CN1320926C - Ginkgo leaf extract composition and its prepn - Google Patents
Ginkgo leaf extract composition and its prepn Download PDFInfo
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- CN1320926C CN1320926C CNB2005100952462A CN200510095246A CN1320926C CN 1320926 C CN1320926 C CN 1320926C CN B2005100952462 A CNB2005100952462 A CN B2005100952462A CN 200510095246 A CN200510095246 A CN 200510095246A CN 1320926 C CN1320926 C CN 1320926C
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Abstract
The present invention relates to the technical field of medicine preparation of natural medicines, more specifically a ginkgo leaf extract composition and a preparation process thereof, which is characterized in that the composition of the present invention contains a ginkgo leaf extract and/or a ginkgo leaf extract phospholipid compound, and surface active agent. The composition of the present invention can obviously enhance the bioavailability of the ginkgo leaf extract to achieve better curative effect.
Description
Technical field
The present invention relates to the field of pharmaceutical preparations of natural drug, be specifically related to contain the composition and method of making the same of Folium Ginkgo extract.
Background technology
Semen Ginkgo (Ginkgo biloba) is a Ginkgoaceae Ginkgo plant, has another name called maidenhair tree, Gong Sunshu, is one of the most ancient plant, and the title of gymnosperm living fossil is arranged, and its medicinal part mainly is Ye Heguo, and the gingko resource of China occupies first place in the world.Folium Ginkgo extract (Ginkgo biloba L. extract, GbE) be from the dried leaves of Semen Ginkgo, to extract a kind of faint yellow flour that purification forms, its chemical constituent is comparatively complicated, contain more than 160 kind of composition in the assay determination Folium Ginkgo extract at present, but flavone compound, terpene lactone, polyisoamylene alcohols are considered to main active, and gingkolic acid (abbreviation ginkgoic acid) is main toxic ingredient.Wherein flavone compound mainly exists with the form of flavonoid glycoside, has the effect of removing free radical; Terpenoid is potent platelet activating factor (PAF) antagonist, and both are the important effective ingredient in the Folium Ginkgo extract.At present the Folium Ginkgo extract quality standard of generally acknowledging in the world is German Swache company a patent EGb761 standard in 1991, i.e. Ginkgo total flavones＞24%, and Ginkgo total lactones＞6% limits the ginkgoic acid level simultaneously below 5ppm.(2005 editions one one) is also on the books in China's pharmacopeia.The enterprise that produces and sell Folium Ginkgo extract at present has: pine hall Bioisystech Co., Ltd, Linyi Ai Kang pharmaceutcal corporation, Ltd etc. are asked in Plant Research Inst., Jiangsu Prov., Zhejiang Kang Enbei pharmaceutical Co. Ltd, Shandong Green Leaf Pharmaceutical Co., Ltd, Shenzhen Sanjiu Pharmaceutical Co., Ltd, Hangzhou.Modern pharmacological research shows that the pharmacological action of Folium Ginkgo extract is the coefficient result of component that various relative fixed are formed, and its drug action comprises that mainly regulating blood vessel, enhancing cognitive power, relieving stress and gene adjusts four effects greatly.Modern medicine thinks that also Folium Ginkgo has curative effect preferably to cardiovascular and cerebrovascular diseases such as coronary heart disease, cerebral thrombosiss.
But owing to unfavorable factors such as many compositional polarities in the Folium Ginkgo extract are big, and water solublity is big, therefore, causes oral difficult absorption, and bioavailability is low influence drug effect.
Summary of the invention
The invention discloses the improved ginkgo leaf extract composition of a kind of bioavailability, by Folium Ginkgo extract and surfactant are united use, or Folium Ginkgo extract unites use with surfactant after being prepared into phosphatide complexes again, can significantly improve the bioavailability of Folium Ginkgo extract.
In the research process to Folium Ginkgo extract, we find that Folium Ginkgo extract adds surfactant and unites that bioavailability obviously improves when using.
The invention discloses the high ginkgo leaf extract composition of a kind of bioavailability, it is characterized in that containing Folium Ginkgo extract and/or Folium Ginkgo extract phospholipid complex, surfactant.
The ginkgo leaf extract composition of the invention described above, wherein the ratio of weight and number of each component is preferably:
Folium Ginkgo extract and/or Folium Ginkgo extract phospholipid complex 1
Surfactant 0.75～3.
Ginkgo leaf extract composition of the present invention, more the ratio of weight and number of preferred ingredients and each component is:
Folium Ginkgo extract phospholipid complex 1
Surfactant 0.75～1.5.
When Folium Ginkgo extract or Folium Ginkgo extract phospholipid complex added surfactant, bioavailability can improve, but when the amount of surfactant adding less than 0.75 the time, bioavailability slightly increases, and does not reach ideal high bioavailability.And when surfactant added too much (greater than 3), then the increasing bioavailability along with the surface activity consumption no longer improved, and too much surfactant can influence the normal function of body, brought inconvenience also for the prepared of preparation.Therefore, when being 1: 0.75～3, Folium Ginkgo extract and/or Folium Ginkgo extract phospholipid complex and surfactant weight ratio relatively be fit to clinical use.Comprehensive more excellent ratio is 1: 0.75～1.5.
In the technique scheme, surfactant is the mixture of one or more in sucrose fatty acid ester, sorbitan fatty acid ester, Polysorbate, polyoxyethylene fatty acid ester, polyoxyethylene aliphatic alcohol ether, polyoxyethylene-polyoxypropylene copolymer, polyethylene glycol fatty acid glyceride preferably.More preferred surfactants is sorbitol anhydride monolaurate (Span 20), sorbitol anhydride monopalmitate (Span 40), anhydro sorbitol acid anhydride monoleate (Span 80), polyoxyethylene pears alcohol acid anhydride monoleate (Tween 80), polyoxyethylenesorbitan sorbitan monooleate (polysorbas20), polyoxyethylene lauryl ether (Brij 35), Polyethylene Glycol glyceryl laurate ester (Gelucire44/14), Polyethylene Glycol tristerin (Gelucire50/13), Polyethylene Glycol is sad/certain herbaceous plants with big flowers acid glyceride (Labrasol).
Ginkgo leaf extract composition of the present invention can prepare in order to the below method:
When being combined as Folium Ginkgo extract+surfactant, preparation method is as follows:
Get Folium Ginkgo extract and surfactant, stirring or ground and mixed are even, promptly.Add other pharmaceutic adjuvant if desired, then can join in Folium Ginkgo extract and the surfactant, restir or ground and mixed are even, are prepared into various dosage forms.
When being combined as Folium Ginkgo extract phospholipid complex+surfactant, preparation method is as follows:
The preparation of a, Folium Ginkgo extract phospholipid complex:
Get weight ratio and be 1: 0.5～1.75 Folium Ginkgo extract and phospholipid, in organic solvent, mix, react, after decompression or the spray drying, promptly get Folium Ginkgo extract phospholipid complex, wherein organic solvent is selected from chloroform, ether, acetone, dichloromethane, ethyl acetate, dioxane, oxolane, normal hexane, C1～C6 straight or branched low-grade alkane alcohol.Wherein C1～C6 straight or branched low-grade alkane alcohol comprises methanol, ethanol, propanol or butanols etc.
B, preparation of compositions:
Get Folium Ginkgo extract phospholipid complex and surfactant, add other pharmaceutic adjuvant as need, after then adding in the lump, restir or ground and mixed are even, are prepared into various preparations.
Phospholipid is selected natural phospholipid and/or synthetic phospholipid for use.Natural phospholipid is selected from soybean phospholipid and/or egg yolk lecithin, and synthetic phospholipid is selected from dipalmitoyl phosphatidyl choline or two palmityl PHOSPHATIDYL ETHANOLAMINE, and the content of phosphatidylcholine is 65%～98% in the used phospholipid.
In the phosphatide complexes preparation method, wherein Folium Ginkgo extract and the phospholipid temperature of mixing in organic solvent, reacting is 20～90 ℃, and the time is 0.5～6.0 hour; The use amount of organic solvent must not be lower than 20ml for the 1g Folium Ginkgo extract; Decompression or spray drying (logical in case of necessity N
2) remove organic solvent after, can add atent solvent purification Folium Ginkgo extract phospholipid complex, make the Folium Ginkgo extract precipitate and separate that does not form complex, Folium Ginkgo extract phospholipid complex is dissolved in atent solvent, after removing atent solvent, obtain purer Folium Ginkgo extract phospholipid complex.Wherein preferred dichloromethane of atent solvent and/or normal hexane.
In the test of preparation Folium Ginkgo extract phospholipid complex, the influence factor of the recombination rate of phosphatide complexes is a lot.When the weight ratio of Folium Ginkgo extract and phospholipid less than 0.5 the time, recombination rate lower (＜75%), and weight ratio was greater than 1.75 o'clock, the gained Folium Ginkgo extract phospholipid complex is more sticking, take all factors into consideration patient's dosage (as far as possible little), so the mass ratio of preferred Folium Ginkgo extract and phospholipid is 0.5～1.75; The consumption of organic solvent can influence recombination rate, and medicine can not fully contact therein with phospholipid when low excessively, and recombination rate is lower, so select 1g Folium Ginkgo extract consumption of organic solvent to be no less than 20ml, recombination rate can reach more than 98%.Reaction temperature is also influential to recombination rate and phospholipid stability, and when being lower than 20 ℃, recombination rate lower (＜75%) when being higher than 90 ℃, can influence the stability of phospholipid.Response time is more than at least 0.5 hour, is advisable with 2.0～5.0 hours, can extend to 6 hours.
Ginkgo leaf extract composition of the present invention can further add other pharmaceutic adjuvants and be prepared into various clinically dosage forms, as adding in diluent, absorbent, disintegrating agent, binding agent, wetting agent, lubricant and the slow-release material one or more.Be prepared into dosage forms such as oral liquid, tablet, micropill, granule, capsule, soft capsule, drop pill, slow releasing tablet, slow-release micro-pill or slow releasing capsule.Diluent is selected from one or more in starch, pregelatinized Starch, dextrin, Icing Sugar, lactose, mannitol, microcrystalline Cellulose, the calcium sulfate; Absorbent is selected from one or more in calcium sulfate, calcium hydrogen phosphate, light magnesium oxide, calcium carbonate, starch, Aluminium Hydroxide, the micropowder silica gel; Disintegrating agent is selected from one or more in cross-linking sodium carboxymethyl cellulose, polyvinylpolypyrrolidone, starch, carboxymethyl starch sodium, carboxylic propyl group starch, low-substituted hydroxypropyl cellulose, alginic acid, Bentonite, the veegum; Binding agent is selected from one or more in hypromellose, polyvidone, starch slurry, dextrin, syrup, rubber cement, ethyl cellulose, methylcellulose, the sodium carboxymethyl cellulose; Wetting agent is selected from water and/or ethanol, and lubricant is selected from one or more in Pulvis Talci, magnesium stearate, micropowder silica gel, hydrogenated vegetable oil, Stepanol MG (sodium), the sodium stearyl fumarate; Slow-release material is selected from one or more in hypromellose, methylcellulose, ethyl cellulose, carboxyethyl cellulose, polrvinyl chloride, glyceryl monostearate, vinyl acetate, carbomer, acrylic resin, arabic gum, the xanthan gum.
The dosage form of comparative optimization is a slow releasing preparation: add slow-release material and be prepared into slow releasing tablet, slow-release micro-pill or slow releasing capsule.After this ginkgo leaf extract composition and medicinal oral preparation adjuvant are mixed and made into slow releasing preparation, can overcome and take blood drug level peak, the paddy phenomenon that occurs behind the ordinary preparation, and can reduce dosage when keeping equal drug effect, thereby reduce the toxic and side effects of medicine; Can also keep long action time, thereby reduce medicining times, improve compliance of patients.
The prescription of preferred slow releasing preparation is:
Folium Ginkgo extract and/or Folium Ginkgo extract phospholipid complex 10～40%
Slow-release material 4～35%
Other adjuvant (as absorbent, binding agent etc.) 10～55%
Slow-release material is selected from one or more in hypromellose, methylcellulose, ethyl cellulose, carboxyethyl cellulose, polrvinyl chloride, glyceryl monostearate, microcrystalline Cellulose, vinyl acetate, carbomer, acrylic resin, arabic gum, the xanthan gum.
Be part pharmacological testing of the present invention and data below:
Test one:
Subjects: the SD rat, male, body weight 280～320g, n=6
Dosage: Folium Ginkgo extract 140mg/kg
Dosage regimen: 1, Folium Ginkgo extract is suspended in the 0.5%CMC-Na solution, promptly.
2, Folium Ginkgo extract and surfactant are suspended in the 0.5%CMC-Na solution, promptly.
Blood sampling scheme: get rat, fasting is 12 hours under the free conditions of water drinking, labelling also is divided into two groups: Folium Ginkgo extract group and group of surfactants, respectively by the dosage regimen gastric infusion, got blood 1.2～1.5ml in the optical fundus in 2 hours, 5 hours, 8 hours, 10 hours, 16 hours, 24 hours, 4000 rev/mins centrifugal 5 minutes, draw supernatant, be blood plasma.
Blood sample processing method: get blood plasma 0.5ml, add mark liquid 20 μ l in the salicylic acid, hydrochloric acid (3mol/L) 0.5ml, cooling is rapidly taken out in 80 ℃ of hydrolysis 30 minutes, adds ether-acetone (14: 1) 3ml vortex and extracts 3 minutes, 3500 rev/mins centrifugal 10 minutes, draw supernatant, in N
2Flow down and volatilize, face with preceding usefulness 100 μ l mobile phases and redissolve, 12000 rev/mins of high speed centrifugations 3 minutes get final product sample introduction, detect Ginkgo total flavones concentration with the high performance liquid chromatogram method.
Chromatographic condition: Diamond ODS chromatographic column (4.6mm * 250mm, 5 μ m); Mobile phase: methanol: 0.5% phosphoric acid=50: 50; Flow velocity: 1ml/min; Ultraviolet detection wavelength: 360nm; Sample size 20 μ l.
Calculate the concentration (μ g/ml) of Ginkgo total flavones in the blood plasma by Chinese Pharmacopoeia (2005 editions an one), with sample time (hour) be abscissa, concentration (the C of Ginkgo total flavones in the blood plasma, μ g/ml) is vertical coordinate, mapping, and press area (AUC) under the logarithm trapezoidal method calculated curve, the bioavailability situation of comparison surface active groups and Folium Ginkgo extract group.
The blood concentration measurement result shows in the body, after Folium Ginkgo extract and surfactant are united use, compare with Folium Ginkgo extract with single, bioavailability is improved, when the ratio of Folium Ginkgo extract and surfactant was 1: 0.75～1.5, bioavailability can improve 1.8～2.4 times.And when Folium Ginkgo extract is 1, surfactant less than 0.75 the time, bioavailability improves very little.Table 1-1, table 1-2 and Fig. 1 are that 1: 1.1 Folium Ginkgo extract and Polyethylene Glycol glyceryl laurate ester united use gained data and result for weight ratio, from showing 1-1, table 1-2 and Fig. 1 as can be seen, after Folium Ginkgo extract and Polyethylene Glycol glyceryl laurate ester were united use, its bioavailability was single 2.29 times with Folium Ginkgo extract.
Ginkgo total flavones blood drug level in the table 1-1 rat body (μ g/ml, n=6)
| Time (h) | The Folium Ginkgo extract group | Folium Ginkgo extract+group of |
| 0 | 0 | 0 |
| 2 | 0.040342 | 0.202799 |
| 5 | 0.173666 | 0.363344 |
| 8 | 0.157473 | 0.4032 |
| 10 | 0.13877 | 0.343963 |
| 16 | 0.0809 | 0.153627 |
| 24 | 0.051884 | 0.069266 |
Table 1-2 pharmacokinetic parameters table
| The Folium Ginkgo extract group | Folium Ginkgo extract+group of surfactants | |
| Maximum plasma concentration (Cmax, μ g/ml) | 0.173666 | 0.4032 |
| Peak time (Tp, h) | 5 | 8 |
| Lower area of blood concentration-time curve (AUC, μ g/mlh) | 2.27 | 5.19 |
Table 2-1, table 2-2 and Fig. 2 are that 1: 0.5 Folium Ginkgo extract and Polyethylene Glycol glyceryl laurate ester united use gained data and result for weight ratio, from showing 2-1, table 2-2 and Fig. 2 as can be seen, Folium Ginkgo extract: after surfactant=administration in 1: 0.5, compare with Folium Ginkgo extract, group of surfactants AUC is 1.11 times of raw material group, suitable with the raw material group, bioavailability improves very little.
Ginkgo total flavones blood drug level in the table 2-1 rat body (μ g/ml, n=6)
| Time (h) | The Folium Ginkgo extract group | Folium Ginkgo extract+group of |
| 0 | 0 | 0 |
| 2 | 0.200526 | 0.189725 |
| 5 | 0.283416 | 0.332265 |
| 8 | 0.278308 | 0.373205 |
| 10 | 0.220174 | 0.239506 |
| 16 | 0.15056 | 0.160716 |
| 24 | 0.106379 | 0.105867 |
Table 2-2 pharmacokinetic parameters table
| The Folium Ginkgo extract group | Folium Ginkgo extract+group of surfactants | |
| Maximum plasma concentration (Cmax, μ g/ml) | 0.283416 | 0.373205 |
| Peak time (Tp, h) | 5 | 8 |
| Lower area of blood concentration-time curve (AUC, μ g/mlh) | 4.37 | 4.85 |
Phosphatide complexes is compared with parent drug, can improve interior absorption of body of active skull cap components effectively, significantly improves its biological effectiveness, and pharmacological action is stronger, and rapidly, lastingly.Existing bibliographical information drug effect after Folium Ginkgo is prepared into phosphatide complexes is significantly improved (2003 the 13rd the 1st phases of volume of the pharmacodynamic study of Folium Ginkgo extract phosphatldylcholine complex " medical science new knowledge magazine ").In the present invention, we are prepared into administration behind the phosphatide complexes with Folium Ginkgo extract, the blood concentration measurement result shows in the rat body, bioavailability increases than Folium Ginkgo extract, and Folium Ginkgo extract is made behind the phosphatide complexes and the surfactant coupling again, bioavailability is greatly improved than Folium Ginkgo extract.
Test two:
Subjects: with test one
Dosage: 140mg/kg (in Folium Ginkgo extract)
Dosage regimen: 1, Folium Ginkgo extract is suspended in the 0.5%CMC-Na solution, promptly
2, Folium Ginkgo extract phospholipid complex is suspended in the 0.5%CMC-Na solution, promptly
The blood sampling scheme: with test one, rat is divided into two groups: Folium Ginkgo extract group, Folium Ginkgo extract phospholipid complex group
Chromatographic condition: with test one
Result of the test shows, after Folium Ginkgo extract and phospholipid form complex, compares bioavailability with list with Folium Ginkgo extract and is improved.Table 3, table 4 and Fig. 3 are after 1: 1.25 Folium Ginkgo extract and soybean phospholipid make Folium Ginkgo extract phospholipid complex for getting weight ratio, carry out zooperal data and result, from table 3, table 4 and Fig. 3 as can be seen, after Folium Ginkgo extract and soybean phospholipid formed complex, its bioavailability was single 1.71 times with Folium Ginkgo extract.
Ginkgo total flavones blood drug level in the table 3 rat body (μ g/ml, n=6)
| Time (h) | The Folium Ginkgo extract group | The Folium Ginkgo extract phospholipid complex group |
| 0 | 0 | 0 |
| 2 | 0.067568 | 0.37159 |
| 5 | 0.170782 | 0.186698 |
| 8 | 0.221596 | 0.255377 |
| 10 | 0.157331 | 0.233066 |
| 16 | 0.087452 | 0.177339 |
| 24 | 0.073222 | 0.106923 |
Table 4 pharmacokinetic parameters table
| The Folium Ginkgo extract group | The Folium Ginkgo extract phospholipid complex group | |
| Maximum plasma concentration (Cmax, μ g/ml) | 0.221596 | 0.37159 |
| Peak time (Tp, h) | 8 | 2 |
| Lower area of blood concentration-time curve (AUC, μ g/mlh) | 2.72 | 4.66 |
Test three:
Subjects: with test one
Dosage: 140mg/kg (in Folium Ginkgo extract)
Dosage regimen: 1, Folium Ginkgo extract is suspended in the 0.5%CMC-Na solution, promptly
2, Folium Ginkgo extract phospholipid complex+surfactant is suspended in the 0.5%CMC-Na solution, promptly
The blood sampling scheme: with test one, rat is divided into two groups: Folium Ginkgo extract group, ginkgo leaf extract composition group (being Folium Ginkgo extract phospholipid complex+surfactant)
Chromatographic condition: with test one
Animal test results shows that Folium Ginkgo extract and phospholipid are united use with surfactant after forming complex again, and bioavailability is significantly improved, and its bioavailability can be up to single 3.1 times of using Folium Ginkgo extract.Table 5, table 6 and Fig. 4 get the Folium Ginkgo phosphatide complexes (1: 1.25) that test two methods make, add the surfactant polyethylene caprylin again and unite use, weight ratio is the Folium Ginkgo phosphatide complexes: Polyethylene Glycol caprylin=1: 0.8, from table 5, table 6 and Fig. 4 as can be seen, after Folium Ginkgo extract is prepared into phosphatide complexes, unite use with surfactant again, its bioavailability is single 2.80 times with Folium Ginkgo extract.As can be seen, having added surfactant uses the bioavailability of phosphatide complexes much higher than list.
Ginkgo total flavones blood drug level in the table 5 rat body (μ g/ml, n=6)
| Time (h) | The Folium Ginkgo extract group | The ginkgo leaf |
| 0 | 0 | 0 |
| 2 | 0.078282 | 0.142731 |
| 5 | 0.201373 | 0.634493 |
| 8 | 0.325625 | 0.841101 |
| 10 | 0.203152 | 0.726638 |
| 16 | 0.222423 | 0.686534 |
| 24 | 0.127792 | 0.206297 |
Table 6 pharmacokinetic parameters table
| The Folium Ginkgo extract group | The ginkgo leaf extract composition group | |
| Maximum plasma concentration (Cmax, μ g/ml) | 0.325625 | 0.841101 |
| Peak time (Tp, h) | 8 | 8 |
| Lower area of blood concentration-time curve (AUC, μ g/mlh) | 4.40 | 12.33 |
In sum, unite when using when Folium Ginkgo extract adds surfactant, the bioavailability of Folium Ginkgo extract is improved, after Folium Ginkgo extract is prepared into phosphatide complexes again with the surfactant coupling, bioavailability is higher.
Description of drawings
Fig. 1 is blood medicine (Ginkgo total flavones) concentration-time curve in test one (1: 1.1) rat body
Fig. 2 is blood medicine (Ginkgo total flavones) concentration-time curve in test one (1: 0.5) rat body
Fig. 3 is blood medicine (Ginkgo total flavones) concentration-time curve in the test two rat bodies
Fig. 4 is blood medicine (Ginkgo total flavones) concentration-time curve in the test three rat bodies
The specific embodiment
The Folium Ginkgo extract raw material is purchased in Shanghai XinYi BaiLuDa Medicine Co., Ltd
Tablet
Prescription is formed:
Folium Ginkgo extract 40mg
Gelucire44/14 60mg
Lactose 110mg
Sodium carboxymethyl cellulose 10mg
Magnesium stearate 2.5mg
PVPK30 is an amount of
Take by weighing Folium Ginkgo extract, the Gelucire44/14 of recipe quantity, after 40 ℃ of heating make the Gelucire44/14 fine melt, ground and mixed is even, adds recipe quantity lactose, sodium carboxymethyl cellulose, mix homogeneously, granulate to cross 22 mesh sieves after the moistening of an amount of 5%PVP alcoholic solution, after 35 ℃ of dryings, cross 22 mesh sieve granulate, with the magnesium stearate mix homogeneously, tabletting promptly gets Folium Ginkgo.
Embodiment 2
Granule
Prescription is formed:
Folium Ginkgo extract 40mg
Polyoxyethylenesorbitan sorbitan monooleate 40mg
Micropowder silica gel 35mg
Starch 90mg
Icing Sugar 40mg
Essence is an amount of
Take by weighing recipe quantity Folium Ginkgo extract and polyoxyethylenesorbitan sorbitan monooleate, stirring makes mix homogeneously, add micropowder silica gel, starch, Icing Sugar, essence grind and make mix homogeneously, also crossing 22 mesh sieves with an amount of 65% ethanol moistening granulates, after 35 ℃ of dryings, 22 mesh sieve granulate promptly get the Folium Ginkgo extract granule.
Embodiment 3
Capsule
Prescription is formed:
Folium Ginkgo extract 40mg
Gelucire50/13 80mg
Dextrin 80mg
Icing Sugar 20mg
Recipe quantity Gelucire50/13 behind 50 ℃ of heating and meltings, is added Folium Ginkgo extract, dextrin, the Icing Sugar of recipe quantity, and after ground and mixed was even, filled capsules promptly got the ginkgo leaf extract capsule agent.
Embodiment 4
Micropill
Prescription is formed:
Folium Ginkgo extract 40mg
Polyoxyethylene lauryl ether 90mg
Starch 30mg
Microcrystalline Cellulose 80mg
Respectively with Folium Ginkgo extract and starch, polyoxyethylene lauryl ether and microcrystalline Cellulose mix homogeneously, again with the two mixing, with an amount of mistake 18 mesh sieve system soft materials of 95% ethanol, in coating pan round as a ball 30 minutes, take out, after 35 ℃ of dryings, 18 mesh sieve granulate promptly get the Folium Ginkgo extract micropill, can divide the capsule of packing into.
Slow releasing tablet
Prescription is formed:
Folium Ginkgo extract 40mg
Sorbitol anhydride monolaurate 60mg
HPMC(K15M) 80mg
Calcium hydrogen phosphate 20mg
Microcrystalline Cellulose 60mg
Magnesium stearate 3mg
PVP (K30) is an amount of
Grind with calcium hydrogen phosphate and sorbitol anhydride monolaurate, after making it fully absorb liquid component, with Folium Ginkgo extract, HPMC (K15M), microcrystalline Cellulose mix homogeneously, cross 22 mesh sieve system granules with an amount of moistening of 5%PVP (K30) ethanol liquid, 35 ℃ of dryings are taken out, behind the 22 mesh sieve granulate, with magnesium stearate mix homogeneously, tabletting, promptly get the ginkgo biloba extract sustained-release sheet.
Embodiment 6
Take by weighing Folium Ginkgo extract 1g, be dissolved among the oxolane 40ml the khaki clear liquid, add soybean phospholipid 1.3g, stirring is clear and bright until solution, is incubated 40 ℃ of reaction 3h while stirring, removes reaction dissolvent under reduced pressure, conventional low-temperature vacuum drying gets the sticking slightly Powdered complex of yellowish-brown.Get the 0.5g complex and add the 20ml dichloromethane, airtight stirring 0.5h removes by filter insoluble matter (Folium Ginkgo extract), and atent solvent is removed in decompression, and conventional low-temperature vacuum drying promptly gets the phosphatide complexes of purification.Measure flavonoid of ginkgo biloba in the complex of purification and the complex respectively by flavonoid of ginkgo biloba detection method in 2005 editions 597 pages of Folium Ginkgos of Chinese Pharmacopoeia, ratio between two is that recombination rate is 99.4%.
The Folium Ginkgo extract phospholipid complex 92mg (being equivalent to Folium Ginkgo extract 40mg) that makes and Gelucire44/1475mg in 40 ℃ of heating mix homogeneously, are promptly got ginkgo leaf extract composition.
Embodiment 7
Drop pill
Ginkgo leaf extract composition 167mg
Macrogol 4000 200mg
Behind embodiment 6 prepared ginkgo leaf extract composition 167mg and Macrogol 4000 200mg heating mix homogeneously, be condensed fluid with the dimethicone, drip while hot to condensed fluid, take out, blot condensed fluid, promptly get the Folium Ginkgo extract drop pill.
Embodiment 8
Take by weighing Folium Ginkgo extract 1g, be dissolved among the ethyl acetate 30ml the khaki clear liquid, add egg yolk lecithin 1.0g, stirring is clear and bright until solution, is incubated 45 ℃ of reaction 4h while stirring, and reaction dissolvent is removed in decompression, low-temperature vacuum drying gets the sticking slightly Powdered complex of yellowish-brown.
Folium Ginkgo extract phospholipid complex 80mg (being equivalent to Folium Ginkgo extract 40mg) and polyoxyethylenesorbitan sorbitan monooleate (Tween 20) 90mg are mixed, promptly get ginkgo leaf extract composition.
Embodiment 9
Soft capsule:
Ginkgo leaf extract composition 170mg
Ethyl oleate 500mg
The ginkgo leaf extract composition 170mg that embodiment 8 is made is dissolved in the ethyl oleate, gets yellow clear and bright medicinal liquid; Get gelatin, glycerol, sorbitol, water and be mixed with gelatin solution, put sprawl in the case standby.23 ± 2 ℃ of room temperatures, prepare soft gelatin capsule with dropping preparation method under the condition of relative humidity 40%, and at 23 ± 2 ℃, cold air drying is 24 hours under the condition of relative humidity 40%, promptly gets the Folium Ginkgo extract soft capsule.
Take by weighing Folium Ginkgo extract 1g, be dissolved in and get the khaki clear liquid among methylene chloride-methanol (6: the 1) 35ml, add soybean phospholipid 1.25g, stirring is clear and bright until solution, be incubated 30 ℃ of reaction 2h while stirring, reaction dissolvent is removed in decompression, and low-temperature vacuum drying gets the sticking slightly Powdered complex of yellowish-brown.
Folium Ginkgo extract phospholipid complex 90mg (being equivalent to Folium Ginkgo extract 40mg) and Labrasol70mg is even in the mortar ground and mixed, promptly get ginkgo leaf extract composition.
Embodiment 11
Oral liquid
Ginkgo leaf extract composition (embodiment 10) 160mg
Icing Sugar 1g
Mannitol 0.5g
Sodium carboxymethyl cellulose 10mg
Sodium benzoate 5mg
Essence is an amount of
Deionized water 1.5g
Recipe quantity Icing Sugar, mannitol, sodium carboxymethyl cellulose, sodium benzoate is soluble in water, add the ginkgo leaf extract composition that embodiment 10 makes, suspendible evenly after, add an amount of essence, promptly get ginkgo leaf extract oral liquid.
Embodiment 12
Take by weighing Folium Ginkgo extract 1g, be dissolved among the hot acetone 40ml the khaki clear liquid, add egg yolk lecithin 0.9g, stirring is clear and bright until solution, is incubated 50 ℃ of reaction 4.5h while stirring, and reaction dissolvent is removed in decompression, low-temperature vacuum drying gets the sticking slightly Powdered complex of yellowish-brown.
With the Folium Ginkgo extract phospholipid complex 76mg (being equivalent to Folium Ginkgo extract 40mg) that makes and polyoxyethylene pears alcohol acid anhydride monoleate 60mg, Labrasol 40mg stir, ground and mixed is even, promptly gets ginkgo leaf extract composition.
Embodiment 13
Capsule
Ginkgo leaf extract composition 176mg
Lactose 40mg
Microcrystalline Cellulose 60mg
Calcium hydrogen phosphate 50mg
Ginkgo leaf extract composition, lactose, microcrystalline Cellulose, calcium hydrogen phosphate that embodiment 12 is made grind and/or the mix homogeneously that sieves, and with an amount of moistening of 85% ethanol, cross 22 mesh sieves and granulate, 35 ℃ of dryings are taken out, behind the 22 mesh sieve granulate, divide the capsule of packing into, promptly get ginkgo leaf extract capsule.
Embodiment 14
Take by weighing Folium Ginkgo extract 1g, be dissolved among the oxolane 35ml the khaki clear liquid, add soybean phospholipid 1.5g, stirring is clear and bright until solution, is incubated 40 ℃ of reaction 3h while stirring, and reaction dissolvent is removed in decompression, low-temperature vacuum drying gets the sticking slightly Powdered complex of yellowish-brown.
The Folium Ginkgo extract phospholipid complex 100mg (being equivalent to Folium Ginkgo extract 40mg) that makes is mixed after 50 ℃ of fusions with Gelucire50/1352mg, sorbitol anhydride monolaurate (Span 20) 60mg, promptly get ginkgo leaf extract composition.
Slow releasing capsule
Ginkgo leaf extract composition 212mg
Micropowder silica gel 20mg
Microcrystalline Cellulose 90mg
HPMC(K15M) 100mg
Ginkgo leaf extract composition and micropowder silica gel ground and mixed that embodiment 14 is made are even, after adding microcrystalline Cellulose, HPMC (K4M) mix homogeneously, granulate with an amount of mistake 18 mesh sieves of dehydrated alcohol, put into the round as a ball 30min of coating pan rapidly, in 35 ℃ of oven dryings, 18 mesh sieve granulate promptly get slow-release micro-pill, divide the capsule of packing into, promptly get slow releasing capsule.
Embodiment 16
Take by weighing Folium Ginkgo extract 1g, be dissolved in and get the khaki clear liquid among the normal hexane 30ml, add synthetic phospholipid dipalmitoyl phosphatidyl choline (DPPC) 1.75g, stirring is clear and bright until solution, be incubated 35 ℃ of reaction 3.5h while stirring, reaction dissolvent is removed in decompression, and low-temperature vacuum drying gets the sticking slightly Powdered complex of yellowish-brown.
The Folium Ginkgo extract phospholipid complex 110mg (being equivalent to Folium Ginkgo extract 40mg) that makes is mixed with sorbitol anhydride monolaurate 85mg, promptly get ginkgo leaf extract composition.
Embodiment 17
Slow releasing tablet
Ginkgo leaf extract composition 195mg
Light magnesium oxide 50mg
HPMC(K4M) 60mg
Lactose 80mg
Magnesium stearate 4mg
The Folium Ginkgo extract phospholipid complex that embodiment 16 is made grinds well with the sorbitol anhydride monolaurate and mixes, with calcium hydrogen phosphate it is fully absorbed, add HPMC (K4M) and lactose mix homogeneously, cross 22 mesh sieve system granules with an amount of moistening of dehydrated alcohol, in 35 ℃ of oven dryings, take out, behind the 22 mesh sieve granulate, add magnesium stearate mixing tabletting, promptly get slow releasing tablet.
Embodiment 18
Take by weighing Folium Ginkgo extract 1g, be dissolved in and get the khaki clear liquid among the ethyl acetate 30ml, add synthetic phospholipid dipalmitoyl phosphatidyl choline (DPPC) 1.05g, stirring is clear and bright until solution, be incubated 40 ℃ of reaction 5.0h while stirring, reaction dissolvent is removed in decompression, and low-temperature vacuum drying gets the sticking slightly Powdered complex of yellowish-brown.
The Folium Ginkgo extract phospholipid complex 82mg (being equivalent to Folium Ginkgo extract 40mg) that makes is mixed with sorbitol anhydride monolaurate 30mg, anhydro sorbitol acid anhydride monoleate 40mg, promptly get ginkgo leaf extract composition.
Embodiment 19
Slow-release micro-pill
Ginkgo leaf extract composition 152mg
Calcium hydrogen phosphate 60mg
Microcrystalline Cellulose 120mg
Ethyl cellulose 15mg
The Folium Ginkgo extract that embodiment 18 is made grinds, and behind the 80 mesh sieve mix homogeneously, promptly gets Folium Ginkgo extract medicated powder excessively.Get the microcrystalline Cellulose celphere, spray into 95% ethanol, be sprinkled into above-mentioned Folium Ginkgo extract medicated powder, increase weight to recipe quantity,, promptly get the pastille micropill in 30 ℃ of vacuum dryings 5 hours until micropill.Getting 95% ethanol, to be configured to concentration be 2% ethyl cellulose alcoholic solution, and cryogenic spray increases weight to recipe quantity it on existing pastille micropill, and 30 ℃ of vacuum dryings 12 hours promptly get slow-release micro-pill.
Claims (9)
1, a kind of ginkgo leaf extract composition is characterized in that containing following component and ratio of weight and number and is:
Folium Ginkgo extract phospholipid complex 1
Surfactant 0.75～3.
2, the ginkgo leaf extract composition of claim 1, component wherein and ratio of weight and number are:
Folium Ginkgo extract phospholipid complex 1
Surfactant 0.75～1.5.
3, claim 1 or 2 ginkgo leaf extract composition, wherein surfactant be selected from that sucrose fatty acid ester, fatty acid Pyrusussuriensis are smooth, one or more the mixture in the Polysorbate, polyoxyethylene fatty acid ester, polyoxyethylene aliphatic alcohol ether, polyoxyethylene-polyoxypropylene copolymer, polyethylene glycol fatty acid glyceride.
4, the ginkgo leaf extract composition of claim 3, wherein surfactant be sorbitol anhydride monolaurate, sorbitol anhydride monopalmitate, anhydro sorbitol acid anhydride monoleate, polyoxyethylene pears alcohol acid anhydride monoleate, polyoxyethylenesorbitan sorbitan monooleate, polyoxyethylene lauryl ether, Polyethylene Glycol glyceryl laurate ester, Polyethylene Glycol tristerin, Polyethylene Glycol sad/the certain herbaceous plants with big flowers acid glyceride.
5, claim 1 or 2 ginkgo leaf extract composition also contain pharmaceutically acceptable pharmaceutic adjuvant.
6, the ginkgo leaf extract composition of claim 5, wherein pharmaceutic adjuvant is selected from one or more in diluent, absorbent, disintegrating agent, binding agent, wetting agent, lubricant and the slow-release material.
7, the ginkgo leaf extract composition of claim 6, wherein diluent is selected from one or more in starch, pregelatinized Starch, dextrin, Icing Sugar, lactose, mannitol, microcrystalline Cellulose, the calcium sulfate; Absorbent is selected from one or more in calcium sulfate, calcium hydrogen phosphate, light magnesium oxide, calcium carbonate, starch, Aluminium Hydroxide, the micropowder silica gel; Disintegrating agent is selected from one or more in cross-linking sodium carboxymethyl cellulose, polyvinylpolypyrrolidone, starch, carboxymethyl starch sodium, carboxylic propyl group starch, low-substituted hydroxypropyl cellulose, alginic acid, Bentonite, the veegum; Binding agent is selected from one or more in hypromellose, polyvidone, starch slurry, dextrin, syrup, rubber cement, ethyl cellulose, methylcellulose, the sodium carboxymethyl cellulose; Wetting agent is selected from water and/or ethanol, and lubricant is selected from one or more in Pulvis Talci, magnesium stearate, micropowder silica gel, hydrogenated vegetable oil, Stepanol MG, sodium lauryl sulphate, the sodium stearyl fumarate; Slow-release material is selected from one or more in hypromellose, methylcellulose, ethyl cellulose, carboxyethyl cellulose, polrvinyl chloride, glyceryl monostearate, vinyl acetate, carbomer, acrylic resin, arabic gum, the xanthan gum.
8, the ginkgo leaf extract composition of claim 5 contains following component and percentage by weight:
Folium Ginkgo extract phospholipid complex 10～40%
Surfactant 10～35%
Slow-release material 4～35%
Other pharmaceutic adjuvant 10～55%
Slow-release material is selected from one or more in hypromellose, methylcellulose, ethyl cellulose, carboxyethyl cellulose, polrvinyl chloride, glyceryl monostearate, vinyl acetate, carbomer, acrylic resin, arabic gum, the xanthan gum.
9, the preparation method of each ginkgo leaf extract composition in the claim 1 to 8:
Get weight ratio and be 1: 0.5～1.75 Folium Ginkgo extract and phospholipid, in organic solvent, mix, react, after decompression or the spray drying, promptly get Folium Ginkgo extract phospholipid complex, wherein organic solvent is selected from chloroform, ether, acetone, dichloromethane, ethyl acetate, dioxane, the tetrahydrochysene furan food in one's mouth, normal hexane, C1～C6 straight or branched low-grade alkane alcohol; Get Folium Ginkgo extract phospholipid complex and surfactant, stirring or ground and mixed are even, promptly get the compositions of Folium Ginkgo extract phospholipid complex and surfactant; Add other pharmaceutic adjuvant as need, then above-mentioned composition is mixed with pharmaceutic adjuvant, be prepared into various dosage forms according to a conventional method.
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