CN104306372B - A kind of butylphenyl phthaleine preparation compositions and preparation method thereof and purposes - Google Patents
A kind of butylphenyl phthaleine preparation compositions and preparation method thereof and purposes Download PDFInfo
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Abstract
The invention discloses a kind of butylphenyl phthaleine preparation compositions and preparation method thereof, wherein butylphenyl phthaleine preparation compositions include butylphenyl phthaleine and Ligustilide, the pharmaceutical composition can also add pharmaceutically acceptable auxiliary material, and soft capsule, liquid hard capsule, capsule and pill, dripping pill etc. is made.
Description
Technical field
The invention belongs to pharmaceutical technology field, be related to a kind of butylphenyl phthaleine preparation compositions and preparation method thereof, in particular to
A kind of pharmaceutical composition of butylphenyl phthaleine and Ligustilide as well as preparation method and application thereof.
Background technology
Butylphenyl phthaleine (3-n-butylpHthalide, abbreviation NBP), complete -1 (H)-isobenzofuranone of name 3- butyl, also known as
Butylphthalide, is the raceme extracted from celery seed, also can be artificial synthesized.Butylphenyl phthaleine is a kind of oily liquids, insoluble
Yu Shui, has strong celery taste, and an asymmetric carbon atom is contained in molecule, therefore it is there are two kinds of optical isomers, i.e., left
Revolve butylphenyl phthaleine (l-3-n-butylpHthalide) and d-3-n-butylphthalide (d-3-n-butylpHthalide).Its molecular formula is as follows
Shown in figure
Butylphenyl phthaleine can reduce the infarct after focal cerebral ischemia, and increase ischemic region cerebral blood flow (CBF) and improvement Cerebral Region are micro-
Circulation, protects mitochondrial function, mitigates the degree of nervous function damage, improves the energetic supersession etc. of global cerebral ischemia hindbrain, effect
In multiple links of cerebral ischemia pathology.The and of Chinese patent 98125618.X, 03137457.3,200310100222.2
200410001748.X discloses butylphenyl phthaleine respectively to be prevented and is controlling in antithrombus formation and platelet aggregation-against, levo butyl phthalide
Treat the application in dull-witted, cerebral infarction and brain ischemia medicament.
Ligustilide (Ligustilide) is a kind of volatile oil from the extraction of the root of the umbellate form such as Ligusticum wallichii, Angelica sinensis section plant
Component, it is the faint yellow oily liquids with fragrance of tool, and boiling point is 168~169 DEG C, dissolves in ethanol, methanol, ether, acetic acid
The organic solvents such as ethyl ester, petroleum ether, molecular formula are C12H 14O2, relative molecular mass 190.24, its chemical structural formula is as follows
Shown in figure：
The chemical constitution of Ligustilide is connected with active cyclobutenyl to be similar to butylphenyl phthaleine on 3, be chemically unstable because
Element, under the conditions of room temperature is placed naturally, can occur a variety of isomerization reactions such as dehydrogenation, oxidation, hydrolysis, degraded, easily isomerization
Into other cyclobutenyl furan lactone compounds, place makes sample be progressively transformed into by transparent clarification, flowable liquid for a long time
Brown, sticky semisolid or solid, be oxidized to Various Complex product so that it is last disappear, to use and study bring it is many
It is difficult.
The prior art indicate that：Ligustilide has cardiovascular and cerebrovascular, the circulatory system and immune function etc. stronger pharmacology to make
With.
Chinese patent CN92111278.5, which discloses Ligustilide, to be had very strong spasmolysis, relievings asthma, calm effect, clinically
Available for treatment bronchitis and gynecological disease；It is tired available for treatment eyes since it has smooth muscle obvious relexation
Labor and skin wrinkle resisting；Also having at the same time reduces body temperature, treatment vasculitis and cerebral thrombus and other effects.
Chinese patent CN03123994.3, which discloses Ligustilide, to be had in the related disease of prevention and treatment microcirculation disorder
Application, it also has and improves respiratory function, the effect such as reducing heart rate.
Chinese patent CN200310108859.6 discloses Ligustilide and its dimer to arteriosclerosis with anti-
Control effect.
More than in view of, lack a kind of a kind of medicinal group that butylphenyl phthaleine and Ligustilide etc. are used in combination in the prior art
The effect of compound, it can not only fully play both compounds, and stable quality.
The content of the invention
It is an object of the invention to provide a kind of pharmaceutical composition, including butylphenyl phthaleine and Ligustilide, the pharmaceutical composition
Use in conjunction has synergistic effect, and the stability of Ligustilide is significantly improved.
To achieve these goals, present invention employs following technical scheme：
A kind of pharmaceutical composition, including butylphenyl phthaleine and Ligustilide.
In above-mentioned composition, the butylphenyl phthaleine is dl-3-n-butylphthalide or levo butyl phthalide.
In above-mentioned composition, the Ligustilide for cis form ligustilide or trans-Ligustilide or the two arbitrarily to compare
The mixture of example.
In above-mentioned pharmaceutical composition, the Ligustilide is more than 90% Ligustilide for purity, and preferably purity is big
In the Ligustilide of the Ligustilide of 92% Ligustilide, more preferably greater than 95%, more preferably greater than 97%；More preferably greater than
98% Ligustilide.
In aforementioned pharmaceutical compositions, the weight ratio of butylphenyl phthaleine and Ligustilide is 1:100~100:1, preferred weight ratio is
1:20~20:1；More preferably weight ratio is 1:5~20:1；More preferably weight ratio is：1:5~5:1.
Further, antioxidant can also be added in above-mentioned composition, antioxidant can be tocopherol, lecithin, lemon
Lemon acid, the one or more of ascorbic acid, antioxidant accounts for the 0.01%~0.2% of composition total weight, preferably 0.025%~
0.1%.
Further, above-mentioned composition can also add pharmaceutically acceptable auxiliary material, and soft capsule, liquid hard is made
Capsule, capsule and pill, dripping pill etc..
Wherein：
The auxiliary material pharmaceutically can be vegetable oil, the vegetable oil be selected from be sesame oil, corn oil, peanut oil,
One kind in soybean oil, apricot kernel oil, persic oil, cottonseed oil, sunflower oil, olive oil.Vegetable oil account for composition total weight 0~
90%, preferably 10~80%, more preferably 30~70%.
The auxiliary material pharmaceutically can be cosolvent, and the cosolvent is span 20, sorbester p18, sorbester p17, mountain
Yu acid glycerides, Masine 35-1, single sad propylene glycol ester, mono laurate propylene glycol ester, glyceryl monooleate, high-purity
Diethylene glycol monoethyl ether, -6 glyceride of linoleic acid polyethanol, -6 glyceride of laurate polyethanol, medium chain triglyceride, octanoic acid
One or more of in glycerol decanoate, caprylic capric propylene glycol ester, oleic acid LABRAFIL M 1944CS, cosolvent accounts for composition gross weight
The 0~50% of amount, preferably 0~40%, more preferably 0~20%.
Above-mentioned composition can be prepared into soft capsule or liquid hard capsule, and capsule quality is stablized, and is store at 25 DEG C and 60%RH
Deposit below composition after the period：After 3 months, 6 months, 9 months, 12 months, 18 months, 24 months, in capsule 's content
The content of butylphenyl phthaleine is not less than 98%, and the content of Ligustilide is not less than 95%, it is preferable that the content of Ligustilide is not less than
96%；The content of Ligustilide in further preferred capsule 's content is not less than 97%；More preferably the content of Ligustilide is not
Less than 98%.
Inventor has no more than following by the measure to peroxide value in above-mentioned composition, described pharmaceutical composition
Initial peroxide value：2Meq/kg, below 25 DEG C and 60%RH storage components after the period：3 months, 6 months, 9 months,
After 12 months, 18 months, 24 months, the peroxide value of capsule 's content is no more than 5Meq/kg, is preferably more than 4Meq/kg, is excellent
Choosing is no more than 3Meq/kg, preferably more than 2Meq/kg, more preferably no more than 1Meq/kg.
It is a further object to provide application of the above-mentioned composition in the medicine for the treatment of cardiac-cerebral ischemia.
Embodiment
The invention discloses butylphenyl phthaleine and the composition of Ligustilide, those skilled in the art can use for reference the interior of the present invention
Hold, with reference to pharmacy principle, be suitably modified technological parameter or prescription proportioning to realize.In particular, it is all similar
Replacement and change it is apparent to those skilled in the art, they are considered as being included in the scope of the present invention.
The application of the present invention is described by preferred embodiment, and related personnel can substantially not depart from present invention, essence
To method described herein and apply in god and scope and is modified or suitably changes with combining, to realize and using skill of the present invention
Art.
Next by the following examples the present invention is further explained, but embodiment is not the present invention any restriction.
Comparative example 1：Butylphenyl phthaleine soft capsule, prior art products, according to prescription and system disclosed in Chinese patent CN1623542
It is prepared by Preparation Method
1) composition (1000)：
Content forms：Butylphenyl phthaleine 100g, soybean oil 400g
Capsule skin forms：Gelatin 100g, glycerine 30g, water 130kg, ethylparaben 200mg
2) preparation method：
A, the preparation of capsule skin solution：Taking gelatin to add suitable water makes its water swelling, separately by remaining water, glycerine, Buddhist nun
In golden ethyl ester the being added to glue bucket of pool, warming temperature reaches the gelatin that expansion is added after temperature, makes it complete molten to 70-80 DEG C
Solve, bubble removing is vacuumized in course of dissolution, insulation is spare；
B, the preparation of content：Butylphenyl phthaleine, soybean oil are mixed into dissolving, it is spare；
C, soft capsule is suppressed：With above-mentioned content and capsule skin solution compacting soft capsule, strictly controlled environment in pressing process
Temperature is 18~22 DEG C, and ambient humidity is 10~20%RH, dry 10~40h, packaging, every 100mg containing butylphenyl phthaleine.
Comparative example 2：Ligustilide soft capsule
1) composition (1000)：
Content forms：Ligustilide 100g
Capsule skin forms：Gelatin 100g, glycerine 30g, water 130kg, ethylparaben 200mg
2) preparation method：
A, the preparation of capsule skin solution：Taking gelatin to add suitable water makes its water swelling, separately by remaining water, glycerine, Buddhist nun
In golden ethyl ester the being added to glue bucket of pool, warming temperature reaches the gelatin that expansion is added after temperature, makes it complete molten to 70-80 DEG C
Solve, bubble removing is vacuumized in course of dissolution, insulation is spare；
B, the preparation of content：Ligustilide is mixed and is dissolved, it is spare；
C, soft capsule is suppressed：With above-mentioned content and capsule skin solution compacting soft capsule, strictly controlled environment in pressing process
Temperature is 18~22 DEG C, and ambient humidity is 10~20%RH, dry 10~40h, packaging, every 100mg containing Ligustilide.
Comparative example 3：Ligustilide soft capsule
1) composition (1000)：
Content forms：Ligustilide 100g, soybean oil 100g
Capsule skin forms：Gelatin 100g, glycerine 30g, water 130kg, ethylparaben 200mg
2) preparation method：
A, the preparation of capsule skin solution：With comparative example 1；
B, the preparation of content：Ligustilide, soybean oil are mixed into dissolving, it is spare；
C, soft capsule is suppressed：With above-mentioned content and capsule skin solution compacting soft capsule, strictly controlled environment in pressing process
Temperature is 18~22 DEG C, and ambient humidity is 10~20%RH, dry 10~40h, packaging, every 100mg containing Ligustilide.
Embodiment 1：Butylphenyl phthaleine composition soft
1) composition (1000)：
Liquid forms：Butylphenyl phthaleine 100g, Ligustilide 100g；
Capsule skin forms：With comparative example 1
2) preparation method：
A, the preparation of capsule skin solution：With comparative example 1；
B, the preparation of liquid：Liquid composition each component is mixed into dissolving, it is spare；
C, soft capsule is suppressed：With above-mentioned liquid and capsule skin solution compacting soft capsule, dry, packaging, every contains butylphenyl phthaleine
100mg, Ligustilide 100mg.
Embodiment 2：Butylphenyl phthaleine composition soft
1) composition (1000)：
Liquid forms：Butylphenyl phthaleine 100g, Ligustilide 20g；
Capsule skin forms：With comparative example 1
2) preparation method：With embodiment 1.
Embodiment 3：Butylphenyl phthaleine composition soft
1) composition (1000)：
Liquid forms：Butylphenyl phthaleine 20g, Ligustilide 100g；
Capsule skin forms：With comparative example 1
2) preparation method：With embodiment 1.
Embodiment 4：Butylphenyl phthaleine composition soft
1) composition (1000)：
Liquid forms：Butylphenyl phthaleine 100g, Ligustilide 100g, soybean oil 300g
Capsule skin forms：With comparative example 1
2) preparation method：
A, the preparation of capsule skin solution：With comparative example 1；
B, the preparation of liquid：Liquid composition each component is mixed into dissolving, it is spare；
C, soft capsule is suppressed：With above-mentioned liquid and capsule skin solution compacting soft capsule, dry, packaging, every contains butylphenyl phthaleine
50mg, Ligustilide 100mg.
Embodiment 5：Butylphenyl phthaleine composition soft
1) composition (1000)：
Liquid forms：Butylphenyl phthaleine 100g, Ligustilide 20g, peanut oil 380g
Capsule skin forms：With comparative example 1
2) preparation method：With embodiment 4.
Embodiment 6：Butylphenyl phthaleine composition soft
1) composition (1000)：
Liquid forms：Butylphenyl phthaleine 20g, Ligustilide 100g, soybean oil 380g
Capsule skin forms：With comparative example 1
2) preparation method：With embodiment 4.
Embodiment 7：Butylphenyl phthaleine composition soft
1) composition (1000)：
Liquid forms：Butylphenyl phthaleine 100g, Ligustilide 100g, soybean oil 300g, tocopherol 0.5g
Capsule skin forms：With comparative example 1
2) preparation method：
D, the preparation of capsule skin solution：With comparative example 1；
E, the preparation of liquid：Liquid composition each component is mixed into dissolving, it is spare；
F, soft capsule is suppressed：With above-mentioned liquid and capsule skin solution compacting soft capsule 1000, dry, packaging, every contains fourth
Phthalide 50mg, Ligustilide 100mg.
Embodiment 8：Butylphenyl phthaleine composition soft
1) composition (1000)：
Liquid forms：Butylphenyl phthaleine 100g, Ligustilide 20g, soybean oil 380g, tocopherol 0.3g
Capsule skin forms：With comparative example 1
2) preparation method：With embodiment 7.
Embodiment 9：Butylphenyl phthaleine composition soft
1) composition (1000)：
Liquid forms：Butylphenyl phthaleine 20g, Ligustilide 100g, soybean oil 380g, tocopherol 0.25g
Capsule skin forms：With comparative example 1
2) preparation method：With embodiment 7.
Embodiment 10：Butylphenyl phthaleine composition liquid hard capsule
1) composition (1000)：
Liquid forms：Butylphenyl phthaleine 100g, Ligustilide 50g, peanut oil 350g, tocopherol 0.25g
Liquid hard capsule softgel shell main component：HPMC(2906)
2) preparation method：
A, the preparation of content：Liquid component each component is weighed according to prescription ratio, stirring and dissolving, mixing, what is obtained is mixed
Compound is content；
B, liquid filling body hard shell capsules：By content-filled in hard shell capsules softgel shell, thing liquid is combined up to butylphenyl phthaleine after sealing
Body hard shell capsules.
Embodiment 11：Butylphenyl phthaleine composition liquid hard capsule composition
1) composition (1000)：
Liquid forms：Butylphenyl phthaleine 50g, Ligustilide 100g, peanut oil 350g, lecithin 0.25g
Liquid hard capsule softgel shell main component：HPMC(2906)
2) preparation method：With embodiment 10.
Embodiment 12：Butylphenyl phthaleine composition liquid hard capsule
1) composition (1000)：
Liquid forms：Butylphenyl phthaleine 30g, Ligustilide 100g, peanut oil 370g, tocopherol 0.25g
Liquid hard capsule softgel shell main component：HPMC(2906)
2) preparation method：With embodiment 10.
Embodiment 13：Butylphenyl phthaleine composition soft
1) composition (1000)：
Liquid forms：Butylphenyl phthaleine 10g, Ligustilide 100g, soybean oil 390g；
Capsule skin forms：With comparative example 1
2) preparation method：With embodiment 4.
Embodiment 14：Butylphenyl phthaleine composition soft
1) composition (1000)：
Liquid forms：Butylphenyl phthaleine 8g, Ligustilide 100g, soybean oil 390g；
Capsule skin forms：With comparative example 1
2) preparation method：With embodiment 4.
Embodiment 15：Butylphenyl phthaleine composition soft
1) composition (1000)：
Liquid forms：Butylphenyl phthaleine 5g, Ligustilide 100g, soybean oil 390g；
Capsule skin forms：With comparative example 1
2) preparation method：With embodiment 4.
Embodiment 16：Butylphenyl phthaleine composition soft
1) composition (1000)：
Liquid forms：Butylphenyl phthaleine 100g, Ligustilide 5g, soybean oil 390g；
Capsule skin forms：With comparative example 1
2) preparation method：With embodiment 4.
Embodiment 17：Butylphenyl phthaleine composition soft
1) composition (1000)：
Liquid forms：Butylphenyl phthaleine 100g, Ligustilide 10g, soybean oil 390g；
Capsule skin forms：With comparative example 1
2) preparation method：With embodiment 4.
Embodiment 18：Butylphenyl phthaleine composition soft
1) composition (1000)：
Liquid forms：Butylphenyl phthaleine 100g, Ligustilide 40g, olive oil 230g, Unigly GO 102S 140g.Tocopherol
0.25g capsules skin forms：With comparative example 1
2) preparation method：With embodiment 4.
Embodiment 19：Butylphenyl phthaleine composition soft
1) composition (1000)：
Liquid forms：Butylphenyl phthaleine 100g, Ligustilide 60g, apricot kernel oil 240g, glyceryl monooleate 100g, tocopherol
0.25g capsules skin forms：With comparative example 1
2) preparation method：With embodiment 4.
Embodiment 20：Butylphenyl phthaleine composition soft
1) composition (1000)：
Liquid forms：Butylphenyl phthaleine 40g, Ligustilide 100g, sunflower oil 310g, Compritol 888 ATO 50g, tocopherol
0.25g capsules skin forms：With comparative example 1
2) preparation method：With embodiment 4.
Embodiment 21：Butylphenyl phthaleine composition soft
1) composition (1000)：
Liquid forms：Butylphenyl phthaleine 100g, Ligustilide 40g, corn oil 180g, medium chain triglyceride 180g, tocopherol
0.25g capsules skin forms：With comparative example 1
2) preparation method：With embodiment 4.
Embodiment 22：Butylphenyl phthaleine composition soft
1) composition (1000)：
Liquid forms：Butylphenyl phthaleine 100g, Ligustilide 30g, sunflower oil 240g, glyceryl monooleate 130g tocopherols
0.25g capsules skin forms：With comparative example 1
2) preparation method：With embodiment 4.
Embodiment 23：Butylphenyl phthaleine composition soft
1) composition (1000)：
Liquid forms：Butylphenyl phthaleine 30g, Ligustilide 100g, cottonseed oil 320g, Unigly GO 102S 50g tocopherols 0.25g
Capsule skin forms：With comparative example 1
2) preparation method：With embodiment 4.
Embodiment 24：Butylphenyl phthaleine composition soft
1) composition (1000)：
Liquid forms：Butylphenyl phthaleine 100g, Ligustilide 100g, soybean oil 200g, glyceryl monooleate 50g, single octanoic acid third
Diol ester 50g, tocopherol 0.5g
Capsule skin forms：With comparative example 1
2) preparation method：With embodiment 4.
25 stability test result of embodiment
Take comparative example 1~3,1~24 sample of embodiment appropriate, simulation listing packaging, in 25 DEG C ± 2 DEG C of temperature, relatively wet
Spend to place 24 months under the conditions of 60% ± 10%, sample respectively at the 3rd, 6,9,12,18,24 the end of month, to its character, contain
Amount, related material and oxidation number are determined, and the results are shown in Table 1：
Table 1-1 stability result tables
Table 1-2 stability result tables
Table 1-3 stability result tables
Table 1-4 stability result tables
Table 1-5 stability result tables
Table 1-6 stability result tables
Upper table is analyzed, we can draw：
1st, compare comparative example 2~3 and embodiment 1~3, can significantly find out：The composition of butylphenyl phthaleine and Ligustilide,
The stability of Ligustilide can be obviously improved
By taking comparative example 2~3 and embodiment 1 as an example, when placing 24 months for a long time, its marked difference is as shown in table 2：
Table 2-1：1 contrast table of comparative example 2 and embodiment
Table 2-2：1 contrast table of comparative example 3 and embodiment
Can significantly it be found out by table 2：The composition of butylphenyl phthaleine and Ligustilide, can be obviously improved Ligustilide
The content of stability, i.e. Ligustilide has obtained significant raising, long-term to place 24 months, not less than 95%；Related material obtains
Significant reduction, it is long-term to place 24 months, not higher than 5.0%；Peroxide value has also obtained significant reduction, places 24 for a long time
Month, not higher than 3.0Meq/kg.
2 comparing embodiments 1~3 and embodiment 4~6, can significantly find out：Butylphenyl phthaleine, Ligustilide, the group of vegetable oil
Compound, can further be obviously improved the stability of Ligustilide
By taking embodiment 1 and embodiment 4 as an example, when placing 24 months for a long time, its marked difference is as shown in table 3：
Table 3:4 contrast table of embodiment 1 and embodiment
Can significantly it be found out by table 3：Butylphenyl phthaleine, Ligustilide, the composition of vegetable oil, can be obviously improved Jehol Ligusticum Rhizome
The content of the stability of lactone, i.e. Ligustilide has obtained significant raising, long-term to place 24 months, not less than 97%, related thing
Matter has obtained significant reduction, and long-term to place 24 months, not higher than 3.0%, peroxide value has also obtained significant reduction, puts for a long time
Put 24 months, not higher than 2.0Meq/kg.
3rd, comparing embodiment 4~6 and embodiment 7~12, can significantly find out：Butylphenyl phthaleine, Ligustilide, vegetable oil,
The composition of antioxidant, can further be obviously improved the stability of Ligustilide
By taking embodiment 4 and embodiment 7 as an example, when placing 24 months for a long time, its marked difference is as shown in table 4：
Table 4:7 contrast table of embodiment 4 and embodiment
Can significantly it be found out by table 4：Butylphenyl phthaleine, Ligustilide, vegetable oil, the composition of antioxidant, can be notable
Lifting Ligustilide stability, i.e. the content of Ligustilide obtained significant raising, and long-term placement 24 months, is not less than
98%, related material has obtained significant reduction, and long-term to place 24 months, not higher than 1.0%, peroxide value has also obtained significantly
Reduce, it is long-term to place 24 months, not higher than 1.0Meq/kg.
4th, comparing embodiment 7~12 and embodiment 18~24, can significantly find out：Butylphenyl phthaleine, Ligustilide, plant
Oil, antioxidant, the composition of cosolvent, can further be obviously improved the stability of Ligustilide
By taking embodiment 7 and embodiment 24 as an example, when placing 24 months for a long time, its marked difference is as shown in table 5
Table 5：24 contrast table of embodiment 7 and embodiment
Can significantly it be found out by table 5：Butylphenyl phthaleine, Ligustilide, vegetable oil, antioxidant, the composition of cosolvent, energy
The enough stability for being further obviously improved Ligustilide, the i.e. content of Ligustilide have obtained significant raising, have put for a long time
Put 24 months, not less than 99%, related material has obtained significant reduction, long-term to place 24 months, not higher than 0.6%, peroxide value
Do not change.
Experiment 1：Focal cerebral ischemia mouse Nerve cell function is tested
1st, zoopery material：
The preparation of 1.1 medicines：Butylphenyl phthaleine, Ligustilide are dissolved in soybean oil；
1.2 animal：Adult, healthy male CD1 mouse, 25~30g of weight, Hebei Medical University's Experimental Animal Center carry
For being cleaning grade mouse, with fed standard chow and drinking pure water after buying, being responsible for by animal housing poultry raiser, constant temperature
20~25 DEG C；
1.3 data processing：Data by SPSS11.5 statistical softwares examine between variance analysis and group.
2nd, focal cerebral ischemia mouse Nerve cell function is tested
After 2.1 focal cerebral ischemia in rats prepare mouse pretreatment, fiber crops are injected intraperitoneally with 10% chloraldurate 0.4g/Kg
It is liquor-saturated, right side of mice middle cerebral artery occlusion model (transient middle are prepared using line brush with reference to Longa etc.
Cerebral artery was occluded, tMCAO), cause focal cerebral ischemic in mice, 1 it is small when after pull out Outlet bolt, realize
Fill again.Disinfection, suture subcutaneous tissue and skin, steam again raising.Sham-operation group mouse only separates, exposure right side arteria cerebri media,
Do not ligature and be inserted into line bolt.
2.2 animal packets and administration
Mouse 120, is randomly divided into 10 groups：1. sham-operation group (12)；2. model control group (12)；3. solvent control
Group (12)；4. butylphenyl phthaleine 100mgKg-1Group (12)；5. Ligustilide 50mgKg-1(12)；6. butylphenyl phthaleine
100mg·Kg-1+ Ligustilide 10mgKg-1Group (12)；7. butylphenyl phthaleine 100mgKg-1+ Ligustilide 20mgKg-1Group；
8. butylphenyl phthaleine 100mgKg-1+ Ligustilide 50mgKg-1Group；9. butylphenyl phthaleine 100mgKg-1+ Ligustilide 80mgKg-1
Group；10. butylphenyl phthaleine 100mgKg-1+ Ligustilide 100mgKg-1Group.Line brush making right side of mice with reference to Longa etc. is big
Arterial occlusion model (transient middle cerebral artery was occluded, tMCAO) in brain, it is postoperative vertical
That is gavage gives mouse liquid, the solvent (soybean oil) for the meterings such as solvent control group is given.Sham-operation group, model control group are given
Deng the physiological saline of metering.24 it is small when after each group mouse do Neuroscore, after scoring wherein 6 be served only for brain water content survey
Fixed, 6 are served only for cerebral infarction volume measure.
2.3 observation index
2.3.1 Neuroscore：After success builds animal model, each group mouse 24h after filling again uses improvement
Longa stagings carry out neurological deficit score：0 point, without any neurological dysfunction；1 point, it is impossible to before full extension lesion offside
Limb；2 points, the forelimb flexing of lesion offside；3 points, slightly turn-take to lesion offside；4 points, seriously turn-take to lesion offside；5 points,
Fall to lesion offside.
2.3.2 the measure of brain infarction area：After filling again after 24h, every group takes 6 rats with chloraldurate deep anaesthesia posterior neck
Vertebra dislocation method is put to death, and quickly breaking end takes brain, excision antinion, coronal section 6 (thickness 2mm), is positioned over 2% TTC phosphate
In buffer solution, lucifuge, dyes 15min in 37 DEG C of constant water bath box, TTC is discarded after catching color, is placed in 4% paraformaldehyde solid
Determine 24h, taken pictures with digital camera, image is imported computer, and (5.1 softwares of Image-Pro Plus carry out image point
Analysis), first calculate the gross area of every brain tissue infraction, the gross area of infraction side brain piece and the total face for blocking offside brain piece
Product, finally draws total infarct volume：The thickness of total infarct volume=total infarct size × brain piece.Calculate infarct volume percentage：
Infarction volume percentage (%)={ [infraction cumulative volume-(infraction side hemisphere volume-infraction contralateral hemisphere volume)]/infraction pair
Side hemisphere volume } × 100%.
2.3.3 brain water content measures：Using wet-dry change, after cutting off antinion, in the brain tissue of lesion side draw about 2mm thickness
Measure brain water content.Brain tissue is weighed (weight in wet base)；It is placed in oven after 100 DEG C of baking 24h, weighs again (dry weight).Brain tissue contains
Water (%)=(weight in wet base-dry weight)/weight in wet base × 100%.
3rd, result of the test
3.1 Neuroscore
##P ＜ 0.01, compared with sham-operation group.*P ＜ 0.05,**P ＜ 0.01 are compared with holding agent against group.
ΔP ＜ 0.05,ΔΔP ＜ 0.01 and butylphenyl phthaleine 100mgKg-1Group compares.
Butylphenyl phthaleine, which is administered alone (100mgKg-1), can significantly reduce the Neuroscore of mouse, with solvent control group
Compare, there is significant difference (P ＜ 0.05).
Ligustilide be administered alone it is smaller to the nervous function improvement result of mouse, compared with solvent group, without notable
Sex differernce (P ＞ 0.05).
Butylphenyl phthaleine can significantly reduce the Neuroscore of mouse with Ligustilide administering drug combinations, be contrasted with solvent group
Than having significant differences (P ＜ 0.01).
Information above is prompted：Butylphenyl phthaleine has synergistic effect with Ligustilide administering drug combinations, and use in conjunction can strengthen fourth
Phthalide or Ligustilide have therapeutic effect to the neuroprotective function of focal cerebral ischemia mouse to cerebral ischemia.
3.2 brain infarction area
*P ＜ 0.05,**P ＜ 0.01 are compared with solvent control group.
ΔP ＜ 0.05,ΔΔThe P0.01 and stupid phthalein 100mgKg of fourth-1Group compares.
Normal cerebral tissue, which shows, after TTC is dyed takes on a red color, and infarct tissues following MCAO in rats is shown as white.Sham-operation group presents equal
Even red brain tissue, has no the appearance of pale infarct stove, and the white of model control group and solvent control group then visible large area
Infarct.Compared with sham-operation group, there is very significantly difference.
Butylphenyl phthaleine is administered alone the infarct size that can substantially reduce mouse, compared with solvent group, has significant difference (P<
0.05)。
Ligustilide be administered alone it is smaller to the infarct size improvement result of mouse, compared with solvent group, without notable
Sex differernce (P>0.05).
Butylphenyl phthaleine can substantially reduce the infarct size of mouse with Ligustilide administering drug combinations, compared with solvent group, have
Significant differences (P<0.01).
Information above is prompted：Butylphenyl phthaleine has synergistic effect with Ligustilide administering drug combinations, it will be apparent that butylphenyl phthaleine or Jehol Ligusticum Rhizome
Neuroprotective function of the lactone to focal cerebral ischemia mouse.
Experiment 2：Focal cerebral ischemia mouse Nerve cell function is tested
1st, zoopery material：
1.1 the preparation of medicine：With experiment 1
1.2 animal：With experiment 1
1.3 data processing：Data by SPSS11.5 statistical softwares examine between variance analysis and group.
2nd, focal cerebral ischemia mouse Nerve cell function is tested
2.1 focal cerebral ischemia in rats are prepared with experiment 1.
2.2 animal packets and administration
Mouse 120, is randomly divided into 10 groups：1. sham-operation group (12)；2. model control group (12)；3. solvent control
Group；4. butylphenyl phthaleine 50mgKg-1Group (12)；5. Ligustilide 100mgKg-1(12)；6. butylphenyl phthaleine 10mgKg-1+ ligusticumic
This lactone 100mgKg-1Group (12)；7. butylphenyl phthaleine 20mgKg-1+ Ligustilide 20mgKg-1Group；8. butylphenyl phthaleine
50mg·Kg-1+ Ligustilide 100mgKg-1Group；9. butylphenyl phthaleine 80mgKg-1+ Ligustilide 100mgKg-1Group；10. butylbenzene
Phthalein 100mgKg-1+ Ligustilide 100mgKg-1Group.Right side of mice arteria cerebri media is made with reference to the line brush of Longa etc.
Occlusion Model (transient middle cerebral artery was occluded, tMCAO), postoperative gavage immediately is given
Give mouse liquid, the solvent (soybean oil) for the meterings such as solvent control group is given.Sham-operation group, model control group such as give at the metering
Physiological saline.24 it is small when after each group mouse do Neuroscore, after scoring wherein 6 be served only for brain water content measure, 6 use
Measured in cerebral infarction volume.
2.3 observation index
2.3.1 Neuroscore：With experiment 1
2.3.2 the measure of brain infarction area：With experiment 1
2.3.3 brain water content measures：With experiment 1.
3rd, result of the test
3.1 Neuroscore
**P ＜ 0.01, compared with sham-operation group.*P ＜ 0.05, * * P ＜ 0.01 are compared with solvent control group.
ΔP ＜ 0.05, with the stupid phthalein 50mgKg of fourth-1Group compares.
Compared with sham-operation group, model control group, the mouse Nerve function score of solvent control group significantly raise (P<
0.01), illustrate that model is successfully prepared.
Butylphenyl phthaleine is administered alone (50mgKg-1) Neuroscore of mouse can be significantly reduced, compared with solvent group, tool
There is significant difference (P<0.05).
Ligustilide is administered alone the Neuroscore that can reduce mouse, but compared with solvent group, without conspicuousness
Difference (P>0.05).
Butylphenyl phthaleine can reduce the Neuroscore of mouse with Ligustilide administering drug combinations, compared with solvent group, have
Significant differences (P<0.01).
Information above is prompted：Butylphenyl phthaleine has synergistic effect with Ligustilide administering drug combinations, and use in conjunction can strengthen fourth
Phthalide or Ligustilide have therapeutic effect to the neuroprotective function of focal cerebral ischemia mouse to cerebral ischemia.
3.2 brain infarction area
*P ＜ 0.05,**P ＜ 0.01 are compared with solvent control group.
ΔThe P ＜ 0.05 and stupid phthalein 50mgKg of fourth-1Group compares.
Normal cerebral tissue, which shows, after TTC is dyed takes on a red color, and infarct tissues following MCAO in rats is shown as white.Sham-operation group presents equal
Even red brain tissue, has no the appearance of pale infarct stove, and the white of model control group and solvent control group then visible large area
Infarct.Compared with sham-operation group, there is very significantly difference.
Butylphenyl phthaleine is administered alone the infarct size that can substantially reduce mouse, compared with solvent group, has significant difference (P<
0.05)。
Ligustilide be administered alone it is smaller to the infarct size improvement result of mouse, compared with solvent group, without notable
Sex differernce (P>0.05).
Butylphenyl phthaleine can substantially reduce the infarct size of mouse with Ligustilide administering drug combinations, compared with solvent group, have
Significant differences (P<0.01).
Information above is prompted：Butylphenyl phthaleine has synergistic effect with Ligustilide administering drug combinations, and use in conjunction can strengthen fourth
Phthalide or Ligustilide very significantly reduce brain infarction area, to brain to the neuroprotective function of focal cerebral ischemia mouse
Ischemic has therapeutic effect.
3.3 brain water content
##P ＜ 0.01, compared with sham-operation group.*P ＜ 0.05,**P0.01 is compared with solvent control group.
ΔP ＜ 0.05, with butylphenyl phthaleine 100mgKg-1Group compares.
Compared with sham-operation group, model control group and solvent control group mouse pathological tissues brain water content substantially rise
Height, with significant differences (P<0.01).
Butylphenyl phthaleine, which is administered alone, can significantly reduce mouse pathological tissues brain water content, compared with solvent group, have aobvious
Write sex differernce (P<0.05).
Ligustilide be administered alone it is smaller to mouse pathological tissues brain water content improvement result, compared with solvent group,
Without significant difference (P>0.05).
Butylphenyl phthaleine can significantly reduce mouse pathological tissues brain water content with Ligustilide administering drug combinations, with solvent group
Compare, there is significant differences (P<0.01).
Information above is prompted：Butylphenyl phthaleine has synergistic effect with Ligustilide administering drug combinations, and use in conjunction can strengthen fourth
Phthalide or Ligustilide very significantly reduce the water content of brain tissue to the neuroprotective function of focal cerebral ischemia mouse,
There is therapeutic effect to cerebral ischemia.
Experiment 3：Focal cerebral ischemia mouse Nerve cell function is tested
1st, zoopery material：
The preparation of 1.1 medicines：Butylphenyl phthaleine, Ligustilide are dissolved in soybean oil
1.2 animal：Adult, healthy male CD1 mouse, 25~30g of weight, Hebei Medical University's Experimental Animal Center carry
For being cleaning grade mouse, with fed standard chow and drinking pure water after buying, being responsible for by animal housing poultry raiser, constant temperature
20~25 DEG C.
1.3 data processing：Data by SPSS11.5 statistical softwares examine between variance analysis and group
2nd, focal cerebral ischemia mouse Nerve cell function is tested
2.1 animal packets and administration
Mouse 120, is randomly divided into 10 groups：1. sham-operation group (12)；2. model control group (12)；3. solvent control
Group (12)；4. butylphenyl phthaleine 100mgKg-1Group (12)；5. Ligustilide 50mgKg-1(12)；6. butylphenyl phthaleine
100mg·Kg-1+ Ligustilide 10mgKg-1Group (12)；7. butylphenyl phthaleine 100mgKg-1+ Ligustilide 20mgKg-1Group；
8. butylphenyl phthaleine 100mgKg-1+ Ligustilide 50mgKg-1Group；9. butylphenyl phthaleine 100mgKg-1+ Ligustilide 80mgKg-1
Group；10. butylphenyl phthaleine 100mgKg-1+ Ligustilide 100mgKg-1Group.Solvent control group such as gives at the solvent (soybean of metering
Oil).Sham-operation group, model control group such as give at the physiological saline of metering.According to above-mentioned dosage gavage, once a day, 10 are fed
My god.
2.2 focal cerebral ischemia in rats are prepared the mouse of nursing 10 days, are injected intraperitoneally with 10% chloraldurate 0.4g/Kg
Anesthesia, right side of mice middle cerebral artery occlusion model (transient middle are prepared with reference to Longa etc. using line brush
Cerebral artery was occluded, tMCAO), cause focal cerebral ischemic in mice, 1 it is small when after pull out Outlet bolt, realize
Fill again.Disinfection, suture subcutaneous tissue and skin, steam again raising.Sham-operation group mouse only separates, exposure right side arteria cerebri media,
Do not ligature and be inserted into line bolt.24 it is small when after each group mouse do Neuroscore, after scoring wherein 6 be served only for brain water content survey
Fixed, 6 are served only for cerebral infarction volume measure.
2.3 observation index
2.3.1 Neuroscore：With experiment 1
2.3.2 the measure of brain infarction area：With experiment 1
2.3.3 brain water content measures：With experiment 1
3rd, result of the test
3.1 Neuroscore
##P ＜ 0.01, compared with sham-operation group.
*P ＜ 0.05,**P ＜ 0.01 are compared with solvent control group.
ΔP ＜ 0.05,ΔΔP ＜ 0.01 are compared with butylphenyl phthaleine 100mgKg-1 groups
Compared with sham-operation group, model control group, the mouse Nerve function score of solvent control group significantly raise (P ＜
0.01), illustrate that model is successfully prepared.
Butylphenyl phthaleine is administered alone the Neuroscore that can significantly reduce mouse, poor with conspicuousness compared with solvent group
Different (P ＜ 0.05).
Ligustilide be administered alone it is smaller to the nervous function improvement result of mouse, compared with solvent group, without notable
Sex differernce (P ＞ 0.05).
Butylphenyl phthaleine can significantly reduce the Neuroscore of mouse with Ligustilide administering drug combinations, compared with solvent group,
With significant differences (P ＜ 0.01).
Information above is prompted：Butylphenyl phthaleine has synergistic effect with Ligustilide administering drug combinations, and use in conjunction can strengthen fourth
Phthalide or Ligustilide have prevention effect to the neuroprotective function of focal cerebral ischemia mouse to cerebral ischemia.
3.2 brain infarction area
*P ＜ 0.05,**P0.01 is compared with solvent control group.
ΔΔP ＜ 0.01 are compared with butylphenyl phthaleine 100mgKg-1 groups.
Normal cerebral tissue, which shows, after TTC is dyed takes on a red color, and infarct tissues following MCAO in rats is shown as white.Sham-operation group presents equal
Even red brain tissue, has no the appearance of pale infarct stove, and the white of model control group and solvent control group then visible large area
Infarct.Compared with sham-operation group, there is very significantly difference.
Butylphenyl phthaleine is administered alone the infarct size that can substantially reduce mouse, compared with solvent group, has significant difference (P<
0.05)。
Ligustilide be administered alone it is smaller to the infarct size improvement result of mouse, compared with solvent group, without notable
Sex differernce (P>0.05).
Butylphenyl phthaleine can substantially reduce the infarct size of mouse with Ligustilide administering drug combinations, compared with solvent group, have
Significant differences (P<0.01).
Information above is prompted：Butylphenyl phthaleine has synergistic effect with Ligustilide administering drug combinations, and use in conjunction can strengthen fourth
Phthalide or Ligustilide very significantly reduce brain infarction area, to brain to the neuroprotective function of focal cerebral ischemia mouse
Ischemic has prevention effect.
3.3 brain water content
Compared with sham-operation group, model control group and solvent control group mouse pathological tissues brain water content substantially rise
Height, with significant differences (P<0.01).
Butylphenyl phthaleine, which is administered alone, can significantly reduce mouse pathological tissues brain water content, compared with solvent group, have aobvious
Write sex differernce (P<0.05).
Ligustilide be administered alone it is smaller to mouse pathological tissues brain water content improvement result, compared with solvent group,
Without significant difference (P>0.05).
Butylphenyl phthaleine can significantly reduce mouse pathological tissues brain water content with Ligustilide administering drug combinations, with solvent group
Compare, there is significant differences (P<0.01).
Information above is prompted：Butylphenyl phthaleine has synergistic effect with Ligustilide administering drug combinations, and use in conjunction can strengthen fourth
Phthalide or Ligustilide significantly decrease the water content of brain tissue, to brain to the neuroprotective function of focal cerebral ischemia mouse
Ischemic has prevention effect.
Experiment 4：Focal cerebral ischemia mouse Nerve cell function is tested
1st, zoopery material：
The preparation of 1.1 medicines：With experiment 3
1.2 animal：With experiment 3
1.3 data processing：Data by SPSS11.5 statistical softwares examine between variance analysis and group.
2nd, focal cerebral ischemia mouse Nerve cell function is tested
2.1 animal packets and administration
Mouse 120, is randomly divided into 10 groups：1. sham-operation group (12)；2. model control group (12)；3. solvent control
Group；4. butylphenyl phthaleine 50mgKg-1Group (12)；5. Ligustilide 100mgKg-1(12)；6. butylphenyl phthaleine 10mgKg-1+ ligusticumic
This lactone 100mgKg-1Group (12)；7. butylphenyl phthaleine 20mgKg-1+ Ligustilide 20mgKg-1Group；8. butylphenyl phthaleine
50mg·Kg-1+ Ligustilide 100mgKg-1Group；9. butylphenyl phthaleine 80mgKg-1+ Ligustilide 100mgKg-1Group；10. butylbenzene
Phthalein 100mgKg-1+ Ligustilide 100mgKg-1Group.Solvent control group such as gives at the solvent (soybean oil) of metering.Sham-operation
Group, model control group such as give at the physiological saline of metering.According to above-mentioned dosage gavage, once a day, feed 10 days.
2.2 focal cerebral ischemia in rats are prepared the mouse of nursing 10 days, are injected intraperitoneally with 10% chloraldurate 0.4g/Kg
Anesthesia, right side of mice middle cerebral artery occlusion model (transient middle are prepared with reference to Longa etc. using line brush
Cerebral artery was occluded, tMCAO), cause focal cerebral ischemic in mice, 1 it is small when after pull out Outlet bolt, realize
Fill again.Disinfection, suture subcutaneous tissue and skin, steam again raising.Sham-operation group mouse only separates, exposure right side arteria cerebri media,
Do not ligature and be inserted into line bolt.24 it is small when after each group mouse do Neuroscore, after scoring wherein 6 be served only for brain water content survey
Fixed, 6 are served only for cerebral infarction volume measure.
2.3 observation index
2.3.1 Neuroscore：With experiment 1
2.3.2 the measure of brain infarction area：With experiment 1
2.3.3 brain water content measures：With experiment 1.
3rd, result of the test
3.1 Neuroscore
##P ＜ 0.01, compared with sham-operation group.*P0.05,**P0.01 is compared with flux control group.
ΔP ＜ 0.05, compared with butylphenyl phthaleine 50mgKg-1 groups.
Compared with sham-operation group, model control group, the mouse Nerve function score of solvent control group significantly raise (P ＜
0.01), illustrate that model is successfully prepared.
Butylphenyl phthaleine is administered alone (50mgKg-1) Neuroscore of mouse can be significantly reduced, compared with solvent group, tool
There is significant difference (P ＜ 0.05).
Ligustilide is administered alone the Neuroscore that can reduce mouse, but compared with solvent group, without conspicuousness
Difference (P ＞ 0.05).
Butylphenyl phthaleine can reduce the Neuroscore of mouse with Ligustilide administering drug combinations, compared with solvent group, have
Significant differences (P ＜ 0.01).
Information above is prompted：Butylphenyl phthaleine has synergistic effect with Ligustilide administering drug combinations, and use in conjunction can strengthen fourth
Phthalide or Ligustilide have prevention effect to the neuroprotective function of focal cerebral ischemia mouse to cerebral ischemia.
3.2 brain infarction area
*P ＜ 0.05, * * P ＜ 0.01 are compared with solvent control group.
ΔΔP ＜ 0.01, compared with butylphenyl phthaleine 50mgKg-1 groups.
Normal cerebral tissue, which shows, after TTC is dyed takes on a red color, and infarct tissues following MCAO in rats is shown as white.Sham-operation group presents equal
Even red brain tissue, has no the appearance of pale infarct stove, and the white of model control group and solvent control group then visible large area
Infarct.Compared with sham-operation group, there is very significantly difference.
Butylphenyl phthaleine is administered alone the infarct size that can substantially reduce mouse, compared with solvent group, has significant difference (P<
0.05)。
Ligustilide be administered alone it is smaller to the infarct size improvement result of mouse, compared with solvent group, without notable
Sex differernce (P>0.05).
Butylphenyl phthaleine can substantially reduce the infarct size of mouse with Ligustilide administering drug combinations, compared with solvent group, have
Significant differences (P<0.01).
Information above is prompted：Butylphenyl phthaleine has synergistic effect with Ligustilide administering drug combinations, and use in conjunction can strengthen fourth
Phthalide or Ligustilide very significantly reduce brain infarction area, to brain to the neuroprotective function of focal cerebral ischemia mouse
Ischemic has therapeutic effect.
3.3 brain water content
##P ＜ 0.01, compared with sham-operation group.*P ＜ 0.05,**P ＜ 0.01 are compared with solvent control group.
ΔP ＜ 0.05, compared with butylphenyl phthaleine 50mgKg-1 groups.
Compared with sham-operation group, model control group and solvent control group mouse pathological tissues brain water content substantially rise
Height, with significant differences (P ＜ 0.01).
Butylphenyl phthaleine, which is administered alone, can significantly reduce mouse pathological tissues brain water content, compared with solvent group, have aobvious
Write sex differernce (P ＜ 0.05).
Ligustilide be administered alone it is smaller to mouse pathological tissues brain water content improvement result, compared with solvent group,
Without significant difference (P ＞ 0.05).
Butylphenyl phthaleine can significantly reduce mouse pathological tissues brain water content with Ligustilide administering drug combinations, with solvent group
Compare, there are significant differences (P ＜ 0.01).
Information above is prompted：Butylphenyl phthaleine has synergistic effect with Ligustilide administering drug combinations, and use in conjunction can strengthen fourth
Phthalide or Ligustilide significantly decrease the water content of brain tissue, to brain to the neuroprotective function of focal cerebral ischemia mouse
Ischemic has prevention effect.
Claims (7)
- A kind of 1. butylphenyl phthaleine preparation compositions, it is characterised in that including butylphenyl phthaleine and Ligustilide, butylphenyl phthaleine and Ligustilide Weight ratio is 1:5~5:1.
- 2. composition as claimed in claim 1, it is characterised in that the weight ratio of butylphenyl phthaleine and Ligustilide is 1:2~2:1.
- 3. composition as claimed in claim 1, it is characterised in that the butylphenyl phthaleine is dl-3-n-butylphthalide or levo butyl phthalide.
- 4. composition as claimed in claim 1, it is characterised in that add antioxidant, antioxidant for tocopherol, lecithin, The one or more of citric acid, ascorbic acid, antioxidant account for the 0.025%~0.1% of composition total weight.
- 5. such as Claims 1-4 any one of them composition, it is characterised in that add pharmaceutically acceptable auxiliary material, be made Soft capsule, liquid hard capsule, capsule and pill, dripping pill.
- 6. composition as claimed in claim 5, it is characterised in that the pharmaceutically acceptable auxiliary material is vegetable oil, institute The vegetable oil stated is selected from sesame oil, corn oil, peanut oil, soybean oil, apricot kernel oil, persic oil, cottonseed oil, sunflower oil, olive oil In one kind；Vegetable oil accounts for the 30~70% of composition total weight.
- 7. such as application of claim 1 to 5 any one of them composition in the medicine for preparing treatment cardiac-cerebral ischemia.
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2004017983A1 (en) * | 2002-08-20 | 2004-03-04 | National University Of Singapore | Method for the preparation of phytoprogestogenic extracts from rhizoma ligusticum chuanxiong and uses thereof |
| CN1605336A (en) * | 2003-10-10 | 2005-04-13 | 中国医学科学院药物研究所 | Application of L-butylphthalide in the process for preparing cerebral infarction preventing and treating medicine |
| CN1732921A (en) * | 2005-07-15 | 2006-02-15 | 钱忠明 | Application of ligustilide in preparation of medicine for preventing and treating cerebral ischemia diseases |
| CN102716160A (en) * | 2012-06-28 | 2012-10-10 | 天津大学 | Hemlock parsley phthalide type ingredient effective part as well as preparation method and application of hemlock parsley phthalide type ingredient effective part |
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2014
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Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2004017983A1 (en) * | 2002-08-20 | 2004-03-04 | National University Of Singapore | Method for the preparation of phytoprogestogenic extracts from rhizoma ligusticum chuanxiong and uses thereof |
| CN1605336A (en) * | 2003-10-10 | 2005-04-13 | 中国医学科学院药物研究所 | Application of L-butylphthalide in the process for preparing cerebral infarction preventing and treating medicine |
| CN1732921A (en) * | 2005-07-15 | 2006-02-15 | 钱忠明 | Application of ligustilide in preparation of medicine for preventing and treating cerebral ischemia diseases |
| CN102716160A (en) * | 2012-06-28 | 2012-10-10 | 天津大学 | Hemlock parsley phthalide type ingredient effective part as well as preparation method and application of hemlock parsley phthalide type ingredient effective part |
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