CN102716121B - A kind of butylphthalide medicine active composition and preparation method thereof - Google Patents
A kind of butylphthalide medicine active composition and preparation method thereof Download PDFInfo
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- CN102716121B CN102716121B CN201210184391.8A CN201210184391A CN102716121B CN 102716121 B CN102716121 B CN 102716121B CN 201210184391 A CN201210184391 A CN 201210184391A CN 102716121 B CN102716121 B CN 102716121B
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/365—Lactones
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D307/87—Benzo [c] furans; Hydrogenated benzo [c] furans
- C07D307/88—Benzo [c] furans; Hydrogenated benzo [c] furans with one oxygen atom directly attached in position 1 or 3
Abstract
The present invention provides a kind of butylphthalide medicine active composition, includes following components：Components I：Butylphthalide content >=98.0%；Compositionⅱ：One or more in methylene phthalide, ethene phthalide, propylene phthalide, butylidenephthalide, amylene phthalide, phthalide, toluene phthalein, ethylbenzene phthalein, propyl benzene phthalein, penta phthalide, and the content ＞ 0 of compositionⅱ and≤2.0%；When any for the moment comprising methylene phthalide, ethene phthalide, propylene phthalide, butylidenephthalide, amylene phthalide in compositionⅱ, comprising one of any composition content not more than 0.5%, when any for the moment comprising phthalide, toluene phthalein, ethylbenzene phthalein, propyl benzene phthalein, penta phthalide in compositionⅱ, comprising one of any composition content not more than 1.0%.The compsn. consisting of influenza virus surface steady quality, ensure that the clinical efficacy and drug safety of butylphenyl phthaleine preparation.
Description
Technical field
The invention belongs to pharmaceutical technology field, and in particular to one kind includes 3- butyl-l (H)-isobenzofuranone（Butylbenzene
Phthalein）Compsn. consisting of influenza virus surface and preparation method thereof.
Background technology
Butylphenyl phthaleine, chemical entitled 3- butyl-l (H)-isobenzofuranone, also known as Butylphthalide, are extracted from celery seed
Raceme out, also can be artificial synthesized；In Chinese patent CN1100097, disclose Butylphthalide and preparing prevention and controlling
The application in the medicine of disease caused by mammal or mankind's cerebral ischemia is treated, Butylphthalide is the photoactive butylbenzene of irrotationality
Phthalein, butylphenyl phthaleine is oily liquids, and with strong celery fragrance, chemical structural formula is as shown in Equation 1：
。
1
Butylphenyl phthaleine is by improving cerebrovascular endothelial NO and PGI2Level, reduce intracellular calcium concentration, suppress glutamic acid release
Put, reduce arachidonic acid content, suppress oxygen radical and improve the machining functions such as activities of antioxidant enzymes caused by cerebral ischemia
Multiple pathology links, clinical study results show, butylphenyl phthaleine to light, the moderate acute ischemic cerebral apoplexy effect of being significantly improved,
Patient's functional rehabilitation can be promoted.
On butylphenyl phthaleine product, prior art report is as follows：
Li Shao is waited in vain《The synthesis of (±) Butylphthalide》Disclose a kind of butylphenyl phthaleine product and preparation method thereof, preparation side
Phthalic acid acid anhydrides shown in method using formula 2 carries out at 300 DEG C being heated to reflux anti-as raw material, with anhydrous sodium acetate, valeric anhydride
Should, intermediate butylidenephthalide 3 is obtained by extraction in ether, and intermediate butylidenephthalide 3 is dissolved in ether, and 10%Pd/C catalytic hydrogenations are obtained
Butylphenyl phthaleine 1.Reaction scheme is as follows：
2 3 1。
Using prepare butylphenyl phthaleine product of the above method the disadvantage is that,（1）Product content is low, and content is only capable of reaching
95% or so, and impurity content is up to more than 4%, influences clinical efficacy and drug safety；（2）Product stability is poor, is placing
Cheng Zhong, the content of product is significantly reduced, and impurity is significantly raised, and quality is very unstable, it is impossible to controlled；Therefore the product cannot function as
Medicine is used.
With the appearance of problem above, prior art occurs in that the improvement to butylphenyl phthaleine product：
Chinese patent CN101962374 discloses a kind of butylphenyl phthaleine product and preparation method thereof, and preparation method is with adjacent benzene two
Formic acid anhydrides 2 are raw material, and the adjacent valeryl yl benzoic acid 4 of intermediate is obtained by the RMgBr addition with butyl halide, then through boron
Hydrogenation sodium reduction, acid cyclization obtain butylphenyl phthaleine 1, and reaction scheme is as follows：
2 4 1
The indexs such as the butylphenyl phthaleine product content, the impurity that are prepared using the above method are increased, such as butylphthalide content
About 97% is brought up to, impurity content is reduced to about 3.0%, but the product stability is still poor, in placement process, product contains
Amount substantially reduction, impurity is significantly raised, therefore the product can not be used as medicine；（2）This method is in production process simultaneously
In used grignard reagent, grignard reagent needs anhydrous and oxygen-free Seal and preservation, cumbersome now with now doing, production process exist
Potential safety hazard, is not suitable for industrialized production.
In view of the content of above product（Or purity）Relatively low, in placement process, quality is unstable, it is impossible to control, no
It can be used as medicine, therefore still need to be improved prior art, the content of all kinds of impurity, obtains matter in reduction butylphenyl phthaleine
Stable butylphenyl phthaleine product is measured, the butylphenyl phthaleine product of steady quality is used to prepare pharmaceutical preparation, it is ensured that the clinical efficacy of preparation
And drug safety.
The content of the invention
The present inventor has carried out systematic research and analysis by the impurity of the butylphenyl phthaleine product to prior art, finds production
Impurity in product mainly has following a few classes：
1. Li Shao is waited in vain《The synthesis of (±) Butylphthalide》Disclosed butylphenyl phthaleine product：
（1）Butylphenyl phthaleine analog, mainly there is two classes,（a）Be mixed with alkenyl phthalide, initiation material valeric anhydride first, second, third,
Fourth, oneself etc. acid anhydrides, and phthalic acid anhydride reaction, phthalide or the phthalide such as generation methene, vinyl, acrylic, pentenyl,
These alkenyl phthalides or phthalide are close with butylidenephthalide property, remove difficulty, can bring next step reaction into until in butylphenyl phthaleine；
（b）Alkyl phthalide, in catalytic hydrogenation, if being mixed with methene, vinyl, acrylic, pentenyl in butylidene phthalide
Deng phthalide, equally it is hydrogenated and obtains the phthalides such as methyl, ethyl, propyl group, amyl group, these phthalides is close with butylphenyl phthaleine property, remove
Difficulty is gone, is present in final products butylphenyl phthaleine.（2）Other impurities, including unreacted raw material, acid anhydrides, brought into by raw material
Other impurities etc..（3）Inorganic impurity, including catalyst, heavy metal etc..（4）Residual solvent.
2. butylphenyl phthaleine product disclosed in CN101962374：
（1）Butylphenyl phthaleine analog, mainly there is two classes,（a）Intermediate before butylphenyl phthaleine cyclization, adjacent valeryl yl benzoic acid and its class
Like the adjacent acetylbenzoic acid of thing, adjacent propionyl yl benzoic acid, adjacent butyryl yl benzoic acid, adjacent hexanoyl yl benzoic acid（By grignard reagent not
It is pure to bring into）；（b）Alkyl phthalide, in cyclization reduction process, if being mixed with its above-mentioned analog in adjacent valeryl yl benzoic acid, together
Sample is reduced by cyclization and obtains the phthalides such as methyl, ethyl, propyl group, amyl group and phthalide, these butylphenyl phthaleine analogs and butylphenyl phthaleine
Matter is close, removes difficulty, is present in final products butylphenyl phthaleine.（2）Other impurities, including unreacted raw material, grignard reagent,
Other impurities brought into by raw material etc..（3）Inorganic impurity, including catalyst, heavy metal etc..（4）Residual solvent.
The present inventor has found by substantial amounts of experimental study：In butylphenyl phthaleine product 1. being planted the, the quality of butylphenyl phthaleine product
Alkenyl phthalide such as methylene phthalide, ethene phthalide, propylene phthalide, butylidenephthalide, the amylene phthalide of stability mainly with wherein containing
The content of component is relevant, as their any component content ＞ 0.5%, will significantly affect the matter of butylphthalide medicine active composition
Measure stability；In 2. planting butylphenyl phthaleine product the, the quality stability of butylphenyl phthaleine product is mainly closed with the butylphenyl phthaleine that wherein contains
Before ring intermediate as adjacent acetylbenzoic acid, adjacent propionyl yl benzoic acid, adjacent butyryl yl benzoic acid, adjacent valeryl yl benzoic acid, it is adjacent oneself
The content of acyl group benzoic acid components is relevant, as their any component content ＞ 0.5%, will significantly affect butylphenyl phthaleine pharmaceutical activity
The quality stability of composition.
In addition, the other alkyl phthalides contained in butylphthalide medicine active composition, although to the steady quality of composition
Property influence it is smaller, but due to they activity well below butylphenyl phthaleine, will be to butylbenzene as any of which component content ＞ 1.0%
Phthalein drug effect produces considerable influence；The presence of the impurity of other residual volumes will aggravate the unstability of butylphenyl phthaleine product.
Either intermediate or other alkyl phthalides before alkenyl phthalide, butylphenyl phthaleine cyclization, are butylphenyl phthaleine analog, with
Butylphenyl phthaleine property is close, removes difficult.The present inventor finds finally by long-term substantial amounts of butylphenyl phthaleine product quality Optimization Work
A kind of preparation method of butylphthalide medicine active composition, by respective components control to significantly affect content and stability with
Under, so as to obtain a kind of butylphthalide medicine active composition of steady quality, ensure the clinic of butylphenyl phthaleine preparation from source
Curative effect and drug safety.
Therefore, one aspect of the present invention provides a kind of butylphthalide medicine active composition, it is characterised in that comprising with the following group
Point：
Components I：Butylphenyl phthaleine, content >=98.0%；
Compositionⅱ：Selected from methylene phthalide, ethene phthalide, propylene phthalide, butylidenephthalide, amylene phthalide, phthalide, toluene phthalein,
One or more in ethylbenzene phthalein, propyl benzene phthalein, penta phthalide, and the content ＞ 0 of compositionⅱ and≤2.0%；And, when compositionⅱ is included
Methylene phthalide, ethene phthalide, propylene phthalide, butylidenephthalide, amylene phthalide are any for the moment, comprising one of any composition
Content not more than 0.5%；When compositionⅱ includes phthalide, toluene phthalein, ethylbenzene phthalein, propyl benzene phthalein, penta phthalide any a period of time, institute
Comprising one of any composition content not more than 1.0%.
It is preferred that, above-mentioned butylphthalide medicine active composition, described components I：Butylphthalide content >=98.5%, compositionⅱ：
Content ＞ 0 and≤1.5%.
It is preferred that, above-mentioned butylphthalide medicine active composition, described components I：Butylphthalide content >=99.0%；Compositionⅱ：
Content ＞ 0 and≤1.0%, and, when compositionⅱ includes methylene phthalide, ethene phthalide, propylene phthalide, butylidenephthalide, amylene phthalide
Arbitrarily for the moment, comprising one of any composition content not more than 0.3%；, when compositionⅱ comprising phthalide, toluene phthalein,
Ethylbenzene phthalein, propyl benzene phthalein, penta phthalide are any for the moment, comprising one of any composition content not more than 0.5%.
It is preferred that, the compositionⅱ is one or more of in phthalide, butylidenephthalide, propyl benzene phthalein.
Another aspect of the present invention also provides the preparation method of above-mentioned butylphthalide medicine active composition, including following step
Suddenly：
A. feed：Butylphenyl phthaleine crude product is added in rectifying column；
B. it is optional, air-distillation：Butylphenyl phthaleine crude product is warming up to 60 ~ 110 DEG C, evaporating at this temperature is collected in no backflow
Point, discard；
C. vacuum distillation, it is 1 ~ 5mmHg to control vacuum, and butylphenyl phthaleine crude product is warming up into 130 ~ 150 DEG C, the temperature is collected
Under cut, discard；154 ~ 180 DEG C are continuously heating to, 0 ~ 300min of infinite reflux controls constant reflux ratio, collects the temperature
Under cut；
D. it is optional, according to the constituent content in collected cut, above-mentioned B, step C are repeated, butylphenyl phthaleine pharmaceutical activity is obtained
Composition.
Above-mentioned preparation method, described step C, control vacuum preferably 4 ~ 5 mmHg；More preferably 5 mmHg.
Butylphenyl phthaleine crude product is warming up to preferably 140 ~ 150 DEG C, more preferably 150 DEG C by above-mentioned preparation method, described step C.
Above-mentioned preparation method, described step C is continuously heating to preferably 154 ~ 160 DEG C, more preferably 154 DEG C.
Above-mentioned preparation method, described step C controls constant reflux ratio preferably 1~10:1, more preferably 3~7:1.
In preparation method of the present invention, heating, the operation of rectifying column, the control of temperature, collection of cut etc. according to
Conventional method is carried out.
The method of the invention below corresponding index, has obtained the butylbenzene of steady quality effectively by various Control of Impurities
Phthalein compsn. consisting of influenza virus surface.
Butylphenyl phthaleine crude product of the present invention refers to that content does not reach the butylphenyl phthaleine of medicinal requirements.Butylphenyl phthaleine of the present invention
Crude product can exist according to Li Shaobai etc.《The synthesis of (±) Butylphthalide》Disclosed preparation method, can also be according to other method
Prepare.Preparation method disclosed in Chinese patent CN101962374 is not suitable for industrialized production due to severe reaction conditions, this
Not used in invention.
Another aspect of the present invention also provides a kind of pharmaceutical composition, includes above-mentioned butylphthalide medicine active composition and pharmacy
Upper acceptable carrier, optionally, other therapeutic components also may be present in described pharmaceutical composition.
, can when described pharmaceutical composition includes above-mentioned butylphthalide medicine active composition and pharmaceutically acceptable carrier
It is made into oral formulations, preferably soft capsule, tablet, sustained release tablets, dripping pill；Also ejection preparation can be made into, is preferably freezed
Powder-injection, vein breast, these preparations can use corresponding auxiliary material known to persons skilled in the art, using corresponding known medicine
The technology of preparing of thing preparation is made.
Other therapeutic components can produce synergy with butylphenyl phthaleine, especially have when preventing and treating cerebrovascular disease
Profit.
Another aspect of the present invention also provides above-mentioned butylphthalide medicine active composition or the pharmaceutical composition comprising it is being made
Application in the medicine of disease caused by standby cerebral ischemia.
Butylphthalide medicine active composition of the present invention, indices meet medicinal requirements, in placement process, matter
Amount is stable, ensure that the clinical efficacy and drug safety of butylphenyl phthaleine preparation.
Brief description of the drawings
Fig. 1：The chromatograms of the relevant material detection of butylphenyl phthaleine prepared by preparation example 1.
Fig. 2：The chromatograms of the relevant material detection of butylphthalide medicine active composition prepared by embodiment 1.
Fig. 3：The chromatograms of the relevant material detection of butylphthalide medicine active composition prepared by embodiment 5.
Fig. 4：The chromatograms of the relevant material detection of butylphthalide medicine active composition prepared by embodiment 6.
Fig. 5：The chromatograms of the relevant material detection of butylphthalide medicine active composition prepared by embodiment 7.
Component I butylphenyl phthaleines and each component content detection method in compositionⅱ：According to high effective liquid chromatography for measuring
Chromatographic condition and system suitability：It is filler with octadecylsilane chemically bonded silica, with methanol-water（65:
35）For mobile phase, Detection wavelength 280nm, number of theoretical plate is calculated by butylphenyl phthaleine peak is not less than 1500；
Determination method：Butylphthalide medicine active composition about 50mg is taken, it is accurately weighed, put in 100ml measuring bottles, plus methanol dissolving
And scale is diluted to, shake up, as need testing solution, take the μ l of need testing solution 20, inject liquid chromatograph, record chromatogram is extremely
3 times of components I peak retention time, the content of each composition in components I and compositionⅱ is calculated with area normalization method；
Each composition is with the relative retention times of component I butylphenyl phthaleines in compositionⅱ：
1st, phthalide peak：Relative retention time is 0.35-0.39 peak；
2nd, toluene phthalein peak：Relative retention time is 0.40-0.44 peak；
3rd, ethylbenzene phthalein peak：Relative retention time is 0.46-0.50 peak；
4th, methylene phthalide peak：Relative retention time is 0.56-0.60 peak；
5th, propyl benzene phthalein peak：Relative retention time is 0.66-0.69 peak；
6th, ethene phthalide peak：Relative retention time is 0.70-0.74 peak；
7th, butylphenyl phthaleine peak：Appearance time is 10.5 ~ 10.9 minutes；
8th, propylene phthalide peak：Relative retention time is 1.05-1.09 peak；
9th, penta phthalide peak：Relative retention time is 1.53-1.58 peak；
10th, butylidenephthalide peak：Relative retention time is 1.63-1.67 peak；
11st, amylene phthalide peak：Relative retention time is 2.83-2.87 peak.
Embodiment
With reference to specific embodiment, the present invention is further detailed explanation.
Preparation example 1：Butylphenyl phthaleine, prior art products exist according to Li Shaobai etc.《The synthesis of (±) Butylphthalide》It is disclosed
It is prepared by preparation method
（1）The preparation of butylidenephthalide
Phthalic acid acid anhydrides 148.0Kg, anhydrous sodium acetate 82.0Kg and positive valeric anhydride 300.0L are heated to reflux at 300 DEG C
4h, is evaporated off low boiler cut（Control is below 150 DEG C）, residue is with hot water dissolving, then uses NaHCO3PH=6~7 are neutralized to,
Extracted with 7 × 500L ether, merge organic layer, anhydrous Na2SO4Dry, filter out drier, ether, silica gel column chromatography, chlorine is evaporated off
Imitative-petroleum ether elution, obtains butylidenephthalide 45.0Kg.
（2）The preparation of butylphenyl phthaleine
3- butylidenephthalides 45.0Kg is dissolved in ether, is added the Pd/C of 4.5Kg 10%, is used H2Gas is replaced 6 times, is filled with H2, stir
Mix, react at room temperature 24h, filter out and concentrated after Pd/C, silica gel column chromatography, chloroform-petroleum ether elution obtains butylphenyl phthaleine 43.0Kg.I
Products obtained therefrom has been carried out quality research and（40 DEG C, 75%RH）Under the conditions of acceleration for stabilization Journal of Sex Research, the results are shown in Table 1.
Preparation example 2：Butylphenyl phthaleine, prior art products, according to preparation method disclosed in Chinese patent CN101962374
（1）The preparation of NBB grignard reagent
Under nitrogen protection, tetrahydrofuran is added in the retort equipped with stirring, thermometer and with reflux condensate device
200L, magnesium sheet 6.0Kg and iodine 0.1Kg, are warming up to 50 DEG C, and the 31.50Kg butyl bromides for being dissolved in 40L tetrahydrofurans, control is added dropwise
Temperature is no more than 70 DEG C, after completion of dropping, continues to stir 1h, obtains the RMgBr of butyl bromide.
（2）The preparation of adjacent valeryl yl benzoic acid
Under nitrogen protection, 300L tetrahydrofurans, 30Kg phthalic anhydride and 2.5Kg cupric iodides are added, -10 are cooled to
DEG C, step is added dropwise（1）The RMgBr of the butyl bromide of gained, controls 1h or so completion of dropping；After completion of dropping, it is further continued for stirring
2h is mixed, it is 2 that addition 1mol/L hydrochloric acid solution, which is hydrolyzed into pH, stands branch vibration layer, water layer is extracted twice with methyl tertiary butyl ether(MTBE),
Merge organic phase, saturated nacl aqueous solution is washed to neutrality, and anhydrous magnesium sulfate is dried, then depressurize and slough solvent and obtain adjacent valeryl
Benzoic acid 35Kg.
（3）The preparation of butylphenyl phthaleine
160Kg 5% sodium hydroxide solution and above-mentioned steps is added in retort（2）The adjacent valeryl benzene first of gained
Acid, stirring at normal temperature 1h is cooled to 0 DEG C, is slowly added to 6Kg sodium borohydrides, control temperature be 0 DEG C~10 DEG C, addition finish after
Normal temperature continues to stir 1h, and 6mol/L HCl are added afterwards and are acidified to pH for 4.0, with methyl tertiary butyl ether(MTBE) aqueous layer extracted three times, closes
And organic phase, washed respectively with 5% sodium acid carbonate and saturated nacl aqueous solution to neutrality, anhydrous magnesium sulfate is dried, and controls 180-
185 DEG C/1mmHg conditions carry out vacuum distillation and obtain butylphenyl phthaleine 19Kg.We products obtained therefrom has been carried out quality research and（40 DEG C,
75%RH）Under the conditions of acceleration for stabilization Journal of Sex Research, the results are shown in Table 2.
Table 1：The butylphenyl phthaleine sample detection result of preparation example 1 and stability result（40 DEG C, 75%RH）
As can be seen from Table 1：Li Shao is waited in vain《The synthesis of (±) Butylphthalide》Disclosed butylphenyl phthaleine product, is adding
Placed 6 months under the conditions of speed, the content of butylphenyl phthaleine is drastically reduced, and falls below less than 90%；The content and residual volume impurity of compositionⅱ
Significantly increase, rise to more than 5.0%, illustrate that the gained butylphenyl phthaleine product quality stability of preparation example 1 is very poor, it is impossible to be used as medicine
Product are used.
Table 2：The butylphenyl phthaleine sample detection result of preparation example 2 and stability result（40 DEG C, 75%RH）
As can be seen from Table 2：Butylphenyl phthaleine product, puts under acceleration conditions disclosed in Chinese patent CN101962374
Put 6 months, the content of butylphenyl phthaleine is significantly reduced, and falls below less than 95%；The content and residual volume impurity of compositionⅱ rise appreciably,
More than 3.0% is risen to, illustrates that the gained butylphenyl phthaleine product quality stability of preparation example 2 is very poor, it is impossible to use as medicine.
Embodiment 1：Butylphthalide medicine active composition
Butylphenyl phthaleine crude product：Butylphenyl phthaleine prepared by preparation example 1
A. butylphenyl phthaleine crude product 3.0Kg is added in rectifying column；
B. it is 5mmHg to control vacuum, is heated to 130 DEG C or so, collects cut at this temperature, discards；Continue
154 DEG C are warming up to, it is 3 to control reflux ratio:1, collect cut at this temperature；
C. the cut being collected into is rejoined in rectifying column, repeat step B2 times, obtains butylphenyl phthaleine 2.7Kg.
Embodiment 2：Butylphthalide medicine active composition
Butylphenyl phthaleine crude product：Butylphenyl phthaleine prepared by preparation example 1
A. butylphenyl phthaleine crude product 3.0Kg is added in rectifying column；
B. 110 DEG C are warming up to, no backflow is collected cut at this temperature, discarded；
C. it is 5mmHg to control vacuum, is heated to 130 DEG C or so, collects cut at this temperature；Discard；Continue
154 DEG C or so are warming up to, it is 4 to control reflux ratio:1, collect cut at this temperature；
D. the cut being collected into is rejoined in rectifying column, repeat step B3 times, obtains butylphenyl phthaleine 2.7Kg.
Embodiment 3：Butylphthalide medicine active composition
Butylphenyl phthaleine crude product：Butylphenyl phthaleine prepared by preparation example 1
A. butylphenyl phthaleine crude product 3.0Kg is added in rectifying column；
B. 110 DEG C are warming up to, no backflow is collected cut at this temperature, discarded；
C. it is 5mmHg to control vacuum, is heated to 150 DEG C or so, collects cut at this temperature；Discard；Continue
154 DEG C or so are warming up to, it is 3 to control reflux ratio:1, collect cut at this temperature；
D. the cut being collected into is rejoined in rectifying column, repeat step B 4 times obtains butylphenyl phthaleine 2.6Kg.
Embodiment 4：Butylphthalide medicine active composition
Butylphenyl phthaleine crude product：Butylphenyl phthaleine prepared by preparation example 1
A. butylphenyl phthaleine crude product 3.0Kg is added in rectifying column；
B. 110 DEG C are warming up to, no backflow is collected cut at this temperature, discarded；
C. it is 5mmHg to control vacuum, is heated to 140 DEG C or so, collects cut at this temperature；Discard；Continue
154 DEG C or so are warming up to, it is 6 to control reflux ratio:1, collect cut at this temperature；
D. the cut being collected into is rejoined in rectifying column, repeat step B 7 times obtains butylphenyl phthaleine 2.5Kg.
Embodiment 5：Butylphthalide medicine active composition
Butylphenyl phthaleine crude product：Butylphenyl phthaleine prepared by preparation example 1
A. butylphenyl phthaleine crude product 3.0Kg is added in rectifying column,
B. it is 4mmHg to control vacuum, is heated to 135 DEG C or so, collects cut at this temperature, discards；Continue
160 DEG C or so are warming up to, it is 5 to control reflux ratio:1, collect cut at this temperature；
C. the cut being collected into is rejoined in rectifying column, repeat step B 3 times obtains butylphenyl phthaleine 2.7Kg.
Embodiment 6：Butylphthalide medicine active composition
Butylphenyl phthaleine crude product：Butylphenyl phthaleine prepared by preparation example 1
A. butylphenyl phthaleine crude product 3.0Kg is added in rectifying column；
B. it is 4mmHg to control vacuum, is heated to 140 DEG C or so, collects cut at this temperature, discards；Continue
160 DEG C are warming up to, it is 1 to control reflux ratio:1, cut at this temperature is collected, butylphenyl phthaleine 2.8Kg is obtained.
Embodiment 7：Butylphthalide medicine active composition
Butylphenyl phthaleine crude product：Butylphenyl phthaleine prepared by preparation example 1
A. butylphenyl phthaleine crude product 3.0Kg is added in rectifying column,
B. 90 DEG C are warming up to, no backflow is collected cut at this temperature, discarded；
C. it is 4mmHg to control vacuum, is heated to 135 DEG C or so, collects cut at this temperature, discards；Continue
160 DEG C or so are warming up to, it is 7 to control reflux ratio:1, collect cut at this temperature；
D. the cut being collected into is rejoined in rectifying column, repeat step B 7 times obtains butylphenyl phthaleine 2.6Kg.
Embodiment 8：Butylphthalide medicine active composition
Butylphenyl phthaleine crude product：Butylphenyl phthaleine prepared by preparation example 1
A. butylphenyl phthaleine crude product 3.0Kg is added in rectifying column,
B. 60 DEG C are warming up to, no backflow is collected cut at this temperature, discarded；
C. it is 5mmHg to control vacuum, is heated to 150 DEG C or so, collects cut at this temperature, discards；Continue
154 DEG C or so are warming up to, it is 4 to control reflux ratio:1, collect cut at this temperature；
D. the cut being collected into is rejoined in rectifying column, repeat step B 4 times obtains butylphenyl phthaleine 2.7Kg.
Embodiment 9：Butylphthalide medicine active composition
Butylphenyl phthaleine crude product：Butylphenyl phthaleine prepared by preparation example 1
A. butylphenyl phthaleine crude product 3.0Kg is added in rectifying column,
B. 90 DEG C are warming up to, no backflow is collected cut at this temperature, discarded；
C. it is 5mmHg to control vacuum, is heated to 150 DEG C or so, collects cut at this temperature, discards；Continue
154 DEG C or so are warming up to, it is 6 to control reflux ratio:1, collect cut at this temperature；
D. the cut being collected into is rejoined in rectifying column, repeat step B 7 times obtains butylphenyl phthaleine 2.6Kg.
We the products obtained therefrom of embodiment 1 ~ 9 has been carried out quality research and（40 DEG C, 75%RH）Under the conditions of accelerated stability
Research, the results are shown in Table 3-1, table 3-2, table 3-3, table 3-4, table 3-5, table 3-6, table 3-7, table 3-8 and table 3-9,
Remarks：40 DEG C, 75%RH acceleration environment is preserved 2 years for 6 months equivalent to shady place.
Conclusion：
It can be seen that from the data of embodiment 6：Components I butylphthalide content is 98.0%；Content≤2.0% of compositionⅱ, methylene
Phthalide, ethene phthalide, propylene phthalide, butylidenephthalide, amylene phthalide（Alkenyl phthalide in abbreviation compositionⅱ, similarly hereinafter）It is one of any
The content of composition not more than 0.5%, phthalide, toluene phthalein, ethylbenzene phthalein, propyl benzene phthalein, penta phthalide（Alkyl in abbreviation compositionⅱ
Phthalide, similarly hereinafter）The butylphthalide medicine active composition of the content of one of any composition not more than≤1.0%, in acceleration environment
It is lower place 6 months, components I butylphthalide content change it is smaller, be 97.8%, the content of compositionⅱ is smaller ,≤2.0%, quality compared with
It is stable, it can be used substantially as medicine.
It can be seen that from the data of embodiment 1：Components I butylphthalide content ＞ 98.0%；Content≤2.0% of compositionⅱ, component
One of any composition of alkyl phthalide in the content not more than 0.5% of one of any composition of alkenyl phthalide in II, compositionⅱ
Content not more than 1.0% butylphthalide medicine active composition, under acceleration conditions place 6 months, component components I fourth
Phthalide changes of contents is smaller, and >=98.0%, the content of compositionⅱ is smaller ,≤2.0%, and quality is relatively stablized, and can be used as medicine
Use.
It can be seen that from embodiment 2, embodiment 5, the data of embodiment 8：Components I butylphthalide content >=98.5%；Compositionⅱ
Alkyl in the content not more than 0.5% of one of any composition of alkenyl phthalide in content≤1.5%, compositionⅱ, compositionⅱ
The butylphthalide medicine active composition of one of any content not more than 1.0% of composition of phthalide, places 6 under acceleration conditions
Individual month, the change of components I butylphthalide content was small, and >=98.4%, the changes of contents of compositionⅱ is small ,≤1.5%, steady quality, energy
It is enough to be used as medicine.
It can be seen that from embodiment 3, embodiment 4, embodiment 7, the data of embodiment 9：Components I butylphthalide content >=99.0%；
Alkane in one of any component content not more than 0.30% of alkenyl phthalide, compositionⅱ in content≤1.0% of compositionⅱ, compositionⅱ
The butylphthalide medicine active composition of one of any component content not more than 0.50% of base phthalide, puts under acceleration conditions
Put 6 months, the change of components I butylphthalide content is smaller, >=98.9%, the changes of contents of compositionⅱ is smaller ,≤1.0%, quality
It is more stable, it can be used for medicine.
In summary, the butylphthalide medicine active composition that the present invention is provided, components I butylphthalide content >=98.0%；Component
Alkylbenzene in one of any component content not more than 0.5% of alkenyl phthalide, compositionⅱ in II content≤2.0%, compositionⅱ
One of any component content not more than 1.0% of phthalein, its steady quality can be used as medicine, carry out the preparation of preparation.
Embodiment 10：Butylphenyl phthaleine soft capsule
Bulk drug：Butylphthalide medicine active composition prepared by embodiment 6
Composition：
| Component | Consumption (g) |
| Butylphthalide medicine active composition | 100 |
| Soybean oil | 350 |
| Gelatin | 100 |
| Glycerine | 30 |
| Water | 130 |
| Ethylparaben | 200mg |
Preparation method：
The preparation of gelatin solution：Taking gelatin to add appropriate water makes its water swelling.Separately by glycerine, ethylparaben and remainder
Water put colloidal sol pot in be heated to 70-80 DEG C, be well mixed, add expansion gelatin stirring, melting, be incubated l~2 hour, it is quiet
Put, foam is floated, scrape off the foam of floating, filtered with clean calico, heat preservation for standby use, be made into gelatin viscosity be generally 2.8~
3.2 degree.
The preparation of decoction oil：Weigh butylphthalide medicine active composition 100g and fully stirred evenly with soybean oil 350g and produced.
Suppress soft capsule：Produced gelatin glycerine and butylphthalide medicine active composition are loaded into automatic rotation rolling capsule machine
In, temperature control suppresses the soft capsule of every capsule decoction containing 450mg oil at 40~50 DEG C.
Embodiment 11：Butylphenyl phthaleine soft capsule
Bulk drug：Butylphthalide medicine active composition prepared by embodiment 5.
Preparation method：Be the same as Example 10.
Embodiment 12：Butylphenyl phthaleine soft capsule
Bulk drug：Butylphthalide medicine active composition prepared by embodiment 7.
Preparation method：Be the same as Example 10.
Embodiment 13：Butylbenzene phthalein tablet
Bulk drug：Implement 5 butylphthalide medicine active compositions prepared
Composition：
Label：
| Component | Consumption |
| Butylphthalide medicine active composition | 100 g |
| Poloxamer | 0.1 g |
| Cyclodextrin | 899.9 g |
| Starch | 100 g |
| The sodium carboxymethylcellulose of crosslinking | 150 g |
| Talcum powder | 23 g |
| Magnesium stearate | 12 g |
| The hydroxypropyl methyl cellulose aqueous solution | In right amount |
Preparation method：
Butylphthalide medicine active composition and emulsifying agent poloxamer are weighed, plus a small amount of water is uniformly mixed, and weighs ring
Dextrin, is dissolved in water, and two solution are mixed, quick stirring l hours, is put and (5 DEG C) is refrigerated in refrigerator 12 hours, takes out filtering, will
Gained solid obtains butylphenyl phthaleine solid powder in 60 DEG C of dryings.
Weigh butylphenyl phthaleine solid powder appropriate, add lactose, partial cross-linked sodium carboxymethylcellulose, after being well mixed, use
Hydroxypropyl methyl cellulose (2%) aqueous solution is pelletized, and is dried, whole grain, additional Ac-Di-Sol, magnesium stearate, talcum
The auxiliary materials such as powder, tabletting.
Sugar coating：Label is weighed, 10% appropriate gelatin bag separation layer is added, after drying, syrup, talcum powder or cunning is added
The mixed powder of stone flour and starch, sugar coating, slice is dried.
Embodiment 14：Butyl benzene phthalein vein breast
Bulk drug：Implement 4 butylphthalide medicine active compositions prepared
Composition：
| Component | Consumption |
| Butylphthalide medicine active composition | 10 g |
| Soybean lecithin | 12 g |
| Soybean oil | 100 g |
| Vitamin E | l g |
| Sorbierite | 25 g |
| Water for injection | Add to l000ml |
Preparation method：
The butylphthalide medicine active composition of recipe quantity, vitamin E is weighed to mix with soybean oil, it is pre- in 60 DEG C of water-baths
Heat；The soybean lecithin and sorbierite of recipe quantity are weighed in water, is preheated in 60 DEG C of water-baths；Oil phase is poured slowly into aqueous phase,
Disperse 5min, l0000rpm with high speed shear dispersion emulsifying machine, circulated 5 times on high pressure homogenizer, first class pressure 100Mpa, two
Stage pressure 10Mpa, adjusts pH to 8, filters, and sterilize 15min at 121 DEG C.Whole process wants nitrogen charging gas shielded.
Embodiment 15:Butylphenyl phthaleine freeze drying powder injection
Bulk drug：Implement 4 butylphthalide medicine active compositions prepared
Composition：
| Component | Consumption |
| Butylphthalide medicine active composition | 200 g |
| Soybean lecithin（Injection stage） | 80 g |
| Mannitol | 2000 g |
| Water for injection | Add to 4000ml |
Preparation method：
1st, butylphthalide medicine active composition, soybean lecithin and mannitol are weighed respectively by recipe quantity；
2nd, butylphthalide medicine active composition adds 2000ml waters for injection high-speed stirred uniformly together with soybean lecithin, extremely
Clear solution, no oil droplet；
3rd, mannitol is added after the dissolving of 1500ml waters for injection, and 100 DEG C of activated carbon for adding up weight 0.1% is heated 15 minutes
Charcoal is taken off afterwards；
4th, after (2) are mixed with (3) solution, after the activated carbon of addition gross weight 0.01% stirs, filtering decarbonization is added
Water for injection is surveyed after pH value, content, refined filtration, in sub-bottling to full dose；
5th, the bottle for dispensing decoction is put in freeze dryer, it is lyophilized to produce.
Comparative example 1：Butylphenyl phthaleine soft capsule
Bulk drug：Butylphenyl phthaleine product prepared by preparation example 1
Preparation method：Be the same as Example 10.
Comparative example 2：Butylphenyl phthaleine soft capsule
Bulk drug：Butylphenyl phthaleine product prepared by preparation example 1
Preparation method：Be the same as Example 10.
The present inventor is devoted for years in the research of butylphenyl phthaleine preparation, in order to obtain the butylphenyl phthaleine preparation of steady quality, invention
People has carried out the stability study of accelerated test, and testing result is as shown in table 4-1,4-2.
Table 4-1：The butylphenyl phthaleine preparation stability result of embodiment 10 ~ 15
Table 4-2：The butylphenyl phthaleine preparation stability result of comparative example 1 ~ 2
Remarks：40 DEG C, 75%RH acceleration environment is preserved 2 years for 6 months equivalent to shady place.
Conclusion：It can be seen that by table 4-1,4-2 data：
It can be seen that from the data of embodiment 10：The butylphthalide medicine active composition of embodiment 6（Components I butylphthalide content is
98.0%；The content not more than 0.5% of one of any composition of alkenyl phthalide in content≤2.0% of compositionⅱ, compositionⅱ,
The content of one of any composition of alkyl phthalide in compositionⅱ is not more than≤1.0%）The butylphenyl phthaleine soft capsule of preparation, is adding
Under the conditions of speed place 6 months, the change of impurity is smaller, total impurities≤2.0%, show the butylphthalide medicine active composition with
Auxiliary material compatibility preferably, relatively stablize by the quality of the pharmaceutical preparations.
It can be seen that from the data of embodiment 11：The butylphthalide medicine active composition of embodiment 5（Components I butylphthalide content >=
98.5%；The content not more than 0.5% of one of any composition of alkenyl phthalide in content≤1.5% of compositionⅱ, compositionⅱ,
The content not more than 1.0% of one of any composition of alkyl phthalide in compositionⅱ）The butylphenyl phthaleine soft capsule of preparation, is accelerating
Under the conditions of place 6 months, the change of impurity is small, total impurities≤1.5%, shows the butylphthalide medicine active composition and auxiliary material
Compatibility is good, and the quality of the pharmaceutical preparations is stable.
It can be seen that from the data of embodiment 12：The butylphthalide medicine active composition of embodiment 7（Components I butylphthalide content
≥99.0%；One of any component content not more than 0.30% of alkenyl phthalide in content≤1.0% of compositionⅱ, compositionⅱ,
One of any component content not more than 0.50% of alkyl phthalide in compositionⅱ）The butylphenyl phthaleine soft capsule of preparation, is accelerating bar
Placed 6 months under part, the change of impurity is smaller, total impurities≤1.0%, shows the butylphthalide medicine active composition and auxiliary material
More preferably, quality is more stable for compatibility.
It can be seen that from the data of embodiment 10 ~ 12：The stability influence preparation of butylphthalide medicine active composition it is steady
Qualitative, the stability of butylphthalide medicine active composition is improved, and the stability of preparation is also improved therewith.
It can be seen that from the data of embodiment 10 ~ 15：By the present invention butylphthalide medicine active composition preparation of preparation,
Placed 6 months under acceleration environment, the indices of preparation are varied less, steady quality, ensure that the clinical efficacy of butylphenyl phthaleine
And drug safety.
Butylphenyl phthaleine flexible glue prepared by the butylphenyl phthaleine product that can be seen that prior art from comparative example 1 and the data of comparative example 2
Capsule, is placed 6 months, impurity is dramatically increased, content is significantly reduced under acceleration conditions, show the butylphenyl phthaleine product of prior art with
Auxiliary material poor compatibility, quality is highly unstable.
Butylphenyl phthaleine product impurity of the prior art is high it can be seen from data above, content is low, itself and auxiliary material compatibility
Difference, during storage, its impurity is drastically raised, and content is drastically reduced, it is impossible to ensure clinical efficacy and drug safety, because
This cannot be used for clinical research；The butylphthalide medicine active composition that the present invention is provided, components I butylphthalide content >=98.0%；Group
The content not more than 0.5% of one of any composition of alkenyl phthalide in point II content ＞ 0 and≤2.0%, compositionⅱ, component
The content not more than 1.0% of one of any composition of alkyl phthalide in II, it is good with auxiliary material compatibility, put under acceleration conditions
Put 6 months, each component has no significant change, disclosure satisfy that medicine it is safe and effective, quality controllable the characteristics of, ensure that clinic
Curative effect and drug safety.
Embodiment 16：Butylphenyl phthaleine animal acute toxicity test
Test objective：The butylphenyl phthaleine product for comparing the butylphthalide medicine active composition of the invention provided and prior art exists
The difference of acute toxicity.
Experimental animal：Mouse：Healthy Kunming kind, 18 ~ 21g of body weight；Wistar rats, 120 ~ 130g of body weight.
Test drug：The prior art that butylphthalide medicine active composition, the preparation example 1 ~ 2 of the preparation of embodiment 5 ~ 7 are obtained
Butylphenyl phthaleine product.
Test method：By two kinds of animals of mouse and rat, acute toxicity test is carried out with oral administration route.It is administered orally
Fasting 12 hours before person's administration, free water, experiment room temperature is at 22 ~ 24 DEG C, Continuous Observation 7 days after administration.Mouse 0.1ml/
10g, 3 ~ 3.5ml/kg of rat.
Result of the test：It is shown in Table 5
Table 5：Butylphenyl phthaleine acute toxicity result table
As can be seen from the above table：The LD of embodiment 5 ~ 750Apparently higher than the LD of preparation example 1 ~ 250Value, illustrates present invention offer
Butylphthalide medicine active composition compared with the butylphenyl phthaleine product of prior art, with good security.
Embodiment 17：Effect of the butylphenyl phthaleine to rat brain artery ligation encephaledema
Test objective：The butylphenyl phthaleine product for comparing the butylphthalide medicine active composition of the invention provided and prior art exists
Treat the difference of drug effect in disease caused by cerebral ischemia.
Experimental animal：Male Wistar Rats, 300 ~ 350g of body weight.
Test drug：The prior art that butylphthalide medicine active composition, the preparation example 1 ~ 2 of the preparation of embodiment 5 ~ 7 are obtained
Butylphenyl phthaleine product.
Experimental design：Cerebral hypoxia ischemic causes energy exhaustion, and cell membrane function is damaged, it is impossible to maintain ion gradient,
Cause brain tissue oedema, Na+Accumulation, K+Concentration declines, and major injury neuronal function or causes neuronal death, this experiment sight
Examine influence of the butylphenyl phthaleine to local rats with cerebral ischemia encephaledema.
Test method：Implement right side cerebral middle artery occlusion to rat, cause encephaledema, after 15 minutes, oral embodiment 1
~ 3, the butylphenyl phthaleine (160mg, 240mg/kg) of preparation example 1 ~ 2, puts to death, takes forebrain, claim left and right brain hemisphere weight in wet base for postoperative 24 hours；
100 DEG C claim dry weight after roasting 24 hours, and brain water weight is calculated with wet-dry change；Tissue is nitrified 4 hours, pH value is adjusted with HCI, is used
ISE is connected on oxygen Texture Analyzer, surveys brain tissue Na+、K+Concentration.
Result of the test：It is shown in Table 6, table 7.
Table 6：Influence of the butylphenyl phthaleine to rat brain water content
Table 7：Influence of the butylphenyl phthaleine to rat brain cation concn
Remarks：Every group of number of animals 10-14 is only；Left side is non-ischemic side, and right side is ischemic side.
It can be seen that by table 6, table 7：5 ~ 7 groups of embodiment（160mg、240mg/kg）Reduce brain water and Na+Content, increase
K+Content highly significant, and have dose-effect relationship, illustrate that the butylphthalide medicine active composition that the present invention is provided can be substantially
Mitigate encephaledema caused by local cerebral ischemia；1 ~ 2 group of preparation example (160,240mg/kg) can reduce brain water and Na+Content, increases
Plus K+ contents, but effect is worse than 5 ~ 7 groups of embodiment.
Embodiment 16：Butylphenyl phthaleine soft capsule treats the clinical research of light moderate acute ischemic cerebral apoplexy
Medicine：Butylphenyl phthaleine soft capsule prepared by embodiment 10.
Research object：(1) First episode<72h acute Internal Carotid System infarct.(2) NIH
Stroke Scale scoring (NIHSS) neurological deficits score is 5-25 points.(3) nineteen ninety-five national 4th cerebrovascular disease is met
Diagnostic criteria (4) age of onset of academic conference revision<75 years old.(5) head CT examination Cerebral hemorrhage.(6) unconscious barrier
Hinder, check cooperation and function of deglutition is normal.
Experimental design：(1) randomized controlled trial, the sequencing and random digits table gone to a doctor according to subject determines people
Group situation, is divided into A, two groups of B；Subject is treated according to each group therapeutic scheme.（2）Open trial：All subject's clothes
Prescription method is 3 times/d.
Medication：（1）Randomized controlled trial：A group subjects drug dose is 200 mg/ times, 3 times/d (7:00,15:
00,21:00)；B groups dosage is 200 mg/ times, 2 times/d (7:00,21:00);The d of the course for the treatment of 20.Basic pharmaceutical is noted for compound Danshen Root
Penetrate the ml of liquid 16 plus the ml iv drips of 0.9% salt solution of people 500,1 time/d, continuous application 14d.(2) open trial：Drug dose
200 mg/ times, 3 times/d (7:00,15:00,21:00), the d of the course for the treatment of 20.Basic pharmaceutical is identical with randomized controlled trial, 1 time/d,
Continuous application 14d.
Therapeutic evaluation：Standard neurological deficits score is divided into 5 grades：It is almost recovered, neurological deficits score subtracts
Few 91%-100%；Marked improvement, neurological deficits score reduces 46%-90%；Progressive, neurological deficits score reduces 18%-
45%；Unchanged, neurological deficits score is decreased or increased<17%；Deteriorate, neurological deficits score increase ＞ 18%.Always have
Efficiency=(number of cases that is almost recovered+marked improvement number of cases)/total number of cases x100%.
Observation of curative effect：
1st, randomized controlled trial：
（1）It is selected in 30 patients, is divided into two groups, A groups 20, B groups 10 by admission order and random digits table.
To the general clinical data of two groups of subjects, including age, sex, disease accompanied scoring, past medical history scoring, and god before treatment
Harmonious inspection, no significant difference (P ＞ are carried out through functional impairment scoring and activities of daily living scale scoring etc.
0.05), with comparativity, 8 are specifically shown in Table,
Note：Equal P ＞ 0.05
（2）Comparitive study：After two groups of subject's butylphenyl phthaleine soft capsule treatments, A groups effective percentage is 85.0% (17/20), B
Efficient group is 40% (4/10), and group difference has statistical significance (P<0.05)；
（3）The comparison of neurological deficits score：Neurological deficits score difference is without statistics before two groups of subjects
Learn meaning（P ＞ 0.05)；The 11st day and the 21st day are treated, A group scorings are above B groups (equal P<0.05) 9, are specifically shown in Table,
；
（4）The comparison of activities of daily living scale scoring：Daily life active ability amount before two groups of subjects
Table diversity of values learns meaning without system（P ＞ 0.05)；Treat the 11st day and A group scorings in the 21st day are above B groups（P< 0.01）, tool
It is statistically significant, 10 are specifically shown in Table,
。
2nd, open trial：
It is selected in 34 patients altogether, 3 times/d medications are 200mg/ times, efficient for 76.47% (26/34).
3rd, net assessment：
（1）Observation of curative effect:Open trial 34 is total 64 with randomized controlled trial 30, and overall therapeutic effective percentage is
73.44%(47/64)；
（2）Neurological deficits score (table 4)：Compared with pre-treatment, the 11st day neurological deficits score is bright after treatment
Aobvious to reduce, difference has height statistical significance (q=5.575, P<0.01)；The 21st day neurological functional recovery degree is better than after treatment
11st day, therebetween difference have height statistical significance (q=3.256, P<0.01)；
（3）Activities of daily living scale scores：Compared with pre-treatment, the 11st day daily life active ability after treatment
Scale score shows increase clearly, and difference has height statistical significance (q=3.615, P<0.01)；Daily life in 21st day after treatment
While still alive kinetic force scale score difference compared with the 11st day also has height statistical significance (q=2.756, P<0.01).Specifically it is shown in Table
11；
Result above is shown：Treatment safety, curative effect affirmative of the butylphenyl phthaleine soft capsule to light moderate acute ischemic cerebral apoplexy,
Can as patients with acute ischemic cerebral stroke early treatment medicine.
Claims (25)
1. a kind of butylphthalide medicine active composition, it is characterised in that including following components：
Components I：Butylphenyl phthaleine, content >=98.0%；
Compositionⅱ：Selected from methylene phthalide, ethene phthalide, propylene phthalide, butylidenephthalide, amylene phthalide, phthalide, toluene phthalein, ethylbenzene
One or more in phthalein, propyl benzene phthalein, penta phthalide, and component II content ＞ 0 and≤2.0%；When component II includes methylene benzene
Phthalein, ethene phthalide, propylene phthalide, butylidenephthalide, amylene phthalide are any for the moment, comprising one of any composition content most
Height is no more than 0.5%, and when component II is included, phthalide, toluene phthalein, ethylbenzene phthalein, propyl benzene phthalein, penta phthalide are any for the moment, comprising
The content not more than 1.0% of one of any composition；
The compsn. consisting of influenza virus surface is obtained through following method：
A. feed：Butylphenyl phthaleine crude product is added in rectifying column；
B. it is optional, air-distillation：Butylphenyl phthaleine crude product is warming up to 60~110 DEG C, cut at this temperature is collected in no backflow,
Discard；
C. vacuum distillation, it is 4~5mmHg to control vacuum, and butylphenyl phthaleine crude product is warming up into 130~150 DEG C, is collected at this temperature
Cut, discard；154~160 DEG C are continuously heating to, 0~300min of infinite reflux controls constant reflux ratio, collects the temperature
Under cut；
Optional, according to the constituent content in collected cut, above-mentioned B, step C are repeated, butylphthalide medicine active composition is obtained.
2. butylphthalide medicine active composition according to claim 1, it is characterised in that the compositionⅱ is selected from butylene benzene
One or more in phthalein, phthalide, propyl benzene phthalein.
3. butylphthalide medicine active composition according to claim 1, it is characterised in that described components I：Butylphenyl phthaleine contains
Amount >=98.5%, compositionⅱ：Content ＞ 0 and≤1.5%.
4. butylphthalide medicine active composition according to claim 3, it is characterised in that the compositionⅱ is selected from butylene benzene
One or more in phthalein, phthalide, propyl benzene phthalein.
5. butylphthalide medicine active composition according to claim 1, it is characterised in that described components I：Butylphenyl phthaleine contains
Amount >=99.0%；Compositionⅱ：0 ＜ content≤1.0%, when component II includes methylene phthalide, ethene phthalide, propylene phthalide, butylene
Phthalide, amylene phthalide are any for the moment, comprising one of any composition content not more than 0.3%, when in component II
It is any for the moment comprising phthalide, toluene phthalein, ethylbenzene phthalein, propyl benzene phthalein, penta phthalide, comprising one of any composition content highest
No more than 0.5%.
6. butylphthalide medicine active composition according to claim 5, it is characterised in that the compositionⅱ is selected from butylene benzene
One or more in phthalein, phthalide, propyl benzene phthalein.
7. the butylphthalide medicine active composition according to claim any one of 1-6, it is characterised in that described step C,
It is 5mmHg to control vacuum.
8. the butylphthalide medicine active composition according to claim any one of 1-6, it is characterised in that described step C,
Butylphenyl phthaleine crude product is warming up to 140~150 DEG C.
9. the butylphthalide medicine active composition according to claim any one of 1-6, it is characterised in that described step C,
Butylphenyl phthaleine crude product is warming up to 150 DEG C.
10. the butylphthalide medicine active composition according to claim any one of 1-6, it is characterised in that described step
C, is continuously heating to 154 DEG C.
11. the butylphthalide medicine active composition according to claim any one of 1-6, it is characterised in that described step
C, it is 1~10 to control constant reflux ratio:1.
12. the butylphthalide medicine active composition according to claim any one of 1-6, it is characterised in that described step
C, it is 3~7 to control constant reflux ratio:1.
13. a kind of preparation method of butylphthalide medicine active composition, comprises the following steps：
A. feed：Butylphenyl phthaleine crude product is added in rectifying column；
B. it is optional, air-distillation：Butylphenyl phthaleine crude product is warming up to 60~110 DEG C, cut at this temperature is collected in no backflow,
Discard；
C. vacuum distillation, it is 4~5mmHg to control vacuum, and butylphenyl phthaleine crude product is warming up into 130~150 DEG C, is collected at this temperature
Cut, discard；154~160 DEG C are continuously heating to, 0~300min of infinite reflux controls constant reflux ratio, collects the temperature
Under cut；
D. it is optional, according to the constituent content in collected cut, above-mentioned B, step C are repeated, the combination of butylphenyl phthaleine pharmaceutical activity is obtained
Thing.
14. preparation method according to claim 13, it is characterised in that described step C, it is 5mmHg to control vacuum.
15. preparation method according to claim 14, it is characterised in that described step C, butylphenyl phthaleine crude product is warming up to
140~150 DEG C.
16. preparation method according to claim 15, it is characterised in that described step C, butylphenyl phthaleine crude product is warming up to
150℃。
17. preparation method according to claim 16, it is characterised in that described step C, is continuously heating to 154 DEG C.
18. preparation method according to claim 17, it is characterised in that described step C, the constant reflux ratio is controlled to be
1~10:1.
19. preparation method according to claim 18, it is characterised in that described step C, the constant reflux ratio is controlled to be
3~7:1.
20. a kind of pharmaceutical composition, includes any butylphthalide medicine active composition and pharmacy as described in claim 1 to 12
Upper acceptable carrier, optionally, also there are other therapeutic components in described pharmaceutical composition.
21. pharmaceutical composition as claimed in claim 20, it is characterised in that it is oral formulations.
22. pharmaceutical composition as claimed in claim 21, it is characterised in that it is soft capsule, tablet, sustained release tablets, dripping pill.
23. pharmaceutical composition as claimed in claim 20, it is characterised in that it is ejection preparation.
24. pharmaceutical composition as claimed in claim 23, it is characterised in that it is freeze drying powder injection, vein breast.
25. any butylphthalide medicine active composition as described in claim 1 to 12, or appointing described in claim 20 to 24
One pharmaceutical composition, the application in the medicine of disease caused by treatment cerebral ischemia is prepared.
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| CN107648222A (en) * | 2012-06-06 | 2018-02-02 | 石药集团中奇制药技术（石家庄）有限公司 | A kind of butylphthalide medicine active composition and preparation method thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN109939102B (en) * | 2013-06-13 | 2022-05-17 | 石药集团中奇制药技术（石家庄）有限公司 | Pharmaceutical composition containing butylphthalide and borneol and application thereof |
| CN105130934B (en) * | 2015-08-15 | 2018-11-23 | 石药集团恩必普药业有限公司 | A kind of butylphenyl phthaleine bulk pharmaceutical chemicals product and preparation method thereof |
| CN105418564B (en) * | 2015-08-21 | 2017-12-01 | 石药集团恩必普药业有限公司 | A kind of new preprocess method of butylphenyl phthaleine |
| CN105968077B (en) * | 2015-12-31 | 2019-03-01 | 石药集团恩必普药业有限公司 | A kind of butylphenyl phthaleine composition of high-content and preparation method thereof |
| CN105859670B (en) * | 2016-04-19 | 2019-04-05 | 丽珠医药集团股份有限公司 | A kind of preparation method of high purity butylene phthalide |
| CN115554289A (en) * | 2022-10-28 | 2023-01-03 | 成都施贝康生物医药科技有限公司 | Pharmaceutical active composition containing butylphthalide and preparation method thereof |
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| CN1623542A (en) * | 2003-12-05 | 2005-06-08 | 中奇制药技术（石家庄）有限公司 | Butyl benzene phthalein soft capsule and its preparation method |
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| CN1623542A (en) * | 2003-12-05 | 2005-06-08 | 中奇制药技术（石家庄）有限公司 | Butyl benzene phthalein soft capsule and its preparation method |
| CN1823729A (en) * | 2005-12-16 | 2006-08-30 | 中山大学 | Butyl benzene phthalein vein emulsion and its application |
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| CN107648222A (en) * | 2012-06-06 | 2018-02-02 | 石药集团中奇制药技术（石家庄）有限公司 | A kind of butylphthalide medicine active composition and preparation method thereof |
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| CN102716121A (en) | 2012-10-10 |
| CN107648222A (en) | 2018-02-02 |
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