CN100402024C - Gingko lactone freeze dried powder injection and its preparation method - Google Patents
Gingko lactone freeze dried powder injection and its preparation method Download PDFInfo
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- CN100402024C CN100402024C CNB2004100009125A CN200410000912A CN100402024C CN 100402024 C CN100402024 C CN 100402024C CN B2004100009125 A CNB2004100009125 A CN B2004100009125A CN 200410000912 A CN200410000912 A CN 200410000912A CN 100402024 C CN100402024 C CN 100402024C
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- bilobalide
- mannitol
- meglumine
- dried
- freeze
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- 238000002347 injection Methods 0.000 title claims abstract description 28
- 239000007924 injection Substances 0.000 title claims abstract description 28
- 239000000843 powder Substances 0.000 title claims abstract description 25
- 238000002360 preparation method Methods 0.000 title claims abstract description 19
- SQOJOAFXDQDRGF-UHFFFAOYSA-N ginkgolide b Chemical compound O=C1OC2CC(C(C)(C)C)C34C(O)C(=O)OC4OC41C32C(O)C1OC(=O)C(C)C41O SQOJOAFXDQDRGF-UHFFFAOYSA-N 0.000 title description 3
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 claims abstract description 28
- 229930195725 Mannitol Natural products 0.000 claims abstract description 28
- 239000000594 mannitol Substances 0.000 claims abstract description 28
- 235000010355 mannitol Nutrition 0.000 claims abstract description 28
- MBBZMMPHUWSWHV-BDVNFPICSA-N N-methylglucamine Chemical compound CNC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO MBBZMMPHUWSWHV-BDVNFPICSA-N 0.000 claims abstract description 22
- 229960003194 meglumine Drugs 0.000 claims abstract description 22
- 229930184727 ginkgolide Natural products 0.000 claims abstract description 10
- MOLPUWBMSBJXER-YDGSQGCISA-N bilobalide Chemical compound O([C@H]1OC2=O)C(=O)[C@H](O)[C@@]11[C@@](C(C)(C)C)(O)C[C@H]3[C@@]21CC(=O)O3 MOLPUWBMSBJXER-YDGSQGCISA-N 0.000 claims description 95
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 claims description 30
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 19
- 238000003756 stirring Methods 0.000 claims description 17
- 229910052799 carbon Inorganic materials 0.000 claims description 11
- 239000000047 product Substances 0.000 claims description 9
- 238000000034 method Methods 0.000 claims description 5
- 238000012856 packing Methods 0.000 claims description 5
- 239000007864 aqueous solution Substances 0.000 claims description 4
- 239000000706 filtrate Substances 0.000 claims description 4
- 238000001914 filtration Methods 0.000 claims description 4
- 238000004108 freeze drying Methods 0.000 claims description 4
- 239000012528 membrane Substances 0.000 claims description 4
- 239000003643 water by type Substances 0.000 claims description 4
- 239000007788 liquid Substances 0.000 description 11
- 238000012360 testing method Methods 0.000 description 8
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 8
- 230000000694 effects Effects 0.000 description 6
- 241000218628 Ginkgo Species 0.000 description 5
- 235000011201 Ginkgo Nutrition 0.000 description 5
- 235000008100 Ginkgo biloba Nutrition 0.000 description 5
- 239000003814 drug Substances 0.000 description 5
- -1 flavone compound Chemical class 0.000 description 5
- 238000005516 engineering process Methods 0.000 description 4
- 238000011160 research Methods 0.000 description 4
- 239000003795 chemical substances by application Substances 0.000 description 3
- 238000004128 high performance liquid chromatography Methods 0.000 description 3
- 239000008176 lyophilized powder Substances 0.000 description 3
- 238000004519 manufacturing process Methods 0.000 description 3
- GAMYVSCDDLXAQW-AOIWZFSPSA-N Thermopsosid Natural products O(C)c1c(O)ccc(C=2Oc3c(c(O)cc(O[C@H]4[C@H](O)[C@@H](O)[C@H](O)[C@H](CO)O4)c3)C(=O)C=2)c1 GAMYVSCDDLXAQW-AOIWZFSPSA-N 0.000 description 2
- 238000010521 absorption reaction Methods 0.000 description 2
- 239000003146 anticoagulant agent Substances 0.000 description 2
- 239000008280 blood Substances 0.000 description 2
- 210000004369 blood Anatomy 0.000 description 2
- 230000000052 comparative effect Effects 0.000 description 2
- 239000000945 filler Substances 0.000 description 2
- 229930003944 flavone Natural products 0.000 description 2
- 235000011949 flavones Nutrition 0.000 description 2
- 239000010212 ginaton Substances 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- 238000007689 inspection Methods 0.000 description 2
- 238000005457 optimization Methods 0.000 description 2
- 230000000144 pharmacologic effect Effects 0.000 description 2
- 150000003505 terpenes Chemical class 0.000 description 2
- VHBFFQKBGNRLFZ-UHFFFAOYSA-N vitamin p Natural products O1C2=CC=CC=C2C(=O)C=C1C1=CC=CC=C1 VHBFFQKBGNRLFZ-UHFFFAOYSA-N 0.000 description 2
- 102000015427 Angiotensins Human genes 0.000 description 1
- 108010064733 Angiotensins Proteins 0.000 description 1
- 244000194101 Ginkgo biloba Species 0.000 description 1
- 108700023400 Platelet-activating factor receptors Proteins 0.000 description 1
- 208000007536 Thrombosis Diseases 0.000 description 1
- 239000002671 adjuvant Substances 0.000 description 1
- 230000008485 antagonism Effects 0.000 description 1
- 230000003266 anti-allergic effect Effects 0.000 description 1
- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- 230000000702 anti-platelet effect Effects 0.000 description 1
- 230000000703 anti-shock Effects 0.000 description 1
- 229940127219 anticoagulant drug Drugs 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 210000000170 cell membrane Anatomy 0.000 description 1
- WHTVZRBIWZFKQO-UHFFFAOYSA-N chloroquine Chemical compound ClC1=CC=C2C(NC(C)CCCN(CC)CC)=CC=NC2=C1 WHTVZRBIWZFKQO-UHFFFAOYSA-N 0.000 description 1
- 239000006184 cosolvent Substances 0.000 description 1
- 238000011082 depyrogenation Methods 0.000 description 1
- 238000012850 discrimination method Methods 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000000284 extract Substances 0.000 description 1
- 230000008595 infiltration Effects 0.000 description 1
- 238000001764 infiltration Methods 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 238000011835 investigation Methods 0.000 description 1
- 208000037906 ischaemic injury Diseases 0.000 description 1
- 208000028867 ischemia Diseases 0.000 description 1
- 150000002596 lactones Chemical class 0.000 description 1
- 230000004089 microcirculation Effects 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 102000030769 platelet activating factor receptor Human genes 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- 230000001681 protective effect Effects 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 238000003908 quality control method Methods 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 239000002464 receptor antagonist Substances 0.000 description 1
- 229940044551 receptor antagonist Drugs 0.000 description 1
- 239000013558 reference substance Substances 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 238000005070 sampling Methods 0.000 description 1
- 210000000582 semen Anatomy 0.000 description 1
- 239000010068 shuxuening Substances 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 238000001179 sorption measurement Methods 0.000 description 1
- 230000000087 stabilizing effect Effects 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 235000007586 terpenes Nutrition 0.000 description 1
- 231100000027 toxicology Toxicity 0.000 description 1
- 238000002054 transplantation Methods 0.000 description 1
- 239000008215 water for injection Substances 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
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- Medicinal Preparation (AREA)
Abstract
The present invention discloses a ginkgolide freeze-dried powder injection which comprises ginkalide, meglumine and mannitol, wherein the ginkalide comprises ginkalide A, ginkalide B and ginkalide C. The present invention also discloses a preparation method of the ginkgolide freeze-dried powder injection.
Description
Technical field
The invention relates to preparation of bilobalide and preparation method thereof, particularly about lyophilized injectable powder of bilobalide and preparation method thereof, this injection is that effective ingredient is prepared from the extract bilobalide of Chinese medicine Folium Ginkgo, belongs to drug world.
Background technology
The Folium Ginkgo main component is flavone compound, terpenoid.Wherein terpenoid is based on bilobalide.Modern pharmacological research shows that bilobalide is the medicine that potential applicability in clinical practice is arranged in present natural antiplatelet activity factor (PAF) receptor antagonist most, and wherein the selectivity of ginkalide B antagonism paf receptor and activity are the strongest.Bilobalide can anticoagulant, and blood viscosity lowering improves ischemia patient's microcirculation, reduces thrombosis; Stabilizing cell membrane reduces the infiltration of angiotensin simultaneously; Have antiallergic, antiinflammatory, Antishock function, the rejection of ischemic injuries and organ transplantation is also had protective effect
[2]
The production of external gingko leaf preparation mainly contains the Ginaton (Ginaton) and the French Tanakan (Da Nakang) of Germany; The kind of domestic production has SHUXUENING ZHUSHEYE, taponin Semen Ginkgo sheet etc., and its main component is flavone compound and terpene lactones chemical compound.Research to bilobalide and preparation thereof in the prior art has had some reports.Disclose a kind of preparation method of freeze-dried ginkgolide powder injection as Chinese patent literature CN1390542, document number is that CN1424031A discloses a kind of bilobalide injector and preparation technology thereof.Zhao Yanzhong, Chen Yuxiang, Liu Ting, Wen Jifang test and study the safety and the toxicology of injection bilobalide lyophilized powder, and outcome research shows that freeze-dried powder is safe and reliable as injection.Bilobalide injector is raw material with the Folium Ginkgo among the present invention, and through extracting the effective site bilobalide chemical compound that purification makes, bilobalide makes the injection bilobalide through processing; And preparation technology, quality standard and the stability of injection bilobalide done research, thus controlled the stability of gingko lactone lyophilized powder better, improved bioavailability.
Summary of the invention
The object of the present invention is to provide a kind of lyophilized injectable powder of the preparation that contains bilobalide, particularly bilobalide, the preparation technology of this lyophilized injectable powder also is provided simultaneously.
Lyophilized injectable powder of the present invention is mainly formed with total bilobalide, bilobalide-containing A:46～56% wherein, and ginkalide B: 38～48%, ginkalide C 3～13%.
This lyophilized injectable powder also contains meglumine, mannitol simultaneously, and each components by weight is: bilobalide: meglumine: mannitol=5: (5～7): (30～40).
The weight ratio of said components can be bilobalide: meglumine: mannitol=5: 6: 40.
The preferential weight ratio of said components is: bilobalide: meglumine: mannitol=5: 6: 35.
Wherein also can add 8% an amount of citric acid soln.
The present invention also provides the preparation method of gingko lactone lyophilized powder, and is specific as follows:
Bilobalide 5.0 weight portions
Meglumine 5.0～7.0 weight portions
Mannitol 30.0g～40.0 weight portions
8% citric acid soln
Get in right amount in 80 ℃ of waters for injection of meglumine adding 1000ml, stir and make dissolving, add bilobalide, stir and make dissolving, add mannitol, stir and make dissolving, be cooled to after the room temperature aqueous solution of citric acid accent pH to 7.5～9.0, be stirred to dissolving with 8%, add active carbon, stirring and adsorbing 15～25min under the room temperature filters carbon removal, with 0.22 μ m microporous filter membrane aseptic filtration, filtrate sabot, lyophilization, dried frozen aquatic products is pulverized, and sieves packing, lid is rolled in tamponade, makes freeze-dried powder.
Bilobalide is atomic water-soluble, if being prepared into injection then must add an amount of adjuvant, to increase its dissolubility in water.The pharmaceutic adjuvant meglumine has been applied in bilobalide preparation aspect as a kind of solubilizing agent commonly used, the lactonic ring part salify in meglumine and the bilobalide, thereby the water solublity of increase bilobalide.Lactonic ring is all arranged in the structure of each component of bilobalide, and lactonic ring is unstable in water, is subjected to the influence of factor such as pH value or ambient temperature in the water and open loop and change the structure of component, makes this component lose distinctive pharmacological effect.The medicine stability investigation method of the present invention by system compares the stability of freeze-dried ginkgolide powder injection and bilobalide injection, and result of the test shows, liquid preparation (injection) is under 40 ℃ of accelerated tests, placed 2 months, sampling and measuring content, content descend about 20%; And solid preparation (injectable powder) was placed 6 months under similarity condition, and its physicochemical property and content almost do not change, and the effect duration that can predict this injectable powder is 2 years.So the stability of freeze-dried ginkgolide powder injection is than the good stability of bilobalide injection.Select for use mannitol as the skeleton agent in the injectable powder, the bilobalide powder is scattered in the skeleton agent, then dissolving rapidly when adding water and fully shaking.
Discriminating aspect, the discrimination method of employing are TLC or HPLC, and result of study shows, this product and reference substance are consistent with the identification result of TLC or HPLC; Quality control is carried out with reference to Chinese Pharmacopoeia 2000 editions one appendix I U injection item and appendix IX S injection related substance inspection technique in the inspection aspect, in conjunction with the testing result of three batch samples, has determined the limit of each project.The assay aspect, bilobalide has absorption maximum at the terminal 220nm wavelength of ultraviolet place, and we have selected the HPLC method, and have made methodological study.The result shows that linear relationship, precision, stability, repeatability and the response rate all meet the requirements.
Following experimental example is used to further specify the present invention.
Experimental example 1: the selection of cosolvent optimum amount
Take by weighing bilobalide 0.25g respectively, in varing proportions meglumine adds in the 60ml water for injection, and heating in water bath to 80 ℃ adds bilobalide, being stirred to dissolving as far as possible, relatively appearance character of each test.The results are shown in Table 1.
The experimental result of the different supplementary material ratios of table 1
Result of the test shows that bilobalide and meglumine amount ratio are, solubilization-aid effect is preferably arranged at 1: 1～1.4 o'clock, considers from the stable aspect of Chinese medicine, and medicinal liquid is unsuitable long heat time heating time; So the amount ratio of getting Ginkgo total lactones and meglumine be 1: 1.2 more suitable.
The adjustment of experimental example 2:pH value
The pH value requirement of injection equates with blood of human body or is approaching that in order to avoid body is had side effects, generally should control pH is 4～9.This product is when preparation, and its pH value is about 10, needs to adjust the medicinal liquid pH value to suitable requirement.Taking liquid is an amount of, is the pH value regulator with 8% citric acid soln, places the appearance character of medicinal liquid when examining or check different pH value 24 hours.Result of the test sees Table 2.
The pH value comparative result of table 2 bilobalide injection
Result of the test shows that the pH value of sample is best 7.5～9.0 o'clock clarity, and this moment, sample was the most stable.Because of after medicinal liquid regulates pH value and make the powder pin, its pH value slightly raises, so medicinal liquid should be regulated pH value to 7.5～8.0.
Experimental example 3: the selection of activated carbon dosage
Taking liquid 100ml adds not commensurability active carbon (pin is used) respectively, and at room temperature stirring and adsorbing is 20 minutes.The results are shown in Table 3.
Table 3 activated carbon dosage comparative result
Active carbon has medicinal liquid and adsorbs depyrogenation, decolouring, deimpurity effect preferably.Consider the adsorption of active carbon, so its consumption is screened to bilobalide.The result shows, 0.06%～0.15% better, considers the influence factor in the production, so this process choice activated carbon dosage is 0.10% with activated carbon dosage.
Experimental example 4: the optimization of mannitol (filler) consumption
Taking liquid (with mannitol) is an amount of, is divided into four parts, adds mannitol respectively, makes the solution that contains mannitol 4%, 6%, 8%, 10%, is loaded in the lyophilizing dish, and the appearance character of its dried frozen aquatic products is observed in lyophilizing.The results are shown in Table 4.
The optimization result of table 4 mannitol consumption
| Mannitol (g/ml) | 4％ | 6％ | 8％ | 10％ |
| The dried frozen aquatic products outward appearance | Bulk is more loose | Bulk, full, face is smooth | Bulk, full, face is smooth | Bulk, full, face is smooth |
The result shows that the mannitol consumption is advisable 6%～8%, and when promptly preparing the medicinal liquid of 1000ml, the consumption of mannitol is 60～80 grams.Less because of the dosage of principal agent, should appropriateness increase filler, be beneficial to the packing of medicated powder after the lyophilizing, so selection mannitol consumption is 7%.Mannitol does not have and draws moistly, and the dried frozen aquatic products that makes is difficult for the moisture absorption and soluble in water.
Embodiment 1:
Bilobalide 10.0g
Meglumine 12.0g
Mannitol 70.0g
8% citric acid soln
Get in 80 ℃ of waters for injection of meglumine adding 1000ml, stir and make dissolving, add bilobalide, stir and make dissolving, add mannitol, stir and make dissolving, be cooled to after the room temperature aqueous solution of citric acid accent pH to 7.5～8.0, be stirred to dissolving with 8%, add active carbon, stirring and adsorbing 20min under the room temperature filters carbon removal, with 0.22 μ m microporous filter membrane aseptic filtration, filtrate sabot, lyophilization, dried frozen aquatic products is pulverized, and crosses 30～40 mesh sieves, packing, lid is rolled in tamponade, makes 200.
Embodiment 2:
Bilobalide 10.0g
Meglumine 12.0g
Mannitol 80.0g
8% citric acid soln
Get in 80 ℃ of waters for injection of meglumine adding 1000ml, stir and make dissolving, add bilobalide, stir and make dissolving, add mannitol, stir and make dissolving, be cooled to after the room temperature aqueous solution of citric acid accent pH to 7.5～8.0, be stirred to dissolving with 8%, add active carbon, stirring and adsorbing 25min under the room temperature filters carbon removal, with 0.22 μ m microporous filter membrane aseptic filtration, filtrate sabot, lyophilization, dried frozen aquatic products is pulverized, and crosses 30～40 mesh sieves, packing, lid is rolled in tamponade, makes 200.
Claims (4)
1. freeze-dried ginkgolide powder injection is characterized in that mainly forming with total bilobalide, bilobalide-containing A:46～56% wherein, and ginkalide B: 38～48%, ginkalide C 3～13%; This injectable powder also contains meglumine, mannitol; Each components by weight is: bilobalide: meglumine: mannitol=5: 5～7: 30～40.
2. freeze-dried ginkgolide powder injection as claimed in claim 1 is characterized in that the weight ratio of component is: bilobalide: meglumine: mannitol=5: 6: 40.
3. freeze-dried ginkgolide powder injection as claimed in claim 1 is characterized in that the weight ratio of component is: bilobalide: meglumine: mannitol=5: 6: 35.
4. the preparation method of freeze-dried ginkgolide powder injection as claimed in claim 1 is characterized in that this method is:
Bilobalide 10.0g
Meglumine 12.0g
Mannitol 70.0g
8% citric acid soln
Get in 80 ℃ of waters for injection of meglumine adding 1000ml, stir and make dissolving, add bilobalide, stir and make dissolving, add mannitol, stir and make dissolving, be cooled to after the room temperature aqueous solution of citric acid accent pH to 7.5～8.0, be stirred to dissolving with 8%, add active carbon, stirring and adsorbing 20min under the room temperature filters carbon removal, with 0.22 μ m microporous filter membrane aseptic filtration, filtrate sabot, lyophilization, dried frozen aquatic products is pulverized, and crosses 30～40 mesh sieves, packing, lid is rolled in tamponade, makes 200.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB2004100009125A CN100402024C (en) | 2004-01-14 | 2004-01-14 | Gingko lactone freeze dried powder injection and its preparation method |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB2004100009125A CN100402024C (en) | 2004-01-14 | 2004-01-14 | Gingko lactone freeze dried powder injection and its preparation method |
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| CN1557296A CN1557296A (en) | 2004-12-29 |
| CN100402024C true CN100402024C (en) | 2008-07-16 |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN100393313C (en) * | 2006-02-17 | 2008-06-11 | 夏中宁 | Bilobalide B powder injection and its preparing method |
| CN100341502C (en) * | 2006-04-18 | 2007-10-10 | 张国清 | Vein administration ginkgolactone B powder injection and its preparation method |
| CN107929283B (en) * | 2017-12-29 | 2019-05-07 | 江苏康缘药业股份有限公司 | Ginkgo diterpenoid-lactone composition |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1390542A (en) * | 2002-06-21 | 2003-01-15 | 张平 | Freeze-dried ginkgolide powder injection and its preparing process |
| CN1424031A (en) * | 2002-08-23 | 2003-06-18 | 江苏康缘药业股份有限公司 | Preparation containing Gingkolactone and its producing process |
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1390542A (en) * | 2002-06-21 | 2003-01-15 | 张平 | Freeze-dried ginkgolide powder injection and its preparing process |
| CN1424031A (en) * | 2002-08-23 | 2003-06-18 | 江苏康缘药业股份有限公司 | Preparation containing Gingkolactone and its producing process |
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| CN1557296A (en) | 2004-12-29 |
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Owner name: HAINAN CHUNTCH PHARMACEUTICAL CO., LTD. Free format text: FORMER NAME: ZHONGHUA LIANHE PHARMACEUTICAL INDUSTRY CO., LTD., HAINAN |
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Address after: 570216 No. 6 workshop, Haikou Free Trade Zone, Hainan Patentee after: HAINAN CHUNTCH PHARMACEUTICAL Co.,Ltd. Address before: 570216 No. 6 workshop, Haikou Free Trade Zone, Hainan Patentee before: HAINAN CHUNTCH PHARMACEUTICAL Co.,Ltd. |
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