CN1850097A - Scutellarin injection preparation and its preparing method - Google Patents
Scutellarin injection preparation and its preparing method Download PDFInfo
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- CN1850097A CN1850097A CN 200610010907 CN200610010907A CN1850097A CN 1850097 A CN1850097 A CN 1850097A CN 200610010907 CN200610010907 CN 200610010907 CN 200610010907 A CN200610010907 A CN 200610010907A CN 1850097 A CN1850097 A CN 1850097A
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Abstract
The present invention relates to a breviscapine injection preparation and its preparation method. It includes a water injection preparation formed from breviscapine-Na and aqueous solution stable system composed of medicinal organic alkali whose pH value is 7-8 and organic acid. The medicinal excipient also can be added into the above-mentioned material for making water injection preparation so as to obtain the invented breviscapine freeze-dried powder injection preparation. Besides, said invention also provides the concrete steps of its preparation method.
Description
Technical field
The present invention relates to the pharmaceutics field.
Background technology
Herba Erigerontis is feverfew Erigeron breviscapus (Vant.) Hand.-Mazz. (Erigeron breviscapus (vant) Hand-Mazz), record in " the southern regions of the Yunnan Province book on Chinese herbal medicine " 1974 annual income Yunnan Province drug standards (Herba Erigerontis (Herba Erigerontis), Yunnan Q/W62-1974) the earliest, included Chinese Pharmacopoeia (an one, 245 pages) in 1977 in.Yunnan Pharmaceutical Institute in 1980 extract the flavonoid composition of treatment apoplexy and sequela thereof from Herba Erigerontis, and are developed into aqueous injection.The flavonoid composition called after breviscapine (breviscapine, Yunnan Q/W696-1984) that Yunnan Province Department of Public Health in 1984 will extract from Herba Erigerontis, and worked out the quality standard (Breviscapini injection, Yunnan Q/WS697-1984) of aqueous injection, the listing of approval aqueous injection.Breviscapine belongs to flavonoid glycoside (glycosides) class, and is water insoluble, but dissolve in dilute alkaline soln (institute of Materia Medica,Chinese Academy of Medical Sciences is compiled, " research of Chinese herbal medicine active ingredient ", People's Health Publisher's version in 1972, P220).Breviscapini injection comes down to the breviscapine sodium salt that will generate after breviscapine and the reaction of sodium bicarbonate, and therefore, Yunnan Pharmaceutical Institute has solved the water-fast problem of breviscapine (Herba Erigerontis flavonoid composition).After 1989, breviscapine be made into iron salt, magnesium salt, calcium salt (the Wang Zhao battle-axe used in ancient China, etc., Chinese herbal medicine, 1989,20 (2): 23～25) and alkaline amino acid salt (CN1049121C) be applied to pharmacological research or clinical.
Breviscapine dissolves in the dilute alkaline soln, when PH can not cause breviscapine chain rupture or oxidation (the preparation PH of the quality standard of Breviscapini injection and injection breviscapine regulation was 6～8 so far from 1980) below 8.Yet, the alkaline solution instability of breviscapine: the one, the flavonoid composition of non-flavonoid glycoside (glycosides) class is gathered into flocculent deposit and separates out along with the prolongation of time, cause the clarity of preparation defective; The 2nd, can separate out precipitation when mixing use with glucose injection acid medicinal liquids such as (PH3.2～5.5).For solving the unstability of breviscapine injection, many patents are disclosed.Summary is got up, and the instable method that these solve the breviscapine injection is to add " stabilizing agent " in the breviscapine injection." a kind of stability-enhanced breviscapine injection and preparation method thereof " described stabilizing agent as CN1555807A is organic base, organic acid, antioxidant.A kind of in citrate in the organic base, meglumine, sodium pantothenate, L-cysteine, benzene methanamine, nicotiamide, thiourea, ethanolamine, the urea or two kinds; A kind of in citric acid in the organic acid, acetic acid, oxalic acid, maleic acid, succinic acid, fumaric acid, malic acid, tartaric acid, the ascorbic acid or two kinds; Antioxidant has one or more in sodium sulfite, sodium sulfite, sodium pyrosulfite, L-cysteine, the ascorbic acid.What also have uses the metal ion intercalating agent as stabilizing agent, " prescription that Breviscapini injection is stable and technical process " as CN1187356A, EDTA-2Na is used as the stabilizing agent of Breviscapini injection, L-cysteine, hexamethylenamine, sodium pyrosulfite, phosphoric acid salt, nicotiamide, ethanolamine, propylene glycol, sodium sulfite, carbonate or bicarbonate, thiourea etc. have also been announced simultaneously.CN1476840A discloses " a kind of preparation method of stable Breviscapini injection ", with CN1187356A is example, negated above-mentioned series of stable agent: " Chinese patent CN1187356A disclosed in 1998; disclose the stable prescription of a kind of Breviscapini injection; adopt the series of stable agent; pH value is transferred to 7.0～7.8, in fact still can not solve stability problem ".This patent application has proposed to think and can solve the method for stablizing the breviscapine injection: be Main Ingredients and Appearance with the breviscapine, in preparation process, add arginine, and adjusting pH value to 4.5～6.5, and incite somebody to action " add the L-arginine in the preparation process; adjusting pH value to 4.5～5.6, the arginic amount of L-is 40～80mg/100ml " and included claim in.
The breviscapine injection is except because preparation itself instability, separate out precipitation in the storage easily, cause clarity defective outside, when the Herba Erigerontis injection mixes use with glucose injection (PH3.2～5.5), Dextrose and Sodium Chloride Inj., if the pH value of these preparations is lower than 4, then in preparation or infusion process, can separate out precipitation, bring safety problem.
Breviscapine), rather than lamp-dish flower acetic (scutellarin) the legal notion of breviscapine is flavonoid composition (the 20 in Ministry of Health of the People's Republic of China's drug standard Chinese traditional patent formulation preparation, the P103: in the Herba Erigerontis.A kind of in the plain just breviscapine of second, however but be main efficacy component.Therefore, all be amount with the quality standard of all preparations of breviscapine using names with efficacy component in the content decision preparation of lamp-dish flower acetic.Because the method for legal detection lamp-dish flower acetic content is the uv-spectrophotometric absorption coefficient method in the quality standard before 2005, this method is all thought every absorption value at the 335nm wavelength by mistake to be the absorption value of lamp-dish flower acetic, to not lamp-dish flower acetic, but also there is the material of absorption all to be used as the plain content that calculates of second at the 335nm wavelength, thereby measurement result is inevitable higher, causes the second cellulose content in the now commercially available Breviscapine (oral agents, tablet, aqueous injection, injectable powder etc.) to detect generally all below 90% with high performance liquid chromatography.That is to say that Shang Shi breviscapine and preparation thereof are not pure lamp-dish flower acetic preparations now, but contain the mixture of 6-11 kind Herba Erigerontis Flavonoid substances.The applicant discloses the preparation method of lamp-dish flower acetic content at the breviscapine B raw material medicine that (detects with high performance liquid chromatography) more than 98% in application in 2004, disclosed " preparation technology of high-purity medicine with lamp-dish flower acetic as raw material " (application number is respectively: CN200410010182.1, CN200410040352.6, CN200410062573.3) in 2005, prepares lamp-dish flower acetic (rather than breviscapine) crude drug first.
That is to say, above the technical scheme of the solution breviscapine injection stability problem reported all be at the breviscapine crude drug, rather than at breviscapine B raw material medicine.
The lamp-dish flower acetic of having purified, because its structure is 4 ', 5 ', 6 '-trihydroxyflavone-7-O-glucuronide, (the metal ion displacement of hydrion COOH) and organic base or inorganic base or basic salt of carboxyl on its glucose, the plain salt of the second that generates and soluble in water than breviscapine (mixture of 4-11 kind flavone), but the injection of scutellarin (aqueous injection, injectable powder) also exists the injection lower with PH (is the glucose injection of 3.2-5.5 as PH) to mix when using sedimentary problem can occur; When the breviscapine B injection liquid of preparation high concentration, be prone to the underproof problem of clarity.The instability problem that does not relate to above-mentioned breviscapine B injection agent among the Chinese patent application CN1640409A " a kind of highly purified breviscapine B injection agent ".But for highly purified lamp-dish flower acetic, its stability problem is more outstanding than the low-purity lamp-dish flower acetic.
Therefore, the stability problem of breviscapine B injection agent is still unresolved so far.
Summary of the invention
Purpose of the present invention is intended to overcome the deficiencies in the prior art, and providing a kind of is ejection preparation crude drug, stable with the high-purity scutellarin.
Another object of the present invention is to provide the preparation method of this ejection preparation.
Breviscapine B injection preparation of the present invention is the aqueous injection that the medicinal organic base of 7-8 and stabilized aqueous solution system that organic acid is formed form by lamp-dish flower acetic-Na and PH, or adds the lyophilized injectable powder that medicinal vehicle group becomes again.
Described lamp-dish flower acetic-Na is a purity greater than the lamp-dish flower acetic sodium that generates after 98% breviscapine B raw material medicine and the reaction of sodium bicarbonate; Described organic base is the L-arginine; Described organic acid is a glacial acetic acid; Described stabilized aqueous solution system is the L-arginine: the mass ratio of glacial acetic acid is 1: 0.28～0.33 aqueous solution system that is formed.The arginic weight ratio of lamp-dish flower acetic in this preparation: L-is 1: 0.3～0.6; The arginic concentration of L-is 1500～3000mg/100ml injection.Described pharmaceutical excipient is a kind of in mannitol, low molecular dextran, the glycine etc. or 2 kinds.
Breviscapine B injection agent of the present invention (aqueous injection and lyophilized injectable powder) is to be efficacy component with the lamp-dish flower acetic more than 98%, is dissolved in water with the form of the plain sodium of second, is stabilisation systems with L-arginine-glacial acetic acid, and PH is 7-8.
The preparation method of breviscapine B injection preparation of the present invention is made up of following steps: preparation lamp-dish flower acetic sodium water solution; Preparation PH is L-arginine-glacial acetic acid stabilisation systems of 7-8; The two mixing is added water for injection to desired concn, and the aseptic filtration packing is aqueous injection; Or add excipient again, and add water for injection to desired concn, the aseptic filtration packing, lyophilizing is lyophilized injectable powder.
Concrete steps are:
One, preparation stabilisation systems: get the L-arginine of described amount, after the dissolving, add the glacial acetic acid of described amount in the adding injection water; Mixing is added water for injection, and survey PH is 7-8, is L-arginine-glacial acetic acid stabilisation systems;
Two, preparation lamp-dish flower acetic-Na solution: take by weighing breviscapine B raw material medicine, add in the injection water, the heating hydrotropy adds NaHCO
3Transfer PH to 7-8, mixing is the lamp-dish flower acetic sodium salt solution;
Three, step (), (two) are mixed, add water for injection, make wherein that the arginic concentration of L-is 1500～3000mg/100ml injection to 1000ml, aseptic filtration or autoclaving, packing promptly obtains breviscapine B injection liquid; Or injection adds excipient again, aseptic filtration or autoclaving, and packing, lyophilization is injection lamp-dish flower acetic lyophilized injectable powder.
The present invention is that the plain monomer of pure second that reaches more than 98% with purity is a crude drug, thereby breviscapine B injection preparation of the present invention is a kind of brand-new ejection preparation.The present invention and CN1476840A are essentially different: 1. the present invention is a scutellarin monomer injection, rather than breviscapine (total flavones) injection.2, stabilisation systems is made up of L-arginine and glacial acetic acid.(3) PH of adding stabilisation systems is 7-8, and promptly injection PH is 7-8, rather than 4.5～6.5.4, the arginic concentration C N1476840A of L-is 40-80mg/100ml, and this patent is 1500～3000mg/100ml, is 37.5 times of CN1476840A patent consumption.5, CN1476840A breviscapine: arginine=1: 2.5, L-arginine consumption are nearly 2.5 times of efficacy component; Patent lamp-dish flower acetic of the present invention: L-arginine=1: 0.3～0.6 is 30%～60% of an efficacy component.
The not mentioned L-arginine of the difference of the present invention and CN155807A: CN155807A.In hundreds of related technical scheme of CN155807A, all do not relate to L-arginine of the present invention-glacial acetic acid system.
Therefore, the stabilisation systems of lamp-dish flower acetic aqueous solution of the present invention is brand-new stabilisation systems.
1, stability test of the present invention:
Detect through HPLC, the plain purity of second reaches more than 98%; Embodiment 1 injection is 3.2 at PH, concentration is in 5% the glucose injection＞solution was limpid in 8 hours, and do not have precipitation and separates out; In PH is 4.2 above-mentioned glucose solution＞and solution was limpid in 24 hours, and do not have precipitation and separates out.The lamp-dish flower acetic sodium-salt parenteral solution that does not add stabilisation systems of the present invention is 2 minutes solution muddinesses in 3.2,5% the glucose injection at PH, and there is the graininess precipitation to separate out, at PH is 6 hours muddinesses in 4.2 5% the glucose injection, and has the graininess precipitation to separate out (seeing Table 1).
Table 1 reaches more than 98% at 5% glucose injection (250ml) moderate purity of different PH
The stable contrast table of breviscapine B injection liquid (50mg/ml)
| The plain sodium of second+stabilisation systems injection | Second element-sodium injection (not adding stabilisation systems) | ||
| 5% Glucose Liquid pH value | Particulate matter or muddy zero-time are arranged | 5% Glucose Liquid pH value | Particulate matter or muddy zero-time are arranged |
| 3.2 | ＞8h | 3.2 | 2′ |
| 3.3 | ＞8h | 3.3 | 3′ |
| 3.4 | ＞8h | 3.4 | 4′ |
| 3.5 | ＞8h | 3.5 | 7′ |
| 3.6 | ＞16h | 3.6 | 10′ |
| 3.7 | ＞24h | 3.7 | 14′ |
| 3.8 | ＞24h | 3.8 | 42′ |
| 3.9 | ＞24h | 3.9 | 56′ |
| 4.0 | ＞24h | 4.0 | 2h23′ |
| 4.1 | ＞36h | 4.1 | 4h38′ |
| 4.2 | ＞48h | 4.2 | 6h |
2, to the influence of rabbit platelet aggregation rate
Carried out the anticoagulant test with embodiment 1 injection lamp-dish flower acetic with rabbit.36 of the big ear rabbits of Japan are divided into 5,10,20,40, five administration groups of 80mg/kg and 1 normal saline matched group.Every group from ear vein administration 1 time, injected for 3 weeks continuously, behind the 21st day intravenously administrable, got blood from quiet, arterial cannulation in 10 minutes, survey platelet aggregation rate with the LBY-NJ blood agglutometer that Pulisheng Precision Instruments Research Center, Beijing produces, calculate platelet aggregation inhibition rate with the BornShi method, with SPSS 11.5 computer software multiple dosing one factor analysis of variance method Processing Test data, 80mg/kg body weight group is 37.46% (seeing Table 2) to the suppression ratio of platelet aggregation as a result.
Many ear vein injections of table 2 lamp-dish flower acetic lyophilized injectable powder is to the influence of rabbit platelet aggregation rate
| Group | Dosage (mg/kg) | Maximum agglutination rate (%) | Suppression ratio (%) |
| The normal saline scutellarin | 5 10 20 40 80 | 70.10±4.99 64.63±8.70 52.29±4.27 * 56.62±7.08 ** 53.86±9.96 ** 43.84±8.51 *** | 7.8 15.4 19.23 23.17 37.46 |
Annotate: x ± S, n=6, one factor analysis of variance,
*P＜0.05,
*P＜0.01,
* *P＜0.001.
3, safety testing
2% rabbit erythrocyte there is not haemolysis; Acute toxicity test in mice records median lethal dose(LD 50) LD
50(95% confidence region is 1477.412～1904.02mg), far above the median lethal dose(LD 50) 1314mg/kg of breviscapine for 1677.212mg/kg; In above 13 weeks of 32 continuous quiet notes 40mg/kg of Begle dog (2400mg/60kg), in 4 weeks of convalescent period, do not see any toxic reaction; 3 continuous intravenous injection 200mg/kg of machin (12000mg/60kg) in 10 weeks of test period, do not observe the overt toxicity reaction.Therefore, the breviscapine B injection agent of the present invention's preparation is safer and more effective.
The specific embodiment
Embodiment 1: injection (50mg/ml/ bottle):
(1) preparation of lamp-dish flower acetic-Na (PH7.5) ∷
Lamp-dish flower acetic (purity is more than 98%) 50g
NaHCO
3(being mixed with 10% aqueous solution) 8.5～9.5g
Injection water adds to 750ml
(2) stabilisation systems preparation (PH 7.5):
L-arginine 17g
Glacial acetic acid 5ml
Injection water adds to 200ml
(3) injection lamp-dish flower acetic:
Lamp-dish flower acetic-Na (1) 750ml
Stabilisation systems (2) 200ml
Injection water is added to 1000ml
Be distributed into 1000 bottles of injection.
Embodiment 2: injection lyophilized preparation (100mg/2ml/ bottle)
(1) preparation of lamp-dish flower acetic-Na (PH7.5)
Lamp-dish flower acetic (purity is more than 98%) 100g
NaHCO
3(being mixed with 10% aqueous solution) 17～19g
Injection water is added to 1500ml
(2) stabilisation systems preparation (PH7.5)
L-arginine 34g
Glacial acetic acid 10ml
Injection water adds to 400ml
(3) injection lamp-dish flower acetic prescription
Lamp-dish flower acetic-Na 1500ml
Stabilisation systems 400ml
Mannitol (dry powder) 100g
Injection water adds to 2000ml
Be distributed into 1000 bottles, lyophilizing promptly gets lyophilized formulations.
Claims (6)
1, a kind of breviscapine B injection preparation is characterized in that by lamp-dish flower acetic-Na and PH be the aqueous injection that the medicinal organic base of 7-8 and stabilized aqueous solution system that organic acid is formed form, or adds the lyophilized injectable powder that medicinal vehicle group becomes again.
2, breviscapine B injection preparation as claimed in claim 1 is characterized in that described lamp-dish flower acetic-Na is a purity greater than the lamp-dish flower acetic sodium that generates after 98% breviscapine B raw material medicine and the reaction of sodium bicarbonate.
3, breviscapine B injection preparation as claimed in claim 1, it is characterized in that described stabilized aqueous solution system is the L-arginine: the mass ratio of glacial acetic acid is 1: 0.28～0.33 aqueous solution system that is formed.
4,, it is characterized in that the arginic weight ratio of wherein lamp-dish flower acetic: L-is 1: 0.3～0.6 as claim 2,3 described breviscapine B injection preparations; The arginic concentration of L-is 1500～3000mg/100ml injection.
5, breviscapine B injection preparation as claimed in claim 1 is characterized in that described pharmaceutical excipient is a kind of in mannitol, low molecular dextran, the glycine etc. or 2 kinds.
6, a kind of preparation method of breviscapine B injection preparation as claimed in claim 1 is characterized in that being made up of following steps: preparation lamp-dish flower acetic sodium water solution; Preparation PH is L-arginine-glacial acetic acid stabilisation systems of 7-8; The two mixing is added water for injection to desired concn, and the aseptic filtration packing is aqueous injection; Or add excipient again, and add water for injection to desired concn, the aseptic filtration packing, lyophilizing is lyophilized injectable powder.
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105399788A (en) * | 2015-12-29 | 2016-03-16 | 云南生物谷药业股份有限公司 | Scutellarin sodium salt crystal I and preparation method thereof |
| CN106806348A (en) * | 2015-11-30 | 2017-06-09 | 湖南恒生制药股份有限公司 | The preparation method of Breviscapine |
| CN110478361A (en) * | 2018-05-14 | 2019-11-22 | 昆明龙津药业股份有限公司 | A kind of highly-safe lamp-dish flower acetic pharmaceutical composition and preparation method thereof |
Family Cites Families (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1055844C (en) * | 1995-04-10 | 2000-08-30 | 昆明龙津药业有限公司 | Erigeron breviscapus basic element freezed drying preparation for injection and preparation process |
| CN1062161C (en) * | 1997-01-08 | 2001-02-21 | 大连弘丰制药厂 | Stable prescription and process of fleabane extract injection |
| CN1476840A (en) * | 2003-07-15 | 2004-02-25 | 上海博泰医药科技有限公司 | Preparation method of stable fleabane extract injection |
| CN1605342A (en) * | 2003-10-08 | 2005-04-13 | 云南创立投资管理有限公司 | Breviscapine injection for perfusion and its preparing process |
| CN1297280C (en) * | 2003-11-15 | 2007-01-31 | 昆明紫健生物技术有限公司 | Breviscapine amino acid transfusion liquid and its producing method |
| CN1245987C (en) * | 2004-01-08 | 2006-03-22 | 中国药科大学 | Stability enhanced erigeron breviscapus injection and its preparation method |
| CN1672687A (en) * | 2004-03-23 | 2005-09-28 | 杭州民生药业集团有限公司 | Transfused breviscapine prepn |
| CN1709351A (en) * | 2005-06-01 | 2005-12-21 | 王衡新 | Chinese medicine injection agent for treating cardio-cerebrovascular diseases and its preparing method |
-
2006
- 2006-05-19 CN CNB2006100109071A patent/CN100396289C/en active Active
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106806348A (en) * | 2015-11-30 | 2017-06-09 | 湖南恒生制药股份有限公司 | The preparation method of Breviscapine |
| CN105399788A (en) * | 2015-12-29 | 2016-03-16 | 云南生物谷药业股份有限公司 | Scutellarin sodium salt crystal I and preparation method thereof |
| CN110478361A (en) * | 2018-05-14 | 2019-11-22 | 昆明龙津药业股份有限公司 | A kind of highly-safe lamp-dish flower acetic pharmaceutical composition and preparation method thereof |
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