seed element L1Even in low concentration（1-3 µM）Also may be used Recover the toxicity of vinblastine, taxol and adriamycin cancer therapy drug to MES-SA/ DX5 cells.
But the plain polarity of moleplant seed is small, belongs to refractory components, solubility is small in water.Li Fengying etc.（Li Fengying, Wang Ying Appearance, Li Shaojing waits rat intestinal absorption characteristic research [J] of main diterpene alcohol ester constituents in extract before and after moleplant seed making drugs into frostlike powder Liaoning University of TCM's journal, 2017,19 (5):17-19）Research shows that the dissolubility of moleplant seed element is poor, it is impossible to be directly dissolved in K- In R liquid, a small amount of Tween 80 is added when test liquid is configured, as a result solubilizing effect is obvious.Wu Ruihuan etc.（Wu Ruihuan, Zhang Zhenling, king Auspicious life, waits the Chinese traditional Chinese medicine information magazines of 4 kinds of active constituent content measuring [J], 2015,22 (7) in moleplant seed decocting liquids: 89-92）It was found that the 3 kinds of diterpene alkoxide compositional polarities contained in moleplant seed are smaller, boiled with decocting and be difficult to dissolution, so moleplant seed （Smash）3 kinds of diterpene alkoxide component contents are relatively low in decocting liquid, and the moleplant seed do not smashed enters decoction and do not detected then.Duan Feipeng etc. （Duan Feipeng, Wang Yingzi, Li Shaojing, wait Absorption Study [J] the medium-height grass of moleplant seed sterols in Caco-2 cell monolayer models Medicine, 2014,45 (21):3136-3140）Research finds various concentrations moleplant seed element L1Papp between 1 × 10-5-1×10-6, Show that it is absorbed as moderate absorption in enteron aisle.It can be seen that, moleplant seed element poorly water-soluble, gastrointestinal absorption effect is undesirable, makes to dive Activity can not give full play to, and then have impact on exploitation of such compound in clinic with using.
The content of the invention
For the plain poorly water-soluble of moleplant seed, gastrointestinal absorption effect is undesirable, potential activity is asked from giving full play to etc. Topic, the present invention provides a kind of moleplant seed fat oil-cholate mixed micelle of the element containing moleplant seed.
It is a further object of the present invention to provide a kind of preparation method of simple and feasible above-mentioned mixed micelle.
Another object of the present invention is to provide a kind of moleplant seed fat oil-cholate mixed micelle of the element containing moleplant seed and prepared Application in antineoplastic.
To achieve the above object, the present invention is adopted the following technical scheme that.
A kind of moleplant seed fat oil-cholate mixed micelle of the element containing moleplant seed, including following component：Moleplant seed element, a thousand pieces of gold Sub- fat oil and dexycholate, the mass ratio of the moleplant seed element, moleplant seed fat oil and dexycholate is 1-3:20- 200:8-16。
Moleplant seed fat oil-cholate mixed micelle of the element containing moleplant seed, is prepared using following methods：
Moleplant seed element, moleplant seed fat oil, dexycholate are dissolved in appropriate solvent respectively；Moleplant seed element solution and moleplant seed Adipose membrane is made in fatty oil solution mixing, desolventizing；Ultrasound after deoxycholate solution is mixed with adipose membrane, centrifugation takes supernatant mistake Filter, filtrate is moleplant seed fat oil-cholate mixed micelle solution of the element containing moleplant seed, and freeze-drying produces the element containing moleplant seed Moleplant seed fat oil-cholate mixed micelle preparation.
The average grain diameter of moleplant seed fat oil-cholate mixed micelle of the element containing moleplant seed is 100-200nm.
The moleplant seed element is moleplant seed element L1, L2, at least one of L3 and L8, its structural formula such as following formula（I）- formula （IV）It is shown：
Formula（I）Formula（II）
Formula（III）Formula（IV）
The moleplant seed fat oil, without moleplant seed element.
The moleplant seed fat oil, alcohol extracting is obtained through column chromatography after being crushed using moleplant seed.
A kind of preparation method of moleplant seed fat oil-cholate mixed micelle of the above-mentioned element containing moleplant seed, comprises the following steps：
（1）Moleplant seed element, moleplant seed fat oil, dexycholate are dissolved in appropriate solvent respectively, solution is made；
（2）The plain solution of moleplant seed is mixed with the fatty oil solution of moleplant seed, adipose membrane is made in desolventizing；
（3）Ultrasound after deoxycholate solution is mixed with adipose membrane, centrifugation takes supernatant liquid filtering, and filtrate is the element containing moleplant seed Moleplant seed fat oil-cholate mixed micelle solution；
（4）By the moleplant seed fat oil of the element containing moleplant seed-cholate mixed micelle solution freeze-drying, produce.
Step（1）The solvent of middle moleplant seed element and moleplant seed fat oil is ethyl acetate；The solvent of dexycholate is 0.01mol/L pH 7.0-7.4 phosphate buffer；
The concentration of the moleplant seed element is 1-3mg/mL；The concentration of moleplant seed fat oil is preferably 10-100 mg/mL；Deoxidation courage The concentration of hydrochlorate is 0.1-2 mg/mL；
The dexycholate is NaTDC.
Step（2）The volume ratio of moleplant seed element solution and the fatty oil solution of moleplant seed is 1:1.
Step（3）Ultrasonic temperature is 35-65 DEG C, and ultrasonic time is 20-60min；
Centrifugal speed is 5000-18000 r/min, and centrifugation time is 2-30min；
Filter type is membrane filtration, and filter sizes are 0.22 μm.
Step（4）Mannitol is added before freeze-drying, consumption is the 5% of liquor capacity.
A kind of preparation method of above-mentioned moleplant seed fat oil, using following steps：
（1）It is moleplant seed powder that moleplant seed, which is crushed,；
（2）By moleplant seed powder alcohol extracting, alcohol extract is obtained；
（3）Column chromatography will be crossed after alcohol extract desolventizing, eluate is moleplant seed fat oil.
The granularity of the moleplant seed powder is less than 20 mesh；
The mass ratio of the moleplant seed powder and lower aliphatic alcohols is 1:8-20；
The alcohol is lower aliphatic alcohols, selected from least one of methanol, ethanol, isopropanol, preferably ethanol；
The alcohol extracting number of times is 1-3 times；
The column chromatography filler is silica gel, and granularity is 100-200 mesh；
The eluting solvent of the column chromatography is selected from petroleum ether or n-hexane, and the petroleum ether is 60-90 DEG C of boiling range.
A kind of moleplant seed fat oil-cholate mixed micelle answering in antineoplastic is prepared of the above-mentioned element containing moleplant seed With.
The present invention has advantages below：
The present invention is using the fat oil and the self-assembled micelle ability of additional dexycholate contained by moleplant seed itself, by moleplant seed Diterpene alkoxide compound is wrapped up or load, and uniform, stably nanoscale mixed micelle has been made.Change the presence shape of medicine State, not only significantly improves solubility of the Lathyrol ester compounds in water, also helps passive transmembrane transport process, So that the intestinal absorption effect of such compound is significantly improved.
Brief description of the drawings
Fig. 1 is the displaing micro picture of moleplant seed fat oil-cholate mixed micelle of the element containing moleplant seed；
Fig. 2 is the displaing micro picture of moleplant seed element-cholate micella without moleplant seed fat oil；
Fig. 3 is the grain size distribution of moleplant seed fat oil-cholate mixed micelle of the element containing moleplant seed；
Fig. 4 is the grain size distribution of moleplant seed element-cholate micella without moleplant seed fat oil；
Fig. 5 is solubilizing effect figure of the moleplant seed fat oil-cholate mixed micelle to moleplant seed element of the element containing moleplant seed；
Fig. 6 is containing K of the moleplant seed element in full intestinal segment in the plain moleplant seed fat oil-cholate mixed micelle of moleplant seedaVariation diagram；
Fig. 7 is containing P of the moleplant seed element in full intestinal segment in the plain moleplant seed fat oil-cholate mixed micelle of moleplant seedeffVariation diagram.
Embodiment
With reference to embodiment and accompanying drawing, the present invention will be further described, but the present invention is not limited by following embodiments System.
The preparation of the moleplant seed fat oil of embodiment 1.
（1）Moleplant seed is crushed as by the moleplant seed powder of 20 mesh sieves；
（2）1000g moleplant seeds powder is extracted 3 times with 20000g ethanol, merges to obtain alcohol extract；
（3）Alcohol extract is reclaimed to remove and makes the silica gel column chromatography by the way that granularity is 100-200 mesh after ethanol, with petroleum ether（60-90 ℃）Eluted for eluting solvent, eluate is moleplant seed fat oil.
The preparation of moleplant seed fat oil-cholate mixed micelle of the element containing moleplant seed of embodiment 2.
（1）200mg NaTDCs are dissolved in 0.01 M phosphate buffers of pH=7.4（PBS）In, obtain the de- of 0.2 mg/mL Oxycholic acid sodium solution；
Moleplant seed element L1, L2, L3 and the L8 for weighing 5mg dissolve in ethyl acetate, and it is respectively 1mg/mL's to obtain each monomer concentration Moleplant seed element mixed solution；
Weigh the moleplant seed fat oil 2g obtained in embodiment 1 to dissolve in ethyl acetate, obtain 20 mg/mL fatty oil solution.
（2）The plain mixed solution of above-mentioned moleplant seed and the fatty oil solution of moleplant seed are respectively taken into 1 mL respectively, same round bottom is put and burns In bottle, in 40 DEG C of water-bath rotary evaporations, wave most ethyl acetate, round-bottomed flask put into vacuum drying chamber, normal temperature vacuumize overnight with The ethyl acetate of remaining is removed, adipose membrane is made.
（3）80 mL sodium deoxycholate solutions are taken to add in the round-bottomed flask of above-mentioned adipose membrane, by adipose membrane and cholate solution 35 Ultrasonic mixing 60min in DEG C water-bath, is transferred in centrifuge tube, normal temperature 5000r/min centrifugation 30min, Aspirate supernatant, 0.22 μ M membrane filtrations, the solution clarified is moleplant seed fat oil-cholate mixed micelle solution S 1 of the element containing moleplant seed.
The preparation of moleplant seed element-cholate micella of the comparative example 1 without moleplant seed fat oil.
（1）200 mg NaTDCs are dissolved in 0.01 M phosphate buffers of pH=7.4（PBS）In, obtain 0.2 mg/mL's Sodium deoxycholate solution；
Moleplant seed element L1, L2, L3 and the L8 for weighing 5mg dissolve in ethyl acetate, and it is respectively 1mg/mL's to obtain each monomer concentration Moleplant seed element mixed solution.
（2）The plain mL of mixed solution 1 of above-mentioned moleplant seed is taken, puts in round-bottomed flask, in 40 DEG C of water-bath rotary evaporations, waves most second Acetoacetic ester, vacuum drying chamber is put by round-bottomed flask, and normal temperature is vacuumized overnight to remove the ethyl acetate of remaining, and adipose membrane is made.
（3）80 mL sodium deoxycholate solutions are taken to add in the round-bottomed flask of above-mentioned adipose membrane, by adipose membrane and cholate solution 35 Ultrasonic mixing 60min in DEG C water-bath, is transferred in centrifuge tube, normal temperature 5000r/min centrifugation 30min, Aspirate supernatant, 0.22 μ M membrane filtrations, the solution clarified is moleplant seed element-cholate micellar solution C1.
The sign of moleplant seed fat oil-cholate mixed micelle of the element containing moleplant seed of embodiment 3.
3.1 form
Embodiment 2 is characterized with the solution in comparative example 1 by high resolution transmission electron microscope, the element containing moleplant seed The microphoto of moleplant seed fat oil-cholate mixed micelle solution as shown in figure 1, moleplant seed element-cholate micellar solution it is micro- Photo is as shown in Figure 2.In the presence of Fig. 1 and Fig. 2, moleplant seed fat oil, Lathyrol ester type compound The micellar conformation formed in sodium deoxycholate solution is more regular, and particle diameter is more homogeneous, is more evenly distributed.
3.2 particle diameter distributions and Zeta potential
The HS instrument of Zetasizer 3000 (Malvern Instruments, Malvern, UK) are in 25oC, He- The sample solution S1 of the Ne laser determinations embodiment 2 and sample solution C1 of comparative example 1 particle diameter and Zeta potential.Sample solution S1's Average grain diameter is 135.8nm, and Zeta potential is -22.35mV, and grain size distribution is as shown in Figure 3；Sample solution C1 average grain diameter For 565.2nm, Zeta potential is -1.58 mV, and grain size distribution is as shown in Figure 4；Abscissa is that particle diameter is big in grain size distribution Small, ordinate is particle diameter distribution.From both average grain diameter numerical value and Fig. 3 and Fig. 4, moleplant seed element is in sodium deoxycholate solution In can generate micella, but the particle size of micella differs, and Zeta potential is smaller, and generation micella stability is poor；But having appropriate thousand In the presence of gold fat oil, more uniform micella particle diameter is formed, the micella particle diameter of formation is more uniform, stability is more preferable.
The assay of moleplant seed element in moleplant seed fat oil-cholate mixed micelle of the element containing moleplant seed of embodiment 4
The content of moleplant seed element in mixed micelle is determined using HPLC methods, method is as follows：
It is prepared by reference substance solution：Take moleplant seed element L1, L2, L3 and L8 reference substance appropriate, it is accurately weighed, plus every 1mL is made in methanol In the mixed solution containing the μ g of moleplant seed element L1, L2, L3 and L8 50, shake up, produce.
The preparation of need testing solution：Precision measures the element containing moleplant seed of different moleplant seed fatty oil contents made by 10mL Mixed micelle solution, puts in separatory funnel, is extracted 2 times with ethyl acetate, each 10mL, merges extract solution, water bath method, with first Alcohol is dissolved, and dilution is settled in 2mL measuring bottles, is shaken up, is used as need testing solution.
Chromatographic condition：Inertsil ODS-3 (5 μm, the mm of 250 mm × 4.6), mobile phase is methanol-water (75: 25), The mLmin of flow velocity 1.0-1, Detection wavelength 275nm, the μ L of sample size 20.
Solubilising of the moleplant seed fat oil-cholate mixed micelle of the element containing moleplant seed of embodiment 5 to moleplant seed element.
Take different amounts of moleplant seed fat oil to put volumetric flask, add ethyl acetate dissolved dilution to scale respectively, obtain concentration For 0,2.5,5,7.5,10,15,20,25,50,100mg/mL fatty oil solution.Different a thousand pieces of golds are made as described in Example 2 The plain mixed micelle solution of the moleplant seed of sub- fatty oil content.4 kinds of moleplant seed elements in mixed micelle are determined according to the method for embodiment 5 Content.
With the fatty oil concentration of different moleplant seeds（Different moleplant seed fat oil additions）For abscissa, with 4 kinds of moleplant seed elements Solubility in the solution is mapped for ordinate, sees Fig. 5.As seen from Figure 5, the addition of fat oil, makes the dissolving of moleplant seed element Amount increase；Also, within the specific limits, with fatty oil concentration（That is addition）Increase, moleplant seed element solubility it is notable Improve.When fatty oil concentration is 10mg/mL, the solubility of moleplant seed element has just increased 2-3 times, and fatty oil concentration reaches 100mg/ ML, the solubility of moleplant seed element just reaches platform, is further added by the consumption of fat oil, its solubilizing effect is not notable, therefore moleplant seed fat The concentration of fat oil is preferably 10-100 mg/mL.
Absorption of the moleplant seed element in enteron aisle in moleplant seed fat oil-cholate mixed micelle of the element containing moleplant seed of embodiment 6 Effect.
The preparation of 6.1 perfusates
Take different amounts of moleplant seed fat oil to put volumetric flask, respectively plus ethyl acetate dissolved dilution is to scale, obtain concentration be 0, 10th, 20,50,100mg/mL fatty oil solution.Converted in view of people and rat dosage, moleplant seed element L1, L2, L3 and L8 Dissolved in ethyl acetate, obtain the plain mixed solution of moleplant seed that each monomer concentration is respectively 20 μ g/mL.As described in Example 2 The plain mixed micelle solution of moleplant seed of different moleplant seed fatty oil contents is made, perfusate is used as.
6.2 the unidirectional intestines perfusion experiment model of body foundation
Female wistar rats adaptability is raised one week, the h of fasting 12, free water before perfusion experiment.10% water is injected intraperitoneally Close chloral（3 mL·kg-1）Anesthesia, the back of the body position be fixed on operating table, along rat ventrimeson xiphoid-process under 2 cm, open abdominal cavity, separation Intestinal segment to be investigated（Full section small intestine：Upper end is from the descending 1cm of stomach pylorus, and lower end is from the up 1cm of caecum）, one is respectively cut at two ends V type osculums, silicone tube is carefully inserted and ligatured, it should be noted that avoid injuring blood vessel, and being appropriately flapped toward experiment intestinal segment makes perfusion liquid energy Circulation is smooth to be advisable, and wound moisturizing is covered with the absorbent cotton for being soaked with physiological saline, while infrared lamp is incubated.With the life of 37 DEG C of preheatings Salt solution is managed from the light and slow flushing enteron aisle of intestines upper end open（Direction is not anti-）, until intestinal contents is rinsed well, blowing air emptying life Salt solution is managed, then intestines perfusate is used as with the PH6.8 of preheating Krebs-Ringer ' s buffer solutions（37℃）Carry out unidirectional in body Perfusion, to set up perfusion system, perfusion direction is consistent with enteral irrigation direction.Test before starting to test perfusate（37℃） Intestinal segment is filled, with 0.2 mLmin-1Velocity balance l h after, the timing since dripping the first drop test liquid uses oneself at import Know the bottle perfusion equipped with experiment perfusate of weight, keep constant current flow rate pump constant, while another known weight is put in exit Empty bottle collect efflux, every 15 min change rapidly it is next to weighed weight fill experiment perfusate bottle and Empty collection liquid bottle, is let cool to room temperature, weighs the weight of perfusate bottle and collection liquid bottle, and 8 periods are collected altogether Sample, duration of experiment be 120 min.After experiment terminates, the intestinal segment is cut, cut off along intestinal tube, graph paper is laid in On, measurement small intestine internal diameter and length.
The measure of moleplant seed element in 6.3 intestines perfusates
The content of 4 kinds of moleplant seed elements is determined by method in embodiment 4.
6.4 data processing
The inflow of perfusate is corrected with elution volume using mass analysis（Calculated using gravimetric method, it is assumed that import and export Perfusate density it is the same, and indicate entry into the quality for entering liquid and efflux the volume of liquid and efflux respectively）, by following Equation calculates absorption rate constant KaWith small intestine apparent absorption coefficient Peff。
；
。
In formula：
CinAnd CoutRespectively the intestinal segment enters the concentration of liquid and efflux（µg·mL-1）；
VinAnd VoutThe respectively inflow of the intestinal segment perfusate and elution volume（ML, is distinguished with the quality for entering liquid and efflux Represent）；
QinFor perfusion rate（mL·min-1）；
V is the volume of the perfusion intestinal segment（cm3）, V=π R2L, 1mL=1cm3；
A is the surface area of the perfusion intestinal segment（cm2）, the π RL of A=2；
R is the intestinal segment radius（cm）；
L is the length of the intestinal segment（cm）；
KaFor absorption rate constant（min-1）；
PeffFor the intestinal segment apparent absorption coefficient（cm·min-1）.
With the fatty oil concentration of different moleplant seeds（Different moleplant seed fat oil additions）For abscissa, with 4 kinds of moleplant seed elements Ka the and Peff values absorbed in full intestinal segment are mapped for ordinate, see Fig. 6 and Fig. 7.From Fig. 6, Fig. 7, the addition of fat oil makes The K of moleplant seed elementaAnd PeffValue increase；Also, within the specific limits, with the increase of fat oil addition, the K of moleplant seed elementa And PeffValue significantly rise, absorptivity is significantly improved.The appropriate addition of moleplant seed fat oil can improve the intestinal absorption effect of moleplant seed element Really.
The preparation of moleplant seed fat oil-cholate mixed micelle of the element containing moleplant seed of embodiment 6.
（1）100 mg NaTDCs are dissolved in 0.01 M phosphate buffers of pH=7.4（PBS）In, obtain 1mg/mL deoxidation Sodium cholate solution；
5mg moleplant seeds element L1, L2, L3, L8 is weighed respectively to dissolve in ethyl acetate, obtain 1mg/mL moleplant seed element L1, L2, L3, L8 mixed solution；
Weigh the moleplant seed fat oil 1g obtained in embodiment 1 to dissolve in ethyl acetate, the fat oil for obtaining 100 mg/mL is molten Liquid.
（2）The plain mixed solution of above-mentioned moleplant seed and the fatty oil solution of moleplant seed respectively take 1 mL, put in round-bottomed flask, in 40 DEG C Water-bath rotary evaporation, waves most ethyl acetate, and round-bottomed flask is put into vacuum drying chamber, and normal temperature vacuumizes second overnight to remove remaining Acetoacetic ester, is made adipose membrane.
（3）80 mL sodium deoxycholate solutions are taken to add in the round-bottomed flask of above-mentioned adipose membrane, by adipose membrane and cholate solution 45 Ultrasonic mixing 60min in DEG C water-bath, is transferred in centrifuge tube, normal temperature 12000r/min centrifugation 20min, Aspirate supernatant, 0.22 μm membrane filtration, the solution clarified is moleplant seed fat oil-cholate mixed micelle solution S 2 of the element containing moleplant seed.
（4）By step（3）The solution S 2 of acquisition adds freeze drying protectant mannitol and is freeze-dried, and produces containing moleplant seed Moleplant seed fat oil-cholate mixed micelle solid pharmaceutical preparation of element.
The preparation of moleplant seed fat oil-cholate mixed micelle of the element containing moleplant seed of embodiment 7.
（1）50mg NaTDCs are dissolved in 0.01 M phosphate buffers of pH=7.4（PBS）In, obtain 0.5mg/mL deoxidation Sodium cholate solution；
10mg moleplant seeds element L1, L2, L3, L8 is weighed respectively to dissolve in ethyl acetate, obtain 2mg/mL moleplant seed element L1, L2, L3, L8 mixed solution；
Weigh the moleplant seed fat oil 0.5g obtained in embodiment 1 to dissolve in ethyl acetate, the fat oil for obtaining 50 mg/mL is molten Liquid.
（2）The plain mixed solution of above-mentioned moleplant seed and the fatty oil solution of moleplant seed respectively take 1 mL, put in round-bottomed flask, in 40 DEG C Water-bath rotary evaporation, waves most ethyl acetate, and round-bottomed flask is put into vacuum drying chamber, and normal temperature vacuumizes second overnight to remove remaining Acetoacetic ester, is made adipose membrane.
（3）80 mL sodium deoxycholate solutions are taken to add in the round-bottomed flask of above-mentioned adipose membrane, by adipose membrane and cholate solution 50 Ultrasonic mixing 40min in DEG C water-bath, is transferred in centrifuge tube, normal temperature 15000r/min centrifugation 15min, Aspirate supernatant, 0.22 μm membrane filtration, the solution clarified is moleplant seed fat oil-cholate mixed micelle solution S 3 of the element containing moleplant seed.
（4）By step（3）The solution S 3 of acquisition adds freeze drying protectant mannitol and is freeze-dried, and produces containing moleplant seed Moleplant seed fat oil-cholate mixed micelle solid pharmaceutical preparation of element.
The preparation of moleplant seed fat oil-cholate mixed micelle of the element containing moleplant seed of embodiment 8.
（1）0.2g NaTDCs are dissolved in 0.01 M phosphate buffers of pH=7.4（PBS）In, obtain 2mg/mL deoxidation courage Acid sodium solution；
15mg moleplant seeds element L1, L2, L3, L8 is weighed respectively to dissolve in ethyl acetate, obtain 3mg/mL moleplant seed element L1, L2, L3, L8 mixed solution；
Weigh the moleplant seed fat oil 0.8g obtained in embodiment 1 to dissolve in ethyl acetate, the fat oil for obtaining 80 mg/mL is molten Liquid.
（2）The plain mixed solution of above-mentioned moleplant seed and the fatty oil solution of moleplant seed respectively take 1 mL, put in round-bottomed flask, in 40 DEG C Water-bath rotary evaporation, waves most ethyl acetate, and round-bottomed flask is put into vacuum drying chamber, and normal temperature vacuumizes second overnight to remove remaining Acetoacetic ester, is made adipose membrane.
（3）80 mL sodium deoxycholate solutions are taken to add in the round-bottomed flask of above-mentioned adipose membrane, by adipose membrane and cholate solution 60 Ultrasonic mixing 20min in DEG C water-bath, is transferred in centrifuge tube, normal temperature 8000r/min centrifugation 30min, Aspirate supernatant, 0.22 μ M membrane filtrations, the solution clarified is moleplant seed fat oil-cholate mixed micelle solution S 4 of the element containing moleplant seed.
（4）By step（3）The solution S 4 of acquisition adds freeze drying protectant mannitol and is freeze-dried, and produces moleplant seed element Moleplant seed fat oil-cholate mixed micelle solid pharmaceutical preparation.
The preparation of moleplant seed fat oil-cholate mixed micelle of the element containing moleplant seed of embodiment 9.
（1）40mg NaTDCs are dissolved in 0.01 M phosphate buffers of pH=7.4（PBS）In, obtain 0.4mg/mL deoxidation Sodium cholate solution；
5mg moleplant seeds element L1, L2, L3, L8 is weighed respectively to dissolve in ethyl acetate, obtain 1mg/mL moleplant seed element L1, L2, L3, L8 mixed solution；
Weigh the moleplant seed fat oil 0.2g obtained in embodiment 1 to dissolve in ethyl acetate, the fat oil for obtaining 20 mg/mL is molten Liquid.
（2）The plain mixed solution of above-mentioned moleplant seed and the fatty oil solution of moleplant seed respectively take 1 mL, put in round-bottomed flask, in 40 DEG C Water-bath rotary evaporation, waves most ethyl acetate, and round-bottomed flask is put into vacuum drying chamber, and normal temperature vacuumizes second overnight to remove remaining Acetoacetic ester, is made adipose membrane.
（3）80 mL sodium deoxycholate solutions are taken to add in the round-bottomed flask of above-mentioned adipose membrane, by adipose membrane and cholate solution 35 Ultrasonic mixing 40min in DEG C water-bath, is transferred in centrifuge tube, normal temperature 5000r/min centrifugation 30min, Aspirate supernatant, 0.22 μ M membrane filtrations, the solution clarified is moleplant seed fat oil-cholate mixed micelle solution S 5 of the element containing moleplant seed.
（4）By step（3）The solution S 5 of acquisition adds freeze drying protectant mannitol and is freeze-dried, and produces moleplant seed element Moleplant seed fat oil-cholate mixed micelle solid pharmaceutical preparation.
The preparation of moleplant seed fat oil-cholate mixed micelle of the element containing moleplant seed of embodiment 10.
（1）80mg NaTDCs are dissolved in 0.01 M phosphate buffers of pH=7.4（PBS）In, obtain 0.8mg/mL deoxidation Sodium cholate solution；
15mg moleplant seeds element L1, L2, L3, L8 is weighed respectively to dissolve in ethyl acetate, obtain 1.5mg/mL moleplant seed element L1, L2, L3, L8 mixed solution；
Weigh the moleplant seed fat oil 0.5g obtained in embodiment 1 to dissolve in ethyl acetate, the fat oil for obtaining 50 mg/mL is molten Liquid.
（2）The plain mixed solution of above-mentioned moleplant seed and the fatty oil solution of moleplant seed respectively take 1 mL, put in round-bottomed flask, in 40 DEG C Water-bath rotary evaporation, waves most ethyl acetate, and round-bottomed flask is put into vacuum drying chamber, and normal temperature vacuumizes second overnight to remove remaining Acetoacetic ester, is made adipose membrane.
（3）80 mL sodium deoxycholate solutions are taken to add in the round-bottomed flask of above-mentioned adipose membrane, by adipose membrane and cholate solution 37 Ultrasonic mixing 30min in DEG C water-bath, is transferred in centrifuge tube, normal temperature 15000r/min centrifugation 10min, Aspirate supernatant, 0.22 μm membrane filtration, the solution clarified is moleplant seed fat oil-cholate mixed micelle solution S 6 of the element containing moleplant seed.
（4）By step（3）The solution S 6 of acquisition adds freeze drying protectant mannitol and is freeze-dried, and produces containing moleplant seed Moleplant seed fat oil-cholate mixed micelle solid pharmaceutical preparation of element.

Claims (10)

1. a kind of moleplant seed fat oil-cholate mixed micelle of the element containing moleplant seed, it is characterised in that including following component：A thousand pieces of gold Sub- element, moleplant seed fat oil and dexycholate, its mass ratio are 1-3:20-200:8-16；
Prepared using following methods：Moleplant seed element, moleplant seed fat oil, dexycholate are dissolved in appropriate solvent respectively In；Moleplant seed element solution is mixed with the fatty oil solution of moleplant seed, and adipose membrane is made in desolventizing；Deoxycholate solution is mixed with adipose membrane Ultrasonic afterwards, centrifugation takes supernatant liquid filtering, and filtrate freeze-drying is produced.
2. according to claim 1 containing the plain moleplant seed fat oil-cholate mixed micelle of moleplant seed, it is characterised in that average Particle diameter is 100-200nm.
3. according to claim 1 containing the plain moleplant seed fat oil-cholate mixed micelle of moleplant seed, it is characterised in that described Moleplant seed element is moleplant seed element L1, L2, at least one of L3 and L8.
4. according to claim 1 containing the plain moleplant seed fat oil-cholate mixed micelle of moleplant seed, it is characterised in that described Moleplant seed fat oil, without moleplant seed element.
5. according to claim 1 containing the plain moleplant seed fat oil-cholate mixed micelle of moleplant seed, it is characterised in that a thousand pieces of gold The preparation method of sub- fat oil uses following steps：
（1）It is moleplant seed powder that moleplant seed, which is crushed,；
（2）By moleplant seed powder alcohol extracting, alcohol extract is obtained；
（3）Column chromatography will be crossed after alcohol extract desolventizing, eluate is moleplant seed fat oil.
6. moleplant seed fat oil-cholate mixed micelle of the element according to claim 5 containing moleplant seed, it is characterised in that institute The granularity for stating moleplant seed powder is less than 20 mesh；The mass ratio of the moleplant seed powder and lower aliphatic alcohols is 1:8-20；
The alcohol is lower aliphatic alcohols, selected from least one of methanol, ethanol, isopropanol, preferably ethanol；The alcohol extracting time Number is 1-3 times；
The column chromatography filler is silica gel, and granularity is 100-200 mesh；The eluting solvent of the column chromatography is selected from petroleum ether or just oneself Alkane.
7. a kind of preparation method of moleplant seed fat oil-cholate mixed micelle of the element as claimed in claim 1 containing moleplant seed, its It is characterised by, comprises the following steps：
（1）Moleplant seed element, moleplant seed fat oil, dexycholate are dissolved in appropriate solvent respectively, solution is made；
（2）The plain solution of moleplant seed is mixed with the fatty oil solution of moleplant seed, adipose membrane is made in desolventizing；
（3）Ultrasound after deoxycholate solution is mixed with adipose membrane, centrifugation takes supernatant liquid filtering, and filtrate is the element containing moleplant seed Moleplant seed fat oil-cholate mixed micelle solution；
（4）Above-mentioned micellar solution is freeze-dried, produced.
8. preparation method according to claim 7, it is characterised in that step（1）Middle moleplant seed element and moleplant seed fat oil Solvent be ethyl acetate；The solvent of dexycholate is 0.01 mol/L pH 7.0-7.4 phosphate buffer；Described a thousand pieces of gold The concentration of sub- element is 1-3mg/mL；The concentration of moleplant seed fat oil is 10-100 mg/mL；The concentration of dexycholate is 0.1-2 mg/mL；
Step（2）The volume ratio of moleplant seed element solution and the fatty oil solution of moleplant seed is 1:1；
Step（3）Ultrasonic temperature is 35-65 DEG C, and ultrasonic time is 20-60min；Centrifugal speed is 5000-18000 r/min, from The heart time is 2-30min；Filter type is membrane filtration, and filter sizes are 0.22 μm；
Step（4）Mannitol is added before freeze-drying, consumption is the 5% of liquor capacity.
9. preparation method according to claim 7, it is characterised in that the dexycholate is NaTDC.
10. a kind of moleplant seed fat oil-cholate mixed micelle of the element containing moleplant seed as claimed in claim 1 prepare it is antitumor Application in medicine.
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