CN108434166A

CN108434166A - A kind of " Xuesaitong Injection " pharmaceutical composition and preparation method thereof, preparation and application

Info

Publication number: CN108434166A
Application number: CN201810227117.1A
Authority: CN
Inventors: 周荣光; 赵加强; 顾静波; 文冰亭; 郭泽剑
Original assignee: KPC Pharmaceuticals Inc
Current assignee: KPC Pharmaceuticals Inc
Priority date: 2018-03-20
Filing date: 2018-03-20
Publication date: 2018-08-24
Anticipated expiration: 2038-03-20
Also published as: CN108434166B

Abstract

The invention discloses a kind of " Xuesaitong Injection " pharmaceutical composition and preparation method thereof, preparation and applications.The " Xuesaitong Injection " pharmaceutical composition includes the drug component of following mass percent：Ginsenoside Rb2 0.001 ~ 99.996%, ginsenoside Rb1 0.001 ~ 99.996%, ginsenoside Rg1 0.001 ~ 99.996%, Ginsenoside Rc 0.001 ~ 99.996% and notoginsenoside R 0.001 ~ 99.996%.Pharmaceutical composition of the present invention and its preparation to ischemic angiocardiopathy and cerebrovascular diseases such as myocardial infarction, headstroke, cerebral infarction, brain hemiparalysis and due to ischemic angiocardiopathy and cerebrovascular disease, diabetes etc. caused by retinopathy or optic nerve injury disease have significant curative effect, have broad application prospects.Compared with the prior art and product, " Xuesaitong Injection " pharmaceutical composition and its preparation better efficacy of the present invention, safety higher can preferably meet the requirement of clinical application.Preparation method provided by the invention is simple for process, mild condition, easy to operation, stable and controllable for quality, is suitable for industrialization large-scale production.

Description

A kind of " Xuesaitong Injection " pharmaceutical composition and preparation method thereof, preparation and application

Technical field

The invention belongs to pharmaceutical technology fields, and in particular to a kind of " Xuesaitong Injection " pharmaceutical composition and preparation method thereof, preparation With application.

Background technology

Radix Notoginseng is the drying root and rhizome of Araliaceae Panax Notoginseng (Burk) F. H Chen, also known as Radix notoginseng, pseudo-ginseng are the rare Chinese medicines of Chinese traditional treatment cardiovascular and cerebrovascular disease, there is the effect of dissipate stasis of blood hemostasis, detumescence ding-tong.《Jade is seized Medicine solution》Record, Radix Notoginseng can " and battalion hemostasis, the row stasis of blood of promoting blood circulation, row hemostasis and hold back new blood.All postpartum, menstrual period, bruise, carbuncle swells, all Hemostasis is all broken；All hematemesiss, uterine bleeding, knife wound, arrow wound, all new blood all stop.”

Arasaponin (PNS) is a series of saponin(es extracted from Chinese medicine Radix Notoginseng and its general name of aglycon constituents, composition The more various complexity of ingredient, some ingredients have detached confirmation, but still have a large amount of non-principal components not yet to be made clear by the mankind.So far Until, people detach from PNS and identify a saponin monomer ingredient more than 100, such as ginsenoside Rb1, Rb2, Rb3, Rc, Rd, Re, Ro, Rh1, Rg1, Rg2, Rg3, Rg4, Rg5, notoginsenoside R, R2, R3, R4 etc..These saponin(es, according to its aglycon Difference is broadly divided into three alcohol type and diol type.Diol type (PDS) mainly has Panaxadiol Saponin Rb1, Rb2, Rc, Rd, Rh2 Deng three alcohol type (PTS) mainly have Panaxatriol saponin Re, Rg1, Rg2, Rh1, R1 etc..It has been reported that Radix Notoginseng in cultivation root Saponin content is from high to low Rg1 (43.36%), Rb1 (41.08%), R1 (3.65%), Re (3. 42%), Rh1 (0. 22%), His saponin(e 8.26%.Also literature research shows that PNS mainly contains ginsenoside Rb1's (about 30%), ginsenoside Rg1 (about 20%), notoginsenoside R (about 5 %) and ginsenoside Re's (about 2.5%).Also document is thought, Radix Notoginseng under ground portion is with triol soap Based on glycosides, the content with diol type is than about 3: 1, and aerial part is then on the contrary, based on diol type (PDS).

Presently commercially available " Xuesaitong Injection " product be it is a kind of with arasaponin (PNS) for medicine material, be aided with necessary medicinal Auxiliary material and manufactured Chinese medicine preparation.At present the " Xuesaitong Injection " product that has listed have freeze-dried, injection, capsule, soft capsule, tablet, The dosage forms such as dripping pill have promoting blood circulation, active effect of promoting blood circulation, the ischemia apoplexy being clinically used for caused by stagnation of blood stasis（Brain Infraction）Apoplex involving the channels and collaterals convalescence symptoms include hemiplegia, hemianesthesia, dispute are crooked, aphasia etc..However, coming in existing market Derived from arasaponin (PNS) raw material of different manufacturers, since the place of production of medicinal material Radix Notoginseng used in extraction arasaponin is different, uses Medicine position difference, collecting time and time limit difference and extracting method and process conditions difference, gained arasaponin (PNS) Chemical composition be not quite similar, even same producer production different batches arasaponin (PNS), chemical composition and The composition of arasaponin, content are also multifarious.Just because of the above reason, lead to the drug effect of commercially available " Xuesaitong Injection " product Ingredient and composition are not fixed, unintelligible, and the effective component of product and composition and ratio are multifarious between different manufacturers or different batches It causes, seriously affects the performance of product clinical efficacy, and cause a series of adverse reactions and safety issue, therefore, in a hurry Researcher is needed to be researched and solved.

Invention content

The first object of the present invention is to provide a kind of " Xuesaitong Injection " pharmaceutical composition；Second is designed to provide the blood Plug leads to the preparation method of pharmaceutical composition；Third is designed to provide the preparation of the " Xuesaitong Injection " pharmaceutical composition；4th mesh Be the soft capsule preparation of the " Xuesaitong Injection " pharmaceutical composition is provided；5th is designed to provide the " Xuesaitong Injection " drug The preparation method of the soft capsule preparation of composition；6th is designed to provide the " Xuesaitong Injection " pharmaceutical composition and/or its system The application of agent.

The first object of the present invention is achieved in that the " Xuesaitong Injection " pharmaceutical composition includes following mass percent Drug component：

Ginsenoside Rb2 0.001 ~ 99.996%

Ginsenoside Rb1 0.001 ~ 99.996%

Ginsenoside Rg1 0.001 ~ 99.996%

Ginsenoside Rc 0.001 ~ 99.996%

Notoginsenoside R 0.001 ~ 99.996%.

Preferably, which includes the monomer medicine component of following mass percent：

Ginsenoside Rb2 0.01 ~ 99.96%

Ginsenoside Rb1 0.01 ~ 99.96%

Ginsenoside Rg1 0.01 ~ 99.96%

Ginsenoside Rc 0.01 ~ 99.96%

Notoginsenoside R 0.01 ~ 99.96%

It is further preferable that the pharmaceutical composition includes the monomer medicine component of following mass percent：

54.6 % of ginsenoside Rb2

Ginsenoside Rb1 21.1%

Ginsenoside Rg1 11.3%

Ginsenoside Rc 8.5%

Notoginsenoside R 4.5%

Or：

20.5 % of ginsenoside Rb2

Ginsenoside Rb1 47.8%

Ginsenoside Rg1 23.4%

Ginsenoside Rc 6.7%

Notoginsenoside R 1.6%

Or：

1.2 % of ginsenoside Rb2

Ginsenoside Rb1 14.6%

Ginsenoside Rg1 55.7%

Ginsenoside Rc 19.3%

Notoginsenoside R 9.2%

Or：

21.1 % of ginsenoside Rb2

Ginsenoside Rb1 2.5%

Ginsenoside Rg1 28.2%

Ginsenoside Rc 37.6%

Notoginsenoside R 10.6%

Or：

20.9 % of ginsenoside Rb2

Ginsenoside Rb1 2.7%

Ginsenoside Rg1 21.5%

Ginsenoside Rc 10.2%

Notoginsenoside R 44.7%

In the present invention, ginsenoside Rb2 is monomeric compound, and chemical constitution sees below formulaIt is shown, English name Ginsenoside Rb2, the entitled 20- of English language Chemical ((6-O-alpha-L-Arabinopyranosyl-beta-D-glucopyranosyl) oxy)-12beta-hydroxydammar-24-en-3beta-yl 2-O-beta-D-glucopyranosyl-beta-D- Glucopyranoside, molecular formula C₅₃H₉₀O₂₂, molecular weight 1079.27；

Ginsenoside Rb1's chemical constitution sees below formulaShown, English name Ginsenoside Rb1, English language Chemical is entitled (3beta,12beta)-20-[(6-O-beta-D-Glucopyranosyl-beta-D-glucopyranosyl)oxy]-12- Hydroxydammar-24-en-3-yl2-O-beta-D-glucopyranosyl-beta-D-glucopyranoside, molecule Formula C54H92O23, molecular weight 1109.29；

Ginsenoside Rg1's chemical constitution sees below formulaIt is shown, English name Ginsenoside Rg1, alias notoginsenoside C1, English Literary alias Sanchinoside C1, molecular formula C₄₂H₇₂O₁₄, molecular weight 801.01；

Ginsenoside Rc, chemical constitution see below formulaIt is shown, English name Ginsenoside Rc, the entitled 20- of English language Chemical [(6-O-alpha-L-Arabinofuranosyl-beta-D-glucopyranosyl)oxy]-12b-hydroxydammar- 24-en-3b-yl 2-O-beta-D-glucopyranosyl-beta-D-glucopyranoside, molecular formula C₅₃H₉₀O22, Molecular weight 1079.27；

Sanchinoside R1, chemical constitution see below formulaShown, English name Notoginsenoside R1, English language Chemical is entitled glucopyranosyloxy)-3,12-dihydroxydammar-24-en-6-yl2-O-β-D-xylopyranosyl-;(3β, 6α,12β)-20-(β-D-Glucopyranosyloxy)-3,12-dihydroxydammar-24-en-6-yl 2-O-β-D- Xylopyranosyl- β-D-glucopyranoside, molecular formula C₄₇H₈₀O₁₈, molecular weight 933.131.

Above-mentioned ginsenoside Rb2, ginsenoside Rb1, ginsenoside Rg1, Ginsenoside Rc and notoginsenoside R compound, It can be by plant extraction process, such as from Radix Notoginseng, ginseng, American Ginseng, radix pseudostellariae, wilsonii, Sedum uizoon, chrysanthemum Radix Notoginseng, blood 37, height Beautiful ginseng etc. is extracted in plants isolated, can be also prepared by the methods of artificial fully synthetic, semi-synthetic or biosynthesis.Mesh Before, it can be bought directly from the market, purity is up to 98 % or more.

The present invention is control with commercially available arasaponin drug, using ICR mouse peritoneal drug administration by injection, has carried out the present invention The acute toxicity testing research of pharmaceutical composition intravenous injection administration, the results showed that：The pharmaceutical composition ICR mouse of the present invention are single The LD50 of secondary intravenous injection is 397mg/kg, is significantly higher than the LD50 value 306mg/kg of commercially available arasaponin, illustrates the present invention There is pharmaceutical composition high pharmaceutical safety, safety to be better than existing arasaponin drug.Refer to experimental example 4.

In addition, the present invention is also control with commercially available arasaponin drug, the blood vessel of pharmaceutical composition of the present invention has been carried out Irritation, hemolytic and anaphylaxis experimental study, the results showed that, pharmaceutical composition of the present invention without obvious irritation, hemolytic and The adverse reactions such as anaphylaxis, comply fully with pharmaceutical safety requirement, and every adverse reaction Safety Evaluation Index is superior to Radix Notoginseng Total saposins control drug.Refer to experimental example 5.

The second object of the present invention, which is achieved in that, to be included the following steps：

Step 1):Notoginsenoside R is weighed, is placed in alcohol solvent, stirring and dissolving obtains solution A；

Step 2):Ginsenoside Rb2, ginsenoside Rb1, ginsenoside Rg1 and Ginsenoside Rc are weighed, sets in distilled water and stirs Dissolving is mixed, is heated to 50-70 DEG C, solution A is added while stirring, needle-use activated carbon is added, heating is boiled 30-50 minutes, is stood It is cooled to room temperature, filtering abjection activated carbon；

Step 3):Above-mentioned filtrate, sets in vacuum freeze drier, and cooling down to -40 ~ -30 DEG C, then control by pre-freeze 3 ~ 5 hours Then -25 ~ -20 DEG C, 10 ~ 20Pa of pressure of temperature processed, lyophilization 3 ~ 5 hours control 30 ~ 50 DEG C, 1 ~ 10Pa of pressure of temperature again, Parsing-desiccation 4 ~ 6 hours to get.

Traditional pharmaceutical composition preparation method often takes the modes such as mechanical lapping, mixing to realize, there are it is various at It point is difficult to uniform mixing, the problems such as product quality lacks homogeneity.Especially raw material is in mixing, process of lapping, by mechanical shear The effect of shear force and impact force, raw material phase mutual friction generate hot-spot, cause raw material stability and pharmacological activity by one It is fixed to destroy.To overcome drawbacks described above, the present invention to prepare pharmaceutical composition by the way of solvent dissolving plus frozen drying, On the one hand it ensure that the mass uniformity of composition, on the other hand also fully ensured that the stability and pharmacological activity of drug ingedient It is not damaged.

The third object of the present invention is achieved in that the " Xuesaitong Injection " pharmaceutical preparation of the present invention is by the " Xuesaitong Injection " medicine Compositions with pharmaceutically auxiliary material, carrier, made by matrix, including injection, tablet, oral solution, capsule, soft capsule, drop Ball, sustained release preparation, controlled release preparation.

The " Xuesaitong Injection " pharmaceutical preparation of the present invention is by " Xuesaitong Injection " pharmaceutical composition of the present invention and auxiliary material pharmaceutically, load Made by body, matrix, administration route can be enteron aisle or non-bowel, such as oral, intravenous injection, intramuscular injection, hypodermic injection, nose Chamber, oral mucosa, eye, lung and respiratory tract, skin, vagina, rectum etc., dosage form can be tablet, capsule, soft capsule, granule, ball Agent, dripping pill, injection, freeze drying powder injection, oral solution, patch, paste, cataplasm or sustained release preparation, controlled release preparation etc..

The pharmaceutical dosage form of pharmaceutical composition of the present invention can be liquid dosage form, solid dosage forms or semisolid dosage form.Liquid agent Type can be solution (including true solution and colloidal solution), emulsion (including o/w types, w/o types and emulsion), suspension, injection Agent (including liquid drugs injection, powder-injection and infusion), eye drops, nasal drop, lotion, oral solution and liniment etc.；Solid dosage forms can be Tablet (including ordinary tablet, enteric coatel tablets, lozenge, dispersible tablet, chewable tablets, effervescent tablet, oral disnitegration tablet, sustained release tablets, controlled release tablet), glue Wafer (including hard capsule, soft capsule, capsulae enterosolubilis, spansule, controlled release capsule), granule, powder, pellet, dripping pill, bolt Agent, film, patch, the agent of gas (powder) mist, spray etc.；Semisolid dosage form can be ointment, gelling agent, paste etc..

Ordinary preparation can be made in pharmaceutical composition of the present invention, may be made as sustained release preparation, controlled release preparation, targeting preparation and Various particulate delivery systems.

In order to which tablet is made in pharmaceutical composition of the present invention, various excipient well known in the art can be widely used, wrap Include diluent, binder, wetting agent, disintegrant, lubricant, glidant.Diluent can be starch, dextrin, sucrose, grape Sugar, lactose, mannitol, sorbierite, xylitol, microcrystalline cellulose, calcium sulfate, calcium monohydrogen phosphate, calcium carbonate etc.；Wetting agent can be Water, ethyl alcohol, isopropanol etc.；Adhesive can be starch slurry, dextrin, syrup, honey, glucose solution, microcrystalline cellulose, I Primary rubber cement, gelatine size, sodium carboxymethylcellulose, methylcellulose, hydroxypropyl methyl cellulose, ethyl cellulose, acrylic acid tree Fat, carbomer, polyvinylpyrrolidone, polyethylene glycol etc.；Disintegrant can be dried starch, microcrystalline cellulose, low-substituted hydroxypropyl Base cellulose, crosslinked polyvinylpyrrolidone, croscarmellose sodium, sodium carboxymethyl starch, sodium bicarbonate and citric acid, Polyoxyethylene sorbitol aliphatic ester, dodecyl sodium sulfate etc.；Lubricant and glidant can be talcum powder, titanium dioxide Silicon, stearate, tartaric acid, atoleine, polyethylene glycol etc..Tablet can also be further made to coating tablet, such as sugar packet Garment piece, thin membrane coated tablet, enteric coated tablets or double-layer tablets and multilayer tablet.

In order to which capsule is made in pharmaceutical composition of the present invention, can by pharmaceutical composition of the present invention and diluent, help stream Agent mixes, and mixture is placed directly in hard capsule or soft capsule.It also can pharmaceutical composition of the present invention is first and diluent, bonding Particle or pellet is made in agent, disintegrant, then is placed in hard capsule or soft capsule.

For injection is made in pharmaceutical composition of the present invention, can use water, ethyl alcohol, isopropanol, propylene glycol, polyethylene glycol or Their mixture as solvent, and appropriate solubilizer commonly used in the art, cosolvent, pH adjusting agent, osmotic pressure regulator is added. Solubilizer or cosolvent can be ethyl alcohol, isopropanol, propylene glycol, polyethylene glycol, poloxamer, lecithin, hydroxy propyl-Beta-ring paste Essence etc.；PH adjustment agent can be citrate, phosphate, carbonate, acetate, hydrochloric acid, hydroxide etc.；Osmotic pressure regulator Can be sodium chloride, mannitol, glucose, phosphate, citrate, acetate etc..Freeze drying powder injection is such as prepared, can be also added Mannitol, glucose etc. are used as proppant.

In addition, if desired, colorant, preservative, fragrance, corrigent or other additions can also be added into pharmaceutical preparation Agent.

To reach medication purpose, enhance therapeutic effect, drug of the invention or pharmaceutical composition, pharmaceutical preparation can be with any Well known medication administration.

The dosage of pharmaceutical composition of the present invention is according to the property and severity to be prevented or be treated disease, patient Or the individual instances of animal, administration route and dosage form etc. can have large-scale variation.In general, pharmaceutical composition of the present invention Daily Suitable dosage ranges be 0.001 ~ 1000mg/Kg weight, preferably 0.01 ~ 500mg/Kg weight, more preferably 0.1 ~ 200mg/Kg weight.Above-mentioned dosage with a dosage unit or can be divided into several dosage unit administrations, this depends on facing for doctor Bed experience and include dosage regimen with other treatment means.

Pharmaceutical composition of the present invention can individually be taken, or merge use with other treatment drug or symptomatic drugs.When this hair When bright compound has synergistic effect with other medicines, its dosage should be adjusted according to actual conditions.

The fourth object of the present invention is achieved in that the soft capsule for removing thromboembolism preparation of the present invention is with the " Xuesaitong Injection " Active ingredient of the pharmaceutical composition as drug, and it is aided with auxiliary material and/or auxiliary agent is process.

In particular, the soft capsule for removing thromboembolism preparation of the present invention contains the effective ingredient of following mass percent：

Ginsenoside Rb2 0.001 ~ 99.996%

Ginsenoside Rb1 0.001 ~ 99.996%

Ginsenoside Rg1 0.001 ~ 99.996%

Ginsenoside Rc 0.001 ~ 99.996%

Notoginsenoside R 0.001 ~ 99.996%

Preferably, the soft capsule for removing thromboembolism preparation of the present invention contains the effective ingredient of following mass percent：

Ginsenoside Rb2 0.01 ~ 99.96%

Ginsenoside Rb1 0.01 ~ 99.96%

Ginsenoside Rg1 0.01 ~ 99.96%

Ginsenoside Rc 0.01 ~ 99.96%

Notoginsenoside R 0.01 ~ 99.96%

As still more preferably, soft capsule for removing thromboembolism preparation of the invention contain the drug of following mass percent effectively at Point：

54.6 % of ginsenoside Rb2

Ginsenoside Rb1 21.1%

Ginsenoside Rg1 11.3%

Ginsenoside Rc 8.5%

Notoginsenoside R 4.5%

Or

20.5 % of ginsenoside Rb2

Ginsenoside Rb1 47.8%

Ginsenoside Rg1 23.4%

Ginsenoside Rc 6.7%

Notoginsenoside R 1.6%

Or

1.2 % of ginsenoside Rb2

Ginsenoside Rb1 14.6%

Ginsenoside Rg1 55.7%

Ginsenoside Rc 19.3%

Notoginsenoside R 9.2%

Or

21.1 % of ginsenoside Rb2

Ginsenoside Rb1 2.5%

Ginsenoside Rg1 28.2%

Ginsenoside Rc 37.6%

Notoginsenoside R 10.6%

Or

20.9 % of ginsenoside Rb2

Ginsenoside Rb1 2.7%

Ginsenoside Rg1 21.5%

Ginsenoside Rc 10.2%

Notoginsenoside R 44.7%

The fifth object of the present invention be achieved in that weigh the " Xuesaitong Injection " pharmaceutical composition as drug it is effective at Point, be added in solvent, stir evenly, be placed in pellet press, and capsule skin pelleting, it is dry to get.

In above-mentioned soft capsule for removing thromboembolism preparation method, the solvent is water, ethyl alcohol, ethylene glycol, propylene glycol, glycerine, spits Temperature, sesame oil, peanut oil, ginger oil, Zanthoxylum essential oil, attar of rose, linseed oil, rapeseed oil, perilla herb oil, peony seed oil, spade oil, sunflower It is more than any one of oil, palchouli oil, fiery sesame oil, lard, butter, sheep oil, fish oil, shark oil, snake oil etc. or any two With the mixture of arbitrary proportion.

In above-mentioned soft capsule for removing thromboembolism preparation method, the capsule skin by colloid and solvent, blender through thermosol, modulation, Plastic cement, steady glue and be made.The colloid for preparing capsule skin is selected from animal glue such as gelatin, animal glue, dogskin glue, pig skin gelatin, also optional From natural plant gum such as carragheen, guar gum, algin, locust bean gum, konjac glucomannan, xanthans etc..The solvent for preparing capsule skin is Any one in water, ethyl alcohol, propyl alcohol, ethylene glycol, isopropyl triol, positive glycerine, isobutanol, the tert-butyl alcohol, n-butanol, polyethylene glycol More than kind or any two with the mixture of arbitrary proportion.The blender for preparing capsule skin includes toner such as lutein, kermes Red, amaranth, olive green etc. also include regulating acid agent such as citric acid, sodium citrate, carbonic acid, sodium carbonate, sodium bicarbonate, phosphoric acid, phosphorus Sour trisodium, disodium hydrogen phosphate, monosodium phosphate, malic acid, natrium malicum, lactic acid, sodium lactate also include adjusting soft dose such as cellulose, first Base cellulose, carboxymethyl cellulose, hydroxymethyl cellulose, beeswax, paraffin, stearic acid, single hard fatty acids glyceride etc..

The sixth object of the present invention is achieved in that prepared by the " Xuesaitong Injection " pharmaceutical composition and/or its preparation Prevent and/or treat the application in cardiovascular and cerebrovascular diseases medicament.

The " Xuesaitong Injection " pharmaceutical composition and/or its preparation is preparing prevention and/or treatment ischemic angiocardiopathy and cerebrovascular disease Application in medicine.

The " Xuesaitong Injection " pharmaceutical composition and/or its preparation is preparing prevention and/or treatment ischemia apoplexy, cerebral infarction Application in plug, brain hemiparalysis disease medicament.

The " Xuesaitong Injection " pharmaceutical composition and/or its preparation is in preparing prevention and/or treatment retinopathy drug Application.

The " Xuesaitong Injection " pharmaceutical composition and/or its preparation is prevented preparing and/or is treated because of optic atrophy, view Asthenopia caused by membranochromic pigments denaturation or macula retinae or the application in visual impairment drug.

The " Xuesaitong Injection " pharmaceutical composition and/or its preparation is preparing prevention and/or is treating because of diabetes, cardiovascular disease Application in retinopathy drug caused by disease, cranial vascular disease, neurogenic disease.

The present invention is control with drugs such as commercially available arasaponins, using SD myocardial ischemia in rats animal models, is carried out Protective effect experimental study of the pharmaceutical composition of the present invention to SD myocardial ischemia in rats, the results showed that：The pharmaceutical composition of the present invention Object can substantially reduce the myocardial infarction area of rats with myocardial ischemia, have significant protective effect to myocardial ischemia；It can significantly improve The heart work(index of rats with myocardial ischemia, is significantly improved the cardiac dysfunction caused by treating myocardial ischemia damage；It can significantly drop Serum LDH after low rat coronary ligation, CK, GOT and the active raisings of HBDH, show it to caused by following coronary artery occlusion Myocardial ischemia has protective effect.Experiment is also shown that the above-mentioned protective effect effect to myocardial ischemia of pharmaceutical composition of the present invention It is superior to the control drugs such as the commercially available arasaponin of same dosage.Above studies have shown that pharmaceutical composition of the present invention can be used for The prevention or treatment of ischemic angiocardiopathy and cerebrovascular disease, curative effect are better than existing arasaponin drug.Refer to experimental example 1.

The present invention is also control with drugs such as commercially available arasaponins, using SD cerebral ischemia/reperfusion injury of rats animal moulds Type has carried out protective effect experimental study of the pharmaceutical composition of the present invention to SD cerebral ischemia/reperfusion injury of rats, the results showed that： The pharmaceutical composition of the present invention can significantly improve the nervous symptoms of ischemia-reperfusion rat, caused by ischemia-reperfusion apoplexy, Hemiplegia symptom has obvious therapeutic action；The cerebral infarction volume of ischemia-reperfusion rat can be significantly reduced；Ischemic can be significantly reduced again The Evans blue content of rat brain is perfused, the pharmaceutical composition of the present invention is prompted to have the blood-brain barrier of ischemia-reperfusion rat There is protective effect.Experiment is also shown that the above-mentioned to cerebral ischemia re-pouring injured protective effect effect of pharmaceutical composition of the present invention It is superior to the control drugs such as the commercially available arasaponin of same dosage.Above studies have shown that pharmaceutical composition of the present invention can be used for The prevention or treatment of the ischemic cerebrovascular disease such as ischemia apoplexy, cerebral infarction, brain hemiparalysis, curative effect are better than existing Radix Notoginseng Total saposins drug.Refer to experimental example 2.

Secondly, the present invention also provides the pharmaceutical compositions to be used to prepare prevention or treatment retinopathy or regard refreshing grade Application in the drug of damage, in particular, being that it prevents preparing or treats because of optic atrophy, retinal pigment degeneration or view Application in the drug of asthenopia or visual impairment caused by film macula lutea and its prevent preparing or treat because of diabetes, the heart Application in the drug of retinopathy caused by vascular diseases, cranial vascular disease, neurogenic disease.

The present invention is control with drugs such as commercially available arasaponins, is damaged using SD rat continuous intraocular hypertension retina neurals Hinder animal model, carried out protective effect experimental study of the pharmaceutical composition of the present invention to SD rat retina neurotrosises, ties Fruit shows：The pharmaceutical composition of the present invention can significantly reduce damage of the durative intraocular hypertension to retina neural, be damaged to neuron Wound has good protection and repair.This experiment is it is also shown that the protection to optic nerve injury of pharmaceutical composition of the present invention is made It is better than with control drugs such as the commercially available arasaponins of dosage with effect.Therefore, pharmaceutical composition of the present invention can be used as retina Or the medicine that optic nerve venereal disease becomes.Refer to experimental example 3.

Compared with the arasaponin drug of the prior art, " Xuesaitong Injection " pharmaceutical composition provided by the invention has with preparation Following significant advantage and feature：

1, pharmaceutical component is clear, clear, and ingredient is fixed, and product quality is uniform, stably and controllable.

2, poisonous and harmful non-pharmacological ingredient or non-principal component are free of, toxic side effect and adverse reaction are low, have higher use Medicine security performance；

3, pharmacological action is clear, clinical efficacy higher.

The arasaponin of the prior art, containing more than 100 kinds of saponin constituent and many non-principal components, component is complicated and changeable, Quality is difficult to control, and especially perhaps multi-component mechanism of action, pharmacological action and interaction to each other and influences so far still Indefinite, adverse reaction takes place frequently, this brings problems to the safety of clinical application and validity.With the prior art and production Condition ratio, " Xuesaitong Injection " pharmaceutical composition of the invention and its preparation curative effect higher, and ingredient is clear, fixed, product quality Uniform, stable, toxic side effect and adverse reaction are low, substantially increase safety and validity that drug uses.

Specific implementation mode

With reference to embodiment, the present invention is further illustrated, but is not limited in any way to the present invention, Based on present invention teach that made by it is any transform or replace, all belong to the scope of protection of the present invention.

" Xuesaitong Injection " pharmaceutical composition of the present invention includes the drug component of following mass percent：

Ginsenoside Rb2 0.001 ~ 99.996%

Ginsenoside Rb1 0.001 ~ 99.996%

Ginsenoside Rg1 0.001 ~ 99.996%

Ginsenoside Rc 0.001 ~ 99.996%

Notoginsenoside R 0.001 ~ 99.996%.

The " Xuesaitong Injection " pharmaceutical composition includes the drug component of following mass percent：

Ginsenoside Rb2 0.01 ~ 99.96%

Ginsenoside Rb1 0.01 ~ 99.96%

Ginsenoside Rg1 0.01 ~ 99.96%

Ginsenoside Rc 0.01 ~ 99.96%

Notoginsenoside R 0.01 ~ 99.96%.

54.6 % of ginsenoside Rb2

Ginsenoside Rb1 21.1%

Ginsenoside Rg1 11.3%

Ginsenoside Rc 8.5%

Notoginsenoside R 4.5%.

20.5 % of ginsenoside Rb2

Ginsenoside Rb1 47.8%

Ginsenoside Rg1 23.4%

Ginsenoside Rc 6.7%

Notoginsenoside R 1.6%.

1.2 % of ginsenoside Rb2

Ginsenoside Rb1 14.6%

Ginsenoside Rg1 55.7%

Ginsenoside Rc 19.3%

Notoginsenoside R 9.2%.

21.1 % of ginsenoside Rb2

Ginsenoside Rb1 2.5%

Ginsenoside Rg1 28.2%

Ginsenoside Rc 37.6%

Notoginsenoside R 10.6%.

20.9 % of ginsenoside Rb2

Ginsenoside Rb1 2.7%

Ginsenoside Rg1 21.5%

Ginsenoside Rc 10.2%

Notoginsenoside R 44.7%.

The preparation method of " Xuesaitong Injection " pharmaceutical composition of the present invention, includes the following steps：

Step 1）The mass ratio of middle notoginsenoside R and alcohol solvent is 0.05 ~ 5:100, the concentration expressed in percentage by volume of ethyl alcohol is 50~100%。

Step 2）In the mass ratio of four kinds of ginsenosides and needle-use activated carbon, distilled water be 0.1 ~ 10:0.01~0.5：100.

Step 3）Middle pre-freeze rate of temperature fall is 5 ~ 15 DEG C/h.

" Xuesaitong Injection " pharmaceutical preparation of the present invention is auxiliary with pharmaceutically by the " Xuesaitong Injection " pharmaceutical composition Material, carrier, made by matrix, including injection, tablet, oral solution, capsule, soft capsule, dripping pill, sustained release preparation, controlled release preparation.

Soft capsule for removing thromboembolism preparation of the present invention is using the " Xuesaitong Injection " pharmaceutical composition as the effective of drug Ingredient, and it is aided with auxiliary material and/or auxiliary agent is process.

The soft capsule for removing thromboembolism preparation contains the effective ingredient of following mass percent：

Ginsenoside Rb2 0.001 ~ 99.996%

Ginsenoside Rb1 0.001 ~ 99.996%

Ginsenoside Rg1 0.001 ~ 99.996%

Ginsenoside Rc 0.001 ~ 99.996%

Notoginsenoside R 0.001 ~ 99.996%.

Ginsenoside Rb2 0.01 ~ 99.96%

Ginsenoside Rb1 0.01 ~ 99.96%

Ginsenoside Rg1 0.01 ~ 99.96%

Ginsenoside Rc 0.01 ~ 99.96%

Notoginsenoside R 0.01 ~ 99.96%.

54.6 % of ginsenoside Rb2

Ginsenoside Rb1 21.1%

Ginsenoside Rg1 11.3%

Ginsenoside Rc 8.5%

Notoginsenoside R 4.5%.

20.5 % of ginsenoside Rb2

Ginsenoside Rb1 47.8%

Ginsenoside Rg1 23.4%

Ginsenoside Rc 6.7%

Notoginsenoside R 1.6%.

1.2 % of ginsenoside Rb2

Ginsenoside Rb1 14.6%

Ginsenoside Rg1 55.7%

Ginsenoside Rc 19.3%

Notoginsenoside R 9.2%.

21.1 % of ginsenoside Rb2

Ginsenoside Rb1 2.5%

Ginsenoside Rg1 28.2%

Ginsenoside Rc 37.6%

Notoginsenoside R 10.6%.

20.9 % of ginsenoside Rb2

Ginsenoside Rb1 2.7%

Ginsenoside Rg1 21.5%

Ginsenoside Rc 10.2%

Notoginsenoside R 44.7%.

The preparation method of soft capsule for removing thromboembolism preparation of the present invention is to weigh the " Xuesaitong Injection " pharmaceutical composition to make For the active ingredient of drug, be added in solvent, stir evenly, be placed in pellet press, and capsule skin pelleting, it is dry to get.

The solvent is water, ethyl alcohol, ethylene glycol, propylene glycol, glycerine, tween, peanut oil, ginger oil, Zanthoxylum essential oil, rose Appointing in oil, rapeseed oil, peony seed oil, spade oil, sunflower oil, palchouli oil, lard, butter, sheep oil, fish oil, shark oil, snake oil More than a kind of what or any two with the mixture of arbitrary proportion.

The capsule skin by colloid and solvent, blender through thermosol, modulation, plastic cement, steady glue and be made.

The colloid for preparing capsule skin is selected from animal glue or natural plant gum.

The animal glue includes gelatin, animal glue, dogskin glue or pig skin gelatin.

The natural plant gum includes carragheen, guar gum, algin, locust bean gum, konjac glucomannan, xanthans.

The solvent for preparing capsule skin is water, ethyl alcohol, propyl alcohol, ethylene glycol, isopropyl triol, positive glycerine, isobutanol, tertiary fourth More than any one of alcohol, n-butanol, polyethylene glycol or any two with the mixture of arbitrary proportion.

The blender for preparing capsule skin includes toner and regulating acid agent.

The toner includes carmine, amaranth or olive green.

The regulating acid agent includes citric acid, sodium citrate, carbonic acid, sodium carbonate, sodium bicarbonate, phosphoric acid, tertiary sodium phosphate, phosphorus Acid disodium, monosodium phosphate, malic acid, natrium malicum, lactic acid or sodium lactate.

The blender for preparing capsule skin further includes adjusting soft dose.

Soft dose of the tune includes cellulose, methylcellulose, carboxymethyl cellulose, hydroxymethyl cellulose, beeswax, stone Wax, stearic acid or single hard fatty acids glyceride.

The application of " Xuesaitong Injection " pharmaceutical composition of the present invention and/or its preparation is the " Xuesaitong Injection " pharmaceutical composition And/or its preparation is preparing the application in preventing and/or treating cardiovascular and cerebrovascular diseases medicament.

With reference to specific implementation case, the present invention will be further described：

The preparation of 1 1# pharmaceutical compositions of embodiment

Raw material forms：

54.6 g of ginsenoside Rb2

21.1 g of ginsenoside Rb1

11.3 g of ginsenoside Rg1

8.5 g of Ginsenoside Rc

Notoginsenoside R 4.5g

Total 100g

Preparation method：

1）4.5 g of notoginsenoside R is weighed, is placed in the alcohol solvent that 100 g concentration expressed in percentage by volumes are 50%, stirring and dissolving obtains Solution A；

2）Weigh 54.6 g of ginsenoside Rb2,21.1 g of ginsenoside Rb1,11.3 g of ginsenoside Rg1 and ginsenoside 8.5 g of Rc set stirring and dissolving in 900 g of distilled water, are heated to 50-70 DEG C, and solution A is added while stirring, and needle activity is added Charcoal 2.0g, heating are boiled 30-50 minutes, and standing is cooled to room temperature, filtering abjection activated carbon；

3）Above-mentioned filtrate, sets in vacuum freeze drier, with the rate of temperature fall cooling down of 5 DEG C/h to -40 ~ -30 DEG C, pre-freeze 3 ~ 5 hours, temperature -25 ~ -20 DEG C, 10 ~ 20Pa of pressure are then controlled, then lyophilization 3 ~ 5 hours controls temperature 30 ~ 50 again DEG C, 1 ~ 10Pa of pressure, parsing-desiccation 4 ~ 6 hours, restore to atmospheric pressure at room to get.

The preparation of 2 2# pharmaceutical compositions of embodiment

Raw material forms：

20.5 g of ginsenoside Rb2

47.8 g of ginsenoside Rb1

23.4 g of ginsenoside Rg1

6.7 g of Ginsenoside Rc

1.6 g of notoginsenoside R

Total 100g

Preparation method：

1）1.6 g of notoginsenoside R is weighed, is placed in the alcohol solvent that 100 g concentration expressed in percentage by volumes are 80%, stirring and dissolving obtains Solution A；

2）Weigh 20.5 g of ginsenoside Rb2,47.8 g of ginsenoside Rb1,23.4 g of ginsenoside Rg1 and ginsenoside 6.7 g of Rc set stirring and dissolving in 950 g of distilled water, are heated to 50-70 DEG C, and solution A is added while stirring, and needle activity is added Charcoal 1.0g, heating are boiled 30-50 minutes, and standing is cooled to room temperature, filtering abjection activated carbon；

3）Above-mentioned filtrate, sets in vacuum freeze drier, with extremely -40 ~ -30 DEG C of the rate of temperature fall cooling down of 15 DEG C/h, pre-freeze 3 ~ 5 hours, temperature -25 ~ -20 DEG C, 10 ~ 20Pa of pressure are then controlled, then lyophilization 3 ~ 5 hours controls temperature 30 ~ 50 again DEG C, 1 ~ 10Pa of pressure, parsing-desiccation 4 ~ 6 hours, restore to atmospheric pressure at room to get.

The preparation of 3 3# pharmaceutical compositions of embodiment

Raw material forms：

1.2 g of ginsenoside Rb2

14.6 g of ginsenoside Rb1

55.7 g of ginsenoside Rg1

19.3 g of Ginsenoside Rc

9.2 g of notoginsenoside R

Total 100g

Preparation method：

1）9.2 g of notoginsenoside R is weighed, is placed in the alcohol solvent that 500 g concentration expressed in percentage by volumes are 100%, stirring and dissolving, Obtain solution A；

2）Weigh 1.2 g of ginsenoside Rb2,14.6 g of ginsenoside Rb1,55.7 g of ginsenoside Rg1 and Ginsenoside Rc 19.3 g set stirring and dissolving in 1000 g of distilled water, are heated to 50-70 DEG C, and solution A is added while stirring, and needle activity is added Charcoal 3.0g, heating are boiled 30-50 minutes, and standing is cooled to room temperature, filtering abjection activated carbon；

3）Above-mentioned filtrate, sets in vacuum freeze drier, with extremely -40 ~ -30 DEG C of the rate of temperature fall cooling down of 10 DEG C/h, pre-freeze 3 ~ 5 hours, temperature -25 ~ -20 DEG C, 10 ~ 20Pa of pressure are then controlled, then lyophilization 3 ~ 5 hours controls temperature 30 ~ 50 again DEG C, 1 ~ 10Pa of pressure, parsing-desiccation 4 ~ 6 hours, restore to atmospheric pressure at room to get.

The preparation of 4 4# pharmaceutical compositions of embodiment

Raw material forms：

21.1 g of ginsenoside Rb2

Ginsenoside Rb1 2.5g

Ginsenoside Rg1 28.2g

Ginsenoside Rc 37.6g

Notoginsenoside R 10.6g

Total 100g

Preparation method：

1）Notoginsenoside R 10.6g is weighed, is placed in the alcohol solvent that 1500 g concentration expressed in percentage by volumes are 60%, stirring and dissolving, Obtain solution A；

2）Weigh 21.1 g of ginsenoside Rb2, ginsenoside Rb1 2.5g, ginsenoside Rg1 28.2g and Ginsenoside Rc 37.6g sets stirring and dissolving in 5000 g of distilled water, is heated to 50-70 DEG C, and solution A is added while stirring, and needle-use activated carbon is added 8.0g, heating are boiled 30-50 minutes, and standing is cooled to room temperature, filtering abjection activated carbon；

3）Above-mentioned filtrate, sets in vacuum freeze drier, with extremely -40 ~ -30 DEG C of the rate of temperature fall cooling down of 12 DEG C/h, pre-freeze 3 ~ 5 hours, temperature -25 ~ -20 DEG C, 10 ~ 20Pa of pressure are then controlled, then lyophilization 3 ~ 5 hours controls temperature 30 ~ 50 again DEG C, 1 ~ 10Pa of pressure, parsing-desiccation 4 ~ 6 hours, restore to atmospheric pressure at room to get.

The preparation of 5 5# pharmaceutical compositions of embodiment

Raw material forms：

20.9 g of ginsenoside Rb2

Ginsenoside Rb1 2.7g

Ginsenoside Rg1 21.5g

Ginsenoside Rc 10.2g

Notoginsenoside R 44.7g

Total 100g

Preparation method：

1）Notoginsenoside R 44.7g is weighed, is placed in the alcohol solvent that 4500 g concentration expressed in percentage by volumes are 90%, stirring and dissolving, Obtain solution A；

2）Weigh 20.9 g of ginsenoside Rb2, ginsenoside Rb1 2.7g, ginsenoside Rg1 21.5g and Ginsenoside Rc 10.2g sets stirring and dissolving in 3000 g of distilled water, is heated to 50-70 DEG C, and solution A is added while stirring, and needle-use activated carbon is added 1.0g, heating are boiled 30-50 minutes, and standing is cooled to room temperature, filtering abjection activated carbon；

The preparation of 6 1# control samples of embodiment

Raw material forms：

Ginsenoside Rb1 50g

Ginsenoside Rg1 50g

Total 100g

Preparation method：

Weigh ginsenoside Rb1 50g, ginsenoside Rg1 50g is placed in the alcohol solvent that 1000 g concentration expressed in percentage by volumes are 75% In, needle-use activated carbon 1.5g is added in stirring and dissolving, and heating is boiled 30-50 minutes, and standing is cooled to room temperature, filtering abjection activity Charcoal, filtrate are set in vacuum freeze drier, with the rate of temperature fall cooling down of 15 DEG C/h to -40 ~ -30 DEG C, pre-freeze 3 ~ 5 hours, Then temperature -25 ~ -20 DEG C, 10 ~ 20Pa of pressure are controlled, then lyophilization 3 ~ 5 hours controls 30 ~ 50 DEG C of temperature, pressure 1 again ~ 10Pa, parsing-desiccation 4 ~ 6 hours, restore to atmospheric pressure at room to get.

The preparation of 7 2# control samples of embodiment

Raw material forms：

Notoginsenoside R 30g

Ginsenoside Rb1 35g

Ginsenoside Rg1 35g

Total 100g

Preparation method：

It weighs notoginsenoside R 30g, ginsenoside Rb1 35g, ginsenoside Rg1 35g and is placed in 1000 g concentration expressed in percentage by volumes For in 75% alcohol solvent, needle-use activated carbon 1.5g is added in stirring and dissolving, and heating is boiled 30-50 minutes, and standing is cooled to room Temperature, filtering abjection activated carbon, filtrate is set in vacuum freeze drier, with the rate of temperature fall cooling down of 15 DEG C/h to -40 ~ -30 DEG C, then pre-freeze 3 ~ 5 hours controls temperature -25 ~ -20 DEG C, 10 ~ 20Pa of pressure, then lyophilization 3 ~ 5 hours controls temperature again Degree 30 ~ 50 DEG C, 1 ~ 10Pa of pressure, parsing-desiccation 4 ~ 6 hours, restore to atmospheric pressure at room to get.

The preparation of 8 3# control samples of embodiment

Raw material forms：

25 g of ginsenoside Rb2

Notoginsenoside R 25g

Ginsenoside Rb1 25g

Ginsenoside Rg1 25g

Total 100g

Preparation method：

25 g of ginsenoside Rb2, notoginsenoside R 25g, ginsenoside Rb1 25g, ginsenoside Rg1 25g is weighed to be placed in In the alcohol solvent that 1000 g concentration expressed in percentage by volumes are 75%, needle-use activated carbon 1.5g is added in stirring and dissolving, and 30-50 is boiled in heating Minute, standing is cooled to room temperature, and filtering abjection activated carbon, filtrate is set in vacuum freeze drier, with the rate of temperature fall of 15 DEG C/h For cooling down to -40 ~ -30 DEG C, then pre-freeze 3 ~ 5 hours controls temperature -25 ~ -20 DEG C, 10 ~ 20Pa of pressure, lyophilization 3 ~ 5 Hour, then control 30 ~ 50 DEG C, 1 ~ 10Pa of pressure of temperature again, parsing-desiccation 4 ~ 6 hours, restore to atmospheric pressure at room to get.

9 tablet of embodiment

Drug prescription (mass percent)：

The 1# pharmaceutical compositions 15.0% of the embodiment of the present invention 1

Starch 62.5%

Microcrystalline cellulose 13.2%

9.3 % of sodium carboxymethyl starch

Total 100%

It is matched by above-mentioned prescription, by the 1# pharmaceutical compositions of the embodiment of the present invention 1 and starch, microcrystalline cellulose, carboxymethyl starch Sodium mixing after in tabletting on tablet press machine to get.

10 capsule of embodiment

Drug prescription (mass percent)：

The 2# pharmaceutical compositions 10.0% of the embodiment of the present invention 2

Starch 69.0%

Microcrystalline cellulose 12.5%

Magnesium stearate 3.2%

Sodium carboxymethyl starch 5.3%

Total 100%

It is matched by above-mentioned prescription, by the 2# pharmaceutical compositions of the embodiment of the present invention 2 and starch, microcrystalline cellulose, carboxymethyl starch Sodium, magnesium stearate mixing after be packed into hard gelatin capsule to get.

11 liquid oral of embodiment

Drug prescription (mass percent)：

The 3# pharmaceutical compositions 5.2% of the embodiment of the present invention 3

Sucrose 12.3%

Ethyl alcohol 0.5%

Distilled water 82.0%

Total 100%

It is matched by above-mentioned prescription, after the 3# pharmaceutical compositions of the embodiment of the present invention 3 and sucrose, ethyl alcohol, distilled water mixed dissolution, Filtering, by 10mL/ branch embeddings in oral solution, 100 DEG C of moist heat sterilization 30min to get.

12 injection of embodiment

Drug prescription：

The 4# pharmaceutical compositions 55g of the embodiment of the present invention 4

Sodium chloride 90g

Appropriate water for injection

1000ml is made

It is matched by above-mentioned prescription, by the 4# pharmaceutical compositions of the embodiment of the present invention 4, adds sodium chloride and appropriate water for injection, stirred Uniformly, 0.1% needle activated carbon is added, decarburization is filtered in absorption, and benefit injects water to specified amount, and micro porous filtration membrane filtration is pressed 5mL/ branch embeddings, 100 DEG C of moist heat sterilization 30min, through lamp inspection qualification to get.

13 freeze drying powder injection of embodiment

Drug prescription：

The 5# pharmaceutical compositions 100g of the embodiment of the present invention 5

Sodium chloride 90g

Mannitol 75g

Appropriate water for injection

1000ml is made

It is matched by above-mentioned prescription, the 5# pharmaceutical compositions of the embodiment of the present invention 5 is added into sodium chloride, mannitol and appropriate injection Water stirs evenly, and 0.1% needle activated carbon is added, and decarburization is filtered in absorption, and benefit injects water to specified amount, micropore filtering film Filtering, by 2mL/ branch dispense, be freeze-dried, encapsulation, through examine qualification to get.

The preparation of 14 1# soft capsule for removing thromboembolism of embodiment

Drug prescription：

The 1# pharmaceutical compositions 100g of the embodiment of the present invention 1

250 g of 1# solvents

100 g of 1# capsules skin

1000 soft capsules are made altogether

Preparation method：

The 1# pharmaceutical composition 100g of the embodiment of the present invention 1 are weighed, 1# solvent 250g are added, stirs evenly, is placed in pellet press, With 1# capsule skin pelletings, the dry soft capsule for removing thromboembolism to get every 100mg containing active ingredient.

1# solvent prescriptions（Mass percent）

Positive glycerine 48.5%

Ethyl alcohol 20.0%

Water 25.8%

Attar of rose 0.1%

Spade oil 5.6%

Total 100%

1# solvent preparations：

By above-mentioned prescription match, weigh positive glycerine, ethyl alcohol, water, attar of rose, spade oil, mixing, stir evenly to get.

1# capsule skin prescriptions（Mass percent）：

Gelatin 18.2%

Water 75.9%

Citric acid 0. 2%

Single hard fatty acids glyceride 0.5%

Carboxymethyl cellulose 5.2%

Total 100%

1# capsule peel preparation methods：It is matched by above-mentioned prescription, weighs gelatin, be added to the water, dissolved in 60-80 DEG C of heating stirring, Then sequentially add carboxymethyl cellulose, single hard fatty acids glyceride and citric acid be modulated, plastic cement, in 30-40 DEG C of steady glue 24 hours to obtain the final product.

The preparation of 15 2# soft capsule for removing thromboembolism of embodiment

Drug prescription：

The 2# pharmaceutical compositions 120g of the embodiment of the present invention 2

2# solvents 350g

2# capsule skins 150g

2000 soft capsules are made altogether

Preparation method：

The 2# pharmaceutical composition 120g of the embodiment of the present invention 2 are weighed, 2# solvent 350g are added, stirs evenly, is placed in pellet press, With 2# capsule skin pelletings, the dry soft capsule for removing thromboembolism to get every 60mg containing active ingredient.

2# solvent prescriptions（Mass percent）

Ethylene glycol 42.3%

Ethyl alcohol 15.2%

Water 18.6%

Polysorbate60 2.8%

Peanut oil 21.1%

Total 100%

2# solvent preparations：

By above-mentioned prescription match, weigh ethylene glycol, ethyl alcohol, water, polysorbate60, peanut oil, mix, stir evenly to get.

2# capsule skin prescriptions（Mass percent）：

Algin 23.2%

Water 70.4%

Amaranth 0.02%

Disodium hydrogen phosphate 0.87%

Monosodium phosphate 0.21%

Methylcellulose 5.3%

Total 100%

2# capsule peel preparation methods：It is matched by above-mentioned prescription, weighs algin, be added to the water, it is molten in 60-80 DEG C of heating stirring Solution, then sequentially add methylcellulose, amaranth, disodium hydrogen phosphate and monosodium phosphate be modulated, plastic cement, it is steady in 30-40 DEG C Glue 24 hours to obtain the final product.

The preparation of 16 3# soft capsule for removing thromboembolism of embodiment

Drug prescription：

The 3# pharmaceutical compositions 60g of the embodiment of the present invention 3

3# solvents 400g

3# capsule skins 200g

2000 soft capsules are made altogether

Preparation method：

The 3# pharmaceutical composition 60g of the embodiment of the present invention 3 are weighed, 3# solvent 400g are added, stirs evenly, is placed in pellet press, With 3# capsule skin pelletings, the dry soft capsule for removing thromboembolism to get every 30mg containing active ingredient.

3# solvent prescriptions（Mass percent）

Propylene glycol 35.3%

Polyethylene glycol-400 26.5%

Polysorbate60 6.8%

Fish oil 31.4%

Total 100%

3# solvent preparations：

By above-mentioned prescription match, weigh propylene glycol, polyethylene glycol-400, polysorbate60, fish oil, mix, stir evenly to get.

3# capsule skin prescriptions（Mass percent）：

Guar gum 16.3%

Xanthans 7.5%

Water 60.4%

Ethylene glycol 6.2%

Sodium lactate 1.3%

Beeswax 4.8%

Hydroxymethyl cellulose 3.5%

Total 100%

3# capsule peel preparation methods：It is matched by above-mentioned prescription, weighs guar gum, xanthans, ethylene glycol, be added to the water, in 60- The dissolving of 80 DEG C of heating stirrings, then sequentially add hydroxymethyl cellulose, beeswax, sodium lactate be modulated, plastic cement, in 30-40 DEG C Steady glue 24 hours to obtain the final product.

The preparation of 17 4# soft capsule for removing thromboembolism of embodiment

Drug prescription：

The 4# pharmaceutical compositions 50g of the embodiment of the present invention 4

4# solvents 300g

4# capsule skins 150g

2000 soft capsules are made altogether

Preparation method：

The 4# pharmaceutical composition 50g of the embodiment of the present invention 4 are weighed, 4# solvent 300g are added, stirs evenly, is placed in pellet press, With 4# capsule skin pelletings, the dry soft capsule for removing thromboembolism to get every 25mg containing active ingredient.

4# solvent prescriptions（Mass percent）

Water 79.3%

Positive glycerine 20.7%

Total 100%

4# solvent preparations：

By above-mentioned prescription match, weigh water, positive glycerine, mix, stir evenly to get.

4# capsule skin prescriptions（Mass percent）：

Gelatin 12.5%

Carragheen 6.9%

Water 65.4%

Polyethylene glycol-400 9.7%

Sodium bicarbonate 0.9%

Paraffin 1.5%

Cellulose 3.1%

Total 100%

4# capsule peel preparation methods：It is matched by above-mentioned prescription, weighs gelatin, carragheen, polyethylene glycol-400, be added to the water, in The dissolving of 60-80 DEG C of heating stirring, then sequentially add cellulose, paraffin, sodium bicarbonate be modulated, plastic cement, it is steady in 30-40 DEG C Glue 24 hours to obtain the final product.

The preparation of 18 5# soft capsule for removing thromboembolism of embodiment

Drug prescription：

The 5# pharmaceutical compositions 150g of the embodiment of the present invention 5

5# solvents 400g

5# capsule skins 200g

1000 soft capsules are made altogether

Preparation method：

The 5# pharmaceutical composition 150g of the embodiment of the present invention 5 are weighed, 5# solvent 400g are added, stirs evenly, is placed in pellet press, With 5# capsule skin pelletings, the dry soft capsule for removing thromboembolism to get every 150mg containing active ingredient.

5# solvent prescriptions（Mass percent）

Ethyl alcohol 58.1%

Water 27.6%

Ethylene glycol 14.3%

Total 100%

5# solvent preparations：

By above-mentioned prescription match, weigh ethyl alcohol, water, ethylene glycol, mix, stir evenly to get.

5# capsule skin prescriptions（Mass percent）：

Animal glue 5.3%

Locust bean gum 13.7%

Water 75.4%

Olive green 0.03%

Natrium malicum 0.97%

Single hard fatty acids glyceride 1.5%

Methylcellulose 3.1%

Total 100%

5# capsule peel preparation methods：It is matched by above-mentioned prescription, weighs animal glue, locust bean gum, be added to the water, added in 60-80 DEG C Thermal agitation is dissolved, and is then sequentially added olive green, methylcellulose, single hard fatty acids glyceride, natrium malicum and is modulated, moulds Glue, in 30-40 DEG C of steady glue 24 hours to obtain the final product.

Protective effect of 1 pharmaceutical composition of the present invention of experimental example to SD myocardial ischemia in rats

1. materials and methods

1.1 drugs and reagent

1# pharmaceutical compositions：Ginsenoside Rb2 54.6%, and ginsenoside Rb1 21.1%, 11.3 % of ginsenoside Rg1, ginseng 8.5 % of saponin(e Rc, 4.5 % of notoginsenoside R are prepared by embodiment 1.

2# pharmaceutical compositions：Ginsenoside Rb2 20.5%, and ginsenoside Rb1 47.8%, and ginsenoside Rg1 23.4%, people Join saponin(e Rc 6.7 %, 1.6 % of notoginsenoside R, is prepared by embodiment 2.

3# pharmaceutical compositions：Ginsenoside Rb2 1.2%, and ginsenoside Rb1 14.6%, and ginsenoside Rg1 55.7%, people Join saponin(e Rc 19.3 %, 9.2 % of notoginsenoside R, is prepared by embodiment 3.

4# pharmaceutical compositions：Ginsenoside Rb2 21.1%, and ginsenoside Rb1 2.5%, and ginsenoside Rg1 28.2%, people Join saponin(e Rc 37.6%, 10.6 % of notoginsenoside R, is prepared by embodiment 4.

5# pharmaceutical compositions：Ginsenoside Rb2 20.9%, and ginsenoside Rb1 2.7%, and ginsenoside Rg1 21.5%, people Join saponin(e Rc 10.2%, 44.7 % of notoginsenoside R, is prepared by embodiment 5.

1# control samples：Ginsenoside Rb1 50%, and ginsenoside Rg1 50%, is prepared by embodiment 6.

2# control samples：Ginsenoside Rb1 35%, and ginsenoside Rg1 35%, notoginsenoside R 30%, by embodiment 7 Prepare

3# control samples：Ginsenoside Rb1 25%, and ginsenoside Rg1 25%, notoginsenoside R 25%, ginsenoside Rb2 25%, it is prepared by embodiment 8.

Commercially available arasaponin：Quality meets 2015 editions《Chinese Pharmacopoeia》One requirement, is purchased from Chinese Medicine Co., Ltd.

Triphenyltetrazolium chloride (TTC)：Beijing geneva fine chemicals Co., Ltd provides.

Yellow Jackets：Beijing chemical reagents corporation provides.

Heparin sodium injection：Jiangsu Wanbang Biological Pharmaceutical Co., Ltd. provides.

Creatine kinase (CK) kit and lactic dehydrogenase (LDH) kit：Beijing Zhong Shengbei controls biotechnology share Co., Ltd provides.

1. 2 key instruments

HX-300 animal respirators and BL-420S biological function instrument：Chengdu TME Technology Co., Ltd.；

TGL-16G-A high speed freezing centrifuges：Town in Shanghai pavilion Scientific Medical instrument plant；

7600 automatic clinical chemistry analyzer of Hitachi：Japanese SHIMADZU companies；

BS 110S electronic balances：German Sartorius companies.

1.3 animal packets and administration

SD male rats 110,250 ± 30g of quality are randomly divided into 11 groups：Sham-operation group, model group, 1# pharmaceutical compositions Group, 2# pharmaceutical compositions group, 3# pharmaceutical compositions group, 4# pharmaceutical compositions group, 5# pharmaceutical compositions group, 1# control samples group, 2# control samples group, 3# control samples group, commercially available arasaponin group, every group 10.

Ig gives 50 mg.kg to each medicine group rat respectively^-1, sham-operation group, model group give the solvent of equivalent, and daily 2 It is secondary, successive administration 7 days.After 30 min of last dose, following coronary artery occlusion descending anterior branch prepares Model of Acute Myocardial Ischemia.

1.4 the preparation of acute myocardial ischemia animal model

Rat ip gives 1% yellow Jackets 60 mg.kg^-1Anesthesia, four limbs subcutaneously connect ECG electrode, record standard II Lead electrocardiogram.Orally slotting tracheae, connects animal respirator.In left side, the 4th intercostal opens chest, gently squeezes out heart, with silk thread in lung Heart, is put back to thoracic cavity by arterious cone and left auricle of heart boundary lower edge 1~2 mm ligation rapidly, to ligature part cyanosis, swollen Go out to be lifted with ECG ST section and successfully indicate as ligation.Sham-operation group is only threaded a needle in left anterior descending branch corresponding position without beating Knot, remaining operation are identical as operation group.10 min of hand clinical follow squeezes out chest chamber air and successively closes chest, restores rat certainly Main breathing extracts trachea cannula and removes tracheae endocrine, gives feed and water feeds 24 h.In experimentation, Suo Youyin The death of the reasons such as operation, anesthetic accident and survival time after surgical operation not up to materials time requirement rat, is not included in reality It tests within observation item.

1. 5 heart functions detect

After 24 h of rat following coronary artery occlusion left anterior descending branch, ip gives 1% yellow Jackets 60 mgkg^{- 1}Anesthesia, lies on the back Position is fixed, and neck midsection skin, haemostatic clamp blunt separation musculi colli exposes right carotid.Near head end silk Line passes through, and is distally clamped with artery clamp, and a V type notch is cut in right common carotid artery, is inserted into and is full of 250 kUL^{- 1}Heparin is given birth to The conduit for managing saline solution, is used in combination silk thread to fix.Artery clamp is unclamped, test tube of hepari PE conduits are intubated through right common carotid artery to a left side Ventricle changes according to pressure figure shown in display, judges whether intubation enters ventricular chamber.Conduit other end is connected to pressure and changes Energy device, inputs a signal into BL-420S biological signal collecting analysis systems, to monitor left ventricle blood stream rheology.It is inserted into After left ventricle balances 30 min, record left ventricular systolic pressure (LVSP), Left ventricular end diastolic pressure (LVEDP), while will be left Ventricular pressure electric signal synchronizes input differentiator, measures isovolumic contraction period maximal ascending rate of internal pressure of left ventricle (+dp/dt ) and isovolumic relaxation period maximal descending rate of internal (- dp/dt max) max.

1. 6 TTC dyeing measures myocardial infarction area

Heart function detect after, take out heart rapidly, set in ice-cold normal saline rinse remove blood stains, reject atrium, blood vessel, Fatty Deng Fei cardiac muscular tissues are placed in -20 DEG C of refrigerators and place 30 min.Under heart ligature, parallel coronary sulcus by heart from The apex of the heart to heart bottom transverse is cut into 5 (1.5~2 mm of thickness), be placed in 1% TTC phosphate buffers (pH 7.4) in It is incubated 10 min in 37 DEG C of waters bath with thermostatic control.Heart transverse section after dyeing is placed in 4% paraformaldehyde solution to fixed, scanning The tow sides of heart sections are calculated infarction size with Photoshop softwares, the percentage of whole-heartedly room area are accounted for infarct size Than indicating.

1. the detection of 7 Serum fibrosis markers

After heart function detects, abdominal aortic blood centrifuges 15 min at 1200 r/min, 4 DEG C, obtains serum sample Product freeze spare in -80 DEG C of refrigerators.Serum myocardial enzyme spectrum detection includes CK, LDH, α-hydroxybutyrate dehydrogenase (α-HBDH), paddy third Transaminase (GPT) and glutamic-oxalacetic transaminease (GOT), are measured using 7600 automatic clinical chemistry analyzer of Hitachi.

2. experimental result

The influence of 2.1 pairs for the treatment of myocardial ischemia damage rat infarct sizes

It is above-mentioned the experimental results showed that, pharmaceutical composition of the present invention can substantially reduce the myocardial infarction area of rats with myocardial ischemia, right Myocardial ischemia has significant protective effect, effect to be better than 1-3# control samples and commercially available arasaponin control drug.

2. the influence of 2 pairs of rats with myocardial ischemia heart functions

It is above-mentioned the experimental results showed that, pharmaceutical composition of the invention can significantly improve the heart work(index of rats with myocardial ischemia, to the heart Cardiac dysfunction caused by myocardial ischemia damage is significantly improved, and effect is better than 1-3# control samples and the total soap of commercially available Radix Notoginseng Glycosides control drug.

2. the influence of 3 pairs of rats with myocardial ischemia Serum fibrosis markers

It is above-mentioned the experimental results showed that, pharmaceutical composition of the invention can significantly reduce Serum LDH after rat coronary ligation, CK, The active raisings of GOT and HBDH show that the pharmaceutical composition of the present invention has guarantor to the myocardial ischemia caused by following coronary artery occlusion Shield acts on, and effect is better than 1-3# control samples and commercially available arasaponin control drug.

Conclusion：The pharmaceutical composition of the present invention can significantly reduce myocardial infarct size after rat coronary ligation, improve heart infarction The cardiac function of rat afterwards, and Serum LDH after rat coronary ligation, CK, GOT and the active raisings of HBDH can be reduced, Show that the pharmaceutical composition of the present invention has protective effect to the myocardial ischemia caused by following coronary artery occlusion, moreover, its effect is better than Control sample and commercially available arasaponin.

Experimental example 2 studies the protective effect of cerebral ischemia/reperfusion injury of rats

1. material and instrument

1.1 drugs and reagent

The above test medicine converts the solution use for 1.0% with 0.9% physiological saline.

Interleukin-β (IL-1 β), tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), interleukin-8 ( IL-8) ABC-ELISA detects box：Sigma companies provide.

Evans blue (Evans Blue)：Fluka companies provide；

Formamide：Tianjin outer shroud chemical company；

2% tetrazole is red (TTC)：Sigma companies provide.

1.2 key instrument

CR-412 low temperature normal speed centrifuges：French Jouan companies provide；

721 spectrophotometers：Shanghai third instrument plant provides；

Computer digital image analysis：Shanghai Medical Univ produces.

2. experimental method

The foundation of 2.1 cerebral ischemia re-pouring models

SD rats 330, are randomly divided into 11 groups：Sham-operation group, model group, 1# pharmaceutical compositions group, 2# pharmaceutical compositions group, 3# pharmaceutical compositions group, 4# pharmaceutical compositions group, 5# pharmaceutical compositions group, 1# control samples group, 2# control samples group, 3# controls Sample sets, commercially available arasaponin group, every group 30.Model group and each 10% chloraldurates 3. 5 of medicine group rat ip mL.kg^{- 1}Anesthesia, fixation of lying on the back, separation left common carotid (CCA), internal carotid (ICA) and external carotid artery (ECA), knot ECA and CCA is pricked, after closing ICA distal ends with artery clamp folder, rapidly in away from ECA's and about 0. 5 cm of ICA crotches Make a kerf at arteria carotis communis, be inserted into the nylon wire of a diameter of 0. 3 mm of one end round blunt, insertion depth be (20. 0 ± 2. 0 mm realizes that middle cerebral artery occlusion leads to cerebral ischemia.Inlet is ligatured, about 1 cm, skin suture are stayed outside nylon wire.2 Stayed the end of a thread is gently lifted after h to slightly resistance to realize arteria cerebri media Reperfu- sion.Rats in sham-operated group only detaches neck and always moves Arteries and veins, internal carotid and external carotid artery (same to modeling group), but do not ligature CCA.

2.2 animals are administered and processing

Each medicine group 6 h after 15min and ischemic before ischemic, ip administrations are each primary, 10 mgkg of each dosage^{- 1}.Sham-operation group gives normal saline with model group ip.

2.3 Neurological deficits

After recovery from anesthesia, animal is put back into mouse cage, ad lib, postoperative 24 h carries out Neurological deficits.With reference to Zea 5 points of scales processed of Longa score：Impassivity injury symptoms are 0 point, are unable to the strong side fore paw of full extension and are 1 point, it is 2 points to turn-take to strong side, and it is 3 points to be fallen to strong inclination, spontaneous cannot be walked, and the loss of consciousness is 4 points.

2. 4 Infarction volumes measure

Each group takes rat 10, and broken end takes brain after 2 h Reperfu- sions of rat cerebral ischemia, 22 h, and 2 mm are pressed with brain section device Thickness, the coronal incision brain at away from 1,3,5,7 mm of antinion.Brain section is immersed to 37 DEG C of 2% tetrazole red colouring, It takes out to be placed in 10% formaldehyde after 30 min and fix, take pictures after 24 h.Infarct size is calculated using image analysis system, it will The infarct size of each brain piece and the product of thickness add up, and obtain Infarction volume.

2. 5 brain tissue Evans blues quantitative determine

Each group takes rat 10, in 10% chloraldurate (3. 5 mL.kg^{- 1}) under anesthesia, filled with physiological saline by left ventricle Note is injected intravenously 2% Evans blue, 1 mL/ is only until efflux is colourless by right lateral thigh.Win brain tissue electronic balance It after accurately claiming its weight in wet base, puts into medium size test tube, is separately added into 3 mL formamides, the water bath after capping in 45 DEG C is incubated 48 h, gently shake up, and 3 000 r/min centrifuge 15 min, and supernatant is taken to survey absorbance (A) under the nm of λ=632, calculate brain Organize Evans blue content.

The measurement of 2.6 cytokine contents

Each group takes rat 10, and 24 h put to death rat after surgery, in quickly removing brain tissue on ice pan, with ice-cold PBS It rinses, filter paper blots, and immediately in electronic balance weighing, 10% brain tissue homogenate is made, homogenate is at 4 DEG C with 4 000 r/ The speed of min centrifuges 15 min, takes supernatant, using double-antibody sandwich ABC-ELISA methods, is detected in 492 nm of wavelength IL-1 β, TNF-α, the content of IL-6, IL-8.

3. experimental result

3. the influence of 1 pair of ischemia-reperfusion rat nerve symptom

There is hemiplegia sample symptom, are mainly shown as operation in experiment display, model group rats 22 h of Reperfu- sion after 2 h of ischemic It is received in offside forelimb, shoulder inward turning, forelimb Muscle tensility reduces, and shoulder drag declines, and rolls to strong.This experimental results showed that, this The pharmaceutical composition of invention can significantly improve the nervous symptoms of ischemia-reperfusion rat, caused by ischemia-reperfusion apoplexy, partially Paralysed symptom has obvious therapeutic action, and its effect is better than 1-3# control samples and commercially available arasaponin control drug.

2. the influence pair ischemia-reperfusion rat cerebral infarction volume

It is above-mentioned the experimental results showed that, pharmaceutical composition of the invention can significantly reduce the cerebral infarction volume of ischemia-reperfusion rat, And its effect is better than 1-3# control samples and commercially available arasaponin control drug.

3, to the influence of ischemia-reperfusion rat cerebral tissue Evans blue content

Blood-brain barrier (BBB) destruction is the important pathophysiological basis of cerebral ischemia re-pouring cerebral injury.Small point of Evans blue system Son is common BBB indicator.Evans indigo plants can be combined with plasma protein, cannot pass through blood-brain barrier when normal.And brain lacks When blood Reperfu- sion, BBB is destroyed, and the Evans indigo plant contents in brain tissue increase, and by measuring, Evans indigo plant contents can in brain tissue Reflect the extent of the destruction of blood-brain barrier.

It is above-mentioned the experimental results showed that, pharmaceutical composition of the invention can significantly reduce the Yi Wen of ischemia-reperfusion rat brain Think blue content, prompts the pharmaceutical composition of the present invention that there is protective effect, Er Qieqi to the blood-brain barrier of ischemia-reperfusion rat Effect is better than 1-3# control samples and commercially available arasaponin control drug.

Conclusion：

Pharmaceutical composition of the present invention can significantly improve the nervous symptoms of ischemia-reperfusion rat, caused by ischemia-reperfusion in Wind, hemiplegia symptom have obvious therapeutic action；The cerebral infarction volume of ischemia-reperfusion rat can be significantly reduced；Ischemic can be significantly reduced The Evans blue content of Reperfu- sion rat brain prompts the pharmaceutical composition of the present invention to the blood-brain barrier of ischemia-reperfusion rat With protective effect.Experiment is it is also shown that the above-mentioned of pharmaceutical composition of the present invention imitates cerebral ischemia re-pouring injured protective effect Fruit is superior to the control drugs such as the commercially available arasaponin of same dosage.Above studies have shown that pharmaceutical composition of the present invention can be used In the prevention or treatment of the ischemic cerebrovascular disease such as ischemia apoplexy, cerebral infarction, brain hemiparalysis, curative effect is better than existing three Seven total saposins drugs.

Experimental example 3 studies the protective effect of rat retina neurotrosis

1. materials and methods

1.1 drugs and reagent

Magnificent cresol-purple (Cresyl Vio-let)：Shanghai Sinopharm Chemical Reagent Co., Ltd. provides.

1.2 laboratory apparatus

Surgical operation microscope：GX.SS.ZZ-3 types, Shanghai medical optical instrument factory；

Ophthalmology micro-surgical instrument：Suzhou Ming Ren medical apparatus corporation, Ltds；

Nikon light microscopes：Alphaphot -2 YS2 and YS100 types, Nikon companies provide；Electronic analytical balance： AB204-N types, Mettler ToledoGroup) company's offer；Digital photography microscope：Model BX51, OLYMPUS companies It provides.

1.3 experimental animal

SD rats, Kunming Medical University's Experimental Animal Center provide, half male and half female, 200 ~ 240 g of weight, 8 ~ 12 week old, warp Check that corneal transparency, iris vessels are clear without apparent bend neck, isocoria etc. is round, and light reflex is sensitive.Adaptability raises and train 3 3 days intraocular pressures are continuously surveyed after it, Trimmed mean intraocular pressure is higher or lower than normal intraocular tension section (9 ~ 16mmHg) person.

1.4 animal packets and administration

SD rats 110, are randomly divided into 11 groups：Normal group, model group, 1# pharmaceutical compositions group, 2# pharmaceutical compositions Group, 3# pharmaceutical compositions group, 4# pharmaceutical compositions group, 5# pharmaceutical compositions group, 1# control samples group, 2# control samples group, 3# Control sample group, commercially available arasaponin group, every group 10.In addition to Normal group, remaining 100 are ironed by Akira methods Rat right eye episcleral vein is closed, rat continuous intraocular hypertension Retinal nerve injury model is made, 10 days intraocular pressures of observation are steady It is scheduled on the above persons of 30mm Hg and is included in experiment.Each medicine group gavage treats 1 month, daily 1 time, Normal group and model Group gavage gives equivalent distilled water.Intraocular pressure is measured weekly 1 time.Each group experiment takes retina to do holostrome tile, cresols after expiring Garm's stain row RGCL neuron counts.

1.5 computer image analysis

Every inner nuclear layer retina to be measured by regarding the symmetrical setting-out of nipple, be classified as on temporo, under temporo, on nose, lower 4 quadrants of nose , each quadrant retina is divided into 3 equal portions, i.e., center, intermediate and 3rd area of periphery, each subregion take 3 points at random, often Point area is 32500 μm, and every square millimeter of cell number is converted into after being counted to every retinal neuronal cell (cell number/mm²), using the mean of 3 cell densities in every area as the neuron density in the area.It is easy to distinguish by morphology Vascular endothelial cell in other RGCL, the core with dense dye and the cell without nissl substance are spongiocyte, both cells It is not included in RGCL neuron counts

2 experimental results

It is above-mentioned the experimental results showed that, pharmaceutical composition of the present invention can significantly reduce damage of the durative intraocular hypertension to retina neural Wound, has good protection and repair to Retinal nerve injury, can be used as the medicine of retina or optic neuropathy.

4 acute toxicity testing of experimental example

1 materials and methods：

1.1 test medicine：5# pharmaceutical compositions are prepared by embodiment 5.

1.2 control drug：Commercially available arasaponin, quality meet 2015 editions《Chinese Pharmacopoeia》One requirement, purchased from China Pharmaceuticals Ltd.

1.3 experimental animal：SPF grades of health ICR mouse, 130,3~4 week old, 18.0~22.0g of weight.

1.4 test method：ICR mouse 130, are randomly divided into 13 groups：Blank control group, test medicine 1-6 dosage groups, Control drug 1-6 dosage groups, every group 10, half male and half female.According to trial test as a result, test medicine and control drug with The dosage of 550mg/kg weight is maximum dose level, with ratio between 0.80 agent to 5 dosage are divided into, totally 6 dosage groups.Each group is small Mouse, after 12 h are deprived of food but not water before experiment, intraperitoneal injection 1 time, isometric physiology salt is injected intraperitoneally in blank control group Water.Normal to raise after administration, after medicine within 2 h, every 15 min is observed 1 time；After medicine within 2 ~ 4 h, every 30 min Observation 1 time；After medicine within 4 ~ 8 h, observed 1 time per 1h；After medicine within 8 ~ 24 h, every 4 h is observed 1 time； 2d rises after medicine, daily observation 1 time, weighs weight, the feed of dynamic degree, drinking-water situation and 14 d of each mouse of close observation Dynamic degree, abnormal muscle movement, external reaction, pupil change, abnormal secretion, stool and urine exception, the eyeball being inside likely to occur are convex Go out, ptosis, adnormal respiration, skin color change etc. toxic reactions and death condition.It, will be dead small if there is dead mouse Mouse is dissected, and checks that the pathological change of the internal organs such as the heart, liver, spleen, lung, kidney, brain, stomach, small intestine, 14 d are seen.According to each dosage group mouse The dead quantity and dosage calculate 50 values of LD of test medicine and control drug using Bliss methods.

2, experimental results

It is once injected intravenously using mouse and measures LD50 test methods, observed, compare 5# pharmaceutical compositions and the total soap of commercially available Radix Notoginseng The acute toxic reaction of glycosides.The results show that the LD50 of 5# pharmaceutical composition ICR mouse single intravenous injections is 397mg/kg, city The LD50 for selling arasaponin ICR mouse single intravenous injections is 306mg/kg, illustrates the median lethal of real 5# pharmaceutical compositions Dosage is higher than commercially available arasaponin.

With reference to above-mentioned experimental program, acute toxicity test is carried out to the 1-4# pharmaceutical compositions of embodiment 1-4, as a result table Bright, similar to the acute toxicity tests of 5# pharmaceutical compositions of embodiment 5, difference is not statistically significant between group.

Above-mentioned experiment shows that pharmaceutical composition of the present invention has high pharmaceutical safety, and safety is better than existing Arasaponin drug.

5 blood vessel irritation of experimental example, hemolytic and anaphylaxis experimental study

1. material and instrument

1.1 drugs, reagent

1.1 drugs and reagent

The above drug faces the used time with the dissolving of 0.9%NaCl injections.

Bovine serum albumin(BSA)：Genbase Bio-science Co companies provide.

Evans blue：Shanghai Ru Ji biotechnologies Development Co., Ltd provides.

1.2 key instrument

TP1020 dewaterers, EG1160 embedding machines, RM2235 electric slicers, the booth HI1210 piece machine, HI1220 dry piece Machine, MLB biomicroscopes：German Leica Instrument Ltd. provides；

MR231 type table-type high-speed refrigerated centrifuges：French Jie An groups provide；

T6 ultraviolet-uisible spectrophotometers：Beijing Puxi General Instrument Co., Ltd provides.

1.3 experimental animal

New zealand rabbit：Regular grade, half male and half female, 2. 0 ~ 2.5 kg of weight, Guangdong Medical Lab Animal Center provide.

Adult healthy ICR mouse, 22 ~ 25 g of weight, Guangdong Medical Lab Animal Center provide.

2. experimental method

2.1 vascular stimulation tests

New zealand rabbit 70 is chosen, is randomly divided into 7 groups：Negative control group, 1# pharmaceutical compositions group, 2# pharmaceutical compositions group, 3# Pharmaceutical composition group, 4# pharmaceutical compositions group, 5# pharmaceutical compositions group, commercially available arasaponin group, every group 10, male and female are each Half.Selection left side auricular vein carries out intravenous drip, and negative control group gives equivalent 0.9% NaCl injections, and droping rate is about 50 drop per minute, qd, 7 d of successive administration, 48 and 72 h, visually observes new west before daily administration and after the last administration Blue rabbit injection site reaction situation is given a mark by vascular stimulation reaction score criteria (being shown in Table 1), and it is average to calculate each position After marking stimulate the reaction degree is evaluated by vascular stimulation reaction evaluating standard (being shown in Table 2).The general shape of new zealand rabbit is observed simultaneously Condition, hair, excrement, activity etc..72 h after the last administration, every group takes 2 (half male and half female) new zealand rabbits, executes mercy killing, (administration side) the rabbit ear on the left of the ear portion excision new zealand rabbit, respectively at injection site, injection site proximal part and injection site Distal end respectively takes 1 piece of tissue to carry out histopathological examination.Every group of remaining 2 (half male and half female) new zealand rabbits continue to observe It draws materials again after 14 d and does histopathological examination, to understand the degree of reversibility of irritative response.

1 vascular stimulation of table reacts score criteria

2 vascular stimulation reaction evaluating standard of table

2.2 hemolysis in vitro are tested

New zealand rabbit Culling heart blood about 30mL, is put into the conical flask containing bead and shakes 10 min, except defibrinating Original makes into defibrinated blood, and about 10 times of amounts of NaCl injections are added, shake up, 1 200 r/min, 15 min of centrifugation, in removing The red blood cell of clear liquid, precipitation is washed 2~3 times with NaCl injections as stated above again, until the not aobvious red of supernatant, Gained red blood cell is made into NaCl injections 2% suspension it is spare.Clean tube 80 is taken, it is No. 1-8 that sequence, which is compiled, 10 every number.By 2% red cell suspension, NaCl injections, pure water and liquid is sequentially added shown in table 3, after mixing, immediately It sets in the water bath with thermostatic control of (37 ± 0.5) DEG C and is incubated.It is observed after incubating 3 h：If solution is in clear and bright red, tube bottom is acellular It remains or there is a small amount of red blood cell to remain, show there is haemolysis；Red blood cell all sinks, and supernatant fluid achromatism and clarity shows nothing Haemolysis occurs.There are brownish red or rufous flocculent deposit in solution, does not disperse after shaking, show there is red blood cell condensation.Such as There is the phenomenon that red blood cell condensation, condensation product can be placed on glass slide, 2 drop NaCl solution are added dropwise at coverslip edge, it is micro- Under the microscope, cohesion red blood cell can be pseudo agglutination by the person of breaking up, and not be really to agglomerate by the person of breaking up.After observation, supernatant is taken, is being divided On light photometer, at 545 nm, the A values of each pipe are read using pure water as blank, the haemolysis of each developmental tube is calculated with following formula Rate:

Hemolysis rate=(A t-A nc)/(A pc-A nc) × 100%.In formula:A t represent developmental tube extinction Degree, A nc represent negative control pipe absorbance（I.e. No. 7 pipes）, A pc represent positive control pipe absorbance（I.e. No. 8 pipes）.If molten Blood rate ＞ 5%, shows haemolysis occurred.

Hemolysis in vitro experiment sample-adding table (ml)

2.3 sensitivity test

80 adult healthy ICR mouse, 22~25 g of weight are randomly divided into 8 groups：Saline control group, positive drug Bovine serum albumin(BSA) control group, 1# pharmaceutical compositions group, 2# pharmaceutical compositions group, 3# pharmaceutical compositions group, 4# pharmaceutical compositions Group, 5# pharmaceutical compositions group, commercially available arasaponin group.Containing 0. 4% Evans blue, each group in above each tested material Mouse is through the corresponding tested material of tail vein injection.The behaviouristics variation of 30 min mouse and auricle indigo plant contaminate situation after observation administration. Record every group of number of animals for auricle indigo plant dye occur, the total ear number of blue dye, auricle blued area.Auricle blued area (S) contaminates for ear indigo plant Area/auricle area contaminates score value according to following table grade scale assessment ear indigo plant.Each group mouse cervical dislocation is put to death again, ears is taken, cuts It is broken, 2 d are impregnated with 2 mL formamides, the filtering of 400 mesh sieve takes supernatant to survey absorbance A at 630 nm.According to Evans blue standard curve calculates the Evans blue dyestuff seepage discharge (μ g) of each mouse ears.It is contaminated according to every group of generation auricle indigo plant dynamic Object number calculates each group vascular reaction positive rate (abbreviation reactivity)；Ear indigo plant dye rate is calculated according to indigo plant dye ear number.

Indigo plant dye rank scores index

3, experimental result

3.1 vascular stimulation tests

It is above-mentioned the experimental results showed that, pharmaceutical composition of the present invention exists to the vascular stimulation of new zealand rabbit intravenous drip reaction score value Between 0.11 ~ 0.23, belong to " nonirritant " rank, blood vessel irritation is significantly lower than the commercially available arasaponin of control drug.

3.2 hemolytics are tested

It is above-mentioned the experimental results showed that, for pharmaceutical composition of the present invention without apparent hemolytic, hemolysis rate is significantly lower than control drug city Sell arasaponin.

3.3 anaphylaxis

It is above-mentioned the experimental results showed that, inflammatory reaction degree is slight caused by pharmaceutical composition anaphylaxis of the present invention, hence it is evident that less than pair According to the commercially available arasaponin of drug.

Conclusion：It is above-mentioned the experimental results showed that, pharmaceutical composition of the present invention without obvious irritation, hemolytic and anaphylaxis etc. no Good reaction, complies fully with pharmaceutical safety requirement, and every adverse reaction Safety Evaluation Index is superior to arasaponin control Drug.

Model case：

1, Zhang, man 65 years old, suffer from diabetes 7 years.From in May, 2014, feel that binocular vision declines, the right side of testing eyesight Eye 0.5, left eye 0.1, the visible microaneurysm of retina, the reflective disappearance of central socket are diagnosed as diabetic retinopathy.Take this The 5# soft capsule for removing thromboembolism of inventive embodiments 18, after daily 1,3 months, on inspection, and right vision 1.0, left vision 0.6, Eyes vitreum internal haze absorbs, and capilary extravasated blood mitigates.Follow-up half a year is without recurrence.

2, Mr. Li, female 58 years old, suffer from diabetes 7 years, from 2014 8, feel that binocular vision declines, muscae genetic vision It dances in the air.On inspection, retinal vein is expanded, and has microaneurysm, blood spots, left vision 0.3, right vision 0.4 to be diagnosed as sugar The sick retinopathy of urine.It takes the 4# soft capsule for removing thromboembolism of the embodiment of the present invention 17, after daily 1,3 months, flies shadow depending on object and subtract Gently, capilary extravasated blood mitigates, and left vision is restored to 0.9, and right vision is restored to 1.0.Follow-up half a year is without recurrence.

3, Mr. Wang, female, 14 years old, junior middle school tertion, usually schoolwork burden was big, daytime learn one day after eyes very Fatigue, daytime, eye was swollen, had arrived at night with regard to frequent ophthalmodynia, when there is situations such as blurred vision, shed tears to take the embodiment of the present invention 16 3# soft capsule for removing thromboembolism, eye is swollen after daily 1,1 month, ophthalmodynia, situations such as shedding tears disappear, and visual fatigue situation is obviously improved.

4, Xiao, man, 35 years old, certain pharmaceuticals industry investigator, work was commonly using computer, mobile phone.From 2015 9 It rises, feels that eyes are particularly easy to fatigue, eyes are dry, itch, ache, blurred vision.The eyedrops such as point Ofloxacin, it is above-mentioned Symptom is not improved.Take the 2# soft capsule for removing thromboembolism of the embodiment of the present invention 15, after daily 1,3 months, eye does, itches, Symptom of aching disappears, and eyesight is obviously improved.Follow-up half a year is without recurrence.

Claims

1. a kind of " Xuesaitong Injection " pharmaceutical composition, it is characterised in that the " Xuesaitong Injection " pharmaceutical composition includes following mass percent Drug component：

Ginsenoside Rb2 0.001 ~ 99.996%

Ginsenoside Rb1 0.001 ~ 99.996%

Ginsenoside Rg1 0.001 ~ 99.996%

Ginsenoside Rc 0.001 ~ 99.996%

Notoginsenoside R 0.001 ~ 99.996%.

2. " Xuesaitong Injection " pharmaceutical composition according to claim 1, it is characterised in that the " Xuesaitong Injection " pharmaceutical composition packet Include the drug component of following mass percent：

Ginsenoside Rb2 0.01 ~ 99.96%

Ginsenoside Rb1 0.01 ~ 99.96%

Ginsenoside Rg1 0.01 ~ 99.96%

Ginsenoside Rc 0.01 ~ 99.96%

Notoginsenoside R 0.01 ~ 99.96%.

3. " Xuesaitong Injection " pharmaceutical composition according to claim 1 or 2, it is characterised in that the " Xuesaitong Injection " pharmaceutical composition Include the drug component of following mass percent：

54.6 % of ginsenoside Rb2

Ginsenoside Rb1 21.1%

Ginsenoside Rg1 11.3%

Ginsenoside Rc 8.5%

Notoginsenoside R 4.5%.

4. " Xuesaitong Injection " pharmaceutical composition according to claim 1 or 2, it is characterised in that the " Xuesaitong Injection " pharmaceutical composition Include the drug component of following mass percent：

20.5 % of ginsenoside Rb2

Ginsenoside Rb1 47.8%

Ginsenoside Rg1 23.4%

Ginsenoside Rc 6.7%

Notoginsenoside R 1.6%.

5. " Xuesaitong Injection " pharmaceutical composition according to claim 1 or 2, it is characterised in that the " Xuesaitong Injection " pharmaceutical composition Include the drug component of following mass percent：

1.2 % of ginsenoside Rb2

Ginsenoside Rb1 14.6%

Ginsenoside Rg1 55.7%

Ginsenoside Rc 19.3%

Notoginsenoside R 9.2%.

6. " Xuesaitong Injection " pharmaceutical composition according to claim 1 or 2, it is characterised in that the " Xuesaitong Injection " pharmaceutical composition Include the drug component of following mass percent：

21.1 % of ginsenoside Rb2

Ginsenoside Rb1 2.5%

Ginsenoside Rg1 28.2%

Ginsenoside Rc 37.6%

Notoginsenoside R 10.6%.

7. " Xuesaitong Injection " pharmaceutical composition according to claim 1 or 2, it is characterised in that the " Xuesaitong Injection " pharmaceutical composition Include the drug component of following mass percent：

20.9 % of ginsenoside Rb2

Ginsenoside Rb1 2.7%

Ginsenoside Rg1 21.5%

Ginsenoside Rc 10.2%

Notoginsenoside R 44.7%.

8. a kind of preparation method of any " Xuesaitong Injection " pharmaceutical composition of claim 1 ~ 7, it is characterised in that including as follows Step：

9. the preparation method of " Xuesaitong Injection " pharmaceutical composition according to claim 8, it is characterised in that step 1）Middle Radix Notoginseng soap The mass ratio of glycosides R1 and alcohol solvent is 0.05 ~ 5:100, the concentration expressed in percentage by volume of ethyl alcohol is 50 ~ 100%.

10. the preparation method of " Xuesaitong Injection " pharmaceutical composition according to claim 8, it is characterised in that step 2）In four kinds of people The mass ratio for joining saponin(e and needle-use activated carbon, distilled water is 0.1 ~ 10:0.01~0.5：100.

11. the preparation method of " Xuesaitong Injection " pharmaceutical composition according to claim 8, it is characterised in that step 3）Middle pre-freeze drop Warm rate is 5 ~ 15 DEG C/h.

12. a kind of " Xuesaitong Injection " pharmaceutical preparation, it is characterised in that be by any " Xuesaitong Injection " pharmaceutical composition of claim 1 ~ 7 Object with pharmaceutically auxiliary material, carrier, made by matrix, including injection, tablet, oral solution, capsule, soft capsule, dripping pill, sustained release Preparation, controlled release preparation.

13. a kind of soft capsule for removing thromboembolism preparation, it is characterised in that using any pharmaceutical composition of claim 1 ~ 7 as medicine The active ingredient of object, and be aided with auxiliary material or auxiliary agent appropriate and be process.

14. soft capsule for removing thromboembolism preparation according to claim 13, it is characterised in that the soft capsule for removing thromboembolism preparation Effective ingredient containing following mass percent：

Ginsenoside Rb2 0.001 ~ 99.996%

Ginsenoside Rb1 0.001 ~ 99.996%

Ginsenoside Rg1 0.001 ~ 99.996%

Ginsenoside Rc 0.001 ~ 99.996%

Notoginsenoside R 0.001 ~ 99.996%.

15. soft capsule for removing thromboembolism preparation according to claim 13, it is characterised in that the soft capsule for removing thromboembolism preparation Effective ingredient containing following mass percent：

Ginsenoside Rb2 0.01 ~ 99.96%

Ginsenoside Rb1 0.01 ~ 99.96%

Ginsenoside Rg1 0.01 ~ 99.96%

Ginsenoside Rc 0.01 ~ 99.96%

Notoginsenoside R 0.01 ~ 99.96%.

16. soft capsule for removing thromboembolism preparation according to claim 13, it is characterised in that the soft capsule for removing thromboembolism preparation Effective ingredient containing following mass percent：

54.6 % of ginsenoside Rb2

Ginsenoside Rb1 21.1%

Ginsenoside Rg1 11.3%

Ginsenoside Rc 8.5%

Notoginsenoside R 4.5%.

17. soft capsule for removing thromboembolism preparation according to claim 13, it is characterised in that soft capsule for removing thromboembolism preparation contain as The effective ingredient of lower mass percent：

20.5 % of ginsenoside Rb2

Ginsenoside Rb1 47.8%

Ginsenoside Rg1 23.4%

Ginsenoside Rc 6.7%

Notoginsenoside R 1.6%.

18. soft capsule for removing thromboembolism preparation according to claim 13, it is characterised in that the soft capsule for removing thromboembolism preparation Effective ingredient containing following mass percent：

1.2 % of ginsenoside Rb2

Ginsenoside Rb1 14.6%

Ginsenoside Rg1 55.7%

Ginsenoside Rc 19.3%

Notoginsenoside R 9.2%.

19. soft capsule for removing thromboembolism preparation according to claim 13, it is characterised in that the soft capsule for removing thromboembolism preparation Effective ingredient containing following mass percent：

21.1 % of ginsenoside Rb2

Ginsenoside Rb1 2.5%

Ginsenoside Rg1 28.2%

Ginsenoside Rc 37.6%

Notoginsenoside R 10.6%.

20. soft capsule for removing thromboembolism preparation according to claim 13, it is characterised in that the soft capsule for removing thromboembolism preparation Effective ingredient containing following mass percent：

20.9 % of ginsenoside Rb2

Ginsenoside Rb1 2.7%

Ginsenoside Rg1 21.5%

Ginsenoside Rc 10.2%

Notoginsenoside R 44.7%.

21. a kind of preparation method of any soft capsule for removing thromboembolism preparation of claim 13 ~ 20, it is characterised in that weigh power Profit requires 13 ~ 20 any one of them effective ingredients, is added in solvent, stirs evenly, be placed in pellet press, with capsule skin Pelleting, it is dry to get.

22. the preparation method of soft capsule for removing thromboembolism preparation according to claim 21, it is characterised in that the solvent be water, Ethyl alcohol, ethylene glycol, propylene glycol, glycerine, tween, peanut oil, ginger oil, Zanthoxylum essential oil, attar of rose, rapeseed oil, peony seed oil, spade It is more than any one of oil, sunflower oil, palchouli oil, lard, butter, sheep oil, fish oil, shark oil, snake oil or any two with The mixture of arbitrary proportion.

23. the preparation method of soft capsule for removing thromboembolism preparation according to claim 21, it is characterised in that the capsule skin by Colloid and solvent, blender through thermosol, modulation, plastic cement, steady glue and be made.

24. the preparation method of soft capsule for removing thromboembolism preparation according to claim 21, it is characterised in that prepare capsule skin Colloid is selected from animal glue or natural plant gum.

25. the preparation method of soft capsule for removing thromboembolism preparation according to claim 24, it is characterised in that the animal glue Including gelatin, animal glue, dogskin glue or pig skin gelatin.

26. the preparation method of soft capsule for removing thromboembolism preparation according to claim 24, it is characterised in that the natural plant gum Including carragheen, guar gum, algin, locust bean gum, konjac glucomannan, xanthans.

27. the preparation method of soft capsule for removing thromboembolism preparation according to claim 21, it is characterised in that prepare capsule skin Solvent is in water, ethyl alcohol, propyl alcohol, ethylene glycol, isopropyl triol, positive glycerine, isobutanol, the tert-butyl alcohol, n-butanol, polyethylene glycol More than any type or any two with the mixture of arbitrary proportion.

28. the preparation method of soft capsule for removing thromboembolism preparation according to claim 21, it is characterised in that prepare capsule skin Blender includes toner and regulating acid agent.

29. the preparation method of soft capsule for removing thromboembolism preparation according to claim 28, it is characterised in that the toner Including carmine, amaranth or olive green.

30. the preparation method of soft capsule for removing thromboembolism preparation according to claim 28, it is characterised in that the regulating acid agent Including citric acid, sodium citrate, carbonic acid, sodium carbonate, sodium bicarbonate, phosphoric acid, tertiary sodium phosphate, disodium hydrogen phosphate, monosodium phosphate, apple Acid, natrium malicum, lactic acid or sodium lactate.

31. the preparation method of soft capsule for removing thromboembolism preparation according to claim 28, it is characterised in that prepare capsule skin Blender further includes adjusting soft dose.

32. the preparation method of soft capsule for removing thromboembolism preparation according to claim 31, it is characterised in that soft dose of the tune Including cellulose, methylcellulose, carboxymethyl cellulose, hydroxymethyl cellulose, beeswax, paraffin, stearic acid or single hard fatty acids Glyceride.

33. a kind of application of any " Xuesaitong Injection " pharmaceutical composition and/or its preparation of claim 1 ~ 7, it is characterised in that The " Xuesaitong Injection " pharmaceutical composition and/or its preparation is preparing the application in preventing and/or treating cardiovascular and cerebrovascular diseases medicament.

34. a kind of application of any " Xuesaitong Injection " pharmaceutical composition and/or its preparation of claim 1 ~ 7, it is characterised in that The " Xuesaitong Injection " pharmaceutical composition and/or its preparation is in preparing prevention and/or treatment ischemic angiocardiopathy and cerebrovascular disease drug Application.

35. a kind of application of any " Xuesaitong Injection " pharmaceutical composition and/or its preparation of claim 1 ~ 7, it is characterised in that The " Xuesaitong Injection " pharmaceutical composition and/or its preparation is prevented in preparation and/or treatment ischemia apoplexy, cerebral infarction, brain are inclined Application in paralysed disease medicament.

36. a kind of application of any " Xuesaitong Injection " pharmaceutical composition and/or its preparation of claim 1 ~ 7, it is characterised in that The " Xuesaitong Injection " pharmaceutical composition and/or its preparation is preparing the application in preventing and/or treating retinopathy drug.

37. a kind of application of any " Xuesaitong Injection " pharmaceutical composition and/or its preparation of claim 1 ~ 7, it is characterised in that The " Xuesaitong Injection " pharmaceutical composition and/or its preparation is preparing prevention and/or is treating because optic atrophy, retinal pigment become Asthenopia caused by property or macula retinae or the application in visual impairment drug.

38. a kind of application of any " Xuesaitong Injection " pharmaceutical composition and/or its preparation of claim 1 ~ 7, it is characterised in that The " Xuesaitong Injection " pharmaceutical composition and/or its preparation is prevented preparing and/or is treated because of diabetes, angiocardiopathy, brain blood Application in retinopathy drug caused by pipe disease, neurogenic disease.