CN1772011A - Ginkgo leaf extract composition and its prepn - Google Patents

Abstract

The invention relates to the field of pharmaceutical preparations of natural medicines, in particular to a composition of ginkgo biloba extract and a preparation method thereof. It is characterized in that the composition of the invention contains ginkgo leaf extract and/or ginkgo leaf extract phospholipid complex and surfactant. The composition of the invention can significantly improve the bioavailability of the ginkgo leaf extract and achieve better curative effect.

Description

Ginkgo biloba extract composition and preparation method thereof

technical field

The invention relates to the field of pharmaceutical preparations of natural medicines, in particular to a composition containing ginkgo biloba extract and a preparation method thereof.

Background technique

Ginkgo biloba (Ginkgo biloba) is a plant of the genus Ginkgo in the Ginkgo family, also known as ginkgo tree and Gongsun tree. It is one of the oldest plants and is known as a gymnosperm living fossil. Its medicinal parts are mainly leaves and fruits. Ginkgo resources in my country rank first No. 1 in the world. Ginkgo biloba L.extract (GbE) is a light yellow powdery substance extracted and purified from the dried leaves of Ginkgo biloba. However, flavonoids, terpenoid lactones, and polyprenyl alcohols are considered to be the main active ingredients, and ginkgolic acid (abbreviated as ginkgolic acid) is the main toxic ingredient. Among them, flavonoids mainly exist in the form of flavonoid glycosides, which have the effect of scavenging free radicals; terpenoids are potent platelet activating factor (PAF) antagonists, and both are important active ingredients in Ginkgo biloba extract. The currently internationally recognized quality standard for Ginkgo biloba extract is the 1991 patent EGb761 standard of the German Swache company, that is, the total ginkgo flavonoids > 24%, the total ginkgo lactones > 6%, and the ginkgolic acid level is limited to below 5ppm. It is also recorded in Chinese Pharmacopoeia (2005 edition one). At present, enterprises that produce and sell Ginkgo biloba extract include: Jiangsu Institute of Botany, Zhejiang Kangenbei Pharmaceutical Co., Ltd., Shandong Luye Pharmaceutical Co., Ltd., Shenzhen Sanjiu Pharmaceutical Co., Ltd., Hangzhou Wensongtang Biotechnology Co., Ltd., Linyi Aikang Pharmaceutical Co., Ltd., etc. Modern pharmacological research shows that the pharmacological effect of Ginkgo biloba extract is the result of the joint action of various relatively fixed components. Its pharmacological effects mainly include regulating blood vessels, enhancing cognition, relieving stress and gene adjustment. Modern medicine also believes that ginkgo biloba has a good effect on cardiovascular and cerebrovascular diseases such as coronary heart disease and cerebral thrombosis.

However, due to the high polarity and high water solubility of many components in the Ginkgo biloba extract, unfavorable factors such as difficult absorption and low bioavailability after oral administration affect the efficacy of the medicine.

Contents of the invention

The invention discloses a ginkgo leaf extract composition with improved bioavailability, which is combined with the ginkgo leaf extract and a surfactant, or the ginkgo leaf extract is prepared into a phospholipid complex and then used in combination with a surfactant , can significantly improve the bioavailability of Ginkgo biloba extract.

During the research on Ginkgo biloba extract, we found that the bioavailability of Ginkgo biloba extract was significantly improved when it was used in combination with surfactants.

The invention discloses a ginkgo leaf extract composition with high bioavailability, which is characterized by containing the ginkgo leaf extract and/or the ginkgo leaf extract phospholipid complex and a surfactant.

The above-mentioned Ginkgo biloba extract composition of the present invention, wherein the weight and number ratio of each component is preferably:

Ginkgo biloba extract and/or Ginkgo biloba phospholipid complex 1

Surfactant 0.75～3.

Ginkgo biloba extract composition of the present invention, more preferred components and the weight and number ratio of each component are:

Ginkgo biloba extract phospholipid complex 1

Surfactant 0.75～1.5.

When Ginkgo biloba extract or Ginkgo biloba extract phospholipid complex is added surfactant, bioavailability can be improved, but when the amount of surfactant added is less than 0.75, bioavailability increases slightly, does not reach ideal high of bioavailability. And when surfactant adds too much (greater than 3), then along with the increase of surfactant dosage, bioavailability no longer improves, and too much surfactant can affect the normal function of body, also affects the technology preparation of preparation. Bring a lot of inconvenience. Therefore, when the weight ratio of the ginkgo leaf extract and/or the ginkgo leaf extract phospholipid complex to the surfactant is 1:0.75-3, it is more suitable for clinical use. The more optimal ratio in comprehensive comparison is 1:0.75-1.5.

In the above technical scheme, the surfactant is preferably selected from sucrose fatty acid ester, sorbitan fatty acid ester, polysorbate, polyoxyethylene fatty acid ester, polyoxyethylene fatty alcohol ether, polyoxyethylene-polyoxypropylene copolymer , Polyethylene glycol fatty acid glycerides of one or more mixtures. More preferred surfactants are sorbitan monolaurate (Span 20), sorbitan monopalmitate (Span 40), sorbitan monooleate (Span 80), polyoxyethylene pitol Anhydride monooleate (Tween 80), polyoxyethylene sorbitan monooleate (Tween 20), polyoxyethylene lauryl ether (Brij 35), polyethylene glycol laurate (Gelucire44/14 ), macrogol stearate (Gelucire50/13), macrogol caprylic/capric glyceride (Labrasol).

Ginkgo biloba extract composition of the present invention can be prepared by the following methods:

When combined as ginkgo biloba extract + surfactant, the preparation method is as follows:

Take ginkgo biloba extract and surface active agent, stir or grind and mix evenly to get ready. If other pharmaceutical excipients need to be added, they can be added to ginkgo biloba extract and surfactant, and then stirred or ground to mix evenly, and prepared into various dosage forms.

When combined as ginkgo biloba extract phospholipid complex + surfactant, the preparation method is as follows:

a, preparation of Ginkgo biloba extract phospholipid complex:

Take ginkgo leaf extract and phospholipid with a weight ratio of 1:0.5-1.75, mix and react in an organic solvent, and after decompression or spray drying, the ginkgo leaf extract phospholipid complex is obtained, wherein the organic solvent is selected from chloroform, ether , acetone, dichloromethane, ethyl acetate, dioxane, tetrahydrofuran, n-hexane, C1 ~ C6 straight chain or branched lower alkanol. Wherein C1-C6 straight chain or branched lower alkanols include methanol, ethanol, propanol or butanol and the like.

B, the preparation of composition:

Ginkgo biloba extract phospholipid complex and surfactant are taken, and other pharmaceutical auxiliary materials are added together if necessary, and then stirred or ground to mix evenly to prepare various preparations.

Phospholipids are selected from natural phospholipids and/or synthetic phospholipids. The natural phospholipid is selected from soybean phospholipid and/or egg yolk phospholipid, the synthetic phospholipid is selected from dipalmitoyl phosphatidylcholine or dipalmitoyl phosphatidylethanolamine, and the content of phosphatidylcholine in the used phospholipid is 65% to 98%.

In the preparation method of the phospholipid complex, wherein the ginkgo leaf extract and the phospholipid are mixed in an organic solvent, the reaction temperature is 20-90°C, and the reaction time is 0.5-6.0 hours; the amount of the organic solvent used is not less than 1g of the ginkgo leaf extract 20ml; decompression or spray drying (N ₂ if necessary) to remove the organic solvent, add an inert solvent to purify the ginkgo leaf extract phospholipid complex, so that the ginkgo leaf extract that does not form a complex is precipitated and separated, and the ginkgo leaf extract phospholipid The complex is dissolved in an inert solvent, and after the inert solvent is removed, a relatively pure ginkgo leaf extract phospholipid complex is obtained. Wherein the inert solvent is preferably dichloromethane and/or n-hexane.

In the test of preparing the phospholipid complex of Ginkgo biloba extract, there are many factors influencing the complex rate of the phospholipid complex. When the weight ratio of Ginkgo biloba extract and phospholipid was less than 0.5, the complex rate was low (＜75%), and when the weight ratio was greater than 1.75, the gained Ginkgo biloba extract phospholipid complex was more sticky, comprehensively considering the patient's dosage (as much as possible small), so the mass ratio of Ginkgo biloba extract to phospholipid is preferably 0.5-1.75; the amount of organic solvent will affect the recombination rate. The amount of organic solvent used in the extract is not less than 20ml, and the compounding rate can reach more than 98%. The reaction temperature also has an impact on the recombination rate and the stability of phospholipids. When it is lower than 20°C, the recombination rate is low (<75%), and when it is higher than 90°C, it will affect the stability of phospholipids. The reaction time is at least 0.5 hours, preferably 2.0-5.0 hours, and can be extended to 6 hours.

The Ginkgo biloba extract composition of the present invention can be further prepared into various clinical dosage forms by adding other pharmaceutical excipients, such as adding diluents, absorbents, disintegrating agents, binders, wetting agents, lubricants and slow-release materials one or more of them. It is prepared into dosage forms such as oral liquid, tablet, micropill, granule, capsule, soft capsule, drop pill, sustained-release tablet, sustained-release pellet or sustained-release capsule. The diluent is selected from one or more of starch, pregelatinized starch, dextrin, powdered sugar, lactose, mannitol, microcrystalline cellulose, and calcium sulfate; the absorbent is selected from calcium sulfate, calcium hydrogen phosphate, light One or more of magnesium oxide, calcium carbonate, starch, dry aluminum hydroxide, and micropowder silica gel; the disintegrant is selected from croscarmellose sodium, crospovidone, starch, and sodium carboxymethyl starch , carboxypropyl starch, low-substituted hydroxypropyl cellulose, alginic acid, bentonite, colloidal magnesium aluminum silicate or one or more; the binder is selected from hypromellose, povidone, starch slurry , dextrin, syrup, mucilage, ethyl cellulose, methyl cellulose, sodium carboxymethyl cellulose or one or more; the wetting agent is selected from water and/or ethanol, and the lubricant is selected from talcum powder , magnesium stearate, micropowder silica gel, hydrogenated vegetable oil, magnesium lauryl sulfate (sodium), sodium stearyl fumarate or one or more; slow-release materials are selected from hypromellose, methyl One or more of cellulose, ethyl cellulose, carboxyethyl cellulose, polyvinyl chloride, glyceryl monostearate, vinyl acetate, carbomer, acrylic resin, gum arabic, and xanthan gum.

A more preferred dosage form is a sustained-release preparation: slow-release materials are added to prepare sustained-release tablets, sustained-release pellets or sustained-release capsules. After the ginkgo leaf extract composition is mixed with medicinal oral preparation auxiliary materials to make sustained-release preparations, it can overcome the peak and valley phenomena of blood drug concentration after taking common preparations, and the dosage can be reduced while maintaining the same drug effect, thereby Reduce the toxic and side effects of drugs; it can also maintain a longer duration of action, thereby reducing the number of medications and improving patient compliance.

The formula of preferred sustained-release preparation is:

Ginkgo biloba extract and/or ginkgo biloba extract phospholipid complex 10～40%

Surfactant 10～35%

Sustained release material 4～35%

Other auxiliary materials (such as absorbents, adhesives, etc.) 10～55%

Sustained-release materials are selected from hypromellose, methylcellulose, ethylcellulose, carboxyethylcellulose, polyvinyl chloride, glycerol monostearate, microcrystalline cellulose, vinyl acetate, carbomer, One or more of acrylic resin, gum arabic, and xanthan gum.

Below are part pharmacological tests and data of the present invention:

Test one:

Test object: SD rats, male, weighing 280-320g, n=6

Dosage: Ginkgo biloba extract 140mg/kg

Dosing regimen: 1. Ginkgo biloba extract is suspended in 0.5% CMC-Na solution.

2. Ginkgo biloba extract and surfactant are suspended in 0.5% CMC-Na solution.

Blood collection scheme: Take rats, fast for 12 hours under free drinking conditions, mark and divide them into two groups: Ginkgo biloba extract group and surfactant group, and administer them by intragastric administration according to the dosage plan, at 2 hours and 5 hours At 8 hours, 10 hours, 16 hours, and 24 hours, 1.2-1.5ml of blood was collected from the fundus, centrifuged at 4000 rpm for 5 minutes, and the supernatant was absorbed to obtain plasma.

Blood sample processing method: Take 0.5ml of plasma, add 20μl of salicylic acid internal standard solution, 0.5ml of hydrochloric acid (3mol/L), hydrolyze at 80°C for 30 minutes, take it out and cool it quickly, add ether-acetone (14:1) 3ml and vortex extract 3 minutes, centrifuge at 3500 rpm for 10 minutes, absorb the supernatant, and evaporate it to dryness under N ₂ flow. Determination of the concentration of total flavonoids in Ginkgo biloba by phase method.

Chromatographic conditions: Diamond ODS chromatographic column (4.6mm×250mm, 5μm); mobile phase: methanol: 0.5% phosphoric acid = 50:50; flow rate: 1ml/min; UV detection wavelength: 360nm; injection volume 20μl.

Calculate the concentration (μg/ml) of total ginkgo flavonoids in the plasma according to the Chinese Pharmacopoeia (2005 edition one), take the sampling time (hour) as the abscissa, and the concentration of the total ginkgo flavonoids in the plasma (C, μg/ml) as the vertical Coordinates, plot, and calculate the area under the curve (AUC) according to the logarithmic trapezoidal method, and compare the bioavailability status of the surfactant group and the Ginkgo biloba extract group.

The results of blood concentration measurement in vivo showed that the bioavailability of ginkgo leaf extract and surfactant was improved compared with that of ginkgo leaf extract alone, when the ratio of ginkgo leaf extract and surfactant was 1:0.75 When ~1.5, the bioavailability can be increased by 1.8 to 2.4 times. And when the Ginkgo biloba extract was 1 and the surfactant was less than 0.75, the bioavailability increased little. Table 1-1, Table 1-2 and Fig. 1 are that the ginkgo biloba extract and macrogol laurate glycerin joint use gained data and result with the weight ratio of 1: 1.1, from Table 1-1, Table 1-2 It can be seen from Figure 1 that after the combined use of Ginkgo biloba extract and polyethylene glycol laurate, its bioavailability is 2.29 times that of Ginkgo biloba extract alone.

Table 1-1 Blood concentration of ginkgo total flavonoids in rats (μg/ml, n=6) time (h) Ginkgo biloba extract group Ginkgo biloba extract + surfactant group 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 twenty four 0.051884 0.069266

Table 1-2 Pharmacokinetic parameter table Ginkgo biloba extract group Ginkgo biloba extract + surfactant group Maximum plasma concentration (Cmax, μg/ml) 0.173665 0.4032 Peak time (Tp, h) 5 8 Area under the plasma concentration-time curve (AUC, μg/ml h) 2.27 5.19

Table 2-1, Table 2-2 and Fig. 2 are the data and results obtained from the joint use of ginkgo biloba extract and polyethylene glycol laurate glycerin with a weight ratio of 1: 0.5, from Table 2-1, Table 2-2 As can be seen from Fig. 2, after administration of Ginkgo biloba extract: surfactant = 1: 0.5, compared with Ginkgo biloba extract, the AUC of surfactant group is 1.11 times of raw material group, equivalent to raw material group, bioavailability Increased slightly.

Table 2-1 Blood concentration of ginkgo total flavonoids in rats (μg/ml, n=6) time (h) Ginkgo biloba extract group Ginkgo biloba extract + surfactant group 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 twenty four 0.106379 0.105867

Table 2-2 Pharmacokinetic parameter table Ginkgo biloba extract group Ginkgo biloba extract + surfactant group Maximum plasma concentration (Cmax, μg/ml) 0.283416 0.373205 Peak time (Tp, h) 5 8 Area under the plasma concentration-time curve (AUC, μg/ml h) 4.37 4.85

Compared with the parent drug, the phospholipid complex can effectively improve the in vivo absorption of natural active ingredients, significantly improve its bioavailability, and have stronger, faster and longer-lasting pharmacological effects. It has been reported in the literature that the drug efficacy is significantly improved after the preparation of ginkgo leaves into phospholipid complexes (Pharmacological Research on Phosphatidylcholine Complexes of Ginkgo Leaf Extracts "Journal of Medical News", Volume 13, Issue 1, 2003) . In the present invention, we prepared Ginkgo biloba extract into phospholipid complex and administered it. The blood concentration measurement results in rats showed that the bioavailability was improved compared with Ginkgo biloba extract, and Ginkgo biloba extract was made into When the phospholipid complex is used in combination with a surfactant, the bioavailability is greatly improved compared with the Ginkgo biloba extract.

Test two:

Test object: same as test one

Dosage: 140mg/kg (based on ginkgo biloba extract)

Dosing regimen: 1. Ginkgo biloba extract is suspended in 0.5% CMC-Na solution to obtain

2. Ginkgo biloba extract phospholipid complex is suspended in 0.5% CMC-Na solution to obtain

Blood collection scheme: Same as Experiment 1, the rats were divided into two groups: Ginkgo biloba extract group, Ginkgo biloba extract phospholipid complex group

Chromatographic conditions: same as test one

The test results show that the bioavailability of Ginkgo biloba extract is improved compared with that of Ginkgo biloba extract alone after forming a complex with phospholipids. Table 3, table 4 and Fig. 3 are to get the ginkgo leaf extract and soybean lecithin that the weight ratio is 1: 1.25 after making ginkgo leaf extract phospholipid complex, carry out the data and the result of animal experiment, from table 3, table 4 and It can be seen from Figure 3 that after the complex of Ginkgo biloba extract and soybean lecithin is formed, its bioavailability is 1.71 times that of Ginkgo biloba extract alone.

Table 3 Blood concentration of ginkgo total flavonoids in rats (μg/ml, n=6) time (h) Ginkgo biloba extract group Ginkgo biloba 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 twenty four 0.073222 0.106923

Table 4 Pharmacokinetic parameter table Ginkgo biloba extract group Ginkgo biloba extract phospholipid complex group Maximum plasma concentration (Cmax, μg/ml) 0.221596 0.37159 Peak time (Tp, h) 8 2 Area under the plasma concentration-time curve (AUC, μg/ml h) 2.72 4.66

Test three:

Test object: same as test one

Dosage: 140mg/kg (based on ginkgo biloba extract)

Dosing regimen: 1. Ginkgo biloba extract is suspended in 0.5% CMC-Na solution to obtain

2. Ginkgo biloba extract phospholipid complex + surfactant, suspended in 0.5% CMC-Na solution, to obtain

Blood collection scheme: Same as Experiment 1, the rats were divided into two groups: Ginkgo biloba extract group, Ginkgo biloba extract composition group (ie Ginkgo biloba extract phospholipid complex + surfactant)

Chromatographic conditions: same as test one

The results of animal experiments show that the bioavailability of Ginkgo biloba extract is significantly improved after it forms a complex with phospholipids, and then used in combination with surfactants, and its bioavailability can be as high as 3.1 times that of Ginkgo biloba extract alone. Table 5, Table 6 and Fig. 4 are to get the ginkgo leaf phospholipid complex (1: 1.25) that test two methods make, then add surfactant macrogol caprylic glyceride to use jointly, weight ratio is ginkgo leaf phospholipid complex : Polyethylene glycol caprylic acid glyceride=1: 0.8, as can be seen from Table 5, Table 6 and Fig. 4, after Ginkgo biloba extract is prepared into phospholipid complex, then used in conjunction with surfactant, its bioavailability is 2.80 times that of ginkgo biloba extract alone. It can be seen that the bioavailability of the addition of surfactant is much higher than that of the phospholipid complex alone.

Table 5 Blood concentration of ginkgo total flavonoids in rats (μg/ml, n=6) time (h) Ginkgo biloba extract group Ginkgo biloba extract composition group 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 twenty four 0.127792 0.206297

Table 6 Pharmacokinetic parameter table Ginkgo biloba extract group Ginkgo biloba extract composition group Maximum plasma concentration (Cmax, μg/ml) 0.325625 0.841101 Peak time (Tp, h) 8 8 Area under the plasma concentration-time curve (AUC, μg/ml h) 4.40 12.33

In summary, when Ginkgo biloba extract is used in combination with surfactants, the bioavailability of Ginkgo biloba extract is improved. higher degree.

Description of drawings

Fig. 1 is test one (1: 1.1) rat blood drug (Ginkgo total flavonoids) concentration-time curve

Fig. 2 is test one (1: 0.5) rat blood drug (Ginkgo total flavonoids) concentration-time curve

Fig. 3 is the concentration-time curve of plasma drug (Ginkgo total flavonoids) in test two rats

Fig. 4 is the concentration-time curve of blood drug (Ginkgo total flavonoids) in test three rats

Detailed ways

The raw materials of Ginkgo biloba extract were purchased from Shanghai Xinyi Biorod Pharmaceutical Co., Ltd.

Example 1

tablet

Prescription composition:

Ginkgo biloba extract 40mg

Gelucire44/14 60mg

Lactose 110mg

Sodium carboxymethylcellulose 10mg

Magnesium stearate 2.5mg

PVPK30 Appropriate amount

Weigh the prescribed amount of ginkgo leaf extract and Gelucire44/14, heat at 40°C to melt Gelucire44/14, grind and mix evenly, add the prescribed amount of lactose and sodium carboxymethyl cellulose, mix evenly, and add an appropriate amount of 5% PVP After wetting the ethanol solution, pass through a 22-mesh sieve to granulate, after drying at 35°C, pass through a 22-mesh sieve for granulation, mix with magnesium stearate evenly, and press into tablets to obtain Ginkgo biloba leaves.

Example 2

Granules

Prescription composition:

Ginkgo biloba extract 40mg

Polyoxyethylene sorbitan monooleate 40mg

Micropowder silica gel 35mg

Starch 90mg

Powdered sugar 40mg

Fragrance Appropriate amount

Weigh the prescription amount of ginkgo biloba extract and polyoxyethylene sorbitan monooleate, stir to mix evenly, add micropowder silica gel, starch, sugar powder, essence, grind to mix evenly, moisten with appropriate amount of 65% ethanol and pass Granulate with a 22-mesh sieve, dry at 35°C, and granulate with a 22-mesh sieve to obtain Ginkgo biloba extract granules.

Example 3

Capsules

Prescription composition:

Ginkgo biloba extract 40mg

Gelucire50/13 80mg

Dextrin 80mg

Powdered sugar 20mg

Heat and melt the prescribed amount of Gelucire 50/13 at 50°C, add the prescribed amount of Ginkgo biloba extract, dextrin, and powdered sugar, grind and mix evenly, and fill capsules to obtain Ginkgo biloba extract capsules.

Example 4

Pellets

Prescription composition:

Ginkgo biloba extract 40mg

Polyoxyethylene lauryl ether 90mg

Starch 30mg

Microcrystalline Cellulose 80mg

Ginkgo biloba extract, starch, polyoxyethylene lauryl ether and microcrystalline cellulose were mixed evenly, and then the two were mixed, and an appropriate amount of 95% ethanol was passed through a 18-mesh sieve to make a soft material, which was spheronized in a coating pan for 30 minutes. Take it out, dry it at 35°C, and sieve it through a 18-mesh sieve to obtain ginkgo biloba extract pellets, which can be divided into capsules.

Example 5

Sustained Release Tablets

Prescription composition:

Ginkgo biloba extract 40mg

Sorbitan Monolaurate 60mg

HPMC(K15M) 80mg

Calcium hydrogen phosphate 20mg

Microcrystalline Cellulose 60mg

Magnesium stearate 3mg

PVP(K30) Appropriate amount

Grind with calcium hydrogen phosphate and sorbitan monolaurate to make it fully absorb the liquid components, mix evenly with ginkgo biloba extract, HPMC (K15M), and microcrystalline cellulose, and add an appropriate amount of 5% PVP (K30) ethanol solution Moisten and pass through a 22-mesh sieve to make granules, dry at 35°C, take out, granulate through a 22-mesh sieve, mix evenly with magnesium stearate, and press into tablets to obtain Ginkgo biloba extract sustained-release tablets.

Example 6

Weigh 1g of Ginkgo biloba extract, dissolve it in 40ml of tetrahydrofuran to obtain a khaki-yellow clear liquid, add 1.3g of soybean lecithin, stir until the solution is clear, keep it warm at 40°C for 3 hours while stirring, evaporate the reaction solvent under reduced pressure, and dry in a vacuum at low temperature , to obtain yellow-brown slightly viscous powder complex. Take 0.5 g of the complex and add 20 ml of dichloromethane, stir in a closed chamber for 0.5 h, filter to remove the insoluble matter (Ginkgo biloba extract), remove the inert solvent under reduced pressure, and vacuum dry at conventional low temperature to obtain the purified phospholipid complex. The purified compound and the content of ginkgo flavonoids in the compound were respectively measured according to the detection method for the content of ginkgo flavonoids in ginkgo leaves on page 597 of the Chinese Pharmacopoeia 2005 edition. The ratio between the two, namely the compound rate, was 99.4%.

Heat and mix 92 mg of the prepared ginkgo leaf extract phospholipid complex (equivalent to 40 mg of ginkgo leaf extract) and Gelucire 44/1475 mg at 40° C. to obtain the ginkgo leaf extract composition.

Example 7

Dropping pills

Ginkgo biloba extract composition 167mg

Macrogol 4000 200mg

After heating and mixing 167 mg of the ginkgo leaf extract composition prepared in Example 6 with 4,000 to 200 mg of polyethylene glycol, use simethicone as the condensate, drop it into the condensate while it is hot, take it out, and dry the condensate. That is, ginkgo biloba extract dripping pills are obtained.

Example 8

Weigh 1g of Ginkgo biloba extract, dissolve it in 30ml of ethyl acetate to obtain a khaki clear liquid, add 1.0g of egg yolk phospholipid, stir until the solution is clear, keep warm at 45°C for 4h while stirring, remove the reaction solvent under reduced pressure, and dry in vacuum at low temperature , to obtain yellow-brown slightly viscous powder complex.

Stir and mix 80 mg of ginkgo leaf extract phospholipid complex (equivalent to 40 mg of ginkgo leaf extract) and 90 mg of polyoxyethylene sorbitan monooleate (Tween 20) to obtain the ginkgo leaf extract composition.

Example 9

Softgels:

Ginkgo biloba extract composition 170mg

Ethyl oleate 500mg

Dissolve 170 mg of the Ginkgo biloba extract composition prepared in Example 8 in ethyl oleate to obtain a yellow and clear medicinal liquid; take gelatin, glycerin, sorbitol, and water to prepare a gelatin solution, and put it in a spreading box for subsequent use. The capsules were prepared by drop method at room temperature 23±2°C and relative humidity 40%, and dried in cold air for 24 hours at 23±2°C and relative humidity 40% to obtain Ginkgo biloba extract soft capsules.

Example 10

Weigh 1 g of Ginkgo biloba extract, dissolve it in 35 ml of dichloromethane-methanol (6:1) to obtain an earthy yellow clear liquid, add 1.25 g of soybean lecithin, stir until the solution is clear, keep warm at 30°C for 2 h while stirring, and then depressurize The reaction solvent was removed and vacuum-dried at low temperature to obtain a yellow-brown slightly viscous powder compound.

Ginkgo biloba extract phospholipid complex 90mg (equivalent to ginkgo biloba extract 40mg) and Labrasol 70mg were ground and mixed in a mortar to obtain the ginkgo biloba extract composition.

Example 11

oral liquid

Ginkgo biloba extract composition (Example 10) 160mg

powdered sugar 1g

Mannitol 0.5g

Sodium carboxymethylcellulose 10mg

Sodium Benzoate 5mg

Fragrance Appropriate amount

Deionized water 1.5g

Dissolve the prescription amount of powdered sugar, mannitol, sodium carboxymethyl cellulose, and sodium benzoate in water, add the ginkgo leaf extract composition prepared in Example 10, suspend evenly, and add an appropriate amount of essence to obtain the ginkgo leaf extract Oral liquid.

Example 12

Weigh 1g of Ginkgo biloba extract, dissolve it in 40ml of hot acetone to obtain a clear khaki liquid, add 0.9g of egg yolk phospholipid, stir until the solution is clear, keep warm at 50°C for 4.5h while stirring, remove the reaction solvent under reduced pressure, and dry in vacuum at low temperature , to obtain yellow-brown slightly viscous powder complex.

Stir, grind and mix the prepared ginkgo leaf extract phospholipid complex (equivalent to 40 mg of ginkgo leaf extract) with 60 mg of polyoxyethylene sorbitol monooleate and 40 mg of Labrasol to obtain the ginkgo leaf extract composition .

Example 13

Capsules

Ginkgo biloba extract composition 176mg

Lactose 40mg

Microcrystalline Cellulose 60mg

Dicalcium Phosphate 50mg

Grind and/or sieve the Ginkgo biloba extract composition prepared in Example 12, lactose, microcrystalline cellulose, calcium hydrogen phosphate and mix evenly, moisten with 85% ethanol in an appropriate amount, pass through a 22-mesh sieve and granulate at 35°C Dry, take out, sieve through a 22-mesh sieve, and pack into capsules to obtain ginkgo leaf extract capsules.

Example 14

Weigh 1 g of Ginkgo biloba extract, dissolve it in 35 ml of tetrahydrofuran to obtain a khaki clear liquid, add 1.5 g of soybean lecithin, stir until the solution is clear, keep warm at 40°C for 3 h while stirring, remove the reaction solvent under reduced pressure, and dry in vacuum at low temperature to obtain Yellow-brown slightly viscous powder compound.

Melt 100 mg of the prepared ginkgo leaf extract phospholipid complex (equivalent to 40 mg of ginkgo leaf extract) with Gelucire 50/1352 mg and 60 mg of sorbitan monolaurate (Span20) at 50 ° C, stir and mix evenly to obtain Ginkgo biloba Extract composition.

Example 15

Sustained Release Capsules

Ginkgo biloba extract composition 212mg

Micropowder silica gel 20mg

Microcrystalline Cellulose 90mg

HPMC(K15M) 100mg

The ginkgo leaf extract composition prepared in Example 14 was ground and mixed with micropowder silica gel, added microcrystalline cellulose and HPMC (K4M) and mixed evenly, passed an appropriate amount of dehydrated alcohol through a 18-mesh sieve to granulate, and quickly put it into a bag Roll in a clothes pot for 30 minutes, dry in an oven at 35°C, and sieve through a 18-mesh sieve to obtain sustained-release pellets, which are divided into capsules to obtain sustained-release capsules.

Example 16

Weigh 1g of Ginkgo biloba extract, dissolve it in 30ml of n-hexane to obtain a khaki-yellow clear liquid, add 1.75g of synthetic phospholipid dipalmitoylphosphatidylcholine (DPPC), stir until the solution is clear, keep warm at 35°C for 3.5h while stirring , the reaction solvent was removed under reduced pressure, and vacuum-dried at low temperature to obtain a yellow-brown slightly viscous powder compound.

110 mg of the prepared ginkgo leaf extract phospholipid complex (equivalent to 40 mg of ginkgo leaf extract) and 85 mg of sorbitan monolaurate were stirred and mixed uniformly to obtain the ginkgo leaf extract composition.

Example 17

Sustained Release Tablets

Ginkgo biloba extract composition 195mg

Light magnesium oxide 50mg

HPMC(K4M) 60mg

Lactose 80mg

Magnesium stearate 4mg

Grind and mix the Ginkgo biloba extract phospholipid complex prepared in Example 16 with sorbitan monolaurate, fully absorb it with calcium hydrogen phosphate, add HPMC (K4M) and lactose and mix evenly, add an appropriate amount of dehydrated alcohol Wet and pass through a 22-mesh sieve to make granules, dry in an oven at 35°C, take out, sieve through a 22-mesh sieve, add magnesium stearate, mix evenly, and press into tablets to obtain sustained-release tablets.

Example 18

Weigh 1 g of ginkgo biloba extract, dissolve it in 30 ml of ethyl acetate to obtain a khaki-yellow clear liquid, add 1.05 g of the synthetic phospholipid dipalmitoylphosphatidylcholine (DPPC), stir until the solution is clear, and keep warm at 40°C while stirring for 5.0 h, the reaction solvent was removed under reduced pressure, and vacuum-dried at low temperature to obtain a yellow-brown slightly viscous powder compound.

Stir and mix the prepared ginkgo leaf extract phospholipid complex (equivalent to 40 mg of ginkgo leaf extract) with 30 mg of sorbitan monolaurate and 40 mg of sorbitan monooleate to obtain the ginkgo leaf extract combination.

Example 19

Sustained-release pellets

Ginkgo biloba extract composition 152mg

Dicalcium Phosphate 60mg

Microcrystalline Cellulose 120mg

Ethylcellulose 15mg

Grind the ginkgo leaf extract prepared in Example 18, pass through an 80-mesh sieve and mix evenly to obtain the ginkgo leaf extract medicinal powder. Take microcrystalline cellulose blank ball cores, spray with 95% ethanol, sprinkle the above-mentioned ginkgo leaf extract powder until the weight of the pellets increases to the prescribed amount, and vacuum-dry them at 30°C for 5 hours to obtain drug-containing pellets. Take 95% ethanol to prepare ethyl cellulose ethanol solution with a concentration of 2%, spray it on the existing drug-containing pellets at low temperature, increase the weight to the prescription amount, and vacuum dry at 30°C for 12 hours to obtain sustained-release pellets .

Claims (10)

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 and/or Folium Ginkgo extract phospholipid complex 1

Surfactant 0.75～3.

2, the ginkgo leaf extract composition of claim 1, wherein the ratio of weight and number of each component is:

Folium Ginkgo extract and/or Folium Ginkgo extract phospholipid complex 1

Surfactant 0.75～1.5.

3, 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.

4, claim 1,2 or 3 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.

5, the ginkgo leaf extract composition of claim 4, 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.

6, claim 1,2 or 3 ginkgo leaf extract composition also contain pharmaceutically acceptable pharmaceutic adjuvant.

7, the ginkgo leaf extract composition of claim 6, wherein pharmaceutic adjuvant is selected from one or more in diluent, absorbent, disintegrating agent, binding agent, wetting agent, lubricant and the slow-release material.

8, the ginkgo leaf extract composition of claim 7, 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.

9, the ginkgo leaf extract composition of claim 6 contains following component and percentage by weight:

Folium Ginkgo extract and/or 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.

10, the preparation method of each ginkgo leaf extract composition in the claim 1 to 9:

If the combination of Folium Ginkgo extract phospholipid complex and surfactant, make by following method: 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; 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;

If Folium Ginkgo extract and surfactant are then got in the combination of Folium Ginkgo extract and surfactant, stirring or ground and mixed are even, promptly get the compositions of Folium Ginkgo extract 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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