CN1823803B - Erigeron breviscapus injection preparation and its preparation method - Google Patents

Erigeron breviscapus injection preparation and its preparation method Download PDF

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CN1823803B
CN1823803B CN2005101355007A CN200510135500A CN1823803B CN 1823803 B CN1823803 B CN 1823803B CN 2005101355007 A CN2005101355007 A CN 2005101355007A CN 200510135500 A CN200510135500 A CN 200510135500A CN 1823803 B CN1823803 B CN 1823803B
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dish flower
flower acetic
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CN1823803A (en
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张玉梅
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WANSHENG LIANHE PHARMACEUTICAL CO Ltd
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DUPROFIT PHARMACY Co Ltd
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Abstract

An injection of breviscapine B for promoting blood circulation and unblocking collaterals to relieve pain and its preparing process using reverse-phase efficient liquid chromatography for purifying are disclosed.

Description

A kind of breviscapine B injection preparation and preparation method thereof
Technical field
The invention belongs to the pharmaceutical technology field, specifically disclose a kind of breviscapine B injection preparation and preparation method thereof.
Background technology
Breviscapine be from the basis of medication among the people from Herba Erigerontis isolated flavone constituents, mainly containing lamp-dish flower acetic (is 5,6,7,4 '-four light basic flavone-7-O-glucuronic acid former times), oil lamp cycle of sixty years is plain and other related substances, wherein lamp-dish flower acetic is a strongest active effective ingredient.Modern pharmacological research shows that breviscapine has following effect: 1, cerebral blood flow increasing amount, reduce vascular resistance, and improve blood-brain barrier permeability; 2, the platelet aggregation and the blood high viscosity syndrome that are caused by Adenosine diphosphate former times of antagonism suppresses thrombosis; 3, effectively reduce plasma viscosity, packed cell volume, platelet aggregation rate and the Fibrinogen of Cerebral Infarction Patients, the lipoprotein metabolism that suppresses the ischemic cerebrovascular patient is unusual; 4, myocardial nutrition blood volume, microcirculation improvement, coronary artery dilator, decreased heart rate reduces myocardial contraction, reduces Peripheral resistance, reduces myocardial oxygen consumption, resists myocardial ischemia.Breviscapine is used for the treatment of paralysis, the sequela due to the cerebral hemorrhage and the ischemic cerebrovascular due to the obliterated cerebral vascular disease.As the dizziness due to cerebral thrombosis, cerebral embolism, the cerebral hemorrhage, headache, nose heave, spoken unclear, numb limbs and tense tendons apoplectic hemiplegia, paralysis etc.
In Breviscapini injection (20 in the Chinese medicine promulgated by the ministries or commissions of the Central Government) standard from checking that down the weight percentage of lamp-dish flower acetic (scutellarin) is only about 90% to the mensuration of related substance as can be seen.Note a next explanation at it: after using this product, phenomenons such as accidental itch all over, uncomfortable in chest, weak, erythra, cardiopalmus.As seen, fleabane injection in use, with the generation of untoward reaction.There are many documents that the report of Breviscapini injection untoward reaction is also arranged, and analyze because purity is high causes.In order to improve the purity of lamp-dish flower acetic, many research worker have been made very big effort: the patent documentation of application number CN200410000002.7 discloses a kind of highly purified breviscapine B injection agent, the purity of lamp-dish flower acetic wherein reaches 90%-99.5%, its content range interval is very big, illustrates for the removal effect of other composition limited; And do not mention the preparation method and the source of high-purity scutellarin in the description.The patent documentation of application number CN03130257.2 discloses preparation of a kind of administrated by injection that contains the scutellarin active component and preparation method thereof, the content of lamp-dish flower acetic wherein is 98%-102%, but do not disclose the preparation method of high-purity scutellarin in the description, make those skilled in the art to implement.
Summary of the invention
At above the deficiencies in the prior art, research worker of the present invention is furtherd investigate the purification process of the strongest effective ingredient lamp-dish flower acetic of the activity in the breviscapine, finally makes the content of lamp-dish flower acetic reach more than 98%.Research worker of the present invention is found in experiment unexpectedly, for the raising of lamp-dish flower acetic purity is not only to have removed easy initiation class pyrogen reaction and anaphylactoid impurity, further improved the purity and the stability of medicinal ingredient, but has improved the curative effect of medicine greatly.
An object of the present invention is to provide a kind of breviscapine B injection preparation.
Another object of the present invention provides the preparation method of above-mentioned ejection preparation.
Lamp-dish flower acetic of the present invention is that feedstock production forms with the breviscapine.
Above-mentioned breviscapine is the extract based on flavones ingredient that extracts from the medical material Herba Erigerontis.
Above-mentioned raw material breviscapine can be that the Herba Erigerontis medical material is prepared from according to the method for making under 20 breviscapine quality standards of Chinese medicine promulgated by the ministries or commissions of the Central Government item, also can be the commercially available prod that meets its standard, and wherein the content of lamp-dish flower acetic is about 90%.
The purity of contained active component lamp-dish flower acetic is 98%-99.6% in the breviscapine B injection preparation of the present invention, is breviscapine is obtained by the method for preparing type reversed-phase high-performance liquid chromatography column purification.
Specifically, above-mentioned lamp-dish flower acetic is by breviscapine is passed through with octadecylsilane chemically bonded silica (C 18) obtain for the method for preparing type reversed-phase high-performance liquid chromatography column purification of filler.
In particular, above-mentioned lamp-dish flower acetic prepares by the following method:
Breviscapine is dissolved with small amount of ethanol, and being added to filler diameter 20-40 μ m, internal diameter 10-20cm, column length is internal diameter 4-5 preparation type C doubly 18On the performance liquid chromatographic column, with 40-80% alcoholic solution eluting, detector detects at wavelength 335nm place, collects the eluent that is rich in lamp-dish flower acetic, merges, and membrance concentration is scraped in rotation, and drying promptly gets lamp-dish flower acetic, and its purity is greater than 98%.
Above-mentioned preparation type C 18Performance liquid chromatographic column is preferably filler diameter 30 μ m, internal diameter 20cm, column length is 4 times of internal diameters.
Above-mentioned eluent is preferably the alcoholic solution of 60-70%.
Above-mentioned lamp-dish flower acetic can be prepared into the above various dosage forms of pharmaceutics, comprises oral formulations and ejection preparation, is preferably ejection preparation.
Comprise injection with small volume and high-capacity injection in the above-mentioned ejection preparation, secondly also comprise injectable powder and lyophilized injectable powder, be preferably high-capacity injection.
The preparation method of breviscapine B injection preparation of the present invention is as follows:
The preparation of injection with small volume: get above-mentioned lamp-dish flower acetic and dissolve with water for injection, adjust pH is 6.0-7.0, and with 0.22 μ m filtering with microporous membrane, sterilization is prepared into injection with small volume.
The preparation of high-capacity injection: get above-mentioned lamp-dish flower acetic and dissolve with water for injection, add isoosmotic adjusting agent, adjust pH is 6.0-7.0, and with 0.22 μ m filtering with microporous membrane, sterilization is prepared into high-capacity injection.
The preparation of powder injection formulation: get above-mentioned lamp-dish flower acetic and dissolve with water for injection, add the water-soluble injection excipient, adjust pH is 6.0-7.0, and with 0.22 μ m filtering with microporous membrane, drying is prepared into powder injection formulation.
The preparation of freeze-dried powder: get above-mentioned lamp-dish flower acetic and dissolve with water for injection, add the water-soluble injection excipient, adjust pH is 6.0-7.0, and with 0.22 μ m filtering with microporous membrane, lyophilization is prepared into freeze-dried powder.
In the preparation method of above-mentioned high-capacity injection, described isoosmotic adjusting agent can be sodium chloride, glucose etc., is preferably glucose.
In the above-mentioned preparation method, described water-soluble injection excipient can be a kind of, two or more the mixture in mannitol, fructose, glucosan, polyvinylpyrrolidone, the dextran etc.
Lamp-dish flower acetic high-capacity injection of the present invention, character are colourless or xanchromatic clear liquid, and specification can be 100ml, 250ml, 500ml, and most preferred specification is 250ml, and every bottle contains lamp-dish flower acetic 20mg and isoosmotic adjusting agent 12.5g.
Breviscapine B injection liquid of the present invention when clinical practice, intramuscular injection, a 5mg, 2 times on the one; Intravenous drip, one time 1 bottle, 1 time on the one.
Breviscapine B injection preparation of the present invention has activating blood circulation to dissipate blood stasis, the effect of removing obstruction in the collateral to relieve pain can be used for clinically: ischemic cerebrovascular and sequela thereof such as cerebral thrombosis, cerebral embolism, transient ischemic attack, cerebral arteriosclerosis, vascular dementia; The sequela of hemorrhagic apoplexy; Ischemic cardio cerebrovascular diseases such as coronary heart disease, angina pectoris, myocardial infarction; All ischemias reach with diseases with microcirculatory disturbance; Multiple organ injury, acute brain decline, renal failure, exhale disease such as decline.
Lamp-dish flower acetic is the Flavonoid substances that extracts in the Herba Erigerontis, and it can make, and platelet content reduces in the thrombosis, and alleviates hematoblastic destruction and 5-hydroxy tryptamine release reaction, to the arachidonic acid metabolite TXB of platelet and vascular endothelial cell 2With 6-Keto-PEG 1 αGeneration all inhibited; Lamp-dish flower acetic can also obviously reduce cerebral vascular resistance and periphery blood pressure; In addition, lamp-dish flower acetic can also increase coronary flow, causes that the outer platelet cAMP content of human body increases, and improves blood-brain barrier permeability.
The raising of lamp-dish flower acetic purity has been removed easy initiation class pyrogen reaction and anaphylactoid impurity, has further been improved the purity and the stability of medicinal ingredient.
Research worker of the present invention is measured the purity of 6 batches of lamp-dish flower acetics of the present invention.Method is according to " high performance liquid chromatography under Chinese pharmacopoeia 2005 the version Herba Erigerontis (Herba Erigerontis) is measured.Assay the results are shown in Table 1.
Table 1 lamp-dish flower acetic purity testing result
By above-mentioned assay result as can be seen, the purity of 6 batches of lamp-dish flower acetics is between 98.0%-99.6%.
Breviscapine high-capacity injection and lamp-dish flower acetic high-capacity injection of the present invention that research worker of the present invention is prepared into 100 bottles respectively with breviscapine and the lamp-dish flower acetic of the present invention of 2g.Under home, placed 2 years, observe stability.
The result: breviscapine high-capacity injection less stable, the situation that had color exception, precipitation foreign body to separate out in 2 years takes place; And breviscapine high-capacity injection good stability of the present invention, little abnormal phenomena takes place in 2 years.
Research worker of the present invention is the contrast medicine with the Breviscapini injection, and breviscapine B injection liquid of the present invention has been carried out the anaphylaxis observation.
Anaphylaxis is an allergy, belong to the Type B untoward reaction, be and the irrelevant abnormal response of the conventional pharmacological action of medicine, be difficult to prediction usually and whether can occur on one's body concrete patient, be difficult in the conventional toxicology test in drug research stage find that general and dosage has nothing to do.Allergy is a kind of abnormal immunoreaction that is taken place between exogenous antigen material and internal antibody.Hapten material and body internal protein in the Chinese medicine injection are combined into holoantigen, thereby cause allergic reaction.
For the ease of relatively, research worker of the present invention with anaphylaxis be divided into slightly, moderate, 3 grades of severe: slightly the person shows skin pruritus with the red grouper pimple etc.; Moderate person is dyspnea then, headache, nervous, uncomfortable in chest, rapid breathing, and the while is with in various degree skin allergy; Severe person shows as anaphylactic shock, and the patient breathes hard uncomfortable in chest, dyspnea, and pale complexion, cold limbs, lip cyanosis, dripping sweat, blood pressure reduces.
The clinical practice data: patient 60 people, each 30 people of matched group and medicine group of the present invention, men and women are half-and-half.Intravenous drip gives control drug Breviscapini injection and breviscapine B injection liquid of the present invention, observed result.
The result: matched group has 4 examples allergy to occur, and wherein 2 examples are mild reaction, and 2 examples are the moderate reaction; Allergy does not then appear in medicine group of the present invention.Illustrate that breviscapine B injection preparation comparison of the present invention is safer according to medicine.
Research worker of the present invention finds, the raising of lamp-dish flower acetic purity is not only to have removed easy initiation class pyrogen reaction and anaphylactoid impurity, further improved the purity and the stability of medicinal ingredient, but can improve the curative effect of medicine greatly.
Research worker of the present invention is found: the dose-effect curve instability of Breviscapini injection, along with the increase of dosage, the effect that medicine produced is the raising of fluctuation formula.Promptly in a certain dosage scope, the effect that the effect that high dose produced produces less than low dosage on the contrary.And the dose-effect curve of lamp-dish flower acetic of the present invention is proportionate, and promptly along with the increase of dosage, the effect that medicine produced is also increasing.Under the identical condition of the dosage of Breviscapini injection and breviscapine B injection preparation of the present invention, the effect that breviscapine B injection preparation of the present invention produces is apparently higher than fleabane injection.Illustrate that the raising of lamp-dish flower acetic purity in the breviscapine B injection preparation of the present invention can obviously improve the curative effect of medicine.
The specific embodiment
Following embodiment further describes the present invention, but described embodiment only is used to illustrate the present invention rather than restriction the present invention.
Embodiment 1
The Herba Erigerontis medical material is prepared into breviscapine according to the method for making under the Herba Erigerontis prime implicant in 20 in the Chinese medicine promulgated by the ministries or commissions of the Central Government.
Embodiment 2
Above-mentioned breviscapine is dissolved with small amount of ethanol, be added to filler diameter 20 μ m, internal diameter 20cm, column length is the preparation type C of 5 times of internal diameters 18On the performance liquid chromatographic column, with 40% alcoholic solution eluting, detector detects at wavelength 335nm place, collects the eluent that is rich in lamp-dish flower acetic, merges, and membrance concentration is scraped in rotation, and drying promptly gets lamp-dish flower acetic.
Embodiment 3
Commercially available standard compliant breviscapine is dissolved with small amount of ethanol, be added to filler diameter 40 μ m, internal diameter 10cm, column length is the preparation type C of 4 times of internal diameters 18On the performance liquid chromatographic column, with 80% alcoholic solution eluting, detector detects at wavelength 335nm place, collects the eluent that is rich in lamp-dish flower acetic, merges, and membrance concentration is scraped in rotation, and drying promptly gets lamp-dish flower acetic.
Embodiment 4
Above-mentioned breviscapine is dissolved with small amount of ethanol, be added to filler diameter 30 μ m, internal diameter 15cm, column length is the preparation type C of 5 times of internal diameters 18On the performance liquid chromatographic column, with 60% alcoholic solution eluting, detector detects at wavelength 335nm place, collects the eluent that is rich in lamp-dish flower acetic, merges, and membrance concentration is scraped in rotation, and drying promptly gets lamp-dish flower acetic.
Embodiment 5
Above-mentioned breviscapine is dissolved with small amount of ethanol, be added to filler diameter 30 μ m, internal diameter 20cm, column length is the preparation type C of 4 times of internal diameters 18On the performance liquid chromatographic column, with 70% alcoholic solution eluting, detector detects at wavelength 335nm place, collects the eluent that is rich in lamp-dish flower acetic, merges, and membrance concentration is scraped in rotation, and drying promptly gets lamp-dish flower acetic.
Embodiment 6
Get above-mentioned lamp-dish flower acetic and dissolve with water for injection, adjust pH is 6.0, and with 0.22 μ m filtering with microporous membrane, sterilization is prepared into injection with small volume.
Embodiment 7
Get above-mentioned lamp-dish flower acetic and dissolve with water for injection, add glucose, adjust pH is 6.5, and with 0.22 μ m filtering with microporous membrane, sterilization is prepared into high-capacity injection.
Embodiment 8
Get above-mentioned lamp-dish flower acetic and dissolve with water for injection, add mannitol and glucosan, adjust pH is 7.0, and with 0.22 μ m filtering with microporous membrane, drying is prepared into powder injection formulation.
Embodiment 9
Get above-mentioned lamp-dish flower acetic and dissolve with water for injection, add polyvinylpyrrolidone, dextran, adjust pH is 6.5, and with 0.22 μ m filtering with microporous membrane, lyophilization is prepared into freeze-dried powder.

Claims (8)

1. a breviscapine B injection preparation is characterized in that, the purity of contained active component lamp-dish flower acetic is 98%-99.6% in the described ejection preparation, is that breviscapine is obtained by the method for preparing type reversed-phase high-performance liquid chromatography column purification;
Described lamp-dish flower acetic prepares by the following method:
Breviscapine is dissolved with small amount of ethanol, and being added to filler diameter 20-40 μ m, internal diameter 10-20cm, column length is internal diameter 4-5 preparation type C doubly 18On the performance liquid chromatographic column, with 40-80% alcoholic solution eluting, detector detects at wavelength 335nm place, collects the eluent that is rich in lamp-dish flower acetic, merges, and membrance concentration is scraped in rotation, and drying promptly gets lamp-dish flower acetic.
2. the preparation method of the described ejection preparation of claim 1 is characterized in that, may further comprise the steps:
Breviscapine is dissolved with small amount of ethanol, and being added to filler diameter 20-40 μ m, internal diameter 10-20cm, column length is internal diameter 4-5 preparation type C doubly 18On the performance liquid chromatographic column, with 40-80% alcoholic solution eluting, detector detects at wavelength 335nm place, collects the eluent that is rich in lamp-dish flower acetic, merges, and membrance concentration is scraped in rotation, and drying promptly gets lamp-dish flower acetic.
3. preparation method according to claim 2 is characterized in that, described chromatographic column filler diameter 30 μ m, internal diameter 20cm, column length are 4 times of internal diameters.
4. preparation method according to claim 2 is characterized in that, described eluent is the alcoholic solution of 60-70%.
5. preparation method according to claim 2 is characterized in that, and is further comprising the steps of:
The preparation of injection with small volume: get above-mentioned lamp-dish flower acetic and dissolve with water for injection, adjust pH is 6.0-7.0, and with 0.22 μ m filtering with microporous membrane, sterilization is prepared into injection with small volume;
The preparation of high-capacity injection: get above-mentioned lamp-dish flower acetic and dissolve with water for injection, add isoosmotic adjusting agent, adjust pH is 6.0-7.0, and with 0.22 μ m filtering with microporous membrane, sterilization is prepared into high-capacity injection;
The preparation of powder injection formulation: get above-mentioned lamp-dish flower acetic and dissolve with water for injection, add the water-soluble injection excipient, adjust pH is 6.0-7.0, and with 0.22 μ m filtering with microporous membrane, drying is prepared into powder injection formulation;
The preparation of freeze-dried powder: get above-mentioned lamp-dish flower acetic and dissolve with water for injection, add the water-soluble injection excipient, adjust pH is 6.0-7.0, and with 0.22 μ m filtering with microporous membrane, lyophilization is prepared into freeze-dried powder.
6. preparation method according to claim 5 is characterized in that, described isoosmotic adjusting agent is a glucose.
7. preparation method according to claim 5 is characterized in that, described water-soluble injection excipient is selected from one or both the mixture in mannitol, fructose, glucosan, polyvinylpyrrolidone, the dextran.
8. the described ejection preparation of claim 1 has the effect of blood circulation promoting and blood stasis dispelling, removing obstruction in the collateral to relieve pain.
CN2005101355007A 2005-12-31 2005-12-31 Erigeron breviscapus injection preparation and its preparation method Active CN1823803B (en)

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CN101493444B (en) * 2009-02-23 2011-10-05 云南植物药业有限公司 Quality control method for breviscapine precursor lipidosome

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1565465A (en) * 2003-06-26 2005-01-19 天津药物研究院 Injection preparation containing breviscapine active component and its preparation method
CN1640409A (en) * 2004-01-02 2005-07-20 广东奇方药业有限公司 High-purity scutellarin injection agent

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1565465A (en) * 2003-06-26 2005-01-19 天津药物研究院 Injection preparation containing breviscapine active component and its preparation method
CN1640409A (en) * 2004-01-02 2005-07-20 广东奇方药业有限公司 High-purity scutellarin injection agent

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