CN102058528B - Daidzein micelles and preparation method thereof - Google Patents
Daidzein micelles and preparation method thereof Download PDFInfo
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- CN102058528B CN102058528B CN 200910198808 CN200910198808A CN102058528B CN 102058528 B CN102058528 B CN 102058528B CN 200910198808 CN200910198808 CN 200910198808 CN 200910198808 A CN200910198808 A CN 200910198808A CN 102058528 B CN102058528 B CN 102058528B
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Abstract
The invention relates to daidzein micelles and a preparation method thereof. The daidzein micelles contain 1 part of daidzein, 12 to 30 parts of phospholipid and 1 to 25 parts of additive. The preparation method comprises: preparing a daidzein and phospholipid composite, namely, adding daidzein and 50 to 95 percent of phospholipid into an organic solvent, heating the solution to 40 to 60 DEG C, refluxing under reduced pressure, keeping temperature and stirring for 2 to 10 hours, recovering the organic solvent, drying and crushing to obtain the daidzein and phospholipid composite; and preparing daidzein micelles from the phospholipid composite, namely, dissolving the daidzein and phospholipid composite, the rest phospholipid and the additive in an organic solvent, subjecting the solution to rotary evaporation to form a film, and hydrating at 40 to 60 DEG C to obtain daidzein micelle suspension with opalescence. The average particle size of the daidzein micelles is less than 50 nanometers. The daidzein micelles can be further prepared into oral or injection preparations including capsules, oral mixed suspension, oral liquid, injection, injection freeze-dried powder injection.
Description
Technical field
The present invention relates to a kind of daidzein micelle and this micellar method for preparing.
Background technology
Daidzein (Daidzein) has another name called daidzein, Daidezin, be from the dry root of legume pueraria lobata and Pachyrhizua angulatus or Semen sojae atricolor extraction separation and a kind of isoflavonoid.It is allevating angina pectoris obviously, has arrhythmia, antioxidation, pharmacologic efficacy in regulating blood sugar level, and acute myocardial ischemia and cerebral ischemia are also had protective effect.At present, daidzein is mainly used in the treatment of cardiovascular and cerebrovascular disease clinically, and for hypertension, coronary heart disease, cerebral thrombosis, brain injury, prevention of arterial sclerosis, cerebral ischemia etc. have significant curative effect.But, influenced absorption and the distribution behind the oral administration, thereby bioavailability is poor because its water solublity and fat-soluble homogeneous phase are on duty.Bibliographical information, absolute bioavailability was merely 12.22% after the filling stomach gave the rat daidzein.
Daidzein belongs to the isoflavone structure, and its structural formula is following.Its water solublity and fat-soluble all very poor is difficult to be absorbed after oral, so oral administration biaavailability is very low, this has limited daidzein application clinically.In order to improve the oral administration biaavailability of daidzein; Have through daidzein is carried out structure of modification; Promptly replace with groups such as methoxyl group, hydroxyl, amino, acetylamino 4 or 7 to the isoflavone structure; The water solublity that increases daidzein through the method for cyclodextrin inclusion compound, solid dispersion or phosphatide complexes is also arranged, thereby increase the oral administration biaavailability of daidzein.
The structural formula of daidzein
For insoluble drug, process micelle a kind of method that increases dissolubility of can yet be regarded as.Micelle is a kind of in the colloidal dispersion, belongs to association colloid, and it can increase the slightly solubility solubility of substances and play the effect of solubilising.Conventional micelle method for preparing is solvent evaporated method, dialysis, emulsion process etc., all need medicine dissolution be carried out next step operation behind organic solvent.For daidzein; The maximum difficulty of preparation micelle is that daidzein dissolubility in the receptible organic solvent on various pharmaceuticss is all very poor, owing to can not be dissolved in this type organic solvent, the micellar carrying drug ratio of daidzein of conventional method preparation is very low; Even after forming micelle reluctantly; Stability is also poor, and daidzein is easy to separate out, and the micelle suspension that can observe after the preparation becomes muddy very soon.Through measuring, can only discharge 25% daidzein (seeing the extracorporeal releasing test in the application's test implementation example), and measure its oral administration biaavailability, AUC in external 24 hours
0-∞Be 30128nghmL
-1(seeing that bioavailability is measured in the rat body in the application's test implementation example).
Therefore, the present invention is prepared into phosphatide complexes with daidzein and phospholipid earlier in the micellar process of this daidzein of preparation, further be prepared into the daidzein micelle again, has overcome the difficult point of above-described daidzein micelle preparation.
Summary of the invention
One object of the present invention is to provide the daidzein micelle of a kind of particle diameter less than 50nm, and it can increase the dissolving and the stripping of medicine, thereby increases the bioavailability of daidzein.
Another object of the present invention is to provide a kind of above-mentioned daidzein micellar method for preparing.
According to one object of the present invention, the invention provides a kind of daidzein micelle, by weight, this micelle contains:
1 part of daidzein
2～30 parts of phosphatidase 11s
1～25 part of additives.
Preferably, daidzein micelle of the present invention, by weight, this micelle comprises:
1 part of daidzein
5～30 parts of phosphatidase 11s
10～25 parts of additives.
More preferably, daidzein micelle of the present invention, by weight, this micelle comprises:
1 part of daidzein,
0～30 part of phosphatidase 12,
20～25 parts of additives.
The micellar mean diameter of daidzein of the present invention is less than 50nm.
Wherein, said phospholipid is selected from soybean phospholipid, Ovum Gallus domesticus Flavus lecithin, hydrogenated soya phosphatide and the hydrogenated yolk lecithin.
Said additives are selected from glycerol and the sodium cholate.
Daidzein micelle of the present invention can further be prepared into oral formulations or ejection preparation, comprises capsule, oral administration mixed suspension, oral liquid, injection, injection freeze-dried powder.
According to another object of the present invention; The invention provides the micellar method for preparing of above-mentioned daidzein: get daidzein and the phospholipid that accounts for whole phosphatidase 15s 0%～95% earlier, add organic solvent, be heated to 40 ℃～60 ℃ reduced-pressure backflows; Insulated and stirred 2～10 hours; Reclaim organic solvent, drying, pulverize the daidzein phosphatide complexes; Get this daidzein phosphatide complexes and remaining phospholipid, additives then and be dissolved in organic solvent, solution rotating is evaporated film forming after, 40 ℃～60 ℃ aquations promptly get and are with opalescent micelle suspension.
Wherein, when preparation daidzein phosphatide complexes, the ratio of daidzein and organic solvent is 1: 10～50 (w/v).
Wherein, said organic solvent is selected from methanol, ethanol, ether, acetone, oxolane and the isopropyl alcohol.
Described aquation is: more than the phase transition temperature of film, add water membrane elution is got off, form uniformly the operating procedure with the micelle liquid of certain grain size distribution.
Daidzein micelle provided by the invention; Because the effect of phospholipid, the hydrophilic and the lipotropy of medicine significantly improve, and micellar solubilization improves its dissolubility widely; Release in vitro is faster than daidzein and daidzein phosphatide complexes; Daidzein micelle mean diameter of the present invention makes the absorption of medicine easier less than 50nm, and these all characteristics make daidzein micelle of the present invention bioavailability in vivo improve significantly.
The present invention is prepared into the daidzein phosphatide complexes with daidzein earlier, and this daidzein phosphatide complexes of reuse prepares the daidzein micelle.The micelle that makes is the opalescent suspension of homogeneous band.Through measuring, its particle diameter is all less than 50nm, and release in vitro is all above 80%.AUC
0-∞Greater than 95000nghmL
-1, improved 3 times than the micellar AUC that directly prepares without phosphatide complexes at least.
Daidzein micelle of the present invention, it is oral further to be prepared into confession such as the preparation that comprises capsule, oral administration mixed suspension, oral liquid, to improve its oral bioavailability.Simultaneously, because this micellar particle diameter is all less than 50nm, but filtration sterilization supplies injection to use, and processes preparations such as injection and injection freeze-dried powder, is route of administration of clinical practice increase of daidzein.
Description of drawings
Fig. 1 is non-phosphatide complexes micelle of daidzein, daidzein and the micellar release profiles of daidzein phosphatide complexes of the present invention.
Fig. 2 is that (wherein, the unit of abscissa is nm to the micellar particle size distribution spectrogram of daidzein of the present invention; The unit of vertical coordinate is %).
Fig. 3 is that the non-phosphatide complexes micelle of daidzein, daidzein and daidzein phosphatide complexes micelle of the present invention are at the intravital average blood drug level-time graph of rat.
Specific embodiment
The following example is intended to further describe for example the present invention, rather than limits the present invention by any way.
Preparation embodiment
The daidzein raw material sources are plant development corporation, Ltd. of intelligent section in Shaanxi; Soybean phospholipid derives from Shanghai Taiwei Pharmaceutical Co., Ltd.; Ovum Gallus domesticus Flavus lecithin, hydrogenated soya phosphatide and hydrogenated yolk lecithin derive from German Lipoid company; Glycerol derives from Hunan that health adjuvant company limited; Sodium cholate derives from Shaoxing according to Mactra sulcatria Deshayes nurse Chemical Industry Science Co., Ltd.
Embodiment 1 (daidzein in the present embodiment: phospholipid: the weight ratio of additives is 1: 12: 10)
Get daidzein 1.0g and soybean phospholipid 10g, add 10mL acetone, be heated to 60 ℃ of reduced-pressure backflows, insulated and stirred 10 hours reclaims acetone, and drying is pulverized and promptly got phosphatide complexes; In this phosphatide complexes, add soybean phospholipid 2.0g, glycerol 10g is dissolved in the 200mL ethanol, the rotary evaporation film forming, and 50 ℃ of aquations promptly get the daidzein micelle.Recording its mean diameter is 30nm, and 24 hours dissolution in vitro is 82%.Measure its oral administration biaavailability, the micellar AUC of daidzein
0-∞Be 97152nghmL
-1Add water for injection and dilute the injection that can be made into 10mg/mL.
Embodiment 2 (daidzein in the present embodiment: phospholipid: the weight ratio of additives is 1: 25: 20)
Get daidzein 1.0g and Ovum Gallus domesticus Flavus lecithin 20g, add 50mL ethanol, be heated to 40 ℃ of reduced-pressure backflows, insulated and stirred 5 hours reclaims ethanol, and drying is pulverized and promptly got phosphatide complexes; In this phosphatide complexes, add Ovum Gallus domesticus Flavus lecithin 5.0g, sodium cholate 20g is dissolved in the 200mL ethanol, the rotary evaporation film forming, and 50 ℃ of aquations promptly get the daidzein micelle.Recording its mean diameter is 20nm, and 24 hours dissolution in vitro is 92%.Measure its oral administration biaavailability, the micellar AUC of daidzein
0-∞Be 131571nghmL
-1Add 0.02% saccharin sodium and distilled water, can be made into the oral liquid of 50mg/mL.
Embodiment 3 (daidzein in the present embodiment: phospholipid: the weight ratio of additives is 1: 30: 4)
Get daidzein 1.0g and soybean phospholipid 15g, add 20mL methanol, be heated to 60 ℃ of reduced-pressure backflows, insulated and stirred 2 hours reclaims methanol, and drying is pulverized and promptly got phosphatide complexes; In this phosphatide complexes, add soybean phospholipid 15g, sodium cholate 4g is dissolved in the 300mL ether, the rotary evaporation film forming, and 50 ℃ of aquations promptly get the daidzein micelle.Recording its mean diameter is 30nm, and 24 hours dissolution in vitro is 84%.Measure its oral administration biaavailability, the micellar AUC of daidzein
0-∞Be 116254nghmL
-1Add mannitol and water for injection, the injection freeze-dried powder is processed in lyophilization.
Embodiment 4 (daidzein in the present embodiment: phospholipid: the weight ratio of additives is 1: 20: 1)
Get daidzein 1.0g and hydrogenated yolk lecithin 10g, add the 30mL oxolane, be heated to 60 ℃ of reduced-pressure backflows, insulated and stirred 2 hours reclaims oxolane, and drying is pulverized and promptly got phosphatide complexes; In this phosphatide complexes, add hydrogenation Ovum Gallus domesticus Flavus lecithin 10g, sodium cholate 1g is dissolved in the 600mL isopropyl alcohol, the rotary evaporation film forming, and 50 ℃ of aquations promptly get the daidzein micelle.Recording its mean diameter is 40nm, and 24 hours dissolution in vitro is 81%.Measure its oral administration biaavailability, the micellar AUC of daidzein
0-∞Be 96596nghmL
-1Add sodium carboxymethyl cellulose and distilled water, process the 50mg/mL oral administration mixed suspension.
Embodiment 5 (daidzein in the present embodiment: phospholipid: the weight ratio of additives is 1: 24: 5)
Get daidzein 1.0g and Ovum Gallus domesticus Flavus lecithin 12g, add the 40mL oxolane, be heated to 50 ℃ of reduced-pressure backflows, insulated and stirred 4 hours reclaims oxolane, and drying is pulverized and promptly got phosphatide complexes; In this phosphatide complexes, add Ovum Gallus domesticus Flavus lecithin 12g, sodium cholate 5g is dissolved in the 600mL isopropyl alcohol, the rotary evaporation film forming, and 50 ℃ of aquations promptly get the daidzein micelle.Recording its mean diameter is 40nm, and 24 hours dissolution in vitro is 83%.Survey it and orally decide bioavailability, the micellar AUC of daidzein
0-∞Be 104650nghmL
-1Add 0.02% saccharin sodium and distilled water, can be made into the oral liquid of 50mg/mL.
Embodiment 6 (daidzein in the present embodiment: phospholipid: the weight ratio of additives is 1: 30: 25)
Get daidzein 1.0g and soybean phospholipid 15g, add 40mL ethanol, be heated to 60 ℃ of reduced-pressure backflows, insulated and stirred 4 hours reclaims ethanol, and drying is pulverized and promptly got phosphatide complexes; In this phosphatide complexes, add soybean phospholipid 15g, glycerol 25g is dissolved in the 200mL ethanol, the rotary evaporation film forming, and 40 ℃ of aquations promptly get the daidzein micelle.Recording its mean diameter is 20nm, and 24 hours dissolution in vitro is 98%.Measure bioavailability, the micellar AUC of daidzein
0-∞Be 15296nghmL
-1Add sodium carboxymethyl cellulose and distilled water, process the 50mg/mL oral administration mixed suspension.
Embodiment 7 (daidzein in the present embodiment: phospholipid: the weight ratio of additives is 1: 27: 25)
Get daidzein 1.0g and soybean phospholipid 25g, add 50mL ethanol, be heated to 40 ℃ of reduced-pressure backflows, insulated and stirred 4 hours reclaims ethanol, and drying is pulverized and promptly got phosphatide complexes; In this phosphatide complexes, add soybean phospholipid 2g, glycerol 25g is dissolved in the 200mL ethanol, the rotary evaporation film forming, and 60 ℃ of aquations promptly get the daidzein micelle.Recording its mean diameter is 20nm, and 24 hours dissolution in vitro is 96%.Measure its oral administration biaavailability, the micellar AUC of daidzein
0-∞Be 135681nghmL
-1Be packed into capsule, process soft capsule.
Embodiment 8 (daidzein in the present embodiment: phospholipid: the weight ratio of additives is 1: 15: 15)
Get daidzein 1.0g and Ovum Gallus domesticus Flavus lecithin 10g, add 20mL methanol, be heated to 50 ℃ of reduced-pressure backflows, insulated and stirred 5 hours reclaims methanol, and drying is pulverized and promptly got phosphatide complexes; In this phosphatide complexes, add Ovum Gallus domesticus Flavus lecithin 5g, sodium cholate 15g is dissolved in the 200mL isopropyl alcohol, the rotary evaporation film forming, and 40 ℃ of aquations promptly get the daidzein micelle.Recording its mean diameter is 40nm, and 24 hours dissolution in vitro is 85%.Measure its oral administration biaavailability, the micellar AUC of daidzein
0-∞Be 105712nghmL
-1Add 0.02% saccharin sodium and distilled water, can be made into the oral liquid of 50mg/mL.
Embodiment 9 (daidzein in the present embodiment: phospholipid: the weight ratio of additives is 1: 20: 5)
Get daidzein 1.0g and hydrogenated soya phosphatide 10g, add the 50mL oxolane, be heated to 60 ℃ of reduced-pressure backflows, insulated and stirred 2 hours reclaims oxolane, and drying is pulverized and promptly got phosphatide complexes; In this phosphatide complexes, add hydrogenation soybean phospholipid 10g, sodium cholate 5g is dissolved in the 200mL oxolane, the rotary evaporation film forming, and 40 ℃ of aquations promptly get the daidzein micelle.Recording its mean diameter is 30nm, and 24 hours dissolution in vitro surpasses 80%.Measure bioavailability, the micellar AUC of daidzein
0-∞Be 98091nghmL
-1Add sodium carboxymethyl cellulose and distilled water, process the suspension of 50mg/mL.
Embodiment 10 (daidzein in the present embodiment: phospholipid: the weight ratio of additives is 1: 25: 1.5)
Get daidzein 1.0g and soybean phospholipid 15g, add the 50mL oxolane, be heated to 60 ℃ of reduced-pressure backflows, insulated and stirred 2 hours reclaims oxolane, and drying is pulverized and promptly got phosphatide complexes; In this phosphatide complexes, add soybean phospholipid 10g, glycerol 1.5g is dissolved in the 200mL ethanol, the rotary evaporation film forming, and 40 ℃ of aquations promptly get the daidzein micelle.Recording its mean diameter is 30nm, and 24 hours dissolution in vitro is 90%.Measure bioavailability, the micellar AUC of daidzein
0-∞Be 126967nghmL
-1Add 0.02% saccharin sodium and distilled water, can be made into the oral liquid of 50mg/mL.
The test implementation example
Through to the micellar various determination experiments of daidzein of the present invention, further specify the micellar advantage of daidzein provided by the present invention below.
One, the micellar extracorporeal releasing test of daidzein of the present invention
Draw daidzein suspension (getting in the aqueous solution that daidzein is suspended in sodium carboxymethyl cellulose) respectively, (be non-phosphatide complexes micelle with the daidzein micelle of conventional method preparation; Get daidzein 1g and add oxolane, add hydrogenation soybean phospholipid 20g, sodium cholate 5g, add in the oxolane; The rotary evaporation film forming, 40 ℃ of aquations promptly get), the present invention prepares the daidzein micelle of embodiment 9; The daidzein that contains equal in quality in three duplicate samples; The bag filter (MWCO=12K) that places an end to seal, get rid of in the bag filter behind the bubble its other end sealed after, place the conical flask that is preheated to 37, contains 100mL phosphate buffer (pH=6.8).37 ℃ of constant temperature air baths, rotating speed are 30rpm, and in 0,1,2,3,4,5,6,8,12, the 24h 1.0mL phosphate buffer of respectively taking a sample, and the phosphate buffer of additional respective volume and uniform temp is in conical flask.Draw 20 μ L and inject chromatograph of liquid (Agilent1100) (ZORBAX SB-C18 chromatographic column (250mm * 4.6mm, 5 μ m); Mobile phase: acetonitrile-water (35: 65, v/v); Detect wavelength: 248nm; Column temperature: 25 ℃; Flow velocity: 1.0ml/min) measure daidzein content in above-mentioned each solution.The release in vitro curve of three duplicate samples is seen Fig. 1.The result is visible: 24 hours daidzein external can only stripping 10%, can stripping 25% with the daidzein micelle (non-phosphatide complexes micelle) of conventional method preparation, and daidzein micelle of the present invention can stripping surpass 80%.Can find out that the micellar stripping of daidzein of the present invention increases greatly.
Two, particle size determination
Get the daidzein micelle 1mL that the present invention prepares embodiment 6, be diluted to 100 times, measure its particle diameter with NICOMP 380ZLS particle size determination appearance with water.The result sees Fig. 2.Can find out that the micellar mean diameter of daidzein of the present invention is 20nm.
Three, bioavailability is measured in the rat body
Get 18 of healthy SD rats, male, body weight 200-220g is divided into 3 groups at random, 6 every group.Irritate stomach respectively and give above-mentioned daidzein, the daidzein micelle (non-phosphatide complexes micelle) of preparation as stated above, the daidzein micelle that the present invention prepares embodiment 2, dosage is 20mgkg
-1Fasting 12h before the test freely drinks water.The unified feed of 2h after the administration.10min, 0.5h, 1.0h, 2.0h, 3.0h, 4.0h, 6.0h, 8.0h, 12h and 24h get blood through the rat eye rear vein beard after the administration; After plasma sample is handled; Auto injection 20 μ L carry out LC-MS/MS (Varian 1200) (Capcell PAK-C18 post (150mm * 4.6mm, 5 μ m); Mobile phase: acetonitrile-5mmolL
-1Ammonium acetate-formic acid solution (54: 46: 0.2, v/v/v); Detect wavelength: 248nm; Column temperature: 25 ℃; Flow velocity: 1.0mLmin
-1) analyze, the peak area inner mark method ration is measured.The result sees Fig. 3.Bioavailability is measured the result and is shown in the rat body, and daidzein micelle of the present invention has significantly improved the oral administration biaavailability of daidzein.And the effect of the daidzein micelle (non-phosphatide complexes micelle) of the conventional method of same amount preparation can not show a candle to daidzein micelle of the present invention.
Claims (7)
1. daidzein micelle, it is characterized in that: by weight, this micelle comprises:
1 part of daidzein
2～30 parts of phosphatidase 11s
1～25 part of additives
And said daidzein micelle prepares according to following method: get daidzein and the phospholipid that accounts for whole phosphatidase 15s 0%～95% earlier, add organic solvent, be heated to 40 ℃～60 ℃ reduced-pressure backflows; Insulated and stirred 2～10 hours; Reclaim organic solvent, drying, pulverize the daidzein phosphatide complexes; Get this daidzein phosphatide complexes and remaining phospholipid, additives then and be dissolved in organic solvent, solution rotating is evaporated film forming after, 40 ℃～60 ℃ aquations promptly get and are with opalescent micelle suspension;
Wherein, said additives are selected from glycerol and sodium cholate;
Wherein, said organic solvent is selected from methanol, ethanol, ether, acetone, oxolane and isopropyl alcohol;
Wherein, during preparation daidzein phosphatide complexes, the ratio of said daidzein and said organic solvent is 1:10～50 (w/v).
2. daidzein micelle according to claim 1 is characterized in that: by weight, this micelle comprises:
1 part of daidzein
5～30 parts of phosphatidase 11s
10～25 parts of additives.
3. daidzein micelle according to claim 2 is characterized in that: by weight, this micelle comprises:
1 part of daidzein
0～30 part of phosphatidase 12
20～25 parts of additives.
4. according to each described daidzein micelle in the claim 1～3, it is characterized in that: this micellar mean diameter is less than 50nm.
5. according to each described daidzein micelle in the claim 1～3, it is characterized in that: said phospholipid is selected from soybean phospholipid, Ovum Gallus domesticus Flavus lecithin, hydrogenated soya phosphatide and hydrogenated yolk lecithin.
6. the micellar method for preparing of each described daidzein in the claim 1～3; It is characterized in that: get daidzein and the phospholipid that accounts for whole phosphatidase 15s 0%～95% earlier, add organic solvent, be heated to 40 ℃～60 ℃ reduced-pressure backflows; Insulated and stirred 2～10 hours; Reclaim organic solvent, drying, pulverize the daidzein phosphatide complexes; Get this daidzein phosphatide complexes and remaining phospholipid, additives then and be dissolved in organic solvent, solution rotating is evaporated film forming after, 40 ℃～60 ℃ aquations promptly get and are with opalescent micelle suspension;
Wherein, during preparation daidzein phosphatide complexes, the ratio of said daidzein and said organic solvent is 1:10～50 (w/v).
7. according to each described daidzein micelle in the claim 1 ~ 3, it is characterized in that, can further be prepared into capsule, oral administration mixed suspension, oral liquid, injection and injection freeze-dried powder.
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4158707A (en) * | 1976-07-12 | 1979-06-19 | Hoffmann-La Roche Inc. | Parenteral preparations |
| CN1138585A (en) * | 1995-03-07 | 1996-12-25 | 弗·哈夫曼-拉罗切有限公司 | Mixed micelles |
| US6086915A (en) * | 1998-04-01 | 2000-07-11 | Bioresponse L.L.C. | Compositions and methods of adjusting steroid hormone metabolism through phytochemicals |
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