CN1994361A - Chinese medicinal formulation for treating cardiovascular and cerebrovascular disease and preparation process thereof - Google Patents
Chinese medicinal formulation for treating cardiovascular and cerebrovascular disease and preparation process thereof Download PDFInfo
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- CN1994361A CN1994361A CN 200610000242 CN200610000242A CN1994361A CN 1994361 A CN1994361 A CN 1994361A CN 200610000242 CN200610000242 CN 200610000242 CN 200610000242 A CN200610000242 A CN 200610000242A CN 1994361 A CN1994361 A CN 1994361A
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Abstract
The invention provides a Chinese medicinal preparation for treating cardiovascular and cerebrovascular diseases and its preparing process, wherein the preparation is prepared from astragalus root saponins liposome or precursor liposome, astragalus root polysaccharides liposome or precursor liposome, ginkgo leaf lactones liposome or precursor liposome, ginkgo biloba leaf flavonoids 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
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 is meant that blood contamination causes atherosclerosis, thereby causes the corresponding pathological changes that cardiac-cerebral ischemia causes.Comprise: hypertension, atherosclerosis, coronary heart disease (heart infarction and angina pectoris), cerebral ischemia pathological changes (cerebral blood supply insufficiency, cerebral thrombosis, cerebral infarction) and cerebral hemorrhage.Atherosclerosis that causes behind the blood contamination and complication thereof are to cause the first dead killer.Atherosclerosis thrombosis and cause dead ratio to account for 52% of whole death tolls worldwide is considerably beyond the tumor (24%) of second cause of the death.Better prevent and treat purpose in order to reach, a large amount of research has been done by many inventors and medicine enterprise, and some outstanding treatment products also are 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 the Radix Astragali, Folium Ginkgo effective site 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 Radix Astragali total saponins liposome, astragalus polysaccharides liposome and Folium Ginkgo total flavones liposome, 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 is pure Chinese medicinal preparation, 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 Radix Astragali total saponins liposome or pro-liposome, astragalus polysaccharides liposome or pro-liposome 1～99% and Folium Ginkgo total flavones liposome or pro-liposome, 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 Radix Astragali total saponins liposome or pro-liposome, astragalus polysaccharides liposome or pro-liposome 20～80% and Folium Ginkgo total flavones liposome or pro-liposome, 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 Radix Astragali total saponins liposome or pro-liposome, astragalus polysaccharides liposome or pro-liposome 40～60% and Folium Ginkgo total flavones liposome or pro-liposome, Folium Ginkgo total lactones liposome or pro-liposome 60～40% and suitable adjuvant.
Radix Astragali total saponins liposome in the described prescription or pro-liposome, astragalus polysaccharides liposome or pro-liposome can be to make on the basis of the highly finished product of (+)-Astragenol extract, Radix Astragali water extract, Radix Astragali water extract-alcohol precipitation extract, Radix Astragali semi-bionic extraction thing, Radix Astragali supercritical extract or above each extract; Folium Ginkgo total flavones liposome or pro-liposome, 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 saponins is not less than 50% in the Radix Astragali total saponins liposome, the content of polysaccharide is not less than 50% in the astragalus polysaccharides liposome, content of total flavone is not less than 50% in the Folium Ginkgo total flavones liposome, the content of total lactone is not less than 50% in the Folium Ginkgo total lactones liposome, and liposome encapsulation is not less than 60%.
The preparation method of described liposome is: Folium Ginkgo total lactones liposome, Folium Ginkgo total flavones liposome and Radix Astragali total saponins liposome, Radix Astragali Mongolici total polysaccharide liposome 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-isopropyl alcohol; Other gets Folium Ginkgo total lactones or Folium Ginkgo total flavones is dissolved in the phosphate buffer of 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 Radix Astragali total saponins liposome and Radix Astragali Mongolici total polysaccharide liposome turbid liquor with legal system, mix the back with Folium Ginkgo total lactones liposome, Folium Ginkgo total flavones 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 Astragali total saponins, Radix Astragali Mongolici total polysaccharide or Folium Ginkgo total lactones, Folium Ginkgo total flavones 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, repeat once promptly to get Radix Astragali total saponins pro-liposome, Radix Astragali Mongolici total polysaccharide pro-liposome or Folium Ginkgo total lactones pro-liposome, Folium Ginkgo total flavones pro-liposome, Radix Astragali total saponins pro-liposome, Radix Astragali Mongolici total polysaccharide pro-liposome and Folium Ginkgo total lactones pro-liposome, Folium Ginkgo total flavones pro-liposome are mixed the back make various preparations with diverse ways.
Dispersible tablet in the described preparation prepares like this: get the Radix Astragali total saponins liposome, the Radix Astragali Mongolici total polysaccharide liposome, the Folium Ginkgo total lactones liposome, the Folium Ginkgo total flavones 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=3: 1, evenly mixed, make soft material in right amount with 70% 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.
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 Radix Astragali total saponins liposome, astragalus polysaccharides liposome, Folium Ginkgo total flavones liposome, Folium Ginkgo total lactones liposome, and best compatibility scope is Folium Ginkgo total flavones liposome, Folium Ginkgo total lactones liposome 40～60% and Radix Astragali total saponins liposome, astragalus polysaccharides 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 | |||
| Prescription is formed and ratio | The screening and assessment index | ||
| Formula number | Radix Astragali total saponins liposome, astragalus polysaccharides liposome: Folium Ginkgo total lactones liposome, Folium Ginkgo total flavones | 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 liposome model group | 0.17％ 50.3％ 52.7％ 58.3％ 61.8％ 52.1％ 46.2％ 62.9％ | -0.24％ 24.2％ 33.8％ 45.1％ 44.2％ 30.4％ 26.0％ 43.5％ |
By experimental result as can be known, Radix Astragali total saponins liposome, astragalus polysaccharides liposome, Folium Ginkgo total flavones liposome, the best compatibility scope of Folium Ginkgo total lactones liposome are Radix Astragali total saponins liposome, astragalus polysaccharides liposome 40～60% and Folium Ginkgo total flavones liposome, Folium Ginkgo total lactones liposome 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 Astragali total saponins, Radix Astragali Mongolici total polysaccharide or Folium Ginkgo total lactones, Folium Ginkgo total flavones solution, under the electromagnetic agitation, slowly splash into 1% Radix Astragali total saponins, Radix Astragali Mongolici total polysaccharide or Folium Ginkgo total lactones, Folium Ginkgo total flavones 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 Astragali total saponins, Radix Astragali Mongolici total polysaccharide or Folium Ginkgo total lactones, Folium Ginkgo total flavones 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 Astragali total saponins, Radix Astragali Mongolici total polysaccharide or Folium Ginkgo total lactones, Folium Ginkgo total flavones, 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 Astragali total saponins, Radix Astragali Mongolici total polysaccharide, Folium Ginkgo total lactones or Folium Ginkgo total flavones 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 5mL1% Radix Astragali total saponins, Radix Astragali Mongolici total polysaccharide, Folium Ginkgo total lactones or Folium Ginkgo total flavones solution and in bag filter, dialyse,, 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 Astragali total saponins (%) | 28.6 | 65.4 | 42.6 | 27.3 |
| Radix Astragali Mongolici total polysaccharide envelop rate (%) | 31.7 | 62.8 | 37.5 | 42.3 |
| Folium Ginkgo total lactones (%) | 24.6 | 63.1 | 38.7 | 30.3 |
| Folium Ginkgo total flavones envelop rate (%) | 46.1 | 66.2 | 27.0 | 25.9 |
The result: by experimental result as can be known, Radix Astragali total saponins, Radix Astragali Mongolici total polysaccharide liposome, Folium Ginkgo total lactones, Folium Ginkgo total flavones 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
Protective effect to Acute Myocardial Ischemia in Rats: get the SD rat; body constitution amount 230～250g; male and female half and half; be divided into model control group, Radix Astragali total saponins-Radix Astragali Mongolici total polysaccharide-Folium Ginkgo total lactones-Folium Ginkgo total flavones injection 0.3g/kg group, injection 0.3g/kg of the present invention group, oral liquid 0.3g/kg of the present invention group at random; every group 10; continuous 7 days, 1h ligation rat coronary artery left anterior descending branch after the last administration.Ventricle is got blood 3ml behind coronary ligation 3h, and centrifugal 5min prepares serum with the speed of 3000 * g, gets serum, measures corresponding index in the serum respectively with superoxide dismutase (SOD), malonaldehyde (MDA) test kit.Win rat heart and discharge hematocele in the chambers of the heart, inhale the branch that anhydrates, reject non-cardiac muscular tissues such as fatty blood vessel, wipe out atrium and right ventricle, stay left ventricle and weigh, calculate infarcted region (weight in wet base) and account for left ventricle (weight in wet base) percentage ratio with normal saline flushing and with filter paper.The results are shown in following table.
| Influence to SOD, MDA in myocardial infarct size and the serum behind the rat coronary ligation | |||
| Group | Heart infarction scope (%) | SOD(NU/ml) | MDA(nmol/ml) |
| Model group | 23.4±2.7 | 199.3±23.5 | 8.14±2.14 |
| Astragalus root total saponin-total polysaccharides of astragalus membranaceus-ginkgo biloba leaf total terpene lactone-ginkgo leaf total flavonoid parenteral solution 0.3g/kg group | 14.8±3.1 | 283.6±21.5 | 5.62±1.71 |
| Injection group of the present invention | 11.8±2.2 | 356.3±21.5 | 4.32±0.87 |
| Oral liquid group of the present invention | 13.9±1.8 | 318.5±27.1 | 4.98±1.47 |
By experimental result as can be known, pharmaceutical preparation of the present invention can obviously improve SOD activity in the coronary ligation rat blood serum, significantly suppressed the generation of MDA, obviously reduce myocardial infarction district area, and under the situation that reduces consumption greatly, curative effect still is better than Radix Astragali total saponins, Radix Astragali Mongolici total polysaccharide, Folium Ginkgo total lactones, Folium Ginkgo total flavones normal injection.
Concrete embodiment
Embodiments of the invention 1: Radix Astragali total saponins liposome 30g, astragalus polysaccharides liposome 30g, Folium Ginkgo total flavones liposome 20g, Folium Ginkgo total lactones liposome 20g
Get Radix Astragali total saponins liposome, astragalus polysaccharides liposome, Folium Ginkgo total flavones liposome, 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.
Embodiments of the invention 2: Radix Astragali total saponins liposome 20g, astragalus polysaccharides liposome 20g, Folium Ginkgo total flavones liposome 30g, Folium Ginkgo total lactones liposome 30g
Get Radix Astragali total saponins liposome, astragalus polysaccharides liposome, Folium Ginkgo total flavones liposome, 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.
Embodiments of the invention 3: Radix Astragali total saponins liposome 25g, astragalus polysaccharides liposome 25g Folium Ginkgo total flavones liposome 25g, Folium Ginkgo total lactones liposome 25g
Get Radix Astragali total saponins liposome, astragalus polysaccharides liposome, Folium Ginkgo total flavones liposome, the mixing of Folium Ginkgo total lactones liposome, the gained suspension is filled in the soft capsule, promptly get soft capsule.
Embodiments of the invention 4: Radix Astragali total saponins liposome 15g, astragalus polysaccharides liposome 25g Folium Ginkgo total flavones liposome 30g, Folium Ginkgo total lactones liposome 30g
Get Radix Astragali total saponins liposome, astragalus polysaccharides liposome, Folium Ginkgo total flavones liposome, the mixing of Folium Ginkgo total lactones liposome, the gained suspension is mixed with pregelatinized Starch, ethanol liquid with poly-second ketopyrrolidine is that binding agent is granulated, dry back granulate, with an amount of polyethylene glycol 6000 mix homogeneously, tabletting is tablet again.
Embodiments of the invention 5: Radix Astragali total saponins liposome 15g, astragalus polysaccharides liposome 35g, Folium Ginkgo total flavones liposome 25g, Folium Ginkgo total lactones liposome 25g
Get Radix Astragali total saponins liposome, astragalus polysaccharides liposome, Folium Ginkgo total flavones liposome, 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=3: 1, evenly mixed, make soft material in right amount with 70% 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.
Embodiments of the invention 6: Radix Astragali total saponins liposome 25g, astragalus polysaccharides liposome 35g, Folium Ginkgo total flavones liposome 15g, Folium Ginkgo total lactones liposome 25g
Get Radix Astragali total saponins liposome, astragalus polysaccharides liposome, Folium Ginkgo total flavones liposome, the mixing of Folium Ginkgo total lactones liposome, add 2.5 times of amount dextrin, 0.4% stevioside, 1.5% microcrystalline Cellulose with an amount of alcoholic solution system soft material, is granulated, 65 ℃ of forced air dryings, granulate, granulate promptly gets granule.
Embodiments of the invention 7: Radix Astragali total saponins liposome 20g, astragalus polysaccharides liposome 35g, Folium Ginkgo total flavones liposome 15g, Folium Ginkgo total lactones liposome 30g
Get Radix Astragali total saponins liposome, astragalus polysaccharides liposome, Folium Ginkgo total flavones liposome, Folium Ginkgo total lactones liposome,
Embodiments of the invention 8: Radix Astragali total saponins liposome 20g, astragalus polysaccharides liposome 25g Folium Ginkgo total flavones liposome 30g, Folium Ginkgo total lactones liposome 25g
Get Radix Astragali total saponins liposome, astragalus polysaccharides liposome, Folium Ginkgo total flavones liposome, Folium Ginkgo total lactones liposome, to be that 1.8: 1 sodium stearate is put in the rustless steel container with the principal agent ratio, mix homogeneously, be heated to 80-85 ℃, after treating whole fusions, 70-75 ℃ of insulation, mechanical high-speed are stirred 15min to evenly, are 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.
Embodiments of the invention 9: Radix Astragali total saponins liposome 5g, astragalus polysaccharides liposome 15g, Folium Ginkgo total flavones liposome 30g, Folium Ginkgo total lactones liposome 50g
With Radix Astragali total saponins liposome, astragalus polysaccharides liposome and Folium Ginkgo total flavones liposome, Folium Ginkgo total lactones liposome mix homogeneously, add 7% carboxymethyl starch sodium and 1.5% mannitol, compacting promptly gets oral cavity disintegration tablet in flakes.
Embodiments of the invention 10: Radix Astragali total saponins liposome 50g, astragalus polysaccharides liposome 30g, Folium Ginkgo total flavones liposome 10g, Folium Ginkgo total lactones liposome 10g
With the Radix Astragali total saponins liposome, astragalus polysaccharides liposome and Folium Ginkgo total flavones liposome, Folium Ginkgo total lactones liposome mix homogeneously, to be that 1: 1.5 stearic acid is put in the rustless steel container with the principal agent ratio, add extract, mix homogeneously, be heated to 80-85 ℃, treat whole fusions after, 70-75 ℃ of insulation, mechanical high-speed stirs 15min to even, be transferred in the reservoir, the dropping liquid valve is regulated in 70～75 ℃ of insulations, splash in 30～35 ℃ the vegetable oil, drip apart from 5～6cm, drip 40～45 droplets/minute of speed, to the greatest extent and wipe vegetable oil the drop pill drop that forms, packing promptly gets drop pill.
Embodiments of the invention 11: Radix Astragali total saponins liposome 44g, astragalus polysaccharides liposome 45g Folium Ginkgo total flavones liposome 0.5g, Folium Ginkgo total lactones liposome 0.5g
With Radix Astragali total saponins liposome, astragalus polysaccharides liposome and Folium Ginkgo total flavones liposome, Folium Ginkgo total lactones liposome mix homogeneously, in principal agent: the ratio of adjuvant=1.3: 1 adds calcium carbonate, in principal agent: the ratio of adjuvant=1.1: 1 adds pregelatinized starch, and press principal agent: the methylcellulose of adjuvant=4: 1, evenly mixed, make soft material in right amount with 70% 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.
Embodiments of the invention 12: Radix Astragali total saponins liposome 0.5g, astragalus polysaccharides liposome 0.5g, Folium Ginkgo total flavones liposome 44g, Folium Ginkgo total lactones liposome 45g
With Radix Astragali total saponins liposome, astragalus polysaccharides liposome and Folium Ginkgo total flavones liposome, Folium Ginkgo total lactones liposome mix homogeneously, add 2 times of amount sucrose, 0.6% lactose, 1.2% microcrystalline Cellulose with an amount of alcoholic solution system soft material, is granulated, 60 ℃ of forced air dryings, granulate, granulate promptly gets granule.
Embodiments of the invention 13: Radix Astragali total saponins liposome 15g, astragalus polysaccharides liposome 15g, Folium Ginkgo total flavones liposome 35g, Folium Ginkgo total lactones liposome 35g
With Radix Astragali total saponins liposome, astragalus polysaccharides liposome and Folium Ginkgo total flavones liposome, Folium Ginkgo total lactones liposome mix homogeneously, add the sucrose of equivalent, mix homogeneously is granulated, and is encapsulated, promptly gets capsule.
Embodiments of the invention 14: Radix Astragali total saponins liposome 35g, astragalus polysaccharides liposome 35g Folium Ginkgo total flavones liposome 15g, Folium Ginkgo total lactones liposome 15g
With Radix Astragali total saponins liposome, astragalus polysaccharides liposome and Folium Ginkgo total flavones liposome, Folium Ginkgo total lactones liposome mix homogeneously, add distilled water, filter repeatedly, till the filtrate clarification., filter with absorbent cotton after the stirring and dissolving in filtrate with sucrose, it is an amount of to add distilled water on filter, shakes up, and promptly gets syrup.
Embodiment 15: above Radix Astragali total saponins liposome, astragalus polysaccharides liposome and Folium Ginkgo total flavones liposome, 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 Astragali total saponins, Radix Astragali Mongolici total polysaccharide, Folium Ginkgo total lactones or Folium Ginkgo total flavones solution, under the electromagnetic agitation, slowly splash into 1% Radix Astragali total saponins, Radix Astragali Mongolici total polysaccharide, Folium Ginkgo total lactones or Folium Ginkgo total flavones 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 Astragali total saponins, Radix Astragali Mongolici total polysaccharide, Folium Ginkgo total lactones or Folium Ginkgo total flavones, 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 Astragali total saponins, Radix Astragali Mongolici total polysaccharide, Folium Ginkgo total lactones or Folium Ginkgo total flavones 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 Astragali total saponins, Radix Astragali Mongolici total polysaccharide, Folium Ginkgo total lactones or Folium Ginkgo total flavones, 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 Astragali total saponins, Radix Astragali Mongolici total polysaccharide, Folium Ginkgo total lactones or Folium Ginkgo total flavones 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 Astragali total saponins, Radix Astragali Mongolici total polysaccharide, Folium Ginkgo total lactones or Folium Ginkgo total flavones 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;
(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 Astragali total saponins, Radix Astragali Mongolici total polysaccharide, Folium Ginkgo total lactones or Folium Ginkgo total flavones 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 Astragali total saponins, Radix Astragali Mongolici total polysaccharide, Folium Ginkgo total lactones or Folium Ginkgo total flavones 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 Astragali total saponins, Radix Astragali Mongolici total polysaccharide, Folium Ginkgo total lactones or Folium Ginkgo total flavones pH value of solution 5-8, hatch for 65 ℃.Under 65 ℃ of incubation conditions, liposome turbid liquor is mixed with Radix Astragali total saponins, Radix Astragali Mongolici total polysaccharide, Folium Ginkgo total lactones or Folium Ginkgo total flavones 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 Astragali total saponins, Radix Astragali Mongolici total polysaccharide, Folium Ginkgo total lactones or Folium Ginkgo total flavones 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 Astragali total saponins, Radix Astragali Mongolici total polysaccharide, Folium Ginkgo total lactones or Folium Ginkgo total flavones 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 the non-encapsulated Radix Astragali total saponins of macroporous resin adsorption, Radix Astragali Mongolici total polysaccharide, Folium Ginkgo total lactones, silver or Folium Pruni total flavones, promptly get liposome;
(11) preparation liposome aerosols: 5ml Radix Astragali total saponins, Radix Astragali Mongolici total polysaccharide, Folium Ginkgo total lactones or Folium Ginkgo total flavones solution, the dichlorodifluoromethane of 280mg/ml lecithin ethanol liquid and 6.0g is mixed into organic facies, containing 7% ethanol 50ml water is water, each valve is emitted 50ul organic facies and water, promptly.
Embodiment 16: above Radix Astragali total saponins pro-liposome, Radix Astragali Mongolici total polysaccharide pro-liposome, Folium Ginkgo total lactones pro-liposome, Folium Ginkgo total flavones 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 Astragali total saponins, Radix Astragali Mongolici total polysaccharide, Folium Ginkgo total lactones or Folium Ginkgo total flavones 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;
(2) spray drying method: the Radix Astragali total saponins that will accurately take by weighing; Radix Astragali Mongolici total polysaccharide; Folium Ginkgo total lactones or Folium Ginkgo total flavones; 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 nitrogen current protection then; 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 Astragali total saponins; Radix Astragali Mongolici total polysaccharide; Folium Ginkgo total lactones or Folium Ginkgo total flavones liposome.Adopt spray dry, experiment condition is: 125 ℃ of inlet temperature, charging rate 60mL/min, cyclone separator pressure reduction 55mmH2O, 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, fling to rotary evaporator decompression add that Radix Astragali total saponins, the Radix Astragali are total after the chloroform film forming, sugar or Folium Ginkgo total lactones or Folium Ginkgo total flavones phosphate buffer.After soaking thin film.Ultrasonic under frequency 35kHz, prime time duty, promptly get Radix Astragali total saponins, Radix Astragali Mongolici total polysaccharide, Folium Ginkgo total lactones or Folium Ginkgo total flavones 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 17: Radix Astragali total saponins, astragalus polysaccharides and Folium Ginkgo total flavones, Folium Ginkgo total lactones can be commercially available, or prepare in order to the below method:
(1) gets the Radix Astragali, be ground into the coarse powder of 10 mesh sieves, add 5～15 times of volume 50～80% alcohol reflux 1～4 time, each 0.5～3.5 hour, merge extractive liquid,, measuring relative density when being concentrated into 60 ℃ is 1.05～1.15, add 1～4 times of saturated n-butyl alcohol of water gaging, shaking out 1～8 time merges n-butyl alcohol liquid, measuring relative density during decompression and solvent recovery to 60 ℃ is 1.05～1.15, dry Radix Astragali Mongolici total polysaccharide;
(2) get the Radix Astragali, be ground into the coarse powder of 10 mesh sieves, add 6～12 times of volume 50～80% alcohol reflux 1～4 time, merge extractive liquid,, filter, measuring relative density when filtrate is concentrated into 60 ℃ is 1.05～1.15, the water dissolution that adds 1～3 times of medical material bulking value, filter, filtrate is crossed the AB-8 macroporous adsorptive resins, with 3～6 times of resinite hydrops and 1～4 times of resin volume 15% alcohol flushing resin post, uses 40～70% alcohol desorptions then, collect the ethanolysis imbibition, reclaim ethanol and get Radix Astragali Mongolici total polysaccharide;
(3) get the Radix Astragali, be ground into the coarse powder of 10 mesh sieves, add 5～15 times of volume 50～80% alcohol reflux 1～4 time, each 0.5～3.5 hour, merge extractive liquid,, measuring relative density when being concentrated into 60 ℃ is 1.05～1.15, add 1～4 times of saturated n-butyl alcohol of water gaging, shaking out 1～8 time merges n-butyl alcohol liquid, measuring relative density during decompression and solvent recovery to 60 ℃ is 1.05～1.15, dry Radix Astragali total saponins;
(4) get the Radix Astragali, be ground into the coarse powder of 10 mesh sieves, add 6～12 times of volume 50～80% alcohol reflux 1～4 time, merge extractive liquid,, filter, measuring relative density when filtrate is concentrated into 60 ℃ is 1.05～1.15, the water dissolution that adds 1～3 times of medical material bulking value, filter, filtrate is crossed the AB-8 macroporous adsorptive resins, with 3～6 times of resinite hydrops and 1～4 times of resin volume 15% alcohol flushing resin post, uses 40～70% alcohol desorptions then, collect the ethanolysis imbibition, reclaim ethanol and get Radix Astragali total saponins;
(5) 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;
(6) Folium Ginkgo adds 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, Shen is taken off liquid recovery ethanol and is concentrated, vacuum drying gets Folium Ginkgo total lactones;
(7) 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 flavones;
(8) Folium Ginkgo adds 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 flavones.
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 Radix Astragali total saponins liposome or pro-liposome, astragalus polysaccharides liposome or pro-liposome 1～99% and Folium Ginkgo total flavones liposome or pro-liposome, 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 Radix Astragali total saponins liposome or pro-liposome, astragalus polysaccharides liposome or pro-liposome 20～80% and Folium Ginkgo total flavones liposome or pro-liposome, 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 Radix Astragali total saponins liposome or pro-liposome, astragalus polysaccharides liposome or pro-liposome 40～60% and Folium Ginkgo total flavones liposome or pro-liposome, 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: Radix Astragali total saponins liposome in the described prescription or pro-liposome, astragalus polysaccharides liposome or pro-liposome can be to make on the basis of the highly finished product of (+)-Astragenol extract, Radix Astragali water extract, Radix Astragali water extract-alcohol precipitation extract, Radix Astragali semi-bionic extraction thing, Radix Astragali supercritical extract or above each extract; Folium Ginkgo total flavones liposome or pro-liposome, 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 saponins is not less than 50% in the Radix Astragali total saponins liposome, the content of polysaccharide is not less than 50% in the astragalus polysaccharides liposome, content of total flavone is not less than 50% in the Folium Ginkgo total flavones liposome, the content of total lactone is not less than 50% in the Folium Ginkgo total lactones liposome, 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, Folium Ginkgo total flavones liposome and Radix Astragali total saponins liposome, Radix Astragali Mongolici total polysaccharide liposome 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 Folium Ginkgo total lactones or Folium Ginkgo total flavones is dissolved in the phosphate buffer of 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 Radix Astragali total saponins liposome and Radix Astragali Mongolici total polysaccharide liposome turbid liquor with legal system, mix the back with Folium Ginkgo total lactones liposome, Folium Ginkgo total flavones 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 Astragali total saponins, Radix Astragali Mongolici total polysaccharide or Folium Ginkgo total lactones, Folium Ginkgo total flavones 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, repeat once promptly to get Radix Astragali total saponins pro-liposome, Radix Astragali Mongolici total polysaccharide pro-liposome or Folium Ginkgo total lactones pro-liposome, Folium Ginkgo total flavones pro-liposome, Radix Astragali total saponins pro-liposome, Radix Astragali Mongolici total polysaccharide pro-liposome and Folium Ginkgo total lactones pro-liposome, Folium Ginkgo total flavones pro-liposome are mixed the back make 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 the Radix Astragali total saponins liposome, the Radix Astragali Mongolici total polysaccharide liposome, the Folium Ginkgo total lactones liposome, the Folium Ginkgo total flavones 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=3: 1, evenly mixed, make soft material in right amount with 70% ethanol, cross 20 mesh sieve system granules, 55 ℃ 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.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2010111807A1 (en) * | 2009-04-03 | 2010-10-07 | 武汉大安制药有限公司 | A polysaccharide liposome, the preparation method and use of it |
| CN102973508A (en) * | 2012-10-31 | 2013-03-20 | 河南牧翔动物药业有限公司 | Compound astragalus polysaccharide liposome long-acting injection and preparation method thereof |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2010111807A1 (en) * | 2009-04-03 | 2010-10-07 | 武汉大安制药有限公司 | A polysaccharide liposome, the preparation method and use of it |
| CN102973508A (en) * | 2012-10-31 | 2013-03-20 | 河南牧翔动物药业有限公司 | Compound astragalus polysaccharide liposome long-acting injection and preparation method thereof |
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