CN113730368A - A dripping pill containing ginkgolide and its preparation method - Google Patents

A dripping pill containing ginkgolide and its preparation method Download PDF

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CN113730368A
CN113730368A CN202111156822.5A CN202111156822A CN113730368A CN 113730368 A CN113730368 A CN 113730368A CN 202111156822 A CN202111156822 A CN 202111156822A CN 113730368 A CN113730368 A CN 113730368A
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ginkgolide
dripping
dripping pill
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王嘉锋
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Shandong Renhe Pharmaceutical Co ltd
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Abstract

The invention relates to the technical field of medicine production, in particular to a ginkgolide dripping pill and a preparation method thereof. The feed is prepared from the following raw materials in parts by mass: 10 parts of ginkgolide, 30-40 parts of matrix, 1 part of disintegrant and 0.1 part of surfactant. The invention obtains the ginkgolide by extraction and ethanol recrystallization; and then the bilobalide is taken as a raw material, a proper forming material is selected, a disintegrating agent and a surfactant are added, and the bilobalide dripping pill is prepared by the steps of heating and melting, dripping, cooling and the like, so that the water solubility of the bilobalide is improved, the bioavailability is improved, the stability is increased, the irritation is reduced, and the unpleasant odor is covered. The ginkgolide dripping pill has the advantages of large surface area, high dissolution speed, accurate dosage, convenient administration, good curative effects on treating thrombus, senile dementia, Alzheimer's disease, memory improvement and the like, simple preparation process, good reproducibility, suitability for large-scale production, and low environmental protection pressure.

Description

A dripping pill containing ginkgolide and its preparation method
Technical Field
The invention relates to the technical field of medicine production, in particular to a ginkgolide dripping pill 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 medicines (such as dripping pill, tablet, granule and 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 (CN106924197A) discloses a ginkgolide drop pill, which is prepared from the following raw and auxiliary materials in parts by weight: 10 parts of ginkgolide, 20-40 parts of matrix and 2-6 parts of disintegrant. The patent document also provides a preparation method of the dripping pill. Accelerated experiment results show that after the disintegrant CMC-Na is added into the preparation formula disclosed in the patent document, the in-vitro dissolution rate and the dissolution time limit of the prepared dripping pill are not obviously changed after 6 months, which shows that the ginkgolide dripping pill has good stability and can effectively avoid the aging problem.
Chinese patent document (CN110339174A) provides a ginkgolide drop pill, which comprises the following raw and auxiliary materials by weight: 5-20 parts of ginkgolide, 20-40 parts of a matrix and 0.2-5 parts of a surfactant; wherein, the surfactant is preferably selected from soybean phospholipid and/or poloxamer. The patent document discloses a technical content that the raw materials are dispersed in a matrix to prepare the dripping pill, which improves the solubility, dissolution rate, absorption rate and bioavailability of the raw materials, and the bilobalide preparation has high stability, is not easy to hydrolyze and oxidize, and is convenient to use and carry.
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 ginkgolide dripping pill 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 ginkgolide dripping pill is characterized in that: the feed is prepared from the following raw materials in parts by mass: 10 parts of ginkgolide, 30-40 parts of matrix, 1 part of disintegrant and 0.1 part of surfactant.
Preferably: the content of ginkgolide A in the ginkgolide is 55-60%, the content of ginkgolide B is 30-35%, and the content of ginkgolide C is 5-10%.
Preferably: the disintegrant is croscarmellose sodium.
Preferably: the matrix is a mixture of polyethylene glycol 4000 and polyethylene glycol 6000 in a weight ratio of 1: 1.
Preferably: the surfactant is sodium dodecyl sulfate.
The preparation method of the ginkgolide dripping pill 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 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 55-60%, the content of the ginkgolide B is 30-35%, and the content of the ginkgolide C is 5-10%;
2. pulverizing ginkgolide, and sieving with 100-200 mesh sieve to obtain fine powder of ginkgolide;
3. mixing matrix, surfactant and disintegrating agent, heating to melt, adding fine powder of ginkgolide at 85-90 deg.C, stirring to make it suspended; dripping the suspension into 10-15 deg.C condensate via dripper, cooling, and molding.
Preferably: the condensate is liquid paraffin, vegetable oil or dimethyl silicone oil.
Preferably: the disintegrant is croscarmellose sodium.
Preferably: the matrix is a mixture of polyethylene glycol 4000 and polyethylene glycol 6000 in a weight ratio of 1: 1.
Preferably: the surfactant is sodium dodecyl sulfate.
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 then using GA, GB and GC as raw materials, selecting a proper forming material (polyethylene glycol PEG4000/6000) to compare the roundness, hardness and color appearance indexes of the dripping pill, determining the optimal proportion of the forming material and the medicament, determining quantitative quality indexes such as dissolving time, pill weight difference and the like of the dripping pill, adding a disintegrant cross-linked sodium carboxymethylcellulose and a surfactant sodium dodecyl sulfate to improve the dissolving rate, preparing the ginkgo diterpene lactone dripping pill by heating, melting, dripping, cooling and other steps, improving the water solubility of the ginkgo diterpene lactone, improving the bioavailability, increasing the stability, reducing the irritation, covering up bad smell. Compared with the prior art, the ginkgolide dripping pill has the advantages of large surface area, high dissolution speed, accurate dosage and convenient administration, has better curative effects on treating thrombus, senile dementia, Alzheimer's disease, improving memory and the like, has simple preparation process and good reproducibility, is suitable for large-scale production, and has less environmental protection pressure.
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)55.0 to 60.0 percent of ginkgolide B (C)20H24O10) 30.0-35.0% of ginkgolide C (C)20H24O11) 5.0-10.0 percent, and the percentage of the total content of the ginkgolide A, the ginkgolide B and the ginkgolide C in the ginkgolide is more than 90 percent.
The preparation process 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 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 1A with 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 formula of the ginkgolide dripping pill comprises the following raw materials:
Figure BDA0003288605770000051
the preparation process of the ginkgolide dripping pill comprises the following steps:
1. taking 1.33kg of ginkgolide, crushing the ginkgolide, and sieving the crushed ginkgolide with a 150-mesh sieve to obtain fine powder of ginkgolide for later use;
2. taking 4.0kg of polyethylene glycol mixture (polyethylene glycol 4000/polyethylene glycol 6000 is 1:1), adding 0.01kg of sodium dodecyl sulfate, adding 0.1kg of croscarmellose sodium, and heating to melt; adding fine powder of ginkgolide at 85 deg.C, stirring to make suspension, dripping the suspension into dimethyl silicon oil at 10 deg.C, cooling, and forming to obtain dripping pill of 10 ten thousand pills, 46mg per pill.
Example 2:
the formula of the ginkgolide dripping pill comprises the following raw materials:
Figure BDA0003288605770000052
the preparation process of the ginkgolide dripping pill comprises the following steps:
1. taking 1.33kg of ginkgolide, crushing the ginkgolide, and sieving the crushed ginkgolide with a 150-mesh sieve to obtain fine powder of ginkgolide for later use;
2. taking 4.0kg of polyethylene glycol 6000, adding 0.01kg of sodium dodecyl sulfate, then adding 0.1kg of croscarmellose sodium, and heating to melt; adding fine powder of ginkgolide at 90 deg.C, stirring to make suspension, dripping the suspension into dimethyl silicon oil at 10 deg.C, cooling, and forming to obtain 10 million dripping pills, each pill being 50 mg.
Example 3:
the formula of the ginkgolide dripping pill comprises the following raw materials:
Figure BDA0003288605770000061
the preparation process of the ginkgolide dripping pill comprises the following steps:
1. taking 1.33kg of ginkgolide, crushing the ginkgolide, and sieving the crushed ginkgolide with a 150-mesh sieve to obtain fine powder of ginkgolide for later use;
2. taking 4.0kg of polyethylene glycol 4000, firstly adding 0.01kg of sodium dodecyl sulfate, then adding 0.1kg of croscarmellose sodium, and heating to melt; adding fine powder of ginkgolide at 90 deg.C, stirring to make suspension, dripping the suspension into 15 deg.C dimethyl silicone oil via dripper, cooling, and forming to obtain 10 million dripping pills, each pill being 50 mg.
Example 4:
the formula of the ginkgolide dripping pill comprises the following raw materials:
Figure BDA0003288605770000062
the preparation process of the ginkgolide dripping pill comprises the following steps:
1. taking 1.33kg of ginkgolide, pulverizing ginkgolide, and sieving with 200 mesh sieve to obtain fine powder of ginkgolide for use;
2. taking 4.0kg of polyethylene glycol mixture (polyethylene glycol 4000/polyethylene glycol 6000-2: 1), adding 0.01kg of sodium dodecyl sulfate, adding 0.1kg of croscarmellose sodium, and heating to melt; adding fine powder of ginkgolide at 90 deg.C, stirring to make suspension, dripping the suspension into dimethyl silicon oil at 10 deg.C, cooling, and forming to obtain 10 million dripping pills, each pill is 45 mg.
Example 5:
the formula of the ginkgolide dripping pill comprises the following raw materials:
Figure BDA0003288605770000071
the preparation process of the ginkgolide dripping pill comprises the following steps:
1. taking 1.33kg of ginkgolide, pulverizing ginkgolide, and sieving with 200 mesh sieve to obtain fine powder of ginkgolide for use;
2. taking 4.0kg of polyethylene glycol mixture (polyethylene glycol 4000/polyethylene glycol 6000 is 1:2), adding 0.01kg of sodium dodecyl sulfate, adding 0.1kg of croscarmellose sodium, and heating to melt; adding fine powder of ginkgolide at 85 deg.C, stirring to make suspension, dripping the suspension into 15 deg.C dimethyl silicone oil via dripper, cooling, and forming to obtain 10 million dripping pills, each 46 mg.
[ Ginkgo diterpene lactone dripping pill quality evaluation ]
According to the requirements of Chinese pharmacopoeia 2020 edition appendix dripping pill preparation items, each sample is checked, and the checking items are respectively: the indicators of appearance (yellowish to brownish translucent pellets), hardness (KN, kilonewtons), rounding of the drop pills (scored from 0 to 10, 10 being the most rounded and 0 being the least rounded), tailing of the drop pills (scored from 0 to 10, 10 being the best and 0 being the worst), time limit of dissolution (min), dissolution in vitro (15min, X > 75.0%) were tested. The results are shown in Table 2.
Table 2: quality evaluation result of ginkgolide dripping pill
Figure BDA0003288605770000081
From the above table, example 1 is the best recipe and process, and three pilot studies were performed as in example 1, with 20 million pieces per batch.
The pilot experiment prescription and the process are as follows:
1. prescription:
Figure BDA0003288605770000082
2. the process comprises the following steps:
1. taking 2.7kg of ginkgolide, pulverizing ginkgolide, and sieving with 150 mesh sieve to obtain fine powder of ginkgolide for use;
2. taking 8.0kg of polyethylene glycol mixture (polyethylene glycol 4000/polyethylene glycol 6000 ═ 1:1), adding 0.02kg of sodium dodecyl sulfate, then adding 0.2kg of croscarmellose sodium, and heating to melt; adding fine powder of ginkgolide at 85 deg.C, stirring to make suspension, dripping the suspension into dimethyl silicon oil at 10 deg.C, cooling, and forming to obtain 20 million dripping pills, 46mg each.
Three-batch pilot test sample stability survey
Referring to the requirements of Chinese pharmacopoeia 2020 edition appendix dropping pill preparation items, the following experiments are carried out:
1. accelerated testing: standing at 40 + -2 deg.C and 75% + -5% relative humidity for 6 months;
2. long-term experiments: the mixture 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.
And (4) inspecting the sample, wherein the inspection items are indexes such as characters, content, dissolution time limit and dissolution rate. The results are shown in tables 3, 4, 5, 6, 7 and 8.
Table 3: accelerated experimental results for 200101 batches of samples
Figure BDA0003288605770000091
Table 4: 200102 sample accelerated test results
Figure BDA0003288605770000092
Table 5: 200103 sample accelerated test results
Figure BDA0003288605770000101
As can be seen from the experimental results in tables 3, 4 and 5, the quality indexes of the three batches of pilot samples are stable, which indicates that the prescription and the process meet the design requirements and have the conditions of batch production.
Table 6: long term stability test results for 200101 batches of samples
Figure BDA0003288605770000102
Table 7: 200102 batch sample long term stability test results
Figure BDA0003288605770000111
Table 8: 200103 batch sample long term stability test results
Figure BDA0003288605770000112
As can be seen from tables 6, 7 and 8, after the three batches of pilot samples are tested for 24 months for a long time, the characteristics, the dissolution time limit, the dissolution rate and the content change are not large and are basically stable, which shows that the formula and the process design of the ginkgolide dripping pill are reasonable, and the effectiveness of clinical medication can be ensured.
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 (10)

1. A ginkgolide dripping pill is characterized in that: the feed is prepared from the following raw materials in parts by mass: 10 parts of ginkgolide, 30-40 parts of matrix, 1 part of disintegrant and 0.1 part of surfactant.
2. The ginkgolide dripping pill as claimed in claim 1, wherein: the content of ginkgolide A in the ginkgolide is 55-60%, the content of ginkgolide B is 30-35%, and the content of ginkgolide C is 5-10%.
3. The ginkgolide dripping pill as claimed in claim 1, wherein: the disintegrant is croscarmellose sodium.
4. The ginkgolide dripping pill as claimed in claim 1, wherein: the matrix is a mixture of polyethylene glycol 4000 and polyethylene glycol 6000 in a weight ratio of 1: 1.
5. The ginkgolide dripping pill as claimed in claim 1, wherein: the surfactant is sodium dodecyl sulfate.
6. The method for preparing ginkgolide dripping pills as claimed in claim 1, 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 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 55-60%, the content of the ginkgolide B is 30-35%, and the content of the ginkgolide C is 5-10%;
(2) pulverizing ginkgolide, and sieving with 100-200 mesh sieve to obtain fine powder of ginkgolide;
(3) mixing matrix, surfactant and disintegrating agent, heating to melt, adding fine powder of ginkgolide at 85-90 deg.C, stirring to make it suspended; dripping the suspension into 10-15 deg.C condensate via dripper, cooling, and molding.
7. The method for preparing ginkgolide dripping pills according to claim 6, wherein said method comprises the steps of: the condensate is liquid paraffin, vegetable oil or dimethyl silicone oil.
8. The method for preparing ginkgolide dripping pills according to claim 6, wherein said method comprises the following steps: the disintegrant is croscarmellose sodium.
9. The method for preparing ginkgolide dripping pills according to claim 6, wherein said method comprises the following steps: the matrix is a mixture of polyethylene glycol 4000 and polyethylene glycol 6000 in a weight ratio of 1: 1.
10. The method for preparing ginkgolide dripping pills according to claim 6, wherein said method comprises the following steps: the surfactant is sodium dodecyl sulfate.
CN202111156822.5A 2021-09-30 2021-09-30 A dripping pill containing ginkgolide and its preparation method Pending CN113730368A (en)

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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
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
CN106924197A (en) * 2015-12-30 2017-07-07 成都百裕制药股份有限公司 A kind of Ginkgolides drop pills and preparation method thereof

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN106924197A (en) * 2015-12-30 2017-07-07 成都百裕制药股份有限公司 A kind of Ginkgolides drop pills 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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