CN113730347A - Ginkgo diterpene lactone injection and preparation method thereof - Google Patents

Ginkgo diterpene lactone injection and preparation method thereof Download PDF

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CN113730347A
CN113730347A CN202111157028.2A CN202111157028A CN113730347A CN 113730347 A CN113730347 A CN 113730347A CN 202111157028 A CN202111157028 A CN 202111157028A CN 113730347 A CN113730347 A CN 113730347A
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ginkgolide
injection
ethanol
propylene glycol
content
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王嘉锋
王爱明
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Shandong Renhe Pharmaceutical Co ltd
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Abstract

The invention relates to the technical field of medicine production, and particularly relates to a ginkgo diterpene lactone injection and a preparation method thereof. The formula of the raw materials is as follows: 1-5mg/ml of ginkgolide, 0.1-0.5ml/ml of propylene glycol, 0.1-0.5ml/ml of ethanol, 0.1-0.5ml/ml of polyethylene glycol and 0.1-1ml/ml of water for injection. The invention obtains the ginkgolide by extraction and ethanol recrystallization; the ginkgolide injection prepared by taking the ginkgolide as a raw material, adding a proper water-soluble solvent (such as ethanol, propylene glycol, polyethylene glycol and the like), filtering and sterilizing through a microporous filter membrane, filling and sealing, steam sterilizing and the like has good curative effects on the aspects of treating hemiplegia, inflammation, cardiovascular diseases and the like caused by thrombus, and has the advantages of simple preparation process, good reproducibility, suitability for large-scale production and low environmental protection pressure.

Description

Ginkgo diterpene lactone injection and preparation method thereof
Technical Field
The invention relates to the technical field of medicine production, and particularly relates to a ginkgo diterpene lactone injection and a preparation method thereof.
Background
Ginkgolides (ginkggolides) are important components with special structures and remarkable pharmacological activities only found in ginkgo leaves, are internationally recognized as the most important pharmacodynamic components in ginkgo leaves, and are listed as important medicaments for treating cardiovascular and cerebrovascular diseases.
Compared with ginkgetin, bilobalide has the following differences: 1. is a PAF antagonist; 2. has neuroprotective effect; 3. the molecular weight is small (400), and the blood brain barrier can pass through easily; 4. has obvious effect on cerebral vessels and cranial nerves, has pharmacological actions of dilating coronary vessels, improving cerebral circulation, inhibiting platelet aggregation, preventing atherosclerosis, antagonizing increase of vascular permeability, relieving bronchoconstriction and the like, has protection effect on the ischemic injury of heart and brain and the central nervous system, and can resist aging, shock, allergy, bacteria, inflammation, tumor and rejection in organ transplantation.
The ginkgolide comprises Ginkgolide A (GA), Ginkgolide B (GB), Ginkgolide C (GC), Ginkgolide J (GJ) and the like, and is clinically used for treating thrombus, inflammation, cardiovascular diseases and the like. Ginkgolide A, B, C was a platelet-activating factor (PAF) receptor antagonist, Ginkgolide B (GB) was the most active, Ginkgolide A (GA) was the second, Ginkgolide C (GC) was the second, and its anti-PAF activity was shown in Table 1.
TABLE 1 conditions of the anti-PAF Activity of ginkgolides
Compound (I) IC50(ug)
Ginkgolide A 1.36
Ginkgolide B 0.24
Ginkgolide C 5.59
Bilobalide J 27.44
Note: IC50 is the concentration that produced a 50% inhibitory effect.
The Ginkgolide B (GB) in the ginkgolide is the strongest platelet activating factor antagonist discovered in nature so far, has the effects of clearing oxygen free radicals, inhibiting lipid peroxidation and the like, and can be used for treating senile dementia, Alzheimer's disease, improving memory and the like. As can be seen from Table 1, the anti-PAF activity of ginkgolide C is only 1/4 for ginkgolide A and 1/23 for ginkgolide B; the anti-PAF activity of ginkgolide J is only 1/20 of GA and 1/114 of GB. The bilobalide J (GJ) has low content and low utilization value, and the bilobalide A (GA), the bilobalide B (GB) and the bilobalide C (GC) are insoluble in water, poor in absorption in vivo and low in bioavailability, so that the research focuses on the extraction, separation and refining of the bilobalide A (GA), the bilobalide B (GB) and the bilobalide C (GC), the scientific extraction method is selected, the appropriate extraction solvent and the recrystallization method are selected, the effective components are concentrated to the maximum extent, and the ineffective components are removed, so that the bilobalide with higher purity is obtained. The high-purity ginkgolide composition can be used as effective component to prepare injection for treating cardiovascular and cerebrovascular diseases.
Chinese patent document (CN101085780A) discloses a method for preparing ginkgolide, comprising extracting crude extract of folium Ginkgo with ethyl acetate, recovering ethyl acetate, and drying to obtain crude extract of ginkgolide; loading the crude bilobalide extract on acidic alumina column, collecting ethanol eluate, concentrating, crystallizing to obtain bilobalide crystal mixture, and recrystallizing to obtain high purity bilobalide A and bilobalide B.
Chinese patent document (CN102293790A) discloses a preparation method of ginkgolides, which comprises the steps of taking ginkgo leaves as a raw material, heating and refluxing the ginkgo leaves with ethanol, concentrating an extracting solution to recover ethanol, separating the ginkgo leaves by using a macroporous resin column, desorbing the ethanol, adding water to dilute a product, adsorbing and desorbing the product by using gel type hydrogen bond adsorption resin, collecting an effluent liquid and a desorption liquid, concentrating, drying, dissolving the product by using ethanol, decoloring, concentrating and drying to obtain the ginkgolides, wherein the total lactone content is 80-95%.
The two methods for preparing ginkgolides disclosed in the above two patent documents both adopt column chromatography separation and purification processes, and have complicated production processes and high production cost, which are not favorable for large-scale production.
Chinese patent document (CN102626383A) discloses a ginkgolide injection, which has the advantages of clear components and fixed proportion, the active ingredient is ginkgolide with high purity and clear components and fixed proportion, and the content of the effective part is more than 95%. The ginkgolide injection comprises the following components: bilobalide (in terms of BB, GA, GB, GC): 1-10mg/ml, glycerol: 0.2-0.5mg/ml, ethanol: 0.2-0.5mg/ml, water for injection: 0-0.5 mg/ml.
Chinese patent document (CN1594319A) provides an aqueous solution prepared by solubilizing ginkgolides by hydroxypropyl-beta-cyclodextrin, and the preparation method comprises the following steps: adding hydroxypropyl-beta-cyclodextrin into water for injection, stirring for dissolving, adding bilobalide, stirring and heating for dissolving, adding isotonic regulator and chelating agent, stirring for dissolving, adding active carbon for treating, coarse filtering, adding water for injection to desired volume, fine filtering, packaging, and sterilizing under hot pressure.
In the technical contents disclosed in the above two patent documents, the bulk drug contains bilobalide (BB), which is not a PAF receptor antagonist and has weak effects in scavenging oxygen free radicals and inhibiting lipid peroxidation.
Disclosure of Invention
The invention aims to provide a ginkgo diterpene lactone injection and a preparation method thereof, and aims to solve the technical problems.
In order to achieve the purpose, the technical scheme adopted by the invention is as follows:
a ginkgo diterpene lactone injection is characterized in that: the formula of the raw materials is as follows: 1-5mg/ml of ginkgolide, 0.1-0.5ml/ml of propylene glycol, 0.1-0.5ml/ml of ethanol, 0.1-0.5ml/ml of polyethylene glycol and 0.1-1ml/ml of water for injection.
Preferably, the ginkgo diterpene lactone injection is prepared from the following raw materials: 50mg of ginkgolide, 4ml of propylene glycol, 8ml of ethanol and 1ml of polyethylene glycol, and adding water for injection to 20 ml.
Preferably, the ginkgo diterpene lactone injection is prepared from the following raw materials: 75mg of ginkgolide, 4ml of propylene glycol, 8ml of ethanol and 1ml of polyethylene glycol, and adding water for injection to 20 ml.
Preferably, the content of bilobalide A in the bilobalide is 50-60%, the content of bilobalide B is 30-40%, and the content of bilobalide C is 5-10%.
Preferably, the volume ratio of the ethanol to the propylene glycol is 1: 1-5: 1.
Preferably, the volume ratio of the propylene glycol to the polyethylene glycol is 2: 1-5: 1.
The preparation method of the ginkgolide injection comprises the following steps:
1. preparation of ginkgolide
1A, adding 6-8 times of water into the ginkgo leaf extract for dissolving, extracting for 3 times by 10 times of ethyl acetate, each time for 0.5-1 hour, stirring at the rotating speed of 500 r/min; concentrating the obtained organic layer extractive solution, and pumping to obtain extract with total content of ginkgolide greater than 30%;
1B, dissolving the extract prepared in the step 1A with 50% ethanol with the mass of 8 times that of the extract at 60 ℃; standing at 10 deg.C for 36 h; performing suction filtration to obtain a filter cake, and drying at 60 ℃ to obtain the ginkgolide, wherein the content of the ginkgolide A is 50-60%, the content of the ginkgolide B is 30-40%, and the content of the ginkgolide C is 5-10%;
2. preparation: preparing various raw materials according to a raw material formula; mixing ethanol, propylene glycol and polyethylene glycol, adding ginkgolide, dissolving completely, and adding ethanol or water for injection; adjusting the pH value to 3.5-6.5 by using 5-10% citric acid solution or 1-10% hydrochloric acid solution;
3. filtering and sterilizing;
4. encapsulating and checking lamps;
5. and (5) sterilizing.
Has the advantages that: the invention takes ginkgo biloba extract as a main raw material, and obtains Ginkgolide A (GA), Ginkgolide B (GB) and Ginkgolide C (GC) through extraction and ethanol recrystallization, wherein the percentage of the sum of the contents of the three diterpene lactones in the ginkgolide is more than 90 percent; and adding appropriate water soluble solvent (such as ethanol, propylene glycol, polyethylene glycol, etc.) into the mixture, filtering with microporous membrane for sterilization, bottling, and steam sterilizing to obtain the final product. Compared with the prior art, the ginkgolide injection has better curative effects on treating hemiplegia, inflammation, cardiovascular diseases and the like caused by thrombus, has simple preparation method and good reproducibility, is suitable for large-scale production, and has lower environmental protection pressure. Meanwhile, through accelerated experiments and long-term stability experiments, the quality of the ginkgo diterpene lactone injection is stable in 12 months, the reliability and operability of the preparation method are verified, and quality assurance is provided for next animal experiments and clinical researches.
Detailed Description
The invention is further described with reference to specific examples.
It should be noted that the auxiliary materials and equipment used in the embodiments of the present invention are all known products in the prior art, and the main raw material of the ginkgo diterpene lactone is obtained by the self-made method of the present invention. The following bilobalide is bilobalide A (C) in dry weight percentage20H24O9) 50-60 percent of ginkgolide B (C)20H24O10)30 to 40 percent of ginkgolide C (C)20H24O11) 5-10 percent of ginkgolide A, ginkgolide B and ginkgolide C, and the sum of the contents of ginkgolide A, ginkgolide B and ginkgolide C accounts for the percentage of the ginkgolideThe ratio is more than 90 percent.
The preparation method of the ginkgolide comprises the following steps:
1. adding 6-8 times of water into folium Ginkgo extract, dissolving, extracting with 10 times of ethyl acetate for 3 times (each time for 0.5-1 hr), stirring at 500 r/min; concentrating the obtained organic layer extractive solution, and pumping to obtain extract with total content of ginkgolide greater than 30%;
2. dissolving the extract prepared in the step 1 in 50% ethanol with the mass of 8 times that of the extract at 60 ℃; standing at 10 deg.C for 36 h; and (3) carrying out suction filtration to obtain a filter cake, and drying at 60 ℃ to obtain the ginkgolide, wherein the content of the ginkgolide A is 55-60%, the content of the ginkgolide B is 30-35%, and the content of the ginkgolide C is 5-10%.
Example 1:
the embodiment is a raw material formula for preparing 1000 ginkgo diterpene lactone injection (specification: 50mg:20 ml/branch):
Figure BDA0003288655360000051
the preparation method of the ginkgolide injection comprises the following steps:
1. preparing various raw materials according to a raw material formula; firstly, uniformly mixing ethanol, propylene glycol and polyethylene glycol, then adding the ginkgolide, fully dissolving, and then adding the water for injection to full dose; adjusting the pH value to 3.5-6.5 by using 5-10% citric acid solution or 1-10% hydrochloric acid solution;
2. filtering and sterilizing;
3. encapsulating and checking lamps;
4. sterilizing;
5. packaging;
6. and (3) observation: standing at 5 deg.C for 72h, and observing whether particles are separated out in 24h, 48h, and 72 h; no particles are separated out in 72 hours, which indicates that the prescription of the injection is reasonably designed.
Example 2:
the embodiment is a raw material formula for preparing 1000 ginkgo diterpene lactone injection (specification: 50mg:20 ml/branch):
Figure BDA0003288655360000052
the preparation method of the ginkgolide injection comprises the following steps:
1. preparing various raw materials according to a raw material formula; firstly, uniformly mixing ethanol and propylene glycol, then adding the ginkgolide, fully dissolving, and then adding the water for injection to full dose; adjusting the pH value to 3.5-6.5 by using 5-10% citric acid solution or 1-10% hydrochloric acid solution;
2. filtering and sterilizing;
3. encapsulating and checking lamps;
4. sterilizing;
5. packaging;
6. and (3) observation: standing at 5 deg.C for 72h, and observing whether particles are separated out in 24h, 48h, and 72 h; no particles are separated out in 72 hours, which indicates that the prescription of the injection is reasonably designed.
Example 3:
the embodiment is a raw material formula for preparing 1000 ginkgo diterpene lactone injection (specification: 50mg:20 ml/branch):
Figure BDA0003288655360000061
the preparation method of the ginkgolide injection comprises the following steps:
1. preparing various raw materials according to a raw material formula; mixing ethanol and polyethylene glycol, adding ginkgolide, dissolving, and adding water for injection; adjusting the pH value to 3.5-6.5 by using 5-10% citric acid solution or 1-10% hydrochloric acid solution;
2. filtering and sterilizing;
3. encapsulating and checking lamps;
4. sterilizing;
5. packaging;
6. and (3) observation: standing at 5 deg.C for 72h, and observing whether particles are separated out in 24h, 48h, and 72 h; no particles are separated out in 72 hours, which indicates that the prescription of the injection is reasonably designed.
In this example, the ethanol dosage reaches 60%, which has a certain effect on the tolerance of the human body.
Example 4:
the embodiment is a raw material formula for preparing 1000 ginkgo diterpene lactone injection (specification: 50mg:20 ml/branch):
Figure BDA0003288655360000071
the preparation method of the ginkgolide injection comprises the following steps:
1. preparing various raw materials according to a raw material formula; firstly, uniformly mixing propylene glycol and polyethylene glycol, then adding ginkgolide, fully dissolving, and then adding water for injection to full dose; adjusting the pH value to 3.5-6.5 by using 5-10% citric acid solution or 1-10% hydrochloric acid solution;
2. filtering and sterilizing;
3. encapsulating and checking lamps;
4. sterilizing;
5. packaging;
6. and (3) observation: standing at 5 deg.C for 72h, and observing whether particles are separated out in 24h, 48h, and 72 h; no particles are separated out in 72 hours, which indicates that the prescription of the injection is reasonably designed.
In this example, the propylene glycol amount reaches 60%, which has a certain effect on the tolerance of the human body.
Example 5:
the embodiment is a raw material formula for preparing 1000 ginkgo diterpene lactone injection (specification: 75mg:20 ml/branch):
Figure BDA0003288655360000072
the preparation method of the ginkgolide injection comprises the following steps:
1. preparing various raw materials according to a raw material formula; firstly, uniformly mixing ethanol, propylene glycol and polyethylene glycol, then adding the ginkgolide, fully dissolving, and then adding the water for injection to full dose; adjusting the pH value to 3.5-6.5 by using 5-10% citric acid solution or 1-10% hydrochloric acid solution;
2. filtering and sterilizing;
3. encapsulating and checking lamps;
4. sterilizing;
5. packaging;
6. and (3) observation: standing at 5 deg.C for 72h, and observing whether particles are separated out in 24h, 48h, and 72 h; no particles are separated out in 72 hours, which indicates that the prescription of the injection is reasonably designed.
[ METHOD OF USE ] the ginkgolide injection prepared in examples 1-5 was diluted with 250ml of 0.9% sodium chloride injection or 250ml of 5% glucose injection and then intravenously instilled.
[ stability study of Pilot samples ]
An enlarged experimental study was conducted according to the raw material formulation and preparation method of example 1, and three batches of 1 ten thousand samples were prepared. And (3) carrying out stability experiments on three batches of samples to verify the stability of the injection, wherein:
1. the test sample is placed for 6 months under the conditions of the temperature of 40 +/-2 ℃ and the relative humidity of 75 +/-5 percent;
2. the test sample is placed for 12 months under the conditions of the temperature of 25 ℃ plus or minus 2 ℃ and the relative humidity of 60 percent plus or minus 5 percent.
The results are shown in tables 2, 3, 4, 5, 6 and 7.
Table 2: 190201 sample accelerated test results
Figure BDA0003288655360000081
Table 3: 190202 sample accelerated test results
Figure BDA0003288655360000091
Table 4: 190203 sample accelerated test results
Figure BDA0003288655360000092
As can be seen from the experimental results in tables 2, 3 and 4, the three batches of pilot samples have stable quality indexes within 6 months of the accelerated experiment, which indicates that the prescription and the method meet the design requirements and have the conditions of batch production.
Table 5: long term experimental results of 190201 batches of samples
Figure BDA0003288655360000093
Table 6: 190202 sample long-term experimental results
Figure BDA0003288655360000101
Table 7: 190203 sample long-term experimental results
Figure BDA0003288655360000102
As can be seen from the experimental results in tables 5, 6 and 7, the three batches of pilot samples have stable quality indexes within 12 months of long-term experiments, and the reasonability and operability of the raw material formula and the method are verified.
While the preferred embodiments of the present invention have been illustrated and described, it will be understood by those skilled in the art that various changes in form and details may be made therein without departing from the spirit and scope of the invention as defined in the appended claims.

Claims (7)

1. A ginkgo diterpene lactone injection is characterized in that: the formula of the raw materials is as follows: 1-5mg/ml of ginkgolide, 0.1-0.5ml/ml of propylene glycol, 0.1-0.5ml/ml of ethanol, 0.1-0.5ml/ml of polyethylene glycol and 0.1-1ml/ml of water for injection.
2. The ginkgolide injection of claim 1, wherein: the formula of the raw materials is as follows: 50mg of ginkgolide, 4ml of propylene glycol, 8ml of ethanol and 1ml of polyethylene glycol, and adding water for injection to 20 ml.
3. The ginkgolide injection of claim 1, wherein: the formula of the raw materials is as follows: 75mg of ginkgolide, 4ml of propylene glycol, 8ml of ethanol and 1ml of polyethylene glycol, and adding water for injection to 20 ml.
4. The ginkgolide injection according to any one of claims 1-3, wherein: the content of ginkgolide A in the ginkgolide is 50-60%, the content of ginkgolide B is 30-40%, and the content of ginkgolide C is 5-10%.
5. The ginkgolide injection according to any one of claims 1-3, wherein: the volume ratio of the ethanol to the propylene glycol is 1: 1-5: 1.
6. The ginkgolide injection according to any one of claims 1-3, wherein: the volume ratio of the propylene glycol to the polyethylene glycol is 2: 1-5: 1.
7. A method for preparing ginkgolide injection as claimed in claim 2 or 3, wherein: the method comprises the following steps:
(1) preparation of ginkgolide
(1A) Adding 6-8 times of water into folium Ginkgo extract, dissolving, extracting with 10 times of ethyl acetate for 3 times (each time for 0.5-1 hr), stirring at 500 r/min; concentrating the obtained organic layer extractive solution, and pumping to obtain extract with total content of ginkgolide greater than 30%;
(1B) dissolving the extract prepared in the step (1A) with 50% ethanol with the mass of 8 times that of the extract at 60 ℃; standing at 10 deg.C for 36 h; performing suction filtration to obtain a filter cake, and drying at 60 ℃ to obtain the ginkgolide, wherein the content of the ginkgolide A is 50-60%, the content of the ginkgolide B is 30-40%, and the content of the ginkgolide C is 5-10%;
(2) preparing an injection: preparing various raw materials according to a raw material formula; mixing ethanol, propylene glycol and polyethylene glycol, adding ginkgolide, dissolving completely, and adding ethanol or water for injection; adjusting the pH value to 3.5-6.5 by using 5-10% citric acid solution or 1-10% hydrochloric acid solution;
(3) filtering and sterilizing;
(4) encapsulating and checking lamps;
(5) and (5) sterilizing.
CN202111157028.2A 2021-09-30 2021-09-30 Ginkgo diterpene lactone injection and preparation method thereof Pending CN113730347A (en)

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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101491519A (en) * 2008-01-22 2009-07-29 南京克温生物科技有限公司 Bilobalide injector and preparation method thereof
CN106727491A (en) * 2016-12-08 2017-05-31 河北润茂制药有限公司 A kind of Bilobanoate medicinal raw material

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101491519A (en) * 2008-01-22 2009-07-29 南京克温生物科技有限公司 Bilobalide injector and preparation method thereof
CN106727491A (en) * 2016-12-08 2017-05-31 河北润茂制药有限公司 A kind of Bilobanoate medicinal raw material

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