CN107648222A - 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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- CN107648222A CN107648222A CN201710834316.4A CN201710834316A CN107648222A CN 107648222 A CN107648222 A CN 107648222A CN 201710834316 A CN201710834316 A CN 201710834316A CN 107648222 A CN107648222 A CN 107648222A
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- butylphenyl phthaleine
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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%；It is any for the moment when including methylene phthalide, ethene phthalide, propylene phthalide, butylidenephthalide, amylene phthalide in compositionⅱ, comprising one of any composition content not more than 0.5%, phthalide, toluene phthalein, ethylbenzene phthalein, propyl benzene phthalein, penta phthalide are any for the moment when being included in compositionⅱ, comprising one of any composition content not more than 1.0%.The compsn. consisting of influenza virus surface steady quality, the clinical efficacy and drug safety of butylphenyl phthaleine preparation can be ensured.
Description
The application be Application No. CN201210184391.8, the applying date be on 06 06th, 2012, entitled " one
The divisional application of the application for a patent for invention of kind butylphthalide medicine active composition and preparation method thereof ".
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, entitled 3- butyl-l (the H)-isobenzofuranone of chemistry, 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 are oily liquids, have strong celery fragrance, and chemical structural formula is as shown in Equation 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
Method carries out being heated to reflux instead using the phthalic acid acid anhydrides shown in formula 2 as raw material, with anhydrous sodium acetate, valeric anhydride at 300 DEG C
Should, intermediate butylidenephthalide 3 is obtained by extraction in ether, and intermediate butylidenephthalide 3 is dissolved in ether, 10%Pd/C catalytic hydrogenations, is obtained
To butylphenyl phthaleine 1.Reaction scheme is as follows：
The shortcomings that butylphenyl phthaleine product being prepared using the above method, 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
During, the content of product significantly reduces, and impurity significantly raises, and quality is very unstable, uncontrollable；Therefore the product can not be made
Used for medicine.
With the appearance of problem above, there is the improvement to butylphenyl phthaleine product in prior art：
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 intermediate neighbour's valeryl yl benzoic acid 4 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：
The indexs such as the butylphenyl phthaleine product content that is prepared using the above method, impurity 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
Content substantially reduces, and impurity is significantly raised, therefore the product can not use as medicine；(2) while this method was producing
Grignard reagent is used in journey, grignard reagent needs anhydrous and oxygen-free Seal and preservation, current now to do, and cumbersome, production process is deposited
In potential safety hazard, be not suitable for industrialized production.
In view of the content (or purity) of above product is relatively low, in placement process, quality is unstable, uncontrollable, no
It can be used as medicine, therefore still need to be improved prior art, reduce the content of all kinds of impurity in butylphenyl phthaleine, obtain matter
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) alkenyl phthalide, be mixed with 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 reaction in next step 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 are two classes, intermediate before the cyclization of (a) butylphenyl phthaleine, adjacent valeryl yl benzoic acid and its class
Like thing neighbour acetylbenzoic acid, 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 1. the plants butylphenyl phthaleine product, the quality of butylphenyl phthaleine product
Main alkenyl phthalide such as methylene phthalide, ethene phthalide, propylene phthalide, butylidenephthalide, the amylene phthalide with wherein containing of stability
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. the plants butylphenyl phthaleine product, the quality stability of butylphenyl phthaleine product is mainly closed with the butylphenyl phthaleine wherein contained
For example adjacent acetylbenzoic acid of intermediate before ring, 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 the steady quality to composition
Property influence it is smaller, but due to they activity well below butylphenyl phthaleine, will be to fourth as any of which component content ＞ 1.0%
Phthalide drug effect produces considerable influence；The presence of the impurity of other residual volumes will aggravate the unstability of butylphenyl phthaleine product.
Intermediate or other alkyl phthalides either 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 includes following components：
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 includes
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%.
Preferably, above-mentioned butylphthalide medicine active composition, described components I：Butylphthalide content >=98.5%, component
Ⅱ：Content ＞ 0 and≤1.5%.
Preferably, above-mentioned butylphthalide medicine active composition, described components I：Butylphthalide content >=99.0%；Component
Ⅱ：Content ＞ 0 and≤1.0%, and, when compositionⅱ includes methylene phthalide, ethene phthalide, propylene phthalide, butylidenephthalide, amylene benzene
Phthalein is any for the moment, comprising one of any composition content not more than 0.3%；, when compositionⅱ includes 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%.
Preferably, 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, no backflow, collects evaporating at this temperature
Point, discard；
C. it is evaporated under reduced pressure, it is 1~5mmHg to control vacuum, and butylphenyl phthaleine crude product is warming up into 130~150 DEG C, collects the temperature
Cut under degree, is discarded；154~180 DEG C, 0~300min of infinite reflux are continuously heating to, controls constant reflux ratio, collecting should
At a temperature of cut；
D. it is optional, according to the constituent content in collected cut, above-mentioned B, step C are repeated, obtains butylphenyl phthaleine pharmaceutical activity
Composition.
Above-mentioned preparation method, described step C, control vacuum preferably 4~5mmHg；More preferably 5mmHg.
Above-mentioned preparation method, described step C, butylphenyl phthaleine crude product is warming up to preferably 140~150 DEG C, more preferably 150
℃。
Above-mentioned preparation method, described step C, it is continuously heating to preferably 154~160 DEG C, more preferably 154 DEG C.
Above-mentioned preparation method, described step C, control 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 system
It is standby.Preparation method disclosed in Chinese patent CN101962374 is not suitable for industrialized production, this hair due to severe reaction conditions
Not used in bright.
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, it is preferably lyophilized
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 made comprising its pharmaceutical composition
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, can ensure 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) it is 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, add methanol to dissolve
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) 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 (controlling below 150 DEG C), and 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) preparation of butylphenyl phthaleine
3- butylidenephthalides 45.0Kg is dissolved in ether, is added 4.5Kg 10%Pd/C, is used H2Gas is replaced 6 times, is filled with H2, stir
Mix, react at room temperature 24h, concentrated after filtering out Pd/C, silica gel column chromatography, chloroform-petroleum ether elution, obtain butylphenyl phthaleine 43.0Kg.I
Acceleration for stabilization Journal of Sex Research under the conditions of quality research and (40 DEG C, 75%RH) has been carried out to products obtained therefrom, 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) preparation of NBB grignard reagent
Under nitrogen protection, tetrahydrofuran is added in equipped with stirring, thermometer and retort with reflux condensate device
200L, magnesium sheet 6.0Kg and iodine 0.1Kg, 50 DEG C are warming up to, the 31.50Kg butyl bromides for being dissolved in 40L tetrahydrofurans, control is added dropwise
Temperature is no more than 70 DEG C, after being added dropwise, and continues to stir 1h, obtains the RMgBr of butyl bromide.
(2) preparation of adjacent valeryl yl benzoic acid
Under nitrogen protection, 300L tetrahydrofurans, 30Kg phthalic anhydride and 2.5Kg cupric iodides are added, is cooled to -10
DEG C, the RMgBr, control 1h or so that the butyl bromide obtained by step (1) is added dropwise is added dropwise；After being added dropwise, it is further continued for stirring
2h is mixed, the hydrochloric acid solution for adding 1mol/L is hydrolyzed into pH as 2, stands branch vibration layer, and 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 is depressurized and sloughed solvent and obtain adjacent valeryl
Benzoic acid 35Kg.
(3) preparation of butylphenyl phthaleine
In retort add 160Kg 5% sodium hydroxide solution and above-mentioned steps (2) obtained by adjacent valeryl benzene first
Acid, stirring at normal temperature 1h, be cooled to 0 DEG C, be slowly added to 6Kg sodium borohydrides, control temperature be 0 DEG C~10 DEG C, after addition
Normal temperature continues to stir 1h, adds 6mol/L HCl afterwards and is acidified to pH as 4.0, with methyl tertiary butyl ether(MTBE) aqueous layer extracted three times, conjunction
And organic phase, washed to neutrality, anhydrous magnesium sulfate dry with 5% sodium acid carbonate and saturated nacl aqueous solution respectively, control 180-
185 DEG C/1mmHg conditions carry out being evaporated under reduced pressure to butylphenyl phthaleine 19Kg.We products obtained therefrom has been carried out quality research and (40 DEG C,
Acceleration for stabilization Journal of Sex Research under the conditions of 75%RH), the results are shown in Table 2.
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 B 2 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, cut at this temperature is collected, discards；
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 B 3 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, cut at this temperature is collected, discards；
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, cut at this temperature is collected, discards；
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, obtains butylphenyl phthaleine 2.8Kg.
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, cut at this temperature is collected, discards；
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, cut at this temperature is collected, discards；
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, cut at this temperature is collected, discards；
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 have carried out the acceleration for stabilization under the conditions of quality research and (40 DEG C, 75%RH) to the products obtained therefrom of embodiment 1~9
Journal of Sex Research, it 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 preserves 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, first
Alkene phthalide, ethene phthalide, propylene phthalide, butylidenephthalide, amylene phthalide (the alkenyl phthalide in abbreviation compositionⅱ, similarly hereinafter) it is any it
The content of one composition not more than 0.5%, phthalide, toluene phthalein, ethylbenzene phthalein, propyl benzene phthalein, the penta phthalide (alkane in abbreviation compositionⅱ
Base phthalide, the similarly hereinafter) butylphthalide medicine active composition of the content of one of any composition not more than≤1.0%, is accelerating
Under the conditions of place 6 months, components I butylphthalide content change it is smaller, be 97.8%, the content of compositionⅱ is smaller ,≤2.0%,
Quality is relatively stable, 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, group
The content not more than 0.5% of one of any composition of alkenyl phthalide in point II, alkyl phthalide in compositionⅱ are one of any
The butylphthalide medicine active composition of the content of composition not more than 1.0%, place 6 months under acceleration conditions, component group
Divide the change of I butylphthalide content smaller, equal >=98.0%, the content of compositionⅱ is smaller, and≤2.0%, quality is relatively stable, Neng Gouzuo
Used for medicine.
It can be seen that from embodiment 2, embodiment 5, the data of embodiment 8：Components I butylphthalide content >=98.5%；Compositionⅱ
Content≤1.5%, the content not more than 0.5% of one of any composition of alkenyl phthalide in compositionⅱ, in compositionⅱ
The butylphthalide medicine active composition of one of any content not more than 1.0% of composition of alkyl phthalide, under acceleration conditions
To place 6 months, the change of components I butylphthalide content is small, and >=98.4%, the changes of contents of compositionⅱ is small ,≤1.5%, quality
It is stable, it can 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%；One of any component content not more than 0.30% of alkenyl phthalide in content≤1.0% of compositionⅱ, compositionⅱ,
The butylphthalide medicine active composition of one of any component content not more than 0.50% of alkyl phthalide, is adding in compositionⅱ
Placed 6 months under the conditions of speed, the change of components I butylphthalide content is smaller, and >=98.9%, the changes of contents of compositionⅱ is smaller,
≤ 1.0%, quality is more stable, can be that medicine uses.
In summary, butylphthalide medicine active composition provided by the invention, components I butylphthalide content >=98.0%；Group
Point II content≤2.0%, one of any component content not more than 0.5% of alkenyl phthalide in compositionⅱ, alkane in compositionⅱ
One of any component content not more than 1.0% of base phthalide, its steady quality, can use as medicine, carry out preparation
Prepare.Embodiment 10：Butylphenyl phthaleine soft capsule
Bulk drug：Butylphthalide medicine active composition prepared by embodiment 6
Composition：
| Component | Dosage (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 in colloidal sol pot and be heated to 70-80 DEG C, be well mixed, add the gelatin stirring of expansion, 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：With embodiment 10.
Embodiment 12：Butylphenyl phthaleine soft capsule
Bulk drug：Butylphthalide medicine active composition prepared by embodiment 7.
Preparation method：With embodiment 10.
Embodiment 13：Butylbenzene phthalein tablet
Bulk drug：Implement 5 butylphthalide medicine active compositions prepared
Composition：
Label：
Preparation method：
Butylphthalide medicine active composition and emulsifying agent poloxamer are weighed, adds a small amount of water to be uniformly mixed, weighs ring
Dextrin, it is dissolved in water, two solution is mixed, it is quick to stir l hours, put and (5 DEG C) are refrigerated in refrigerator 12 hours, take out filtering, will
Gained solid obtains butylphenyl phthaleine solid powder in 60 DEG C of dryings.
It is appropriate to weigh butylphenyl phthaleine solid powder, adds lactose, partial cross-linked sodium carboxymethylcellulose, after being well mixed, uses
Hydroxypropyl methyl cellulose (2%) aqueous solution is pelletized, and is dried, whole grain, additional Ac-Di-Sol, magnesium stearate, cunning
The auxiliary materials such as stone flour, tabletting.
Sugar coating：Label is weighed, adds 10% appropriate gelatin bag separation layer, after drying, adds syrup, talcum powder or cunning
The mixed powder of stone flour and starch, sugar coating, slice are dried.
Embodiment 14：Butyl benzene phthalein vein breast
Bulk drug：Implement 4 butylphthalide medicine active compositions prepared
Composition：
| Component | Dosage |
| Butylphthalide medicine active composition | 10g |
| Soybean lecithin | 12g |
| Soybean oil | 100g |
| Vitamin E | l g |
| Sorbierite | 25g |
| Water for injection | Add to l000ml |
Preparation method：
Weigh the butylphthalide medicine active composition of recipe quantity, vitamin E mixes with soybean oil, pre- in 60 DEG C of water-baths
Heat；Weigh recipe quantity soybean lecithin and sorbierite in water, 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, pH to 8 is adjusted, filtered, 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 | Dosage |
| Butylphthalide medicine active composition | 200g |
| Soybean lecithin (injection stage) | 80g |
| Mannitol | 2000g |
| Water for injection | Add to 4000ml |
Preparation method：
1st, butylphthalide medicine active composition, soybean lecithin and mannitol are weighed respectively by recipe quantity.
2nd, it is uniform to add 2000ml water for injection high-speed stirreds together with soybean lecithin for butylphthalide medicine active composition, extremely
Clear solution, no oil droplet.
3rd, after mannitol adds the dissolving of 1500ml waters for injection, 100 DEG C of activated carbon for adding up weight 0.1% heats 15 minutes
Charcoal is taken off afterwards.
4th, after (2) mix with (3) solution, add gross weight 0.01% activated carbon stir after, filtering decarbonization, add
Water for injection surveys pH value, content to full dose, after refined filtration, in sub-bottling.
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：With embodiment 10.
Comparative example 2：Butylphenyl phthaleine soft capsule
Bulk drug：Butylphenyl phthaleine product prepared by preparation example 1
Preparation method：With embodiment 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 preserves 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：(components I butylphthalide content is the butylphthalide medicine active composition of embodiment 6
98.0%；Content≤2.0% of compositionⅱ, the content of one of any composition of alkenyl phthalide in compositionⅱ is not more than
0.5%, the content of one of any composition of alkyl phthalide in compositionⅱ is not more than≤1.0%) the butylphenyl phthaleine flexible glue for preparing
Capsule, place 6 months under acceleration conditions, the change of impurity is smaller, total impurities≤2.0%, shows the butylphenyl phthaleine pharmaceutical activity
Composition and auxiliary material compatibility are preferable, and the quality of the pharmaceutical preparations is relatively stable.
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%；Content≤1.5% of compositionⅱ, the content of one of any composition of alkenyl phthalide in compositionⅱ is not more than
0.5%, 1.0%) butylphenyl phthaleine soft capsule that the content of one of any composition of alkyl phthalide in compositionⅱ is not more than prepared,
Place 6 months under acceleration conditions, the change of impurity is small, total impurities≤1.5%, shows the butylphthalide medicine active composition
Good with auxiliary material compatibility, the quality of the pharmaceutical preparations is stable.
It can be seen that from the data of embodiment 12：Butylphthalide medicine active composition (the components I butylphthalide content of embodiment 7
>=99.0%；One of any component content of alkenyl phthalide in content≤1.0% of compositionⅱ, compositionⅱ is not more than
0.30%, 0.50%) butylphenyl phthaleine soft capsule that one of any component content of alkyl phthalide in compositionⅱ is not more than prepared,
Place 6 months under acceleration conditions, the change of impurity is smaller, total impurities≤1.0%, shows that the butylphenyl phthaleine pharmaceutical activity combines
Thing and auxiliary material compatibility are more preferable, and quality is more stable.
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 improves, and the stability of preparation also improves therewith.
It can be seen that from the data of embodiment 10~15：By the present invention butylphthalide medicine active composition preparation of preparation,
Place 6 months under acceleration conditions, the indices of preparation vary less, steady quality, can ensure the clinical treatment of butylphenyl phthaleine
Effect and drug safety.
The butylphenyl phthaleine flexible glue of the butylphenyl phthaleine product preparation of prior art is can be seen that from comparative example 1 and the data of comparative example 2
Capsule, place 6 months under acceleration conditions, impurity dramatically increases, content significantly reduces, show the butylphenyl phthaleine product of prior art with
Auxiliary material poor compatibility, quality are 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 drastically raises, and content drastically reduces, and can not ensure clinical efficacy and drug safety, because
This cannot be used for clinical research；Butylphthalide medicine active composition provided by the invention, components I butylphthalide content >=98.0%；
The content ＞ 0 of compositionⅱ and≤2.0%, the content not more than 0.5% of one of any composition of alkenyl phthalide in compositionⅱ,
The content not more than 1.0% of one of any composition of alkyl phthalide in compositionⅱ, it is good with auxiliary material compatibility, in acceleration environment
It is lower place 6 months, each component has no significant change, disclosure satisfy that medicine it is safe and effective, quality controllable the characteristics of, can ensure
Clinical efficacy and drug safety.
Embodiment 16：Butylphenyl phthaleine animal acute toxicity test
Test objective：The butylphenyl phthaleine product of butylphthalide medicine active composition and prior art more provided by the invention 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 existing skill that butylphthalide medicine active composition, the preparation example 1~2 of the preparation of embodiment 5~7 obtain
Art 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 that the present invention carries
The butylphthalide medicine active composition of confession has good security compared with the butylphenyl phthaleine product of prior art.
Embodiment 17：Effect of the butylphenyl phthaleine to rat brain artery ligation encephaledema
Test objective：The butylphenyl phthaleine product of butylphthalide medicine active composition and prior art more provided by the invention 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 existing skill that butylphthalide medicine active composition, the preparation example 1~2 of the preparation of embodiment 5~7 obtain
Art butylphenyl phthaleine product.
Experimental design：Cerebral hypoxia ischemic causes energy exhaustion, and cell membrane function is damaged, it is impossible to ion gradient is maintained,
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, put to death within postoperative 24 hours, take forebrain, claim left and right brain hemisphere wet
Weight；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 is adjusted with HCI
Value, is connected on oxygen Texture Analyzer with ISE, 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) reduces brain water and Na+Content, increase
Add K+Content highly significant, and have dose-effect relationship, illustrate that butylphthalide medicine active composition provided by the invention can be bright
It is aobvious to mitigate encephaledema caused by local cerebral ischemia；1~2 group of preparation example (160,240mg/kg) can reduce brain water and Na+Content,
Increase 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 scores (NIHSS) neurological deficits score as 5-25 points.(3) nineteen ninety-five national 4th cerebrovascular disease is met
Diagnostic criteria (4) age of onset of art meeting revision<75 years old.(5) head CT examination Cerebral hemorrhage.(6) unconscious obstacle, inspection
Look into 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 determine 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 200mg/ times, 3 times/d (7:00,15:
00,21:00)；B groups dosage is 200mg/ times, 2 times/d (7:00,21:00)；Course for the treatment of 20d.Basic pharmaceutical is injected for compound Danshen Root
Liquid 16ml adds the salt solution 500ml iv drips of people 0.9%, 1 time/d, continuous application 14d.(2) open trial：Drug dose
200mg/ times, 3 times/d (7:00,15:00,21:00), course for the treatment of 20d.Basic pharmaceutical is identical with randomized controlled trial, 1 time/d, even
It is continuous to apply 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 reduce 46%-90%；Progressive, neurological deficits score is reduced
18%-45%；Unchanged, neurological deficits score decreases or increases<17%；Deteriorate, neurological deficits score increase ＞
18%.Total effective rate=(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 by admission order and random digits table, A groups 20, B groups 10.
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), there is comparativity, be specifically shown in Table 8,
Table 8：The comparison of clinical data before two groups of subjects of randomized controlled trial
Note：Equal P ＞ 0.05
(2) curative effect compares：After the treatment of two groups of subject's butylphenyl phthaleine soft capsules, A groups effective percentage is 85.0% (17/20), B groups
Effective percentage is 40% (4/10), and group difference has statistical significance (P<0.05).
(3) 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), are specifically shown in Table 9.
Table 9：The comparison of neurological deficits score before and after two groups of subjects of randomized controlled trial
Note：*P ＜ 0.005；**P ＜ 0.001
(4) comparison of activities of daily living scale scoring：Daily life active ability amount before two groups of subjects
Table diversity of values learns meaning (P ＞ 0.05) without system；Treat the 11st day and A group scorings in the 21st day are above B groups (P ＜ 0.01), have
It is statistically significant, specifically it is shown in Table 10.
Table 10：The comparison that activities of daily living scale scores before and after two groups of subjects of randomized controlled trial
Note：**P ＜ 0.01
2nd, open trial：
It is selected in 34 patients altogether, 3 times/d medications, 200mg/ times, effective percentage is 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 excellent after treatment
In the 11st day, difference had height statistical significance (q=3.256, P ＜ 0.01) therebetween.
(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)；After treatment the 21st day it is daily
Life activity ability 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.
Table 11：The overall pretherapy and post-treatment neurological deficits score of case and the comparison of activities of daily living scale scoring
Note：aFor treat before with treat after compared with the 11st day,
bTo treat 11 days after treatment compared with the 21st day,
cFor for treat before with treat after compared with the 21st day
**P ＜ 0.01
Result above is shown：Treatment safety, curative effect affirmative of the butylphenyl phthaleine soft capsule to light moderate acute ischemic cerebral apoplexy,
Can be as the early treatment medicine of patients with acute ischemic cerebral stroke.
Claims (13)
1. a kind of butylphthalide medicine active composition, it is characterised in that include 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 the content ＞ 0 of compositionⅱ and≤2.0%；When compositionⅱ 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 compositionⅱ includes, 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.
2. 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%.
3. butylphthalide medicine active composition according to claim 1, it is characterised in that described components I：Butylphenyl phthaleine contains
Amount >=99.0%；Compositionⅱ：Content ＞ 0 and≤1.0%, when compositionⅱ includes methylene phthalide, ethene phthalide, propylene phthalide, fourth
Alkene phthalide, amylene phthalide are any for the moment, comprising one of any composition content not more than 0.3%, work as compositionⅱ
In it is any for the moment comprising phthalide, toluene phthalein, ethylbenzene phthalein, propyl benzene phthalein, penta phthalide, comprising one of any composition content most
Height is no more than 0.5%.
4. butylphthalide medicine active composition according to any one of claims 1 to 3, it is characterised in that the compositionⅱ choosing
One or more from butylidenephthalide, phthalide, propyl benzene phthalein.
5. a kind of preparation method of butylphthalide medicine active composition as claimed in claim 1, 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, no backflow, collects cut at this temperature,
Discard；
C. it is evaporated under reduced pressure, it is 1~5mmHg to control vacuum, and butylphenyl phthaleine crude product is warming up into 130~150 DEG C, collected at this temperature
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, obtains the combination of butylphenyl phthaleine pharmaceutical activity
Thing.
6. preparation method according to claim 5, it is characterised in that described step C, control vacuum for 4~
5mmHg, preferably 5mmHg.
7. preparation method according to claim 5, it is characterised in that described step C, butylphenyl phthaleine crude product is warming up to
140~150 DEG C, preferably 150 DEG C.
8. preparation method according to claim 5, it is characterised in that described step C, be continuously heating to 154~160
DEG C, preferably 154 DEG C.
9. preparation method according to claim 5, it is characterised in that described step C, it is 1 to control constant reflux ratio
~10:1, preferably 3~7:1.
10. a kind of pharmaceutical composition, include any butylphthalide medicine active composition and pharmacy as described in Claims 1-4
Upper acceptable carrier, optionally, other therapeutic components also may be present in described pharmaceutical composition.
11. pharmaceutical composition as claimed in claim 10, it is characterised in that it is oral formulations, preferably soft capsule, piece
Agent, sustained release tablets, dripping pill.
12. pharmaceutical composition as claimed in claim 10, it is characterised in that it is ejection preparation, preferably freeze drying powder injection,
Vein breast.
13. any butylphthalide medicine active composition as described in Claims 1-4, or appointing described in claim 10 to 12
One pharmaceutical composition, the application in the medicine of disease caused by treatment cerebral ischemia is prepared.
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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 |
| CN101962374A (en) * | 2010-10-21 | 2011-02-02 | 上海应用技术学院 | Preparation method of butylphthalide |
| CN102716121B (en) * | 2012-06-06 | 2017-10-24 | 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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| CN100367951C (en) * | 2005-12-16 | 2008-02-13 | 石药集团恩必普药业有限公司 | Butyl benzene phthalein vein emulsion and its application |
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2012
- 2012-06-06 CN CN201210184391.8A patent/CN102716121B/en active Active
- 2012-06-06 CN CN201710834316.4A patent/CN107648222A/en active Pending
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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 |
| CN101962374A (en) * | 2010-10-21 | 2011-02-02 | 上海应用技术学院 | Preparation method of butylphthalide |
| CN102716121B (en) * | 2012-06-06 | 2017-10-24 | 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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| CN102716121B (en) | 2017-10-24 |
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