CN115728404B - Control extract of Lanqin oral liquid and its preparation method and application - Google Patents
Control extract of Lanqin oral liquid and its preparation method and application Download PDFInfo
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- CN115728404B CN115728404B CN202111016424.3A CN202111016424A CN115728404B CN 115728404 B CN115728404 B CN 115728404B CN 202111016424 A CN202111016424 A CN 202111016424A CN 115728404 B CN115728404 B CN 115728404B
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- oral liquid
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- water
- acid
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Landscapes
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Medicines Containing Plant Substances (AREA)
Abstract
The application discloses a radix scutellariae oral liquid control extract and a preparation method and application thereof. The radix scutellariae control extract is derived from the following steps: the extract is prepared from the combined extracts of baical skullcap root, amur corktree bark, cape jasmine fruit, indigowoad root and boat-fruited scaphium seed medicinal materials or the intermediate extract of Lanqin oral liquid by further separation and purification. The radix scutellariae oral liquid of the invention has stable and even property of the control extract, is used for mixing the control, has rich information of the identification components, has high detection efficiency and low cost, and can be used for quality detection of radix scutellariae traditional Chinese medicine preparations.
Description
Technical Field
The present invention relates to medicine technology, and is especially one kind of Qin oral liquid extract and its preparation process and application.
Background
The Lanqin oral liquid is a pure traditional Chinese medicine preparation which is independently developed by Yangzi river pharmaceutical industry groups according to clinical proved recipe, is composed of five traditional Chinese medicines of radix isatidis, radix scutellariae, cortex phellodendri, fructus gardeniae and semen sterculiae lychnophorae, has obvious effects of relieving fever, easing pain, resisting inflammation, resisting bacteria and resisting viruses, is mainly used for treating symptoms such as pharyngalgia, dry pharynx, glowing throat and the like caused by acute pharyngitis and excessive heat of lung and stomach, has obvious effects of resisting viruses, resisting bacteria and diminishing inflammation on upper respiratory tract infection and the like, and has definite curative effects especially in aspects of relieving fever, eliminating symptoms such as pharyngalgia and cough and the like. The Lanqin oral liquid has wide curative effect, less adverse reaction, wider use population, and great development prospect, and is more and more valued by society.
The quality of the medicine is the premise of ensuring the safety and effectiveness of clinical medication, and the method for evaluating the quality of the Lanqin oral liquid preparation is to control the content of the geniposide, but the method can not reflect the overall curative effect of the traditional Chinese medicine on the whole. To control the quality of Chinese patent medicine, the whole mass of the substance group needs to be controlled; chinese patent CN110108825a discloses a method for establishing a fingerprint of a lanqin oral liquid, and the fingerprint and use thereof; preparing test solution from Lanqin oral liquid, taking solution containing adenosine, epigoitrin, phellodendrine hydrochloride, chlorogenic acid, magnolol, geniposide, benzoic acid, berberine hydrochloride, baicalin, wogonin, baicalin and wogonin as reference solution, and measuring liquid chromatograph with high performance liquid chromatograph; and (3) introducing the obtained liquid chromatograph into a traditional Chinese medicine chromatographic fingerprint similarity evaluation system for analysis, performing multi-point correction, performing data matching, and analyzing to obtain the Lanqin oral liquid fingerprint. The method for establishing the fingerprint of the Lanqin oral liquid can comprehensively reflect the quality information of the Lanqin oral liquid, thereby ensuring uniform and stable product quality.
Disclosure of Invention
The control extract is prepared by extraction, contains various main effective components or index components, and is used as standard substance for identifying or measuring content of medicinal materials (decoction pieces), extract, chinese patent medicine, etc. The calibrated control extract is used for chromatographic peak positioning and content measurement, so that the use of a monomer control substance is greatly saved, the detection cost is reduced, and the further popularization is facilitated. The traditional Chinese medicine control extract is used as a control, and can be used for controlling the quality of products, but the traditional Chinese medicine control extract which is disclosed at present is mainly made of traditional Chinese medicinal materials and rarely relates to Chinese patent medicines. The reasons for the situation may be related to the more medicinal ingredients, complex ingredients, interaction of medicinal materials and the like of the Chinese patent medicine. The application starts from the compound, and the control extract with measurable quality and stable quality is prepared by taking the multiple components as detection indexes, so that the application value is higher.
The application provides a radix scutellariae oral liquid control extract and a preparation method and application thereof, thereby realizing improvement of quality control of radix scutellariae oral liquid.
In one aspect, the present application provides a control extract of an oral liquid of lupeol, the control extract comprising genipin gentiobioside, geniposide, phellodendrine hydrochloride, baicalin, berberine hydrochloride, oroxylin A-7-O-beta-D-glucuronide, wogonin, and one or two of 5-O-feruloyl quinic acid and 4-O-feruloyl quinic acid.
In some embodiments, the control extract comprises genipin gentiobioside, geniposide, phellodendrine hydrochloride, baicalin, berberine hydrochloride, oroxylin a-7-O-beta-D-glucuronide, wogonin, and 5-O-feruloyl quinic acid.
In some embodiments, the control extract comprises genipin gentiobioside, geniposide, phellodendrine hydrochloride, baicalin, berberine hydrochloride, oroxylin a-7-O-beta-D-glucuronide, wogonin, and 4-O-feruloyl quinic acid.
In other embodiments, the control extract comprises genipin gentiobioside, geniposide, phellodendrine hydrochloride, baicalin, berberine hydrochloride, orotidine A-7-O-beta-D-glucuronide, wogonin, 4-O-feruloyl quinic acid, and 5-O-feruloyl quinic acid.
In some embodiments, the control extract comprises one or both of methyl deacetylate, neochlorogenic acid, cryptochlorogenic acid, genipin gentiobioside, geniposide, phellodendrine hydrochloride, baicalin, berberine hydrochloride, oroxylin a-7-O- β -D-glucuronide, wogonin, and 5-O-feruloyl quinic acid and 4-O-feruloyl quinic acid.
In some embodiments, the control extract comprises methyl deacetylate, neochlorogenic acid, cryptochlorogenic acid, genipin gentiobioside, geniposide, phellodendrine hydrochloride, baicalin, berberine hydrochloride, oroxylin a-7-O-beta-D-glucuronide, wogonin, and 5-O-feruloyl quinic acid.
In some embodiments, the control extract comprises methyl deacetylate, neochlorogenic acid, cryptochlorogenic acid, genipin gentiobioside, geniposide, phellodendrine hydrochloride, baicalin, berberine hydrochloride, oroxylin a-7-O-beta-D-glucuronide, wogonin, and 4-O-feruloyl quinic acid.
In other embodiments, the control extract comprises methyl deacetylate, neochlorogenic acid, cryptochlorogenic acid, genipin gentiobioside, geniposide, phellodendrine hydrochloride, baicalin, berberine hydrochloride, oroxylin A-7-O-beta-D-glucuronide, wogonin, 4-O-feruloyl quinic acid, and 5-O-feruloyl quinic acid.
In some embodiments, the control extract comprises one or both of isogeniposide, 6-p-coumaroyl geniposide, methyl deacetylate, neochlorogenic acid, cryptochlorogenic acid, genipin gentiobioside, geniposide, phellodendrine hydrochloride, baicalin, berberine hydrochloride, oroxylin a-7-O-beta-D-glucuronide, wogonin, and 5-O-feruloyl quinic acid and 4-O-feruloyl quinic acid.
In some embodiments, the control extract comprises isogeniposide, 6-p-coumaroyl genipin gentiobioside, methyl deacetylate, neochlorogenic acid, cryptochlorogenic acid, genipin gentiobioside, geniposide, phellodendrine hydrochloride, baicalin, berberine hydrochloride, oroxylin a-7-O-beta-D-glucuronide, wogonin, and 5-O-feruloyl quinic acid.
In some embodiments, the control extract comprises isogeniposide, 6-p-coumaroyl genipin gentiobioside, methyl deacetylate, neochlorogenic acid, cryptochlorogenic acid, genipin gentiobioside, geniposide, phellodendrine hydrochloride, baicalin, berberine hydrochloride, oroxylin a-7-O-beta-D-glucuronide, wogonin, and 4-O-feruloyl quinic acid.
In other embodiments, the control extract comprises isogeniposide, 6-p-coumaroyl genipin gentiobioside, methyl deacetylate, neochlorogenic acid, cryptochlorogenic acid, genipin gentiobioside, geniposide, phellodendrine hydrochloride, baicalin, berberine hydrochloride, oroxylin A-7-O-beta-D-glucuronide, wogonin, 4-O-feruloyl quinic acid, and 5-O-feruloyl quinic acid.
In the above embodiment, the control extract contains genipin gentiobioside not less than 26.83mg, geniposide not less than 126.19mg, phellodendrine hydrochloride not less than 2.76mg, the sum of 4-O-feruloylquinic acid and 5-O-feruloylquinic acid not less than 12.29mg, baicalin not less than 90.50mg, berberine hydrochloride not less than 6.62mg, oroxylin A-7-O-beta-D-glucuronide not less than 12.78mg, and wogonin not less than 21.69mg per 1g of the control extract calculated on a dry basis.
In the above embodiment, the control extract contains 26.83 to 56.88mg geniposide Ping Longdan, 126.19 to 261.22mg geniposide, 2.76 to 7.50mg phellodendrine hydrochloride, 12.29 to 35.36mg 4-O-feruloyl quinic acid and 5-O-feruloyl quinic acid, 90.50 to 196.05mg baicalin, 6.62 to 26.10mg berberine hydrochloride, 12.78 to 26.14mg orotidine A-7-O-beta-D-glucuronide, and 21.69 to 44.20m.
In the above embodiment, the control extract is measured according to a high performance liquid phase method (for example, the 2015 edition of chinese pharmacopoeia, general rule 0512) to obtain a feature spectrum of the control extract, and at least 9, 10, 11, 12, 13 or 14 feature peaks should be in the feature spectrum; preferably, there are at least 14 characteristic peaks. In some embodiments, in the profile, the relative retention times of the 9, 10, 11, 12, 13, or 14 characteristic peaks are within ±10% retention having the following values: 0.170 (Peak 1), 0.191 (Peak 2), 0.209 (Peak 3), 0.296 (Peak 4), 0.314 (Peak 5), 0.365 (Peak 6), 0.395 (Peak 7), 0.521 (Peak 8), 0.538 (Peak 9), 0.875 (Peak 10), 1.000 (Peak 11), 1.091 (Peak 12), 1.197 (Peak 13), 1.274 (Peak 14).
In the above embodiment, the control extract has a moisture content of not more than 4.5% as measured by a moisture measurement method (e.g., chinese pharmacopoeia 2015, second method of general rule 0832).
In the above embodiment, the control extract has a total ash content of no more than 3.5% as determined by ash assay (e.g., chinese pharmacopoeia 2015 edition, general rule 2302). In some embodiments, the control extract has an acid insoluble ash of no more than 0.2% as determined by ash assay (e.g., chinese pharmacopoeia 2015, general rule 2302).
In a second aspect, the present application provides a method for preparing a glabrous greenbrier rhizome oral liquid control extract, the method comprising the steps of:
the control extract is obtained by purifying the combined extracts of radix scutellariae, cortex phellodendri, fructus gardeniae, radix isatidis and boat-fruited scaphium seed medicinal materials or the intermediate extract of the radix scutellariae oral liquid by macroporous resin adsorption and medium pressure chromatographic separation (MCI) column, concentrating and drying.
In some embodiments, the preparation method of the glabrous greenbrier rhizome oral liquid control extract provided by the application comprises the following steps:
step S100
Weighing radix Isatidis, scutellariae radix, fructus Gardeniae, cortex Phellodendri, and semen Scaphii Lychnophori decoction pieces according to the prescription, decocting in water for three times, mixing decoctions, filtering, centrifuging, collecting supernatant, and concentrating; or concentrating the intermediate extract of Lanqin oral liquid;
step S200
Taking the concentrated solution obtained in the step S100, adding water for dilution, shaking uniformly, refining by macroporous adsorption resin, and separating into water and ethanol for elution; discarding water eluting part, mixing ethanol eluting parts, concentrating under reduced pressure, and lyophilizing the concentrated solution to obtain lyophilized powder;
step S300
Dissolving the freeze-dried powder obtained in the step S200 by using a methanol aqueous solution, purifying by using a medium-pressure chromatographic separation column, and eluting by using gradient methanol; collecting eluate, concentrating, mixing, and lyophilizing to obtain control extract.
In the above embodiment, in the step S100, the prescription of the lan qin oral liquid is 150-450 g of radix isatidis, 150-450 g of radix scutellariae, 150-450 g of fructus gardeniae, 20-200 g of cortex phellodendri and 20-200 g of semen sterculiae lychnophorae; optionally, the prescription of the Lanqin oral liquid comprises 300g of radix isatidis, 240g of radix scutellariae, 300g of fructus gardeniae, 120g of cortex phellodendri and 100g of boat-fruited scaphium seed.
In some embodiments, in the step S100, the three times of decocting with water are: in the step S100, the water is added for 2-4 times of decoction: each time for 1-3 hours; and/or adding 3-6 times of water by weight each time;
preferably, the first time is 2 hours, and the second time and the third time are 1 hour each; and/or, adding 6 times of water by weight for the first time, adding 4 times of water by weight for the second time, and adding 3 times of water by weight for the third time.
In some embodiments, in the step S100, the concentrated solution obtained after the concentration has a relative density of 1.10-1.12 (70 ℃).
In some embodiments, in the step S200, the macroporous adsorbent resin is based on divinylbenzene or modified polystyrene, such as HP20, SP207, SP825L, SP, SP850, SP700, SP70, etc.; in one embodiment, in the step S200, the macroporous adsorbent resin is SP825L.
In some embodiments, in step S200, the concentration of ethanol is 60% v/v to 90% v/v, optionally 80% v/v.
In some embodiments, in the step S300, the medium pressure chromatographic separation column is a medium pressure chromatographic separation gel MCI column, preferably the packing is polystyrene or methacrylate, such as CHP20P, HP SS, CA08P, CHP MGY, and the like. In one embodiment, in the step S300, the packing of the chromatographic separation column is HP20SS.
In some embodiments, in the step S300, the concentration of the aqueous solution of methanol for dissolution is 5% v/v.
In some embodiments, in step S300, the different gradient of methanol comprises 5% v/v methanol, 20% v/v methanol, 70% v/v methanol.
In some embodiments, the step S300 is: dissolved in 5% v/v methanol (3 g of lyophilized powder was sonicated with 5% v/v methanol in 30 mL) and purified on HP20SS column at a material ratio of 3g:200mL eluting with two volumes of 5% methanol (400 mL), two volumes of 10% v/v methanol (400 mL), 3 volumes of 20% v/v methanol (600 mL) and 6 volumes of 70% v/v methanol (1200 mL) in this order. Collecting the eluates of each part, concentrating to small volume, mixing, and lyophilizing to obtain control extract.
In a third aspect, the present application provides a radix scutellariae oral liquid control extract obtained according to the above preparation method.
In a fourth aspect, the application provides an application of the glaucescent fissistigma root oral liquid control extract in controlling the quality of glaucescent fissistigma root oral liquid, the application includes an identification method of the glaucescent fissistigma root oral liquid control extract in a high performance liquid chromatography characteristic spectrum of index components of the glaucescent fissistigma root oral liquid preparation, and the identification method includes:
determining chromatographic conditions of high performance liquid chromatography;
preparing control extract solution from the control extract of the Lanqin oral liquid;
preparing a sample solution by using a Lanqin oral liquid preparation;
respectively sucking the control extract solution and the sample solution, injecting into high performance liquid chromatograph, and measuring.
In some embodiments, the identification method may include preparing a reference solution with baicalin, sucking the reference solution, and injecting into a high performance liquid chromatograph for positioning; for example, a proper amount of baicalin reference substance is taken, precisely weighed, and methanol is added to prepare a solution containing 100.0 reference substances of baicalin per 1ml of the solution as reference substance solution of the reference substance.
In some embodiments, the identification method, wherein the chromatographic conditions are:
octadecylsilane chemically bonded silica is used as a filler (column length is 250mm, inner diameter is 4.6mm, and particle diameter is 5 μm);
acetonitrile is taken as a mobile phase A, and 0.2% v/v phosphoric acid aqueous solution is taken as a mobile phase B for gradient elution;
the column temperature is 30 ℃;
the detection wavelength is 230nm.
In some embodiments, the identification method, wherein the gradient elution procedure is:
in some embodiments, the identification method, wherein the control extract solution is prepared by: taking about 0.03g of a blue qin oral liquid control extract, precisely weighing, placing in a conical flask, precisely adding 10mL of 50% methanol solution, fixing the volume to a scale, performing ultrasonic treatment (power 250W, frequency 45 KHZ) for 30 minutes, cooling, supplementing weightlessness, filtering with a 0.45 μm filter membrane, and taking the subsequent filtrate.
In some embodiments, the identification method, wherein the test solution is formulated by: precisely weighing 1mL of Lanqin oral liquid, placing in a 25mL volumetric flask, diluting with water to scale, mixing, filtering with 0.45 μm filter membrane, and collecting the filtrate.
In some embodiments, the identification method, wherein the determination is: respectively precisely sucking 10 μl of control extract solution and sample solution, and injecting into high performance liquid chromatograph for measurement.
Compared with the prior art, the invention has the beneficial effects that: in the application, a two-step resin separation process is adopted in the development of a control extract preparation process, and the method is different from organic solvent extraction, and the organic solvent is only ethanol and methanol, so that the extract obtained by separation and purification can be more comprehensively subjected to chromatographic peak information under the reduction detection condition. The control extract obtained by the extraction and purification process set by the application can be used for performing multi-index identification and performing the function of a control substance with simultaneous multi-component measurement content in the corresponding quality control application of Chinese patent medicine products.
In the research and development of the control extract, the genipin gentiobioside, the geniposide, the phellodendrine hydrochloride, the baicalin, the berberine hydrochloride, the oroxylin A-7-O-beta-D-glucuronide, the wogonin, the 5-O-feruloyl quinic acid and the 4-O-feruloyl quinic acid are selected as the components of the glabrous greenbrier rhizome control extract according to the characteristics of high content, good stability and strong activity of index components and the operational difficulty of the process. The components have relatively high content, have the advantages of good reproducibility, easy quantification, easy industrialization implementation and the like, can better monitor the quality of the Lanqin oral liquid, and avoid the influence caused by unstable factors of raw materials, processes or operation. Therefore, the method can effectively realize the advantages of stability, controllability, good reproducibility, strong operability, high accuracy and the like by selecting the glaucescent fissistigma root extract as a component of the glaucescent fissistigma root control extract,
and, the mass transfer in the process is highly traceable.
Additional features and advantages of the application will be set forth in the description which follows, and in part will be obvious from the description, or may be learned by practice of the application. Other advantages of the present application may be realized and attained by the structure particularly pointed out in the written description and drawings.
Drawings
The accompanying drawings are included to provide an understanding of the technical aspects of the present application, and are incorporated in and constitute a part of this specification, illustrate the technical aspects of the present application and together with the examples of the present application, and not constitute a limitation of the technical aspects of the present application.
FIG. 1 is an HPLC profile of a control extract of the present application;
FIG. 2 is an HPLC plot of three batches of oral formulations;
FIG. 3 is a HPLC profile comparing a control extract with three batches of oral formulations;
figure 4 is a characteristic HPLC profile of a control extract.
Detailed Description
For the purposes of clarity, technical solutions and advantages of the present application, the following detailed description will describe embodiments of the present invention. It should be noted that, in the case of no conflict, the embodiments and features in the embodiments may be arbitrarily combined with each other.
Instrument and reagent
Rotary evaporator (Shanghai Ailang instruments Co., ltd., N-1100); oil baths (OSB-2100, shanghai ai's instruments, inc.); vacuum pumps (WELCH, 114184). Prefreezing machine (EYELA, PFR-1000); freeze dryer (CHRIST, alpha 1-2LD plus). Electronic balance (Shanghai Cyanine instruments Co., ltd., YP 3002N). Ultrasonic cleaners (SK 7210HP,53kHz, 350W power consumption, 390W heating power), shanghai Kochia Utility ultrasonic instruments Inc.
Inlet resin 2: the No. 1 resin was HP2-MGL and the No. 2 resin was SEPABEADS SP825L (Mitsubishi), all available from Beijing Green hundred grass technology development Co.
Domestic resin 5: the 3# resin was HPD-400,4# resin, HPD-600,5# resin, HPD-826,6# resin, NKA-9, and 7# resin was ADS-17, all available from Cangzhou Baohan adsorption materials science and technology Co.
Ext> reversedext> phaseext> Cext> 18ext> Sext> 03230ext> Gext> -ext> Aext> (ext> 50ext>.ext> muext>.ext>,ext> Mitsubishiext>)ext>,ext> MCIext> GELext> CHPext> Pext> /ext> Pext> 120ext> (ext> 75ext> -ext> 150ext>.ext> muext>.ext>,ext> Mitsubishiext>)ext>,ext> MCIext> HPext> 20ext> SSext> (ext> 75ext> -ext> 150ext>.ext> muext>.ext>,ext> Mitsubishiext>)ext> andext> MCIext> SPext> 20ext> SSext> (ext> 63ext> -ext> 75ext>.ext> muext>.ext>,ext> Mitsubishiext>)ext> wereext> allext> purchasedext> fromext> Beijingext> greenext> hundredext> grassext> technologyext> developmentext> Coext>.ext>
Methanol or ethanol are analytically pure and are purchased from national pharmaceutical systems chemical reagent Inc. or Shanghai Michelin Biochemical technologies Inc. (MACHLIN). Medical ethanol with an ethanol content of about 95% is commercially available. The water is laboratory high purity water.
The raw materials are as follows: semen Scaphii Lychnophori (lot number 2004005), radix Isatidis (lot number 2003017), cortex Phellodendri (lot number 2002001), fructus Gardeniae (lot number 2004008) and radix Scutellariae (lot number 2004027); 3 batches of concentrated extract, batch number in turn: 21051262, 21051163, 21051164 for pilot scale up experiments; the rest concentrated solution, fluid extract and finished product preparation are provided by Yangzi river pharmaceutical group Co., ltd (purchased on the market or prepared according to the Lanqin oral liquid technology) for sample measurement.
The chromatographic condition and system applicability test uses octadecylsilane chemically bonded silica as filler; acetonitrile is taken as a mobile phase A, 0.2% phosphoric acid solution is taken as a mobile phase B, and gradient elution is carried out according to the specifications in the following table; the detection wavelength is 230nm, and the column temperature is 30 ℃. The theoretical plate number should be not less than 3000 calculated according to baicalin peak.
Agilent 1260HPLC instrument (Agilent technologies limited); waters2695-2998 high performance liquid chromatograph (Waters, USA); shimadzu LC-20AT high performance liquid chromatography (Shimadzu corporation); electronic balances (YP 50002, 31772, shanghai plain scientific instruments limited); freeze-dryer (Lab-1-50, beijing Bo Yikang laboratory instruments Co., ltd.) with an XSE105 ten-thousandth analytical balance (METLER). Specific information for different brands of columns is shown in Table 3-1 below.
TABLE 3-1 column information
Purified water (chen food and beverage limited, guangzhou), phosphoric acid (national pharmaceutical group chemical agent limited); the geniposide control (Chengdoremineramexane biosciences, RFS-Z00311802022), genipin gentiobioside control (Chengdoremineramexane biosciences, RFS-J07502101007), 5-O-feruloylquinic acid control (Chengdoremineramexane biosciences, RFS-DFZY-AWXKN-210312), berberine hydrochloride control (Chengdoremineramexane biosciences, RFS-Y03511811015), wogonide control (Chengdoremineramexane biosciences, RFS-H01911809030), baicalin control (China medicine biosystems, wholesale, 110715-201016), oroxylin A-7-O-201 glucuronide control (Chengdoleigh biosciences, RFS-Q04602005021), phellodine hydrochloride control (Chedoleigh biosciences, S-Y08601905015), norbornyl methyl acetate (Chenopodictes, RFS-37, RFS-37, crypton-X-37).
Example 1
Control extract of Lanqin oral Liquid (LQ)
[ prescription ] Isatis root 300g, baikal skullcap root 240g, cape jasmine 300g, phellodendron bark 120g, sterculia seed 100g
The preparation method comprises the following steps: weighing the above medicinal materials according to a certain proportion, decocting with water for three times (first 2 hours, second and third 1 hour respectively; and/or adding water of 6 times weight ratio for the first time, adding water of 4 times weight ratio for the second time and adding water of 3 times weight ratio for the third time), mixing decoctions, filtering, centrifuging, collecting supernatant, and concentrating to a certain density (70 ℃ C., relative density of 1.10-1.12).
The rough separation process comprises the following steps: taking 250mL of concentrated solution, adding equal volume of water for dilution, shaking uniformly, refining by macroporous resin (SP 825L,5000 mL), and separating into water (3 column volumes, 15000 mL) and 80% v/v ethanol (4 column volumes, 20000 mL). Discarding the water elution part, combining the 80% v/v ethanol elution parts, concentrating under reduced pressure, and freeze-drying the concentrated solution to obtain freeze-dried powder.
The purification process comprises the following steps: the freeze-dried powder is taken and dissolved by 5% v/v methanol (3 g of freeze-dried powder is dissolved by 30mL of 5% v/v methanol) and purified by an MCI (HP 20 SS) column, and the material ratio is 3g:200mL was eluted sequentially with two volumes of 5% methanol (400 mL), two volumes of 10% methanol (400 mL), 3 volumes of 20% methanol (600 mL), and 6 volumes of 70% methanol (1200 mL). Collecting the eluates of each part, concentrating to small volume, mixing, and lyophilizing to obtain radix Scutellariae control extract.
Example 2
Preparation process research of blue qin control extract
1. Coarse separation process
1.1 preparation of sample substances
(1) Extraction batch 1
Taking crude drugs provided by Yangtze river pharmaceutical company Limited, decocting semen Scaphii Lychnophori, breaking fructus Gardeniae shell, cutting cortex Phellodendri into small pieces of about 2cm, cutting Scutellariae radix and radix Isatidis into small pieces of about 1 cm. 100g of boat-fruited sterculia seed, 300g of radix isatidis, 120g of amur corktree bark, 240g of baical skullcap root and 300g of cape jasmine. Together, it is: 1060g of the original drug. Decocting in water for three times, the first time for 2 hours and 6 times of water; the second 1 hour, 4 times of water; the third 1 hour, 3 times of water. The decoctions were combined and filtered (200 mesh) to give 9200ml of filtrate as an aqueous extract (sampling). Taking 2000ml of water extract and freeze-drying to obtain 129.84g of extract freeze-dried powder (hereinafter referred to as "freeze-dried powder"); the remaining 7200ml was concentrated to 700ml (70 ℃ C., relative density 1.10-1.12). Taking 580ml of concentrated solution, adding 920ml of medical 95 ethanol, precipitating with ethanol for more than 24 hours, centrifuging (4000 rpm,30 min), taking 1140ml of supernatant, concentrating under reduced pressure to 390ml to obtain fluid extract (60 ℃ C., 1.19).
1.2 selection of sample substances (including Freeze-dried powder cycle sample)
Taking 1# and 2# resins as study objects, comparing three forms of concentrated solution, clear paste and freeze-dried powder (extraction batch 1 under 1.1 item), and determining one of the three forms as a loading mode.
(1) Method of loading (small column, thin column, inner diameter about 3.8 cm):
200ml of resin (after 24 hours of soaking in 95% ethanol, naturally settled to a constant volume). Filling the column, flushing 6 column volumes (1200 ml) with 95% ethanol, flushing 6 column volumes with water, shaking uniformly, naturally settling until the resin volume is unchanged, flushing 2 column volumes with water, standing overnight after loading, flushing one column volume with water the next day, mixing water eluents, shaking uniformly, and sampling; the 3 column volumes were sequentially rinsed with 30% ethanol and 3 column volumes were rinsed with 60% ethanol.
The concentrated solution loading method comprises the following steps: 10ml of the concentrated solution was poured into a resin column and stirred, and the rest were the same as above.
The method for loading the clear paste comprises the following steps: taking 10ml of the clear paste, pouring into a resin column without stirring, and the rest are the same as above.
The freeze-dried powder loading method comprises the following steps: taking 3.2g of freeze-dried powder, adding 20ml of water, carrying out ultrasonic treatment for 20min, and the rest being the same.
The freeze-dried powder cyclic loading method comprises the following steps: collecting 3.2g of freeze-dried powder, adding 20ml of water, carrying out ultrasonic treatment for 20min, collecting water eluting part of the first column volume after sample loading, adding into the column, and continuing washing until the total volume of the water eluting part is 600ml.
(2) Measurement results
The results showed that the components of the respective elution sites (water, 30% ethanol, 60% ethanol and 95% ethanol elution sites) of the concentrated solution and the fluid extract were similar by HPLC analysis. The extraction liquid freeze-dried powder has the water solution leakage phenomenon when the No. 1 resin is loaded. And the elution behavior of the concentrated solution, the clear paste and the freeze-dried powder of the extracting solution is consistent with that of the 2# resin.
Meanwhile, the concentrated solution is obtained by concentrating after extraction, and the method is simple and convenient to operate, good in reproducibility and most suitable. Although the elution behavior of the clear paste is consistent, the operation is complicated due to the steps of alcohol precipitation, standing and concentration. The freeze-dried powder of the extracting solution is sampled, the cost is high, the steps are complicated, the risk that the extracting solution cannot be completely redissolved exists, and the component leakage phenomenon of some resins also occurs. Finally, selecting the concentrated solution as a loading substance.
1.3 repeatability test
(1) Method of
The resin No. 1 and the concentrated solution were sampled with stirring, and the influence of the column inner diameter thickness on the eluting component was compared with the resin amount of 200ml (95% ethanol). Fine column: the inner diameter is about 3.8cm; coarse column: the inner diameter is about 4.6cm. The method of 30% +60% ethanol elution was used.
The elution method is described in item 1.2 (1).
(2) Results
HPLC detection results show that the process repeatability test 1 (thin column) and the repeatability test 2 (thick column) are compared, the water washing parts are not different twice, the 30% ethanol washing parts are different, the 60% ethanol washing parts are different, but the 30% +60% ethanol parts are not different. The resin column thickness has no significant effect on water elution fraction, 30% +60% ethanol total component and 95% ethanol elution fraction.
4 selection of macroporous resin 1# -7#:
taking concentrated solution (1-1 extraction batch 1) as research object, comparing different elution behaviors of 7 resins (1 # -7 #) and taking the comprehensiveness of chromatographic peak information retention as index, and preferably performing rough separation research on 1-2 resins.
After the freeze-dried powder of the concentrated solutions of the resin No. 1 and the resin No. 7 is sampled, the leakage phenomenon of the components of the water eluent occurs. Resin 2# was not so apparent from all three loading substances. The characteristic patterns obtained by the elution parts are similar to the resin components 1# and 2# and the target components are hardly found in the water parts; 30% ethanol fraction, geniposide, alkaloid and part of baicalin component are eluted; eluting baicalin and part of alkaloid at 60% ethanol position; the 95% ethanol fraction showed no target component. And the 6# residue is excessive and discarded. Since the particle uniformity and clarity of # 4 is better than that of # 3 and # 5 resins. Therefore, the resin No. 2 (SP-825L) and the resin No. 4 (SP-600) were selected.
2. Study of purification Process
2.1 selection of MCI model
(1) Method of
Comparing the capability of the 80% ethanol elution parts of the MCI purified 2# resin with different types, and selecting the MCI with the optimal type to prepare the LQ control extract. MCI HP20SS, GEL CHP20P/P120, SP20SS.
Ram and balance (1 column volume = 200 mL):
1) Methanol was flushed through the column for 10 column volumes (2000 mL).
2) The 20% methanol solution equilibrates 3 column volumes (600 mL).
3) 10% methanol solution equilibrates 3 column volumes (600 mL).
4) 5% methanol solution equilibrates 3 column volumes (600 mL).
5) 1 column volume of 5% methanol solution was added to equilibrate prior to loading.
Loading sample
3g of freeze-dried powder (30 ml of 5% methanol is dissolved, 170ml of 5% methanol is added for washing, standing and adsorption are carried out for more than 8 hours, and the sample liquid is clarified and discarded)
Elution
2 column volumes (400 mL) were eluted with 5% methanol.
2 column volumes (400 mL) were eluted with 10% methanol.
3 column volumes (600 mL) were eluted with 20% methanol.
70% methanol solution was eluted for 6 column volumes (1200 mL).
100% methanol solution was eluted for 2 column volumes (400 mL).
Elution rate (estimated): v (MCI HP20 SS) =12.5 mL/min
V(MCI GEL CHP20P/P120)＝8.0mL/min
V(MCI SP20SS3)＝6.7mL/min
(2) Results
The purification effect of the 2# resin crude extract is compared with that of HP20SS, CHP20/P120 and SP20SS, and the results show that the three resins have consistent elution behaviors, and the operation is the most convenient and fast with HP20SS.
Example 3
Amplification experiment of rough separation process
(1) Method of
Taking concentrated solution (example 2) as study object, selecting 2# resin (one of which is amplified, 2# -1) and 4# resin (two of which are amplified, 4# -1,4# -2), and loading from 10ml to 250ml of concentrated solution; the resin amount was increased from 200ml to 50000ml, all at 25-fold expansion. The components of the 30% ethanol, 60% ethanol and 95% ethanol eluted portions of the two resin amplification tests and the hand sample test were compared, respectively, and the mass of the lyophilized powder was measured.
(2) Results
The amplification results of three columns of two resins show that 30% +60% of measurable components are consistent with the measurement results of the small columns, and the technical parameters of the process are feasible; although 95% of the parts were darker, the amount of lyophilized powder was very small (only 1.15g,1.35g and 1.13 g), the content of measurable components was low (18.55%, 8.04% and 1.78%), and no increase in effective measurable components was observed. Therefore, the part belongs to an invalid part and is not recycled in the later stage to obtain the freeze-dried powder, in consideration of the time and energy consumption cost of later-stage eluent recycling, freeze-drying and the like.
Determination of quality and quantifiable component of freeze-dried powder at each part in resin No. 2 and No. 4 amplification experiments
The No. 2 resin and the No. 4 resin have good component enrichment effect, and the No. 2 resin has uniform particles and less resin residues; meanwhile, although the particle uniformity of the No. 4 resin is slightly poor, the resin residue is slightly more, and the resin can be used as a substitute resin.
Alcohol precipitation impurity removal efficiency: taking 100ml of 3 batches of mixed batch samples of concentrated solutions (21051262, 21051163 and 21051164) provided by Yangzu river pharmaceutical industry group Co-Ltd, wherein the equivalent mass is 35g; adding 95% medical ethanol to adjust ethanol concentration to 60%, standing at 4deg.C for more than 24 hr, centrifuging (8000 rpm,10min, 4deg.C), drying the obtained precipitate at 105deg.C to obtain 10.35g, wherein the mass of the precipitate is 29.6% of that of the concentrated solution.
The purifying capacity (> 65%) of the macroporous resin is significantly higher than that of the alcohol precipitation (about 30%).
Example 4
Column packing selection in purification process
(1) Method of
Comparing the two finely divided fillers of MCI (CHP 20/P120, particle size 75-150 μ) and ODS (octadecylsilane chemically bonded silica, particle size 50 μ), elution behavior was similar. Because the ODS column filler has small particle size and too low flow velocity under normal pressure, pressurizing equipment and pressure control are needed to be added; and the MCI column can complete component separation work under normal pressure.
(2) Results
Therefore, the MCI is selected as a secondary purification method according to the operation method difficulty of the elution process and the requirement on instruments. And because the polarity difference of the components is larger, 5% methanol is determined to be loaded from 5% to 70% and then 2 column volumes are washed by 5% methanol, 2 column volumes are washed by 10% methanol, 3 column volumes are eluted by 20% methanol and 6 column volumes are eluted by 70% alcohol, and 5% -70% fractions are combined and concentrated to enrich and retain the components of the larger part.
Example 5
Method for identifying Lanqin oral Liquid (LQ) control extract
The measurement was performed by high performance liquid chromatography (China pharmacopoeia 2015 edition general rule 0512).
Chromatographic conditions and System applicability test octadecylsilane chemically bonded silica was used as filler (DM plus C18, column length of 250mm, inner diameter of 4.6mm, particle size of 5 μm); acetonitrile was used as mobile phase A, 0.2% phosphoric acid aqueous solution was used as mobile phase B, and gradient elution was carried out according to the following table, the column temperature was 30℃and the detection wavelength was 230nm.
Preparation of reference solution baicalin reference solution, accurately weighing appropriate amount of baicalin reference solution, and adding methanol to obtain 100.0 reference solution containing baicalin per 1 ml.
Preparation of a Qin oral liquid control extract solution the Qin oral liquid control extract (example 1) was prepared by weighing about 0.03g, placing in a conical flask, adding 10mL of 50% methanol solution, metering to volume, performing ultrasonic treatment (power 250W, frequency 45 KHZ) for 30min, cooling, adding a 0.45 μm filter membrane, and filtering to obtain the final product.
The preparation method comprises precisely measuring 1mL of Lanqin oral liquid preparation (batch numbers 19120221, 19112721, 19112622 respectively), placing in 25mL volumetric flask, diluting with water to scale, mixing, filtering with 0.45 μm filter membrane, and collecting the filtrate.
The measurement method comprises precisely sucking 10 μl of each of the reference solution, the reference extract solution and the sample solution, and injecting into high performance liquid chromatograph for measurement. FIG. 1 is an HPLC profile of a control extract; FIG. 2 is an HPLC plot of three batches of oral formulations; fig. 3 is an HPLC profile comparing the control extract with three batches of oral formulations.
Example 6
1. Characteristic peak and content
The control extract solution and the mixed control solution of example 5 were subjected to sample injection analysis according to the aforementioned chromatographic conditions, and 14 peaks ubiquitous in each batch of samples were preliminarily selected as characteristic peaks:
1. characteristic peak 1 (methyl deacetylate) 2 (isogeniposide) 3 (neochlorogenic acid) 4 (neo-chlorogenic acid) 4 (geniposide) 5 (cryptochlorogenic acid) 6 (geniposide) 7 (phellodendrine) 8 (4-O-feruloylquinic acid) 9 (5-O-feruloylquinic acid) 10 (6-p-coumaroylgeniposide) 11 (baicalin) 12 (berberine) 13 (orotidine A-7-O-. Beta. -D-glucuronide) 14 (wogonin) 14)
Combining the relative retention time of the 3 batches of radix scutellariae oral liquid control extract samples, and determining the characteristic spectrum identification standard of the radix scutellariae oral liquid control extract: the characteristic spectrum of the sample has 14 characteristic peaks, the peak corresponding to the baicalin reference peak is S peak, and the relative retention time of each characteristic peak and the S peak is calculated and is within +/-10% of the specified value. The predetermined values were 0.170 (peak 1) 0.191 (peak 2), 0.209 (peak 3), 0.296 (peak 4), 0.314 (peak 5), 0.365 (peak 6), 0.395 (peak 7), 0.521 (peak 8), 0.538 (peak 9), 0.875 (peak 10), 1.000 (peak 11 (S)), 1.091 (peak 12), 1.197 (peak 13), and 1.274 (peak 14). The results are shown in FIG. 4.
The relative retention time of genipin gentiobioside, geniposide, phellodendrine hydrochloride, 4-O-feruloyl quinic acid, 5-O-feruloyl quinic acid, berberine hydrochloride, oroxyline A-7-O-base, polyglucuroside and wogonin is calculated by taking baicalin reference substance and corresponding peak as S peak, and the relative retention time is within + -10% of the specified value, and the contents of genipin gentiobioside, geniposide, phellodendrine hydrochloride, 4-O-feruloyl quinic acid, 5-O-feruloyl quinic acid, berberine hydrochloride, oroxyline A-7-O-beta-D-glucuronide and wogonin are calculated by reference substance respectively.
The genipin Ping Longdan disaccharide content in 3 batches of the radix Scutellariae oral liquid control extract (example 1) samples ranges from 42.91 mg/g to 43.75mg/g, and the RSD values in the batches are all less than 3%; the content of the geniposide is in the range of 193.18-196.24mg/g, and the RSD values in the batch are all less than 3%; the content range of the phellodendrine hydrochloride is between 4.40 and 4.82mg/g, and the RSD values in the batch are all less than 3 percent; the content of 4-O-feruloyl quinic acid and 5-O-feruloyl quinic acid ranges from 17.56 mg/g to 18.74mg/g, and the RSD values in the batch are all less than 3%; the berberine hydrochloride content range is 9.45-11.65mg/g, and the RSD values in the batch are all less than 3%; the content of oroxylin A-7-O-beta-D-glucuronide is 18.25-18.38mg/g, and the RSD value in the batch is less than 3%; the content of wogonin is 30.98-31.80mg/g, and the RSD values in batches are all less than 3%; the baicalin content range is 149.28-150.81mg/g, and the RSD values in the batch are all less than 3%.
The product contains genipin gentiobioside (C) 1g per dry product 23 H 34 O 15 ) Not less than 30.4mg containing geniposide (C) 17 H 24 O 10 ) Not less than 91.32mg, contains phellodendrine hydrochloride (C) 20 H 24 ClNO 4 ) Not less than 3.3mg containing 4-O-feruloyl quinic acid (C) 17 H 20 O 9 ) And 5-O-feruloyl quinic acid (C) 17 H 20 O 9 ) The total content is not less than 12.7mg, and contains baicalin (C 21 H 18 O 11 ) Not less than 105.1mg, contains berberine hydrochloride (C 20 H 18 ClNO 4 ) Not less than 7.5mg, contains oroxylin A-7-O-beta-D-glucuronide (C) 22 H 20 O 11 ) Not less than 12.8mg, containing wogonin (C) 22 H 20 O 11 ) Not less than 21.9mg.
2. Inspection of
2.1 Properties
(1) The product is orange-yellow to orange-red powder.
(2) The extract is easily soluble in water, and is hardly soluble in methanol or ethanol.
2.2 moisture
The measuring method comprises the following steps: the second method (oven drying method) under the water content measurement method of "Chinese pharmacopoeia (four parts)" version 2020.
MCI part purified freeze-dried powder moisture (n=2)
According to the measurement results of the above table, the water content was not more than 4.5%.
2.3 ash content
The total ash assay and the acid insoluble ash assay under the ash assay item of the Chinese pharmacopoeia (four parts) 2302 were used in 2020 edition.
Table 2 ash determination of MCI lyophilized powder
According to the measurement results of the above table, the total ash content was not more than 3.5%, and the acid-insoluble ash content was not more than 0.2%.
Although the embodiments disclosed in the present application are described above, the embodiments are only used for facilitating understanding of the present application, and are not intended to limit the present application. Any person skilled in the art to which this application pertains will be able to make any modifications and variations in form and detail of implementation without departing from the spirit and scope of the disclosure, but the scope of the application is still subject to the scope of the claims appended hereto.
Claims (14)
1. A preparation method of a radix scutellariae oral liquid control extract comprises the following steps:
step S100
Weighing radix Isatidis, scutellariae radix, fructus Gardeniae, cortex Phellodendri, semen Scaphii Lychnophori according to the prescription of Lanqin oral liquid, decocting in water for three times, mixing decoctions, filtering, and concentrating; or an intermediate extract of the concentration process of the Lanqin oral liquid;
step S200
Taking the concentrated solution obtained in the step S100, adding water for dilution, shaking uniformly, refining by macroporous adsorption resin, and separating into water and ethanol for elution; discarding water eluting part, mixing ethanol eluting parts, concentrating under reduced pressure, and lyophilizing the concentrated solution to obtain lyophilized powder;
the macroporous adsorption resin takes divinylbenzene or modified polystyrene as a matrix;
the concentration of the ethanol is 60% v/v to 90% v/v;
step S300
Dissolving the freeze-dried powder obtained in the step S200 by using 5% v/v methanol aqueous solution, purifying by using a medium-pressure chromatographic separation column, eluting by using gradient methanol, and eluting by using 5% methanol two column volumes, 10% v/v methanol two column volumes, 20% v/v methanol 3 column volumes and 70% v/v methanol 6 column volumes in sequence; collecting eluate, concentrating, mixing, and lyophilizing to obtain control extract;
the medium-pressure chromatographic separation column is a medium-pressure chromatographic separation gel MCI column, and the filler is polystyrene.
2. The method for preparing a glabrous greenbrier rhizome oral liquid control extract according to claim 1, wherein in the step S100, the prescription of the glabrous greenbrier rhizome oral liquid comprises 150-450 g of isatis root, 150-450 g of baical skullcap root, 150-450 g of cape jasmine fruit, 20-200 g of amur corktree bark and 20-200 g of boat-fruited scaphium seed; preferably, the prescription of the Lanqin oral liquid comprises 300g of radix isatidis, 240g of radix scutellariae, 300g of fructus gardeniae, 120g of cortex phellodendri and 100g of boat-fruited scaphium seed.
3. The method for preparing a glabrous greenbrier rhizome oral liquid control extract according to claim 1, wherein in the step S100, the steps of decocting with water are performed for 2-4 times: each time for 1-3 hours; and/or adding 3-6 times of water by weight each time.
4. The method for preparing a glabrous greenbrier rhizome oral liquid control extract as claimed in claim 3, wherein in the step S100, the water-adding decoction is performed three times: the first time is 2 hours, the second time and the third time are 1 hour each; and/or, adding 6 times of water by weight for the first time, adding 4 times of water by weight for the second time, and adding 3 times of water by weight for the third time.
5. The method for preparing a Qin oral liquid control extract as claimed in claim 1, wherein in the step S200, the macroporous adsorbent resin is HP20, SP207, SP825L, SP, SP850, SP700, SP70, HPD-400 or HPD-600; and/or
In the step S200, the concentration of the ethanol is 80% v/v.
6. The method for preparing a Lanqin oral liquid control extract as claimed in claim 5, wherein in the step S200, the macroporous adsorbent resin is SP825L.
7. The method for preparing a glabrous greenbrier rhizome oral liquid control extract as claimed in claim 1, wherein in the step S300, the packing of the medium pressure chromatographic separation column is SP20SS, CHP20P or HP20SS.
8. The method for preparing a control extract of lupeol oral liquid as claimed in any one of claims 1 to 7, wherein the control extract comprises genipin gentiobioside, geniposide, phellodendrine hydrochloride, baicalin, berberine hydrochloride, oroxylin a-7-O-beta-D-glucuronide, wogonin and 5-O-feruloyl quinic acid; or (b)
The control extract comprises genipin gentiobioside, geniposide, phellodendrine hydrochloride, baicalin, berberine hydrochloride, oroxylin A-7-O-beta-D-glucuronide, wogonin and 4-O-feruloyl quinic acid; or (b)
The control extract comprises genipin gentiobioside, geniposide, phellodendrine hydrochloride, baicalin, berberine hydrochloride, oroxylin A-7-O-beta-D-glucuronide, wogonin, 4-O-feruloyl quinic acid and 5-O-feruloyl quinic acid.
9. The method for preparing a control extract of glabrous greenbrier rhizome oral liquid according to any one of claims 1 to 7, wherein the control extract comprises one or two of methyl deacetylate, neochlorogenic acid, cryptochlorogenic acid, genipin gentiobioside, geniposide, phellodendrine hydrochloride, baicalin, berberine hydrochloride, oroxylin a-7-O-beta-D-glucuronide, wogonin, and 5-O-feruloyl quinic acid and 4-O-feruloyl quinic acid.
10. The method for preparing a control extract of lupeol oral liquid as claimed in any one of claims 1 to 7, wherein the control extract comprises one or two of isogeniposide, 6-p-coumaroyl genipin gentiobioside, methyl deacetylate, neochlorogenic acid, cryptochlorogenic acid, genipin gentiobioside, geniposide, phellodendrine hydrochloride, baicalin, berberine hydrochloride, oroxylin a-7-O-beta-D-glucuronide, wogonin, and 5-O-feruloyl quinic acid and 4-O-feruloyl quinic acid.
11. The method for preparing a control extract of lupeum album according to any one of claims 1 to 7, wherein the control extract contains genipin gentiobioside not less than 26.83mg, geniposide not less than 126.19mg, phellodendrine hydrochloride not less than 2.76mg, the sum of 4-O-feruloylquinic acid and 5-O-feruloylquinic acid not less than 12.29mg, baicalin not less than 90.50mg, berberine hydrochloride not less than 6.62mg, oroxylin a-7-O- β -D-glucuronide not less than 12.78mg, and wogonin not less than 21.69mg per 1g calculated on dry basis.
12. The method for preparing a control extract of baikal skullcap root oral liquid as claimed in any one of claims 1 to 7, wherein the control extract comprises 26.83 to 56.88mg of geniposide Ping Longdan, 126.19 to 261.22mg of geniposide, 2.76 to 7.50mg of phellodendrine hydrochloride, 12.29 to 35.36mg of 4-O-feruloyl quinic acid and 5-O-feruloyl quinic acid, 90.50 to 196.05mg of baicalin, 6.62 to 26.10mg of berberine hydrochloride, 12.78 to 26.14mg of orotidine a-7-O-beta-D-glucuronide, and 21.69 to 44.20mg of wogonin per 1g of dried product.
13. A baphicanthus cusia oral liquid control extract prepared by the method of preparing the baphicanthus cusia oral liquid control extract of any one of claims 1 to 12.
14. The use of the baphicanthus cusia oral liquid control extract of claim 13 in controlling baphicanthus cusia oral liquid quality.
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