WO2015081702A1 - 药物组合物及其制备方法和用途 - Google Patents
药物组合物及其制备方法和用途 Download PDFInfo
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- WO2015081702A1 WO2015081702A1 PCT/CN2014/082233 CN2014082233W WO2015081702A1 WO 2015081702 A1 WO2015081702 A1 WO 2015081702A1 CN 2014082233 W CN2014082233 W CN 2014082233W WO 2015081702 A1 WO2015081702 A1 WO 2015081702A1
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- desmodium
- extract
- ethanol
- pharmaceutical composition
- alcohol extract
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Definitions
- the invention belongs to the field of traditional Chinese medicine, and in particular relates to a pharmaceutical composition, a preparation method thereof and use thereof. More specifically, the present invention provides pharmaceutical compositions, uses of the pharmaceutical compositions in the preparation of medicaments, and methods of preparing pharmaceutical compositions. Background technique
- Guangcaocao is a leguminous plant, and the dried aerial part of dium ⁇ yra «;/ tom (Osb.) Merr. is a traditional Chinese medicine contained in the 2010 edition of the Chinese Pharmacopoeia. Yellow, the effect of diuretic Tonglin.
- the prescription preparation of Shilintong tablets is mainly composed of broad-leaf grass, which is used for bladder dampness, stone drenching pain, urinary calculi, and urinary tract infection is hepatobiliary bladder damp heat.
- the preparation of the raw material of Shilintong Tablet is a crude extract of Dianthus chinensis obtained by the traditional water extraction and alcohol precipitation extraction process.
- the drug still has a clear basis for the pharmacodynamic substance and the clinical dose is too large. (6 times a day, 3 tablets each time, sugar-coated tablets or film-coated tablets, each containing 0.12 g of dry extract), and the quality control standards are not perfect.
- Western medicine is commonly used in the treatment of urinary calculi, such as potassium citrate, thiazide diuretics, magnesium, acetylcysteine, etc., and its efficacy is not ideal, and the toxicity and side effects are obvious.
- Chinese patent medicines such as Shishitong, Paishi Granules, and Shilintong tablets are commonly used drugs with exact curative effects.
- these traditional Chinese patent medicines like Shilintong tablets, still have problems such as primitive pharmaceutical technology, difficult quality control, inaccurate quantitative detection methods, and large doses. They are far from international standards and do not conform to modern clinical practice. Medication requirements.
- the present invention is directed to solving at least some of the above technical problems or at least providing a useful commercial choice. Therefore, the present invention provides a pharmaceutical composition, a preparation method thereof and a medical use for the case where the drug for treating urinary calculi is insufficient at the present stage.
- the present invention provides a pharmaceutical composition
- a pharmaceutical composition comprising an extract of total flavonoids of Rhododendron chinense as an active ingredient, and a pharmaceutically acceptable pharmaceutical excipient, wherein the broad The 5% to 95% by weight of the total flavonoids of the extract of the medicinal composition of the medicinal composition.
- the pharmaceutically acceptable pharmaceutical excipient is selected from the group consisting of corn starch, dextrin, lactose, pregelatinized starch, sucrose, microcrystalline cellulose, mannitol, sorbitol, xylitol, Calcium hydrogen phosphate, calcium carbonate, starch paste, hypromellose, povidone K 3 Q, povidone K 25 , polyethylene glycol 2000, polyethylene glycol 4000, polyethylene glycol 6000, tannic acid , succinic acid, dextran, galactose, sucrose, glucose, modified starch, microcrystalline cellulose, poloxamer 188, D-mannitol, methylcellulose, sodium carboxymethyl starch, low-substituted hydroxypropylcellulose, crospovidone, sodium carboxymethyl starch, croscarmellose sodium, carboxymethyl Cellulose calcium, coconut oil amine polyglycol ether, glycerol ethoxylate, Twe
- the total flavonoid extract of Herba Lysimachia is prepared by the following steps: adding alcohol extract to alcohol extract to obtain the extract of Herba Lysimachia, and purifying the extract of Herba Lysimachia, In order to obtain the total flavonoid extract of the broadbread.
- the obtained extract after obtaining the total flavonoid extract of Herba Lysimachia, the obtained extract can be dried as needed to obtain a solid substance.
- the alcohol extraction of the polysaccharides further comprises: heating and refluxing the medicinal herbs with 50% to 95% ethanol of 8 to 14 times the weight of the medicinal materials, and extracting 1 to 3 times, each 1 to 3 hours, and the alcohol extract is combined to obtain the extract of the broad-leaved grass.
- purifying the extract of the broad-leaf grass extract further comprises: concentrating the extract of the broad-leaf grass extract to remove ethanol; and performing the macroporous adsorption resin column on the extract of the broad-leaf grass extract Treatment to obtain purified total flavonoid extract of Herba Lysimachia.
- the method for preparing a total flavonoid extract of Dioscorea opposita L. may comprise the following steps:
- the alcohol extract is concentrated to a certain volume, so that the volume of the liquid is 2 to 8 times the amount of the medicine, and after standing and filtering, the filtrate is obtained; c the filtrate is passed through the AB-8 at a flow rate of 1 to 3 times per minute of the bed volume.
- the pore adsorption resin column after the adsorption is completed, first elute with 8 ⁇ 12 times of resin amount of water, and then use 6 ⁇ 10 times the bed volume of 40% ⁇ 95% ethanol to 2 ⁇ 4 times of bed bed per hour. The flow rate of the volume is eluted to obtain an eluent;
- the eluate is recovered from ethanol, and concentrated to a relative density of 1. 10 ⁇ 1.
- 30 concentrated liquid the concentrated liquid is dried and pulverized to obtain a fine powder of total flavonoid extract of the broadbread, the fine powder has a particle size of 50- 100 mesh.
- the content of the total flavonoids in the extract can reach 50% ⁇ 80%, and the content of the sulphate is 3. 0% ⁇ 12. 0%. Collect the dried extract, seal, weigh, and store in a dry place.
- the ethanol concentration referred to in the present invention means the volume fraction (V/V) of ethanol contained in a 100 mL volume of aqueous ethanol solution.
- V/V volume fraction of ethanol contained in a 100 mL volume of aqueous ethanol solution.
- the method for preparing the total flavonoid extract of Herba Lysimachia can be Includes the following steps:
- the alcohol extract is concentrated to a certain volume, so that the volume of the liquid is 5 times the amount of the drug, and after standing and filtering, the filtrate is obtained; c the filtrate passes through the AB-8 macroporous adsorption resin column at a flow rate of 3 times the bed volume per hour. After the adsorption is completed, the impurity is eluted with 10 times of resin amount of water, and then eluted with 8 times of bed volume of 60% ethanol at a flow rate of 3 times of bed volume per hour to obtain an eluent;
- the eluate is recovered from ethanol, concentrated to a concentrate having a relative density of 1.22, and the concentrate is dried under reduced pressure at 75 ° C, and pulverized to obtain a total flavonoid extract of Herba fuliginea, and the fine powder has a particle size of 80 mesh.
- the invention improves the content of active ingredients and effective substances in the medicinal herbs of the medicinal herbs, and the total flavonoid content of the cynomolgus sinensis (in terms of dry products) is 50% ⁇ 80%, wherein the buddha is The content of glucoside (% by dry product) is 3.0% ⁇ 12 ⁇ 0% ⁇
- the pharmaceutical composition of the present invention is composed of a total flavonoid extract of Dianthus chinensis and a pharmaceutically acceptable pharmaceutical excipient, thereby enabling the pharmaceutical composition to exhibit a form suitable for administration of a clinical pharmaceutical preparation.
- the pharmaceutical composition of the present invention may be in the form of an oral preparation selected from the group consisting of at least one of a tablet, an effervescent capsule, a hard capsule, a soft capsule, a granule, a granule, a pill, and a powder, wherein the tablet is a sugar-coated tablet. , film-coated tablets, enteric-coated tablets, dispersible tablets, sustained-release tablets, controlled-release tablets or effervescent tablets.
- a pharmaceutical composition according to an embodiment of the present invention for the preparation of a medicament, which pharmaceutical composition can be used for treating urinary calculi, that is, the medicament of the present invention can be effectively used for removal Damp heat, diuretic row stones, leaching and pain caused by damp heat accumulation, urinary calculi and the above-mentioned syndromes, and can be used for the preparation of clinical therapeutic drugs for the treatment of moist heat removal and diuretic drainage (damp heat accumulation).
- Total flavonoids of Rhododendron chinense can significantly inhibit the amount of calcium oxalate crystal aggregates in the kidney, reduce the formation rate of kidney stones and serum creatinine and uric acid content, and improve rat kidney Function; It has the function of dissolving stone and reducing the formation of new stones; It has the effect of diuresis; and the total flavonoids of Radix Paeoniae Alba can alleviate the swelling degree and swelling rate caused by the injection of fresh egg white in rats, suggesting that the total flavonoid capsule of Desmodium styracifolium has certain Anti-inflammatory effect, and has a significant inhibitory effect on granulation tissue proliferation.
- the medicament may be in the form of an oral preparation selected from the group consisting of at least one of a tablet, an effervescent capsule, a hard capsule, a soft capsule, a granule, a granule, a pill, and a powder, wherein the tablet is a sugar coating. Tablets, film-coated tablets, enteric-coated tablets, dispersible tablets, sustained-release tablets, controlled-release tablets or effervescent tablets.
- the present invention provides a method of preparing a pharmaceutical composition.
- the method comprises: providing an extract of oleracea alcohol, the extract of the polysaccharide of Lysimachia glabra L. containing as an active ingredient.
- the method further comprises the step of adding a pharmaceutically acceptable pharmaceutical excipient, wherein the total flavonoid content of the broad-leaved grass is 2.5 to 95% by weight based on the total weight of the pharmaceutical composition.
- the preparation of the total flavonoid extract of Rhododendron chinense comprises: extracting alcohol extracts to obtain the extract of Dianthus chinensis, and purifying the extract of Dianthus chinensis to obtain the total flavonoids of the broadbread An extract, wherein the concentration of the ethanol is 50 to 95%, and the weight of the ethanol is 8 to 14 times that of the polysaccharide material; the extract of the polysaccharide of Lysimachia chinensis is concentrated to remove ethanol; And the concentrated Lysimachia chinensis extract is subjected to a macroporous adsorption resin column to obtain the extract of the polysaccharide.
- the obtained extract may be dried as needed to obtain a solid substance.
- the alcohol extraction of the polysaccharides may further comprise: heating and refluxing the medicinal herbs with 50% to 95% ethanol of 8 to 14 times the weight of the medicinal materials, and extracting 1 to 3 times, Each time for 1 to 3 hours, the alcohol extract is combined to obtain the extract of the broad-leaved grass.
- purifying the extract of the broad-leaf grass extract further comprises: concentrating the extract of the broad-leaf grass extract to remove ethanol; and performing the macroporous adsorption resin column on the extract of the broad-leaf grass extract Treatment to obtain purified total flavonoid extract of Herba Lysimachia.
- the preparation method of the extract of the broadgrass extract according to the embodiment of the present invention may be as follows:
- the extract of the extract of Dianthus chinensis as follows: take 50 grams of medicinal herbs, add the first 80 times of the amount of 80% ethanol, and heat and reflux at 55 ° C for 2 hours, second. Adding 10 times of the amount of 80% ethanol, and heating and refluxing at 55 ° C for 1.5 hours, combining the alcohol extract; concentrating the alcohol extract to a certain volume, so that the volume of the liquid is 5 times the amount of the drug, and static filtration. The filtrate (as the sample solution) was obtained and used. Will be 100 kg of pharmaceutical grade AB-8 The macroporous resin is soaked in an appropriate amount of ethanol, packed in a wet manner, and disposed of after use.
- the above filtrate (loading solution) is passed through the AB-8 macroporous adsorption resin column at a flow rate of 2 times the bed volume per hour. After the adsorption is completed, the impurity is eluted with 10 times of resin amount, and then 8 times column is used.
- the bed volume of 60% ethanol is eluted at a flow rate of 2 times the bed volume per hour to obtain an eluate; the eluate is recovered from ethanol, and concentrated to a concentration of 1.22, which is reduced by 75 ° C. ⁇
- the dried whey extract product 1. 10 grams.
- the method for producing a medicament of the present invention may further comprise the step of adding a pharmaceutically acceptable pharmaceutical excipient to prepare a traditional Chinese medicine preparation.
- the method for preparing a medicament of the present invention may further comprise the steps of: forming the medicament into at least one selected from the group consisting of a tablet, an effervescent capsule, a hard capsule, a soft capsule, a granule, a granule, a pill, and a powder.
- An oral preparation form, wherein the tablet is a sugar-coated tablet, a film-coated tablet, an enteric-coated tablet, a dispersible tablet, a sustained-release tablet, a controlled release tablet or an effervescent tablet.
- the preparation method thereof may include: dissolving a prescribed amount of the binder in water, stirring and uniformly formulating the solution, and standby; and prescribing the amount of the total flavonoid extract of the broadbread
- the filler is mixed, put into the fluidized bed, and the binder solution is sprayed into the fluidized bed by using a spray gun to perform granulation; after the granulation is finished, the mixture is dried and discharged, and the mixed powder is obtained, and the obtained mixed powder is filled.
- a pharmaceutical composition in the form of granules may include: dissolving a prescribed amount of the binder in water, stirring and uniformly formulating the solution, and standby; and prescribing the amount of the total flavonoid extract of the broadbread
- the filler is mixed, put into the fluidized bed, and the binder solution is sprayed into the fluidized bed by using a spray gun to perform granulation; after the granulation is finished, the mixture is dried and discharged, and the mixed powder is obtained, and the obtained
- the preparation method may further comprise: respectively, prescribing a total amount of the total flavonoid extract raw material of the polysaccharide, and a pharmaceutically acceptable pharmaceutical excipient, through a 60-100 mesh sieve;
- the binder is dissolved in a solvent and stirred to prepare a solution for use; according to the prescription, the material is put into a fluidized bed, preheated for 5 to 60 minutes, and preheated to 35 ° C - 55 ° C; adjust the parameters, and use
- the inlet air temperature of 50 ° C -65 ° C, keep the material temperature at 40 ° C -55 ° C, spray the adhesive after 5-60 minutes; after the granulation is finished, adjust the parameters to dry, through adjustment
- the air temperature is 60 ° C - 7 (TC, the temperature of the material is raised to 40 ° C - 55 ° C, and the drying is carried out for 5 to 60 minutes; the dried particles are cooled and discharged, and the mixed powder is obtained, and the obtained mixed powder is granulated.
- the agent is filled to obtain a pharmaceutical composition in the form of granules.
- the granule preparation method of the composition product of the present invention is as follows: The binder povidone K 3 is used . 1 g is dissolved in 120 g of water, stirred and evenly mixed into a solution, ready for use; 133 g of total flavonoid extract of D. chinensis, 110 g of microcrystalline cellulose and 60 g of lactose are mixed and put into a fluidized bed, preheated for 20 minutes. , preheating to 45 ° C; adjust the parameters, and use a spray gun to spray the binder solution into the fluidized bed for granulation, maintaining the atomization pressure of 0.
- the spray speed is 20 rev / min, through Adjust the inlet air temperature to 55 °C, keep the material temperature at 45 °C, and spray the adhesive for 15 minutes. After the granulation is finished, adjust the parameters for drying. Adjust the inlet air temperature to 65 °C to raise the material temperature to 45 °. C, drying for 10 minutes; the dried granules were cooled and discharged to obtain a mixed powder, and the obtained mixed powder was granulated to obtain 1000 bags of the pharmaceutical composition in the form of granules.
- the preparation method thereof may include: dissolving a prescribed amount of the binder In water, stir and mix into a solution, and set aside; mix the prescribed amount of the total flavonoid extract of the cynomolgus extract with the filler, put it into the fluidized bed, and spray the binder solution into the fluidized bed using a spray gun. After the granulation is finished, the mixture is dried and discharged to obtain a mixed powder, and the obtained mixed powder is filled on a capsule machine to obtain a composition in the form of a capsule.
- the preparation method may further comprise: separately applying a prescribed amount of the total flavonoid extract raw material of the polysaccharide, and a pharmaceutically acceptable pharmaceutical excipient, through a 60-100 mesh sieve;
- the binder is dissolved in a solvent and stirred to prepare a solution for use; according to the prescription, the material is put into a fluidized bed, preheated for 5 to 60 minutes, and preheated to 35 ° C - 55 ° C; adjust the parameters, and use
- the capsule preparation method of the composition product of the present invention is as follows: The adhesive povidone K 3 is used . 1 g is dissolved in 120 g of water, stirred and evenly mixed into a solution, ready for use; 133 g of total flavonoid extract of D. chinensis, 30 g of microcrystalline cellulose and 37 g of lactose are mixed and put into a fluidized bed, preheated for 20 minutes. , preheating to 45 ° C; adjust the parameters, and use a spray gun to spray the binder solution into the fluidized bed for granulation, maintaining the atomization pressure of 0.
- the spray speed is 20 rev / min, through Adjust the inlet air temperature to 55 °C, keep the material temperature at 45 °C, and spray the adhesive for 15 minutes. After the granulation is finished, adjust the parameters for drying. Adjust the inlet air temperature to 65 °C to raise the material temperature to 45 °. C, drying for 10 minutes; the dried granules were cooled and discharged to obtain a mixed powder, and the obtained mixed powder was filled on a capsule machine to obtain 1000 tablets of the pharmaceutical composition in the form of a capsule.
- the preparation method may include: prescribing a total amount of the total flavonoids of the polysaccharide, a solid dispersion carrier, and a surfactant, sieving, adding 50% ethanol, heating and stirring to dissolve The solvent is evaporated under reduced pressure, dried in a vacuum, and pulverized to obtain a solid dispersion of total flavonoids of Rhododendron chinense; a filler, a disintegrant is weighed, and after being sieved, it is uniformly mixed with the solid dispersion of total flavonoids of Herba fuliginea , granulating, drying, granulating, adding a lubricant to mix uniformly, in order to obtain granules of total flavonoids of cynomolgus, and granules are pressed on a tableting machine to obtain a pharmaceutical composition in the form of a tablet. Further, the above tablets are sugar coated or film coated to obtain a pharmaceutical
- the preparation method thereof may further include: separately weighing a prescribed amount of the total flavonoids of the polysaccharide, the solid dispersion carrier, and the surfactant, and after adding the 40-100 mesh sieve, adding 50% ethanol, heated to 50 ° C ⁇ 75 ° C stir to dissolve, 30 ° C ⁇ 75 ° C under reduced pressure evaporation to remove the solvent, 30 ° C ⁇ 6 (TC vacuum drying, after drying, smashed through 40-200 mesh sieve , spare; weigh filler, disintegrant, after 40-100 mesh sieve, with broad money grass
- the solid flavonoid solid dispersion is uniformly mixed, made into a soft material, granulated with a 10-30 mesh sieve, dried at 30 ° C to 75 ° C, whole granules, and uniformly mixed with a lubricant to obtain a total flavonoid granule of Compressed on a tablet machine to obtain a pharmaceutical composition in the form
- the tablet preparation method of the composition product of the present invention is as follows: a prescribed amount of total flavonoids of P. chinensis 66.5 g, povidone K 3Q 266 g, poloxamer 188 133 g, and 39.9 g of sodium decyl sulfate, after passing through a mesh of 80 mesh, adding 50% ethanol, heating to 65 ° C, stirring and dissolving, evaporating the solvent under reduced pressure at 50 ° C, vacuum drying at 4 CTC, after drying, smashing through 80 mesh sieve , Decopolysaccharide total flavonoid solid dispersion spare; Weigh 10g of lactose, 15g of croscarmellose sodium, after 80 mesh sieve, mix with the obtained solid dispersion of total flavonoids of Herba fuliginea, use appropriate amount of water The soft material was granulated with a 20-mesh sieve, dried at 55 ° C, and granulated,
- the total flavonoid granules of D. chinensis were compressed on a tablet machine to obtain 1000 tablets of the pharmaceutical composition in the form of tablets. Further, the above tablets are sugar coated or film coated to obtain a pharmaceutical composition in the form of a sugar-coated tablet or a film-coated tablet.
- the preparation method may include: adding a prescribed amount of the oil phase, a surfactant, and a co-surfactant by stirring or ultrasonically, and uniformly mixing the mixture, and then adding a wide prescription amount.
- the total flavonoid extract of Lysimachia chinensis is dissolved by stirring or sonication, and then potted in a soft capsule to obtain a composition in the form of a soft capsule.
- the preparation method may include: 40 g of a prescribed amount of soybean oil, 80 g of polyoxyethylene (40) hydrogenated castor oil, and 30 g of polyethylene glycol 400, by stirring or ultrasonication. The method is to stir the mixture evenly, and then add 133 g of the total amount of the total flavonoid extract of Herba fuliginea, and stir it at 37 ° C or ultrasonic to dissolve it, and evacuate the air bubbles to prepare a content material liquid.
- the content material liquid is placed in a soft capsule pilling machine, filled into soft capsules, and then dried into a drum drying device to dry and soften the soft capsules, and then sterilized by ethanol and scrubbed the pellets, so that the capsule shell moisture and ethanol are naturally evaporated. Drop, drying time for 20 hours, until the surface of the capsule is dry and smooth, slightly elastic, and dry. Finally, the unqualified soft capsules such as the appearance and the joint are sorted and discarded, and the selected qualified soft capsules are packaged in the form of a bottle or a blister sheet to obtain 1000 compositions in the form of soft capsules.
- a medicament prepared by the method for producing a medicament of the present invention can be used for the treatment of urinary calculi.
- the present invention also provides a medicament which is produced by the above method for preparing a medicament. As described above, with this drug, urinary calculi can be effectively treated.
- composition of the present invention its preparation method and use are completed by the inventor of the present application through arduous creative labor and optimization work.
- the invention has the following advantages: 1.
- ethanol is used as an extraction solvent to extract the medicinal materials of the medicinal herbs, and the extract is purified by macroporous adsorption resin to obtain the total flavonoids of the medicinal herb of the genus Lysimachia chinensis, and the oleoresin
- the effective material basis of the extract is clear, the quality standard is controllable, the clinical dose of the drug is reduced, and the clinical adverse reaction is reduced.
- the present invention can directly purify the macroporous resin by recovering the ethanol to a certain volume (5 times the amount of the medicinal material), without concentrating and drying to the extract, saving Production time; Secondly, after the macroporous resin is used, the higher concentration of the active ingredient can be obtained by eluting with the same concentration of ethanol. Compared with the gradient elution with different concentrations of ethanol, the process flow is simple and the operability is strong; After the eluent recovers the ethanol, it is directly dried under reduced pressure. Without the need of adding a suitable solvent for treatment, the total flavonoids of the active part of the broad-leaved grass can be obtained, which saves the production monthly energy. From the perspective of large-scale production, the new extraction and purification process reduces the production cost, shortens the production cycle, and the process is simple and feasible, and meets the requirements of the modernization industry of traditional Chinese medicine.
- the invention adopts AB-8 macroporous adsorption resin technology to extract and purify the effective part, has the advantages of simple process, low cost, reusable resin, and is suitable for industrial production. Moreover, the present invention has carefully and carefully examined the corresponding technical parameters, optimized the optimal conditions, and conducted a pilot test. The method of the present invention can be transitioned to industrialization and the content of the effective portion is improved.
- the pharmaceutical composition of total flavonoids of Radix Paeoniae Alba obtained by the invention has the advantages of advanced production technology, clear basis of effective drug substance, controllable quality standard, relatively accurate clinical indication, and pharmacological efficacy. Significant, less medication, safe and convenient to take, and low adverse reactions, so that it has the advantages of adapting to modern manufacturing technology and quality standards.
- Figure 2 shows the elution profile of total flavonoids in a resin column eluted with 60% ethanol as an eluent according to one embodiment of the present invention.
- Extraction method According to the solubility properties of flavonoids, free flavonoids and flavonoid glycosides can be extracted by organic solvents, and industrial production is usually extracted with higher concentration of ethanol. This study draws on the industrial extraction method of general flavonoids. On the basis of the selection, 60%-95% ethanol is selected as the extraction solvent, and the extraction times are economically and practically extracted twice by the usual methods of production.
- Ethanol reflux extraction process experiment Using L9 ( 3 4 ) orthogonal test method, taking the total flavonoids of Lysimachia chinensis as an indicator to determine the process parameters of ethanol concentration, ethanol dosage (multiple of Guangqian herbal material) and extraction time.
- the content of total flavonoids in the extract was determined by UV-visible spectrophotometry, and the total flavonoid content and the net weight of total flavonoids in the dry paste were used as the evaluation indexes.
- the experimental factors and O level arrangement are shown in Table 1, and the results are shown in Table 2.
- the macroporous resin purification process is carried out by extracting the extract of Dianthus chinensis obtained by the above preferred extraction conditions: 1) screening test of macroporous resin
- Resin source AB-8 resin (Nankai University), D101 resin (Shandong Lukang), HPD100 resin (Hebei Baodi Co., Ltd.).
- Saturated adsorption amount [(initial concentration - concentration after adsorption) X adsorbent volume] / resin amount]
- elution rate (eluent concentration X eluent volume) / saturation
- the adsorption amount is X 100%, and the results are shown in Table 3.
- the experimental results are shown in Table 4.
- the test results show that: AB-8 macroporous resin has better specific adsorption and elution rate of total flavonoids of D. It has high safety and is one of the most widely used macroporous resins in the domestic pharmaceutical production industry. Therefore, this study used AB-8 macroporous resin to simultaneously purify total flavonoids from Herba Lysimachia.
- the orthogonal test method is used to determine the concentration of the above liquid (based on the amount of the original drug contained in the sample), the adsorption flow rate and the aspect ratio as the investigation factor, and apply the (3 4 ) orthogonal table arrangement test. 5.
- the total flavonoid content was determined for the following 9 groups of tests, and the specific adsorption amount was calculated and comprehensively evaluated. The results of the analysis are shown in Table 6.
- the sample was adsorbed according to the above optimal adsorption conditions, the sample loading was 50 mL, and then rinsed with purified water, and the column liquid was 1 part per 20 mL, and the ⁇ -naphthol reaction was detected, and the dry paste weight was measured, and the water was washed. After 300 mL, the ct-naphthol reaction was negative, and the dry paste weight did not change. The results showed that the sugar on the resin column was substantially removed after washing with 300 mL of water (about 15 times the amount of resin).
- the impurity is eluted with 10 times of resin amount, and then 8 times column is used. Bed volume of 60% ethanol, 2 times bed volume per hour The flow rate is eluted to obtain an eluate; the eluate is recovered to ethanol, and concentrated to a relative density of 1.22, dried at 75 ° C under reduced pressure, and pulverized to obtain a total flavonoid extract product of Herba Lysimachia. . 10 grams.
- the above filtrate (loading solution) is passed through the AB-8 macroporous adsorption resin column at a flow rate of 2 times the bed volume per hour. After the adsorption is completed, the impurity is eluted with 10 times of resin amount, and then 8 times column is used.
- the bed volume of 60% ethanol was eluted at a flow rate of 2 times the bed volume per hour to obtain an eluate; the eluate was recovered to ethanol, concentrated to a concentrate having a relative density of 1.22, and dried under reduced pressure at 75 ° C. , crushed, and obtained 4.03 g of total flavonoid extract product of Lysimachia chinensis (preserved in a cool place).
- the extract product was measured by ultraviolet-visible spectrophotometry to obtain the content of the substance in the extract, and the total flavonoid content (% by dry product) was 63.31%, and the content of safflower glycoside (% by dry product) was 5.38%. .
- the above filtrate (loading solution) is passed through the AB-8 macroporous adsorption resin column at a flow rate of 2 times the bed volume per hour. After the adsorption is completed, the impurity is eluted with 10 times of resin amount, and then 8 times column is used.
- the bed volume of 60% ethanol was eluted at a flow rate of 2 times the bed volume per hour to obtain an eluate; the eluate was recovered to ethanol, concentrated to a concentrate having a relative density of 1.22, and dried under reduced pressure at 75 ° C. , crushed, obtained 1.12 kg of total flavonoids extract of Herba Lysimachia (stored in a cool place).
- the extract product was measured by ultraviolet-visible spectrophotometry to obtain the content of the substance in the extract, and the total flavonoid content (% by dry product) was 59.49%, and the content of safflower glycoside (% by dry product) was 5.10%. .
- the above filtrate (loading solution) is passed through the AB-8 macroporous adsorption resin column at a flow rate of 2 times the bed volume per hour. After the adsorption is completed, the impurity is eluted with 10 times of resin amount, and then 8 times column is used.
- the bed volume of 60% ethanol was eluted at a flow rate of 2 bed volumes per hour to obtain an eluate; the eluate was recovered from ethanol and concentrated to a relative density of 1.22.
- the concentrated solution was dried under reduced pressure at 75 ° C and pulverized to obtain 1.14 kg of total flavonoid extract product of Lysimachia chinensis (preserved in a cool place).
- the extract product was measured by ultraviolet-visible spectrophotometry to obtain the content of the substance in the extract, and the total flavonoid content (% by dry product) was 59.37%, and the content of safflower glycoside (% by dry product) was 5.01%. .
- the binder povidone K 3 . 1 g is dissolved in 120 g of water, stirred and evenly mixed into a solution, and used;
- the dried granules are cooled and discharged to obtain a mixed powder, and the obtained mixed powder is filled on a capsule machine to obtain a total flavonoid capsule of Herba fuliginea.
- Micro powder silica gel lg Water 120g is made into a total of 1000 tablets: same as in Example 6
- the binder povidone K 3 . 1 g is dissolved in 120 g of water, stirred and evenly mixed into a solution, and used;
- the dried granules are cooled and discharged to obtain a mixed powder, and the obtained mixed powder is filled with granules to obtain granules of total flavonoids of Herba fuliginea.
- drying time is 20 hours, until the surface of the capsule is dry and smooth, slightly elastic, dry carry out.
- unqualified soft capsules such as the appearance and the joint are sorted and discarded, and the selected qualified soft capsules are packaged in the form of a bottle or a blister board to obtain 1000 compositions in the form of soft capsules.
- Laboratory animals and administration Kunming mice, female, weighing 18-22 g, provided by the Experimental Animal Center of the Academy of Military Medical Sciences, Laboratory Animal Quality License No.: SCXK (Military) 2002-001, animal words raised in the center Rat laboratory, laboratory facility certification number is SYXK (Army) 2002-001.
- Experimental group The experiment was divided into 4 groups, namely, the control group (administered 0.5% sodium carboxymethylcellulose), the low-dose group of total flavonoids of Radix Paeoniae Alba (75 mg/kg), and the middle dose of total flavonoids of Radix Paeoniae Alba (150 mg/ Kg), high-dose total flavonoids (300mg/kg) o 10-20 per group.
- the administration route was a one-time gavage, and the administration volume was 0.6 ml/mouse.
- mice in each group were observed 15 minutes after gavage. The observation included mental, gait, eyes, tail, fur and feces, and observed continuously for 60 minutes. Observe 1 more hour.
- mice After observing the general state and behavior of the mice, the mice were given small, medium and large doses of total flavonoids (75 mg/kg, 150 mg/kg, 300 mg/kg) on animal behavior, response, activity, mood, There was no significant change in gait, and there was no significant difference compared with the control group.
- the specific data are shown in Table 9.
- mice were fed with the total flavonoids of the herb, the appropriate amount of normal saline was applied to the ears of the animals, and the tip of the ear was clamped with a fish mouth clamp.
- the voltage was 110 volts, and the stimulating time was 0.3 seconds. duration.
- mice Effects of total flavonoids from Lysimachia chinensis on central nervous system excitability in mice Number of animals (only) Body weight (g) Dosage (mg/kg) Duration of convulsion (seconds)
- mice in each group were tested. The mice were fasted for 12 hours before the experiment. After 1 hour of total flavonoids of Herba Lysimachia, a suspension made of 5% carbon powder and 10% gum arabic was administered, 0.2 ml. /only. The animals were sacrificed 20 minutes after the gavage, and the entire gastrointestinal tract was taken out and placed on a glass plate. The distance between the pylorus and the leading edge of the carbon was measured with a ruler, and the percentage of the gastrointestinal tract was calculated. The results showed that total flavonoids from Herba Lysimachia had no significant effect on gastrointestinal motility in mice. The specific data is shown in Table 11.
- the four doses of total flavonoids of Lysimachia chinensis can significantly inhibit the amount of calcium oxalate crystal aggregates in the kidney, dose-effect relationship (P ⁇ 0.05-0.01), reduce the formation rate of kidney stones and serum creatinine and uric acid content (P ⁇ 0.05-0.01), Improve renal function in rats.
- control group rats were given 0.5% sodium carboxymethylcellulose
- three doses of total flavonoids of Lysimachia chinensis 50mg/kg/day, 100mg/kg/day, 200mg/kg/day
- the three doses of total flavonoids (100 mg/kg/day, 200 mg/kg/day, 400 mg/kg/day) It has the function of dissolving stone and reducing the formation of new stones.
- the weight of stones in the 100 mg/kg group was reduced (P ⁇ 0.05)
- the weight of stones in the 200 mg/kg group was reduced (P ⁇ 0.05)
- 20% of the stones were dissolved
- the weight of stones in the 400 mg/kg group was reduced (P ⁇ 0.01), and 30% of the stones were dissolved.
- the control group was administered with 0.5% sodium carboxymethylcellulose
- the three doses of total flavonoids 50 mg/kg/day, 100 mg/kg/day, 200 mg/kg/day
- the total amount of urine excretion was 6 hours after administration, and the total amount of normal control was 48.1 ml.
- the drug group 76.4-89.5 ml was 29-36 ml higher than the normal control group.
- 12 Urinary excretion increased significantly during the hour, an increase of 12-36% over the model group.
- the control group was given 0.5% sodium carboxymethylcellulose
- the three doses of total flavonoids 100 mg/kg/day, 200 mg/kg/day, 400 mg/kg/day were all It can alleviate the swelling degree and swelling rate caused by injection of fresh egg white in rats, suggesting that the total flavonoids of Radix Paeoniae Alba have certain anti-inflammatory effects and have obvious inhibitory effects on granulation tissue proliferation.
- Example 19 Animal acute toxicity test of total flavonoids from Herba Lysimachia
- the test was divided into 6 groups, 20 animals in each group, half male and half female, with a distance between the groups of 0.85. After the drug, the animals showed reduced activity, unstable gait, and weak breathing. Most of the dead animals were distributed within 1 hour after the drug, and individual dead animals were distributed 1-6 hours after the drug.
- the LD50 of female animals is 18.162g/kg, 95% confidence limit
- the upper limit is 20.199g/kg
- the lower limit is 16.326g/kg
- the male animal LD50 is 17.084g/kg
- 95% confidence limit The upper limit is 18.975g/kg and the lower limit is 15.301g/kg. There was no significant difference in LD50 between females and males. Based on the above results, it can be considered that the total flavonoids of Lysimachia chinensis is a substantially non-toxic test drug.
- the test was carried out according to the "single oral fixed dose method".
- the rats were administered at 2000 mg/kg, and there was no obvious acute toxicity after the drug was administered. Therefore, a formal test was conducted at a fixed dose of 2000 mg/kg.
- the test was divided into the control group and the total flavonoids group of D. chinensis, with 10 animals in each group, half male and half female.
- the animals in the administration group were intragastrically administered with total flavonoids of 2000 mg/kg, and the volume was 2.0 ml/100 g body weight.
- the control animals were intragastrically administered with 0.5% sodium carboxymethylcellulose 2.0 ml/100 g body weight.
- the lazy movement occurred within 3 hours after the drug was administered.
- the stool was grayish-black on the 1st day after the drug, the food intake decreased slightly, and the body weight growth was slightly inhibited.
- the drug returned to the control level 7 days after the drug.
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CN103893258B (zh) * | 2013-12-05 | 2017-09-29 | 人福医药集团股份公司 | 含有广金钱草总黄酮的口服固体制剂及其应用 |
CN103893246A (zh) * | 2013-12-05 | 2014-07-02 | 人福医药集团股份公司 | 广金钱草总黄酮胶囊及其制备方法和应用 |
CN104974176B (zh) * | 2015-06-19 | 2018-08-14 | 武汉光谷人福生物医药有限公司 | 从广金钱草中提取分离广金钱草碱的方法和系统 |
CN105085500B (zh) * | 2015-06-19 | 2018-09-21 | 武汉光谷人福生物医药有限公司 | 同时提取分离广金钱草中三种黄酮碳苷化合物单体的方法和系统 |
CN105982930A (zh) * | 2016-07-29 | 2016-10-05 | 上海诗丹德生物技术有限公司 | 广金钱草提取物治疗泌尿性结石的应用 |
CN112294751B (zh) * | 2020-10-31 | 2023-10-31 | 郑州大学 | 一种负载过氧化钙的金属有机框架药物组合物的制备方法及其应用 |
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