CN100431532C - Breviscapine and borneol constituted composite injection formulation and preparation method thereof - Google Patents
Breviscapine and borneol constituted composite injection formulation and preparation method thereof Download PDFInfo
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- CN100431532C CN100431532C CNB200610038268XA CN200610038268A CN100431532C CN 100431532 C CN100431532 C CN 100431532C CN B200610038268X A CNB200610038268X A CN B200610038268XA CN 200610038268 A CN200610038268 A CN 200610038268A CN 100431532 C CN100431532 C CN 100431532C
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- injection
- breviscapine
- add
- borneolum syntheticum
- water
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- 238000002347 injection Methods 0.000 title claims abstract description 103
- 239000007924 injection Substances 0.000 title claims abstract description 103
- DJSISFGPUUYILV-ZFORQUDYSA-N scutellarin Chemical compound O1[C@H](C(O)=O)[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1OC(C(=C1O)O)=CC2=C1C(=O)C=C(C=1C=CC(O)=CC=1)O2 DJSISFGPUUYILV-ZFORQUDYSA-N 0.000 title claims abstract description 100
- DJSISFGPUUYILV-UHFFFAOYSA-N UNPD161792 Natural products O1C(C(O)=O)C(O)C(O)C(O)C1OC(C(=C1O)O)=CC2=C1C(=O)C=C(C=1C=CC(O)=CC=1)O2 DJSISFGPUUYILV-UHFFFAOYSA-N 0.000 title claims abstract description 98
- DTGKSKDOIYIVQL-WEDXCCLWSA-N (+)-borneol Chemical compound C1C[C@@]2(C)[C@@H](O)C[C@@H]1C2(C)C DTGKSKDOIYIVQL-WEDXCCLWSA-N 0.000 title claims abstract description 97
- 239000000203 mixture Substances 0.000 title claims abstract description 33
- 238000002360 preparation method Methods 0.000 title claims abstract description 32
- 238000009472 formulation Methods 0.000 title abstract description 9
- REPVLJRCJUVQFA-UHFFFAOYSA-N (-)-isopinocampheol Natural products C1C(O)C(C)C2C(C)(C)C1C2 REPVLJRCJUVQFA-UHFFFAOYSA-N 0.000 title abstract 6
- 229940116229 borneol Drugs 0.000 title abstract 6
- CKDOCTFBFTVPSN-UHFFFAOYSA-N borneol Natural products C1CC2(C)C(C)CC1C2(C)C CKDOCTFBFTVPSN-UHFFFAOYSA-N 0.000 title abstract 6
- 239000002131 composite material Substances 0.000 title abstract 6
- DTGKSKDOIYIVQL-UHFFFAOYSA-N dl-isoborneol Natural products C1CC2(C)C(O)CC1C2(C)C DTGKSKDOIYIVQL-UHFFFAOYSA-N 0.000 title abstract 6
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- 239000001509 sodium citrate Substances 0.000 claims description 4
- NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 claims description 4
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- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Medicinal Preparation (AREA)
Abstract
The present invention relates to a composite injection formulation containing breviscapine and borneol and a preparation method thereof. The present invention particularly relates to a Chinese medicine composite injection formulation which has the functions for activating blood circulation, dissipating blood stasis, activating meridians , stopping pain, inducing reuscitation and restoring consciousness and contains breviscapine and borneol, and a preparation method of the composite injection formulation. The composite injection formulation is prepared from breviscapine which is an effective component, borneol and auxiliary materials which are permitted to be used in an injection medicament according to a compounding ratio. The weight ratio of the borneol which is an effective component of a medicinal raw material to the breviscapine is 1: 1 to 20, and the auxiliary materials which are permitted to be used in the injection medicament are used as the balance. The auxiliary materials which are permitted to be used in the injection medicament is one of solvents, auxiliary solvents, isoosmotic adjusting agents, excipient, stabilizing agents, and pH regulating agents, or a mixture of the solvents, the auxiliary solvents, the isoosmotic adjusting agents, the excipient, the stabilizing agents, and the pH regulating agents. The injection formulation comprises small-volume injection, large-volume injection or powder injection. The present invention also relates to an application of the composite injection formulation which contains breviscapine and borneol in a medicament and is used for treating coronary heart diseases, angina pectoris, cerebral ischemia, cerebral infarction, and sequela of apoplexy angiocarpy and cerebral vessel diseases.
Description
Technical field
But a kind of compound injection of being made up of breviscapine and Borneolum Syntheticum of the present invention and preparation method thereof relates to a kind of blood circulation promoting and blood stasis dispelling, removing obstruction in the collateral to relieve pain, inducing resuscitation, be used for the treatment of the pharmaceutical preparation of cardiovascular and cerebrovascular diseases such as coronary heart disease, angina pectoris, cerebral ischemia, cerebral infarction, apoplexy sequela, especially Chinese medicine compound ejection preparation of forming about breviscapine and Borneolum Syntheticum and preparation method thereof.
Background technology
Cardiovascular and cerebrovascular disease is the topmost disease of harm humans life and health, and according to the statistics of interrelated data in recent years, China accounts for about the half of the dead cause of disease because of cardiovascular and cerebrovascular disease death person every year.And hypertension, apoplexy and coronary heart disease are the representative diseases of cardiovascular and cerebrovascular disease.Along with the raising of social life level and the quickening of work rhythm, cardiovascular and cerebrovascular disease has become the healthy and life-prolonging leading killer of threat middle-aged and elderly people.Add up according to Ministry of Public Health: China cardiovascular and cerebrovascular disease patient's age of onset first 1/3 is below 60 years old, particularly the sickness rate of cardiovascular and cerebrovascular disease, mortality rate, disability rate, relapse rate are all very high, and the characteristics that complication is many: promptly sickness rate is up to 13.6%, and every day is with 20,000 people's speed increase; Mortality rate accounts for 50% of total death toll up to 45%; The disability rate height; Apoplexy patient disability rate up to 75%, coronary heart disease patient becomes the one able to do light manual labor only; The relapse rate height: relapse rate is up to 42% within the cardiovascular and cerebrovascular disease (heart infarction, cerebral infarction) 5 years; Complication etc.: more by (respiratory system, digestive system, urinary system) disease that cordis and cerebral accident causes.
Breviscapine is (to practise and claim Herba Erigerontis from natural plants Herba Erigerontis Herba Erigerontis, be born in the patana or the border of 1200～3500 meters of height above sea level more, be distributed in provinces and regions such as Yunnan Province of China, Hunan, Guangxi, Sichuan, Guizhou, Tibet, Shang Weijian has the report of distribution abroad, main product is in Yunnan Province mountain of papers Zhuang autonomous prefecture) in the flavonoid active ingredient that extracts, mixture for oil lamp cycle of sixty years element, lamp-dish flower acetic is mainly lamp-dish flower acetic.Modern medicines studies have shown that breviscapine has blood flow increasing, effects such as microcirculation improvement, blood vessel dilating, reduction blood viscosity, blood fat reducing, fibrinolysis enhancing, antithrombotic, antiplatelet aggregation.Last century since the seventies, Breviscapine just was applied to clinical.Since the own document record of Herba Erigerontis, mainly be the single medication, compound recipe is rarely seen; And breviscapine is applied to clinical ejection preparation at present, also only is the single medication, and clinical curative effect is limited.
The book on Chinese herbal medicine of Borneolum Syntheticum is called Borneolum Syntheticum, uses the history of existing more than one thousand years as Chinese medicine.The traditional Chinese medical science thinks that Borneolum Syntheticum is arduous and is slightly cold to have the refreshment of having one's ideas straightened out, the effect of clearing away heat to alleviate pain.The pharmacological research of Borneolum Syntheticum is one of focus of recent Chinese scholars research, and Borneolum Syntheticum has the effect of anti-myocardial infarction, and " guiding drug " effect is arranged.Discover that Borneolum Syntheticum can change the permeability of blood brain barrier, increases some water soluble drug, as transhipments in brain such as sulfadiazine, gentamycins.
The compatibility of breviscapine and Borneolum Syntheticum and other drug, present rarely seen oral formulations as 'Yinzhanxinmai ' drop pill, lunar caustic heart and brain clearing soft capsule etc., because the oral formulations onset is slow, can not be applicable to the acute stage of cardiovascular and cerebrovascular vessel, so the clinical scope of application is little.The compatibility of breviscapine and Borneolum Syntheticum does not appear in the newspapers at present.
Summary of the invention
Purpose of the present invention provides a kind of compound injection of being made up of breviscapine and Borneolum Syntheticum at above-mentioned weak point, but blood circulation promoting and blood stasis dispelling, removing obstruction in the collateral to relieve pain, inducing resuscitation, be used for the treatment of cardiovascular and cerebrovascular diseases such as coronary heart disease, angina pectoris, cerebral ischemia, cerebral infarction, apoplexy sequela, the Chinese medicine compound ejection preparation of forming by Borneolum Syntheticum and breviscapine (containing injection with small volume, powder pin and high-capacity injection).The present invention makes injection with breviscapine and Borneolum Syntheticum two flavor drug matchings, and is not only rapid-action, and both synergism are obvious, and clinical therapeutic efficacy is good.
Another object of the present invention is to provide a kind of preparation method of the Chinese medicine compound ejection preparation of forming by breviscapine and Borneolum Syntheticum.
A kind of compound injection of being made up of breviscapine and Borneolum Syntheticum and preparation method thereof is to take following scheme to realize: a kind of compound injection of being made up of breviscapine and Borneolum Syntheticum allows the adjuvant that uses by effective ingredient breviscapine and Borneolum Syntheticum, injectable drug, and it is formulated to press proportioning; Medicinal raw material effective ingredient breviscapine and Borneolum Syntheticum weight ratio are 1: 1～20, and injectable drug allows the adjuvant surplus of use.
Described a kind of compound injection of being made up of breviscapine and Borneolum Syntheticum is injection with small volume, high-capacity injection, injectable powder.
Borneolum Syntheticum in described a kind of compound injection of being made up of breviscapine and Borneolum Syntheticum is artificial Borneolum Syntheticum, or natural Broneolum Syntheticum; Breviscapine is the flavones ingredient that extracts from the Chinese crude drug Herba Erigerontis, is mainly lamp-dish flower acetic.
The adjuvant that injectable drug in described a kind of compound injection of being made up of breviscapine and Borneolum Syntheticum allows to use is a kind of or mixture in solvent, cosolvent, isoosmotic adjusting agent, excipient, stabilizing agent, the pH regulator agent.
Injectable drug in described a kind of compound injection of being made up of breviscapine and Borneolum Syntheticum allows the adjuvant that uses: solvent is selected water for injection or ethanol for use, cosolvent is selected HP-for use, tween 80, glycerol, a kind of or mixture in the ethanol, isoosmotic adjusting agent is selected glucose for use, a kind of or mixture in the sodium chloride, excipient is selected mannitol for use, the levulose acid anhydride, glucose, sodium chloride, sucrose, a kind of or mixture in the lactose, stabilizing agent is selected Calcium Disodium Versenate for use, sodium sulfite, anhydrous sodium sulfite, a kind of or mixture in the cysteine hydrochloride, sodium hydroxide is selected in the pH regulator agent for use, hydrochloric acid, sodium bicarbonate, a kind of or mixture in the sodium citrate.
A kind of preparation method of the compound injection of forming by breviscapine and Borneolum Syntheticum, take following steps: the adjuvant of pressing preparation prescription batching effective ingredient breviscapine, Borneolum Syntheticum, injectable drug permission use, medicinal raw material effective ingredient Borneolum Syntheticum and breviscapine weight ratio are 1: 1～20, and injectable drug allows the adjuvant surplus of use;
Get 1 part of the Borneolum Syntheticum of above-mentioned configuration, add the dissolving of cosolvent and water for injection; Get 1～20 part of breviscapine, add the water for injection that contains stabilizing agent, drip the pH regulator agent and make dissolving; Above-mentioned two liquid are mixed, add the injection water, add needle-use activated carbon absorption 15～30 minutes to certain volume, filtering decarbonization is adjusted to pH3.5～8.5 with the pH regulator agent, sterilizes after the fine straining fill, or fill after the aseptic filtration, lamp inspection promptly gets injection with small volume (liquid drugs injection);
Get isoosmotic adjusting agent,, add needle-use activated carbon heating absorption 20 minutes, filtering decarbonization with the water for injection dissolving; Get 1 part of Borneolum Syntheticum, add the dissolving of cosolvent and water for injection; Get 1～20 part of breviscapine, add the water for injection that contains stabilizing agent, drip the pH regulator agent and make dissolving; Above-mentioned three liquid are mixed, add the injection water, add needle-use activated carbon absorption 15～30 minutes to certain volume, filtering decarbonization is adjusted to pH3.5～8.5 with the pH regulator agent, sterilizes after the fine straining fill, or fill after the aseptic filtration, lamp inspection promptly gets high-capacity injection (transfusion);
Get 1 part of Borneolum Syntheticum, add the dissolving of cosolvent and water for injection; Get 1～20 part of breviscapine, add the water for injection that contains stabilizing agent, drip the pH regulator agent and make dissolving; Above-mentioned two liquid are mixed, add excipient, add the injection water again, add needle-use activated carbon absorption 15～30 minutes, filtering decarbonization to certain volume, be adjusted to pH3.5～8.5 with the pH regulator agent, aseptic filtration, fill is jumped a queue, lyophilization, aluminium lid is pressed mouth, and lamp inspection promptly gets injectable powder.
Adopt microporous filter membrane to carry out fine straining or aseptic filtration in the preparation method of described a kind of compound injection of forming by breviscapine and Borneolum Syntheticum, carry out fine straining or aseptic filtration again after perhaps adopting the ultrafilter membrane ultrafiltration.
The adjuvant solvent that injectable drug allows to use in the preparation method of described a kind of compound injection of being made up of breviscapine and Borneolum Syntheticum is selected water for injection or ethanol for use, cosolvent is selected HP-for use, tween 80, glycerol, a kind of or mixture in the ethanol, isoosmotic adjusting agent is selected glucose for use, a kind of or mixture in the sodium chloride, excipient is selected mannitol for use, the levulose acid anhydride, glucose, sodium chloride, sucrose, a kind of or mixture in the lactose, stabilizing agent is selected Calcium Disodium Versenate for use, sodium sulfite, anhydrous sodium sulfite, a kind of or mixture in the cysteine hydrochloride, sodium hydroxide is selected in the pH regulator agent for use, hydrochloric acid, sodium bicarbonate, a kind of or mixture in the sodium citrate.
The above-mentioned a kind of application of compound injection in treatment coronary heart disease, angina pectoris, cerebral ischemia, cerebral infarction, apoplexy sequela class cardiovascular and cerebrovascular diseases medicament of forming by breviscapine and Borneolum Syntheticum.
Breviscapine is the flavonoid active ingredient that extracts from natural plants Herba Erigerontis Herba Erigerontis, and the mixture for oil lamp cycle of sixty years element, lamp-dish flower acetic is mainly lamp-dish flower acetic.Modern medicines studies have shown that breviscapine has blood flow increasing, effects such as microcirculation improvement, blood vessel dilating, reduction blood viscosity, blood fat reducing, fibrinolysis enhancing, antithrombotic, antiplatelet aggregation.
The book on Chinese herbal medicine of Borneolum Syntheticum is called Borneolum Syntheticum, uses the history of existing more than one thousand years as Chinese medicine.The traditional Chinese medical science thinks that Borneolum Syntheticum is arduous and is slightly cold to have the refreshment of having one's ideas straightened out, the effect of clearing away heat to alleviate pain.The pharmacological research of Borneolum Syntheticum is one of focus of recent Chinese scholars research, and Borneolum Syntheticum has the effect of anti-myocardial infarction, and " guiding drug " effect is arranged.Discover that Borneolum Syntheticum can change the permeability of blood brain barrier, increases some water soluble drug, as transhipments in brain such as sulfadiazine, gentamycins.
The present invention provides safe, controlled, effective first aid Chinese medicine for clinical.The present invention is owing to be active ingredient (active ingredient) with breviscapine and Borneolum Syntheticum in its prescription, add Borneolum Syntheticum in the prescription with the refreshment of having one's ideas straightened out, clearing away heat to alleviate pain effect, the effect that breviscapine is acted on cardiovascular and cerebrovascular vessel has potentiation, so clinical effectiveness of the present invention is better than folk prescription.The present invention is an injection, applicable to the acute attack stage of cardiovascular and cerebrovascular disease, has overcome the slow shortcoming of oral administration onset.And the present invention also provides injection with small volume (liquid drugs injection), the high-capacity injection (transfusion) of the Chinese medicine compound ejection preparation that preparation is made up of breviscapine and Borneolum Syntheticum, the technology preparation of injectable powder, for clinical use provides more choices.
The specific embodiment
The adjuvant that a kind of compound injection of being made up of breviscapine and Borneolum Syntheticum of the present invention is used by effective ingredient breviscapine and Borneolum Syntheticum, injectable drug permission, formulated by proportioning; Medicinal raw material effective ingredient Borneolum Syntheticum and breviscapine weight ratio are 1: 1～20, and injectable drug allows the adjuvant surplus of use.
The said breviscapine of the present invention is meant the flavones ingredient that extracts gained from Herba Erigerontis, presses dry product and calculates, and contains lamp-dish flower acetic (C
21H
18O
12) answer 〉=95.0%, can be used for the preparation of ejection preparation.
The said Borneolum Syntheticum of the present invention can be artificial Borneolum Syntheticum, also can be natural Broneolum Syntheticum, all meets ejection preparation and uses.
The Chinese medicine compound ejection preparation that breviscapine of the present invention and Borneolum Syntheticum are formed, it is characterized in that comprising 1 part of Borneolum Syntheticum, 1～20 part of breviscapine, having added injectable drug allows the adjuvant of use (to comprise solvent, cosolvent, perhaps isoosmotic adjusting agent, perhaps excipient, perhaps stabilizing agent, perhaps pH regulator agent, the perhaps mixture of above-mentioned adjuvant) be prepared from.
Cosolvent is a tween 80, or glycerol, or HP-, or ethanol, the perhaps mixture of above-mentioned adjuvant, and its consumption is 10～30 parts;
Stabilizing agent is 0.1～1 part a Calcium Disodium Versenate, or sodium sulfite, or anhydrous sodium sulfite, or cysteine hydrochloride, the perhaps mixture of above-mentioned adjuvant, and its consumption is 0.1～1 part;
Isoosmotic adjusting agent is a glucose, or sodium chloride, the perhaps mixture of above-mentioned adjuvant, its consumption the sample that makes is reached etc. ooze or slightly height ooze;
The pH regulator agent is a sodium bicarbonate, or sodium hydroxide, or hydrochloric acid, or sodium citrate etc.;
Excipient is a mannitol, or the levulose acid anhydride, or glucose, or sodium chloride, or sucrose, or lactose, the perhaps mixture of above-mentioned adjuvant, and its consumption is 1～200 part.
Chinese medicine compound ejection preparation provided by the invention, its system type can be injection with small volume (liquid drugs injection), injectable powder, high-capacity injection (transfusion), and concrete preparation method is respectively:
Injection with small volume (liquid drugs injection) preparation method: get 1 part of Borneolum Syntheticum, add the dissolving of cosolvent and water for injection; Get 1～20 part of breviscapine, add the water for injection that contains stabilizing agent, drip the pH regulator agent and make dissolving; Above-mentioned two liquid are mixed, add the injection water to certain volume, add needle-use activated carbon absorption 15～30 minutes, filtering decarbonization is adjusted to pH3.5～8.5 with the pH regulator agent, sterilize after the fine straining fill, or fill after the aseptic filtration, lamp inspection, promptly.
High-capacity injection (transfusion) preparation method: get isoosmotic adjusting agent,, add needle-use activated carbon heating absorption 15～30 minutes, filtering decarbonization with the water for injection dissolving; Get 1 part of Borneolum Syntheticum, add the dissolving of cosolvent and water for injection; Get 1～20 part of breviscapine, add the water for injection that contains stabilizing agent, drip the pH regulator agent and make dissolving; Above-mentioned three liquid are mixed, add the injection water to certain volume, add needle-use activated carbon absorption 15～30 minutes, filtering decarbonization, be adjusted to pH3.5～8.5 with the pH regulator agent, sterilize after the fine straining fill, or fill after the aseptic filtration, lamp inspection promptly gets a kind of compound injection of being made up of breviscapine and Borneolum Syntheticum.
Injectable powder preparation method: get 1 part of Borneolum Syntheticum, add the dissolving of cosolvent and water for injection; Get 1～20 part of breviscapine, add water for injection and stir, drip the pH regulator agent and make dissolving; Above-mentioned two liquid are mixed, behind the adding excipient, add the injection water again to certain volume, add needle-use activated carbon absorption 15～30 minutes, filtering decarbonization is adjusted to pH3.5～8.5, aseptic filtration with the pH regulator agent, fill, jump a queue, lyophilization, aluminium lid is pressed mouth, lamp inspection promptly gets a kind of compound injection of being made up of breviscapine and Borneolum Syntheticum.
The Chinese medicine compound ejection preparation that Borneolum Syntheticum of the present invention and breviscapine are formed, the drug effect of two medicines has been given full play in injectable (intramuscular injection or vein) administration; The test of pesticide effectiveness shows that both can produce synergism after merging use, and its curative effect is better than the folk prescription administration.The present invention's energy blood circulation promoting and blood stasis dispelling, removing obstruction in the collateral to relieve pain, inducing resuscitation can be used for treating cardiovascular and cerebrovascular diseases such as coronary heart disease, angina pectoris, cerebral ischemia, cerebral infarction, apoplexy sequela.
Below describe by several specific embodiments, in conjunction with results of pharmacodynamic test, further specify the present invention, following embodiment only is used to the present invention is described and to the present invention without limits.
Embodiment 1
Get Borneolum Syntheticum 10g, behind the adding 100g dissolve with ethanol, add the injection water to 1000ml; Get 1000ml water for injection, add 2.5g Calcium Disodium Versenate used as stabilizers, add breviscapine 10g again and stir, dropping sodium solution makes dissolving; Above-mentioned two liquid are mixed, add the injection water and quantitatively arrive 10000ml, add needle-use activated carbon 5g absorption 20 minutes, filtering decarbonization is adjusted to pH3.7 with hydrochloric acid solution, extremely clear and bright with 0.22 μ m microporous filter membrane fine straining, logical nitrogen fill is sealed to the 5ml glass ampule, 100 ℃ of sterilizations in 30 minutes, lamp inspection promptly gets a kind of compound recipe small-volume injection of being made up of breviscapine and Borneolum Syntheticum.
Embodiment 2
Get Borneolum Syntheticum 10g, after the dissolving of adding 200g glycerol, add the injection water to 1000ml; Get 5000ml water for injection, add 10g cysteine hydrochloride used as stabilizers, add breviscapine 200g again and stir, drip the sodium bicarbonate sodium solution and make dissolving; Above-mentioned two liquid are mixed, add the injection water and quantitatively arrive 10000ml, add needle-use activated carbon 5g absorption 20 minutes, filtering decarbonization is adjusted to pH8.3 with sodium hydroxide solution, extremely clear and bright with 0.22 μ m microporous filter membrane fine straining, logical nitrogen fill is sealed to the 2ml glass ampule, 100 ℃ of sterilizations in 30 minutes, lamp inspection promptly gets a kind of small-volume injection.
Embodiment 3
Get Borneolum Syntheticum 10g, add the 200g tween 80, add the injection water to 1000ml, stirring and dissolving; Get 3000ml water for injection, add 5g sodium sulfite used as stabilizers, add breviscapine 100g again and stir, dropping sodium solution makes dissolving; Above-mentioned two liquid are mixed, add the injection water and quantitatively arrive 10000ml, add needle-use activated carbon 10g absorption 20 minutes, take off charcoal, be adjusted to pH6.5 with hydrochloric acid solution, extremely clear and bright with 0.22 μ m microporous filter membrane aseptic filtration, fill is to the 5ml glass ampule, seal, lamp inspection promptly gets a kind of compound recipe small-volume injection of being made up of breviscapine and Borneolum Syntheticum.
Embodiment 4
Heat-obtaining water for injection 500000ml adds glucose 50000g, needle-use activated carbon 250g, stirs to make to dissolve evenly and boiled 30 minutes.After closing vapour, open cooling water, make 40～50 ℃ of glucose concentrated wiring liquid coolings, return filter 10min, it is standby to take off charcoal; Get Borneolum Syntheticum 10g, add the 20g dissolve with ethanol after, join in the saturated aqueous solution that the 300g HP-is made into, stir or ultrasonic to clarification; Get 1000ml water for injection, add 10g Calcium Disodium Versenate used as stabilizers, add breviscapine 10g again and stir, drip liquor sodii citratis and make dissolving; Above-mentioned three liquid are mixed, add the injection water and quantitatively arrive 1000000ml, add needle-use activated carbon 250g absorption 20 minutes, filtering decarbonization is adjusted to pH4.7 with hydrochloric acid solution, and is extremely clear and bright with 0.22 μ m microporous filter membrane fine straining, logical nitrogen fill is to the 500ml infusion bottle, 115 ℃ of sterilizations in 30 minutes, lamp inspection promptly gets a kind of compound recipe bulk capacity injection of being made up of breviscapine and Borneolum Syntheticum.
Embodiment 5
Heat-obtaining water for injection 500000ml adds sodium chloride 9000g, needle-use activated carbon 250g, stirs to make to dissolve evenly and boiled 30 minutes.After closing vapour, open cooling water, make 40～50 ℃ of sodium chloride concentrated wiring liquid coolings, return filter 10min, it is standby to take off charcoal; Get Borneolum Syntheticum 10g, add 300g glycerol dissolving after, add the injection water to 1000ml; Get 1000ml water for injection, add 8g anhydrous sodium sulfite used as stabilizers, add breviscapine 200g again and stir, drip sodium bicarbonate solution and make dissolving; Above-mentioned three liquid are mixed, add the injection water and quantitatively arrive 1000000ml, add needle-use activated carbon 500g absorption 20 minutes, filtering decarbonization is adjusted to pH6.7 with sodium bicarbonate solution, and is extremely clear and bright with 0.22 μ m microporous filter membrane fine straining, logical nitrogen fill is to the 100ml infusion bottle, 115 ℃ of sterilizations in 30 minutes, lamp inspection promptly gets a kind of compound recipe bulk capacity injection of being made up of breviscapine and Borneolum Syntheticum.
Embodiment 6
Heat-obtaining water for injection 500000ml adds sodium chloride 4500g, glucose 25000g, needle-use activated carbon 250g, stirs to make to dissolve evenly and boiled 30 minutes.After closing vapour, open cooling water, make 40～50 ℃ of concentrated wiring liquid coolings, return filter 10min, it is standby to take off charcoal; Get Borneolum Syntheticum 10g, add the 50g dissolve with ethanol after, add the injection water to 1000ml; Get 1000ml water for injection, add 10g cysteine hydrochloride used as stabilizers, add breviscapine 100g again and stir, dropping sodium solution makes dissolving; Above-mentioned three liquid are mixed, add the injection water and quantitatively arrive 1000000ml, add needle-use activated carbon 250g absorption 20 minutes, filtering decarbonization is adjusted to pH7.8 with onium hydroxide solution, and is extremely clear and bright with 0.22 μ m microporous filter membrane fine straining, logical nitrogen fill is to the 250ml infusion bottle, 115 ℃ of sterilizations in 30 minutes, lamp inspection promptly gets a kind of compound recipe bulk capacity injection of being made up of breviscapine and Borneolum Syntheticum.
Embodiment 7
Get Borneolum Syntheticum 10g, add the dissolving of 300g glycerol, add the injection water, stir to 1000ml; Get 1000ml water for injection and add breviscapine 10g stirring, dropping sodium solution makes dissolving; Above-mentioned two liquid are mixed, add mannitol 200g, add injection and blunge to dissolving fully also quantitatively to 10000ml, adding pin adsorbed 20 minutes with active 10g charcoal, filtering decarbonization is adjusted to pH3.8 with hydrochloric acid solution, and is extremely clear and bright with 0.22 μ m microporous filter membrane aseptic filtration, fill is to cillin bottle, jump a queue, lyophilization, aluminium lid is pressed mouth, lamp inspection promptly gets a kind of compound injection injectable powder of being made up of breviscapine and Borneolum Syntheticum.
Embodiment 8
Get Borneolum Syntheticum 10g, in the saturated aqueous solution that adding 300g HP-is made into, stir or ultrasonic extremely clarification; Get 1000ml water for injection and add breviscapine 10g stirring, dropping sodium solution makes dissolving; Above-mentioned two liquid are mixed, add lactose 200g, add injection and blunge to dissolving fully also quantitatively to 10000ml, adding pin adsorbed 20 minutes with active 10g charcoal, filtering decarbonization is adjusted to pH4.0 with hydrochloric acid solution, and is extremely clear and bright with 0.22 μ m microporous filter membrane aseptic filtration, fill is to cillin bottle, jump a queue, lyophilization, aluminium lid is pressed mouth, lamp inspection promptly gets a kind of compound injection injectable powder of being made up of breviscapine and Borneolum Syntheticum.
Embodiment 9
Get Borneolum Syntheticum 10g, add the 10g dissolve with ethanol, add the injection water to 1000ml; Get 1000ml water for injection and add breviscapine 100g stirring, drip sodium bicarbonate solution and make dissolving; Above-mentioned two liquid are mixed, add levulose acid anhydride 100g, add injection and blunge to dissolving fully also quantitatively to 10000ml, adding pin adsorbed 20 minutes with active 15g charcoal, filtering decarbonization is adjusted to pH8.0 with sodium bicarbonate solution, and is extremely clear and bright with 0.22 μ m microporous filter membrane aseptic filtration, fill is to cillin bottle, jump a queue, lyophilization, aluminium lid is pressed mouth, lamp inspection promptly gets a kind of compound injection injectable powder of being made up of breviscapine and Borneolum Syntheticum.
Embodiment 10
Get Borneolum Syntheticum 10g, add 10g tween and water for injection 200ml stirring and dissolving, add water for injection to 1000ml; Get 1000ml water for injection and add breviscapine 200g stirring, drip sodium bicarbonate solution and make dissolving; Above-mentioned two liquid are mixed, add sucrose 100g, mannitol 200g, add injection and blunge to dissolving fully also quantitatively to 10000ml, adding pin adsorbed 20 minutes with active 25g charcoal, filtering decarbonization is adjusted to pH68.0 with hydrochloric acid solution, and is extremely clear and bright with 0.22 μ m microporous filter membrane aseptic filtration, fill is to cillin bottle, jump a queue, lyophilization, aluminium lid is pressed mouth, lamp inspection promptly gets a kind of compound injection injectable powder of being made up of breviscapine and Borneolum Syntheticum.
A kind of pharmacodynamics test research (1) of the compound injection of forming by breviscapine and Borneolum Syntheticum:
Healthy male SD rat, body weight 250～300g in 10 ages (SPF level) in week, is divided into 7 groups at random: solvent control group (normal saline), compound injection, Borneolum Syntheticum group, the breviscapine group be made up of breviscapine and Borneolum Syntheticum.20min administration before blocking, administration volume 1ml/kg, speed 0.2ml/min.
Rat brain focal ischemia reperfusion injury model preparation: nylon wire one end of diameter 2.8mm is carefully polished smooth, doing sign apart from this end 18mm, 20mm, 22mm place.Adopt improvement Koizumi legal system to make middle cerebral artery blocking-up (MACO) model, monitoring anus temperature makes it to remain on 37 ± 0.5 ℃ in the operation process.Rat is used chloral hydrate anesthesia (300mg/kg, ip), cervical region veutro median incision exposes trachea and right carotid, at internal carotid artery and external carotid artery branch point, from proximal part ligation common carotid artery, separate the ligation external carotid artery from bifurcation, on common carotid artery, cut a little otch apart from bifurcation 2mm, by incision after internal carotid artery is put into the about 20mm of thromboembolism line or is met obstructions, sew up the skin of neck otch, about 10mm thromboembolism line is retained in outside the cervical incision.Extract the about 10mm of thromboembolism line behind the ischemia 2h, make blood flow logical again.Pour into 22h again, reject dead rat.
The perfusion end is with the rat sacrificed by decapitation again, take out brain rapidly, place under-20 ℃ of environment keep 10min after, take out brain, begin coronalplane from front end to cut the about 2mm of brain sheet thickness continuously, every brain is cut 5, downcut the brain sheet and put into 2%TTC solution immediately, solution places under 37 ℃ of airtight light tight environment behind the 15min, with the fixing 24h of 10% formalin, infarcted region is a white, and normal district is for red.With infarcted region and normal distinguish from, weigh respectively, represent the infarcted region scope with the percentage ratio of the shared full brain weight of infarcted region.
Influence to rat brain focal ischemia reperfusion injury hindbrain Infarction volume.X±s。
Test shows, breviscapine and Borneolum Syntheticum compound injection group (1: 1,1: 10,1: 20) can significantly reduce the cerebral infarction volume after focal cerebral ischemia in rats 2h pours into 22h again, breviscapine and Borneolum Syntheticum compound injection group (1: 30), Borneolum Syntheticum group, breviscapine group seemingly have the effect that reduces the cerebral infarction volume, but than breviscapine and Borneolum Syntheticum compound injection group (1: 1,1: 10,1: 20) effect low, Borneolum Syntheticum and breviscapine compatibility (1: 1 within the specific limits is described, 1: 10,1: 20) have synergism, compatibility uses and can strengthen drug effect in this scope.
A kind of pharmacodynamics test research (2) of the compound injection of forming by breviscapine and Borneolum Syntheticum:
According at random, double blinding, contrast and parallel principle, and the SD rat is divided into 5 groups, 8 every group according to the blind table of statistics expert's volume.Be respectively: solvent control group (normal saline), ischemia filling group again (model control group), ligustrazine group (positive drug control group, 30mg/kg), breviscapine and Borneolum Syntheticum compound injection group (1: 1,2mg/kg; 1: 10,11mg/kg; 1: 20,21mg/kg).Each organizes intravenously administrable 1 time, anaesthetizes after the administration and operates on.
Animal model preparation and hemodynamics are measured: carry out in the body multiple filling damaging action method that resists myocardial ischemia by Baines CP etc.Rat is (urethane 1.0gkg under anesthesia
-1, ip) cut skin of neck, endotracheal intubation, pipe connects artificial respirator, respiratory frequency 55～65 times/minute, tidal volume 1.5～2ml.100g
-1, exhale: ratio is 1.5: 1 during suction.Adjust respiration parameter according to the respiratory frequency and the degree of depth.Separate left and right common carotid artery, left common carotid artery is inserted a PE who contains 0.1% heparin-saline and is managed, other gets a PE pipe that is full of 0.1% heparin-saline and inserts left ventricle through right common carotid artery, changes according to pressure figure shown in the display and judges whether intubate enters ventricular chamber.Two conduits all connect pressure transducer and respectively signal are input to the bio signal acquisition processing system, change with monitoring rat blood pressure and left ventricular blood hydromechanics.Observation index comprise systolic pressure (systolic blood pressure, SBP), diastolic pressure (diastolicblood pressure, DBP) and mean arterial pressure (mean arterial blood pressure, MBP).Left ventricular systolic pressure (left ventricular systolic pressure, LVSP), the maximum rate of change (± dp/dt max) of left ventricle isovolumetric phase pressure, left ventricular diastolic pressure (left ventricular diastolic pressure, LVDP), left ventricular end diastolic is pressed (left ventricular end-diastolic pressure, LVEDP), heart rate (heart rate, HR).(left ventricular developed pressure, LVDP ') pressed in the left ventricle development is the difference of LVSP and LVDP.It is subcutaneous with the variation of monitoring limbs II lead electrocardiogram that needle electrode is fixed in the rat extremity.Cut off 3,4,5 ribs along left border of sternum, expose heart, cut off pericardium.With the left coronary artery is sign, with 3/8 circle, 3 * 10 rustless steel round needles, wears a silk thread under left coronary artery.Depth of needle passes about myocardium 1mm, and width is around the tremulous pulse about 1.5～2mm between the turnover pin.Stablized 15 minutes, and treated each values of hemodynamics such as preceding electrocardiogram of the stable back of each index record medicine and blood pressure.Between a tiny latex tubing mat blood vessel and ligature, the tension ligature makes tiny latex tubing compressing left coronary artery and causes obturation.Follow the T wave height to alarm or the ST section is raised with heart local cyanosis after the ligation, as the standard of ligation success.Behind the ligation 30min, unclamp ligature and pour into 90min again, gradually become ruddy, ECG ST section with local cyanosis and revert to the multiple successful sign of irritating gradually.Write down a These parameters every 15 minutes in the ischemic stage and the phase of irritating again.
Experimental result: LVSP, LVDP before the anesthetized rat coronary ligation, ± dp/dtmax, LVDP ', LVEDP, MBP, each is close for the HR basic value, no significant difference between group.Rat heart muscle ischemic stage LVEDP value is meaningful to be higher than pseudo-operation group respective value, and breviscapine and Borneolum Syntheticum compound injection group (1: 1,1: 10,1: 20) and ligustrazine group administration group be meaningful to be lower than model control group; And irritate again phase LVEDP each the group between not statistically significant difference.Give before ischemia is irritated again breviscapine and Borneolum Syntheticum compound injection group (1: 1,1: 10,1: 20) LVDP ', ± all meaningful each the time respective value of model control group (P＜0.05) that is higher than of dp/dtmax equivalence.Except that puppet operation group, in the 130min of whole observation, respectively organize MBP, HR has downward trend, but breviscapine and Borneolum Syntheticum compound injection group (1: 1,1: 10,1: 20) and model control group between relatively ischemia end value is meaningful is lower than matched group, and the multiple meaningful matched group (table 1, table 2) that is higher than of end value of irritating.Ischemia end left ventricular systolic pressure (LVSP) breviscapine and Borneolum Syntheticum compound injection group (1: 1,1: 10,1: 20) and the meaningful model control group (table 3) that is higher than of ligustrazine group.Ischemia end and irritate last left ventricular developed pressure (LVSP-LVEDP, ± dp/dt max) breviscapine again and Borneolum Syntheticum compound injection group (1: 1,1: 10,1: 20) and the meaningful model control group of ligustrazine group (table 4,6,7).Results suggest breviscapine and Borneolum Syntheticum compound injection group (1: 1,1: 10,1: 20) have the rat cardiac function damaging action and the effect that slightly brings high blood pressure down behind the myocardial ischemia-reperfusion of improvement, and not obvious to the heart rate influence.Breviscapine and Borneolum Syntheticum compound injection group (1: 1,1: 10,1: 20) and ligustrazine group ischemia end and irritate again that last LVEDP is meaningful to be lower than model control group, prompting breviscapine and Borneolum Syntheticum compound injection group (1: 1,1: 10,1: 20) can reduce rat heart preload effect (table 5).
MBP (mmhg) influence (8 every group) after the table 1 pair Ischemia and Reperfusion in vivo in Rats
Annotate: compare P＜0.05 with model control group
HR (beat/min) influence (8 every group) after the table 2 pair Ischemia and Reperfusion in vivo in Rats
LVSP (mmHg) influence after the table 3 pair Ischemia and Reperfusion in vivo in Rats
Annotate: compare P＜0.05 with model control group
LVDP ' after the table 4 pair Ischemia and Reperfusion in vivo in Rats (mmHg) influences
Annotate: compare P＜0.05 with model control group
The influence of LVEDP (mmHg) after the table 5 pair Ischemia and Reperfusion in vivo in Rats
Annotate: compare P＜0.05 with model control group
After the table 6 pair Ischemia and Reperfusion in vivo in Rats+dp/dtmax (mm Hgs
-1) influence
Annotate: compare P＜0.05 with model control group
After the table 7 pair Ischemia and Reperfusion in vivo in Rats-dp/dtmax (mmHgs
-1) influence
Annotate: compare P＜0.05 with model control group
Claims (2)
1, a kind of compound injection of being made up of breviscapine and Borneolum Syntheticum is characterized in that allowing the adjuvant that uses by effective ingredient breviscapine and Borneolum Syntheticum, injectable drug, and is formulated by proportioning; Medicinal raw material effective ingredient Borneolum Syntheticum and breviscapine weight ratio are 1: 1～20, and injectable drug allows the adjuvant surplus of use;
Described Borneolum Syntheticum is artificial Borneolum Syntheticum, or natural Broneolum Syntheticum; Breviscapine is the flavones ingredient that extracts from the Chinese crude drug Herba Erigerontis, is mainly lamp-dish flower acetic;
The adjuvant solvent that described injectable drug allows to use is selected water for injection or ethanol for use, cosolvent is selected HP-for use, tween 80, glycerol, a kind of or mixture in the ethanol, isoosmotic adjusting agent is selected glucose for use, a kind of or mixture in the sodium chloride, excipient is selected mannitol for use, the levulose acid anhydride, glucose, sodium chloride, sucrose, a kind of or mixture in the lactose, stabilizing agent is selected Calcium Disodium Versenate for use, sodium sulfite, anhydrous sodium sulfite, a kind of or mixture in the cysteine hydrochloride, sodium hydroxide is selected in the pH regulator agent for use, hydrochloric acid, sodium bicarbonate, a kind of or mixture in the sodium citrate;
The preparation method of described a kind of compound injection of being made up of breviscapine and Borneolum Syntheticum is:
Get 1 part of Borneolum Syntheticum, add the dissolving of cosolvent and water for injection; Get 1～20 part of breviscapine, add the water for injection that contains stabilizing agent, drip the pH regulator agent and make dissolving; Above-mentioned two liquid are mixed, add the injection water to certain volume, add needle-use activated carbon absorption 15～30 minutes, filtering decarbonization is adjusted to pH3.5～8.5 with the pH regulator agent, sterilize after the fine straining fill, or fill after the aseptic filtration, lamp inspection gets injection with small volume;
Get isoosmotic adjusting agent,, add needle-use activated carbon heating absorption 20 minutes, filtering decarbonization with the water for injection dissolving; Get 1 part of Borneolum Syntheticum, add the dissolving of cosolvent and water for injection; Get 1～20 part of breviscapine, add the water for injection that contains stabilizing agent, drip the pH regulator agent and make dissolving; Above-mentioned three liquid are mixed, add the injection water to certain volume, add needle-use activated carbon absorption 15～30 minutes, filtering decarbonization is adjusted to pH3.5～8.5 with the pH regulator agent, sterilize after the fine straining fill, or fill after the aseptic filtration, lamp inspection gets high-capacity injection;
Get 1 part of Borneolum Syntheticum, add cosolvent and an amount of water for injection dissolving; Get 1～20 part of breviscapine, add the water for injection that contains stabilizing agent, drip the pH regulator agent and make dissolving; Above-mentioned two liquid are mixed, add excipient, add the injection water again, add needle-use activated carbon absorption 15～30 minutes, filtering decarbonization to certain volume, be adjusted to pH3.5～8.5 with the pH regulator agent, aseptic filtration, fill is jumped a queue, lyophilization, aluminium lid is pressed mouth, and lamp inspection gets injectable powder.
2, a kind of compound injection of being made up of breviscapine and Borneolum Syntheticum according to claim 1 is characterized in that adopting microporous filter membrane to carry out fine straining or aseptic filtration, carries out fine straining or aseptic filtration again after perhaps adopting the ultrafilter membrane ultrafiltration.
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