CN1276752C - Bilobalide soft capsule and its preparation method - Google Patents
Bilobalide soft capsule and its preparation method Download PDFInfo
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- CN1276752C CN1276752C CN02128964.6A CN02128964A CN1276752C CN 1276752 C CN1276752 C CN 1276752C CN 02128964 A CN02128964 A CN 02128964A CN 1276752 C CN1276752 C CN 1276752C
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- bilobalide
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- ginkalide
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Abstract
The present invention discloses a ginkgo lactone soft capsule which contains 10 % to 40% of total ginkgo lactone, wherein the total ginkgo lactone contains 3 to 16% of ginkgo lactone A, 5 to 26% of ginkgo lactone B and 0.01 to 4% of ginkgo lactone K. Besides, the soft capsule also contains excipient glycerin, PEG 6000 and PEG 400.
Description
Technical field
The invention relates to the preparation of bilobalide, the soft capsule that particularly contains bilobalide, said preparation is that active ingredient is prepared from the extract bilobalide of Chinese medicine Folium Ginkgo, is with ginkalide A specifically, B and K are the medicine that active component is made, and belong to drug world.
Background technology
Bilobalide is to extract the active substance that obtains in the middle of the Chinese herbal medicine Folium Ginkgo, 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 bilobalide has had detailed bibliographical information, for example, people such as Li Xingang have introduced the laboratory extracting method of bilobalide (referring to Li Xingang etc., the laboratory Study on Extraction Method of bilobalide in the Folium Ginkgo, 1998 the 1st phases of Chinese Journal of Pharmaceuticals), Chinese patent literature CN1195665A has introduced the extracting method of bilobalide and has contained the preparation of bilobalide, this method is that Folium Ginkgo is extracted with water boil, with adsorbent extraction filtrate is adsorbed, reuse ethanol desorption, reclaim ethanol, with the crystallization dissolving of separating out, recrystallization, drying makes bilobalide.Chinese patent literature CN1313287A discloses a kind of production technology of bilobalide.The method of separating ginkgolide monomer in the middle of the total extract of bilobalide, a lot of relevant bibliographical informations are also arranged, for example, people such as You Song have introduced the separation of bilobalide in the Folium Ginkgo and structure determination method (referring to You Song etc., the separation of bilobalide and structure determination in the Folium Ginkgo, 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 Folium Ginkgo or Folium Ginkgo extractum.Bilobalide can be prepared into it different clinical medicine dosage forms as an effective active substance.The method for preparing injection with bilobalide is open in the middle of Chinese patent literature CN1315175A.Use Folium Ginkgo injections such as Liu Jie treatments acute cerebral infarction obtained certain curative effect [referring to Liu Jie etc., YINXINGYE ZHUSHEYE to acute cerebral infarction after the influence of extremity motor function and TXB_2,6-Keto-PGF_ (1a)].About the pharmacological action of bilobalide, comparatively detailed bibliographical information (referring to Chen Weijun etc., the chemical constitution of bilobalide and Advance on Pharmacological Activities, 1998 the 9th phases of Chinese Pharmaceutical Journal) has been arranged.Although the research for bilobalide and preparation thereof in the middle of the prior art has had a lot of reports,, never stop for the research of bilobalide, particularly, bibliographical information is arranged constantly for the separation of ginkgolide monomer and the research of derivant thereof.The inventor is on the architecture basics of having found bilobalide K, combination by different ginkgolide monomers, become soft capsule according to specific prepared, make the product quality of bilobalide soft capsule be able to better controlled, suitability for industrialized production is achieved, and research by experiment, has selected ideal excipient, be prepared into soft capsule, finished the present invention.
Summary of the invention
The object of the invention provides a kind of soft capsule that contains bilobalide, and this preparation of soft capsule technology also is provided simultaneously.
Bilobalide soft capsule of the present invention is to be that active ingredient is prepared from highly purified bilobalide.
Institute's bilobalide-containing comprises ginkalide A, B, K in the middle of the bilobalide soft capsule of the present invention, wherein the total content of ginkalide A, B, K is not less than 90%, optimum content is 96.05%, wherein the content of ginkalide A is 30-40%, the content of ginkalide B is 50%-65%, and the content of bilobalide K is 0.5-5%.Preferred each monomeric ratio is ginkalide A 35.59%, ginkalide B 58.39%, bilobalide K 2.07%.
Therefore, bilobalide soft capsule of the present invention can be an active component with ginkalide A, B, K monomer according to aforementioned proportion, is mixed with compositions, adds excipient, is prepared into soft capsule.
In the middle of preparation of soft capsule process of the present invention, glycerol, PEG have been selected according to the physicochemical property of bilobalide
6000And PEG
400As excipient, be prepared into soft capsule.
With ginkalide A, B, K monomer is active component, is mixed with compositions, and one of method for preparing soft capsule is as described below.
Choose raw material according to following ratio, be mixed with active ingredient compositions:
Ginkalide A 30-40%
Ginkalide B 50-65%
Bilobalide K 0.5-5%
In the middle of above-mentioned composition, add excipient glycerol, PEG
6000And PEG
400, be prepared into soft capsule, in 100 gram combinations thereof raw material total amounts, pharmaceutical composition and adding excipient glycerol, PEG
6000And PEG
400Amount ratio be 100: 18: 6: 276.
Bilobalide soft capsule of the present invention also can contain ginkalide A, the monomeric total bilobalide of B, K by extracting or buying, and adds excipient and is prepared into soft capsule.Zhi Bei bilobalide soft capsule contains total bilobalide of 10-40% according to the method, the total bilobalide that preferably contains 20-30%, contain ginkalide A, B, K in the middle of contained total bilobalide, ginkalide A, B, the K total content in the middle of made soft capsule are 9-36%, wherein the content of ginkalide A is 3-16%, the content of ginkalide B is 5-26%, the content of bilobalide K is 0.01-4%, and the optimum content of ginkalide A, B, K is respectively 8.89%, 14.59%, 0.52%.
With total bilobalide is that one of activated feedstock preparation method of preparing bilobalide soft capsule of the present invention is as described below.
Choose raw material according to following ratio:
Bilobalide 100g
Glycerol 18.0g
PEG
6000 6.0g
PEG
400 276.0g
Get PEG
400276.0g put in the appropriate vessel, add PEG
60006.0g heating in water bath dissolves to PEG6000, stirs evenly, add glycerol 18.0g, add bilobalide 100.0g, grind to form even mastic with colloid mill, be transferred to the material storage barrel of encapsulating machine, be pressed into soft capsule, make 1000 of soft capsules with the mould of 0.3ml, the heavily about 0.4g of grain finalized the design 4 hours, with 95% ethanol flush away surface lubricant etc., in 20～30% relative humiditys, be dried to balance under 28 ℃ of conditions, take out, quality inspection, packing
Prepare the employed total ginkgo lactone material of bilobalide soft capsule of the present invention, can extract by known extracting method, perhaps buy by commercially available, still, this raw material need meet the finger printing standard of measuring as follows.
The determining fingerprint pattern of bilobalide:
1. need testing solution preparation
Precision takes by weighing in 105 ℃ of bilobalide 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 microporous filter membrane, promptly.
2. object of reference formulations prepared from solutions
An amount of with the ginkalide 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 appendix VID of Chinese Pharmacopoeia).
4. chromatographic condition and system suitability test
With the octadecyl silane is filler (Hypersil C
185 μ m 250 * 4.6mm): 30 ℃ of column temperatures: mobile phase A be water-methanol-oxolane (redistillation) (85: 10: 5, V/V), Mobile phase B be water-methanol-oxolane (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 chromatograph of liquid, promptly.
6. finger printing and technical parameter
Use high effective liquid chromatography for measuring, be 60 minutes writing time.The finger printing of bilobalide is seen Fig. 1, and the finger printing that write down 2 hours is seen Fig. 2.Blank (Fig. 3) is noiseless on inspection.
In this product finger printing, 4 total fingerprint peakses are arranged.Retention time in ginkalide B is 1, all the other total fingerprint peakses are demarcated with relative retention time, in the finger printing, are 1 with the peak area of ginkalide B, calculate the area ratio of each total fingerprint peaks, relative retention time and relative peak area technical parameter see Table 1.
Table 1 bilobalide fingerprint pattern technology parameter
| Total peak | Relative retention time | Relative peak area | Allowed band |
| 1 2 3 4 | 0.56 0.87 1 1.71 | 0.02 0.56 1 1.0 | ±20％ / ±20％ |
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 ginkalide B, 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%.
Bilobalide in the middle of the bilobalide soft capsule of the present invention comprises ginkalide A, B, C, K, and wherein the total content of ginkalide A, B, K is not less than 90%, and the amount of bilobalide soft capsule content institute bilobalide-containing is not less than 0.18g/g.
For the ginkgo lactone material purity that makes preparation bilobalide soft capsule of the present invention reaches more than 90.0%, with commercially available or homemade ginkgo lactone material, be dissolved in the ethanol of warm (35-45 degree centigrade), filter, 50 degrees centigrade of reclaim under reduced pressure part ethanol, placement, cooling, crystallize filter the residual liquid 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 sucking filtration, press fingerprint atlas detection method and detect, do not reach the finger printing 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 printing requirement.
The contained bilobalide K of bilobalide soft capsule of the present invention is the newfound a kind of chemical compound of inventor, and this chemical compound separate case is applied for a patent, and its extraction separation method is as follows:
Get bilobalide 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 extractum shape, mix sample with kieselguhr, oven dry, porphyrize, use petroleum ether: ethyl acetate/wet method was loaded on low pressure silicagel column (pressure 0.2-0.3k/cm in 9: 1
2), with petroleum ether: the ethyl acetate gradient increases progressively eluting, when petroleum ether: during ethyl acetate/6: 4,97～121 flow points, through TCL check (toluene: ethyl acetate: acetone: methanol/5: 2.5: 2.5: 0.3,4%NaAc silica gel H plate) occur the bilobalide speckle (with the bilobalide reference substance relatively), it merged concentrate, place the appearance precipitation, mother solution is continued to employ.To precipitate with acetone solution,, can get bilobalide K with preparation type high performance liquid chromatogram purification.122～127 flow points are identical through thin layer inspection (condition is the same) speckle, with its merging, concentrate, place, separate out white needle, filter white needle, TCL checks consistent with ginkalide A reference substance Rf value (0.64), and ethyl alcohol recrystallization gets the pure product of ginkalide A (GA).Mother liquid obtained and the above-mentioned mother solution of continuing to employ is merged, concentrates a small amount of silica gel mixed sample in back, oven dry, porphyrize, with the chloroform wet method silicagel column (100-140 order silica gel) of packing into, chloroform: third paulownia/9: 1 eluting, the 5-10 flow point, speckle R after the TCL inspection (condition is the same)
fBe worth identically, merge, be concentrated into small size, place Flos Chrysanthemi shape crystallization (R
fValue 0.62) through ethanol repeatedly recrystallization get colourless prismatic crystallization, be reference substance with ginkalide B, check R with ginkalide B through TCL
fBe worth identically, tentatively be defined as ginkalide B (GB).Column chromatography continues to be eluted to the 15-22 flow point, and TCL checks that speckle 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 chemical 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 chemical compound, and determines that its chemical structural formula is as follows:
The chemical name of the said bilobalide K of the present invention is: 1, and 10-dihydroxy-3,14-two dehydrogenation bilobalides (1,10-Dihydroxy-3,14-didehydroginkgolide).Molecular formula C
20H
22O
9, molecular weight is 406.
Bilobalide soft capsule of the present invention has good pharmacologically active, and its pharmacological experiment study is the result show:
(1), bilobalide soft capsule can make the MDA in the cerebral tissue of focal cerebral ischemia rat reperfusion injury, the LA equal size reduces (P＜0.01), shows that cerebral 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.
(2), bilobalide soft capsule can obviously protect the cerebral tissue structure of focal cerebral ischemia rat reperfusion injury, karyopycnosis, the karyolysis degree of cerebral cortex pyramidal cell and brain essence neurocyte obviously alleviate than ischemic control group, softening kitchen range reduces.
(3), bilobalide soft capsule can make the EEG of diffusivity global brain ischemia rat recover normal time and recovery time is obviously shortened (P＜0.01) in righting reflex, makes the azovan blue permeability significantly reduce (P＜0.01).
(4), bilobalide soft capsule can obviously increase the survival number of acute imperfection cerebral ischemia mice.
(5) but, the time-to-live (P＜0.01) of bilobalide soft capsule significant prolongation mice under anaerobic condition.
(6), bilobalide soft capsule is induced the rabbit extracorporeal platelet aggregation that obvious inhibitory action (P＜0.01) is all arranged to PAF, and obvious depolymerisation (P＜0.01) is arranged.Platelet aggregation in the inductive rabbit body of PAF is all had obvious inhibitory action (P＜0.01), 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).
(7), bilobalide soft capsule 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.
(8), bilobalide soft capsule can obviously prolong clotting time of mice (P＜0.01).
Above-mentioned experiment shows that bilobalide soft capsule of the present invention can be used for the prevention and the clinical treatment of cerebral infarction.
Description of drawings
Fig. 1 bilobalide finger printing
2 hours finger printing of Fig. 2 bilobalide record
Fig. 3 bilobalide finger printing blank
The specific embodiment
Embodiment 1
Choose raw material according to following ratio:
Bilobalide 100g
Glycerol 18.0g
PEG
6000 6.0g
PEG
400 276.0g
Get PEG
400276.0g put in the appropriate vessel, add PEG
60006.0g heating in water bath dissolves to PEG6000, stirs evenly, add glycerol 18.0g, add bilobalide 100.0g, grind to form even mastic with colloid mill, be transferred to the material storage barrel of encapsulating machine, be pressed into soft capsule, make 1000 of soft capsules with the mould of 0.3ml, the heavily about 0.4g of grain finalized the design 4 hours, with 95% ethanol flush away surface lubricant etc., in 20～30% relative humiditys, be dried to balance under 28 ℃ of conditions, take out, quality inspection, packing.
Embodiment 2
Choose raw material according to following ratio:
Ginkalide A 35.59g
Ginkalide B 58.39g
Bilobalide K 2.07g
Glycerol 18.0g
PEG
6000 6.0g
PEG
400 276.0g
Get PEG
400276.0g put in the appropriate vessel, add PEG
60006.0g heating in water bath dissolves to PEG6000, stirs evenly, add glycerol 18.0g, adding ginkalide A, B, K amount to 96.05g, grind to form even mastic with colloid mill, be transferred to the material storage barrel of encapsulating machine, be pressed into soft capsule, make 1000 of soft capsules with the mould of 0.3ml, finalized the design 4 hours, with 95% ethanol flush away surface lubricant etc., in 20～30% relative humiditys, be dried to balance under 28 ℃ of conditions, take out quality inspection, packing.
Claims (5)
1, a kind of bilobalide soft capsule contains total bilobalide of 10-40%, it is characterized in that containing ginkalide A, B, K in total bilobalide that this soft capsule contains, and ginkalide A, B, the K total content in the middle of made soft capsule are 9-36%.
2, bilobalide soft capsule according to claim 1 is characterized in that this soft capsule bilobalide-containing A 3-16%, ginkalide B 5-26%, bilobalide K 0.01-4%.
3, bilobalide soft capsule according to claim 1 is characterized in that this soft capsule bilobalide-containing A 8.89%, ginkalide B 14.59%, bilobalide K 0.52%.
4,, it is characterized in that this bilobalide soft capsule prepares with following method according to claim 1,2 or 3 described bilobalide soft capsules:
Choose raw material according to following ratio
Bilobalide 100g
Glycerol 18.0g
PEG
6000 6.0g
PEG
400 276.0g
Get PEG
400276.0g put in the appropriate vessel, add PEG
60006.0g heating in water bath dissolves to PEG6000, stirs evenly, add glycerol 18.0g, add bilobalide 100.0g, grind to form even mastic with colloid mill, be transferred to the material storage barrel of encapsulating machine, mould with 0.3ml is pressed into soft capsule, makes 1000 of soft capsules, typing, the flush away surface lubricant, in 20～30% relative humiditys, dry under 28 ℃ of conditions, promptly.
5, according to the bilobalide soft capsule of claim 4, it is characterized in that the total bilobalide of raw material for preparing this bilobalide soft capsule adopts its finger printing of high effective liquid chromatography for measuring, be 60 minutes writing time, get 4 total peaks, retention time 1 with ginkalide 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 ginkalide B is 1, and the peak area ratio at these 4 total peaks is 0.02,0.56 ± 20%, 1,1.0 ± 20%.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN02128964.6A CN1276752C (en) | 2002-08-23 | 2002-08-23 | Bilobalide soft capsule and its preparation method |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN02128964.6A CN1276752C (en) | 2002-08-23 | 2002-08-23 | Bilobalide soft capsule and its preparation method |
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| Publication Number | Publication Date |
|---|---|
| CN1476832A CN1476832A (en) | 2004-02-25 |
| CN1276752C true CN1276752C (en) | 2006-09-27 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN02128964.6A Expired - Lifetime CN1276752C (en) | 2002-08-23 | 2002-08-23 | Bilobalide soft capsule and its preparation method |
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Families Citing this family (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
| CN103877130A (en) * | 2013-09-17 | 2014-06-25 | 狄留庆 | Chinese medicinal composition for treating ischemic cerebral paralysis, application thereof to preparation of oral preparation and preparation of Chinese medicinal composition |
| 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 |
| 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 |
| 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 |
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2002
- 2002-08-23 CN CN02128964.6A patent/CN1276752C/en not_active Expired - Lifetime
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