CN1923220A - Ginkgo damo powder injection and its preparing process - Google Patents
Ginkgo damo powder injection and its preparing process Download PDFInfo
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- CN1923220A CN1923220A CN 200510097957 CN200510097957A CN1923220A CN 1923220 A CN1923220 A CN 1923220A CN 200510097957 CN200510097957 CN 200510097957 CN 200510097957 A CN200510097957 A CN 200510097957A CN 1923220 A CN1923220 A CN 1923220A
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- injectable powder
- ginkgo
- antioxidant
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Abstract
The invention discloses a ginkgo leaf extract and diphyridamole powder injection and process for preparation, wherein the powder injection comprises ginko flavones and bilobalide which are effective positions extracted and purified from ginko leaf, and dipyridamole, the constituents include (by weight portions) ginkgo extract 8-15, dipyridamole 2-6, surface active agent 10-80, excipient 50-150, stabilizing agent 0-50, anti-oxidizing agent 0-10.
Description
[technical field]
The invention belongs to the technical field of medicine preparation and preparation method thereof, be specifically related to a kind of ginkgo Damo freeze-drying injectable powder that contains certain proportioning antioxidant and preparation method thereof.
[background technology]
Hematoblastic high coherent condition in the human vas can cause the heart, brain and other arterial circulation disorder diseases.This disease mainly shows as coronary heart disease, cerebral thrombosis, hypertension, they constituted a threat to human life first " killer ".Modern pharmacology shows that Semen Ginkgo and active ingredient thereof have this pharmacological action widely, has blood fat reducing, atherosclerosis, improves effect (Zhuo Bin etc., Chinese Pharmaceutical 11 phases of calendar year 2001: the 67-69 page or leaf) such as microcirculation in heart and brain.Dipyridamole has definite coronary artery dilator and anticoagulant effect.Clinical experiment shows that two medicine couplings can strengthen it and expand crown arteries and veins blood vessel and suppress platelet aggregation, the effect of blood viscosity lowering.
Ginkgo bilobate extract solution is the sterile water solution that is mixed with by Folium Ginkgo extract and dipyridamole, because Folium Ginkgo extract belongs to mixture, composition is not single, contain compositions such as Ginkgo total flavones, terpene lactone, brought certain difficulty for like this preparation and the quality control of injection preparation, and dipyridamole is oxidized easily, has brought certain difficulty for like this preparation and the storage of injection preparation.Ginkgo bilobate extract is in solution state preservation process, the easy polymerization of its Folium Ginkgo extract active ingredient becomes the biological ketone of macromole, cause that anaphylaxis increases in the process of clinical application, thereby influence the quality of medicine, influence the safety of medication simultaneously, Folium Ginkgo extract solution is to photaesthesia in addition, and illumination can make content descend.
Therefore, to those skilled in the art, when Semen Ginkgo and dipyridamole coupling, other quality problems of its compound preparation (especially injection preparation) are difficult to especially expect, and also do not find the clearly instruction of relevant solution in the prior art.
Therefore, this area is starved of Semen Ginkgo and dipyridamole made and has good stability and deliquescent compound injection pharmaceutical composition.
[summary of the invention]
The object of the present invention is to provide a kind of stable ginkgo bilobate extract injectable powder, this medicine injectable powder has dissolubility preferably in aqueous solution, avoided dipyridamole oxidized easily, and it is all more stable to light and heat, decomposition reaction does not take place in long-time placement, avoids simultaneously in the preparation prescription because of using a large amount of organic solvents or surfactant to cause toxic and side effects.
Another object of the present invention provides that a kind of technology is simple, the ginkgo-dipyridamole for injection lyophilized injectable powder of drug safety and preparation method thereof.
To achieve these goals, the present invention adopts following technical measures: this invents described ginkgo bilobate extract is the lyophilized injectable powder of being made by Folium Ginkgo extract and dipyridamole, wherein the Main Ingredients and Appearance of Folium Ginkgo extract is flavonoid and terpenoid, in China, the Folium Pruni extract quality standard of listing " Folium Pruni ketone ester " [national drug standards WS3-227 of State Food and Drug Administration (Z-028)-2002 (Z)] by name, contain total flavones and must not be less than 44% in rutin, contain total flavonoids (Ginkgo total flavones) and must not be less than 24%, contain terpene lactone with ginkalide A, ginkalide B, the content sum of ginkalide C and bilobalide must not calculate and is less than 6%.
With reference to the Ginkgo Leaf Extract and Dipyridamole Injection (former name is a Fructus Pruni fourth injection) that goes on the market at present, Folium Ginkgo extract and dipyridamole ratio of components are about 10: 1 in the prescription, are about 10: 4 in Ginkgo total flavones.The present invention's proportioning in view of the above filters out the composition and the proportioning thereof of powder injection formulation adjuvant.
In embodiments of the invention, every injectable powder is made (consumption is a weight portion) by following raw materials according:
Semen Ginkgo extrac (calculating) 8～15, dipyridamole 2～6, surfactant 10～80, excipient 50～150, stabilizing agent 0～50, antioxidant 0～10 with Ginkgo total flavones.
Preferred version of the present invention is:
Semen Ginkgo extrac (calculating) 9～12, dipyridamole 3～5, surfactant 30～50, excipient 75～125, stabilizing agent 0～25, antioxidant 0～5 with Ginkgo total flavones.
Preferred plan of the present invention is:
Semen Ginkgo extrac (calculating) 10, dipyridamole 4, surfactant 40, excipient 100, stabilizing agent 10, antioxidant 2 with Ginkgo total flavones.
Can be the mixed system of mannitol, Polyethylene Glycol, glucosan, lactose, glycine, colloidal substance or their combination in any at the excipient described in the such scheme; Surfactant described in the such scheme can be the mixed system of tween 20, tween 80, Polyethylene Glycol, polyoxyethylene castor oil, polyoxyethylene hydrogenated Oleum Ricini, polyvinylpyrrolidone, poloxamer or their combination in any; Stabilizing agent described in the such scheme can be the mixed system of nicotiamide, hetastarch and their compositions; Antioxidant described in the such scheme can be the mixed system of alpha-tocopherol, dibutyl cresols, sodium sulfite, sodium pyrosulfite, sodium sulfite, ascorbic acid, thiourea, cysteine, tartaric acid, citric acid, EDTA disodium, EDTA calcium sodium, dimercaptopropanol, BAL or their combination in any, is preferably the mixed system of alpha-tocopherol, dibutyl cresols and their compositions.
The preparation process of ginkgo bilobate extract injectable powder may further comprise the steps:
A. under fully stirring sodium hydroxide solution is splashed in the Folium Ginkgo extract, after waiting to dissolve, ratio adds surfactant by weight, and regulates pH value;
B. under fully stirring hydrochloric acid is splashed in the dipyridamole, after waiting to dissolve, ratio successively adds antioxidant, stabilizing agent and other surfactants by weight, and regulates pH value;
C. under agitation, gained drips of solution among the step B is added in the steps A gained solution, and ratio adding by weight replenishes water for injection through the freeze-dried excipient solution of charcoal treatment then, add proper amount of active carbon, the microporous filter membrane coarse filtration, reuse microporous filter membrane fine straining, gained filtrate is replenished an amount of water for injection, and adjusting pH value, be divided in then in the cillin bottle, deliver to lyophilization in the freeze drying box, promptly get the ginkgo bilobate extract injectable powder.
Wherein the C step is preferably as follows:
C. under agitation, gained drips of solution among the step B is added in the steps A gained solution, ratio adding by weight is through the freeze-dried excipient solution of charcoal treatment then, replenish water for injection, again under 50-60 ℃ of condition, add proper amount of active carbon, stirred about 15 minutes, and used 0.8 μ m microporous filter membrane coarse filtration while hot, reuse 0.2 μ m microporous filter membrane fine straining, gained filtrate is replenished an amount of water for injection, and the adjusting pH value, be divided in the cillin bottle every bottle of 2ml then, deliver to lyophilization in the freeze drying box, promptly get the ginkgo bilobate extract injectable powder.
The last pH value of the Injectable compound preparation that said method makes is 5.0-7.5.
Those skilled in the art can adjust the freeze dried cycle according to the demand of clinical preparation and concrete production equipment.Usually, uniform preparation can be placed the cillin bottle of 5ml to 40ml, pre-freeze temperature-20 ℃ is preferably-40 ℃ to-50 ℃ to-60 ℃, 1 hour to 8 hours pre-freeze time, is preferably 2-4 hour.Freeze temperature-10 ℃ is preferably-15 ℃ to-20 ℃ to-30 ℃, and freeze-drying time 10 hours to 40 hours is preferably 25 hours to 35 hours.The final moisture content of freeze-dried composition generally is lower than 5%, is preferably 1% to 3%.Ginkgo Damo freeze-drying compositions of the present invention is particularly suitable for using clinically.Before use, can add an amount of aseptic medicinal aqueous diluent (for example, water for injection, normal saline, G/W and other known aqueous carriers), be reconstructed into pharmaceutical solutions for intramuscular injection or intravenous drip (intravenous administration) usefulness.
Ginkgo Damo freeze-drying compositions of the present invention is particularly suitable for using clinically.Before use, can add an amount of aseptic medicinal aqueous diluent (for example, water for injection, normal saline, G/W and other known aqueous carriers), be reconstructed into pharmaceutical solutions for intramuscular injection or intravenous drip (intravenous administration) usefulness.
Ginkgo bilobate extract sterile powder injection by this method preparation has advantages such as production technology is simple, with low cost, steady quality, and simultaneously prepared product is all more stable to light and heat.This injectable powder not only can intravenous injection, but also can intramuscular injection, and zest is starkly lower than other ginkgo bilobate extract injection.
[specific embodiment]
Following embodiment further describes the present invention, but described embodiment only is used to illustrate the present invention rather than restriction the present invention.
Embodiment 1 preparation contains the lyophilized formulations (sample A) of antioxidant alpha-tocopherol
Prescription:
Folium Ginkgo extract (calculating) 1g with Ginkgo total flavones
Dipyridamole 0.4g
Alpha-tocopherol 0.2g
Glucosan 10g
Poloxamer 2.5g
Nicotiamide 1g
Polyvinylpyrrolidone 1.5g
Technology:
(1) fully stirring splashes into sodium hydroxide solution in the Folium Ginkgo extract down, after waiting to dissolve, adds poloxamer, regulates pH value to 5.4;
(2) fully stirring splashes into hydrochloric acid in the dipyridamole down, after waiting to dissolve, successively adds alpha-tocopherol, nicotiamide, polyvinylpyrrolidone, regulates pH value to 5.7;
(3) under agitation, step (2) gained drips of solution is added in step (1) the gained solution, add the mannitol solution that charcoal treatment is crossed then, replenish water for injection, again under 50-60 ℃ of condition, add proper amount of active carbon, stirred about 15 minutes, while hot with 0.8 μ m microporous filter membrane coarse filtration, reuse 0.2 μ m microporous filter membrane fine straining, gained filtrate is replenished an amount of water for injection, after being transferred to proper pH value, be divided in the cillin bottle every bottle of 2.0ml, deliver to lyophilization in the freeze drying box, promptly get the ginkgo bilobate extract injectable powder.
Embodiment 2 preparations contain the lyophilized formulations (sample B) of antioxidant alpha-tocopherol
Prescription:
Folium Ginkgo extract (calculating) 1.2g with Ginkgo total flavones
Dipyridamole 0.5g
Alpha-tocopherol 0.15g
Glucosan 10g
Poloxamer 1.5g
Nicotiamide 1g
Polyvinylpyrrolidone 2.5g
Technology:
Prepare lyophilized formulations by embodiment 1 method.
Embodiment 3 preparations contain the lyophilized formulations (sample C) of antioxidant dibutyl cresols
Prescription:
Folium Ginkgo extract (calculating) 1g with Ginkgo total flavones
Dipyridamole 0.4g
Dibutyl cresols 0.2g
Glucosan 10g
Poloxamer 2.5g
Nicotiamide 1g
Polyvinylpyrrolidone 1.5g
Technology:
Prepare lyophilized formulations by embodiment 1 method, but wherein antioxidant is the dibutyl cresols.
Embodiment 4 preparations contain the lyophilized formulations (sample D) of antioxidant dibutyl cresols
Prescription:
Folium Ginkgo extract (calculating) 1g with Ginkgo total flavones
Dipyridamole 0.4g
Alpha-tocopherol 0.1g
Dibutyl cresols 0.1g
Glucosan 10g
Poloxamer 2.5g
Nicotiamide 1g
Polyvinylpyrrolidone 1.5g
Technology:
Prepare lyophilized formulations by embodiment 1 method, but wherein antioxidant is the mixture of alpha-tocopherol and dibutyl cresols (1: 1).
Embodiment 5
With the lyophilized formulations (sample A) of embodiment 1, the lyophilized formulations (sample B) of embodiment 2, the lyophilized formulations (sample C) of embodiment 3 and the lyophilized formulations (sample D) of embodiment 4, placed 0 month, 3 months, 6 months, 9 months, 12 months down at the same terms (50 ℃); Survey the content of its Ginkgo total flavones and dipyridamole in each stage, find that sample A, B, C, D content all meet the preparation requirement.
Embodiment 6 preparations do not contain the lyophilized formulations (sample E) of antioxidant
Prescription and method according to embodiment 4 prepare lyophilized formulations, but wherein do not contain antioxidant, for following comparative experiments.
Comparing embodiment 1
The lyophilized formulations (sample E) of embodiment 6 was placed 0 month, 3 months, 6 months, 9 months, 12 months down at 50 ℃; Compare with other embodiment samples, find that each work-in-process of sample E all is lower than other samples at the content of Ginkgo total flavones and dipyridamole, and clarity also is lower than other samples.And can't obtain qualified settled solution.
Claims (10)
1. a ginkgo damo powder injection contains Semen Ginkgo extrac and dipyridamole and pharmaceutic adjuvant.
2. injectable powder according to claim 1, wherein pharmaceutic adjuvant comprises surfactant, excipient and/or stabilizing agent and/or antioxidant.
3. injectable powder according to claim 2 is characterized in that calculating by weight described injectable powder and contains Semen Ginkgo extrac (calculating with Ginkgo total flavones) 8～15, dipyridamole 2～6, surfactant 10～80, excipient 50～150, stabilizing agent 0～50, antioxidant 0～10.
4. injectable powder according to claim 3 is characterized in that calculating by weight described injectable powder and contains Semen Ginkgo extrac (calculating with Ginkgo total flavones) 9～12, dipyridamole 3～5, surfactant 30～50, excipient 75～125, stabilizing agent 0～25, antioxidant 0～5.
5. injectable powder according to claim 4 is characterized in that calculating by weight described injectable powder and contains Semen Ginkgo extrac (calculating with Ginkgo total flavones) 10, dipyridamole 4, surfactant 40, excipient 100, stabilizing agent 10, antioxidant 2.
6. according to the arbitrary described injectable powder of claim 1～5, it is characterized in that antioxidant in the described injectable powder can be the mixed system of alpha-tocopherol, dibutyl cresols, sodium sulfite, sodium pyrosulfite, sodium sulfite, ascorbic acid, thiourea, cysteine, tartaric acid, citric acid, EDTA disodium, EDTA calcium sodium, dimercaptopropanol, BAL or their combination in any.
7. injectable powder according to claim 6 is characterized in that antioxidant in the described injectable powder is preferably the mixed system that alpha-tocopherol, dibutyl cresols and their are formed.
8. according to the arbitrary described injectable powder of claim 1～5, it is characterized in that surfactant in the described injectable powder can be the mixed system of tween 20, tween 80, Polyethylene Glycol, polyoxyethylene castor oil, polyoxyethylene hydrogenated Oleum Ricini, polyvinylpyrrolidone, poloxamer or their combination in any.
9. according to the arbitrary described injectable powder of claim 1～5, it is characterized in that stabilizing agent in the described injectable powder can be the mixed system that nicotiamide, hetastarch and their are formed.
10. according to the arbitrary described injectable powder of claim 1～5, it is characterized in that in the described injectable powder that excipient wherein can be the mixed system of mannitol, Polyethylene Glycol, glucosan, lactose, glycine, colloidal substance or their combination in any.
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| Application Number | Priority Date | Filing Date | Title |
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| CN 200510097957 CN1923220A (en) | 2005-09-02 | 2005-09-02 | Ginkgo damo powder injection and its preparing process |
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| CN 200510097957 CN1923220A (en) | 2005-09-02 | 2005-09-02 | Ginkgo damo powder injection and its preparing process |
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| CN1923220A true CN1923220A (en) | 2007-03-07 |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101612170B (en) * | 2008-06-25 | 2012-01-25 | 上海信谊百路达药业有限公司 | Compound injection of Ginkgo Biloba extract and dipyridamole and preparation technology thereof |
-
2005
- 2005-09-02 CN CN 200510097957 patent/CN1923220A/en active Pending
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101612170B (en) * | 2008-06-25 | 2012-01-25 | 上海信谊百路达药业有限公司 | Compound injection of Ginkgo Biloba extract and dipyridamole and preparation technology thereof |
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Owner name: DOBORIPHY PHARMACEUTICAL CO., LTD. Free format text: FORMER OWNER: BARRYMORE PHARMACEUTICAL (TONGHUA) CO., LTD. Effective date: 20081031 |
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Effective date of registration: 20081031 Address after: 66, Xiangjiang Road, Jilin, Meihekou Province, China: 135000 Applicant after: Duprofit Pharmacy Company Limited Address before: East section, North Ring Road, Meihekou economic and Trade Development Zone, Jilin Province, China: 135000 Applicant before: Barrymore Pharmaceutical (Tonghua) Co., Ltd. |
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Open date: 20070307 |