CN100401059C - Fingerprint atlas quality investigating method of ginkgo lactone material - Google Patents
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- CN100401059C CN100401059C CNB200610086424XA CN200610086424A CN100401059C CN 100401059 C CN100401059 C CN 100401059C CN B200610086424X A CNB200610086424X A CN B200610086424XA CN 200610086424 A CN200610086424 A CN 200610086424A CN 100401059 C CN100401059 C CN 100401059C
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- ginkgolides
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- bilobalide
- ginkolide
- ginkalide
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Abstract
The invention discloses a fingerprint pattern detection method for gingkgo lactone raw materials, which has four shared peaks, and the area of non-shared peaks is not more than 5%. Gingkgo lactone raw materials which accords with fingerprint patterns have controllable quality and good stability.
Description
The application is dividing an application of 02128962.X application; The applying date of original application is on August 23rd, 2002, and application number is 02128962.X, and invention and created name is " preparation and the preparation technology thereof that contain ginkgolides ".
Technical field
The invention relates to the preparation of ginkgolides, particularly contain the injection of ginkgolides, this injection is that effective ingredient is prepared from the extract ginkgolides of Chinese medicine ginkgo leaf, belongs to drug world.
Background technology
Ginkgolides is to extract the active principle that obtains in the middle of the Chinese herbal medicine ginkgo leaf, this material can also further be subdivided into ginkalide A on structure, B, C, (bilobalide K is the newfound ginkgolide monomer of inventor to K, separate case application) etc., extracting method for ginkgolides has had detailed bibliographical information, for example, people such as Li Xingang have introduced the laboratory extracting method of ginkgolides (referring to Li Xingang etc., the laboratory Study on Extraction Method of ginkgolides in the ginkgo leaf, 1998 the 1st phases of Chinese Journal of Pharmaceuticals), Chinese patent literature CN1195665A has introduced the extracting method of ginkgolides and has contained the preparation of ginkgolides, this method is that ginkgo leaf is extracted with water boil, with adsorbent extraction filtrate is adsorbed, use the ethanol desorption again, reclaim ethanol, with the crystallization dissolving of separating out, recrystallization, drying makes ginkgolides.Chinese patent literature CN1313287A discloses a kind of production technology of ginkgolides.The method of separating ginkgolide monomer in the middle of the total extract of ginkgolides, a lot of relevant bibliographical informations are also arranged, for example, people such as You Song have introduced the separation of ginkgolides in the ginkgo leaf and structure determination method (referring to You Song etc., the separation of ginkgolides and structure determination in the ginkgo leaf, Chinese pharmaceutical chemistry magazine the 4th phase of nineteen ninety-five).Chinese patent literature CN1287121A discloses the method that is prepared medicine ginkalide A, B by ginkgo leaf or ginkgo leaf medicinal extract.Ginkgolides can be prepared into it different clinical medicine formulations as an effective active substance.The method for preparing injection with ginkgolides is open in the middle of Chinese patent literature CN1315175A.Use ginkgo leaf injections such as Liu Jie treatments acute brain infraction has obtained certain curative effect [referring to Liu Jie etc., YINXINGYE ZHUSHEYE is to the influence of acute brain infraction back extremity motor function and TXB_2,6-Keto-PGf_ (1a)].About the pharmacological action of ginkgolides, comparatively detailed bibliographical information (referring to Chen Weijun etc., the chemical constitution of ginkgolides and Advance on Pharmacological Activities, 1998 the 9th phases of Chinese Pharmaceutical Journal) has been arranged.Although the research for ginkgolides and preparation thereof in the middle of the prior art has had a lot of reports,, never stop for the research of ginkgolides, particularly, bibliographical information is arranged constantly for the separation of ginkgolide monomer and the research of derivant thereof.Present research for effective monomer in the middle of the ginkgolides, structures such as ginkalide A, B, C have been reported, ginkgolides is prepared into injection, a very important technical matters is to controllable quality, up to the present, does not still have to find accurately to control the method for the central active constituent content of bilobalide injection product, and, in the middle of the bilobalide injector preparation process, also extremely important for the selection of cosolvent, this directly has influence on the stability and the clinical efficacy of product.The present invention is by the mensuration of effective ingredient finger-print in the middle of the bilobalide injection product, the quality of control product, particularly, on the architecture basics of having found bilobalide K, increased a new quality control index, make the suitability for industrialized production of bilobalide injector be achieved, and research by experiment, select desirable cosolvent, thereby can be good at controlling the stability of bilobalide injector product, finished the present invention.
Summary of the invention
The object of the invention provides a kind of preparation that contains ginkgolides, particularly bilobalide injector, and the preparation technology of this injection also is provided simultaneously.
Bilobalide injector of the present invention is to be that effective ingredient is prepared from highly purified ginkgolides, and the weight ratio of parenteral solution each component is:
Ginkgolides: meglumine: sodium chloride=(2-8): (2-8): (4-12)
The preferred weight proportioning of above-mentioned component is:
Ginkgolides: meglumine: sodium chloride=(4-6): (4-6): (6-10)
The preferred weight proportioning of above-mentioned component is:
Ginkgolides: meglumine: sodium chloride=5: 5: 8
Wherein can also add 10% an amount of citric acid solution.
Calculate to prepare 1000 milliliters of bilobalide injectors of the present invention, it is composed as follows:
Ginkgolides 5.0g
Meglumine 5.0g
NaCl 8.0g
10% citric acid solution is an amount of
The preparation method of bilobalide injector of the present invention is as follows:
Get meglumine and add fresh water for injection 1000ml dissolving, in 120 ℃ of autoclaving 30min, take out the back and be heated to 80 ℃ in gradating material chambers 10,000, add porphyrize and cross the ginkgolides of 80 mesh sieves, be heated to dissolving, transfer pH to 8.0 with 10% aqueous citric acid solution after being cooled to room temperature, add NaCl 8.0g, needle-use activated carbon 2.0g, stirring at room absorption 30min, filter carbon removal, add fresh water for injection, serve as a contrast 0.22 μ m filtering with microporous membrane down with aseptic filter plate in 100 grades of sterile workshop to total amount 1000ml, be sub-packed in the 10ml ampoule fusion sealing, quality inspection, lettering, packing.
Prepare the employed ginkgo lactone material of bilobalide injector of the present invention, can extract by known extracting method, perhaps buy by commercially available, still, this raw material need meet the finger-print standard of measuring as follows.
The determining fingerprint pattern of ginkgolides:
1. need testing solution preparation
Precision takes by weighing in 105 ℃ of ginkgolides sample 30.0mg that are dried to constant weight and puts in the 10.0mL measuring bottle, and with 50% acetone soln dissolving and be diluted to scale, mixing filters through 0.45 μ m miillpore filter, promptly.
2. object of reference formulations prepared from solutions
An amount of with the ginkolide B reference substance, add 50% acetone soln and make the solution that every 1mL contains 1mg, promptly.
3. assay method is measured according to high performance liquid chromatography (2000 editions one appendix VI D of Chinese Pharmacopoeia).
4. chromatographic condition and system suitability test
With the octadecyl silane is filling agent (Hypersil C
185 μ m250 * 4.6mm); 30 ℃ of column temperatures; Mobile phase A be water-methanol-tetrahydrofuran (redistillation) (85: 10: 5, V/V), Mobile phase B be water-methanol-tetrahydrofuran (redistillation) (35: 60: 5, V/V); Gradient 0～5min, 5%B; 5～55min, 5%B～55%B; 55～56min, 55%～100%B, 100%B keeps 10min; Flow velocity 1.0mL/min; Detect wavelength 220nm, theoretical cam curve should be not less than 7000 in lactone B.
5. assay method is drawn need testing solution 20 μ L injection liquid chromatograph, promptly.
6. finger-print and technical parameter
Use high effective liquid chromatography for measuring, be 60 minutes writing time.The finger-print of ginkgolides is seen Fig. 1, and the finger-print that write down 2 hours is seen Fig. 2.Blank (Fig. 3) is noiseless on inspection.
In this product finger-print, 4 total fingerprint peakses are arranged.Retention time in ginkolide B is 1, all the other total fingerprint peakses are demarcated with relative retention time, in the finger-print, are 1 with the peak area of ginkolide B, calculate the area ratio of each total fingerprint peaks, relative retention time and relative peak area technical parameter see Table 1.
Table 1 ginkgolides fingerprint pattern technology parameter
In the middle of above-mentioned 4 total peaks, total peak 1 is a ginkalide C, and total peak 2 is ginkalide As, and total peak 3 is ginkolide Bs, and total peak 4 is bilobalide Ks.
Non-total peak area: the measurement result of test sample, non-total peak area must not be greater than 5%.
Ginkgolides in the middle of the bilobalide injector of the present invention comprises ginkalide A, B, C, K, wherein the total content of ginkalide A, B, K is not less than 90%, optimum content is 96.05%, wherein the content of ginkolide B is 50%-65%, the content of ginkalide A is 30-40%, and the content of bilobalide K is 0.5-5%.Calculate by every ml injection product, every milliliter of injection of the present invention contains total ginkgolides 2-10 milligram, preferred 4 milligrams.The ratio of each monomer is ginkalide A 35.59%, ginkolide B 58.39%, bilobalide K 2.07% in the middle of described total ginkgolides.
Therefore, the invention provides the pharmaceutical composition that contains above-mentioned three kinds of ginkgolides, said composition contains:
Ginkalide A 30-40%, ginkolide B 50%-65%, bilobalide K 0.5-5%.
The best proportioning of above-mentioned each component is: 35.59% ginkalide A, 58.39% ginkolide B, 2.07% bilobalide K.
For the ginkgo lactone material purity that makes preparation bilobalide injector of the present invention reaches more than 90.0%, commercially available or homemade ginkgo lactone material (thin layer is differentiated should check out ginkalide A, B, C, K) is dissolved in the ethanol of warm (35-45 degree centigrade), filter, 50 degrees centigrade of recovered under reduced pressure part ethanol, placement, cooling, crystallization, filter, the raffinate otherwise processed, getting the crystal of separating out detects, do not reach more than 90% as purity, repeat purification step as stated above, until reaching content requirement.
After ginkgo lactone material reached purity requirement, sample thief 100g added cold ethanol or acetone 100ml, stir, leave standstill suction filtration, press fingerprint atlas detection method and detect, do not reach the finger-print requirement, repeat above-mentioned treatment step and reach requirement until sample as ginkgo lactone material.That is ginkalide A, B, K and other components in proportions scopes reach the finger-print requirement.
The product of bilobalide injector of the present invention after testing, should meet the requirement of product fingerprint collection of illustrative plates standard.
The determining fingerprint pattern standard of bilobalide injection product of the present invention is as follows:
1. test sample preparation
Precision is measured sample solution 5.0mL and is put in the 10.0ml volumetric flask, adds 6mol/L hydrochloric acid solution 2mL, and the mixing room temperature is placed 3.5hr, centrifugal (3000 rev/mins) 10min, abandoning supernatant, precipitation is with 50% acetone solution, mixing, through 0.45 μ m filtering with microporous membrane promptly.
2. object of reference formulations prepared from solutions
An amount of with the ginkolide B reference substance, add 50% acetone soln and make the solution that every 1mL contains 1mg, promptly.
3. assay method and determining instrument
Measure according to high performance liquid chromatography (2000 editions one appendix VI D of Chinese Pharmacopoeia).
Instrument: Agilent 1100Series (G1312A Pump, G1313A ALS, G1316AColcom, G1315A DAD);
Chromatographic condition and system suitability test: with the octadecyl silane is filling agent, and Hypersil C is used in suggestion
185 μ, 4.6 * 250mm chromatographic column; 30 ℃ of column temperatures; Mobile phase A be water-methanol-tetrahydrofuran (redistillation) (85: 10: 5, V/V), Mobile phase B be water-methanol-tetrahydrofuran (redistillation) (35: 60: 5, V/V), 0～5min, 5%B; 5～55min, 5%B～55%B; 55～56min, 55%～100%B, 100%B keeps 10min; Flow velocity 1.0mL/min; Detect wavelength 220nm, theoretical cam curve should be not less than 7000 in lactone B.
Assay method is drawn each 20 μ L of need testing solution and is injected the liquid chromatograph analysis, promptly.
4. finger-print and technical parameter
(1) finger-print
Adopt high effective liquid chromatography for measuring, be 60 minutes writing time.The finger-print of bilobalide injection is seen Fig. 4, and the finger-print that write down 2 hours is seen Fig. 5.Blank (Fig. 6) is noiseless on inspection.
(2) demarcation of total fingerprint peaks
In the finger-print, 5 total fingerprint peakses should be arranged.Retention time in ginkolide B is 1, and all the other total fingerprint peakses are demarcated with relative retention time.
The chromatographic peak that all occurs in 10 batches of parenteral solutions is self object of reference as the total peak of parenteral solution with ginkolide B respectively, calculates the relative retention time (table 2) at each total peak, with this foundation of demarcating as total fingerprint peaks.The collection of illustrative plates of each batch test sample is seen accompanying drawing (4), figure (5).
Table 2 bilobalide injection relative retention time
The relative retention time at 5 total peaks is in the finger-print:
0.58(1)、0.87
(2)、1(3)
(S)、1.72(4)、1.75
(5)；
In the middle of these 5 total peaks, the 1st, ginkalide A, the 2nd, ginkalide A, the 3rd, ginkolide B, the 5th, bilobalide K is the ginkalide A conversion product and relative retention time is 1.72 peak.
(3) ratio of total fingerprint peaks area
In the finger-print, be 1 with the peak area of ginkolide B, the area ratio of calculating each total peak should meet the regulation of bilobalide injection fingerprint pattern technology parameter (seeing Table 3).
Table 3 bilobalide injection fingerprint pattern technology parameter
The peak area ratio at 5 total peaks is in the finger-print:
0.03(1)、0.53±25％
(2)、1(3)
(S)、0.25(4)、4.75±20％
(5)；
(4) non-total peak area
The measurement result of test sample, non-total peak area must not be greater than 5%.
The contained bilobalide K of bilobalide injector of the present invention is the newfound a kind of compound of inventor, and this compound separate case is applied for a patent, and its extraction separation method is as follows:
Get ginkgolides crude product 3g and put in the apparatus,Soxhlet's, add ethyl acetate (or acetone) 2500ml and refluxed 24 hours, reclaim ethyl acetate to the medicinal extract shape, mix sample with zeyssatite, oven dry, porphyrize, use sherwood oil: ethyl acetate/wet method was loaded on low pressure silicagel column (pressure 0.2-0.3k/cm in 9: 1
2), with sherwood oil: the ethyl acetate gradient increases progressively wash-out, when sherwood oil: during ethyl acetate/6: 4,97～121 flow points, through TCL check (toluene: ethyl acetate: acetone: methyl alcohol/5: 2.5: 2.5: 0.3,4%NaAc silica gel H plate) occur the ginkgolides spot (with the ginkgolides reference substance relatively), it merged concentrate, place the appearance precipitation, mother liquor is continued to employ.To precipitate with acetone solution,, can get bilobalide K with preparation type high performance liquid chromatogram purifying.122～127 flow points are identical through thin layer inspection (condition is the same) spot, with its merging, concentrate, and place, and separate out white needle, filter white needle, TCL checks and ginkalide A reference substance R
fValue (0.64) unanimity, ethyl alcohol recrystallization gets the pure product of ginkalide A (GA).Mother liquid obtained and the above-mentioned mother liquor of continuing to employ is merged, concentrate a small amount of silica gel mixed sample in back, oven dry, porphyrize is with the chloroform wet method silicagel column (100-140 order silica gel) of packing into, chloroform: third paulownia/9: 1 wash-outs, get the 5-10 flow point, TCL checks that (condition is the same) back spot and R f value is identical, merges, be concentrated into small size, place chrysanthemum shape crystallization (R
fValue 0.62) through ethanol repeatedly recrystallization get colourless prismatic crystallization, be reference substance with ginkolide B, check identically with the Rf value of ginkolide B through TCL, tentatively be defined as ginkolide B (GB).Column chromatography continues to be eluted to the 15-22 flow point, and TCL checks that spot is identical, merges, and concentrates, place white, needle-shaped crystals, check R with the ginkalide C reference substance through TLC
fBe worth identically, tentatively be defined as ginkalide C (GC).
The conclusive evidence of bilobalide K: white needle (MeoH), mp＞300 ℃ (decomposition) is soluble in alcohol, acetone, is slightly soluble in water.Show slightly faint yellow (place in the air and fade to white).
IRV
kBr max(cm
-1)：
3500，3385，3130，2960，2915，2857，1783，1757，1700，1600，1465，1437，1400，1376，1368，1356，1340，1305，1280，1260，1243，1231，1215，1183，1174，1150，1124，1110，1087，1063，1037，1021，957，750；
ECI-MS(m/z)：405[M-H]
-。
This compound carries out full ownership by physico-chemical analysis and spectroscopic technique in modern age (C-H is relevant, H-H is relevant, HMQC and HMBC spectrum) to the hydrocarbon signal of compound, and the result is as follows.
The hydrocarbon signal ownership and the proton signal of being correlated with (DMSO-d6) thereof of bilobalide K
Annotate:
13C-NMR,
1H-NMR, HMBC refer to carbon-13 nmr spectra, proton nmr spectra, the long-range relevant spectrum of two-dimentional C-H respectively.
Determine that according to above-mentioned wave spectrum feature its chemical structural formula is as follows:
The chemical name of bilobalide K of the present invention is: 1, and 10-dihydroxy-3,14-two dehydrogenation ginkgolides (1,10-Dihydroxy-3,14-didehydroginkgolide).Molecular formula C
20H
22O
9, molecular weight is 406.
Bilobalide injector of the present invention has good pharmacologically active, and the result is as follows for its pharmacological experiment study:
1, the general pharmacology of ginkgolides is learned research
(1), bilobalide injection 25,50,100mg/kg tail vein injection all do not have obvious influence to the mouse behavior and the coordinated movement of various economic factors, yellow Jackets to sub-threshold dose also do not have synergy, show that three dosage of this medicine are to mouse spirit nervous system non-evident effect.
(2), bilobalide injection 5,10, the quiet notes administration of 20mg/kg all do not have obvious influence to blood pressure, heart rate, electrocardio, respiratory rate and the amplitude of anesthetized dog, shows that three dosage of this medicine are to the anesthetized dog cardiovascular system respiratory system non-evident effect of unifying.
2, the pharmacodynamic study of ginkgolides
(1), bilobalide injection 7.5,15.0,30.0mg/kg iV can make the cerebral apoplexy scoring of MCAO rat reduce, the MCAO infarction size dwindles, brain water content reduces (P＜0.01), its action intensity and Ginaton parenteral solution comparison no significant difference.
(2), bilobalide injection 7.5,15.0,30.0mg/kg iV can make the MDA in the brain tissue of focal cerebral ischemia rat reperfusion injury, the LA equal size reduces (P＜0.01), shows that brain tissue hypoxic-ischemic and peroxidating degree are subjected to obvious inhibition; SOD and GSH content increase (P＜0.01) simultaneously, have reflected that medicine has raising to antioxidant ability of organism and the ability of removing free radical.
(3), bilobalide injection 7.5,15.0,30.0mg/kg iV can obviously protect the brain tissue structure of focal cerebral ischemia rat reperfusion injury; karyopycnosis, the karyolysis degree of cerebral cortex cones and brain essence neurocyte obviously alleviate than ischemic control group, and softening kitchen range reduces.
(4), bilobalide injection 7.5,15.0,30.0mg/kg iV compare with model group that the EEG that can make diffusivity global brain ischemia rat recovers normal time and (P＜0.01) is obviously shortened in righting reflex release time, make the Evans blue permeability significantly reduce (P＜0.01), its effect does not relatively have statistical significant difference with the Ginaton parenteral solution.
(5), bilobalide injection can obviously increase the survival number of acute imperfection cerebral ischemia mouse.Press the ED that the Bliss method is calculated bilobalide injection iV
50Be 21.3 (17.6-25.6) mg/kg; The ED of ginkgolides ig
50Be 29.2 (16.5-51.7) mg/kg; The ED of Ginkgo Leaf Agent iV
50Count 12.2 (6.3-23.3) mg/kg, ED with ginkgo biloba extract
50Value compares indifference through between t check group.
(6), bilobalide injection iV10min promptly begins onset, about peak time 20min, the duration can reach more than the 90min; And this medicine ig onset time 20-30min, about peak time 45min, the duration can reach more than the 120min.The effect of same dosage group iV is better than ig.
(7) but, bilobalide injection 12.0,24.0, the time-to-live (P＜0.01) of 48.0mg/kg iV significant prolongation mouse under anaerobic condition.
(8), bilobalide injection 2.5,5.0,10.0mg/kg iV all do not have obvious influence (P＞0.05) to anesthetized dog CBF, CVR, SBP, DBP, MBP and HR, shows that three dosage of this medicine do not influence cerebral blood flow (CBF), cerebral vascular resistance, blood pressure and the heart rate of anesthetized dog.
(9), bilobalide injection 0.99,1.96,3.80 μ g/ml induce the rabbit extracorporeal platelet aggregation that obvious inhibiting effect (P＜0.01) is all arranged to PAF, and obvious depolymerisation (P＜0.01) are arranged.To ADP induced platelet congregation weak (P＜0.05 or P＜0.01), there is not obvious depolymerisation (P＞0.05).Platelet aggregation all has obvious inhibiting effect (P＜0.01) in the rabbit body that this medicine iV0.75,1.50,3.0mg/kg induce PAF, and middle and high dosage group also has obvious depolymerisation (P＜0.01).The rabbit platelet number there is not obvious effect (P＞0.05).
(10), bilobalide injection iV1.50,3.0mg/kg can obviously reduce rabbit erythrocyte hematocrit (P＜0.01) and whole blood viscosity (ratio) especially to whole blood viscosity (ratio) effect more obvious (P＜0.01) of high shearing.
(11), it is moving that bilobalide injection iv 0.75,1.50,3.0mg/kg can obviously suppress rabbit--the thrombosis (P＜0.01) of vein bypass.
(12), bilobalide injection iv 3,6,12mg/kg are moving to rat---and vein bypass thrombus has obvious thrombolytic effect (P＜0.01).
(13), bilobalide injection iv6,12,24mg/kg can obviously prolong clotting time of mice (P＜0.01).
(14), obvious prolong rats clotting time during 10min-20min behind the bilobalide injection iv6mg/kg, during the peak about 12min, can make rat cruor time extending about 32%, 45min is effective behind the ig50mg/kg, continue 120mm, during the peak about 69min, rat cruor time extending about 34%.
(15), just can obviously suppress PAF behind the bilobalide injection iv 1.5mg/kg medicine immediately induces and exempts from the body platelet aggregation and obvious depolymerisation (P＜0.01) is arranged, effect continues 30min, be 5min during its peak, the platelet aggregation inhibiting rate can reach about 80%, and depolymerization in 1 minute is about 81%.30min can obviously suppress PAF and induces in the rabbit body platelet aggregation and obvious depolymerisation (P＜0.01) is arranged behind the ginkgolides ig25mg/kg medicine, continue 60min, be about 42min during its peak, the maximum gathering of blood platelet inhibiting rate is about 38%, and the depolymerization rate was about 32% in 1 minute.
(16), bilobalide injection iV prolongs the IC of clotting time of mice
50Be 6.42mg/kg, ginkgolides ig prolongs the IC of clotting time of mice
50Be 29.41mg/kg.Bilobalide injection iv is to the IC of platelet aggregation in tame rabbit platelet and the PAF inductor
50Be 2.32mg/kg, ginkgolides ig is to the IC of platelet aggregation in tame rabbit platelet and the PAF inductor
50Be 87.72mg/kg.
Above-mentioned experiment shows that bilobalide injection of the present invention is safe and effective, can be used for the prevention and the clinical treatment of ishemic stroke.
The advantage of bilobalide injection of the present invention is that constant product quality is controlled, according to the finger-print of injection product, can control the composition of product, particularly increased this controlling index of bilobalide K, cooperate indexs such as other ginkalide As, B, C, make that stablizing of product is more controlled.
Bilobalide injector of the present invention has stability and better curative effect preferably, also because the preparation process of bilobalide injector of the present invention, the selection of cosolvent has significant effects to the preparation and the stability of preparation, in the research process of the present invention, the investigation of system (1) propylene glycol, PEG
400, ethanol, (2) propylene glycol, PVP, ethanol, (3) propylene glycol, sorbierite, ethanol, (4) meglumine, (5) meglumine, glucose, (6) urea, (7) propylene glycol, Tween-80, ethanol, (8) propylene glycol, ethanol, (9) NaOH, (10) Pluronic F-68, (11) Pluronic F-68, propylene glycol, (12) Fabaceous Lecithin, Pluronic F-68, propylene glycol, glycerine, PEG
400, ethanol, (13) HP-CD, (14) propylene glycol, PEG
400, phosphate buffer, (15) propylene glycol, PEG
400, multiple cosolvent such as phosphate solution.By a large amount of tests, find that above-mentioned pharmaceutic adjuvant all help solubilization, wherein with the meglumine best results.This cosolvent all has good hydrotropy effect to the combination (for example: ginkalide A, B, ginkalide A, B, C, ginkolide B, K, ginkalide A, B, C, K, ginkolide B, C, K, ginkalide A, C etc.) of other components of ginkgolides.
Description of drawings
Fig. 1 ginkgolides finger-print
2 hours finger-prints of Fig. 2 ginkgolides record
Fig. 3 ginkgolides finger-print blank
Fig. 4 is the bilobalide injection finger-print
2 hours finger-prints of Fig. 5 bilobalide injection record
Fig. 6 bilobalide injection finger-print blank
Embodiment
Prescription:
Ginkgolides 5.0g
Meglumine 5.0g
NaCl 8.0g
10% citric acid solution is an amount of
Method for making: get meglumine and add fresh water for injection 1000ml dissolving, in 120 ℃ of autoclaving 30min, take out the back and be heated to 80 ℃ in gradating material chambers 10,000, add porphyrize and cross the ginkgolides (ginkgolides meets quality standard of the present invention) of 80 mesh sieves, be heated to dissolving, transfer pH to 8.0 with 10% aqueous citric acid solution after being cooled to room temperature, add NaCl 8.0g, needle-use activated carbon 2.0g, stirring at room absorption 30min, filter carbon removal, add fresh water for injection, serve as a contrast 0.22 μ m filtering with microporous membrane down with aseptic filter plate in 100 grades of sterile workshop to total amount 1000ml, be sub-packed in the 10ml ampoule fusion sealing, quality inspection, lettering, packing.
This product is the sterile water solution of ginkgolides.Every ml bilobalide-containing A, B, K total amount must not be lower than 4.0mg.
Claims (1)
1. fingerprint atlas detection method that contains the ginkgo lactone material of ginkalide A, B, C, K is characterized in that this method is:
Need testing solution preparation: precision takes by weighing in 105 ℃ of ginkgolides sample 30.0mg that are dried to constant weight and puts in the 10.0mL measuring bottle, and with the dissolving of 50% acetone soln and be diluted to scale, mixing filters through 0.45 μ m miillpore filter, promptly; The object of reference formulations prepared from solutions: an amount of with the ginkolide B reference substance, add 50% acetone soln and make the solution that every 1mL contains 1mg, promptly;
Chromatographic condition and system suitability test: with the octadecyl silane is filling agent; 30 ℃ of column temperatures; Mobile phase A is water-methanol-tetrahydrofuran 85: 10: 5, and Mobile phase B is water-methanol-tetrahydrofuran 35: 60: 5; Gradient 0～5min, 5%B; 5～55min, 5%B～55%B; 55～56min, 55%～100%B, 100%B keeps 10min; Flow velocity 1.0mL/min; Detect wavelength 220nm, theoretical cam curve should be not less than 7000 in lactone B;
Assay method: draw need testing solution 20 μ L and inject liquid chromatograph, promptly;
Ginkgolides adopts its finger-print of high effective liquid chromatography for measuring, be 60 minutes writing time, get 4 total peaks, retention time 1 with ginkolide B is self object of reference, the relative retention time at these 4 total peaks is 0.56,0.87,1,1.71, peak area with ginkolide B is 1, and the peak area ratio at these 4 total peaks is 0.02,0.56 ± 20%, 1,1.0 ± 20%;
In the middle of 4 total peaks, total peak 1 is a ginkalide C, and total peak 2 is ginkalide As, and total peak 3 is ginkolide Bs, and total peak 4 is bilobalide Ks;
Non-total peak area: the measurement result of test sample, non-total peak area must not be greater than 5%.
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| CN100402024C (en) * | 2004-01-14 | 2008-07-16 | 海口龙南医药科技开发有限公司 | Gingko lactone freeze dried powder injection and its preparation method |
| CN1919848B (en) * | 2005-08-25 | 2010-12-15 | 江苏康缘药业股份有限公司 | bilobalide K and complex thereof, preparation method and use for the same |
| CN101936958B (en) * | 2009-07-01 | 2013-10-23 | 秦引林 | Method for detecting and analyzing methanesulfonic amine ginkgolide B by using high-performance liquid-evaporative light |
| CN102379886A (en) * | 2010-09-02 | 2012-03-21 | 昆明制药集团股份有限公司 | Scutellarin clinical preparation and preparation method thereof |
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| CN104914174B (en) * | 2014-03-16 | 2017-07-25 | 江苏康缘药业股份有限公司 | A kind of content assaying method of injection ginkgo diterpenoid-lactone |
| CN105486792A (en) * | 2015-11-23 | 2016-04-13 | 江苏康缘药业股份有限公司 | Detection method for macromolecular compounds in diterpene ginkgolides meglumine injection and preparation raw materials thereof |
| CN108096240B (en) * | 2017-11-24 | 2020-05-29 | 江苏康缘药业股份有限公司 | Traditional Chinese medicine composition for treating pulmonary fibrosis |
| CN107929281B (en) * | 2017-11-24 | 2020-06-16 | 江苏康缘药业股份有限公司 | Medical application of ginkgolide composition |
| CN108096243B (en) * | 2017-11-24 | 2020-05-29 | 江苏康缘药业股份有限公司 | Medical application of ginkgolide composition |
| CN107929282B (en) * | 2017-11-24 | 2020-06-16 | 江苏康缘药业股份有限公司 | Medical application of ginkgolide composition |
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| CN108096242B (en) * | 2017-11-24 | 2020-05-29 | 江苏康缘药业股份有限公司 | Traditional Chinese medicine composition for treating chronic obstructive pulmonary disease |
| CN108096241B (en) * | 2017-11-24 | 2020-06-16 | 江苏康缘药业股份有限公司 | Medical application of ginkgolide composition |
| CN107915742B (en) * | 2017-12-29 | 2019-02-22 | 江苏康缘药业股份有限公司 | A kind of extraction separation method of ginkgo diterpenoid-lactone |
| CN107929283B (en) * | 2017-12-29 | 2019-05-07 | 江苏康缘药业股份有限公司 | Ginkgo diterpenoid-lactone composition |
| CN107898782B (en) * | 2017-12-29 | 2019-03-26 | 江苏康缘药业股份有限公司 | A kind of ginkgo diterpenoid-lactone composition |
| CN108969517B (en) * | 2018-09-04 | 2021-05-04 | 江苏康缘药业股份有限公司 | Application of ginkgolide composition in preparation of medicine for treating renal tissue fibrosis |
| CN109045024A (en) * | 2018-09-05 | 2018-12-21 | 江苏康缘药业股份有限公司 | A kind of Chinese medicine composition for treating pancreatic fibrosis |
| CN110051664A (en) * | 2019-04-16 | 2019-07-26 | 江苏康缘药业股份有限公司 | A kind of application of ginkgo lactone composition in drug of the preparation for acute coronary syndrome |
| CN112858550B (en) * | 2019-11-28 | 2022-05-06 | 中国科学院大连化学物理研究所 | A method for the analysis of drug similarity between different manufacturers and/or different batches of Ginkgo biloba leaves from the same manufacturer |
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| CN1279903C (en) | 2006-10-18 |
| CN1869683A (en) | 2006-11-29 |
| CN1424031A (en) | 2003-06-18 |
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