WO2015081703A1 - 一种含有广金钱草总黄酮的固体分散体及其制备方法和用途 - Google Patents
一种含有广金钱草总黄酮的固体分散体及其制备方法和用途 Download PDFInfo
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- WO2015081703A1 WO2015081703A1 PCT/CN2014/082250 CN2014082250W WO2015081703A1 WO 2015081703 A1 WO2015081703 A1 WO 2015081703A1 CN 2014082250 W CN2014082250 W CN 2014082250W WO 2015081703 A1 WO2015081703 A1 WO 2015081703A1
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- desmodium
- total flavonoids
- sodium
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Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
- A61K9/146—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with organic macromolecular compounds
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- A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
- A61K36/18—Magnoliophyta (angiosperms)
- A61K36/185—Magnoliopsida (dicotyledons)
- A61K36/48—Fabaceae or Leguminosae (Pea or Legume family); Caesalpiniaceae; Mimosaceae; Papilionaceae
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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- A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
- A61K9/148—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with compounds of unknown constitution, e.g. material from plants or animals
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- A—HUMAN NECESSITIES
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/1605—Excipients; Inactive ingredients
- A61K9/1617—Organic compounds, e.g. phospholipids, fats
- A61K9/1623—Sugars or sugar alcohols, e.g. lactose; Derivatives thereof; Homeopathic globules
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- A—HUMAN NECESSITIES
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- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
- A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2095—Tabletting processes; Dosage units made by direct compression of powders or specially processed granules, by eliminating solvents, by melt-extrusion, by injection molding, by 3D printing
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/4808—Preparations in capsules, e.g. of gelatin, of chocolate characterised by the form of the capsule or the structure of the filling; Capsules containing small tablets; Capsules with outer layer for immediate drug release
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/4833—Encapsulating processes; Filling of capsules
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/04—Drugs for disorders of the urinary system for urolithiasis
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K2236/00—Isolation or extraction methods of medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicine
Definitions
- the invention belongs to the technical field of pharmaceutical preparations, and in particular relates to an oral solid dispersion containing total flavonoids of Rhododendron chinense and its application. More specifically, the present invention relates to a solid dispersion containing total flavonoids of Rhododendron chinense as an active ingredient, a solid dispersion preparation of total flavonoids of cynomolgus sinensis, a preparation method thereof, and a solid dispersion and a solid dispersion preparation of total flavonoids Use in the preparation of a medicament for treating urinary calculi. Background technique
- the broad-grained grass is a leguminous plant, and the dried aerial part of dium styracifolium (Osb.)Men. is a traditional Chinese medicine contained in the Chinese Pharmacopoeia 2010 edition. It has a dampness and yellowing, and diuretic The effect.
- the prescription preparation of Shilintong tablets is mainly composed of broad-leaf grass, which is used for moist heat of the bladder, stone dripping 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 satisfactory, 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.
- the invention is completed based on the following findings:
- the chemical constituents of the medicinal herbs are flavonoids, alkaloids, phenols, tannins, polysaccharides, etc., wherein the flavonoids are the main medicinal ingredients.
- Pharmacological studies have shown that the effective part of the polysaccharide (the effective substance), the total flavonoids of the Chinese medicinal herb have obvious pharmacological effects such as dissolving stone, discharging stones, and reducing the formation of new stones.
- the inventors of the present invention found that the total flavonoids of Rhododendron chinense L.
- chinensis are prepared into common pharmaceutical preparations, their dissolution in water will be low. Therefore, using the conventional preparation process, the granulation effect is very poor, and it is almost impossible to granulate, which easily causes the prepared oral solid preparation of the total flavonoids of the cynomolgus sinensis to be slowly dissolved, the product quality is unstable, the bioavailability is low, the clinical curative effect is low, and the like. Disadvantages. also because The absorption of drugs is based on the premise of dissolution. The bioavailability of the drug has a certain correlation with the dissolution characteristics in vitro. Therefore, the dissolution of the drug directly affects the absorption of the drug, and the dissolution of the drug in the preparation is whether the drug can exert its function. The control step of efficacy. Further, to increase the absorption rate of the oral preparation in the human body, the most important thing is to increase the dissolution and release of the drug, thereby increasing the maximum blood concentration after oral administration of the active ingredient for 3 hours.
- the inventors of the present invention have obtained a desired beneficial effect through extensive research and experimentation.
- the present invention provides according to the existing pharmaceutically acceptable pharmaceutical excipients and production conditions, while ensuring a low production cost and a simple and easy preparation process, which has been suitable for large-scale industrial production.
- the oral solid dispersion preparation obtained by the present invention has good bioavailability and drug stability.
- the present invention provides a total flavonoid of Lysimachia chinensis.
- the total flavonoids of D. chinensis are alcohol extracts of D. chinensis.
- the present invention provides a solid dispersion containing total flavonoids of Lysimachia chinensis as an active ingredient, wherein the total flavonoids of the broad-leaved grass are provided in the form of an extract of oleracea alcohol.
- the extract of the polysaccharide of the oleic acid is obtained by the following steps: heating and refluxing the medicinal material of the medicinal herb with ethanol to obtain a extract of the cynomolgus extract, wherein the concentration of the ethanol is 50 ⁇ 95%, the weight of the ethanol is 8 to 14 times that of the medicinal herbs; the concentrated extract of the cyanobacteria is concentrated to remove ethanol; and the concentrated extract of the cypress grass is subjected to concentration treatment.
- the macroporous adsorption resin column is treated to obtain the extract of the polysaccharide of the polysaccharide.
- the extract of the Lycium chinensis is heated and refluxed by using 50% to 95% ethanol of the weight of the medicinal material of 8 to 14 times the weight of the herbal medicine, and extracting 1-3 times, each time 1 ⁇ 3 hours, and obtained by combining alcohol extracts.
- the inventors have found that the total flavonoid content of the total flavonoids of the cynomolgus sinensis (% by dry product, %) is 50% to 80%, wherein the content of the sulphate (in dry products, %) ;) is 3.0% ⁇ 12.0%.
- the method of preparing the total flavonoids of the broadbread of the present invention 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 passes 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 use 8 ⁇ 12 times the amount of resin to elute the impurities, and then use 6 ⁇ 10 times the bed volume of 40% ⁇ 95% ethanol to 2 ⁇ 4 times of the column bed per hour. The flow rate of the volume is eluted to obtain an eluent; d.
- the eluate is recovered from ethanol and concentrated to a concentrated liquid having a relative density of 1.10 ⁇ 1.30.
- the concentrated solution is dried and pulverized to obtain an extract product of total flavonoids of the extract of Lysimachia chinensis. Up to 50% ⁇ 80%, wherein the content of sedumin is 3.0% ⁇ 12.0%. Collect the dried extract, seal, weigh, and store in a dry place.
- the ethanol concentration in the present invention refers to a lOOmL volume aqueous ethanol solution containing ethanol in the volume fraction (V / V) 0
- the present invention has carried out detailed and intensive investigation and research on the preparation process and technical parameters of the total flavonoids of Herba Lysimachia, and optimized the optimal conditions, and carried out a pilot test to verify the success. Transition to industrial production.
- the method for preparing total flavonoids of the herb of the present invention may comprise the following steps:
- the eluate is recovered from ethanol, concentrated to a concentrated liquid having a relative density of 1.22, and the concentrated solution is dried under reduced pressure at 75 ° C, and pulverized to obtain total flavonoids of Herba Lysimachia.
- the present invention improves the content of the active ingredient and the effective substance in the herb of the medicinal herb, and the total flavonoid content of the cynomolgus sinensis (in terms of dry product) is 50 % ⁇ 80%, wherein the content of the sulphate (in terms of dry product, %;) is 3.0% to 12.0%.
- the solid dispersion technique of the present invention means that the solid dispersion refers to a system in which a drug is uniformly dispersed in a solid carrier in the form of fine particles, crystallites or molecular states.
- Water-soluble and highly hydrophilic substances are often used as solid dispersion carriers to increase the solubility and dissolution rate of some poorly soluble drugs and increase the bioavailability of the drug after oral administration.
- the state in which the drug is dispersed in the carrier is classified into a simple eutectic mixture, a solid solution, a partial crystal, a glassy solid solution, and a molecular complex.
- the solid dispersion is provided in the form of an oral solid preparation of a capsule, a granule, or a tablet, and optionally, the tablet is a sugar-coated tablet, a film-coated tablet, a dispersible tablet, and a sustained release. Tablet or controlled release tablets.
- the dissolution rate of these oral solid preparations of total flavonoids was significantly improved.
- the oral solid preparation of the total flavonoids of the broad-leaved genus of the present invention is a capsule of a solid dispersion of total flavonoids of Rhododendron chinense, and a tablet of a solid dispersion of total flavonoids of Rhododendron chinense.
- the oral solid preparation of the solid dispersion of total flavonoids of the broad-leaved turf (in this paper, "oral solid preparation of solid dispersion of total flavonoids of Rhododendron chinense” and “oral solid preparation of total flavonoids of Lysimachia chinensis” And “Golden Cordyceps Total Flavonoid Solid Dispersion Formulation” are used interchangeably.)
- the total flavonoids of D. chinensis are an alcohol extract of Dianthus chinensis, and are prepared according to the method for preparing total flavonoids of Lysimachia chinensis.
- the medicinal excipient comprises at least one of a solid dispersion carrier and a surfactant.
- the capsule of the solid dispersion of total flavonoids of the broad-leaved turf includes: total flavonoids of the herb, and medicinal excipients.
- the alcohol extract is prepared according to the method of the present invention for preparing total flavonoids of Lysimachia chinensis, and the medicinal adjuvant comprises at least one of a solid dispersion carrier and a surfactant.
- the tablet of the solid dispersion of total flavonoids of the broad-leaved turfgrass contains: total flavonoids of Lysimachia chinensis, and medicinal excipients.
- the total flavonoids of D. chinensis are prepared as an alcohol extract of Dianthus chinensis, and are prepared according to the method for preparing total flavonoids of Lysimachia chinensis.
- the medicinal excipient comprises at least one of a solid dispersion carrier and a surfactant.
- the oral solid preparation of the solid flavonoid solid dispersion of the present invention may comprise: 33-133 parts by weight of the total flavonoids of the broad-leaved grass, 198-798 parts by weight of the solid dispersion carrier, in parts by weight. 6.6 to 133 parts by weight of the surfactant, 1 to 50 parts by weight of the filler, 1 to 50 parts by weight of the disintegrant, and 1 to 10 parts by weight of the lubricant.
- the solid dispersion carrier is a water-soluble solid dispersion carrier material selected from the group consisting of povidone K 3Q , polyethylene glycol 2000, polyethylene glycol 4000, polyethylene glycol 6000, citric acid, succinic acid, dextran, galactose, sucrose, glucose, modified starch, microcrystalline cellulose, poloxamer 188, At least one of D-mannitol, preferably the solid dispersion carrier is at least one of povidone K 3Q , polyethylene glycol 6000, D-mannitol, poloxamer 188, most preferably the solid dispersion carrier is a poly At least one of ketene K 30 and poloxamer 188.
- the surfactant is selected from the group consisting of coconut oil amine polyglycol ether, glycerol ethoxylate, and spit At least one of temperature 20, Tween 40, Tween 60, Tween 80, sell Ze 40, benzal 30, polyethylene glycol monomethyl ether, sodium dodecyl sulfate, preferably surfactant Tween 80 At least one of polyethylene glycol monomethyl ether and sodium dodecyl sulfate, and most preferably the surfactant is sodium dodecyl sulfate.
- the filler in the oral solid preparation of the solid flavonoid solid dispersion of the present invention, is selected from the group consisting of corn starch, dextrin, lactose, pregelatinized starch, sucrose, and microcrystals. At least one of cellulose, mannitol, sorbitol, xylitol, calcium hydrogen phosphate, calcium carbonate, preferably a filler is at least one of microcrystalline cellulose, lactose, pregelatinized starch, and most preferably the filler is lactose. .
- the disintegrant is selected from the group consisting of sodium carboxymethyl starch and low-substituted hydroxypropyl cellulose (L- At least one of HPC), crospovidone, dry starch, croscarmellose sodium, carboxymethylcellulose calcium, preferably disintegrant is croscarmellose sodium, cross-linked polyvitr At least one of a ketone, sodium carboxymethyl starch, and most preferably a disintegrant is croscarmellose sodium.
- L- At least one of HPC low-substituted hydroxypropyl cellulose
- crospovidone crospovidone
- dry starch croscarmellose sodium
- carboxymethylcellulose calcium preferably disintegrant is croscarmellose sodium, cross-linked polyvitr At least one of a ketone, sodium carboxymethyl starch, and most preferably a disintegrant is croscarmellose sodium.
- the lubricant in the oral solid preparation of the total flavonoids of the broad-leaved genus of the present invention, is selected from the group consisting of magnesium stearate, talc, micronized silica gel, magnesium sulfonate, and ruthenium At least one of sodium sulfate, sodium benzoate, and sodium stearyl fumarate, preferably the lubricant is at least one of magnesium stearate, silica gel, sodium stearyl fumarate, and most preferably the lubricant is hard.
- Sodium acyl fumarate is selected from the group consisting of magnesium stearate, talc, micronized silica gel, magnesium sulfonate, and ruthenium At least one of sodium sulfate, sodium benzoate, and sodium stearyl fumarate, preferably the lubricant is at least one of magnesium stearate, silica gel, sodium stearyl fumarate, and most preferably the
- the oral solid preparation of the solid flavonoid solid dispersion of the present invention may comprise: 33 parts by weight of total flavonoids of Lysimachia chinensis, 128 parts by weight of povidone K 3Q , and poise according to parts by weight. ⁇ sam 188 66 parts by weight, 6.2 parts by weight of sodium decyl sulfate, 50 parts by weight of lactose, 20 parts by weight of crospovidone, and 1 part by weight of silica gel.
- the oral solid preparation of the solid flavonoid solid dispersion of the present invention may comprise: 33 parts by weight of total flavonoids of Lysimachia chinensis L., povidone K 30 132 parts by weight, 188 66 parts by weight of poloxamer, 19.8 parts by weight of sodium decyl sulphate, 30 parts by weight of lactose, 20 parts by weight of croscarmellose sodium, and 3 parts by weight of sodium stearyl fumarate .
- the oral solid preparation of the solid dispersion of the total flavonoids of the broad-leaved genus of the present invention may comprise: 33 parts by weight of the total flavonoids of the polysaccharide, Povidone K 3 o 132 parts by weight, 188 parts by weight of poloxamer, 33 parts by weight of sodium dodecyl sulfate, 10 parts by weight of microcrystalline cellulose, 20 parts by weight of croscarmellose sodium, and 2 parts by weight of magnesium stearate.
- the oral solid preparation of the solid flavonoid solid dispersion of the present invention may comprise: 33 parts by weight of total flavonoids of Daphnia pulcherrima, 128 parts by weight of povidone K 3Q , and poise according to parts by weight. ⁇ sam 188 66 parts by weight, Tween 80 19.8 parts by weight, 40 parts by weight of lactose, 5 parts by weight of sodium carboxymethyl starch, and 4 parts by weight of sodium stearyl fumarate.
- the oral solid preparation of the solid flavonoid solid dispersion of the present invention may comprise: 33 parts by weight of total flavonoids of Lysimachia chinensis, 128 parts by weight of povidone K 3Q , and poise according to parts by weight. ⁇ sam 188 66 parts by weight, polyethylene glycol monomethyl ether 19.8 parts by weight, microcrystalline cellulose 20 parts by weight, sodium carboxymethyl starch 15 parts by weight, and sodium stearyl fumarate 3 parts by weight.
- the oral solid preparation of the solid flavonoid solid dispersion of the present invention may comprise: 50 parts by weight of total flavonoids of Lysimachia chinensis, Povidone K 3Q 200 parts by weight, and poise ⁇ sam 188 100 parts by weight, 10 parts by weight of sodium dodecyl sulfate, 50 parts by weight of lactose, 20 parts by weight of croscarmellose sodium, and 5 parts by weight of sodium stearyl fumarate.
- the oral solid preparation of the solid flavonoid solid dispersion of the present invention may comprise: 50 parts by weight of total flavonoids of Lysimachia chinensis, Povidone K 3Q 200 parts by weight, and poise ⁇ sam 188 100 parts by weight, 30 parts by weight of sodium decyl sulfate, 50 parts by weight of lactose, 20 parts by weight of croscarmellose sodium, and 5 parts by weight of sodium stearyl fumarate.
- the oral solid preparation of the solid flavonoid solid dispersion of the present invention may comprise: 50 parts by weight of total flavonoids of Lysimachia chinensis, Povidone K 3Q 200 parts by weight, and poise ⁇ sam 188 100 parts by weight, 50 parts by weight of sodium dodecyl sulfate, 50 parts by weight of lactose, 20 parts by weight of croscarmellose sodium, and 5 parts by weight of sodium stearyl fumarate.
- the oral solid preparation of the solid flavonoid solid dispersion of the present invention may comprise: 50 parts by weight of total flavonoids of cynomolgus sinensis, 200 parts by weight of povidone K 3Q , and poise according to parts by weight. ⁇ sam 188 100 parts by weight, Tween 80 30 parts by weight, 50 parts by weight of lactose, 20 parts by weight of croscarmellose sodium, and 5 parts by weight of sodium stearyl fumarate.
- the oral solid preparation of the solid flavonoid solid dispersion of the present invention may comprise: 50 parts by weight of total flavonoids of Lysimachia chinensis, Povidone K 3Q 200 parts by weight, and poise ⁇ sam 188 100 parts by weight, 30 parts by weight of polyethylene glycol monomethyl ether, 50 parts by weight of lactose, 20 parts by weight of croscarmellose sodium, and 5 parts by weight of sodium stearyl fumarate.
- the oral solid preparation of the solid flavonoid solid dispersion of the present invention may comprise: 50 parts by weight of total flavonoids of Lysimachia chinensis, Povidone K 3Q 200 parts by weight, and poise ⁇ sam 188 100 parts by weight, 30 parts by weight of sodium dodecyl sulfate, 50 parts by weight of pregelatinized starch, 20 parts by weight of croscarmellose sodium, and 5 parts by weight of sodium stearyl fumarate.
- the oral solid preparation of the solid flavonoid solid dispersion of the present invention may comprise: 50 parts by weight of total flavonoids of cynomolgus, and povidone K 3 o 200 parts by weight, in parts by weight, 188 parts by weight of poloxamer, 50 parts by weight of sodium decyl sulfate, 50 parts by weight of crospovidone, 20 parts by weight of croscarmellose sodium, and 5 parts by weight of sodium stearyl fumarate .
- the oral solid preparation of the solid flavonoid solid dispersion of the present invention is in parts by weight.
- the agent may comprise: 50 parts by weight of total flavonoids of cynomolgus, 100 parts by weight of povidone K 3 o, 188 100 parts by weight of poloxamer, 30 parts by weight of polyethylene glycol monomethyl ether, and 50 parts by weight of microcrystalline cellulose. 20 parts by weight of croscarmellose sodium and 5 parts by weight of micronized silica gel.
- the oral solid preparation of the solid flavonoid solid dispersion of the present invention may comprise: 66.5 parts by weight of total flavonoids of Podophyllum, and Povidone K 3Q 266 parts by weight, in parts by weight ⁇ sam 188 133 parts by weight, 13.3 parts by weight of sodium lauryl sulfate, 20 parts by weight of microcrystalline cellulose, 10 parts by weight of sodium carboxymethyl starch, and 8 parts by weight of sodium stearyl fumarate.
- the oral solid preparation of the solid flavonoid solid dispersion of the present invention may comprise: 66.5 parts by weight of total flavonoids of Polysaccharide, Povidone K 3Q 266 parts by weight, in terms of parts by weight ⁇ sam 188 133 parts by weight, sodium lauryl sulfate 39.9 parts by weight, lactose 10 parts by weight, croscarmellose sodium 15 parts by weight, and stearyl fumarate 6 parts by weight.
- the oral solid preparation of the solid flavonoid solid dispersion of the present invention may comprise: 66.5 parts by weight of total flavonoids of Daphnia pulveris, and Povidone K 3Q 266 parts by weight, in parts by weight. ⁇ sam 188 133 parts by weight, 66.5 parts by weight of sodium dodecyl sulfate, 1 part by weight of lactose, 10 parts by weight of crospovidone, and 10 parts by weight of magnesium stearate.
- the oral solid preparation of the solid flavonoid solid dispersion of the present invention may comprise: 66.5 parts by weight of total flavonoids of cynomolgus sinensis, povidone K 3Q 266 parts by weight, and poise ⁇ sam 188 133 parts by weight, Tween 80 39.9 parts by weight, 10 parts by weight of lactose, 50 parts by weight of croscarmellose sodium, and 1 part by weight of sodium stearyl fumarate.
- the oral solid preparation of the solid flavonoid solid dispersion of the present invention may comprise: 66.5 parts by weight of total flavonoids of Polysaccharide, Povidone K 3Q 266 parts by weight, in terms of parts by weight ⁇ sam 188 133 parts by weight, polyethylene glycol monomethyl ether 39.9 parts by weight, pregelatinized starch 15 parts by weight, croscarmellose sodium 30 parts by weight, and stearyl fumarate 5 parts by weight.
- the oral solid preparation of the solid flavonoid solid dispersion of the present invention may comprise: 100 parts by weight of total flavonoids of cynomolgus sinensis, povidone K 3Q 400 parts by weight, and poise Locham 188 200 parts by weight, 20 parts by weight of sodium dodecyl sulfate, 50 parts by weight of pregelatinized starch, 20 parts by weight of croscarmellose sodium, and 5 parts by weight of sodium stearyl fumarate.
- the oral solid preparation of the solid flavonoid solid dispersion of the present invention may comprise: 100 parts by weight of total flavonoids of cynomolgus sinensis, povidone K 3Q 400 parts by weight, and poise ⁇ sam 188 200 parts by weight, 60 parts by weight of sodium decyl sulfate, 50 parts by weight of lactose, 40 parts by weight of crospovidone, and 8 parts by weight of sodium stearyl fumarate.
- the oral solid preparation of the solid flavonoid solid dispersion of the present invention may comprise: 100 parts by weight of total flavonoids of Daphnia pulcherrima, 400 parts by weight of povidone K 3Q , and poise according to parts by weight. ⁇ sam 188 200 parts by weight, 100 parts by weight of sodium dodecyl sulfate, 10 parts by weight of microcrystalline cellulose, 20 parts by weight of sodium carboxymethyl starch, and 10 parts by weight of sodium stearyl fumarate.
- the oral solid preparation of the solid flavonoid solid dispersion of the present invention may comprise: 100 parts by weight of total flavonoids of cynomolgus sinensis, 400 parts by weight of povidone K 3 o, 188 parts by weight of poloxamer, 60 parts by weight of Tween 80, 10 parts by weight of lactose, 15 parts by weight of croscarmellose sodium, and 8 parts by weight of sodium stearyl fumarate.
- the oral solid preparation of the solid flavonoid solid dispersion of the present invention may comprise: 100 parts by weight of total flavonoids of cynomolgus sinensis, povidone K 3Q 400 parts by weight, and poise Locham 188 200 parts by weight, 60 parts by weight of polyethylene glycol monomethyl ether, 15 parts by weight of lactose, 10 parts by weight of croscarmellose sodium, and 8 parts by weight of sodium stearyl fumarate.
- the oral solid preparation of the solid flavonoid solid dispersion of the present invention may comprise: 133 parts by weight of total flavonoids of cyanobacteria, povidone K 3Q 532 parts by weight, poloxamer 188 266 parts by weight, twelve quinones 26.6 parts by weight of sodium sulfate, 20 parts by weight of lactose, 20 parts by weight of croscarmellose sodium, and 8 parts by weight of sodium stearyl fumarate.
- the oral solid preparation of the solid flavonoid solid dispersion of the present invention may comprise: 133 parts by weight of total flavonoids of cynomolgus sinensis, povidone K 3Q 532 parts by weight, in terms of parts by weight ⁇ sam 188 266 parts by weight, sodium decyl sulfate 79.8 parts by weight, lactose 20 parts by weight, crospovidone 25 parts by weight, and stearyl fumarate 9 parts by weight.
- the oral solid preparation of the solid flavonoid solid dispersion of the present invention may comprise: 133 parts by weight of total flavonoids of cynomolgus sinensis, povidone K 3Q 532 parts by weight, in terms of parts by weight ⁇ sam 188 266 parts by weight, 133 parts by weight of sodium dodecyl sulfate, 1 part by weight of microcrystalline cellulose, 1 part by weight of sodium carboxymethyl starch, and 10 parts by weight of sodium stearyl fumarate.
- the oral solid preparation of the solid flavonoid solid dispersion of the present invention may comprise: 133 parts by weight of total flavonoids of Lysimachia chinensis, Povidone K 3Q 532 parts by weight, in terms of parts by weight Loss 188 266 parts by weight, Tween 80 79.8 parts by weight, 10 parts by weight of lactose, 10 parts by weight of croscarmellose sodium, and 8 parts by weight of magnesium stearate.
- the oral solid preparation of the solid flavonoid solid dispersion of the present invention may comprise: 133 parts by weight of total flavonoids of cynomolgus, and povidone K 3 o 532 parts by weight, in parts by weight, 188 parts by weight of poloxamer, 79.8 parts by weight of polyethylene glycol monomethyl ether, 5 parts by weight of pregelatinized starch, 5 parts by weight of crospovidone, and 5 parts by weight of magnesium stearate.
- the present invention provides a method for preparing an oral solid preparation of total flavonoids of Herba.
- the method comprises: (1) providing total flavonoids of Lysimachia chinensis, wherein the total flavonoids of the cynomolgus sinensis is provided in the form of an extract of oleracea alcohol; and (2) Polysaccharide extract of chlorpyrifos is made into capsules or tablets.
- the extract of the polysaccharide of the oleic acid is obtained by the following steps: heating and refluxing the medicinal material of the medicinal herb with ethanol to obtain a extract of the cynomolgus extract, wherein the concentration of the ethanol is 50 ⁇ 95%, the weight of the ethanol is 8 to 14 times that of the medicinal herbs; the concentrated extract of the cyanobacteria is concentrated to remove ethanol; and the concentrated extract of the cypress grass is subjected to concentration treatment.
- the macroporous adsorption resin column is treated to obtain the extract of the polysaccharide of the polysaccharide.
- the extract of the broad-grass extract is heated and refluxed by using 50% to 95% ethanol of the weight of the medicinal material of 8 to 14 times, and extracted 1-3 times each time. 1 to 3 hours, and obtained by combining alcohol extracts.
- the step (2) further comprises: (2-1) mixing the extract of the polysaccharide of the polysaccharide with a solid dispersion carrier and a surfactant, and preparing the total a solid dispersion of flavonoids; (2-2) mixing a solid dispersion of the total flavonoids of the broad-leaved turfgrass with a filler and a disintegrating agent, and after adding a soft material, granulating, granulating, adding a lubricant, and mixing, Filling is further performed on the capsule machine to obtain the total flavonoid capsule of the broad-leaf grass; or it is tableted on a tableting machine to obtain the total flavonoid tablet of the broad-leaved grass.
- the solid dispersion carrier is at least one of povidone K 3Q and poloxamer 188.
- the surfactant is at least one of Tween 80, polyethylene glycol monomethyl ether, and sodium dodecyl sulfate.
- the filler is at least one of microcrystalline cellulose, lactose, and pregelatinized starch.
- the disintegrant is at least one of croscarmellose sodium, crospovidone, and sodium carboxymethyl starch.
- the lubricant is at least one of magnesium stearate, silica gel, and sodium stearyl fumarate.
- the inventors of the present invention uniformly mix lactose, microcrystalline cellulose and total flavonoids of Dianthus chinensis by the experiment of ordinary wet granulation, then add povidone K 3Q aqueous solution, stir well, and soften, granulate and bake. Dry, whole granules, tableting, and total flavonoids of Herba fuliginea, the weight difference is in line with the requirements of the Chinese Pharmacopoeia 2010 edition of an appendix ID tablet. However, the total flavonoids of Rhododendron chinense are insoluble in water.
- the inventors of the present invention have obtained a desired beneficial effect through extensive experimentation and research.
- the present inventors have discovered through research and experiment that the total flavonoids of D. chinensis are dispersed in a certain proportion of the hydrophilic solid dispersion carrier material composition by a solid dispersion technique, and a certain amount of surface is added.
- the active agent will promote drug dissolution and absorption.
- the inventors have surprisingly found that when the hydrophilic carrier material of the solid dispersion is a combination of povidone K 3Q and poloxamer 188 (the ratio of the ratio of povidone K 3 o to poloxamer 188 is 2: 1), and adding a surfactant (the weight ratio of the solid dispersion hydrophilic carrier composition to the surfactant is 10:1), can greatly promote the dissolution and absorption of total flavonoids .
- the present invention determined that the optimal formulation of the total dispersion of the total flavonoids of the broad-leaved genus of the medicinal herb is: when the total dispersion of the total flavonoids in the solid dispersion: Povidone K 3Q: Poloxamer 188: Twelve The weight ratio of sodium sulphate is 1: 4: 2: 0.6, and the oral solid preparation (capsule or tablet) of total flavonoids of Lycium chinense L. has high dissolution rate and good quality stability.
- the oral solid preparation of the total flavonoids of the medicinal herbs obtained by the solid dispersion process preparation method significantly improves the dissolution of the oral solid preparation (capsule or tablet) of the total flavonoids of the polysaccharide, and the dissolution rate thereof is stable between 88 and 92%, and the difference in dissolution between the batch and the batch is small.
- the preparation method of the oral solid preparation (capsule or tablet) of the total flavonoids of the broad-leaved genus of the present invention comprises: providing total flavonoids of the broad-leaved turfgrass, the total flavonoid of the broad-leaved grass is an alcohol extract of the broad-leaved grass And the medicinal excipient, the total flavonoids of the cynomolgus sinensis and the medicinal excipients are made into capsules or tablets by using the solid dispersion technology.
- the ratio of each raw material in the oral solid preparation of the total flavonoids of the broad-leaved genus of the present invention is 33-133 parts by weight of the total flavonoids of the medicinal herb, and 198-798 parts by weight of the solid dispersion carrier.
- Surface activity The agent is 6.6 to 133 parts by weight, 1 to 50 parts by weight of the filler, 1 to 50 parts by weight of the disintegrant, and 1 to 10 parts by weight of the lubricant.
- the preparation of the total flavonoids of the genus Lysimachia further comprises the steps of: adding alcoholic extraction to the extract of the genus Lysimachia so as to obtain the extract of the cyanocystis, and purifying the extract of the cyanocystis sinensis to obtain The broad-leaf grass extract.
- 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 1-3 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 flavonoids of Herba Lysimachia.
- the method of preparing the total flavonoid capsule of the broad-leaved grass further comprises the following steps:
- Capsule filling The filling of the total flavonoid granules of the cynomolgus sinensis is carried out on a capsule machine to obtain the total flavonoid capsule of the broad-leaved grass.
- the method of preparing the total flavonoid tablet of the cyanobacteria further comprises the following steps:
- the solid dispersion carrier is preferably povidone K 3Q , polyethylene glycol 6000, D-mannitol, orpol At least one of the sam 188, most preferably the solid dispersion carrier is a combination of povidone K3Q and poloxamer 188.
- the surfactant in the method for preparing an oral solid preparation of total flavonoids of Radix Paeoniae Alba, is preferably at least Tween 80, polyethylene glycol monomethyl ether, and sodium dodecyl sulfate.
- the surfactant is sodium dodecyl sulfate.
- the filler in the method for preparing an oral solid preparation of total flavonoids of Radix Paeoniae Alba, is preferably at least one of microcrystalline cellulose, lactose, pregelatinized starch, and most preferably the filler is lactose.
- the disintegrating agent is preferably croscarmellose sodium, crospovidone, sodium carboxymethyl starch. At least one, most preferably the disintegrant is croscarmellose sodium.
- the lubricant is at least one of magnesium stearate, silica gel, sodium stearyl fumarate, and most preferably the lubricant is sodium stearyl fumarate.
- the weight ratio of the total flavonoids as the raw material to the hydrophilic carrier as a solid dispersion is 1: 5 ⁇ 12.
- the weight ratio of the total flavonoids of the sylvestre to the solid dispersion is 1:5.5 to 8.
- the weight ratio of the total flavonoids of the lentinan to the solid carrier of the solid dispersion is 1:6.
- the composition of povidone K 3Q and poloxamer 188 is most preferably used as a hydrophilic carrier material of a solid dispersion, and the total flavonoids of Dianthus chinensis are dispersed in a hydrophilic carrier.
- the surfactant sodium dodecyl sulfate which itself has a solubilizing effect, povidone K 3Q and poloxamer 188, and plus sodium decyl sulfate
- the combination can significantly increase the solubility of poorly soluble drugs, more effectively reduce the contact angle of the drug surface, improve the wettability of the drug, thereby increasing the solubility of the total flavonoids of the polysaccharide, and effectively promoting the dissolution and absorption of the drug.
- the weight ratio with poloxamer 188 is 1:0.05 ⁇ 20. According to some embodiments of the invention, it is preferred that the weight ratio of povidone K 3Q to poloxamer 188 is 1: 0.2 to 4. According to some embodiments of the invention, the weight ratio of povidone K3Q to poloxamer 188 is most preferably 1:0.5. According to some embodiments of the present invention, in the method for preparing an oral solid preparation of total flavonoids of Rhododendron chinense, the weight ratio of the total flavonoids of the broad-leaved grass to the surfactant is 1: 0.05 ⁇ 1.
- the weight ratio of total flavonoids of radix sinensis to surfactant is 1: 0.2 to 0.8.
- the weight ratio of the total flavonoids of the polysaccharide to the surfactant is 1: 0.6.
- the weight ratio of the solid dispersion hydrophilic carrier to the surfactant was 10:1.
- the ratio of the raw materials of the total flavonoids of the total flavonoids of the broad-leaved genus of the present invention is 33-133 parts by weight of the total flavonoids of the broad-leaved grass, 198-798 parts by weight of the solid dispersion carrier, Surfactant 6.6-133 parts by weight, filler 1-50 parts by weight, disintegrant 1-50 parts by weight, lubricant 1-10 parts by weight.
- the ratio of the raw materials of the total flavonoids of the total flavonoids of the present invention is 33 parts by weight of total flavonoids of Lysimachia chinensis, 128 parts by weight of povidone K 3Q , and Polo Sigma 66 parts by weight, 6.6 parts by weight of sodium dodecyl sulfate, 50 parts by weight of lactose, 20 parts by weight of crospovidone, and 1 part by weight of silica gel.
- the ratio of the raw materials of the total flavonoids of the total flavonoids of the present invention is 33 parts by weight of total flavonoids of Lysimachia chinensis, 128 parts by weight of povidone K 3Q , and Polo Sigma 66 parts by weight, 19.8 parts by weight of sodium dodecyl sulfate, 30 parts by weight of lactose, 20 parts by weight of croscarmellose sodium, and 3 parts by weight of sodium stearyl fumarate.
- the total flavonoid oral solid preparation of the present invention is in accordance with the parts by weight.
- the ratio of each raw material is: 33 parts by weight of total flavonoids of Lysimachia chinensis, 132 parts by weight of povidone K 3Q , 188 66 parts by weight of poloxamer, 33 parts by weight of sodium lauryl sulfate, and 10 parts by weight of microcrystalline cellulose. And 20 parts by weight of croscarmellose sodium and 2 parts by weight of magnesium stearate.
- the ratio of the raw materials of the total flavonoids of the total flavonoids of the present invention is 33 parts by weight of total flavonoids of Lysimachia chinensis, 128 parts by weight of povidone K 3Q , and Polo Sigma 66 parts by weight, Tween 80 19.8 parts by weight, 40 parts by weight of lactose, 5 parts by weight of sodium carboxymethyl starch, and 4 parts by weight of sodium stearyl fumarate.
- the ratio of the raw materials of the total flavonoids of the total flavonoids of the present invention is 33 parts by weight of total flavonoids of Lysimachia chinensis, 128 parts by weight of povidone K 3Q , and Polo Sigma 66 parts by weight, 19.8 parts by weight of polyethylene glycol monomethyl ether, 20 parts by weight of microcrystalline cellulose, 15 parts by weight of sodium carboxymethyl starch, and 3 parts by weight of sodium stearyl fumarate.
- the ratio of each raw material of the oral solid preparation of the total flavonoids of the broad-leaved genus of the present invention is 50 parts by weight of total flavonoids of Lysimachia chinensis, 200 parts by weight of povidone K 3Q , and Polo. 30 parts by weight of sam, 10 parts by weight of sodium dodecyl sulfate, 50 parts by weight of lactose, 20 parts by weight of croscarmellose sodium, and 5 parts by weight of sodium stearyl fumarate.
- the ratio of each raw material of the oral solid preparation of the total flavonoids of the broad-leaved genus of the present invention is 50 parts by weight of total flavonoids of Lysimachia chinensis, 200 parts by weight of povidone K 3Q , and Polo. 30 parts by weight of sam, 30 parts by weight of sodium dodecyl sulfate, 50 parts by weight of lactose, 20 parts by weight of croscarmellose sodium, and 5 parts by weight of sodium stearyl fumarate.
- the ratio of each raw material of the oral solid preparation of the total flavonoids of the broad-leaved genus of the present invention is 50 parts by weight of total flavonoids of Lysimachia chinensis, 200 parts by weight of povidone K 3Q , and Polo. 30 parts by weight of sam, 50 parts by weight of sodium decyl sulphate, 50 parts by weight of lactose, 20 parts by weight of croscarmellose sodium, and 5 parts by weight of sodium stearyl fumarate.
- the ratio of each raw material of the oral solid preparation of the total flavonoids of the broad-leaved genus of the present invention is 50 parts by weight of total flavonoids of Lysimachia chinensis, 200 parts by weight of povidone K 3Q , and Polo. 30 parts by weight of sam 188, 30 parts by weight of Tween 80, 50 parts by weight of lactose, 20 parts by weight of croscarmellose sodium, and 5 parts by weight of sodium stearyl fumarate.
- the ratio of each raw material of the oral solid preparation of the total flavonoids of the broad-leaved genus of the present invention is 50 parts by weight of total flavonoids of Lysimachia chinensis, 200 parts by weight of povidone K 3Q , and Polo. 30 parts by weight of sam, 30 parts by weight of polyethylene glycol monomethyl ether, 50 parts by weight of lactose, 20 parts by weight of croscarmellose sodium, and 5 parts by weight of sodium stearyl fumarate.
- the ratio of each raw material of the oral solid preparation of the total flavonoids of the broad-leaved genus of the present invention is 50 parts by weight of total flavonoids of Lysimachia chinensis, 200 parts by weight of povidone K 3Q , and Polo. 30 parts by weight of sam, 30 parts by weight of sodium dodecyl sulfate, 50 parts by weight of pregelatinized starch, 20 parts by weight of croscarmellose sodium, and 5 parts by weight of sodium stearyl fumarate.
- the total flavonoid oral solid preparation of the present invention is in accordance with the parts by weight.
- the ratio of each raw material is: 50 parts by weight of total flavonoids of Lysimachia chinensis, 200 parts by weight of povidone K 3Q , 188 100 parts by weight of poloxamer, 50 parts by weight of sodium decyl sulphate, 50 parts by weight of crospovidone A portion, 20 parts by weight of croscarmellose sodium, and 5 parts by weight of sodium stearyl fumarate.
- the ratio of each raw material of the oral solid preparation of the total flavonoids of the broad-leaved genus of the present invention is 50 parts by weight of total flavonoids of Lysimachia chinensis, 200 parts by weight of povidone K 3Q , and Polo. 30 parts by weight of sam, 30 parts by weight of polyethylene glycol monomethyl ether, 50 parts by weight of microcrystalline cellulose, 20 parts by weight of croscarmellose sodium, and 5 parts by weight of micronized silica gel.
- the ratio of the raw materials of the total flavonoids of the total flavonoids of the present invention is 66.5 parts by weight of total flavonoids of cynomolgus sinensis, povidone K 3Q 266 parts by weight, and Polan Sigma 188 133 parts by weight, 13.3 parts by weight of sodium dodecyl sulfate, 20 parts by weight of microcrystalline cellulose, 10 parts by weight of sodium carboxymethyl starch, and 8 parts by weight of sodium stearyl fumarate.
- the ratio of the raw materials of the total flavonoids of the total flavonoids of the present invention is 66.5 parts by weight of total flavonoids of cynomolgus sinensis, povidone K 3Q 266 parts by weight, and Polan Sigma 188 133 parts by weight, 39.9 parts by weight of sodium dodecyl sulfate, 10 parts by weight of lactose, 15 parts by weight of croscarmellose sodium, and 6 parts by weight of sodium stearyl fumarate.
- the ratio of the raw materials of the total flavonoids of the total flavonoids of the present invention is 66.5 parts by weight of total flavonoids of cynomolgus sinensis, povidone K 3Q 266 parts by weight, and Polan Sigma 188 133 parts by weight, 66.5 parts by weight of sodium dodecyl sulfate, 1 part by weight of lactose, 10 parts by weight of crospovidone, and 10 parts by weight of magnesium stearate.
- the ratio of the raw materials of the total flavonoids of the total flavonoids of the present invention is 66.5 parts by weight of total flavonoids of cynomolgus sinensis, povidone K 3Q 266 parts by weight, and Polan Sigma 188 133 parts by weight, Tween 80 39.9 parts by weight, 10 parts by weight of lactose, 50 parts by weight of croscarmellose sodium, and 1 part by weight of sodium stearyl fumarate.
- the ratio of the raw materials of the total flavonoids of the total flavonoids of the present invention is 66.5 parts by weight of total flavonoids of cynomolgus sinensis, povidone K 3Q 266 parts by weight, and Polan Sigma 188 133 parts by weight, polyethylene glycol monomethyl ether 39.9 parts by weight, pregelatinized starch 15 parts by weight, croscarmellose sodium 30 parts by weight, and stearyl fumarate 5 parts by weight.
- the ratio of the raw materials of the total flavonoids of the total flavonoids of the broad-leaved genus of the present invention is 100 parts by weight of total flavonoids of Lysimachia chinensis, 400 parts by weight of povidone K 3 o, and ⁇ sam 188 200 parts by weight, 20 parts by weight of sodium dodecyl sulfate, 50 parts by weight of pregelatinized starch, 20 parts by weight of croscarmellose sodium, and 5 parts by weight of sodium stearyl fumarate.
- Desmodium oral solid preparations flavonoids of the raw materials as follows: 100 parts by weight of the total flavones Desmodium, povidone ⁇ 3 ⁇ 400 parts by weight, poise ⁇ sam 188 200 parts by weight, 60 parts by weight of sodium decyl sulfate, 50 parts by weight of lactose, 40 parts by weight of crospovidone, and 8 parts by weight of sodium stearyl fumarate.
- the total flavonoid oral solid preparation of the present invention is in accordance with the parts by weight.
- the ratio of each raw material is 100 parts by weight of total flavonoids of cynomolgus sinensis, 400 parts by weight of povidone K 3 o, 188 200 parts by weight of poloxamer, 100 parts by weight of sodium dodecyl sulfate, and 10 parts by weight of microcrystalline cellulose.
- the ratio of the raw materials of the total flavonoids of the total flavonoids of the broad-leafed genus of the present invention is 100 parts by weight of total flavonoids of Lysimachia chinensis, 400 parts by weight of povidone K 3Q , and Polo. Sigma: 188 200 parts by weight, Tween 80 60 parts by weight, 10 parts by weight of lactose, 15 parts by weight of croscarmellose sodium, and 8 parts by weight of sodium stearyl fumarate.
- the ratio of the raw materials of the total flavonoids of the total flavonoids of the broad-leaved genus of the present invention is 100 parts by weight of total flavonoids of Lysimachia chinensis, 400 parts by weight of povidone K 3 o, and ⁇ sam 188 200 parts by weight, 60 parts by weight of polyethylene glycol monomethyl ether, 15 parts by weight of lactose, 10 parts by weight of croscarmellose sodium, and 8 parts by weight of sodium stearyl fumarate.
- the ratio of the raw materials of the total flavonoids of the total flavonoids of the broad-leaved genus of the present invention is 133 parts by weight of total flavonoids of cynomolgus sinensis, povidone K 3Q 532 parts by weight, and poulol according to the parts by weight.
- the ratio of the raw materials of the total flavonoids of the total flavonoids of the broad-leaved genus of the present invention is 133 parts by weight of total flavonoids of cynomolgus sinensis, povidone K 3Q 532 parts by weight, and poulol according to the parts by weight.
- the ratio of the raw materials of the total flavonoids of the total flavonoids of the broad-leaved genus of the present invention is 133 parts by weight of total flavonoids of cynomolgus sinensis, povidone K 3Q 532 parts by weight, and poulol according to the parts by weight.
- Sigma 188 266 parts by weight 133 parts by weight of sodium decyl sulfate, 1 part by weight of microcrystalline cellulose, 1 part by weight of sodium carboxymethyl starch, and 10 parts by weight of sodium stearyl fumarate.
- the ratio of the raw materials of the total flavonoids of the total flavonoids of the broad-leaved genus of the present invention is 133 parts by weight of total flavonoids of cynomolgus sinensis, povidone K 3Q 532 parts by weight, and poulol according to the parts by weight.
- the ratio of the raw materials of the total flavonoids of the total flavonoids of the broad-leaved genus of the present invention is 133 parts by weight of total flavonoids of cynomolgus sinensis, povidone K 3Q 532 parts by weight, and poulol according to the parts by weight.
- the method for preparing a total flavonoid capsule of the herb of the present invention may comprise the following steps:
- the impurities are eluted with 8 to 12 times the amount of resin, and then 6 to 10 times.
- the volume of the bed is 40% ⁇ 95% ethanol, eluting at a flow rate of 2 to 4 times the bed volume per hour to obtain an eluate; the eluate is recovered from ethanol and concentrated to a concentration of 1.10 to 1.30.
- the liquid and the concentrated solution are dried and pulverized to obtain the total flavonoids of the cyanobacteria, and are reserved;
- the method for preparing a total flavonoid capsule of the herb of the present invention may comprise the following steps:
- 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 ethanol is recovered, concentrated to a concentrated liquid having a relative density of 1.22, and the concentrated liquid is dried under reduced pressure at 75 ° C, and pulverized to obtain total flavonoids of Herba Lysimachia var.
- the method for preparing a total flavonoid tablet of the herb of the present invention may comprise the following steps:
- the impurities are eluted with 8 ⁇ 12 times of resin amount of water, and then 6 to 10 times of bed volume is used.
- % ⁇ 95% ethanol to each small Elution is carried out at a flow rate of 2 to 4 times the volume of the column bed to obtain an eluate; the eluate is recovered into ethanol, and concentrated to a concentrate having a relative density of 1.10 to 1.30, and the concentrate is dried and pulverized to obtain total Flavonoids
- Tableting The total flavonoid granules of the medicinal herb are pressed on the tableting machine, that is, the total flavonoid tablets of the medicinal herb.
- the method for preparing a total flavonoid tablet of the herb of the present invention may comprise the following steps:
- a. Preparation of total flavonoids from Herba Lysimachia chinensis Weigh the prescribed amount of medicinal herbs, add the first 12 times of 80% ethanol, 55 °C for 2 hours, and add 10 times for the second time. 80% ethanol, heated at 55 °C for 1.5 hours, in order to obtain the alcohol extract of Herba Lysimachia, and then combined with the alcohol extract; concentrate the alcohol extract to a certain volume, so that the volume of the liquid is 5 times the amount of the drug, static After filtration, the filtrate is obtained; the filtrate is passed through the AB-8 macroporous adsorption resin column at a flow rate of 3 times the bed volume per hour.
- the impurity is eluted with 10 times of resin amount, and then the column is 8 times.
- the volume of 60% ethanol was eluted at a flow rate of 3 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 the concentrate was decompressed at 75 °C. Dry, pulverize, get the total flavonoids of Herba Lysimachia, spare;
- Tableting The total flavonoid granules of the medicinal herb are pressed on the tableting machine, that is, the total flavonoid tablets of the medicinal herb.
- the inventors have experimentally produced three batches of total flavonoid capsules of Dianthus orientalis with the method according to the embodiment of the present invention, and conducted preliminary investigation on the stability thereof.
- the influencing factors test were carried out respectively.
- the results showed that the total flavonoid capsule of D. chinensis under light conditions Stable, high temperature 60 ° C and relative humidity 75% for 10 days, 40 ° C accelerated test for 6 months, long-term test conditions for 6 months, physical and chemical indicators did not change significantly.
- the inventors have experimentally prepared three batches of total flavonoids of D. chinensis using the method according to the embodiment of the present invention, and conducted preliminary investigation on the stability thereof.
- the influencing factors test were carried out respectively.
- the results showed that the total flavonoid tablets of D. chinensis were under light conditions. Stable, high temperature 60 ° C and relative humidity 75% for 10 days, 40 ° C accelerated test for 6 months, long-term test conditions After storage for 6 months, there is no significant change in physical and chemical indicators.
- the invention has been subjected to prescription screening, quality research and stability study, and the results show that the prescription of the oral solid preparation of the total flavonoids of the broad-leaved genus of the present invention is reasonable, the process is feasible, the production cost is lowered, the product quality standard is tested, and the product quality can be controlled, and the product quality can be controlled.
- the present invention provides a medical use of total flavonoids of Herba Lysimachia.
- the oral solid preparation of the total flavonoids of the medicinal herb of the present invention can be used for the preparation of a clinical therapeutic drug for treating 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 acute toxicity test results of the total flavonoids of the medicinal herb of the Chinese medicinal herb show that: the total flavonoids of the cyanobacteria are a substantially non-toxic test drug.
- the results of acute toxicity test of total flavonoids in rats were as follows: Total flavonoids of Radix Paeoniae Alba is a test drug without serious acute poisoning.
- the long-term toxicity test results of the animals also proved that the total flavonoids of D. chinensis were safe.
- the granules of the solid dispersion of the total flavonoids of the medicinal granules of the medicinal herbs have good dissolution and absorption speed and quality. Stable and easy to industrialize.
- the oral solid preparation medicine for total flavonoids of the medicinal herbs of the present invention is characterized in that the total flavonoids of the genus Lysimachia chinensis are screened out from the broad-leaved grass, and the macroporous resin and the like are used to extract and extract the poorly soluble polysaccharides.
- the medicine for preparing oral solid preparation of total flavonoids of Lysimachia chinensis by the solid dispersion technique has high dissolution rate, remarkable clinical curative effect, small adverse reaction, and urinary calculi disease, especially pyelone stone and ureteral calculi disease, Very good therapeutic effect, its therapeutic effect is better than the existing drug Shilintong tablets.
- the active ingredient and content of the oral solid preparation of the total flavonoids of the broad-leaved genus of the present invention are clear, the quality is stable and controllable; the preparation is safe and effective; the administration is convenient, the use is simple, the price is cheap, and the utility model is economical and practical.
- the invention has the following advantages:
- ethanol is used as an extraction solvent to extract the medicinal materials of the medicinal herbs, and the extract is used for the extract
- the macroporous adsorption resin was purified to obtain the total flavonoids of Lysimachia chinensis.
- the extract has an effective material basis, controllable quality standards and reduced drug. The clinical dose is reduced and the clinical adverse reactions are 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 makes a detailed and in-depth examination of the corresponding technical parameters, optimizes the optimal conditions, and carries out the test of the intermediate test, which can be transferred to industrialization and improve the content of the effective part.
- the total flavonoid extracts of Lysimachia chinensis the total flavonoid content of Rhododendron chinense can reach 50%-80%, of which the content of Schiffin can reach
- the total flavonoids of Dianthus chinensis are dispersed in a hydrophilic carrier material, and a certain amount of surfactant is added to improve the wettability of the drug, thereby ensuring Its high dispersion improves the dissolution and absorption of the drug.
- the hydrophilic carrier material of the solid dispersion is a combination of povidone K 3Q and poloxamer 188 (weight ratio of povidone K 3 o to poloxamer 188 is 2: 1 ), and a surfactant is added.
- the dissolution rate of the oral solid preparation medicine of the total flavonoids of the Chinese medicinal herb obtained by the solid dispersion technique can be stabilized between 88-92%, and the difference in dissolution between the batch and the batch is small, and the method is effective.
- the product quality is ensured, the stability of the active ingredient is improved, the process is simple, the operability is strong, and it is completely suitable for industrial large-scale production.
- the oral solid preparation of total flavonoids of Radix Paeoniae Alba obtained by the present invention has the advantages of advanced production technology, effective foundation 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. Indications for this product: Remove damp heat, diuretic stone, for leaching and sputum caused by damp heat accumulation, urinary stones and the above syndrome.
- FIG. 1 shows a leak curve of adsorption of total xanthone on an AB-8 macroporous resin column on a sample of a broad-leaf grass sample according to an embodiment of the present invention
- Figure 3 shows a conventional wet granulation process (Prescription 1) prepared by the solid dispersion preparation process of the total flavonoid tablet (prepared from Example 20) obtained in the solid dispersion preparation process 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 level arrangement are shown in Table 1, and the results are shown in Table 2.
- 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 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.
- a sample solution of 0.2 g/mL was applied to a 20 g AB-8 resin column (20 mm X 400 mm) and passed at a flow rate of 2 Bv/h. 10 mL was collected for each fraction, and the concentration of total flavonoids in the fraction was determined and calculated, and the leak curve was plotted. The results are shown in Fig. 1. It can be seen that when the loading amount is 50mL (that is, 10g of crude drug amount), the total flavonoids begin to leak, and when the loading amount is 600mL (about 30 times the amount of resin), the adsorption saturation state is reached.
- 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 above test results show that when the ethanol concentration is above 60%, the total flavonoid desorption rate and content are higher, and 60%, The desorption capacity of 75% and 90% ethanol is equivalent. Considering the production cost, 60% ethanol is selected as the elution solvent.
- 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, and concentrated to a relative density of 1.22, which was reduced by 75 °C. ⁇
- the dried whey extract product 1. 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 from 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 12 times of the amount of resin, and then 10 times of the column is used.
- the bed volume of 95% 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 relative density of 1.10, and dried under reduced pressure at 75 °C. , crushed, to obtain 4.03 grams 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 71.65%, and the content of sulphate (% by dry product, %) was 10.30. %.
- the above filtrate (loading solution) is passed through the AB-8 macroporous adsorption resin column at a flow rate of 1 column bed 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 from ethanol, concentrated to a concentrate having a relative density of 1.22, and dried under reduced pressure at 75 °C. , smash, get 4.68 grams of total flavonoids extract product of Lysimachia chinensis (preserved in a cool place).
- the extract product was measured by ultraviolet-visible spectrophotometry for the content of the substance in the extract, and the total flavonoid content (% by dry product) was 60.07%, and the content of sedumin (in dry matter, %;) It is 4.45%.
- the above filtrate (loading solution) is passed through an AB-8 macroporous adsorption resin column at a flow rate of 2 times the bed volume per hour.
- the impurity is eluted with 8 times of resin amount of water, and then eluted with 6 times of bed volume of 40% ethanol at a flow rate of 2 times of bed volume per hour to obtain an eluent;
- the liquid was recovered from ethanol, concentrated to a concentrated solution having a relative density of 1.30, dried under reduced pressure at 75 ° C, and pulverized to obtain 3.89 g of a 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 52.64%, and the content of safflower glycoside (as dry product, %) was 4.17. %.
- 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 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 1.14 kg of total flavonoid extract of Herba Lysimachia (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%. .
- Tableting The total flavonoid granules of the medicinal herb are pressed on the tableting machine, that is, the total flavonoid tablets of the medicinal herb. The dissolution rate was determined to be 90.7%.
- Dissolution method According to the Chinese Pharmacopoeia 2010 edition two appendix XC first method of dissolution measurement method, using 1000ml of water as the dissolution medium, the rotation speed is 100 rpm, according to the law, after 5, 15, 25, 35 At 45 and 60 minutes, take 10ml of the solution, filter it, and accurately measure the filtrate into 1ml and 5ml volumetric flask, dilute to the mark with 0.1M hydrochloric acid, shake well, as the test solution; take Xiafu glycoside control amount of goods, accurately weighed, dissolved with appropriate amount of ethanol, and diluted with 0.1M hydrochloric acid quantification is made per lml containing about 15 ⁇ ⁇ schaftoside solution, as the reference solution. The above two solutions were taken, and the absorbance was measured at a wavelength of 270 nm by ultraviolet spectrophotometry (Appendix IV A), and the dissolution rate of each tablet was calculated.
- Appendix IV A ultraviolet spectrophotometry
- Polosham 188 66g Sodium dodecyl sulfate 19.8 g Lactose 30 g Croscarmellose sodium 20 g Sodium stearyl fumarate 3 g
- a total of 1000 tablets were prepared: same as in Example 9.
- Example 14 Preparation of total flavonoid tablets of Herba Lysimachia.
- a total of 1000 pieces of the system is made: the same as the embodiment 9
- a total of 1000 pieces of the system is made: the same as the embodiment 9
- Example 19 Preparation of total flavonoid tablets of Herba Lysimachia.
- a total of 1000 pieces of the system is made: the same as the embodiment 9
- a total of 1000 pieces of the system is made: the same as the embodiment 9
- a total of 1000 pieces of the system is made: the same as the embodiment 9
- Capsule filling The total flavonoid granules of the medicinal herb are filled on the capsule machine, that is, the total flavonoid capsule of the medicinal herb. The dissolution was measured to be 91.1%.
- Example 42 Preparation of total flavonoid capsules of Herba Lysimachia
- a total of 1000 tablets were prepared: Same as Example 37.
- Example 47 was prepared prescription Desmodium total flavonoids capsule:
- 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 group of total flavonoids (300mg/kg). 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. small Observe 1 time.
- 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 (50 mg/kg/day, 100 mg/kg/day, 200 mg/kg/day, 400mg/kg/day) can significantly inhibit the amount of calcium oxalate crystal aggregates in rat 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 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
- the weight of stones in the 100mg/kg group was reduced (P ⁇ 0.05)
- the weight of stones in the 200mg/kg group was reduced (P ⁇ 0.05)
- 20% stones were dissolved
- the weight of stones in the 400mg/kg group was reduced (CP ⁇ 0.01)
- 30% stones were dissolved.
- the control group was given 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.
- the urine output increased significantly within 12 hours, which was 12-36% higher than that of 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
- the total flavonoids of Radix Paeoniae Alba has certain anti-inflammatory effects and has obvious inhibitory effect on granulation tissue proliferation.
- Example 67 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 less 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. According to the Bliss method, the female LD 5Q was 18.162 g/kg, 95% confidence limit, the upper limit was 20.199 g/kg, the lower limit was 16.326 g/kg; the male animal LD 5Q was 17.084 g/kg, 95% The limit of the limit is 18.975g/kg and the lower limit is 15.301g/kg. There was no significant difference in LD 5Q between female and male animals. Based on the above results, it can be considered that the total flavonoids of Herba Lysimachia is a substantially non-toxic test drug.
- 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. Based on the above results, it can be considered that the total flavonoids of D. chinensis are a test drug without the risk of serious acute poisoning.
- the total flavonoids of the cynomolgus sinensis obtained by the conventional wet granulation process were used as a comparative example without using the solid dispersion carrier material, and compared with the preparation method of the present invention.
- the prescription of the comparative example is as follows:
- the preparation method of the comparative example is as follows:
- Dissolution method According to the Chinese Pharmacopoeia 2010 edition two appendix XC first method of dissolution measurement, with water
- 1000ml is the dissolution medium, the rotation speed is 100 rpm, according to the law.
- a solution of 15 ⁇ ⁇ of pagoda as a reference solution were taken, and the absorbance was measured at a wavelength of 270 nm by ultraviolet spectrophotometry (Appendix IV A), and the dissolution rate of each tablet was calculated.
- the dissolution measurement result was 75.0%.
- the weight ratio of the total carrier of the total flavonoids of D. chinensis and the hydrophilic carrier Povidone K 3Q solid dispersion hydrophilic carrier is 1: 5 ⁇ 12, adding 50% ethanol, heating to 65 ° C was stirred and dissolved, and the solvent was evaporated under reduced pressure at 50 ° C, and dried under vacuum at 50 ° C. After drying, the mixture was pulverized through an 80 mesh sieve to obtain a solid dispersion of total flavonoids of Herba fuliginea, and was set aside.
- the hydrophilic carriers of different solid dispersions such as povidone K 3 o, poloxamer 188, polyethylene glycol 6000, etc.
- the weight ratio of the flavonoid to the solid dispersion hydrophilic carrier is 1:6, 50% ethanol is added, heated to 65 ° C, stirred and dissolved, and the solvent is evaporated under reduced pressure at 50 ° C, dried at 40 ° C under vacuum, and after drying, pulverized. After 80 mesh sieve, a solid dispersion of total flavonoids of Rhizoma Lysimachia was obtained, and it was used.
- the screening of Formulation 8 - Prescription 14 for the addition of solid dispersion material is shown in Table 13.
- Preparation process Weigh the solid dispersion of total flavonoids of Lysimachia chinensis, lactose, croscarmellose sodium, after 80 mesh sieve, mix well, add appropriate amount of water soft material, granulate with 20 mesh sieve, Dry at 55 °C, whole grain, add stearyl fumarate and mix well, and compress it.
- Solid dispersing technology can significantly increase the dissolution of total flavonoids of Herba Lysimachia, under the same experimental protocol conditions, prescription 11, total flavonoids of Herba Lysimachia: Povidone K 3Q: Polo The sam 188 solid dispersion (1:4:2 by weight) tablet formulation has a higher dissolution rate than the other solid dispersions. Found in the test results, though Although a certain degree of dissolution is improved, but further improvement is required to improve the dissolution, we have chosen to add a certain amount of surfactant in the total flavonoids of the herb: Povidone K 3Q: poloxamer 188 solid dispersion (1 :4:2) Based on further screening.
- an appropriate amount of a surfactant is added to the solid dispersion, that is, on the basis of different original prescriptions, respectively, adding different weight ratios of sodium dodecyl sulfate, Tween 80, polyethylene glycol monomethyl ether,
- the screening of prescription 15 - prescription 19 is shown in Table 14.
- Preparation process Weigh the solid dispersion of total flavonoids of Lysimachia chinensis, lactose, croscarmellose sodium, after 80 mesh sieve, mix well, add appropriate amount of water soft material, granulate with 20 mesh sieve, Dry at 55 °C, whole grain, add stearyl fumarate and mix well, and compress it.
- Table 14 Formulation screening of surfactants based on solid dispersions of the present invention
- the optimal composition of the total dispersion of the total flavonoids of the cynomolgus sinensis is: Total flavonoids of Radix Paeoniae Alba: Povidone K 3Q: Poloxamer 188: Solid dispersion of sodium decyl sulfate (each weight ratio is 1) : 4: 2: 0.6).
- the terms "one embodiment”, “some embodiments”, “example”, “specific examples”, The description of "some examples” and the like means that the specific features, structures, materials or characteristics described in connection with the embodiments or examples are included in at least one embodiment or example of the invention.
- the schematic representation of the above terms does not necessarily mean the same embodiment or example.
- the particular features, structures, materials, or characteristics described may be combined in a suitable manner in any one or more embodiments or examples.
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JP2016536867A JP2016539173A (ja) | 2013-12-05 | 2014-07-15 | 広金銭草総フラボノイド含有経口固形製剤、及びその使用 |
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US11993588B2 (en) | 2016-11-16 | 2024-05-28 | H. Lundbeck A/S | Crystalline forms of a MAGL inhibitor |
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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 |
CN111116354B (zh) * | 2019-12-17 | 2022-08-09 | 天津大学 | 没食子酸及其衍生物在控制草酸钙结晶过程的应用 |
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US11273159B2 (en) | 2016-11-16 | 2022-03-15 | H. Lundbeck A/S | Pharmaceutical formulations |
US11993588B2 (en) | 2016-11-16 | 2024-05-28 | H. Lundbeck A/S | Crystalline forms of a MAGL inhibitor |
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