CN100404039C - Safflower medicine composition and its prepn process and use - Google Patents
Safflower medicine composition and its prepn process and use Download PDFInfo
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- CN100404039C CN100404039C CNB2004100862137A CN200410086213A CN100404039C CN 100404039 C CN100404039 C CN 100404039C CN B2004100862137 A CNB2004100862137 A CN B2004100862137A CN 200410086213 A CN200410086213 A CN 200410086213A CN 100404039 C CN100404039 C CN 100404039C
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Abstract
The present invention discloses a novel medicinal composition which is prepared from acetylglutamide and safflower, wherein the weight of the safflower is 1 to 50 times heavier than that of the acetylglutamide. The present invention also discloses a method for preparing the medicinal composition, and the application thereof. The medicinal composition of the present invention, which is a compound preparation, has synergistic reaction on organisms through the mutual replenishment of the aceglutamide and the safflower so as to full exert the functions of promoting blood circulation for removing blood stasis, and improving cerebral metabolism and enhancing cerebral functions. Therefore, the medicinal composition can be used for preparing medicines for treating blocked cerebrovascular diseases, hepatic coma, hemiplegia, coma caused by surgical operations or other reasons, paralysis, intelligence deterioration, memory disorder, etc., and can also be used for preparing medicines for treating diseases, such as coronary heart disease, vasculitis, etc.
Description
Technical field
The present invention relates to a kind of pharmaceutical composition, Its Preparation Method And Use, relate in particular to and a kind ofly form by aceglutamide and the assembly of Chinese crude drug Flos Carthami, Flos Carthami makes the novel pharmaceutical combination thing of available dosage form with aceglutamide behind effective component extracting, its preparation method and the treatment obliterated cerebral vascular disease, the purposes of disease aspects such as the stupor that hepatic coma, hemiplegia, neurosurgery etc. cause, paralysis and the hypophrenia, memory disorder.
Background technology
Aceglutamide is N
2-acetyl-L-glutamine (C
7H
12N
2O
4), be white crystalline powder, the clinical cerebral function improving medicine that is commonly used for.This medicine can pass through blood-cerebrospinal fluid barrier, by be decomposed into glutamic acid after the blood-cerebrospinal fluid barrier, γ-An Jidingsuan (GABA) plays a role.Glutamic acid participates in central nervous system's information transmission, and Gabanergic antagonism glutamic acid irritability toxicological effect can improve the neurocyte metabolism, keeps the effect of neural stress ability and reduction blood ammonia, improves brain function.This clinical drug is usually used in stupor, paralysis and the hypophrenia that hepatic coma, hemiplegia, neurosurgery etc. cause, memory disorder etc.
Flos Carthami is the dried floral of feverfew Flos Carthami (Carthamus tinctorins L), contain active ingredients such as glycoside and Flos Carthami flavin such as carthamone, neocarthamin, saffloside, has significant blood circulation invigorating efficacies, has anticoagulation, antithrombotic formation, blood vessel dilating, microcirculation improvement, effects such as the weary oxygen encephalopathy of ischemia resisting.Flos Carthami extract can anticoagulant, and the fortifying fibre protein dissolution obviously reduces the length and the weight of outer fiber albumen thrombosis, can prevent the formation and development of tampon or the dissolving of promotion thrombosis; Flos Carthami extract can significantly improve mice hypoxia-bearing capability, anti-stress ability, can obviously improve survival rate to the weary oxygen encephalopathy animal of acute ischemia, alleviate the cerebral tissue pathologic lesion, make the interior ribonucleic acid of cerebral tissue, adenosine triphosphate, succinate dehydrogenase etc. all near normal, and can recover abnormal electroencephalogram and electromyogram rapidly, show that Flos Carthami has the better protect effect to the weary oxygen encephalopathy of ischemia; Flos Carthami extract has blood vessel dilating, microcirculation improvement effect in addition.
At present, still no-trump Flos Carthami and aceglutamide carry out assembly according to special ratios, and make the report that available medicine carries out clinical practice with aceglutamide after further Flos Carthami being extracted the preparation Flos Carthami extract.
Summary of the invention
The object of the present invention is to provide a kind of safflower medicine composition, this pharmaceutical composition is formed by aceglutamide and the assembly of Chinese crude drug Flos Carthami, and Flos Carthami is made compound preparation with aceglutamide after extracting the preparation Flos Carthami extract.
Another object of the present invention is to provide a kind of preparation method of safflower medicine composition.
A further object of the present invention is to provide a kind of safflower medicine composition in treatment obliterated cerebral vascular disease, the purposes of disease aspects such as the stupor that hepatic coma, hemiplegia, neurosurgery etc. cause, paralysis and the hypophrenia, memory disorder.
A further object of the present invention is to provide a kind of safflower medicine composition in the application that is used to prepare aspect the disease medicaments such as treatment coronary heart disease, vasculitis.
A kind of safflower medicine composition of the present invention comprises that aceglutamide and Chinese crude drug Flos Carthami are the medicament that raw material is made, and wherein the weight of Chinese crude drug Flos Carthami is 1～50 times of aceglutamide weight.
Pharmaceutical composition of the present invention, described Flos Carthami weight are 2～30 times of aceglutamide weight.
Wherein, be preferably 5～20 times; More preferably 15～18 times, most preferably be 50/3 times.
Raw material of Chinese medicine Flos Carthami of the present invention is made Flos Carthami extract through extraction earlier, and its process is: by use water boiling and extraction, extracting liquid filtering concentrates the back precipitate with ethanol with the Flos Carthami of said ratio, the alcohol deposit fluid filtering and concentrating, and then after water precipitating filters, concentrated forming.
Weight portion of the present invention can be the known content units of field of medicaments such as μ g, mg, g, kg.
Aceglutamide of the present invention can adopt the raw material that meets medicinal standard.
The preparation method of safflower medicine composition of the present invention is: elder generation is with the Flos Carthami water boiling and extraction of said ratio, extracting liquid filtering, concentrate the back precipitate with ethanol, the alcohol deposit fluid filtering and concentrating, and then after water precipitating filters, concentrate and promptly get Flos Carthami extract, then Flos Carthami extract and aceglutamide are carried out proportioning and mix, add pharmaceutically acceptable adjuvant again and make acceptable various dosage forms on the pharmaceutics.
Specifically, the Flos Carthami extract preparation process is:
Get the Flos Carthami of said ratio, the decocting that adds 6～10 times of material quantities boils 2～3 times, and each time that decocts is 30～90 minutes, and collecting decoction filters, and it is 1.16～1.26 that filtrate is concentrated into relative density; Again through 1～2 precipitate with ethanol, contain the alcohol amount and be controlled between 65～85%, cold preservation was left standstill 36～48 hours, filtered filtrate recycling ethanol and to be concentrated into relative density be 1.10～1.20; The water that adds 8～10 times of concentrated liquid measures at last, cold preservation was left standstill 16～24 hours, filtered, and it is 1.00～1.06 that filtrate is concentrated into relative density, and it is standby promptly to get Flos Carthami extract.
Preferred Flos Carthami extract preparation process is:
Get Flos Carthami, add 6～10 times of water gagings and decoct 3 times, add 10 times of water gagings for the first time and decocted 1 hour, add 8 times of water gagings for the second time and decocted 50 minutes, adding 6 times of water gagings for the third time decocted 30 minutes, collecting decoction filters, and it is 1.16-1.26 that filtrate is concentrated into relative density, adding ethanol makes and contains alcohol amount and reach 70%, cold preservation was left standstill 48 hours, filtered, filtrate recycling ethanol and to be concentrated into relative density be 1.10～1.14, add ethanol again and make and contain alcohol amount and reach 80%, cold preservation was left standstill 48 hours, filter, filtrate recycling ethanol and to be concentrated into relative density be 1.16～1.20 adds 10 times of water gagings, cold preservation, left standstill 16-24 hour, filter, it is 1.02-1.04 that filtrate is concentrated into relative density, and it is standby promptly to get Flos Carthami extract.
The temperature of described cold preservation is controlled to be between 0～4 ℃.
In general, the Flos Carthami of 1000g extracts by above-mentioned technology, and being concentrated to relative density is 1.00～1.06, can get Flos Carthami extract 300ml～800ml, after this extracting solution suitably dilutes, press spectrophotography again and should (press WS greater than 1.0 in 267 ± 1nm wavelength place mensuration trap
3The prescriptive procedure of-B-3825-98 is measured).
Flos Carthami compositions of the present invention can be prepared into the available dosage form on the various pharmaceuticss, and as lyophilized injectable powder, tablet, capsule, granule, small-volume injection, bulk capacity injection, most preferred dosage form is a small-volume injection.The various dosage forms of safflower medicine composition of the present invention can be according to the conventional production method preparation of pharmaceutical field.Such as using said composition to mix, be made into required dosage form then with one or more carriers.
Research worker of the present invention is tested discovery in a large number, and when Flos Carthami weight was 15～18 times of proportionings of aceglutamide weight in the hot flower pesticide compositions, synergism was better, curative effect is preferable; With 50/3 times is better.
The preferred safflower medicine composition small-volume injection of the present invention specification is 5ml, 10ml, 20ml, and every ml contains aceglutamide (C
7H
12N
2O
4) 30mg, after in addition every ml dilutes 500 times, be blank again with the distilled water, measure trap at 267 ± 1nm wavelength place, must not be lower than 0.3.
Usage is as follows: intravenous drip, and a 5ml～20ml slowly instils with 5% or 10% glucose injection 250ml～500ml dilution back, and once-a-day, 10～15 days is a course of treatment.
Safflower medicine composition of the present invention is the compound preparation that Flos Carthami and aceglutamide form by the special ratios assembly, as preparation treatment obliterated cerebral vascular disease, the application of disease medicament aspects such as the stupor that hepatic coma, hemiplegia, neurosurgery etc. cause, paralysis and the hypophrenia, memory disorder.Also can be used for preparing the application of disease medicament aspects such as treatment coronary heart disease, vasculitis.
Safflower medicine composition of the present invention replenishes synergism mutually by Flos Carthami and aceglutamide can play beyond thought effect.Aceglutamide is the clinical cerebral function improving medicine that is commonly used in the pharmaceutical composition of the present invention, this medicine can pass through blood-cerebrospinal fluid barrier, by be decomposed into glutamic acid after the blood-cerebrospinal fluid barrier, γ-An Jidingsuan (GABA) plays a role, participate in central nervous system's information transmission, can improve the neurocyte metabolism, keep the effect of neural stress ability and reduction blood ammonia, improve brain function.Flos Carthami has significant blood circulation invigorating efficacies, has anticoagulation, antithrombotic formation, blood vessel dilating, microcirculation improvement, effects such as the weary oxygen encephalopathy of ischemia resisting.Flos Carthami extract can anticoagulant, and the fortifying fibre protein dissolution obviously reduces the length and the weight of outer fiber albumen thrombosis, can prevent the formation and development of tampon or the dissolving of promotion thrombosis; Flos Carthami extract can significantly improve mice hypoxia-bearing capability, anti-stress ability, can obviously improve survival rate to the weary oxygen encephalopathy animal of acute ischemia, alleviate the cerebral tissue pathologic lesion, make the interior ribonucleic acid of cerebral tissue, adenosine triphosphate, succinate dehydrogenase etc. all near normal, and can recover abnormal electroencephalogram and electromyogram rapidly, show that Flos Carthami has the better protect effect to the weary oxygen encephalopathy of ischemia; Flos Carthami extract has blood vessel dilating, microcirculation improvement effect in addition.
Safflower medicine composition of the present invention is for the Flos Carthami being the compound preparation of the Flos Carthami extract composition of crude drug preparation, replenish synergism heart and brain portion tissue mutually by the two, give full play to blood circulation promoting and blood stasis dispelling, improve brain function, improve the neurocyte metabolism, effect such as antithrombotic formation, microcirculation improvement, can be used as preparation treatment obliterated cerebral vascular disease, the application of disease medicament aspects such as the stupor that hepatic coma, hemiplegia, neurosurgery etc. cause, paralysis and the hypophrenia, memory disorder.Also can be used for preparing the application of disease medicament aspects such as treatment coronary heart disease, vasculitis.
The specific embodiment
Further describe the present invention with embodiment below, help understanding, but described embodiment only is used to illustrate the present invention rather than restriction the present invention the present invention and advantage thereof, better effects if.
Embodiment 1
Get Flos Carthami 2000g, decoct with water 3 times, add 10 times of Flos Carthami water gagings for the first time and decocted 1 hour, add for the second time 8 times of water gagings and decocted 50 minutes, add 6 times of water gagings for the third time and decocted collecting decoction 30 minutes, filter, it is 1.18 ± 0.02 that filtrate is concentrated into relative density, adds ethanol and makes and contain the alcohol amount and reach 70%, cold preservation, left standstill 48 hours, and filtered, filtrate recycling ethanol and to be concentrated into relative density be 1.12 ± 0.02, adding ethanol again makes and contains alcohol amount and reach 80%, cold preservation was left standstill 48 hours, filtered, filtrate recycling ethanol and to be concentrated into relative density be 1.18 ± 0.02, add 10 times of water gagings, cold preservation was left standstill 20 hours, filter, it is 1.02 that filtrate is concentrated into relative density, is about 1300ml, and it is standby promptly to get Flos Carthami extract, after suitably diluting, press WS
3The prescriptive procedure of-B-3825-98 is measured trap greater than 1.0.
Take by weighing aceglutamide (C
7H
12N
2O
4) 120g, be made into the 40000ml medicinal liquid with extract the gained Flos Carthami extract by the 2000g Flos Carthami, finally make 400 bottles of bulk capacity injections (specification is the 100ml/ bottle).In dense preparing tank, add an amount of 80 ℃ of waters for injection, in dense preparing tank, drop into 360g sodium chloride, add Flos Carthami extract again, fully stir and make, add active carbon by 0.04% of preparation cumulative volume, heat 90 ℃, be incubated 20 minutes, be cooled to 50 ℃, the medicinal liquid decarbonization filtering to dilute preparing tank, is added in dilute preparing tank and used the dissolved aceglutamide of an amount of NaOH, fully stir and make dissolving fully, add active carbon by 0.02% of preparation cumulative volume, left standstill 20 minutes, and added water for injection to the dosing amount, transferring PH is 5.6 ± 0.2, with the medicinal liquid decarbonization filtering, medicinal liquid is again through end-filtration, and embedding is filled nitrogen by bottle during embedding in the 100ml infusion bottle, sterilization promptly gets infusion products.
Embodiment 2
Get Flos Carthami 3000g, decoct with water 2 times, add 10 times of water gagings for the first time and decocted 1.5 hours, add for the second time 6 times of water gagings and decocted 80 minutes, collecting decoction filters, it is 1.22 ± 0.02 that filtrate is concentrated into relative density, adds ethanol and makes and contain alcohol amount and reach 80%, cold preservation, left standstill 44 hours, and filtered, filtrate recycling ethanol and to be concentrated into relative density be 1.16 ± 0.02, add ethanol again and make and contain alcohol amount and reach 70%, cold preservation was left standstill 38 hours, filter, filtrate recycling ethanol and to be concentrated into relative density be 1.16 adds 9 times of water gagings, cold preservation, left standstill 20 hours, and filtered, it is 1.05 that filtrate is concentrated into relative density, be about 1000ml, it is standby promptly to get Flos Carthami extract, after suitably diluting, presses WS
3The prescriptive procedure of-B-3825-98 is measured trap greater than 1.0.
Take by weighing aceglutamide (C
7H
12N
2O
4) 100g, extract the gained Flos Carthami extract with the 3000g Flos Carthami and can be made into the 5000ml medicinal liquid, finally make 1000 of small-volume injections (specification is that 5ml/ props up).In dense preparing tank, add an amount of 85 ℃ of waters for injection, in dense preparing tank, add Flos Carthami extract, fully stir, add active carbon by 0.04% of preparation cumulative volume, heat 90 ℃, be incubated 20 minutes, be cooled to 50 ℃, with the medicinal liquid decarbonization filtering to dilute preparing tank, in dilute preparing tank, add and used the dissolved aceglutamide of an amount of NaOH, fully stir and make dissolving fully, add active carbon, left standstill 20 minutes by 0.02% of preparation cumulative volume, add water for injection to the dosing amount, transferring PH is 5.5 ± 0.1, and with the medicinal liquid decarbonization filtering, medicinal liquid is again through end-filtration, embedding is in the 5ml ampoule, ampoule fills nitrogen by propping up during embedding, and sterilization promptly gets small-volume injection.
After testing, after every ml suitably dilutes, be blank again with the distilled water, measure trap at 267 ± 1nm wavelength place, (press WS greater than 0.3
3The regulation of-B-3825-98).
Embodiment 3
Get Flos Carthami 2250g, decoct with water 3 times, add 9 times of water gagings for the first time and decocted 1.5 hours, add for the second time 8 times of water gagings and decocted 60 minutes, add 7 times of water gagings for the third time and decocted collecting decoction 40 minutes, filter, it is 1.20 ± 0.02 that filtrate is concentrated into relative density, adds ethanol and makes and contain the alcohol amount and reach 65%, cold preservation, left standstill 40 hours, and filtered, filtrate recycling ethanol and to be concentrated into relative density be 1.14 ± 0.02, adding ethanol again makes and contains alcohol amount and reach 75%, cold preservation was left standstill 48 hours, filtered, filtrate recycling ethanol and to be concentrated into relative density be 1.20, add 8 times of water gagings, cold preservation was left standstill 24 hours, filter, it is 1.04 that filtrate is concentrated into relative density, is about 900ml, and it is standby promptly to get Flos Carthami extract, after suitably diluting, press WS
3The prescriptive procedure of-B-3825-98 is measured trap greater than 1.0.
Take by weighing aceglutamide (C
7H
12N
2O
4) 150g, extract the gained Flos Carthami extract with the 2250g Flos Carthami and can be made into the 5000ml medicinal liquid, finally make 1000 of small-volume injections (specification is that 5ml/ props up).In dense preparing tank, add an amount of 90 ℃ of waters for injection, in dense preparing tank, add Flos Carthami extract, fully stir, add active carbon by 0.04% of preparation cumulative volume, heat 90 ℃, be incubated 20 minutes, be cooled to 50 ℃, with the medicinal liquid decarbonization filtering to dilute preparing tank, in dilute preparing tank, add and used the dissolved aceglutamide of an amount of NaOH, fully stir and make dissolving fully, add active carbon, left standstill 20 minutes by 0.02% of preparation cumulative volume, add water for injection to the dosing amount, transferring PH is 5.5 ± 0.1, and with the medicinal liquid decarbonization filtering, medicinal liquid is again through end-filtration, embedding is in the 5ml ampoule, ampoule fills nitrogen by propping up during embedding, and sterilization promptly gets small-volume injection.
After testing, after every ml dilutes 500 times, be blank again with the distilled water, measure trap at 267 ± 1nm wavelength place, (press WS greater than 0.3
3The regulation of-B-3825-98).
Embodiment 4
Get Flos Carthami 2500g, decoct with water 3 times, add 9 times of water gagings for the first time and decocted 1.5 hours, add for the second time 8 times of water gagings and decocted 60 minutes, add 7 times of water gagings for the third time and decocted collecting decoction 40 minutes, filter, it is 1.20 ± 0.02 that filtrate is concentrated into relative density, adds ethanol and makes and contain the alcohol amount and reach 65%, cold preservation, left standstill 40 hours, and filtered, filtrate recycling ethanol and to be concentrated into relative density be 1.14 ± 0.02, adding ethanol again makes and contains alcohol amount and reach 75%, cold preservation was left standstill 48 hours, filtered, filtrate recycling ethanol and to be concentrated into relative density be 1.20, add 8 times of water gagings, cold preservation was left standstill 24 hours, filter, it is 1.04 that filtrate is concentrated into relative density, is about 1000ml, and it is standby promptly to get Flos Carthami extract, after suitably diluting, press WS
3The prescriptive procedure of-B-3825-98 is measured trap greater than 1.0.
Take by weighing aceglutamide (C
7H
12N
2O
4) 150g, extract the gained Flos Carthami extract with the 2500g Flos Carthami and can be made into the 5000ml medicinal liquid, finally make 1000 of small-volume injections (specification is that 5mL/ props up).In dense preparing tank, add an amount of 88 ℃ of waters for injection, in dense preparing tank, add Flos Carthami extract, fully stir, add active carbon by 0.04% of preparation cumulative volume, heat 90 ℃, be incubated 20 minutes, be cooled to 50 ℃, with the medicinal liquid decarbonization filtering to dilute preparing tank, in dilute preparing tank, add and used the dissolved aceglutamide of an amount of NaOH, fully stir and make dissolving fully, add active carbon, left standstill 20 minutes by 0.02% of preparation cumulative volume, add water for injection to the dosing amount, transferring PH is 5.7 ± 0.1, and with the medicinal liquid decarbonization filtering, medicinal liquid is again through end-filtration, embedding is in the 5ml ampoule, ampoule fills nitrogen by propping up during embedding, and sterilization promptly gets small-volume injection.
After testing, after every ml dilutes 500 times, be blank again with the distilled water, measure trap at 267 ± 1nm wavelength place and (press WS greater than 0.3
3The regulation of-B-3825-98).
Embodiment 5
Get Flos Carthami 2000g, decoct with water 3 times, add 10 times of water gagings for the first time and decocted 1 hour, add for the second time 8 times of water gagings and decocted 50 minutes, add 6 times of water gagings for the third time and decocted collecting decoction 30 minutes, filter, it is 1.20 that filtrate is concentrated into relative density, adds ethanol and makes and contain the alcohol amount and reach 70%, cold preservation was left standstill 48 hours, filtered, filtrate recycling ethanol and to be concentrated into relative density be 1.13 adds ethanol again and makes and contain the alcohol amount and reach 80%, cold preservation, left standstill 48 hours, filter, filtrate recycling ethanol and to be concentrated into relative density be 1.19 adds 10 times of water gagings, cold preservation, left standstill 22 hours, and filtered, it is 1.00 that filtrate is concentrated into relative density, be about 1500ml, it is standby promptly to get Flos Carthami extract.
Take by weighing aceglutamide (C
7H
12N
2O
4) 100g, extract the gained Flos Carthami extract with the 2000g Flos Carthami and can be made into the 2500ml medicinal liquid, finally make 1000 of lyophilized injectable powders.In dense preparing tank, add an amount of 80 ℃～90 ℃ waters for injection, in dense preparing tank, add Flos Carthami extract, fully stir, add active carbon by 0.04% of preparation cumulative volume, heat 90 ℃, be incubated 20 minutes, be cooled to 50 ℃, with the medicinal liquid decarbonization filtering to dilute preparing tank, in dilute preparing tank, add and used the dissolved aceglutamide of an amount of NaOH, fully stir and make dissolving fully, add the Dextran 40 excipient, add active carbon by 0.02% of preparation cumulative volume, left standstill 20 minutes, add water for injection to the dosing amount, transferring PH is 5.5～5.8, with the medicinal liquid decarbonization filtering, medicinal liquid is again through end-filtration, medicinal liquid fill behind end-filtration (loading amount 2.5ml/ props up), the lyophilized injectable powder product is made in lyophilizing behind the false add plug.
Embodiment 6
Get Flos Carthami 2500g, decoct with water 3 times, add 10 times of water gagings for the first time and decocted 1 hour, add for the second time 8 times of water gagings and decocted 50 minutes, add 6 times of water gagings for the third time and decocted collecting decoction 30 minutes, filter, it is 1.22 that filtrate is concentrated into relative density, adds ethanol and makes and contain the alcohol amount and reach 70%, cold preservation was left standstill 48 hours, filtered, filtrate recycling ethanol and to be concentrated into relative density be 1.14 adds ethanol again and makes and contain the alcohol amount and reach 80%, cold preservation, left standstill 48 hours, filter, filtrate recycling ethanol and to be concentrated into relative density be 1.18 adds 10 times of water gagings, cold preservation, left standstill 18 hours, and filtered, it is 1.02 that filtrate is concentrated into relative density, be about 1750ml, it is standby promptly to get Flos Carthami extract.
The 2500g Flos Carthami is extracted the gained Flos Carthami extract, and further to be concentrated into relative density be that the thick paste of 1.3-1.4 is standby, with aceglutamide (C
7H
12N
2O
4) 100g preparation finally makes 1000 in tablet.Flos Carthami is extracted thick paste as binding agent, and mix and aceglutamide and 80 gram starch mixed pelletizations, cross 20 mesh sieve granulate, drying adds 2 gram magnesium stearate compactings in flakes, promptly gets the pharmaceutical composition tablet.
Embodiment 7
Get Flos Carthami 200g, decoct with water 3 times, add 10 times of water gagings for the first time and decocted 1 hour, add for the second time 8 times of water gagings and decocted 50 minutes, add 6 times of water gagings for the third time and decocted collecting decoction 30 minutes, filter, it is 1.24 that filtrate is concentrated into relative density, adds ethanol and makes and contain the alcohol amount and reach 75%, cold preservation was left standstill 48 hours, filtered, filtrate recycling ethanol and to be concentrated into relative density be 1.10 adds ethanol again and makes and contain the alcohol amount and reach 80%, cold preservation, left standstill 48 hours, filter, filtrate recycling ethanol and to be concentrated into relative density be 1.16 adds 9 times of water gagings, cold preservation, left standstill 16 hours, and filtered, it is 1.03 that filtrate is concentrated into relative density, be about 120ml, it is standby promptly to get Flos Carthami extract.
The 200g Flos Carthami is extracted the gained Flos Carthami extract further be concentrated into the thick paste that relative density is 1.3-1.4, drying is pulverized back and aceglutamide (C
7H
12N
2O
4) 200g preparation finally makes 1000 of capsules.After Flos Carthami extracted powder and aceglutamide and 40 gram starch, 40 gram Pulvis Talci mixings, cross 100 mesh sieves, encapsulated, the medicament composition capsule agent.
Embodiment 8
Preparation technology is with embodiment 1, and different is that Flos Carthami and aceglutamide weight ratio are 50: 1.
Embodiment 9
Preparation technology is with embodiment 2, and different is that Flos Carthami and aceglutamide weight ratio are 18: 1.
Embodiment 10
Preparation technology is with embodiment 6, and different is that Flos Carthami and aceglutamide weight ratio are 5: 1.
Experimental example 1
(every ml contains aceglutamide (C to this experimental example for the most preferred safflower medicine composition small-volume injection of the present invention
7H
12N
2O
4) 30mg, contain initiation material Flos Carthami 0.5g) detection of the injection inspection item of appearance character, pH value, residue on ignition, heavy metal, protein, pyrogen and other regulation.
Character this product is that yellowish red color is to henna clear liquid.
PH value should be 5.0-7.0 (two appendix VI of Chinese Pharmacopoeia version in 2000).
Residue on ignition is got this product 10ml, puts in the crucible of constant weight, measures (appendix IX J) in accordance with the law, leaves over residue and must not cross 2.0% (g/ml).
Heavy metal is got the residue of leaving under the residue on ignition item, adds nitric acid 2.5ml, and evaporate to dryness after eliminating to the nitrogen oxide steam, is put coldly, adds hydrochloric acid 2ml, puts in the water-bath behind the evaporate to dryness, and residue adds water to be made dissolving and move in the 10ml volumetric flask, adds water to scale, shakes up.Precision is measured 1ml and is added water 15ml, drips ammonia solution to instructions phenolphthalein solution is shown neutral, adds acetate buffer (pH3.5) 2ml again, after the slight fever dissolving, moves in the nessler colorimetric tube, and thin up becomes 25ml as sample cell.Other gets the reagent of preparation need testing solution, puts evaporate to dryness in the porcelain dish, and residue adds acetate buffer (pH3.5) 2ml and water 15ml, after the slight fever dissolving, move in the nessler colorimetric tube, add standard lead solution 1ml, thin up becomes 25ml again, adds thioacetamide test solution 2ml again in two pipes respectively, shakes up, placed 2 minutes, with putting on the blank sheet of paper, supreme downward perspective, color of showing in the sample cell and control tube are relatively, must not be darker, promptly contain heavy metal and must not cross 10/1000000ths.
Pyrogen is got this product, checks (two appendix XI of Chinese Pharmacopoeia version in 2000 D) in accordance with the law, and dosage should be up to specification by the every 1kg injection of rabbit body weight 2ml.
Protein is got this product 1ml, adds 30% sulfosalicylic acid test solution 1ml of new configuration, and mixing was placed 5 minutes, muddiness must not occur.
Other should meet relevant every regulation (2000 editions two appendix IB of Chinese Pharmacopoeia) under the injection item.
Experimental example 2
(every ml contains aceglutamide (C to this experimental example for the most preferred safflower medicine composition small-volume injection of the present invention
7H
12N
2O
4) 30mg, contain initiation material Flos Carthami 0.5g) in the qualitative determination of key component.
1) this product is as need testing solution.Other gets Flos Carthami control medicinal material 0.5g, adds water 10ml, and supersound process 30 minutes filters, and filtrate is concentrated into dried, and residue adds dehydrated alcohol, and stirring is left standstill, and abandons or adopts anhydrous alcohol solution, and residue adds water 1ml makes dissolving, in contrast medical material solution.Test according to thin layer chromatography (2000 editions two appendix VI B of Chinese Pharmacopoeia), draw need testing solution 0.5 μ l, control medicinal material solution 0.3 μ l, put respectively on same silica GF254 lamellae, with n-butyl alcohol-glacial acetic acid-water (6: 2.4: 5) is developing solvent, launch, take out, dry, put under the ultra-violet lamp (254nm) and inspect.In the test sample chromatograph, with the corresponding position of control medicinal material chromatograph on, show identical brown speckle.
2) close this product 1ml of measuring puts in the 500ml volumetric flask, adds water to scale, shakes up.According to spectrophotography (2000 editions two appendix VA of Chinese Pharmacopoeia), be blank with the distilled water, measure trap at 267 ± 1nm wavelength place, must not be lower than 0.3 and (press WS
3The prescriptive procedure of-B-3825-98 is measured).
3) get the about 5ml of this product, add hydrochloric acid solution 2ml, about 30 minutes of heated and boiled, and constantly keep the skin wet, it is 5-6 that pH is regulated in the cooling back, gets 2ml, adds the about 2mg of 1,2,3-indantrione monohydrate, places or heating, solution shows bluish violet.
More than 3 kinds of experiments be the qualitative reactions of the contained component of safflower medicine composition of the present invention, illustrate and contain definite component in the safflower medicine composition of the present invention.
Experimental example 3
(every ml contains aceglutamide (C to this experimental example for the most preferred safflower medicine composition small-volume injection of the present invention
7H
12N
2O
4) 30mg, contain initiation material Flos Carthami 0.5g) middle aceglutamide content quantitative mensuration, every ml contains aceglutamide (C
7H
12N
2O
4) should be 27mg-33mg.
The aceglutamide assay is measured according to high performance liquid chromatography (two appendix VD of Chinese Pharmacopoeia version in 2000).
Chromatographic condition and system suitability test are filler with octadecylsilane chemically bonded silica; (regulating pH value 3.5 with triethylamine)-methanol (95: 5) is mobile phase with 0.2% phosphoric acid solution; The detection wavelength is 210nm.Number of theoretical plate calculates by the aceglutamide peak should be not less than 2500.
It is an amount of that algoscopy is got this product, and accurate the title decides, and with the mobile phase dissolving, and quantitatively is diluted to the solution that contains aceglutamide 0.1mg among every 1ml, as need testing solution, gets 20 μ l and inject chromatograph of liquid, the record chromatogram; It is an amount of that precision takes by weighing the aceglutamide reference substance in addition, makes the solution that contains 0.1mg among every 1ml approximately with mobile phase dissolving and dilution, and product solution is measured with method in contrast, presses external standard method with calculated by peak area.
By three batches of mensuration, every ml content results sees Table 1:
Table 1
| Lot number | Aceglutamide (mg) |
| 20030801 | 29.0 |
| 20030802 | 28.4 |
| 20030803 | 29.2 |
Comparative example 1
(every ml contains aceglutamide (C to this example for the most preferred pharmaceutical composition small-volume injection of the present invention
7H
12N
2O
4) 30mg, contain initiation material Flos Carthami 0.5g) with the clinical comparison of Flos Carthami injection at the treatment acute cerebral infarction, the good efficacy of pharmaceutical composition of the present invention is described, promptly the coordinating effect of aceglutamide and Flos Carthami is better than using separately Flos Carthami injection.
Clinical settings:
This group of physical data 140 examples are the acute cerebral infarction patient, meet the diagnostic criteria [1] that the 4th national cerebrovascular meeting formulated, and confirm through head CT, in the course of disease 3d, are morbidity first.Be divided into 2 groups at random.Male 45 examples are organized in treatment, women 25 examples; 42～74 years old age, average 63 years old; Matched group man 47 examples, women 23 examples; 41～75 years old age, average 61 years old.
According to the 4th the patients with cerebral apoplexy neurological functional deficit standards of grading [2] that the cerebrovascular meeting is passed through in the nineteen ninety-five whole nation, the treatment group is light, in, severe is respectively 23 examples, 32 examples, 15 examples; Matched group patient neurological functional deficit is light, in, severe is respectively 20 examples, 33 examples, 17 examples.
Acute cerebral infarction 60 routine patients are divided into 2 groups at random.
30 examples are organized in treatment, and wherein the male is 22 examples, and the women is 8 examples, 42～74 years old age, average 63 years old, patient's neurological functional deficit is light, in, severe is respectively 10 examples, 14 examples, 6 examples;
Matched group 30 examples, wherein the male is 21 examples, the women is 9 examples.41～75 years old age, average 61 years old, patient's neurological functional deficit is light, in, severe is respectively 11 examples, 15 examples, 4 examples;
All cases all meet the diagnostic criteria that national cerebrovascular meeting is formulated, and confirm through head C T, in the course of disease 3d, are morbidity first.
Therapeutic Method:
Treatment group patient: intravenous drip, 20ml of the most preferred pharmaceutical composition small-volume injection of the present invention after 5% glucose injection 250ml dilution, slowly instils 1 time on the one, treats 15 days;
Matched group patient: with 5% glucose injection 250ml dilution Flos Carthami injection injection 20ml, slowly instil once-a-day, treated 15 days.In therapeutic process, all look the state of an illness and need give dehydrant, antibiotic for two groups, keep corresponding treatments such as water-electrolyte balance.
Efficacy determination:
The basic healing: consciousness recovery is normal, and muscular strength reaches 4～5 grades, and language function is normal substantially, takes care of oneself; Produce effects: language recovery is more obvious, suffers from the limb muscular strength and improves more than 2 grades life partial self-help; Effectively: limb activity scope and function progress, 1 grade of the more preceding raising of muscular strength be can't take care of oneself; Invalid: treatment back sings and symptoms does not have improvement.
Therapeutic outcome:
Treatment group curative effect is better than matched group, and two groups of obvious effective rates (basic healing+produce effects is made the obvious effective rate statistics), total effective rate (basic healing+produce effects+effectively make total effective rate to add up) have significant difference (P＜0.01).The results are shown in Table 2.
Table 2 treatment group and matched group curative effect comparative example (%)
Conclusion:
Flos Carthami is the panacea of Chinese medicine blood circulation promoting and blood stasis dispelling, and its expansible blood vessel reduces cerebral vascular resistance, and significantly the cerebral blood flow increasing amount is improved the brain anoxic conditions, and the protection blood brain barrier alleviates cerebral edema, safeguards that cerebral circulation reconciles automatically, improves brain function.Reduce the effect of viscosity of the blood, anticoagulant, promotion fibrinolytic simultaneously in addition.Aceglutamide is the clinical cerebral function improving medicine that is commonly used for, this medicine can pass through blood-cerebrospinal fluid barrier, by be decomposed into glutamic acid after the blood-cerebrospinal fluid barrier, γ-An Jidingsuan (GABA) plays a role, participate in central nervous system's information transmission, can improve the neurocyte metabolism, keep the effect of neural stress ability and reduction blood ammonia, improve brain function.Pharmaceutical composition of the present invention is that the compound preparation coordinating effect of aceglutamide and Flos Carthami is better than using separately Flos Carthami injection, and coordinating effect is obvious, helps improving cerebral blood supply, and the recovery of accelerator nerve cell function promotes the improvement of clinical symptoms.
Comparative example 2
(every ml contains aceglutamide (C to this example for the most preferred pharmaceutical composition small-volume injection of the present invention
7H
12N
2O
4) 30mg, contain initiation material Flos Carthami 0.5g) contrast with the clinical efficacy of Flos Carthami injection at treatment treatment angina pectoris, the good efficacy of pharmaceutical composition of the present invention is described, promptly the coordinating effect of aceglutamide and Flos Carthami is better than using separately Flos Carthami injection.
Clinical settings:
Angina pectoris patient Patients with Cerebral Infarction 100 examples are divided into treatment group and matched group at random.
50 examples are organized in treatment, wherein male 61 examples, women 39 examples, 40～74 years old age, average 61.5 years old;
Matched group 50 examples, male 61 examples, women 39 examples, 40～75 years old age, average 62.3 years old.All angina pectoris case diagnosis standard reference International Society of Cardiologies and WHO clinical name standardization associating specialist paper " name of ischemic heart desease and diagnostic criteria ".Two groups of equal had palpitation of patient, uncomfortable in chest, breathe hard, one of angina pectoris (being stable angina pectoris) and ischemic ECG change or several.
Therapeutic Method:
Treatment group patient: intravenous drip, 20ml of the most preferred pharmaceutical composition small-volume injection of the present invention after 5% glucose injection 250ml dilution, slowly instils 1 time on the one, treats 15 days;
The matched group patient: with 5% glucose injection 250ml dilution Flos Carthami injection 5ml, intravenous drip once-a-day, was treated 15 days.
Efficacy determination:
Produce effects: transference cure or basic the disappearance, electrocardiogram recovers normally or is roughly normal, effectively: the angina pectoris attacks number of times obviously reduces, degree obviously alleviates, persistent period obviously shortens, ECG ST section reduces, more than rise 0.5mv after the treatment, the negative T wave that mainly leads shoal (reaching more than 25%) or by smooth for upright; Invalid: symptom and electrocardiogram do not have change.Survey blood, urine, just routine and liver, kidney function test before and after the treatment respectively.Observe uncomfortable in chest, cardiopalmus, breathe hard, the untoward reaction of angina pectoris attacks number of times, degree, persistent period and treatment, before and after the treatment and treatment respectively make 1 resting electrocardiogram mid-term and compare.
Therapeutic outcome:
The treatment group all is better than matched group at clinical efficacy, electrocardiogram aspect improving, and learns by statistics and handles (P＜0.05).All have a blood test before and after the cases treatment, urinate, just routine and the no abnormal change of hepatic and renal function, patient's well-tolerated has no adverse reaction, and sees table 3 for details:
Table 3 liang group clinical efficacy and electrocardiogram improvement situation be (example) relatively
Annotate: two groups of total effective rates and electrocardiogram improve relatively P＜0.05
Claims (13)
1. a safflower medicine composition is characterized in that, described pharmaceutical composition is a kind of medicament, and its medicine material consists of aceglutamide and Chinese crude drug Flos Carthami, and wherein the weight of Chinese crude drug Flos Carthami is 1～50 times of aceglutamide weight.
2. safflower medicine composition according to claim 1 is characterized in that, the weight of described Flos Carthami is 2～30 times of aceglutamide weight.
3. safflower medicine composition according to claim 2 is characterized in that, the weight of described Flos Carthami is 5～20 times of aceglutamide weight.
4. safflower medicine composition according to claim 3 is characterized in that, the weight of described Flos Carthami is 15-18 times of aceglutamide weight.
5. safflower medicine composition according to claim 4 is characterized in that, the weight of described Flos Carthami be aceglutamide weight be 50/3 times.
6. according to the arbitrary described safflower medicine composition of claim 1-5, it is characterized in that, described Flos Carthami is made Flos Carthami extract through extraction earlier, its process is: with the Flos Carthami of the weight proportion of described Chinese crude drug Flos Carthami and aceglutamide by using water boiling and extraction, extracting liquid filtering concentrates the back precipitate with ethanol, the alcohol deposit fluid filtering and concentrating, and then after water precipitating filters, concentrated forming.
7. safflower medicine composition according to claim 6 is characterized in that, after Flos Carthami extracts the Flos Carthami extract thin up of gained, is blank again with the distilled water, measures trap at 267 ± 1nm wavelength place greater than 1.0.
8. according to the preparation method of the arbitrary described safflower medicine composition of claim 1-5, it is characterized in that, elder generation is with the Flos Carthami water boiling and extraction of the weight proportion of described Chinese crude drug Flos Carthami and aceglutamide, extracting liquid filtering concentrates the back precipitate with ethanol, the alcohol deposit fluid filtering and concentrating, and then after water precipitating filters, concentrate and promptly get Flos Carthami extract, then Flos Carthami extract and aceglutamide are carried out proportioning and mix, add pharmaceutically acceptable adjuvant again and make acceptable various dosage forms on the pharmaceutics.
9. the preparation method of safflower medicine composition according to claim 8, it is characterized in that, get the Flos Carthami of the weight proportion of described Chinese crude drug Flos Carthami and aceglutamide, the decocting that adds 6～10 times of material quantities boils 2～3 times, each time that decocts is 30～90 minutes, collecting decoction filters, and it is 1.16～1.26 that filtrate is concentrated into relative density; Again through 1～2 precipitate with ethanol, contain the alcohol amount and be controlled between 65～85%, cold preservation was left standstill 36～48 hours, filtered filtrate recycling ethanol and to be concentrated into relative density be 1.10～1.20; The water that adds 8～10 times of concentrated liquid measures at last, cold preservation was left standstill 16～24 hours, filtered, and it is 1.00～1.06 that filtrate is concentrated into relative density, and it is standby promptly to get Flos Carthami extract.
10. the preparation method of safflower medicine composition according to claim 9, it is characterized in that, get the Flos Carthami of the weight proportion of described Chinese crude drug Flos Carthami and aceglutamide, add 6～10 times of material quantity decoctings and boil 3 times, add 10 times of material quantity decoctings for the first time and boiled 1 hour, add 8 times of material quantity decoctings for the second time and boiled 50 minutes, adding 6 times of material quantity decoctings for the third time boiled 30 minutes, collecting decoction filters, and it is 1.16-1.26 that filtrate is concentrated into relative density, adding ethanol makes the alcohol amount of closing reach 70%, cold preservation was left standstill 48 hours, filtered, filtrate recycling ethanol and to be concentrated into relative density be 1.10～1.14, add ethanol again and make and contain alcohol amount and reach 80%, cold preservation was left standstill 48 hours, filter, filtrate recycling ethanol and to be concentrated into relative density be 1.16～1.20 adds 10 times of concentrated solution water gagings, cold preservation, left standstill 16～24 hours, filter, it is 1.02～1.04 that filtrate is concentrated into relative density, and it is standby promptly to get Flos Carthami extract.
11. safflower medicine composition preparation method according to claim 8 is characterized in that, described preparation of compositions becomes one or more to be selected from lyophilized injectable powder, tablet, capsule, granule, small-volume injection, or bulk capacity injection.
12. according to of the application of any described safflower medicine composition of claim 1～5 as preparation treatment acute cerebral infarction disease medicament aspect.
13. according to of the application of any described safflower medicine composition of claim 1～5 as preparation treatment coronary heart disease disease medicament aspect.
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| EP2077110A4 (en) * | 2006-09-29 | 2012-06-27 | Ajinomoto Kk | Glutamine-containing composition for increasing blood flow |
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| CN100441195C (en) * | 2005-10-28 | 2008-12-10 | 多布瑞菲医药有限公司 | Medicinal composition containing safflower total flavone and its preparation process and usage |
| CN1843393B (en) * | 2006-02-17 | 2011-03-23 | 博安兄弟制药（中国）有限公司 | Use of pharmaceutical composition containing aceglutamide and safflower |
| CN1903243B (en) * | 2006-08-08 | 2012-06-27 | 通化特立杰尔医药咨询有限公司 | Guhong control-release tablets and prepn. method therefor |
| CN106581075A (en) * | 2015-10-19 | 2017-04-26 | 云南云域瑞达生物药业有限公司 | Application of flos carthami or extract thereof for removing fishy smell of medicinal material |
| CN106970163B (en) * | 2017-03-28 | 2019-12-10 | 浙江中医药大学 | aceglutamide metabolite identification and detection method |
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| CN1444931A (en) * | 2003-04-18 | 2003-10-01 | 张嵩 | Aceglutamide injection |
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| 红花注射液细菌内毒素的检测. 施震，彭燕，李华.中国药师，第5卷第4期. 2002 |
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| EP2077110A4 (en) * | 2006-09-29 | 2012-06-27 | Ajinomoto Kk | Glutamine-containing composition for increasing blood flow |
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