Technical background
Cardiac and cerebral vascular diseases is one of principal disease of harm humans health, also be harm humans life and healthy commonly encountered diseases and frequently-occurring disease, having sickness rate height, disability rate height, mortality rate height and the high characteristics of relapse rate, is the principal disease that middle age causes death and disables.Because the continuous increase and the growth in the living standard of aging population, the sickness rate of cerebrovascular is still in continuous rising.The most common with ischemic angiopathy again in the middle of cerebrovascular, the reason difference that takes place according to cerebral ischemia can be divided into the cerebral ischemia that cerebral thrombosis, cerebral embolism and hematodinamics obstacle cause.
Cerebral thrombosis makes intracranial or cranium, and arterial lumen is narrow or inaccessible outward, causes its blood supply district cerebral ischaemia, anoxia, infraction, causes the limitation delayed ischemic neurological deficits.As hemiplegia, hemianopsia, aphasia, half body sensation, spirit, disturbance of consciousness etc. often stay sequela.If Therapeutic Method in time, effectively not only can be saved patient's life, and can improve patient's quality of life greatly.
Cerebral embolism morbidity is hurried, and symptom is many to peak in several minutes or short time, and part patient can sicken for consciousness.The patient can enter stupor rapidly and symptoms of intracranial hypertension occur when big thromboembolism or multiple embolism.Local nerve disappearance symptom depends on the tremulous pulse of thromboembolism, mostly is hemiplegia or monoplegia, hemisensory loss, hemianopsia and tic etc.Aphasia, apraxia etc. can appear during the master hemispheric lesions.Most symptoms that protopathy can be arranged.How normal cerebrospinal fluid is except that increased pressure, but red infarct or bacterial embolus when causing brain infection cerebrospinal fluid can contain erythrocyte or be inflammatory and change, albumen also can increase.
In a word, in the ordering of the human various diseases cause of the death, cardiovascular and cerebrovascular disease is listed in first always, and ischemic cardio cerebrovascular diseases has become one of human main causes of death.
Contain Main Ingredients and Appearances such as Ginkgo total flavones glycoside, terpene lactone in the SHUXUENING ZHUSHEYE, they each have between unique effect mutually coordinative role again, terpene lactone is the main effective ingredient of Semen Ginkgo extrac, has the antagonism platelet activating factor, accelerating neurotransmitter upgrades, effectively anticoagulant is regulated blood flow and is reduced blood viscosity, reduces effects such as erythrocyte aggregation.Ginkgo flavonoid glycoside is the agent for capturing and the scavenger of oxygen-derived free radicals; participate in removing superoxide anion; suppress lipid peroxidation; strengthen blood vessel elasticity; thereby play the effect of protection brain cell, effectively improve the blood circulation joint of cardiovascular and cerebrovascular vessel, improve the oxygen delivery capacity of blood the heart and brain; and ginkgo bilobate extract has the protection cell function, so can the improvement effect be arranged to language and the memory dysfunction that the cardiovascular and cerebrovascular vessel embolism class diseases causes." a kind of Shuxuening injection formulation and technology thereof and indication " disclosed among the Chinese patent 200510090733.X.But in this invention, the complicated process of preparation of Shuxuening injection formulation, the production time is long, and the mass parameter of undeclared product.
Therefore, exploitation Shuxuening injection formulation new product will have than great society meaning and economic benefit.
Summary of the invention
The objective of the invention is to develop a kind of Shuxuening injection formulation and preparation method thereof, this Shuxuening injection formulation is used for prevention and treats coronary heart disease, angina pectoris, cerebral embolism, the cerebral vasospasm disease, main component is a ginkgetin alcohol glycosides, ginkalide A, ginkalide B, ginkalide C, bilobalide etc. have the antagonism platelet activating factor, accelerate neurotransmitter and upgrade, reduce blood viscosity, reduce effects such as erythrocyte aggregation.Said preparation has short treating period, instant effect, have no side effect and moderate, and plurality of advantages such as preparation method is easy, with short production cycle, is worth at clinical application.
A kind of Shuxuening injection formulation is characterized in that, described SHUXUENING ZHUSHEYE is to be prepared from by following parts by weight proportioning:
Major ingredient: Folium Ginkgo 50~1000
Adjuvant: ethanol 3000~5000
PH regulator 30~50
Surfactant 1~5
Oxidant 1~2.50
Injection solvent 1000-2000
Described preparation basically by the Folium Ginkgo of 50~1000g through the extraction separation macroporous resin adsorption, ultrafiltration gained content is ginkalide A (C
20H
24O
9) meter, must not be less than 0.03mg, ginkalide B, (C
20H
24O
10) meter, must not be less than 0.01mg, ginkalide C (C
20H
24O
11) must not count and be less than 0.02mg, and the extract that three's sum must not be less than 0.06mg forms, and the solvent of described injection is a distilled water for injection.
Surfactant is that disodiumedetate, oxidant are that sodium metabisulfite, PH regulator are sodium hydroxide in the described adjuvant.
A kind of preparation method of Shuxuening injection formulation is characterized in that, adopts by above-mentioned Shuxuening injection formulation prescription, adopts the preparation method of backflow alcohol extraction, water precipitating, cold preservation, resin absorption, ultrafiltration, and the step of described preparation method is as follows:
A. alcohol extraction refluxes: get Folium Ginkgo 50~1000g, add 65~95% ethanol, 500~5000ml for the first time, heat 60~100 ℃ and refluxed 1.5~2.5 hours.For the second time add 70~95% ethanol, 400~4000ml, heat 60~100 ℃ and refluxed 1.0~1.5 hours.Merge backflow;
B. water precipitating, cold preservation: backflow reclaims ethanol, 35~60 ℃ of temperature, and vacuum pressure 0.02~0.05MPA, gained water mixes liquid, adds purified water 200~1000ml, and cold preservation 8~24 hours with 0.45~0.65 filter membrane leaching supernatant, gets supernatant;
C. resin absorption: supernatant adopts macroporous adsorptive resins with 150~500ml/ hour flow velocity upper prop absorption, after the upper prop absorption, washes post with purification, abandons eluate, clarifies to effluent;
D.50~95% ethanol elution, 150~500ml/ hour flow velocity eluting is collected eluent, reclaim ethanol, 35~60 ℃ of temperature, vacuum pressure 0.02~0.05MPA, dealcoholysis liquid embedding 100~120 ℃ of sterilizations to the 500ml bottle, or vacuum drying promptly get Folium Ginkgo extract;
E. ultrafiltration: get Folium Ginkgo extract 2500~5000g and add water for injection to 200-2000ml, add disodiumedetate 0.1~0.3g again, sodium metabisulfite 0.1~3.0g, sodium hydroxide 20-50g, active carbon 1.0~5.0g boiled 15~30 minutes, Fibrous membrane filtration with 2000~20000 molecular weight, lamp inspection is sterilized 100~120 ℃ in embedding, packing promptly gets SHUXUENING ZHUSHEYE.
The adjuvant that the present invention adopts meets national standard, and rationalizes on consumption.
Preparation of the present invention is every of 5ml, every of 10ml.
Usage and dosage:
10ml of intramuscular injection, 1-2 time on the one.Intravenous drip, every day, 20ml with using behind 5% glucose injection dilution 250ml or the 500ml, or followed the doctor's advice.
The beneficial effect that compared with the prior art the present invention produces is:
1, SHUXUENING ZHUSHEYE of the present invention is applicable to prevention and treats coronary heart disease, angina pectoris, cerebral embolism, diseases such as cerebral vasospasm, expansible blood vessel, microcirculation improvement are applicable to ischemic cardio cerebrovascular diseases, main component is the apricot yellow keto-alcohol glycosides of argentiferous, ginkalide A, ginkalide B, ginkalide C, bilobalide etc., adopt resin absorption technique that every milliliter of flavonol glycosides is reached more than the 9.4mg, ginkalide A (C
20H
24O
9) meter, greater than 0.03mg, ginkalide B, (C
20H
24O
10) meter, greater than 0.01mg, ginkalide C (C
20H
24O
11) meter, greater than 0.02mg, and three's sum is greater than 0.06mg.Have the antagonism platelet activating factor, accelerate neurotransmitter and upgrade, reduce blood viscosity, reduce effects such as erythrocyte aggregation.
2, preparation technology of the present invention has adopted backflow alcohol extraction, water precipitating, cold preservation, resin absorption, and the method for ultrafiltration improves content of medicines, and impurity reduces, and product is more stable.
3, preparation technology of the present invention adopts macroporous adsorbent resin upper prop absorption supernatant.The absorption with macroporous adsorbent resin technology is compared with technology with traditional impurity-removing method has series of advantages: reduce the product moisture absorption, extract obtained color and luster is good, purity height, steady quality; Many operations consuming time such as equipment needed thereby is simple, has removed from staticly settling, and is concentrated, thus the production cycle shortened; Save packing, reduce cost.
4, preparation of the present invention has short treating period, and instant effect has no side effect and plurality of advantages such as moderate cost, therefore is worth at clinical application.
The specific embodiment
The present invention is described further below in conjunction with embodiment, and embodiment only means never that for indicative it limits the scope of the invention by any way.
Embodiment 1
The prescription that present embodiment provides SHUXUENING ZHUSHEYE to adopt is as follows:
Major ingredient: Folium Ginkgo 50g
Adjuvant: ethanol 3500ml
Sodium hydroxide 45g
Disodiumedetate 3g
Sodium metabisulfite 1.18g
Injection solvent 1000ml
Its preparation process:
1, gets Folium Ginkgo 50g, add 65~95% ethanol 500ml for the first time, heat 60~100 ℃ and refluxed 1.5~2.5 hours.For the second time add 70~95% ethanol 400ml, heat 60~100 ℃ and refluxed 1.0~1.5 hours.Merge backflow;
2, backflow reclaims ethanol, 35~60 ℃ of temperature, and vacuum pressure 0.02~0.05MPA, gained water mixes liquid, adds pure water 200~1000ml, and cold preservation 8~24 hours with 0.45~0.65 filter membrane leaching supernatant, gets supernatant;
3, supernatant is with the absorption of 150~500ml/ hour flow velocity upper prop, and macroporous adsorptive resins after the upper prop absorption, is washed post with purification, abandons eluate, clarifies to effluent;
4, the flow velocity eluting of 50~95% ethanol elutions (150~500ml/ hour) is collected eluent, reclaims ethanol, 35~60 ℃ of temperature, vacuum pressure 0.02~0.05MPA, the embedding of dealcoholysis liquid is sterilized 100~120 ℃ to the 500ml bottle, or vacuum drying, that is, and Folium Ginkgo extract;
5, Folium Ginkgo extract 2500~5000g adds water for injection to 1000ml, add disodiumedetate 0.1~0.3g again, sodium metabisulfite 0.1~3.0g, sodium hydroxide 20~50g, active carbon 1.0~5.0g boiled 15~30 minutes, Fibrous membrane filtration with 0.2~0.65, lamp inspection is sterilized 100~120 ℃ in embedding, packing promptly gets SHUXUENING ZHUSHEYE.
Embodiment 2
Major ingredient: Folium Ginkgo 500g
Adjuvant: ethanol 4000ml
Sodium hydroxide 35g
Disodiumedetate 2.5g
Sodium metabisulfite 1.2g
Injection solvent 1000ml
Its preparation process:
1, Folium Ginkgo 500g adds 65~95% ethanol 500ml for the first time, heats 60~100 ℃ and refluxes 1.5~2.5 hours.For the second time add 70~95% ethanol, 400~4000ml, heat 60~100 ℃ and refluxed 1.0~1.5 hours.Merge backflow;
2, backflow reclaims 35~60 ℃ of ethanol temperature, vacuum pressure 0.02~0.05MPA, and gained water mixes liquid, adds pure water 200~1000ml, and cold preservation 8~24 hours with 0.45~0.65 filter membrane leaching supernatant, gets supernatant;
3, supernatant is with the absorption of 150~500ml/ hour flow velocity upper prop, and macroporous adsorptive resins after the upper prop absorption, is washed post with purification, abandons eluate, clarifies to effluent;
4,150~500ml/ hour flow velocity eluting of 50~95% ethanol elutions is collected eluent, reclaims 35~60 ℃ of ethanol temperature, vacuum pressure 0.02~0.05MPA, the embedding of dealcoholysis liquid is sterilized 100~120 ℃ to the 500ml bottle, or vacuum drying, that is Folium Ginkgo extract;
5, Folium Ginkgo extract 2500~5000g adds water for injection to 1000ml, add disodiumedetate 0.1~0.3g again, sodium metabisulfite 0.1~3.0g, sodium hydroxide 20~50g, active carbon 1.0~5.0g boiled 15~30 minutes, Fibrous membrane filtration with 0.2~0.65, embedding, sterilization (100~120 ℃), lamp inspection, packing promptly gets SHUXUENING ZHUSHEYE.
Embodiment 3
Major ingredient: Folium Ginkgo 750g
Adjuvant: ethanol 5000ml
Sodium hydroxide 40g
Disodiumedetate 3.5g
Sodium metabisulfite 1.25g
Injection solvent 1500ml
Its preparation process:
1, Folium Ginkgo 750g adds 65~95% ethanol, 500~5000ml for the first time, heats 60~100 ℃ and refluxes 1.5~2.5 hours.For the second time add 70~95% ethanol, 400~4000ml, heat 60-100 ℃ and refluxed 1.0~1.5 hours.Merge backflow;
2, backflow reclaims 35~60 ℃ of ethanol temperature, vacuum pressure 0.02~0.05MPA, and gained water mixes liquid, adds pure water 200~1000ml, and cold preservation 8~24 hours with 0.45~0.65 filter membrane leaching supernatant, gets supernatant;
3, supernatant is with the absorption of 150~500ml/ hour flow velocity upper prop, and macroporous adsorptive resins after the upper prop absorption, is washed post with purification, abandons eluate, clarifies to effluent;
4,150~500ml/ hour flow velocity eluting of 50~95% ethanol elutions is collected eluent, reclaims 35~60 ℃ of ethanol temperature, vacuum pressure 0.02~0.05MPA, the embedding of dealcoholysis liquid is sterilized 100~120 ℃ to the 500ml bottle, or vacuum drying, that is Folium Ginkgo extract;
5, get Folium Ginkgo extract 2500~5000g and add water for injection to 1500ml, add disodiumedetate 0.1~0.3g again, sodium metabisulfite 0.1~3.0g, sodium hydroxide 20~50g, active carbon 1.0~5.0g boiled 15~30 minutes, Fibrous membrane filtration with 0.2~0.65, lamp inspection is sterilized 100~120 ℃ in embedding, packing promptly gets SHUXUENING ZHUSHEYE.
Embodiment 4
Major ingredient: Folium Ginkgo 1000g
Adjuvant: ethanol 5000ml
Sodium hydroxide 50g
Disodiumedetate 3.5g
Sodium metabisulfite 1.25g
Injection solvent 2000ml
Its preparation process:
1, Folium Ginkgo 1000g adds 65~95% ethanol, 500~5000ml for the first time, heats 60~100 ℃ and refluxes 1.5~2.5 hours.For the second time add 70~95% ethanol, 400~4000ml, heat 60-100 ℃ and refluxed 1.0~1.5 hours.Merge backflow;
2, backflow reclaims 35~60 ℃ of ethanol temperature, vacuum pressure 0.02~0.05MPA, and gained water mixes liquid, adds pure water 200~1000ml, and cold preservation 8~24 hours with 0.45~0.65 filter membrane leaching supernatant, gets supernatant;
3, supernatant is with the absorption of 150~500ml/ hour flow velocity upper prop, and macroporous adsorptive resins after the upper prop absorption, is washed post with purification, abandons eluate, clarifies to effluent;
4,150~500ml/ hour flow velocity eluting of 50~95% ethanol elutions is collected eluent, reclaims 35~60 ℃ of ethanol temperature, vacuum pressure 0.02~0.05MPA, the embedding of dealcoholysis liquid is sterilized 100~120 ℃ to the 500ml bottle, or vacuum drying, that is Folium Ginkgo extract;
5, get Folium Ginkgo extract 2500~5000g and add water for injection to 2000ml, add disodiumedetate 0.1~0.3g again, sodium metabisulfite 0.1~3.0g, sodium hydroxide 20~50g, active carbon 1.0~5.0g boiled 15~30 minutes, Fibrous membrane filtration with 0.2~0.65, lamp inspection is sterilized 100~120 ℃ in embedding, packing promptly gets the SHUXUENING injection
Macroporous adsorbent resin is that a class is not with the polymeric sorbent of the macroporous structure of ion-exchange group, be raw material mainly with styrene, divinylbenzene, in 0.5% gelatin aqueous suspension, adding a certain proportion of porogen is polymerized, can separate the purpose of purifying thereby reach by physical absorption selectable adsorb organic compound matter from aqueous solution.According to the difference of medicine liquid ingredient, the material difference of extraction, the resin of selection different model.Adsorbent resin, the particularly nonpolar adsorption resin composition in the absorption medicinal liquid mainly is that physical arrangement (as specific surface, aperture etc.) works.
The principle of macroporous adsorbent resin technology is: the molecule of any solid interior, the active force that is subjected to around it equates, and the active force that molecule is subjected on the surface of solids is unequal, so run into the material with its opposite charge on the surface, adsorption takes place promptly.And the adsorption of macroporous adsorbent resin mainly is by surface adsorption, surface electrical behavior or form hydrogen bond and wait and realize.
Compare with technology with traditional impurity-removing method, adopt the macroporous adsorbent resin technology to extract effective component of ginkgo leaf, yield and can be removed water-solubility impurity such as saccharide more than 8-10%, reduced the moisture absorption of extract, and color and luster is good, purity height, steady quality.
A, raising Chinese medicine inherent quality and preparation level, the refining thing that obtains after the macroporous adsorbent resin technical finesse can make composition highly enriched, impurity is few, removal of impurity is higher than 95%, general water-boiling method is about 70%-80%, alcohol deposition method is about 85%, and ginkgetin alcohol glycosides content can reach more than 70% after purifying with macroporous adsorption resin technology.
B, reduce the moisture absorption of product, the Chinese patent medicine major part of traditional handicraft preparation has stronger moisture absorption, it is the medium-term and long-term difficult problem that exists of Chinese medicine production and storage, and through after the macroporous adsorbent resin processing, can effectively remove moisture absorption compositions such as saccharides a large amount of in the decocting liquid, inorganic salt, phlegmatic temperament, help the production of plurality of Chinese dosage form, strengthen the stability of product.
C, macroporous adsorbent resin technology can shorten the production cycle, and equipment needed thereby is simple.Removed staticly settling from, many operations consuming time such as concentrated.Save packing, reduce cost, created condition for Chinese medicine enters the international market.
Adopt this extraction process to obtain Folium Ginkgo extract effective site, wherein ginkalide A (C
20H
24O
9) meter, greater than 0.03mg, ginkalide B, (C
20H
24O
10) meter, greater than 0.01mg, ginkalide C (C
20H
24O
11) meter, greater than 0.02mg, and three's sum is greater than 0.06mg.Be this product.
Clinical practice
Use the SHUXUENING ZHUSHEYE treatment and adopt International Society of Cardiology and WHO clinical name standard, make a definite diagnosis angina pectoris 50 examples of coronary heart disease stable type, give SHUXUENING ZHUSHEYE 20ml every day during the treatment, adds normal saline 500ml iv drip, every day 1 time, 14 days courses of treatment.Result (1) antianginal total effective rate: produce effects 16 examples in 50 examples, effective 25 examples, invalid 8 examples, total effective rate 82%.(2) exercise tolerance is improved situation: 50 routine exercise tolerancies are improved produce effects 19 examples, effective 17 examples, and invalid 12 examples worsen 2 examples, and effective percentage is 72%.(3) other: heart rate, blood pressure do not have significant change before and after the treatment.
Organize 56 examples by treatment and give SHUXUENING injection 20ml and add 5% glucose 500ml iv drip, the clinical efficacy of SHUXUENING ZHUSHEYE treatment postinfarction angina pectoris is observed in The control group Radix Astragali injection, Radix Salviae Miltiorrhizae Injection intravenous drip.The produce effects of treatment group as a result 47 examples, effective 5 examples, total effective rate 92.9%; Matched group produce effects 15 examples, effective 28 examples, total effective rate 76.8%.Two groups of curative effect comparing difference significances (p<0.01).SHUXUENING ZHUSHEYE has sure clinical efficacy to postinfarction angina pectoris.