CN1994369A - Chinese medicinal formulation for treating cardiovascular and cerebrovascular disease and preparation process thereof - Google Patents

Abstract

The invention provides a Chinese medicinal preparation for treating cardiovascular and cerebrovascular diseases and its preparing process, wherein the preparation is prepared from total savianolic acid liposome or precursor liposome, ginkgo leaves lactones liposome or precursor liposome and auxiliary materials, and can be prepared into injections or oral preparations. Compared with the prior arts, the present invention achieves targeting property, less medicinal dose, lower toxicity and less side effects.

Description

Chinese medicine preparation of treatment cardiovascular and cerebrovascular disease and preparation method thereof

Technical field

The present invention is a kind of Chinese medicine preparation for the treatment of cardiovascular and cerebrovascular disease and preparation method thereof, belongs to technical field of Chinese medicine.

Technical background

Cardiovascular and cerebrovascular disease such as angina pectoris are commonly encountered diseases, the frequently-occurring diseases of middle-aged and elderly people.Mean that coronary atherosclerosis causes coronary insufficiency, the retrosternal pain that the rapid temporary transient hypoxic-ischemic of cardiac muscle causes.The category such as " thoracic obstruction ", " cardiopalmus ", " angina pectoris " that belongs to the traditional Chinese medical science.Primary disease Chang Fanfu outbreak, touching difficulty heals, and the healthy of people in serious harm.Prevent and treat purpose in order to reach, a large amount of research has been done by many inventors and medicine enterprise, and the product of some treatments also is provided; As: the applicant applies for that name is called the patent application of " Chinese medicine preparation of treatment cardiovascular and cerebrovascular disease and its production and application ", and the disease that it has adopted Folium Ginkgo, active component of red sage root compatibility to be used for the treatment for the treatment of cardiac and cerebral vascular diseases has definite curative effect; But find that in further investigation adopt the Liposomal formulation of effective site to be more suitable in biological vivo degradation, avirulence and non-immunogenicity, particularly liposome is as pharmaceutical carrier, has targeting, thereby reduce drug dose, reduce toxicity, reduce side effect etc.

Summary of the invention

The objective of the invention is to: a kind of Chinese medicine preparation for the treatment of cardiovascular and cerebrovascular disease and its production and application is provided; The present invention is directed to prior art, according to cardiovascular and cerebrovascular disease such as coronary heart disease, cerebral thrombosis, alzheimer disease etc. all contract because of blood vessel is narrow, reason such as blood flow minimizing causes the diseases induced principle of blood supply insufficiency, on the basis of experiment screening, adopt total salvianolic acids liposomes, Folium Ginkgo total lactones liposome compatibility to make preparation, optimize best prescription and technology; The product that obtains, particularly ejection preparation product can play activating blood circulation to dissipate blood stasis, TONGMAI SHULUO, improve blood circulation and metabolism.For example coronary heart disease is that coronary atherosclerosis causes myocardial ischemia, anoxia and the heart disease that causes, and two medicines share, and can play to improve the myocardial metabolism effect, increase coronary flow, and the blood that improves cardiac muscle is provided with the effect of allevating angina pectoris.The present invention has curative effect preferably for treating cardiovascular and cerebrovascular disease such as coronary heart disease, angina pectoris, arrhythmia, cerebral thrombosis, alzheimer disease etc.And the present invention be liposome as pharmaceutical carrier, have targeting, thereby reduce drug dose, reduce toxicity, reduce side effect, but the little patients life-time service of its untoward reaction.

The present invention constitutes like this: calculate according to percentage by weight, it is to be made by total salvianolic acids liposomes or pro-liposome 1～99% and Folium Ginkgo total lactones liposome or pro-liposome 99～1% and suitable adjuvant.Be preferably: calculate according to percentage by weight, it is to be made by total salvianolic acids liposomes or pro-liposome 20～80% and Folium Ginkgo total lactones liposome or pro-liposome 80～20% and suitable adjuvant.Say accurately: calculate according to percentage by weight, it is to be made by total salvianolic acids liposomes or pro-liposome 40～60% and Folium Ginkgo total lactones liposome or pro-liposome 60～40% and suitable adjuvant.

Total salvianolic acids liposomes in the described prescription or pro-liposome can be to make on the basis of the highly finished product of tanshinol extract, Radix Salviae Miltiorrhizae water extract, Radix Salviae Miltiorrhizae water extract-alcohol precipitation extract, Radix Salviae Miltiorrhizae semi-bionic extraction thing, red sage root super critical extract or above each extract; Folium Ginkgo total lactones liposome or pro-liposome can be to make on the basis of the highly finished product of Folium Ginkgo alcohol extract, Folium Ginkgo water extract, Folium Ginkgo water extract-alcohol precipitation extract, Folium Ginkgo semi-bionic extraction thing, Folium Ginkgo supercritical extract or above each extract.

Described preparation can be any acceptable dosage form on the pharmaceutics: be directly used in the injection of drug administration by injection, directly supply the venous transfusion of intravenous drip, need be used for the concentrated solution for injection of intravenous drip and injectable sterile powder and aseptic block and tablet, capsule, granule, drop pill, pill, soft capsule, oral liquid, oral cavity disintegration tablet, Sublingual tablet or the dispersible tablet that makes with freeze-drying or spray drying method after diluting.

Calculate according to percentage by weight, the content of total phenolic acid is not less than 50% in the Radix Salviae Miltiorrhizae total phenolic acids, and the content of total lactone is not less than 50% in the Folium Ginkgo total lactones, and liposome encapsulation is not less than 60%.

The preparation method of described liposome is: Folium Ginkgo total lactones liposome and total salvianolic acids liposomes be adopt membrane process, ammonium sulphate gradient, reverse phase evaporation, solvent injection method, detergent dispersion method, calcium fusion method, freeze the method for melting, initiatively one or more methods in envelope, freeze-drying, multi-emulsion method, centrifuging, pro-liposome method, the preparation liposome aerosols make.

Liposome in the described preparation prepares like this: in principal agent: the ratio of lecithin=1: 10 is got lecithin, and in principal agent: the ratio of phosphatidyl glycerol=1: 1.1 is got phosphatidyl glycerol, is dissolved in the mixed solution of chloroform one isopropyl alcohol; Other gets in the phosphate buffer that Folium Ginkgo total lactones is dissolved in pH5-8, biphase mixing, behind the ultrasonic 8min of water-bath type, in Rotary Evaporators, remove organic solvent and promptly get liposome turbid liquor, be equipped with the total salvianolic acids liposomes suspension with legal system, mix the back with the Folium Ginkgo total lactones liposome turbid liquor and make various preparations with diverse ways.

Pro-liposome in the described preparation prepares like this: get phospholipid and adjuvant and add a certain amount of anhydrous alcohol solution, under the constant temperature stirring condition, inject Radix Salviae Miltiorrhizae total phenolic acids or Folium Ginkgo total lactones solution with certain speed, continuing constant temperature stirs, reduce to room temperature, homogenate, membrane filtration, fill, inflated with nitrogen seals; The gained liposome is put into liquid nitrogen, and take out freezing back; It is molten that room temperature makes it, and repeats once promptly to get Radix Salviae Miltiorrhizae total phenolic acids or Folium Ginkgo total lactones pro-liposome, and Radix Salviae Miltiorrhizae total phenolic acids pro-liposome and Folium Ginkgo total lactones pro-liposome mixing back are made various preparations with diverse ways.

Dispersible tablet in the described preparation prepares like this: get total salvianolic acids liposomes, the mixing of Folium Ginkgo total lactones liposome, in principal agent: the ratio of adjuvant=1.4: 1 adds calcium phosphate, in principal agent: the ratio of adjuvant=1.2: 1 adds the micropowder cellulose, and press principal agent: the crospolyvinylpyrrolidone of adjuvant=2.5: 1, evenly mixed, make soft material in right amount with 70% ethanol, cross 20 mesh sieve system granules, 65 ℃ of dryings are taken out, and cross 30 mesh sieve granulate, add an amount of Pulvis Talci, micropowder silica gel, evenly mixed, tabletting promptly gets dispersible tablet.

Compared with prior art, the applicant carried out lot of experiments, filtering out the prescription for the treatment of diseases such as angina pectoris is total salvianolic acids liposomes, Folium Ginkgo total lactones liposome, and best proportion compatibility is total salvianolic acids liposomes 40%～60% and Folium Ginkgo total lactones liposome 60%～40%.Adopt good, the steady quality of prepared product appearance of the present invention.

For proving that medicine provided by the invention has effective effect, the applicant has carried out a series of experiments:

Experimental example 1: to the comparative study of different proportioning pharmacodynamics

We by antiplatelet aggregation test, suppress the mouse tail thrombotest, the prescription of different proportion has been carried out the screening test of system, the result is as follows:

The prescription research conclusion

Formula number	Prescription is formed and ratio	The screening and assessment index
				Total salvianolic acids liposomes: Folium Ginkgo total lactones liposome	Platelet suppression ratio (%)	Thrombosis suppression ratio (%)
	1 2 3 4 5 6 7 8	1: 99 20: 80 40: 60 60: 40 80: 20 99: 1 positive controls of model group	0.34％ 48.1％ 54.5％ 62.3％ 62.8％ 54.9％ 51.1％ 62.4％				-0.12％ 25.3％ 36.1％ 43.8％ 43.1％ 37.5％ 27.9％ 42.1％

By experimental result as can be known, total salvianolic acids liposomes, the best compatibility scope of Folium Ginkgo total lactones liposome are Folium Ginkgo total lactones liposome 40～60% and total salvianolic acids liposomes 60～40%.

Experimental example 2: method for preparing lipidosome research

2.1 the investigation of the preparation method of liposome

2.1.1 reverse evaporation: get soybean lecithin 100mg, cholesterol 60mg is dissolved in the 20mL ether, places conical flask.Phosphate buffer with pH5-8 is that solvent is prepared 1% Radix Salviae Miltiorrhizae total phenolic acids or Folium Ginkgo total lactones solution, under the electromagnetic agitation, slowly splash into 1% Radix Salviae Miltiorrhizae total phenolic acids or Folium Ginkgo total lactones solution 15mL in the conical flask, stirring makes with ether and forms emulsion, distilling under reduced pressure 1h steams ether and removes, and gets liposome.

2.1.2 ether injection method: the phosphate buffer with pH5-8 is that solvent is prepared 1% Radix Salviae Miltiorrhizae total phenolic acids or Folium Ginkgo total lactones solution, gets 15mL in conical flask.Soybean lecithin 100mg, cholesterol 60mg are dissolved in the 6mL ether.Under the electromagnetic agitation, slowly with diethyl ether solution with even 65 ℃ of the post-heating of No. five syringe needles (needle point is below liquid level), ether is removed in volatilization, liposome.

2.1.3 membrane process: soybean lecithin 100mg, cholesterol 60mg is dissolved in the 20mL ether, remove organic solvent with the Rotary Evaporators decompression, in the pyriform bottle, form uniform immobilized artificial membrane, add the phosphate buffer that 15mL contains the pH5-8 of 1% Radix Salviae Miltiorrhizae total phenolic acids or Folium Ginkgo total lactones, soak, stir the eluting lipid film, can get liposome.

2.1.4 ammonium sulphate gradient: get soybean lecithin 100mg, cholesterol 60mg is dissolved in the 20mL ether, removes organic solvent with the Rotary Evaporators decompression, forms uniform immobilized artificial membrane in the pyriform bottle, in vacuum drying oven, after the drying, add the 20mL ammonium sulfate and soak the eluting lipid film.After the blank liposome usefulness probe ultrasonic cell disintegrator fragmentation with preparation, (about 10mmolL in the bag filter of packing into ^-1), put into the 0.9% sodium chloride solution 48h that dialyses, take out the blank liposome after the dialysis, add 15mL1% Radix Salviae Miltiorrhizae total phenolic acids or Folium Ginkgo total lactones solution, place 60 ℃ of water-baths to hatch 10min, liposome.

2.2 entrapment efficiency determination

Adopt dialysis to measure liposome encapsulation.The liposome 5mL that respectively gets above-mentioned several method preparation places bag filter, puts respectively in the 50mL beaker, and the accurate phosphate buffer 45mL that adds soaks, and stirs 15min every 2h.Get soak 2.5mL behind the 12h and place the 25mL volumetric flask, add pH5-8 phosphate buffer standardize solution.With the pH5-8 phosphate buffer is the blank trap of surveying at the 274nm place.Synchronously, get the 5mL1% Radix Salviae Miltiorrhizae total phenolic acids or Folium Ginkgo total lactones solution is dialysed in bag filter,, adopt the envelop rate computing formula as blank medicine contrast:

Envelop rate=(C total-C free)/C is total * and 100%

Wherein C always is total dose in the liposome turbid liquor, and C is free for not wrapping into liposome Chinese medicine amount.The results are shown in following table.

	Distinct methods prepares the envelop rate of liposome
					The ether injection method	Reverse evaporation	Membrane process	Ammonium sulphate gradient
	Radix Salviae Miltiorrhizae total phenolic acids envelop rate (%) Folium Ginkgo total lactones envelop rate (%)	34.1 33.8	69.2 62.0	32.5 31.1					16.5 22.7

The result: by experimental result as can be known, total salvianolic acids liposomes, Folium Ginkgo total lactones liposome adopt the envelop rate of reverse evaporation higher, determine that therefore reverse evaporation is the method for preparing lipidosome of this preparation.

Experimental example 3: preparation pharmacodynamic experiment

The rat coronary artery ligation causes the influence of myocardial infarction: 50 of extracting male Wistar rats, be divided into 5 groups at random, be Sham-operated control group, model control group, Radix Salviae Miltiorrhizae total phenolic acids-Folium Ginkgo total lactones injection 0.3g/kg group, oral liquid 0.3g/kg of the present invention group, injection 0.3g/kg of the present invention group, every group 10, each respectively administration of group, every day 1 time for three days on end.1h after the last administration is with pentobarbital anesthesia, tracheal intubation, artificial respiration.Open breast in the 3rd～4 intercostal,, cause occlusive arteria coronaria district myocardial infarction apart from coronary artery outlet 5mm place's ligation left anterior descending coronary artery.Behind 4h, use the electromagnetic flowmeter determination coronary artery blood flow, and measure the infarcted region area percentage.The results are shown in following table, the coronary flow of medication group significantly increases, and the infarcted region area obviously reduces.

Influence to coronary artery blood flow and infarct size after the rat coronary artery ligation

Group	Coronary flow (ml/min.100g)	Cerebral infarction dead band area percentage (%)
			Sham-operation group model group salvianolic acid-ginkgo biloba leaf total terpene lactone parenteral solution 0.3g/kg group injection group 0.3g/kg of the present invention oral liquid group of the present invention 0.3g/kg	58.93±3.35 37.91±2.81 46.76±2.47 50.07±1.61 51.42±3.94	—— 8.72±2.09 7.12±2.69 6.31±1.61 6.28±1.73

By experimental result as can be known, pharmaceutical preparation of the present invention causes that to coronary occlusion the myocardial ischemia situation can significantly increase coronary flow, obviously reduce myocardial infarction district area, and under the situation that reduces consumption greatly, curative effect still is better than Radix Salviae Miltiorrhizae total phenolic acids, Folium Ginkgo total lactones normal injection.

Concrete embodiment

Embodiment 1: total salvianolic acids liposomes 50g Folium Ginkgo total lactones liposome 50g

Get total salvianolic acids liposomes, the mixing of Folium Ginkgo total lactones liposome, suspension is placed-20 ℃ of refrigerator pre-freeze 12h, after promptly get lyophilized injectable powder after the lyophilization.Intravenous injection, once-a-day, one time one.

Embodiment 2: total salvianolic acids liposomes 40g Folium Ginkgo total lactones liposome 60g

Get total salvianolic acids liposomes, the mixing of Folium Ginkgo total lactones liposome, filter, add the injection water, divide to install to pacify and cut open bottle, seal sterilization, promptly get injection and concentrated solution for injection.

Embodiment 3: total salvianolic acids liposomes 60g Folium Ginkgo total lactones liposome 40g

Get total salvianolic acids liposomes, the mixing of Folium Ginkgo total lactones liposome, the gained suspension is filled in the soft capsule, promptly get soft capsule.

Embodiment 4: total salvianolic acids liposomes 80g Folium Ginkgo total lactones liposome 20g

Get total salvianolic acids liposomes, the mixing of Folium Ginkgo total lactones liposome, the gained suspension is mixed with pregelatinized Starch, is that binding agent is granulated with the ethanol liquid that gathers the second ketopyrrolidine, dry back granulate, with an amount of polyethylene glycol 6000 mix homogeneously, tabletting is tablet again.

Embodiment 5: total salvianolic acids liposomes 20g Folium Ginkgo total lactones liposome 80g

Get total salvianolic acids liposomes, Folium Ginkgo total lactones liposome and mix, by principal agent: the ratio of adjuvant=1.6: 1 adds calcium phosphate, in principal agent: the ratio adding micropowder cellulose of adjuvant=1.2: 1, and press principal agent: the crospolyvinylpyrrolidone of adjuvant=3: 1, evenly mixed, make soft material in right amount with 75% ethanol, cross 20 mesh sieve system granules, 55 ℃ of dryings are taken out, and cross 30 mesh sieve granulate, add an amount of Pulvis Talci, micropowder silica gel, evenly mixed, tabletting promptly gets dispersible tablet.

Embodiment 6: total salvianolic acids liposomes 1g Folium Ginkgo total lactones liposome 99g

Get total salvianolic acids liposomes, the mixing of Folium Ginkgo total lactones liposome, add 2.5 times of amount dextrin, 0.4% stevioside, 1.4% micropowder cellulose with an amount of alcoholic solution system soft material, is granulated, and 65 ℃ of forced air dryings are granulated, and granulate promptly gets granule.

Embodiment 7: total salvianolic acids liposomes 99g Folium Ginkgo total lactones liposome 1g

Getting total salvianolic acids liposomes, Folium Ginkgo total lactones liposome and mix, will be that 1.3: 1 sodium stearate is put in the rustless steel container mix homogeneously with the principal agent ratio, be heated to 80-85 ℃, treat whole fusions after, 70-75 ℃ of insulation, mechanical high-speed stirs 15min to evenly, is transferred in the reservoir 70～75 ℃ of insulations, regulate the dropping liquid valve, splash in 30～35 ℃ the kerosene, drip apart from 5～6cm, drip 40～45 droplets/minute of speed, kerosene is use up and wiped to the drop pill drop that forms, and packing promptly gets drop pill.

Embodiment 8: above total salvianolic acids liposomes, Folium Ginkgo total lactones liposome can be commercially available or prepare in order to the below method:

(1) reverse evaporation: get soybean lecithin 100mg, cholesterol 60mg is dissolved in the 20mL ether, places conical flask.Phosphate buffer with pH5-8 is that solvent is prepared 1% Radix Salviae Miltiorrhizae total phenolic acids or Folium Ginkgo total lactones solution, under the electromagnetic agitation, slowly splash into 1% Radix Salviae Miltiorrhizae total phenolic acids or Folium Ginkgo total lactones solution 15mL in the conical flask, stirring makes with ether and forms emulsion, distilling under reduced pressure 1h steams ether and removes, and gets liposome;

(2) solvent injection method (ether injection method): the phosphate buffer with pH5-8 is that solvent is prepared 1% Radix Salviae Miltiorrhizae total phenolic acids or Folium Ginkgo total lactones, gets 15mL in conical flask.Soybean lecithin 100mg, cholesterol 60mg are dissolved in the 6mL ether.Under the electromagnetic agitation, slowly diethyl ether solution is injected Radix Salviae Miltiorrhizae total phenolic acids or Folium Ginkgo total lactones solution with No. five syringe needles (needle point is below liquid level).Stir post-heating to 65 ℃, ether is removed in volatilization, liposome;

(3) membrane process: soybean lecithin 100mg, cholesterol 60mg is dissolved in the 20mL ether, remove organic solvent with the Rotary Evaporators decompression, in the pyriform bottle, form uniform immobilized artificial membrane, add the phosphate buffer that 15mL contains the pH5-8 of 1% Radix Salviae Miltiorrhizae total phenolic acids or Folium Ginkgo total lactones, soak, stir the eluting lipid film, can get liposome;

(4) ammonium sulphate gradient: get soybean lecithin 100mg, cholesterol 60mg is dissolved in the 20mL ether, removes organic solvent with the Rotary Evaporators decompression, forms uniform immobilized artificial membrane in the pyriform bottle, in vacuum drying oven, after the drying, add the 20mL ammonium sulfate and soak the eluting lipid film.After the blank liposome usefulness probe ultrasonic cell disintegrator fragmentation with preparation, (about 10mmolL in the bag filter of packing into ^-1), put into the 0.9% sodium chloride solution 48h that dialyses, take out the blank liposome after the dialysis, add 15mL1% Radix Salviae Miltiorrhizae total phenolic acids or Folium Ginkgo total lactones solution, place 60 ℃ of water-baths to hatch 10min, liposome;

(5) freeze the method for melting: get phospholipid and adjuvant and add a certain amount of anhydrous alcohol solution, under the constant temperature stirring condition, inject Radix Salviae Miltiorrhizae total phenolic acids or Folium Ginkgo total lactones solution, continue constant temperature and stir with certain speed, reduce to room temperature, homogenate, membrane filtration, fill, inflated with nitrogen seals.The gained liposome is put into liquid nitrogen, and take out freezing back.It is molten that room temperature makes it, and repeats once promptly;

(6) freeze-drying: get fabaceous lecithin 2.0g, cholesterol 0.5g 80 ℃ of fusions, adds the pH5-8 phosphate buffer with an amount of ethanol, treats to be transferred in the tissue mashing machine after ethanol is waved to the greatest extent naturally, high-speed stirred 10min, filter fiery bacterium, ultrasonic 15min, under aseptic condition, add sterilization Radix Salviae Miltiorrhizae total phenolic acids or Folium Ginkgo total lactones injection raw material 1.0g and sterilization mannitol 2.0g dissolving, fill is in the peace bottle, and lyophilization becomes freeze-dried lipidosome; (7) after the Phosphatidylserine of calcium fusion method: 7umol (PS) is made thin film, with the hydration of 1.5ml normal saline, ultrasonic Treatment 5min.Take out in the calcium chloride solution of equivalent that 0.25ml joins 20mmol/L and mix, hatch 80min for 37 ℃.The centrifugal 10min of volume tub 1800g that generates gets and hatches 15min after precipitation adds Radix Salviae Miltiorrhizae total phenolic acids or Folium Ginkgo total lactones solution.Add the normal saline buffer solution 0.25ml that 45mmol/L contains EDTA subsequently and hatch 50min, promptly get liposome;

(8) envelope initiatively: with pH is that 4 300mmol/L aqueous solution of citric acid is a medium, adopts reverse phase evaporation or membrane process to prepare blank liposome.PH to 7.8 with sodium hydroxide or the sodium carbonate liquor of 1mol/L are regulated the blank liposome suspension makes the inside and outside gradient that forms proton of liposome membrane, and the inside that promptly obtains liposome membrane is for acid, and the outside is the liposome of alkalescence.With the phosphate buffer dissolving of Radix Salviae Miltiorrhizae total phenolic acids or Folium Ginkgo total lactones pH value of solution 5-8, hatch for 65 ℃.Under 65 ℃ of incubation conditions, liposome turbid liquor is mixed with Radix Salviae Miltiorrhizae total phenolic acids or Folium Ginkgo total lactones solution and jog, hatch 12min promptly;

(9) multi-emulsion method: be to get phosphatidylcholine (PC), cholesterol (Ch) and phosphatidic acid (PA) at 7: 2.2: 1.5 in molar ratio, it is dissolved in organic solvent, add certain Radix Salviae Miltiorrhizae total phenolic acids or Folium Ginkgo total lactones solution, put the emulsifying 10min of high-speed tissue mashing machine (10000r/min), add phosphate buffer (pH5-8) again, emulsify at a high speed (8000r/min) gets emulsion again.Under the logical nitrogen condition of decompression, remove organic solution, promptly;

(10) centrifuging: 80mg phospholipid is dissolved in the 5ml butyl oxide, adds the sodium chloride solution 0.2ml of Radix Salviae Miltiorrhizae total phenolic acids or Folium Ginkgo total lactones solution.Supersound process gets clear solution, and dislocation has in the centrifuge tube of sodium chloride solution of the identical osmotic pressure of 20ml, with the centrifugal 30min of 3000r/min, removes the upper strata organic solvent, and lower floor is then for containing the sodium chloride solution of liposome.Through non-encapsulated Radix Salviae Miltiorrhizae total phenolic acids of macroporous resin adsorption or Folium Ginkgo total lactones, promptly get liposome;

(11) preparation liposome aerosols: 5ml Radix Salviae Miltiorrhizae total phenolic acids or Folium Ginkgo total lactones solution, the dichlorodifluoromethane of 280mg/ml lecithin ethanol liquid and 6.0g is mixed into organic facies, containing 7% ethanol 50ml water is water, and each valve is emitted 50ul organic facies and water, promptly.

Embodiment 9: above Radix Salviae Miltiorrhizae total phenolic acids pro-liposome, Folium Ginkgo total lactones pro-liposome can be commercially available or prepare in order to the below method:

(1) freeze-thaw method: get phospholipid and adjuvant and add a certain amount of anhydrous alcohol solution, under the constant temperature stirring condition, inject Radix Salviae Miltiorrhizae total phenolic acids or Folium Ginkgo total lactones solution, continue constant temperature and stir, reduce to room temperature with certain speed, homogenate, membrane filtration, fill, inflated with nitrogen seals.The gained liposome is put into liquid nitrogen, and take out freezing back.It is molten that room temperature makes it, and repeats once promptly;

(2) spray drying method: Radix Salviae Miltiorrhizae total phenolic acids that will accurately take by weighing or Folium Ginkgo total lactones; soybean phospholipid and cholesterol are dissolved in the chloroform jointly; filter; filtrate collection is in round-bottomed flask; rotary evaporation is flung to chloroform and is become thin film; behind the vacuum drying; the phosphate buffer that adds pH5-8; soak 2-8h, high-speed stirred under the nitrogen current protection then is behind the certain hour; to wherein slowly dripping dissolved polyvinylpyrrolidone of same buffer (PVP) and sucrose solution; continue to stir, and supply buffer, then with the liposome turbid liquor filtering with microporous membrane to 150mL; filtrate potting under nitrogen protection promptly gets Radix Salviae Miltiorrhizae total phenolic acids or Folium Ginkgo total lactones liposome.Adopt spray dry, experiment condition is: 125 ℃ of inlet temperature, charging rate 60mL/min, cyclone separator pressure reduction 55mmH20, atomizing disk rotating speed 2700r/min;

(3) rotary evaporation method: take by weighing lecithin, cholesterol, VE respectively, polyvinylpyrrolidone (PVP) etc. is dissolved in an amount of chloroform and is collected in the eggplant type flask, put in the water-bath, add Radix Salviae Miltiorrhizae total phenolic acids or Folium Ginkgo total lactones phosphate buffer after flinging to the chloroform film forming with rotary evaporator decompression.After soaking thin film.Ultrasonic under frequency 35kHz, prime time duty, promptly get Radix Salviae Miltiorrhizae total phenolic acids or Folium Ginkgo total lactones liposome turbid liquor.Get mannitol etc. and place the 150ml eggplant type flask, continue reduction vaporization, take out and place the decompression of vacuum desiccator room temperature to spend the night to dry, packing under the nitrogen behind the finish-drying, promptly.

Embodiment 10: Radix Salviae Miltiorrhizae total phenolic acids, Folium Ginkgo total lactones can be commercially available, or prepare in order to the below method:

(1) gets Radix Salviae Miltiorrhizae, add the water of 4～15 times of amounts after the coarse pulverization, soaked 2～12 hours, heating extraction 1～5 time, each 0.5～2 hour, merge extractive liquid,, filter, filtrate concentrates, and adds 1%～8% gelatin solution, stir evenly, cold preservation is spent the night, and filters, filtrate concentrates, and adds 1～4 times of volumes of acetic acid ethyl ester extraction 1～5 time, combined ethyl acetate liquid, decompression and solvent recovery, vacuum drying gets Radix Salviae Miltiorrhizae total phenolic acids;

(2) get Radix Salviae Miltiorrhizae, be ground into the coarse powder of 10 mesh sieves, add 6～10 times of volume 50%～90% alcohol reflux 1～4 time, each 0.5～4 hour, merge extractive liquid,, measuring relative density during decompression recycling ethanol to 60 ℃ is 1.05～1.15, the water dissolution that adds 2～4 times of medical material volumes, filter, filtrate is crossed D-101 type macroporous adsorbent resin, with 3～10 times of resinite hydrops flushing impurity, use 20%～50% alcohol desorption of 2～8 times of resin volumes then, collect stripping liquid, measuring relative density during decompression recycling ethanol to 60 ℃ is 1.05～1.15, Radix Salviae Miltiorrhizae total phenolic acids;

(3) get Folium Ginkgo, 40%～80% the ethanol that adds 3～12 times of amounts, reflux, extract, 1～5 time each 0.5～3 hour, merges backflow, filter, filtrate recycling ethanol concentrates, and adds 1～4 times of volumes of acetic acid ethyl ester extraction 1～6 time, combined ethyl acetate liquid, decompression and solvent recovery, vacuum drying gets Folium Ginkgo total lactones;

(4) get Folium Ginkgo, add 40%～80% ethanol of 3～12 times of amounts, reflux, extract, 1～5 time, each 0.5～3 hour, merge backflow, filter, filtrate recycling ethanol concentrates, and adds the water for injection dissolving, filters, filtrate is crossed macroporous adsorptive resins or polyamide column and silicagel column, with 0～15% ethanol elution impurity, 40～90% ethanol elutions of 2～8 times of weight resins of reuse, eluent reclaims ethanol and concentrates, vacuum drying gets Folium Ginkgo total lactones.

Claims (10)

1, a kind of Chinese medicine preparation for the treatment of cardiovascular and cerebrovascular disease, it is characterized in that: calculate according to percentage by weight, it is to be made by total salvianolic acids liposomes or pro-liposome 1～99% and Folium Ginkgo total lactones liposome or pro-liposome 99～1% and suitable adjuvant.

2, according to the Chinese medicine preparation of the described treatment cardiovascular and cerebrovascular disease of claim 1, it is characterized in that: calculate according to percentage by weight, it is to be made by total salvianolic acids liposomes or pro-liposome 20～80% and Folium Ginkgo total lactones liposome or pro-liposome 80～20% and suitable adjuvant.

3, according to the Chinese medicine preparation of claim 1 or 2 described treatment cardiovascular and cerebrovascular diseases, it is characterized in that: calculate according to percentage by weight, it is to be made by total salvianolic acids liposomes or pro-liposome 40～60% and Folium Ginkgo total lactones liposome or pro-liposome 60～40% and suitable adjuvant.

4, according to the Chinese medicine preparation of any described treatment cardiovascular and cerebrovascular disease of claim 1～3, it is characterized in that: total salvianolic acids liposomes in the described prescription or pro-liposome can be to make on the basis of the highly finished product of tanshinol extract, Radix Salviae Miltiorrhizae water extract, Radix Salviae Miltiorrhizae water extract-alcohol precipitation extract, Radix Salviae Miltiorrhizae semi-bionic extraction thing, red sage root super critical extract or above each extract; Folium Ginkgo total lactones liposome or pro-liposome can be to make on the basis of the highly finished product of Folium Ginkgo alcohol extract, Folium Ginkgo water extract, Folium Ginkgo water extract-alcohol precipitation extract, Folium Ginkgo semi-bionic extraction thing, Folium Ginkgo supercritical extract or above each extract.

5, according to the Chinese medicine preparation of any described treatment cardiovascular and cerebrovascular disease of claim 1～4, it is characterized in that: described preparation be directly used in the injection of drug administration by injection, directly for the venous transfusion of intravenous drip, need be used for the concentrated solution for injection of intravenous drip and injectable sterile powder and aseptic block and tablet, capsule, granule, drop pill, pill, soft capsule, oral liquid, oral cavity disintegration tablet, Sublingual tablet or the dispersible tablet that makes with freeze-drying or spray drying method after the dilution.

6, according to the Chinese medicine preparation of the described treatment cardiovascular and cerebrovascular disease of claim 4, it is characterized in that: calculate according to percentage by weight, the content of total phenolic acid is not less than 50% in the Radix Salviae Miltiorrhizae total phenolic acids, and the content of total lactone is not less than 50% in the Folium Ginkgo total lactones, and liposome encapsulation is not less than 60%.

7, as the Chinese medicine preparation of any described treatment cardiovascular and cerebrovascular disease in the claim 1～5, it is characterized in that: Folium Ginkgo total lactones liposome and total salvianolic acids liposomes be adopt membrane process, ammonium sulphate gradient, reverse phase evaporation, solvent injection method, detergent dispersion method, calcium fusion method, freeze the method for melting, initiatively one or more methods in envelope, freeze-drying, multi-emulsion method, centrifuging, pro-liposome method, the preparation liposome aerosols make.

8, as the Chinese medicine preparation of any described treatment cardiovascular and cerebrovascular disease in the claim 1～7, it is characterized in that: the liposome in the described preparation prepares like this: in principal agent: the ratio of lecithin=1: 10 is got lecithin, in principal agent: the ratio of phosphatidyl glycerol=1: 1.1 is got phosphatidyl glycerol, is dissolved in the mixed solution of chloroform-isopropyl alcohol; Other gets in the phosphate buffer that Folium Ginkgo total lactones is dissolved in pH5-8, biphase mixing, behind the ultrasonic 8min of water-bath type, in Rotary Evaporators, remove organic solvent and promptly get liposome turbid liquor, be equipped with the total salvianolic acids liposomes suspension with legal system, mix the back with the Folium Ginkgo total lactones liposome turbid liquor and make various preparations with diverse ways.

9, as the Chinese medicine preparation of any described treatment cardiovascular and cerebrovascular disease in the claim 1～7, it is characterized in that: the pro-liposome in the described preparation prepares like this: get phospholipid and adjuvant and add a certain amount of anhydrous alcohol solution, under the constant temperature stirring condition, inject Radix Salviae Miltiorrhizae total phenolic acids or Folium Ginkgo total lactones solution with certain speed, continue constant temperature and stir, reduce to room temperature, homogenate, membrane filtration, fill, inflated with nitrogen seals; The gained liposome is put into liquid nitrogen, and take out freezing back; It is molten that room temperature makes it, and repeats once promptly to get Radix Salviae Miltiorrhizae total phenolic acids or Folium Ginkgo total lactones pro-liposome, and Radix Salviae Miltiorrhizae total phenolic acids pro-liposome and Folium Ginkgo total lactones pro-liposome mixing back are made various preparations with diverse ways.

10, preparation method according to the Chinese medicine preparation of any described treatment cardiovascular and cerebrovascular disease in the claim 1～9, it is characterized in that: the dispersible tablet in the described preparation prepares like this: get total salvianolic acids liposomes, the Folium Ginkgo total lactones liposome mixes, in principal agent: the ratio of adjuvant=1.4: 1 adds calcium phosphate, in principal agent: the ratio of adjuvant=1.2: 1 adds the micropowder cellulose, and press principal agent: the crospolyvinylpyrrolidone of adjuvant=2.5: 1, evenly mixed, make soft material in right amount with 70% ethanol, cross 20 mesh sieve system granules, 65 ℃ of dryings, take out, cross 30 mesh sieve granulate, add an amount of Pulvis Talci, micropowder silica gel, evenly mixed, tabletting promptly gets dispersible tablet.