CN104042644A - Ginkgo biloba extract self-microemulsion preparation and preparation method thereof - Google Patents
Ginkgo biloba extract self-microemulsion preparation and preparation method thereof Download PDFInfo
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Abstract
The invention discloses a ginkgo biloba extract self-microemulsion preparation which consists of ginkgo biloba extract, midchain oil, polyoxyethylene castor oil-EL35 and polyethylene glycol 400 according to a mass ratio of 1 to (0.5-2.) to (1.5-2.25) to (1.5-2.25). The ginkgo biloba extract self-microemulsion preparation can be prepared into microemulsion and soft capsules or can be taken as an adhesive and prepared into granules, tablets and pellets and the like. Through the ginkgo biloba extract self-microemulsion preparation, the solubility of the ginkgo biloba extract is improved, and the dissolution rate in vitro of the ginkgo biloba extract is also increased. Pharmacokinetic study in the beagle body shows that the relative bioavailability of the ginkgo biloba extract self-microemulsion preparation is 160.24% in comparison with the commercially-available preparations, so that the oral bioavailability of the ginkgo biloba extract is effectively improved.
Description
Technical field
The present invention relates to ginkgo flavone and lactone self-micro emulsion formulation and preparation method thereof.
Background technology
Ginkgo flavone and lactone (GBE50) is Semen Ginkgo the 5th generation extract, be mainly used in clinically prevention and Cardiovarscular.Ginkgo flavone and lactone water solublity is not high, and oral administration biaavailability is low, and there are ginkgo flavone and lactone tablet, granule and drop pill in commercial preparation, all needs to take medicine every day repeatedly, causes patient's compliance low, thus economic benefit and the social benefit of restriction ginkgo flavone and lactone.
In the recent period relevant GBE50 novel form and new industrial research mainly concentrate on the oral administration biaavailability that increases dissolubility, improves ginkgo flavone and lactone, as phosphatide complexes, liposome, Benexate Hydrochloride etc. [referring to: rely happy, Lai Chunli, Zhao Jianbin, Deng. the preparation of ginkgo flavone and lactone phosphatide complexes and the research of physicochemical property [J]. Chinese crude drug, 2010,33 (10): 1624-1624; Zhao Jianbin, Chen Jianhai. the quality standard research of ginkgo flavone and lactone-hydroxypropyl-beta-cyclodextrin inclusion [J]. Central-South pharmacy, 2011,9 (002): 107-110; Li Juan, He Jie, Wang Guangji. the preparation of GBE 50 oral proliposome and physicochemical property thereof [J]. Chinese natural drug, 2007,5 (3): 201-206].
Self-microemulsion drug-supplying system (Self-Micoemulsying Drug Delivery System, SMEDDS) be by medicine, oil phase, emulsifying agent, the heterogeneous dispersion that co-emulsifier forms, the microemulsion granule that can spontaneous dispersed formation particle diameter under slight physical agitation or gastrointestinal motility be less than 100nm, to improve the oral microparticle delivery system of drug bioavailability [referring to Date A A, Desai N, Dixit R, et al.Self-nanoemulsifying drug delivery systems:Formulation insights, applications and advances[J] .Nanomedicine, 2010, 5 (10): 1595-1616.Self-micro emulsion formulation forms small breast grain in gastrointestinal inner chamber, can strengthen the dissolubility of medicine, and the distribution of energy regulating drug.
Affect a lot of because have that self-microemulsion drug-supplying system forms, but crucial physical chemistry and the biological physicochemical property that is its composition each several part, as oil phase, emulsifying agent, the kind of co-emulsifier is selected, ratio between oil phase and emulsifying agent and the Determination of oil-water partition coefficient of medicine, the polarity of medicine etc., wherein affect larger still oil phase, emulsifying agent, the selection of these three compositions of co-emulsifier is [referring to Bajaj H, Bisht S, Yadav M, et al.Self emulsifying drug delivery system:An approach to enhance bioavailability[J] .International Journal of Pharma Research and Development, 2011, 3 (1): 59-75].
Oil phase has important effect in self-microemulsion drug-supplying system, can not only dissolve insoluble drug, increases the dissolubility of medicine and the cell membrane permeability of raising medicine, can also promote the transhipment of medicine in gastrointestinal system.Conventionally, select saturated, the unsaturated or local saturated Hydrocarbon of medium chain/long-chain as oil phase, comprise that vegetable oil, mineral oil, fatty acid etc. are [referring to Kohli K, Chopra S, Dhar D, et al.Self-emulsifying drug delivery systems:An approach to enhance oral bioavailability[J] .Drug Discovery Today, 2010,15 (21): 958-965].
The selection of emulsifying agent is also the key that forms self-microemulsion, because the characteristic of emulsifying agent as hydrophilic/lipophilic balance value (HLB), cloud point, viscosity, with affinity, the ratio of emulsifying agent in self-microemulsion system of oil phase, these character greatly have influence on the formation of self-microemulsion system and the size that self-microemulsion drips.Generally, select the higher nonionic emulsifier of HLB, as polyoxyethylene hydrogenated Oleum Ricini, tween, span, poloxamer, sodium lauryl sulphate (SLS), phospholipid, cholesterol, dodecylbenzene sodium sulfonate (Lab) etc.[referring to Anton N, Vandamme T F.The universality of low-energy nano-emulsification[J] .International Journal of Pharmaceutics, 2009,377 (1): 142-147].
Co-emulsifier energy assist in dissolving medicine, embeds in emulsifying agent molecule, and both form the interfacial film of microemulsion, increases interfacial film mobility, thereby improves drug loading, regulates the emulsification times of self-microemulsion system, controls self-microemulsion drop and forms size.Conventional co-emulsifier has the materials such as ethanol, propylene glycol, isopropyl alcohol, Polyethylene Glycol, glycerol, ethylene glycol monoethyl ether [referring to Basalious E B, Shawky N, Badr-Eldin S M.Snedds containing bioenhancers for improvement of dissolution and oral absorption of lacidipine.I:Development and optimization[J] .International journal of pharmaceutics, 2010,391 (1): 203-211].
Summary of the invention
The object of the present invention is to provide a kind of ginkgo flavone and lactone self-micro emulsion formulation, the ginkgo flavone and lactone of poorly water-soluble is prepared into self-micro emulsion formulation, increase the dissolubility of ginkgo flavone and lactone, improve the oral administration biaavailability of ginkgo flavone and lactone.
Another object of the present invention is to provide the preparation method of this ginkgo flavone and lactone self-micro emulsion formulation.
For achieving the above object, the technical solution used in the present invention is as follows:
A kind of ginkgo flavone and lactone self-micro emulsion formulation, it is comprised of ginkgo flavone and lactone, midchain oil, polyoxyethylene castor oil-EL35, PEG400, and the mass ratio between each component is ginkgo flavone and lactone: midchain oil: polyoxyethylene castor oil-EL35: PEG400=1:0.5～2:1.5～2.25:1.5～2.25.
A preparation method for above-mentioned ginkgo flavone and lactone self-micro emulsion formulation, its feature comprises following preparation process:
(1), in above-mentioned prescription, form and ratio, take polyoxyethylene castor oil-EL35, PEG400,37 ℃ of water-baths, stir under mix homogeneously;
(2), slowly add the midchain oil of recipe quantity in the blended emulsifier that makes in step 1,37 ℃ of water-baths, stir under mix homogeneously, obtain blank self-microemulsion;
(3) the ginkgo flavone and lactone crude drug that, finally adds recipe quantity, mix homogeneously under (37 ± 2) ℃ water-bath, stirring, obtains ginkgo flavone and lactone self-micro emulsion formulation.
Above-mentioned ginkgo flavone and lactone self-micro emulsion formulation can be made microemulsion or soft capsule dosage form, or is prepared into granule, tablet or micropill dosage form as binding agent.
Beneficial effect
1, ginkgo flavone and lactone self-micro emulsion formulation has improved ginkgo flavone and lactone at 0.1molL
-1dissolubility in HCl solution, pH5.0PBS solution and distilled water, increases multiple and is respectively 40.36,34.90 and 42.95.
2, ginkgo flavone and lactone self-micro emulsion formulation is at 0.1molL
-1cumulative release amount in HCl solution, pH5.0PBS solution and distilled water, all reaches 85% at 30min, significantly improves the release in vitro behavior of GBE50, has obviously improved the external Cumulative release amount of GBE50.
3, in beasle dog body, pharmacokinetic studies shows, compare with commercial preparation, the relative bioavailability of ginkgo flavone and lactone self-micro emulsion formulation is 160.24% of commercial preparation, has effectively improved the oral administration biaavailability of ginkgo flavone and lactone.
Accompanying drawing explanation
Fig. 1 is the transmission electron microscope picture (* 400k) of the ginkgo flavone and lactone self-micro emulsion formulation of embodiment six preparations.
Fig. 2 is ginkgo flavone and lactone self-micro emulsion formulation and the ginkgo flavone and lactone crude drug of embodiment six preparations, the tablets in vitro curve chart in three kinds of different dissolution mediums.
Fig. 3 is the ginkgo flavone and lactone self-micro emulsion formulation of embodiment six preparations and the blood drug level-time plot of commercial preparation XINGLING KELI.
The specific embodiment
Listed embodiment contributes to those skilled in the art to understand better the present invention below, but does not limit the present invention in any way.
Following examples key instrument used and material
Experiment material: midchain oil (Tieling Beiya Medical Oil Co., Ltd.); Polyoxyethylene castor oil-EL35 (BASF AG); PEG400 (Chemical Reagent Co., Ltd., Sinopharm Group).
Experimental apparatus: ZRS-8G intelligence digestion instrument (Radio Factory of Tianjin Univ.); BI-9100 high concentration laser particle analyzer (U.S. Brooker Hai Wen instrument company); Chromatograph of liquid (comprising LC-20AT pump, Hypersil C18 post, SPD-20A UV-detector) (Japanese Shimadzu company); Climacell stability test case (German MMM company)
Embodiment 1
(1), take 0.9g polyoxyethylene castor oil-EL35,0.9g PEG400, mix homogeneously under 37 ℃ of water-baths, magnetic agitation effect.
(2), slowly add 0.2g midchain oil in the blended emulsifier that makes in step 1, mix homogeneously under 37 ℃ of water-baths, magnetic agitation effect, obtains blank self-microemulsion.
(3), finally add 0.4g ginkgo flavone and lactone crude drug, under 37 ℃ of water-baths, magnetic agitation effect, mix homogeneously, obtains ginkgo flavone and lactone self-micro emulsion formulation.
Embodiment 2
(1), take 0.875g polyoxyethylene castor oil EL35,0.875g PEG400, mix homogeneously under 37 ℃ of water-baths, magnetic agitation effect.
(2), slowly add 0.25g midchain oil in the blended emulsifier that makes in step 1, mix homogeneously under 37 ℃ of water-baths, magnetic agitation effect, obtains blank self-microemulsion.
(3), finally add 0.4g ginkgo flavone and lactone crude drug, under 37 ℃ of water-baths, magnetic agitation effect, mix homogeneously, obtains ginkgo flavone and lactone self-micro emulsion formulation.
Embodiment 3
(1), take 0.85g polyoxyethylene castor oil EL35,0.85g PEG400, mix homogeneously under 37 ℃ of water-baths, magnetic agitation effect.
(2), slowly add 0.3g midchain oil in the blended emulsifier that makes in step 1, mix homogeneously under 37 ℃ of water-baths, magnetic agitation effect, obtains blank self-microemulsion.
(3), finally add 0.4g ginkgo flavone and lactone crude drug, under 37 ℃ of water-baths, magnetic agitation effect, mix homogeneously, obtains ginkgo flavone and lactone self-micro emulsion formulation.
Embodiment 4
(1), take 0.7g polyoxyethylene castor oil EL35,0.7g PEG400, mix homogeneously under 37 ℃ of water-baths, magnetic agitation effect.
(2), slowly add 0.6g midchain oil in the blended emulsifier that makes in step 1, mix homogeneously under 37 ℃ of water-baths, magnetic agitation effect, obtains blank self-microemulsion.
(3), finally add 0.4g ginkgo flavone and lactone crude drug, under 37 ℃ of water-baths, magnetic agitation effect, mix homogeneously, obtains ginkgo flavone and lactone self-micro emulsion formulation.
Embodiment 5
(1), take 0.6g polyoxyethylene castor oil EL35,0.6g PEG400, mix homogeneously under 37 ℃ of water-baths, magnetic agitation effect.
(2), slowly add 0.8g midchain oil in the blended emulsifier that makes in step 1, mix homogeneously under 37 ℃ of water-baths, magnetic agitation effect, obtains blank self-microemulsion.
(3), finally add 0.4g ginkgo flavone and lactone crude drug, under 37 ℃ of water-baths, magnetic agitation effect, mix homogeneously, obtains ginkgo flavone and lactone self-micro emulsion formulation.
Embodiment 6
(1), take 0.8g polyoxyethylene castor oil EL35,0.8g PEG400, mix homogeneously under 37 ℃ of water-baths, magnetic agitation effect.
(2), slowly add 0.4g midchain oil in the blended emulsifier that makes in step 1, mix homogeneously under 37 ℃ of water-baths, magnetic agitation effect, obtains blank self-microemulsion.
(3), finally add 0.4g ginkgo flavone and lactone crude drug, under 37 ℃ of water-baths, magnetic agitation effect, mix homogeneously, obtains ginkgo flavone and lactone self-micro emulsion formulation.The ginkgo flavone and lactone self-micro emulsion formulation making is carried out to Electronic Speculum mensuration, and it the results are shown in Figure 1.Ginkgo flavone and lactone self-micro emulsion formulation and ginkgo flavone and lactone crude drug by preparation, be determined at three kinds of tablets in vitro curves in different dissolution mediums, and it the results are shown in Figure 2.
The accelerated stability test of the ginkgo flavone and lactone self-micro emulsion formulation of embodiment 7 preparations
Get three crowdes of each 10g of ginkgo flavone and lactone self-micro emulsion formulation of embodiment six, be placed in climatic chamber, design temperature is (40 ± 2) ℃, relative humidity is (75% ± 5%), test 3 months, respectively at sampling in 0,1,2,3 month, detect its outward appearance, particle diameter and drug loading situation, result is as table 1.
Table 1
Conclusion: the outward appearance of ginkgo flavone and lactone self-micro emulsion formulation does not change, be still orange-yellow transparency liquid, do not occur muddy lamination, size is all in 50nm left and right, drug loading is measured also there are no change, and at least having good stability in 3 months of ginkgo flavone and lactone self-micro emulsion formulation is described.
Pharmacokinetics experiment in the body of the ginkgo flavone and lactone self-micro emulsion formulation of embodiment 8 preparations
1.1 animals administers and blood sample are processed
The Beagle dog that will grow up, fasting is after 12 hours, and single oral dose is equivalent to the commercially available XINGLING KELI of 40mg ginkgo flavone and lactone and the ginkgo flavone and lactone self-micro emulsion formulation of embodiment six preparations.After administration respectively at 0.5h, l h, 1.5h, 2h, 3h, 4h, 6h, 8h, 12h in forelimb venous blood sampling 2mL, blood sample anticoagulant heparin, centrifuging and taking blood plasma, gets blood plasma 0.2mL and is placed in clean tool plug centrifuge tube, adds the 3molmL of 0.2mL
-1hydrochloric acid solution, mixes, 80 ℃ of water-bath 30min, and ice bath is cooling, adds ɑ-naphthols methanol solution (10 μ gmL
-1) 100 μ L, vortex concussion 5min, adds 4mL ethyl acetate, and vortex mixes 5min, 3000rmin
-1frozen centrifugation 15min, draws supernatant in another clean centrifuge tube, N at 40 ℃
2dry up, in centrifuge tube, add 100 μ L dissolve with methanol, vortex 5min, sample introduction 20 μ L.By HPLC method, measure the drug level of Quercetin, kaempferol and isorhamnetin in blood plasma.Record chromatogram and peak area, according to standard curve, calculate the blood drug level of medicine, by following formula, be converted into the content of total flavonoids.
Total flavonoids content=(quercetin content+kaempferol content+isorhamnetin content) * 2.51
Curve and relative bioavailability during 1.2 blood plasma medicine
Curve while drawing the blood plasma medicine of commercial preparation XINGLING KELI and ginkgo flavone and lactone self-micro emulsion formulation, is shown in Fig. 3.Blood drug level data are through BAPP software (Yao Dai of China Medicine University center provides) matching pharmacokinetic parameters, and supplemental characteristic represents with Mean, the results are shown in Table 2.Relative bioavailability F=AUC
t/ AUC
r* 100%.
Table 2
Conclusion: area under a curve AUC during the medicine of ginkgo flavone and lactone self-micro emulsion formulation
0-24, C
maxall than the AUC of XINGLING KELI
0-24, C
maxgreatly, this just illustrates that GBE50-SMEDDS has increased blood drug level in body, plays solubilizing effect.Compare with commercial preparation, the relative bioavailability of ginkgo flavone and lactone self-micro emulsion formulation is 160.24%.
Claims (3)
1. a ginkgo flavone and lactone self-micro emulsion formulation, it is characterized in that: it is comprised of ginkgo flavone and lactone, midchain oil, polyoxyethylene castor oil-EL35, PEG400, the mass ratio between each component is ginkgo flavone and lactone: midchain oil: polyoxyethylene castor oil-EL35: PEG400=1:0.5～2:1.5～2.25:1.5～2.25.
2. a preparation method for ginkgo flavone and lactone self-micro emulsion formulation claimed in claim 1, its feature comprises following preparation process:
(1), in prescription claimed in claim 1, form and ratio, take polyoxyethylene castor oil-EL35, PEG400,37 ℃ of water-baths, stir under mix homogeneously;
(2), slowly add the midchain oil of recipe quantity in the blended emulsifier that makes in step 1,37 ℃ of water-baths, stir under mix homogeneously, obtain blank self-microemulsion;
(3) the ginkgo flavone and lactone crude drug that, finally adds recipe quantity, mix homogeneously under (37 ± 2) ℃ stirring in water bath, obtains ginkgo flavone and lactone self-micro emulsion formulation.
3. ginkgo flavone and lactone self-micro emulsion formulation claimed in claim 1 can be made microemulsion or soft capsule dosage form, or is prepared into granule, tablet or micropill dosage form as binding agent.
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1951404A (en) * | 2006-01-16 | 2007-04-25 | 杨铁耀 | Oral microemulsion of gingko leaf and preparation method thereof |
| KR20140018913A (en) * | 2011-04-27 | 2014-02-13 | 닥터 빌마르 쉬바베 게엠바하 운트 코 카게 | Controlled release tablet of ginkgo biloba extract and procedure for obtaining it |
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1951404A (en) * | 2006-01-16 | 2007-04-25 | 杨铁耀 | Oral microemulsion of gingko leaf and preparation method thereof |
| KR20140018913A (en) * | 2011-04-27 | 2014-02-13 | 닥터 빌마르 쉬바베 게엠바하 운트 코 카게 | Controlled release tablet of ginkgo biloba extract and procedure for obtaining it |
Non-Patent Citations (1)
| Title |
|---|
| 熊颖: "银杏酮酯口服自微乳化给药系统的研究", 《中国博士学位论文全文数据库医药卫生科技辑》 * |
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Application publication date: 20140917 |