CN115887605B - Traditional Chinese medicine extract, medicine and detection method thereof - Google Patents
Traditional Chinese medicine extract, medicine and detection method thereof Download PDFInfo
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Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K33/00—Medicinal preparations containing inorganic active ingredients
- A61K33/06—Aluminium, calcium or magnesium; Compounds thereof, e.g. clay
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- A—HUMAN NECESSITIES
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
- A61K36/18—Magnoliophyta (angiosperms)
- A61K36/88—Liliopsida (monocotyledons)
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- A61K36/9068—Zingiber, e.g. garden ginger
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- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
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- G01N30/02—Column chromatography
- G01N30/86—Signal analysis
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Abstract
The invention discloses a traditional Chinese medicine extract, which is prepared from the following traditional Chinese medicines: 1 to 100 parts of magnolia officinalis, 1 to 100 parts of charred betel nut, 1 to 100 parts of roasted tsaoko amomum fruit, 1 to 100 parts of ephedra herb, 1 to 100 parts of bitter apricot seed, 1 to 100 parts of notopterygium root, 1 to 100 parts of ginger, 1 to 100 parts of patchouli, 1 to 100 parts of eupatorium, 1 to 100 parts of rhizoma atractylodis, 1 to 100 parts of poria cocos, 1 to 100 parts of bighead atractylodes rhizome, 1 to 100 parts of gypsum, 1 to 100 parts of charred hawthorn fruit, 1 to 100 parts of charred Massa Medicata Fermentata, 1 to 100 parts of charred malt, 1 to 100 parts of earthworm, 1 to 100 parts of paniculate swallowwort root, 1 to 100 parts of rhizoma dryopteris, and 1 to 100 parts of semen lepidii, wherein the ephedrine content of the extract is 0.5 to 1.5mg/g, and the solid content transfer rate is 18 to 25%.
Description
Technical Field
The invention relates to the technical field of traditional Chinese medicines, in particular to a traditional Chinese medicine extract, a medicine and a detection method thereof.
Background
Viral pneumonia is a disease that causes lung inflammation by upper respiratory tract virus infection and downward spreading, resulting in pulmonary ventilation dysfunction. The disease can occur all the year round, but is mostly seen in winter and spring festival, and can occur in outbreak and epidemic or scattered. Clinically, it is mainly manifested as fever, headache, general soreness, dry cough and lung infiltration. Pneumonia caused by influenza viruses is most common, and other pathogens including respiratory syncytial virus, adenovirus, parainfluenza virus have also attracted considerable attention.
Viral infection is mainly manifested as interstitial lesions of the lungs. Ciliated columnar epithelial cells are initially involved and then invade other respiratory tract cells including alveolar cells, mucous gland cells and macrophages. The virus replicates in the cell and then releases the infectious virus to infect neighboring cells. The infected ciliated cells may undergo degeneration including granule degeneration, vacuole formation, cell swelling and nuclear arrest, followed by necrosis and disintegration. Cell debris accumulates in the airways and blocks the small airways and respiratory tract swelling occurs. The alveolar space has obvious inflammatory response, accompanied by lymphocyte and macrophage infiltration, and even plasma cell and neutrophil infiltration and edema. Necrosis and hemorrhagic fibrin thrombus can appear in the alveolar capillaries, and the eosinophilic transparent membrane can be seen in the alveoli. Severe infections may cause pulmonary edema, excessive changes, bleeding, necrosis of lung parenchyma, and atelectasis.
Influenza virus and respiratory syncytial virus are the most common viruses responsible for upper respiratory tract infections. Influenza viruses belong to the orthomyxoviridae family, are RNA viruses, and are classified into type a, type b, and type c 3 according to the antigenicity of viral nucleoprotein and matrix protein. Wherein the influenza A virus has rapid mutation and strong virulence. H1N1/FM1 belongs to influenza virus A mouse lung adaptation strain, and simulates influenza A virus to prepare lung infection injury. Influenza a viruses initiate infection by binding of hemagglutinin to the cell surface of respiratory epithelial cells containing sialic acid receptors, and upon entry into the cell, the viral genome begins transcription and replication. The repeated massive virus particles begin to infect other cells through the diffusion of respiratory mucosa, thereby inducing cytokine storm, leading to systemic inflammatory reaction, and further appearing acute respiratory distress syndrome, shock and multiple organ failure. The respiratory syncytial virus belongs to Paramyxoviridae and is an RNA virus. Pathogenesis includes interactions between viruses and host-affected cell injury, inflammation, humoral and local immune responses, and hyperreactivity.
At present, according to various data and clinical use, the traditional Chinese medicine has the characteristics of remarkable antiviral effect, broad antiviral spectrum and small toxic and side effects. In addition, the medicine has antiviral, antipyretic and antiinflammatory effects, and has multiple effects on infection caused by virus, such as shortened fever time, controlled inflammation diffusion, and promotion of inflammation absorption, i.e. multi-path and multi-azimuth effects; because of the diversification of the effective components of the traditional Chinese medicine in the treatment process, the virus is difficult to generate drug resistance, so that the traditional Chinese medicine has obvious advantages in the aspect of treating virus infectious diseases, and has wide clinical application prospect.
Disclosure of Invention
The invention aims to make up the defects of the prior art and provides a traditional Chinese medicine extract with antiviral effect, which is characterized by being prepared from the following traditional Chinese medicines in parts by weight: 1 to 100 parts of magnolia officinalis, 1 to 100 parts of charred betel nut, 1 to 100 parts of roasted tsaoko cardamon, 1 to 100 parts of ephedra herb, 1 to 100 parts of bitter apricot seed, 1 to 100 parts of notopterygium root, 1 to 100 parts of ginger, 1 to 100 parts of patchouli, 1 to 100 parts of eupatorium, 1 to 100 parts of rhizoma atractylodis, 1 to 100 parts of poria cocos, 1 to 100 parts of bighead atractylodes rhizome, 1 to 100 parts of gypsum, 1 to 100 parts of charred hawthorn fruit, 1 to 100 parts of charred medicated leaven, 1 to 100 parts of charred malt, 1 to 100 parts of earthworm, 1 to 100 parts of paniculate swallowwort root, 1 to 100 parts of rhizoma dryopterygii and 1 to 100 parts of semen lepidii; wherein the ephedrine content of the extract is 0.5-1.5mg/g, and the solid content transfer rate is 18-25%.
Further, the traditional Chinese medicine extract is prepared from the following traditional Chinese medicines: 1 to 80 parts of magnolia officinalis, 1 to 80 parts of baked betel nut, 1 to 80 parts of roasted tsaoko cardamon, 1 to 60 parts of ephedra herb, 1 to 60 parts of bitter apricot seed, 1 to 800 parts of notopterygium root, 1 to 60 parts of ginger, 1 to 80 parts of patchouli, 1 to 60 parts of eupatorium, 1 to 80 parts of rhizoma atractylodis, 1 to 160 parts of poria cocos, 1 to 120 parts of bighead atractylodes rhizome, 1 to 80 parts of gypsum, 1 to 50 parts of baked hawthorn fruit, 1 to 80 parts of baked medicated leaven, 1 to 60 parts of baked malt, 1 to 80 parts of earthworm, 1 to 80 parts of paniculate swallowwort root, 1 to 60 parts of rhizoma dryopterygii and 1 to 80 parts of semen lepidii; wherein the content of the extract of the peucedanum praeruptorum is 2-8mg/g
Further, the traditional Chinese medicine extract is prepared from the following traditional Chinese medicines: 50 parts of magnolia officinalis, 30 parts of charred betel nut, 50 parts of roasted tsaoko cardamon, 30 parts of ephedra, 30 parts of bitter apricot seed, 50 parts of notopterygium root, 50 parts of ginger, 50 parts of patchouli, 30 parts of eupatorium, 50 parts of rhizoma atractylodis, 150 parts of poria cocos, 100 parts of bighead atractylodes rhizome, 50 parts of gypsum, 30 parts of charred hawthorn, 50 parts of charred medicated leaven, 30 parts of charred malt, 50 parts of earthworm, 50 parts of paniculate swallowwort root, 30 parts of rhizoma dryopterygii, and 50 parts of semen lepidii.
Further, the preparation of the traditional Chinese medicine extract comprises the following steps:
weighing magnolia officinalis, betel nut, roasted fructus amomi, ephedra, bitter apricot kernel, notopterygium root, ginger, patchouli, eupatorium, rhizoma atractylodis, poria cocos, bighead atractylodes rhizome, gypsum, hawthorn fruit, jiao Liu medicated leaven, malt, earthworm, paniculate swallowwort root, rhizoma dryopterygii and semen lepidii, respectively adding water to extract twice, adding 6 times of water for the first time, extracting for 1.5 hours, adding 4 times of water for the second time, extracting for 1.0 hour, combining the extracting solutions, filtering, concentrating the filtrate to have a relative density of 1.10-1.15, centrifugally filtering, and drying the filtrate; wherein the ephedrine content of the extract is 1.20-1.50mg/g, the solid content transfer rate is 19-22%, and the content of the peucedanum praeruptorum is 6-8mg/g.
Further, the similarity of the fingerprint of the magnolia officinalis with the reference fingerprint is not lower than 0.90. Wherein the reference fingerprint comprises common peak honokiol and magnolol. The control fingerprint may be, for example, fig. 1.
Further, the degree of similarity of the finger print of the charred betel nut is not lower than 0.90 compared with the reference finger print. Wherein the reference fingerprint comprises common betulin and arecoline. The control fingerprint may be, for example, fig. 2.
Further, the finger print of the roasted fructus Tsaoko has a similarity of not less than 0.90 as compared with the reference finger print. Wherein the control fingerprint comprises common protocatechuic acid. The control fingerprint may be, for example, fig. 3.
A preparation method of a traditional Chinese medicine extract is characterized by comprising the following steps: weighing magnolia officinalis, betel nut, roasted fructus amomi, ephedra, bitter apricot kernel, notopterygium root, ginger, patchouli, eupatorium, rhizoma atractylodis, poria cocos, bighead atractylodes rhizome, gypsum, hawthorn fruit, jiao Liu medicated leaven, malt, earthworm, paniculate swallowwort root, rhizoma dryopterygii and semen lepidii, respectively adding water to extract twice, adding 6 times of water for the first time, extracting for 1.5 hours, adding 4 times of water for the second time, extracting for 1.0 hour, combining the extracting solutions, filtering, concentrating the filtrate to have a relative density of 1.10-1.15, centrifugally filtering, and drying the filtrate; wherein the ephedrine content of the extract is 1.20-1.50mg/g, the solid content transfer rate is 19-22%, and the content of the peucedanum praeruptorum is 6-8mg/g. Wherein the fingerprint of the magnolia officinalis, the charred betel nut or the roasted fructus tsaoko is defined as before. The invention also provides application of the traditional Chinese medicine extract in preparing medicines for treating influenza virus H1N1 or FM1 or respiratory syncytial virus.
The invention also provides a medicine prepared from the traditional Chinese medicine extract and pharmaceutically acceptable auxiliary materials or additives.
Specifically, the medicine is selected from decoction, granule, capsule, tablet, oral liquid, pill, soft capsule, dripping pill, tincture, syrup, suppository, gel, spray, and injection.
Further, the medicine is granule, and the auxiliary materials or additives are preferably dextrin and sucralose.
Further, the medicament may also include an antiviral medicament for upper respiratory tract infections, such as ribavirin and/or oseltamivir phosphate.
The invention also provides a method for detecting the fingerprint of the traditional Chinese medicine extract or the medicine, which is characterized in that a sample solution is taken for HPLC detection, and chromatographic conditions of the HPLC detection comprise: adopting a C18 chromatographic column, taking methanol as a mobile phase A, taking a phosphoric acid aqueous solution with concentration of 0.1% as a mobile phase B, wherein the elution in chromatographic conditions detected by HPLC is gradient elution, and the gradient elution program is as follows: 0-5 min,0% A; 5-25 min, 0-15% A; 25-60 min, 15-55% A; 60-75 min, 55-100% of A; 75-80 min,100% A.
The sample solution is prepared from Chinese medicinal extract or medicine, and can be prepared by, for example, taking 1g of granule, placing into conical flask with plug, adding 25ml of water, and performing ultrasonic treatment for 30 min.
Further, the chromatographic conditions include: the flow rate is 1.0mL/min, the column temperature is 30 ℃, and the detection wavelength is 250nm.
Further, the fingerprint is shown in fig. 14.
Specifically, in the fingerprint, 10 characteristic peaks should be presented in the characteristic spectrum of the sample, the peak corresponding to the reference peak is S peak, the relative retention time of each characteristic peak and S peak is calculated, the relative retention time should be within ±10% of the specified value, and the specified value is: 0.11 (Peak 1), 0.27 (Peak 2), 0.36 (Peak 3), 0.38 (Peak 4), 0.41 (Peak 5), 0.84 (Peak 6), 0.92 (Peak 7), 1.00[ Peak 8 (S) ], 1.19 (Peak 9), 1.29 (Peak 10).
The invention prepares a new traditional Chinese medicine composition, improves the quality standard of the composition, evaluates the effectiveness of the composition particles for treating viral upper respiratory tract infection by adopting an influenza virus H1N1/FM1 strain infection model and a respiratory syncytial virus infection model, shows that the composition can reduce the viral load and inflammatory cytokines in lung tissues, shows that the composition has the effect of enhancing treatment on the common specific viral infection, and provides basis for further clinical research.
Drawings
FIG. 1 is a fingerprint of Magnolia officinalis; peak 6: honokiol peak 7 (S): magnolol;
FIG. 2 is a fingerprint of Arecae semen; peak 1: arecoline peak 3 (S) arecoline;
FIG. 3 is a fingerprint of a roasted fructus Tsaoko drug control; peak 1 protocatechuic acid;
FIG. 4 is a 3D image of a full wavelength scan of a sample solution;
FIG. 5 is a chromatogram of the wavelength investigation of a sample solution;
FIG. 6 is a flow phase contrast survey chromatogram;
FIG. 7 is a chromatogram of a test sample preparation method;
FIG. 8 is a durability review chromatogram;
FIG. 9 is a precision review chromatogram;
FIG. 10 reproducibility of a chromatogram;
FIG. 11 stability review chromatogram;
FIG. 12 is a graph of a batch profile overlay;
FIG. 13 compares feature maps;
FIG. 14 compares the characteristic pattern with the identification results of each characteristic peak; wherein, 1-adenine; 2-uridine; 3-guanosine; 4-inosine; 5-5-hydroxymethylfurfural; 6-magnolol glycoside A; 7-bergamot phenol glucoside; 8-decursin; 9-6' -O- (trans-feruloyl) -peucedanum praeruptorin; 10-p-hydroxy phenethyl anisate.
Detailed Description
Oseltamivir is an inhibitor of neuraminidase of influenza virus and is mainly used for treating influenza a and b clinically. Ribavirin Lin Weian spectrum antiviral drugs are clinically useful for the treatment of respiratory syncytial virus, influenza a and b, but FDA is less recommended. The invention aims at providing a traditional Chinese medicine composition, and a preparation method and application thereof. Hereinafter, a conventional influenza virus or respiratory syncytial virus drug will be described in detail with reference to the experimental contents.
It is particularly pointed out that similar substitutions and modifications to the invention will be apparent to those skilled in the art, which are all deemed to be included in the invention. It will be apparent to those skilled in the relevant art that variations and modifications can be made in the methods and applications described herein, or in the appropriate variations and combinations, without departing from the spirit and scope of the invention. It will be apparent that the described embodiments are only some, but not all, embodiments of the invention.
The invention is carried out according to the conventional conditions or the conditions suggested by manufacturers if the specific conditions are not noted, and the raw materials or auxiliary materials and the reagents or instruments are conventional products which can be obtained commercially if the manufacturers are not noted.
Experimental example 1 examination of the preparation process
1. Investigation of the extraction solvent
Weighing 1 part of magnolia officinalis 15g, betel nut 9g, roasted tsaoko amomum fruit 9g, ephedra 6g, bitter apricot seed 9g, notopterygium root 15g, ginger 15g, patchouli 15g, eupatorium fortunei 9g, rhizoma atractylodis 15g, poria cocos 45g, bighead atractylodes rhizome 30g, gypsum 15g, hawthorn fruit 9g, medicated leaven 9g, malt 9g, earthworm 15g, paniculate swallowwort 15g, rhizoma dryopterygii 9g and semen lepidii 15g, decocting with water twice, extracting for 1.5h for the first time, and extracting for 1.0h for the second time. Mixing the extracting solutions, filtering, concentrating the filtrate to a relative density of 1.10-1.15, centrifugally filtering, vacuum drying the filtrate, and spray drying and crushing to obtain the intermediate composition. The ephedrine transfer rate and solid content transfer rate of different extraction solvent volumes were measured as follows:
The calculation formula is as follows:
wherein the total transfer rate refers to the ratio of the total amount of ephedrine hydrochloride and pseudoephedrine hydrochloride in the extract to the ephedrine hydrochloride and pseudoephedrine hydrochloride in the medicinal material.
Experimental results show that the transfer rate of ephedrine hydrochloride and pseudoephedrine hydrochloride and the transfer rate of solid content increase with the increase of the water adding amount. When the solvent is multiplied by 4 and 3 to 6 and 4 times, the transfer rate of each index is obviously increased, and when the water adding amount is continuously increased, the growth trend of each index is gentle, but when the solvent is too high, the transfer rate is reduced. And comprehensively considering the energy efficiency and the index component transfer rate, determining the water adding amount to be 6 times of the first water adding amount and 4 times of the second water adding amount.
2. Investigation of soaking time
In addition, 15g of magnolia officinalis, 9g of betel nut, 9g of roasted tsaoko amomum fruit, 6g of ephedra herb, 9g of bitter apricot seed, 15g of notopterygium root, 15g of ginger, 15g of patchouli, 9g of eupatorium, 15g of rhizoma atractylodis, 45g of poria cocos, 30g of bighead atractylodes rhizome, 15g of gypsum, 9g of scorched hawthorn fruit, 9g of scorched medicated leaven, 9g of malt, 15g of earthworm, 15g of paniculate swallowwort root, 9g of rhizoma dryopterygii and 15g of semen lepidii are weighed 1 part, 3 parts of the materials are added, the materials are decocted for two times by adding water for the first time, adding water for 1.5 hours, adding water for the second time, and extracting for 1.0 hours, and 3 parts of soaking time are respectively 0, 30 and 60 minutes. Mixing the extracting solutions, filtering, concentrating the filtrate to a relative density of 1.10-1.15, centrifugally filtering, vacuum drying the filtrate, and spray drying and crushing to obtain the intermediate composition.
The influence of the soaking time on the transfer rate of ephedrine hydrochloride and pseudoephedrine hydrochloride and the transfer rate of solid content are examined. The experimental results are as follows:
the calculation formula is as follows:
experimental results show that the soaking time has little influence on the total transfer rate and solid content transfer rate of ephedrine hydrochloride and pseudoephedrine hydrochloride. Therefore, the extraction process is determined to be selected without soaking, and the extraction is directly performed.
3. Investigation of extraction time
In addition, 15g of magnolia officinalis, 9g of betel nut, 9g of roasted tsaoko amomum fruit, 6g of ephedra herb, 9g of bitter apricot seed, 15g of notopterygium root, 15g of ginger, 15g of patchouli, 9g of eupatorium, 15g of rhizoma atractylodis, 45g of poria cocos, 30g of bighead atractylodes rhizome, 15g of gypsum, 9g of scorched hawthorn fruit, 9g of medicated leaven, 9g of scorched malt, 15g of earthworm, 15g of paniculate swallowwort root, 9g of rhizoma dryopterygii and 15g of semen lepidii are weighed and are respectively extracted by adding water for 2 times, 6 times of water for the first time and 4 times of water for the second time, the first extraction time is respectively 60min, 75min, 90min, 105min and 120min, the second extraction time is respectively 30min, 45min, 60min, 75min and 90min, and the influence of the extraction time on ephedrine hydrochloride and pseudoephedrine hydrochloride transfer rate and solid content transfer rate is examined, and experimental results are as follows:
the calculation formula is as follows:
experimental results show that the ephedrine hydrochloride and pseudoephedrine hydrochloride transfer rate and the solid content transfer rate increase with the increase of the extraction time, and the trend is presented. When the extraction time is increased from 60 to 30min to 90 and 60min, the increasing trend of each index is obvious, and the increasing trend of each index is gradually gentle when the extraction time is continuously increased. Therefore, the extraction time is selected to be 90min for the first extraction and 60min for the second extraction.
4. Verification of extraction process
To verify the preferred extraction process, an amplification verification test was performed according to the preferred results of the single factor experiment. In the early experiments, several main components of the extract fluctuate greatly, so that the curative effect is affected, and therefore, the effective and controllable extraction is realized by enhancing the control from raw materials to the preparation process. 15g of magnolia officinalis, 9g of betel nut, 9g of roasted tsaoko cardamom, 6g of ephedra, 9g of bitter apricot seed, 15g of notopterygium root, 15g of ginger, 15g of patchouli, 9g of eupatorium, 15g of rhizoma atractylodis, 45g of poria cocos, 30g of bighead atractylodes rhizome, 15g of gypsum, 9g of hawthorn fruit, 9g of medicated leaven, 9g of malt, 15g of earthworm, 15g of paniculate swallowwort root, 9g of rhizoma dryopterygii, and 15g of semen lepidii are weighed 1 part, 12 parts (certain important medicines of magnolia officinalis, betel nut and roasted tsaoko cardamom all establish special medicinal materials and decoction piece fingerprint control standards, and prescription medicinal materials all meet the requirements of the latest pharmacopoeia standards) are respectively extracted twice by adding water, adding 6 times of water for the first time, extracting for 1.5h, adding 4 times of water for the second time, and extracting for 1.0h. Every 4 parts were pooled as 1 group, 3 groups total. The ephedrine hydrochloride and pseudoephedrine hydrochloride transfer rate, solid content transfer rate and other important indexes are measured, the stability and feasibility of the process are inspected, and the experimental results are as follows:
The verification result shows that the preferred process is stable and feasible and has good reproducibility, so the determined optimal extraction process is to extract twice by adding water for the first time, adding 6 times of water, and extracting for 1.5 hours; adding 4 times of water for the second time, and extracting for 1.0h.
5. Fingerprint control standard for magnolia officinalis, betel nut and roasted tsaoko amomum fruit medicinal material and decoction pieces
5.1 fingerprint control Standard for Magnolia officinalis and decoction pieces
Chromatographic conditions and System applicability test octadecylsilane chemically bonded silica was used as filler (Waters CORTECTS C) 18 A chromatographic column, 150mm x 4.6mm,2.7 μm); acetonitrile is taken as a mobile phase A, 0.1% acetic acid solution is taken as a mobile phase B, and gradient elution is carried out according to the specifications in the following table; the column temperature is 35 ℃; the flow rate is 0.8ml/min; the detection wavelength was 230nm. The theoretical plate number is not lower than 4000 calculated according to magnolol peak.
Preparation of reference solution A. Mu.g of mixed solution containing magnolol and honokiol reference substance (appropriate amount) is prepared by precisely weighing, and adding methanol to obtain each 1ml of mixed solution.
Preparation of sample solution 1g of the sample powder (sieving with a third sieve), precisely weighing, placing into a conical flask with a plug, precisely adding 25ml of 50% methanol solution, shaking, sealing, soaking for 24 hr, filtering, and collecting the subsequent filtrate.
The measurement method comprises precisely sucking 10 μl of each of the reference solution and the sample solution, and injecting into a liquid chromatograph for measurement.
The fingerprint of the sample should show chromatographic peaks with the same retention time as those of the chromatographic peaks of the reference substance in figure 1. According to the similarity evaluation system of the traditional Chinese medicine chromatographic fingerprints, the similarity between the fingerprints of the sample and the reference fingerprints is calculated and is not lower than 0.90.
5.2 Arecae semen medicinal material and decoction piece fingerprint control standard
Chromatographic conditions and System applicability test with strong cation exchange bonded silica gel as filler (Thermo BioBasic SCX column, column length 25cm, inner diameter 4.6mm, particle size 5 μm); acetonitrile-0.2% phosphoric acid solution (pH was adjusted to 3.8 with ammonia) (65:35) as mobile phase; the column temperature is 35 ℃; the flow rate is 1.2ml/min; the detection wavelength was 210nm. The number of theoretical plates should be not less than 10000 calculated by arecoline.
Preparation of reference solution A proper quantity of arecoline hydrobromide reference substance is taken, precisely weighed, and methanol is added to prepare 50 mug solution per 1ml, thus obtaining the arecoline hydrobromide reference substance.
Preparation of sample solution, namely 0.5g of sample powder (sieving with a second sieve), precisely weighing, placing into a conical flask with a plug, precisely adding 50ml of 50% methanol solution, performing ultrasonic treatment for 30 minutes, cooling, shaking, filtering, and collecting subsequent filtrate.
Respectively precisely sucking 10 μl of reference solution and sample solution, injecting into liquid chromatograph, measuring, and recording chromatogram.
The sample fingerprint should show chromatographic peaks with the same retention time as those of the reference chromatographic peak in figure 2. According to the similarity evaluation system of the traditional Chinese medicine chromatographic fingerprints, the similarity between the fingerprints of the sample and the reference fingerprints is calculated and is not lower than 0.90.
5.3 fingerprint control Standard for stewing fructus Tsaoko medicinal materials and decoction pieces
Chromatographic conditions and System applicability octadecylsilane chemically bonded silica was used as filler (Waters CORTECTS T3 column, column length of 15cm, inner diameter of 4.6mm, particle size of 2.7 μm); acetonitrile is taken as a mobile phase A, 0.1% formic acid solution is taken as a mobile phase B, and gradient elution is carried out according to the specification of the table below; the column temperature is 30 ℃; the flow rate is 0.8ml/min; the detection wavelength was 254nm. The theoretical plate number is not less than 10000 calculated according to protocatechuic acid peak.
Preparing reference solution, precisely weighing protocatechuic acid reference, and adding methanol to obtain solution containing 200 μg per 1 ml.
Preparation of sample solution 1g of the sample powder (sieving with a second sieve), precisely weighing, precisely adding 25ml of 50% methanol solution, performing ultrasonic treatment for 30 min, cooling, shaking, filtering, and collecting the subsequent filtrate.
The measuring method comprises the steps of precisely sucking 5-10 mu l of reference solution and 10 mu l of sample solution respectively, injecting into a liquid chromatograph, measuring, and recording a chromatogram.
The sample fingerprint should show chromatographic peaks with the same retention time as those of the reference chromatographic peak in fig. 3. According to the similarity evaluation system of the traditional Chinese medicine chromatographic fingerprints, the similarity between the fingerprints of the sample and the reference fingerprints is calculated and is not lower than 0.90.
Experimental example 2 preparation of the formulation
Preparation example 1 Chinese medicinal compound granule
The formula comprises the following components: 50 parts of magnolia officinalis, 30 parts of charred betel nut, 50 parts of roasted tsaoko cardamon, 30 parts of ephedra, 30 parts of bitter apricot seed, 50 parts of notopterygium root, 50 parts of ginger, 50 parts of patchouli, 30 parts of eupatorium, 50 parts of rhizoma atractylodis, 150 parts of poria cocos, 100 parts of bighead atractylodes rhizome, 50 parts of gypsum, 30 parts of charred hawthorn, 50 parts of charred medicated leaven, 30 parts of charred malt, 50 parts of earthworm, 50 parts of paniculate swallowwort root, 30 parts of rhizoma dryopterygii, and 50 parts of semen lepidii.
The preparation method of the traditional Chinese medicine composition granule comprises the following steps:
reflux extracting the above materials with water for 2 times, adding 6 times of water for 1.5 hr for the first time, adding 4 times of water for the second time, extracting for 1.0 hr, mixing the extractive solutions, filtering, concentrating the filtrate to relative density of 1.10-1.15, centrifuging, filtering, vacuum drying the filtrate, spray drying, pulverizing to obtain intermediate composition, adding sucralose and dextrin, and mixing to obtain granule.
Preparation example 2 Chinese medicinal compound capsule
The formula comprises the following components: 50 parts of magnolia officinalis, 30 parts of charred betel nut, 50 parts of roasted tsaoko cardamon, 30 parts of ephedra, 30 parts of bitter apricot seed, 50 parts of notopterygium root, 50 parts of ginger, 50 parts of patchouli, 30 parts of eupatorium, 50 parts of rhizoma atractylodis, 150 parts of poria cocos, 100 parts of bighead atractylodes rhizome, 50 parts of gypsum, 30 parts of charred hawthorn, 50 parts of charred medicated leaven, 30 parts of charred malt, 50 parts of earthworm, 50 parts of paniculate swallowwort root, 30 parts of rhizoma dryopterygii, and 50 parts of semen lepidii.
The preparation method of the traditional Chinese medicine composition capsule comprises the following steps:
reflux extracting the medicinal materials with water for 2 times, adding 6 times of water for 1.5 hr, adding 4 times of water for 1.0 hr, mixing extractive solutions, filtering, concentrating the filtrate to relative density of 1.10-1.15, centrifuging, filtering, vacuum drying the filtrate, spray drying, granulating, and making into capsule.
Preparation example 3 Chinese medicinal compound tablet
The formula comprises the following components: 50 parts of magnolia officinalis, 30 parts of charred betel nut, 50 parts of roasted tsaoko cardamon, 30 parts of ephedra, 30 parts of bitter apricot seed, 50 parts of notopterygium root, 50 parts of ginger, 50 parts of patchouli, 30 parts of eupatorium, 50 parts of rhizoma atractylodis, 150 parts of poria cocos, 100 parts of bighead atractylodes rhizome, 50 parts of gypsum, 30 parts of charred hawthorn, 50 parts of charred medicated leaven, 30 parts of charred malt, 50 parts of earthworm, 50 parts of paniculate swallowwort root, 30 parts of rhizoma dryopterygii, and 50 parts of semen lepidii.
The preparation method of the traditional Chinese medicine composition tablet comprises the following steps:
Reflux extracting the medicinal materials with water for 2 times, adding 6 times of water for 1.5 hr, adding 4 times of water for 1.0 hr, mixing extractive solutions, filtering, concentrating the filtrate to relative density of 1.10-1.15, centrifuging, filtering, vacuum drying the filtrate, spray drying to obtain extract powder, adding microcrystalline cellulose, etc., and making into tablet.
Experimental example 3 therapeutic Effect of particles of the composition of the present invention on infection of influenza Virus H1N1/FM1 Strain
1 test materials
1.1 test drug preparation example 1 granules, supplied by Jiangsu Kangyuan pharmaceutical Co., ltd.
1.2 Positive control
Oseltamivir phosphate particles (kewei): is suitable for the production of Changjiang pharmaceutical industry, inc., the components: each bag of granules contains 15 mg of oseltamivir phosphate.
1.2.2 ribavirin granules: sichuan Baili pharmaceutical Co., ltd., the ingredients: the main ingredient of the product is ribavirin. Specification of: 50mg.
1.3 reagents
1.4 instruments
1.5 test animals
1.6 viral strains
Influenza a H1N1 virus FM1 strain was purchased from the american standard collection for organisms (ATCC). The ABSL-2 laboratory is used for routine passage and stored at-80 ℃ for standby.
2 dose design and pharmaceutical formulation
2.1 preparation example 1:
preparing a liquid medicine: taking particles before the test, adding distilled water into the particles to a certain volume, and taking the particles to a certain volume, wherein the dosage is 26.4g crude drug/kg/d, and the particles are administrated according to 0.2mL/10g weight/time of stomach irrigation, 1 time/day, and 4 consecutive days.
2.2 oseltamivir phosphate: the dosage of the mice in the test is 27.5mg/kg/d, which is equivalent to the clinical equivalent dose of human, and the mice are administrated according to the dosage of 0.2mL/10g of body weight/time of stomach infusion, 1 time/day and 4 continuous days.
2.3 ribavirin: mice were dosed at 82.5mg/kg/d at the time of trial, at 0.2mL/10g body weight/time of gastric administration, 1 time/day, for 4 consecutive days.
2.4 composition set 1: preparation example 1.2 g crude drug/kg/d+oseltamivir phosphate 13.7mg/kg/d was administered in the same manner as above.
2.5 composition set 2: namely, preparation example 1.13.2 g crude drug/kg/d+ribavirin 41.2mg/kg/d, and the administration mode was the same as above.
3 test method
70 ICR mice are taken, the weight of each half of the ICR mice is 14+/-1 g, and each half of the ICR mice is randomly divided into 7 groups according to the weight grade, namely a normal control group, a model control group, an oseltamivir phosphate group, a ribavirin, a composition group, an oseltamivir phosphate+composition group and a ribavirin+composition group. In addition to the normal control group, mice were lightly anesthetized with isoflurane at 15 LDs 50 Influenza virus liquid (H1N 1/FM1 strain) was infected by nasal drops of 35. Mu.L each. The administration was started on the day of infection, and each time, 0.2mL/10g of the composition was administered by gavage, 1 time a day for 4 consecutive days, and the normal control group and the model control group were administered by gavage with distilled water under the same conditions. On day 5, each group of mice was weighed; the lung weight is dissected, lung tissue is taken for HE pathological detection, and lung index inhibition rate are calculated.
Lung index (%) =wet lung weight (g)/body weight (g) ×100
Under-mirror standard:
"-": the lung interstitial of the mice does not have exudation, blood stasis and enlargement of tissue interstitial cells, inflammation around bronchioles in the lung and normal tissue structure.
"+": the lung tissue and alveolus interstitium of the mice have no obvious exudative inflammation, no large-area blood stasis, and a small amount of limited inflammation around bronchioles in the lungs, mainly lymph.
"++": the pulmonary tissue alveolar interstitium of the mice does not have large-area inflammation and mucus exudation, has limited platelet mucus exudation, has limited inflammation around pulmonary bronchioles, mainly comprises lymph, and has limited increase (segmental) of endoluminal cells.
"+++": the pulmonary tissue of the mice has large-area inflammation and mucus exudation in the alveoli interstitium, the exudation inflammation is mainly composed of lymphocytes, a small number of lobular nuclei and eosinophils, the cell size is uneven, the cells are clustered, and a large amount of pink mucus exists. Perivascular inflammation is obvious, peripulmonary bronchiole inflammation is limited, endoluminal cell proliferation and perivascular inflammation are heavy.
The statistical method comprises the following steps: results were statistically processed using the comparative t-test between groups.
4 effects of the inventive composition particles on the pulmonary index and the inhibition of the pulmonary index
The results of the study (table 1) show: after mice are infected by adopting the influenza A H1N1 virus FM1 strain, the lung index of the mice in a model control group is obviously increased, and compared with a normal control group, the lung index of the mice is obviously different (P < 0.01); the composition particles are administered for treatment for 4 days on the day of infection, the lung indexes of oseltamivir phosphate, the composition group, oseltamivir phosphate+the composition group and ribavirin+the composition group are obviously reduced, and compared with a model control group, obvious differences are shown, so that the composition has obvious synergistic effect on anti-influenza virus on antiviral drugs for upper respiratory tract infection.
TABLE 1 Effect of composition particles on lung index of influenza H1N1/FM1 strain infected mice
Note that: comparison with the Normal control group ## P<0.01; in comparison with the control group of the model, ** P<0.01,*P<0.05。
experimental example 4 therapeutic Effect of the particles of the composition of the invention on respiratory syncytial Virus infection
1 test materials
1.1 test drug preparation example 1 granules, supplied by Jiangsu Kangyuan pharmaceutical Co., ltd.
1.2 Positive control
Oseltamivir phosphate particles (kewei): is suitable for the production of Changjiang pharmaceutical industry, inc., the components: each bag of granules contains 15 mg of oseltamivir phosphate.
1.2.2 ribavirin granules: sichuan Baili pharmaceutical Co., ltd., the ingredients: the main ingredient of the product is ribavirin. Specification of: 50mg.
1.3 reagents
Reagent name | Lot number | Manufacturing factories | Reagent use |
Isoflurane (I-F) | S200106 | Shanghai Jade research science instruments Co., ltd | Anesthesia of mice |
IL-4 | 239645-001 | Thermo Fisher | Lung tissue factor detection |
IL-33 | 230852-006 | Thermo Fisher | Lung tissue factor detection |
1.4 instruments
1.5 test animals
1.6 viral strains
Respiratory Syncytial Virus (RSV) strains were purchased from american standard collection for organisms (ATCC). The ABSL-2 laboratory is used for routine passage and stored at-80 ℃ for standby.
2 dose design and pharmaceutical formulation
2.1 preparation example 1:
preparing a liquid medicine: taking particles, adding distilled water, fixing volume to 40mL, and taking 26.4g crude drug/kg/d, wherein the administration is carried out according to 0.2mL/10g weight/time of stomach irrigation, 1 time/day, and 4 consecutive days.
2.2 oseltamivir phosphate particles: the dosage of the mice in the test is 27.5mg/kg/d, which is equivalent to the clinical equivalent dose of human, and the mice are administrated according to the dosage of 0.2mL/10g of body weight/time of stomach infusion, 1 time/day and 4 continuous days.
2.3 ribavirin granules: mice were dosed at 82.5mg/kg/d at the time of trial, at 0.2mL/10g body weight/time of gastric administration, 1 time/day, for 4 consecutive days.
2.4 composition set 1: namely 13.2g crude drug/kg/d+oseltamivir phosphate 13.7mg/kg/d of the granule of preparation 1, and the administration mode is the same as above.
2.5 composition set 2: namely 13.2g crude drug/kg/d+41.2 mg/kg/d ribavirin of preparation example 1.
3 test method
70 BALB/C mice are taken, the weight is 14+/-1 g, the male and female mice are divided into 7 groups randomly according to the weight grade, and the normal control group, the model control group, the oseltamivir phosphate group, the ribavirin, the composition group, the oseltamivir phosphate+composition group and the ribavirin+composition group are respectively 10. In addition to the normal control group, mice were lightly anesthetized with isoflurane at 100TCID 50 RSV virus droplets are nasally infected, 45 μl each. The administration was started on the day of infection, and each time, 0.2mL/10g of the composition was administered by gavage, 1 time a day for 4 consecutive days, and the normal control group and the model control group were administered by gavage with distilled water under the same conditions. On day 5, each group of mice was weighed; the lung is dissected and weighed, the lung tissue is taken for inflammatory factor detection, and the lung index inhibition rate are calculated.
Lung index (%) =wet lung weight (g)/body weight (g) ×100
4 experimental results
4.1 Effect of composition particles on pulmonary index and pulmonary index inhibition
The results of the study (table 2) show: after mice are infected by Respiratory Syncytial Virus (RSV) nasal drops, the lung index of mice in a model group is obviously increased, and compared with a normal control group, the lung index of mice in the model group is obviously different (P < 0.01); the composition particles are administered for treatment for 4 days on the day of infection, the lung indexes of oseltamivir phosphate, the composition group, oseltamivir phosphate+the composition group and ribavirin+the composition group are obviously reduced, and compared with a model control group, the composition has obvious difference, so that the composition has a certain synergistic effect on anti-respiratory syncytial virus on antiviral drugs for upper respiratory tract infection.
Table 2 effect of composition particles on lung index in mice infected with respiratory syncytial virus
Note that: comparison with the Normal control group ## P<0.01; comparison with modelGroup comparison, P<0.05。
4.2 Effect on cytokine IL-33 in pulmonary tissue
The lung tissue is taken out from a low-temperature refrigerator at-80 ℃, treated by high-efficiency protein lysate (PMSF and protease inhibitor are added), and centrifuged to obtain protein supernatant. Placing the protein sample in an ice box, and delivering the protein sample to the Lez biotechnology Co-Ltd for carrying out high-flux liquid phase protein chip detection on each cytokine condition in mouse lung tissue, wherein specific detection steps are shown in an accessory.
After mice are infected by Respiratory Syncytial Virus (RSV) nasal drops, the lung tissue cytokine IL-33 content of the mice in the model group is obviously increased, and compared with the normal control group, the mice have obvious difference (P < 0.01); the composition particles were administered for 4 days beginning on the day of infection, oseltamivir phosphate, composition, oseltamivir phosphate + composition, ribavirin + composition had significantly reduced IL-33 content, and were significantly different from the model group (P <0.01, P < 0.05). See table 3.
TABLE 3 Effect of composition particles on respiratory syncytial virus infected mouse lung tissue cytokines
And (3) injection: comparison with the Normal control group ## P<0.01, # P<0.05; compared with a model group of the cold-dampness epidemic toxin pneumonia, ** P<0.01。
in this study, 26.4g crude drug/kg/d (1/2 times) mice of the composition particles were administered by intragastric administration for 1 time/day for 3 to 4 consecutive days, and the effectiveness of the composition particles in treating viral upper respiratory tract infection was evaluated by using an influenza virus H1N1/FM1 strain infection model and a respiratory syncytial virus infection model, and the results showed that: the composition can reduce viral load and inflammatory cytokines in lung tissues by combining with antiviral drugs, shows that the composition has a therapeutic effect on common specific viral infections, further promotes and consolidates antiviral effects of other drugs by utilizing the advantages of the traditional Chinese medicines, and provides basis for further clinical research.
Experimental example 5 fingerprint study of the composition of the invention
Instrument and reagent
Instrument: agilent 1260 high performance liquid chromatograph, DAD uv detector; agilent 1260 high performance liquid chromatograph, VWD uv detector; agilent 1290 ultra-high pressure liquid chromatograph, DAD ultraviolet detector, agilent6538Q-TOF-MS mass spectrometer, electrospray (ESI) ion source, agilent company, usa; thermo Fisher Ultimate3000 high performance liquid chromatograph;
mettler Toledo XP6 electronic analytical balance, metrehler company; mettler Toledo AL204 electronic analytical balance, metrehler company; KQ500DB digital control ultrasonic cleaner, kunshan ultrasonic instruments Co., ltd; HH digital display constant temperature water bath, hezhou national instrument manufacturing Co., ltd; milli-Q ultra-pure water instrument, miibo, USA;
Control: adenine, 99.4%, lot B0002908, beijing mann Ha Ge biotechnology limited; uridine, 99.4%, lot B0008580, beijing mann Ha Ge biotechnology limited; guanosine, 96.1%, lot B0006767, beijing Ha Ge biotechnology limited; inosine, 99.2%, lot number 140669-202007, national food and drug verification institute; 5-hydroxymethylfurfural, 95.0%, lot number 8610, shanghai Shidand Standard technology Co., ltd; magnolia bark glycoside A,99.1%, batch No. 7611, shanghai Shidande Standard technology Co., ltd; bergamot phenol glucoside, 98%, lot number CFS202002, wuhan plant biotechnology limited; procyanidine, 99.6%, lot 111821-201604, national food and drug verification institute; 6' -O- (trans-feruloyl) -decursin, 98%, lot CFS202002, wuhan Tianzhi Biotechnology Co., ltd; p-hydroxyphenylethyl anisate, 99.6%, lot A05GB156933, shanghai Yuan Ye Biotechnology Co., ltd;
reagent: methanol (merck, michaux, usa, chromatogrjim); acetic acid (L07203503, merck Feishul technologies Co., ltd.) and other reagents were all analytically pure.
Sample: the granules prepared by the method of preparation example 1 are given in the following batch numbers: 200201, 200202, 200203, 200204, 200205, 200206, 200207, 200208, 200209, 200210, 200211, 200212, 200213, 200214, 200601, 200602, 200603, wherein 200602 is a methodological study batch, all provided by Jiangsu Kangyuan pharmaceutical industry Co., ltd.
1 chromatographic condition selection
Taking a proper amount of the product, grinding, taking about 2g, precisely weighing, placing into a conical flask with a plug, precisely adding 50ml of water, performing ultrasonic treatment for 30 minutes, shaking uniformly, centrifuging, and taking supernatant to obtain a sample solution.
1.1 selection of detection wavelength
The sample solution is taken, DAD is adopted to carry out full-wave scanning, and the result shows that the chromatographic peak information is rich under the condition of 250nm, the response is uniform, the base line is stable, and therefore 250nm is selected as the detection wavelength of the characteristic spectrum. See fig. 4 and 5.
1.2 selection of mobile phases
Based on the water extraction process characteristics of the product, waters Atlantis T with better separation effect on water-soluble components is adopted 3 (4.6×250mm,5μm)C 18 The chromatographic column adopts methanol-0.1% phosphoric acid as a mobile phase system, 250nm is used as a detection wavelength, the separation effect of gradients of different mobile phases is inspected, and as a result, the gradient program IV has better separation degree of each peak, proper retention time and stable base line, so the gradient program IV is preferably used as a mobile phase elution program. The gradient elution procedure is as follows, and the results are shown in FIG. 6.
In summary, chromatographic conditions are assumed to be: octadecylsilane chemically bonded silica is used as filler (Waters Atlantis T, column length of 25cm, inner diameter of 4.6mm, particle diameter of 5 μm); methanol is used as a mobile phase A, 0.1% phosphoric acid is used as a mobile phase B, and gradient elution is carried out according to the specifications in the following table; the flow rate is 1.0ml per minute; the column temperature is 30 ℃; the detection wavelength was 250mn. The theoretical plate number should be not less than 10000 according to the pre-purple flower Hu Ganfeng.
2 selection of preparation method of test sample
The extraction solvent and the extraction mode are examined for optimizing a reasonable and simple preparation method of the sample solution.
Sample solution preparation: taking a proper amount of the product, grinding, taking about 1g, precisely weighing, placing into a conical flask with a plug, precisely adding water and 25ml of 50% methanol respectively, performing ultrasonic treatment for 30 minutes respectively, refluxing for 30 minutes, shaking uniformly, centrifuging, and taking supernatant to obtain 4 parts of sample solution.
Results: the test sample solutions are measured according to the chromatographic conditions, and the result shows that the chromatogram obtained by adopting water as the extraction solvent has higher response of chromatographic peaks with larger polarity before 25min, the overall chromatographic peaks are rich, the response is uniform, and the water extraction process characteristics of the product are combined, preferably, the water is used as the extraction solvent. The richness and response of chromatographic peaks of the chromatogram obtained in the reflux mode and the ultrasonic mode are not obviously different, and the ultrasonic extraction mode is preferred in consideration of the convenience of operation. See fig. 7.
In summary, the test sample treatment method is proposed to be: grinding the materials, precisely weighing about 1g, placing into a conical flask with a plug, precisely adding 25ml of water, performing ultrasonic treatment (power 500W, frequency 40 kHz) for 30 min, shaking, centrifuging, and collecting supernatant.
3 durability inspection
Different wavelengths (245 nm, 250nm, 255 nm), flow rates (0.8 ml/min, 0.9ml/min, 1.0ml/min, 1.1ml/min, 1.2 ml/min), column temperatures (25 ℃, 28 ℃, 30 ℃, 32 ℃, 35 ℃), different batch numbers of columns { column 1: waters Atlantis T 3 (4.6X105 mm,5 μm), SEQ ID NO. 01813017014031; column 2: waters Atlantis T 3 (4.6X105 mm,5 μm), SEQ ID NO. 01813017014008, instrument (instrument 1: agilent 1260, instrument 2: ultimate 3000) for selectionEffect of 10 characteristic peak separation effects.
The results show that the selected characteristic peaks can obtain better separation effect in the wavelength of 250+/-5 nm, the flow rate of 0.8 ml/min-1.2 ml/min and the column temperature of 25-35 ℃ and by using chromatographic columns with different batch numbers and different brands of instruments, thus indicating that the method has good durability. See fig. 8.
4 methodological verification
Precision investigation: the method is used for preparing a sample solution, precisely sucking 10 mu l of the same sample solution, continuously injecting the sample for 6 times, measuring, taking the violaxanthin (peak 8) as a reference peak, and calculating the relative retention time of the calibrated 10 characteristic peaks. The results showed that the RSD values for the relative retention times of the 10 characteristic peaks were all less than 0.5%, indicating good precision of the instrument. See table 4, fig. 9.
Repeatability investigation: 6 parts of test solutions were prepared in parallel according to the above method and measured. The relative retention time of the calibrated 10 characteristic peaks was calculated using decursin (peak 8) as a reference peak. The results showed that the RSD values for the relative retention times of the 10 characteristic peaks were all less than 0.5%, indicating good reproducibility of the method. See table 5, fig. 10.
Stability investigation: taking the same sample solution, respectively injecting 10 mu l of sample at 0h, 3h, 6h, 9h, 12h, 18h, 24h, 30h and 36h, measuring, taking decursin (peak 8) as a reference peak, and calculating the relative retention time of the calibrated 10 characteristic peaks. The results show that the RSD values of the relative retention times of the 10 characteristic peaks are all less than 0.5%, which indicates that the stability of the test sample solution is better within 36 hours. See table 6, fig. 11.
Table 4 results of feature map precision investigation and calculation
Table 5 repeatability investigation calculation results
Table 6 stability investigation calculation results
5 multiple batch measurement and contrast feature map generation
According to the method, 14 batches of samples for clinical practice, 3 batches of pilot samples and 3 batches of process verification samples are measured, 10 peaks are selected as characteristic peaks, 20 batches of preparations are used for generating a control fingerprint, the peak corresponding to the reference peaks of the decursin is used as an S peak, the relative retention time of each characteristic peak is calculated, each peak is within +/-10% of a specified value, and the specified value is: 0.11 (Peak 1), 0.27 (Peak 2), 0.36 (Peak 3), 0.38 (Peak 4), 0.41 (Peak 5), 0.84 (Peak 6), 0.92 (Peak 7), 1.00 (Peak 8), 1.19 (Peak 9), 1.29 (Peak 10). The results of multiple batches are shown in fig. 12 and table 7, and the comparison characteristic map is shown in fig. 13.
TABLE 7 relative retention time results for 20 batches of formulations
6 quality standard of characteristic map
Chromatographic conditions and System applicability test octadecylsilane chemically bonded silica was used as filler (Waters Atlantis T, column length 25cm, inner diameter 4.6mm, particle size 5 μm); methanol is used as a mobile phase A, 0.1% phosphoric acid is used as a mobile phase B, and gradient elution is carried out according to the specifications in the following table; the flow rate is 1.0ml per minute; the column temperature is 30 ℃; the detection wavelength was 250mn. The theoretical plate number should be not less than 10000 according to the pre-purple flower Hu Ganfeng.
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Preparing reference solution, precisely weighing appropriate amount of decursin reference, and adding 50% methanol to obtain solution containing 0.15mg per 1 ml.
The preparation of the sample solution comprises grinding appropriate amount of the sample, precisely weighing about 1g, placing into conical flask with plug, precisely adding 25ml of water, ultrasonic treating (power 500W, frequency 40 kHz) for 30 min, shaking, centrifuging, and collecting supernatant.
The measurement method is to precisely absorb 10 μl of each of the reference solution and the sample solution, inject the sample solution into a liquid chromatograph, measure, and record the chromatograms.
The sample characteristic spectrum should show 10 characteristic peaks, the peak corresponding to the reference peak is S peak, the relative retention time of each characteristic peak is calculated to be within + -10% of the specified value, and the specified value of the relative retention time is: 0.11 (Peak 1), 0.27 (Peak 2), 0.36 (Peak 3), 0.38 (Peak 4), 0.41 (Peak 5), 0.84 (Peak 6), 0.92 (Peak 7), 1.00[ Peak 8 (S) ], 1.19 (Peak 9), 1.29 (Peak 10). The comparison characteristic map is shown in figure 14.
The foregoing is merely a preferred embodiment of the present invention and it should be noted that modifications and adaptations to those skilled in the art may be made without departing from the principles of the present invention, which are intended to be comprehended within the scope of the present invention.
Claims (6)
1. A method for detecting fingerprint of medicine, the medicine is prepared from Chinese medicinal extract and pharmaceutically acceptable auxiliary materials or additives, wherein the auxiliary materials or additives are dextrin and sucralose, and the medicine is granule; wherein, the traditional Chinese medicine extract is prepared from the following traditional Chinese medicines in percentage by weight: 1 to 100 parts of magnolia officinalis, 1 to 100 parts of charred betel nut, 1 to 100 parts of roasted tsaoko cardamon, 1 to 100 parts of ephedra herb, 1 to 100 parts of bitter apricot seed, 1 to 100 parts of notopterygium root, 1 to 100 parts of ginger, 1 to 100 parts of patchouli, 1 to 100 parts of eupatorium, 1 to 100 parts of rhizoma atractylodis, 1 to 100 parts of poria cocos, 1 to 100 parts of bighead atractylodes rhizome, 1 to 100 parts of gypsum, 1 to 100 parts of charred hawthorn fruit, 1 to 100 parts of charred medicated leaven, 1 to 100 parts of charred malt, 1 to 100 parts of earthworm, 1 to 100 parts of paniculate swallowwort root, 1 to 100 parts of rhizoma dryopterygii and 1 to 100 parts of semen lepidii; wherein the ephedrine content of the extract is 0.5-1.5mg/g, and the solid content transfer rate is 18-25%; wherein the method comprises the following steps:
Taking a sample solution for HPLC detection, wherein the chromatographic conditions of the HPLC detection comprise: adopting a C18 chromatographic column, taking methanol as a mobile phase A, taking a phosphoric acid aqueous solution with concentration of 0.1% as a mobile phase B, wherein the elution in chromatographic conditions detected by HPLC is gradient elution, and the gradient elution program is as follows: 0-5 min,0% A; 5-25 min, 0-15% A; 25-60 min, 15-55% A; 60-75 min, 55-100% of A; 75-80 min,100% A; the flow rate is 1.0mL/min, the column temperature is 30 ℃, and the detection wavelength is 250nm; the preparation method of the sample solution comprises the following steps: taking 1g of granules, placing the granules into a conical flask with a plug, adding 25ml of water, and performing ultrasonic treatment for 30 minutes to obtain the traditional Chinese medicine.
2. The method of claim 1, wherein the extract has a level of violaxoside of 2-8mg/g.
3. The method according to claim 1, wherein the extract of chinese medicine is prepared from the following raw materials: 50 parts of magnolia officinalis, 30 parts of charred betel nut, 50 parts of roasted tsaoko cardamon, 30 parts of ephedra, 30 parts of bitter apricot seed, 50 parts of notopterygium root, 50 parts of ginger, 50 parts of patchouli, 30 parts of eupatorium, 50 parts of rhizoma atractylodis, 150 parts of poria cocos, 100 parts of bighead atractylodes rhizome, 50 parts of gypsum, 30 parts of charred hawthorn, 50 parts of charred medicated leaven, 30 parts of charred malt, 50 parts of earthworm, 50 parts of paniculate swallowwort root, 30 parts of rhizoma dryopterygii, and 50 parts of semen lepidii.
4. A method according to any one of claims 1 to 3, wherein the preparation of the herbal extract comprises:
weighing magnolia officinalis, betel nut, roasted fructus amomi, ephedra, bitter apricot kernel, notopterygium root, ginger, patchouli, eupatorium, rhizoma atractylodis, poria cocos, bighead atractylodes rhizome, gypsum, hawthorn fruit, jiao Liu medicated leaven, malt, earthworm, paniculate swallowwort root, rhizoma dryopterygii and semen lepidii, respectively adding water to extract twice, adding 6 times of water for the first time, extracting for 1.5 hours, adding 4 times of water for the second time, extracting for 1.0 hour, combining the extracting solutions, filtering, concentrating the filtrate to have a relative density of 1.10-1.15, centrifugally filtering, and drying the filtrate; wherein the ephedrine content of the extract is 1.20-1.50mg/g, the solid content transfer rate is 19-22%, and the content of the peucedanum praeruptorum is 6-8mg/g.
5. The method according to claim 4, wherein in the preparation of the traditional Chinese medicine extract, the raw materials are as follows:
15 parts of magnolia officinalis, 9 parts of charred betel nut, 9 parts of roasted tsaoko cardamon, 6 parts of ephedra, 9 parts of bitter apricot seed, 15 parts of notopterygium root, 15 parts of ginger, 15 parts of patchouli, 9 parts of eupatorium, 15 parts of rhizoma atractylodis, 45 parts of poria cocos, 30 parts of bighead atractylodes rhizome, 15 parts of gypsum, 9 parts of charred hawthorn, 9 parts of charred medicated leaven, 9 parts of charred malt, 15 parts of earthworm, 15 parts of paniculate swallowwort root, 9 parts of rhizoma dryopterygii and 15 parts of semen lepidii.
6. The method according to claim 1, wherein the fingerprint is characterized in that 10 characteristic peaks are to be displayed in the characteristic spectrum of the sample, the peak corresponding to the reference peak is S peak, the relative retention time between each characteristic peak and S peak is calculated to be within ±10% of the specified value, and the specified value of the relative retention time is: 0.11 (Peak 1), 0.27 (Peak 2), 0.36 (Peak 3), 0.38 (Peak 4), 0.41 (Peak 5), 0.84 (Peak 6), 0.92 (Peak 7), 1.00[ Peak 8 (S) ], 1.19 (Peak 9), 1.29 (Peak 10).
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