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Smart manufacturing still remains critical challenges for pharmaceutical manufacturing. Here, an original data-driven engineering framework was proposed to tackle the challenges. Firstly, from sporadic indicators to five kinds of systematic quality characteristics, nearly 2,000,000 real-world data points were successively characterized from Ginkgo Folium tablet manufacturing. Then, from simplex to the multivariate system, the digital process capability diagnosis strategy was proposed by multivariate Cpk integrated Bootstrap-t. The Cpk of Ginkgo Folium extracts, granules, and tablets were discovered, which was 0.59, 0.42, and 0.78, respectively, indicating a relatively weak process capability, especially in granulating. Furthermore, the quality traceability was discovered from unit to end-to-end analysis, which decreased from 2.17 to 1.73. This further proved that attention should be paid to granulating to improve the quality characteristic. In conclusion, this paper provided a data-driven engineering strategy empowering industrial innovation to face the challenge of smart pharmaceutical manufacturing.
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Objective:To explore the key targets of ginkgo leaves extract against diabetic retinopathy (DR), and the underlying pharmacological mechanism by network pharmacology.Methods:Potential targets of active components in ginkgo folium were searched from the Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform (TCMSP) and Swiss Target Prediction database.Therapeutic targets highly related to DR were retrieved from the GeneCards and DisGENET databases.The intersection targets were subjected to Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis to construct the active components-targets network.Based on the degree of network nodes, key active components and key targets were obtained for molecular docking verification.Results:A total of 27 active components and 34 potential therapeutic targets of ginkgo leaves extract in the treatment of DR were screened out.GO enrichment analysis indicated that these therapeutic targets were mainly enriched in the processes of inflammation, oxidative stress, angiogenesis and hypoxic damage.KEGG pathway enrichment analysis revealed that the advanced glycation end product-receptor for advanced glycation end product, mitogen active protein kinase, phosphatidylinositol-3-kinase-protein kinase B, hypoxia inducible factor-1, tumor necrosis factor (TNF) and interleukin (IL)-17 signaling pathways were mainly enriched.According to degree value calculated from the active components-targets network, the top 4 key active components with higher degrees were quercetin, kaempferol, luteolin and isorhamnetin, and the top 8 key targets were serine/threonine protein kinase 1, vascular endothelial growth factor A, IL-6, TNF, nitric oxide synthase 3, peroxisome proliferator activated receptor-γ, IL-10 and matrix metalloproteinase-9.The binding activity between key active components and key targets was good.Conclusions:A variety of active compounds contained in ginkgo leaves extract can target various therapeutic targets related to DR, and regulate multiple signal pathways, thereby exerting a therapeutic effect on DR.
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In this experiment, an ultra-high performance liquid chromatographytandem triple quadrupole mass spectrometry was established for the determination of caffeine in commercially available Ginkgo Folium. The samples were extracted by ultrasonic method with methanol, and separated on Waters CORTECS T3 column(2.1 mm×100 mm, 2.7 μm), with mobile phase of 0.1% formic acid solution-0.1% formic acid acetonitrile solution for gradient elution, at flow rate of 0.3 mL·min~(-1); column temperature of 30 ℃, and injection volume of 2 μL. Mass spectrometry was conducted at ESI~+ multiple reaction monitoring(MRM) mode; quantitative analysis was conducted with external standard method. The results showed that in the range of 0.099 6-9.96 ng·mL~(-1), there was a good linear relationship between the mass concentration of caffeine and the peak area, R~2=0.999; the average recovery was 84.51%, with RSD of 6.2%. The results of precision, repeatability and stability showed that the RSD was 5.1%, 5.9%, 7.2%, respectively. The content range of caffeine in 10 batches of Ginkgo Folium was 1.52-60.86 μg·kg~(-1). In conclusion, this method is accurate, reliable and reproducible, which provides a reference for the safety study of Ginkgo Folium.
Subject(s)
Caffeine , Chromatography, High Pressure Liquid , Ginkgo biloba , Tandem Mass SpectrometryABSTRACT
Objective:To conduct quality evaluation of Ginkgo Folium preparations by analyzing the national evaluation sampling test results， analyze the quality differences， and put forward suggestions for the improvement of quality standards and market supervision. Method:The contents of total flavonol glycosides and terpene lactones in Ginkgo Folium tablets and Ginkgo Folium capsules were determined according to the methods of determination in the 2015 edition of Chinese Pharmacopoeia （the first volume）， and the contents of free flavonoids （quercetin， kaempferide and isorhamnetin） and sophoricoside in Ginkgo Folium preparations were determined according to related supplementary testing method of Ginkgo Folium tablets and Ginkgo Folium capsules issued by National Medical Products Administration. The quality differences of Ginkgo Folium preparations from different batches and different manufacturers were compared according to the contents of total flavonol glycosides， terpene lactones， free flavonoids and sophoricoside in 328 batches of Ginkgo Folium tablets and Ginkgo Folium capsules manufactured by 48 enterprises. Result:Quality of 328 batches of Ginkgo Folium tablets and Ginkgo Folium capsules was in accordance with the standard， but the contents of terpene lactones and total flavonol glycosides were all distributed in a wide range， and the quality of samples varied greatly among different enterprises. Conclusion:It is recommended that each enterprise should optimize the production process and strictly control the raw materials to ensure the consistency between different batches of samples.
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Objective: To explore the placebo-preparation method of Ginkgo Folium Dropping Pills (GFDP) and evaluate its simulation effect objectively, which could provide production and evaluation reference for Chinese materia medica (CMM) placebo. Methods: Taking the placebo-preparation of GFDP as an example, the simulation effect was evaluated from aspects of appearance, color, smell, and taste. It employed three different approaches as possibility of experimental drug, similarity evaluation between placebo and experimental drug and the similarity analysis among the drugs. Results: The two placebo-preparation prescriptions of GFDP have high similarity with the original drug in terms of appearance, color, smell, and taste. The simulation effect of No. 2 placebo-prescription (0.6 g of sucrose octaacetate as bitter agent, 2.1 g of caramel as colorant, 13.3 g of PVP K30 as fillerz and 44.0 g of PEG 4000 as water-soluble bases to prepare 1 000 pills) is better than No. 1 placebo-prescription (1.2 g of sucrose octaacetate as bitter agent, 2.1 g of caramel as colorant, 12.7 g of PVP K30 as filler, and 44.0 g of PEG 4000 as water-soluble bases to prepare 1 000 pills). Conclusion: The placebo-preparation of GFDP conform to placebo requirements of randomized controlled trials. It fills the vacancy of dropping pills form placebo-preparation in CMM and provides method and idea for placebo-preparation and simulation-effect evaluation of CMM.
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Objective To investigate the influence of Ginkgo biloba L. extract (EGB) on the expression of apoptosis-related protein and NF-κB signaling pathway in the spleen tissue of mice with radiation damage. Methods The mice were divided randomly into normal control group (NC), irradiation control group (IC), low dose EGB group (IC+EGBL), medium dose EGB group (IC+EGBM) and high dose EGB group (IC+EGBH) according to the random number table, with 12 rats in each group. The mice in the low, middle and high dose EGB groups were given EGB respectively by 5, 10, 20 mg/kg, and the normal and irradiation control group were given saline by intraperitoneal injection once daily for 14 days. On the 15th day, the mice in all groups were uniformly irradiated with 4.0 Gy γ-rays for one time except normal control group. After 24 hours, Bcl-2, Bax and caspase-3 protein expression were measured by immunohistochemical method. The IKKβ expression was detected by qRT-PCR method, and the content of NF-κB p65 and IKKα in serum was detected by Elisa method in spleen tissue. Results Comparing with IC group, the expression of Bax (54.31 ± 1.59, 42.04 ± 1.56, 32.08 ± 2.43 vs. 68.68 ± 3.12) and caspase-3 protein (55.73 ± 2.61, 45.81 ± 2.59, 36.78 ± 2.23 vs. 72.18 ± 1.84) in IC+EGBL, IC+EGBM and IC+EGBH group were significantly decreased (P<0.05), the expression of Bcl-2 protein (30.33 ± 1.28, 39.80 ± 2.86, 44.42 ± 3.64 vs. 22.80 ± 2.01) in IC+EGBL, IC+EGBM and IC+EGBH group significantly increased (P<0.05), the expression of IKKβ mRNA (1.43 ± 0.06, 1.31 ± 0.06, 1.17 ± 0.09 vs. 1.64 ± 0.10) and the level of NF-κB p65 (129.38 ± 8.41 pg/ml, 111.28 ± 9.09 pg/ml, 95.41 ± 6.88 pg/ml vs. 145.64 ± 6.29 pg/ml) and IKKα (160.10 ± 8.94 pg/ml, 144.00 ± 8.36 pg/ml, 108.84 ± 13.74 pg/ml vs. 176.38 ± 8.54 pg/ml) in IC+EGBL, IC+EGBM and IC+EGBH group significantly decreased (P<0.05). Conclusions The EGB can reduce the expression of apoptotic protein Bax and caspase-3 in spleen cells induced by radiation, elevate the expression level of apoptotic protein Bcl-2, and inhibit the damage caused by radiation by regulating NF-κB signaling pathway.
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Objective To explore the feasibility of using the quantitative reference extract of ginkgo leaf total lactones instead of single component reference for the quantitative assay of Ginkgo Folium.Methods HPLC-ELSD method was performed by using a Diamonsil C18 column (250 mm×4.6 mm,5 μm) with methanol-water as the mobile phase at the gradient elution mode.Flow rate was 1.0 mL·min-1.The parameters of ELSD detector were as follows,the drifit tube temperature was 105 ℃,and the flow rate of nitrogen(N2) was 3 L·min-1.Results The linear ranges of ginkgolide A,ginkgolide B,ginkgolide C,and bilobalide were 0.735-5.879 μg (r=0.999 6),0.404-6.060 μg (r=0.999 6),0.296-4.439 μg (r=0.999 6),and 1.001-6.006 μg (r=0.999 7),respectively.The recoveries and RSD of the four components were 95.6% (4.0%),97.3% (4.5%),99.3% (5.0%),and 100.4% (2.1%),respectively.Conclusion The quantitative reference extract of ginkgo leaf total lactones can be used as the substitute for the determination of terpene lactones.
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This paper reports the huge chain reactions and shock in the industry triggered by the "Ginkgo Folium event" since May, 2015, to comb, summarize, and analyze special management action on drugs and health food by CFDA and the local bureau, and to lead a multi-angle and multi-level thinking from the application and market, what harm to human health, quality standards, profiteering temptation, supervision, integrity, brand strategy, claims, chase responsibility, and punishment. We think that the quality of products is not dependent on inspection to find problems, which should be strictly regulated, enforced law enforcement, severely punished, severely cracked down on, and governed from the source. Only the law-abiding integrity of enterprise production and management can ensure that product quality has no problem.
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Objective To investigate dynamic metabolism in vivo of Ginkgo Folium Tablet under the guidance of sequential metabolism thoughts. Methods In situ closed-loop in rats was carried out to study sequential metabolism of Ginkgo Folium Tablet through oral digestive system, namely to investigate and compare the intestinal flora metabolism, the gut wall metabolism and hepatic metabolism, combined with chromatographic fingerprint of blood samples. Results The analysis showed that 12 peaks in Ginkgo Folium Tablet were metabolized by intestinal flora, and 7 peaks generated through the gut wall. Most components of Ginkgo Folium Tablet were metabolized in liver, and 3 original medicine components were directly into the blood. Conclusion This study conducts a qualitative description of metabolism of Ginkgo Folium Tablet in different parts of the oral route, and provides references for the quality control, mechanism explanation and secondary development for Ginkgo Folium Tablet.
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OBJECTIVE: To develop an HPLC method for simultaneous determination of ginkgolic acids(C13:0, C15:1, C17:2, C15:0, C17:1) in Ginkgo Folium. METHODS: The HPLC analysis was carried out on Phenomenex Luna C18(4.6 mm × 250 mm, 5 μm) column with acetonitrile-0.1% phosphoric acid (90:10) as mobile phase eluted at the flow rate of 1.0 mL · min-1. The detective wavelength was set at 310 nm, and the column temperature was set at 30℃. RESULTS: The calibration curve was linear within the range of 1.47-29.40 μg · mL-1 for C13:0, 6.05 -121.00 μg · mL-1 for C15:1 and 8.00 - 160.00 μg · mL-1 for C17:1, respectively. The average recoveries for the three marker compounds are 98.6% - 100.1%. CONCLUSION: This method is simple, accurate, and practical for the quality control of Ginkgo Folium. There are some differences in the contents of the five marker compounds from different producing areas and different collection periods.
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In January, 2014, European Medicines Agency (EMEA) issued a draft for community herbal monograph on Ginkgo biloba L., folium. That means the community herbal monograph on Ginkgo biloba L., folium has been settled finally. This assay introduces the new Ginkgo monograph briefly, describes the two registering methods and requirements for herbal medicines in EU, and reads the new monograph in more detail. By analyzing the impact of the new monograph on Ginkgo Folium products, this monograph will offer a very important reference and basis for the herbal registration application of Ginkgo Folium products in EU.
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Objective: There are abundant Chinese medicinal herb resources in Guangxi province. Especially, there are lots of Ginkgo Folium in the north. To detect the contents of the total flavonoid glycoside and lactone in Ginkgo Folium and to find out their best concentration ratio during the year. Methods: The reflux method was used for the distillation of the total flavonoid glycoside and lactone in Ginkgo Folium and HPLC was used for quantitative analysis. The contents of the total flavonoid glycoside and lactone in Ginkgo Folium were determined on a Ultimate XB-C18 (250 mm × 4.6 mm, 5 μm) analytical column with different mobile phases and detectors. Results: The concentration ratio of the total flavonoid glycoside and lactone in Ginkgo Folium in August was the smallest and their contents were high. Conclusion: There is significant difference between total flavonoid glycoside and lactone content in Ginkgo Folium from different picking periods during the year, and the concentration ratio of the two compositions in August is the smallest with high contents, which can be used to provide the basis for guiding the farmer to collect Ginkgo Folium in August.
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Objective: To prepare bi-layer osmotic pump controlled release tablet of total flavonoids from Ginkgo Folium (BOPCRT- TFGF), and to optimize its formulation by central composite design response surface methodology (CCD RSM). Methods: Single-factor test was desigined by screening the formulations of tablet core and coating film. The independent variables comprised of amount of polyethylene glycol in coating solution and coating weight gain, and the dependent variables included the percentages cumulative release of BOPCRT-TFGF after 2 and 14 h and multiple correlation coefficient of druge release profile in 1-12 h. The formulation was optimized by CCD RSM and the optimized formulation was also verified. Results: The optimized formulation was as follows: The tablet weight gain in coating was 7.58%, and PEG 4000 was 3.41 g. There was no significant difference between the measured and the predicted values. The cumulative release of the optimal osmotic pump tablets after 2 h did not appear sudden release, and the cumulative release within 14 h was over 85%. The drug release profile in 1-12 h exhibited a zero order character. Conclusion: A reliable model is established using response surface methodology and the formulation of BOPCRT-TFGF could be optimized. The BOPCRT-TFGF for administration once daily is prepared.
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Objective: To develop a qualitative method for the quick determination of proanthocyanidins in Ginkgo Folium preparation (GFP), and to provide the objective evidence for the quality control of proanthocyanidins. Methods: NP-HPLC and HPLC-DAD-MS methods were developed to analyze the composition of proanthocyanidins in Ginkgo Folium proanthocyanidin extract, grape-seed extract, GFP, and adulterate GFP. Results: The proanthocyanidins were separated in normal phase mode according to their degree of polymerization. The proanthocyanidins from grape-seed extract, which consisted of (epi)catechin, had only one characteristic absorption band in HPLC chromatograms for each degree of polymerization; And proanthocyanidins of GFP, which consisted of (epi)gallocatechin and (epi)catechin, had two or three characteristic absorption bands for each degree of polymerization. Conclusion: The HPLC method is applicable for the qualitative analysis of proanthocyanidins and the identification of authentic and adulterated proanthocyanidins in GFP.