WO2021253803A1 - Preparation method for fire-purging tablet - Google Patents

Preparation method for fire-purging tablet Download PDF

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Publication number
WO2021253803A1
WO2021253803A1 PCT/CN2020/142179 CN2020142179W WO2021253803A1 WO 2021253803 A1 WO2021253803 A1 WO 2021253803A1 CN 2020142179 W CN2020142179 W CN 2020142179W WO 2021253803 A1 WO2021253803 A1 WO 2021253803A1
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Prior art keywords
menthol
preparation
qinghuo
cyclodextrin
tablets
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PCT/CN2020/142179
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French (fr)
Chinese (zh)
Inventor
刘景萍
刘全国
陈克领
王家
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海南葫芦娃药业集团股份有限公司
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Publication of WO2021253803A1 publication Critical patent/WO2021253803A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/185—Magnoliopsida (dicotyledons)
    • A61K36/85—Verbenaceae (Verbena family)
    • A61K36/855—Clerodendrum, e.g. glorybower
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/045—Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A61K33/06—Aluminium, calcium or magnesium; Compounds thereof, e.g. clay
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/185—Magnoliopsida (dicotyledons)
    • A61K36/19—Acanthaceae (Acanthus family)
    • A61K36/195—Strobilanthes
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/185—Magnoliopsida (dicotyledons)
    • A61K36/31—Brassicaceae or Cruciferae (Mustard family), e.g. broccoli, cabbage or kohlrabi
    • A61K36/315—Isatis, e.g. Dyer's woad
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/185—Magnoliopsida (dicotyledons)
    • A61K36/70—Polygonaceae (Buckwheat family), e.g. spineflower or dock
    • A61K36/704—Polygonum, e.g. knotweed
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/185—Magnoliopsida (dicotyledons)
    • A61K36/70—Polygonaceae (Buckwheat family), e.g. spineflower or dock
    • A61K36/708—Rheum (rhubarb)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/69—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit
    • A61K47/6949—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit inclusion complexes, e.g. clathrates, cavitates or fullerenes
    • A61K47/6951—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit inclusion complexes, e.g. clathrates, cavitates or fullerenes using cyclodextrin
    • 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
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • 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
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • 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
    • A61K2236/30—Extraction of the material
    • A61K2236/33—Extraction of the material involving extraction with hydrophilic solvents, e.g. lower alcohols, esters or ketones
    • A61K2236/331—Extraction of the material involving extraction with hydrophilic solvents, e.g. lower alcohols, esters or ketones using water, e.g. cold water, infusion, tea, steam distillation or decoction
    • 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
    • A61K2236/30—Extraction of the material
    • A61K2236/39—Complex extraction schemes, e.g. fractionation or repeated extraction steps

Definitions

  • the invention relates to the field of pharmaceutical preparations, in particular to a preparation method of Qinghuo tablets.
  • Qinghuo Tablets are tablets made of green leaves, rhubarb, gypsum, and menthol. They are included in the second volume of the "Medicine Standards of the Ministry of Health of the People's Republic of China on Prescriptions of Traditional Chinese Medicines". Efficacy, clinically used for sore throat, toothache, dizziness, sores in the mouth and nose, red eyes, obstructed stool and other symptoms. Menthol is one of the main effective ingredients of Qinghuo Tablets. Menthol has good antipyretic, antibacterial, antiviral, and choleretic effects. The menthol contained in the medicine is an active ingredient that can affect the skin or mucous membranes. Cooling sensation to reduce discomfort and pain.
  • Menthol is a saturated cyclic alcohol obtained by steam distillation, freezing, and recrystallization of fresh stems and leaves of mint, a plant of the family Lamiaceae.
  • Menthol is a traditional Chinese medicine with a pungent taste and coolness. It has the effects of dispelling wind, clearing away heat, and detoxifying. It is mainly used to treat headaches, red eyes, exogenous wind-heat, red throat, swelling and pain, and skin itching. It is mainly used in the preparation of traditional Chinese medicine for its functions of cooling, fragrance, flavoring, dispelling wind and relieving pain.
  • menthol is volatile And sublimation, low solubility in water, poor absorption and other reasons have affected its clinical application.
  • Preparation method the above four flavors, rhubarb and gypsum are crushed into fine powder, and then sieved; the green leaves are decocted twice with water, the first time is 2 hours, the second time is 1 hour, the decoction is combined, filtered, and concentrated to a thick paste , Add rhubarb, gypsum powder and auxiliary materials, mix evenly, make granules, and dry; dissolve menthol with a small amount of ethanol, spray into the granules, mix, and press to make 1000 tablets, film-coated or sugar-coated, and get ready.
  • menthol is dissolved with a small amount of ethanol, sprayed into the granules, mixed well, and compressed into the tablet core.
  • the menthol will appear on the surface of the tablet core, and it is easy to be heated and volatilized quickly during coating, resulting in the core of the tablet. Holes are left on the surface.
  • the Chinese invention patent with the patent number 201210254846.9 discloses a preparation method of Qinghuo tablets, which is characterized in that it is made of raw materials with the following weight ratios: 400-800 parts of Daqingye, 100-350 parts of rhubarb, and 50 parts of gypsum.
  • menthol ⁇ 150 parts of menthol, 0.65 ⁇ 3 parts of menthol; its preparation method includes the following steps: decocting large green leaves in water to obtain large green leaf extract; rhubarb ethanol reflux extraction to obtain rhubarb extract; gypsum crushing to extract large green leaves
  • the menthol and rhubarb extract are mixed uniformly and granulated; the menthol is prepared into a cyclodextrin inclusion compound, mixed with granules, tableted, and coated to obtain it.
  • the inclusion technology is to dissolve menthol with 10 times the amount of ethyl acetate, take 8 times the amount of ⁇ -cyclodextrin, dissolve it with 20 times the amount of purified water in the tank, and pour hot water into the jacket of the tank. Keep the temperature of the solution in the tank at 38-42°C, turn on the stirring, slowly add the menthol solution, and maintain stirring for 1 hour after the addition. Pour ice brine into the jacket, keep the temperature of the mixed solution at 0-5°C, stand for 24 hours, filter the precipitate, and dry it at 50-60°C for 2 hours to control the drying loss ⁇ 4.0%.
  • the present invention proposes a preparation method of Qinghuo tablets, the obtained Qinghuo tablets have good formability, good appearance, no irritating odor, increase the content of the active ingredient menthol in the preparation, and the disintegration time limit meets the requirements.
  • the medicinal effect is improved, and the process is simple and easy to implement, which is very suitable for industrialized production.
  • a preparation method of Qinghuo tablets includes the following steps:
  • step S3 Mix the granules from step S1 with the emulsion obtained from step S2, dry, compress into tablets, and coat them to obtain Qinghuo tablets.
  • step S1 the decocting is performed twice, the first time is 2 hours, and the second time is 1 hour. It fully takes into account the decoction efficiency and the decoction effect.
  • step S1 the thick paste is concentrated to a relative density of 1.28 to 1.34 (60°C).
  • the purpose is to shorten the time for subsequent powder mixing, facilitate granulation, and make the obtained Qinghuo tablets have better moldability and solubility. good.
  • the volume concentration of the ethanol solution is 75%-95%, and the mass ratio of the menthol to the ethanol solution is 1.2-5:1.
  • the concentration of the ethanol solution and the ratio are such that the menthol is fully dissolved in the ethanol solution, making it easier to be included by ⁇ -cyclodextrin.
  • step S2 (2) the mass ratio of ⁇ -cyclodextrin to water is 1:1.5-7.
  • the specific mass ratio is preferred to help the inclusion effect to reach a better level. If the water added during the inclusion is too low, it is not conducive to the flow of materials, and the amount of water added is too high to adversely affect the grinding and inclusion effect and affect the product quality.
  • the running-in time of the menthol solution and ⁇ -cyclodextrin solution is 40-50 minutes.
  • the present invention preferably has a running-in time within this specific range. A short running-in time will cause uneven mixing of menthol and ⁇ -cyclodextrin. If a too long time is selected, heat is generated during the grinding and shaking process of the material in the colloid mill, and the grinding time The longer the temperature, the higher the temperature will accelerate the volatilization of menthol, which will affect the inclusion effect.
  • the ratio of menthol to ⁇ -cyclodextrin is 1:1.5-3.5.
  • the menthol clathrate powder prepared with the specific ratio has good shape and uniform size, which lays a foundation for further formulation development.
  • a fire-clearing tablet prepared by the method described in any one of the present invention prepared by the method described in any one of the present invention.
  • the present invention uses the colloidal grinding method to clathrate menthol, while controlling the grinding conditions and the ratio of menthol to dextrin, through a specific process, menthol and ⁇ -cyclodextrin are made into clathrates, and then combined with particles Mixed, film-coated or sugar-coated to prepare Qinghuo tablets, not only has a high inclusion rate, a stable menthol content, but also has a short disintegration time limit, better moldability, and good taste.
  • the use of ethyl acetate is avoided, the preparation time is shortened, the overall method of the present invention is simple to operate, does not require any special equipment, has low cost and high yield, and is suitable for industrialized production.
  • the traditional ultrasonic method will accelerate the volatilization of menthol.
  • the aqueous precipitation method will cause the loss of ⁇ -cyclodextrin due to the addition of more solvents.
  • the invention uses colloidal grinding method to achieve a high inclusion rate of menthol. After the tablet is formed, the content of menthol is increased, the disintegration time is short, the appearance quality is good, the amount of materials used for granulation is reduced, the cost is reduced, and the amount of menthol can be effectively reduced, which is convenient for patients.
  • the present invention adopts the colloidal grinding method to clathrate ⁇ -cyclodextrin and menthol.
  • the three-dimensional structure of ⁇ -cyclodextrin is a ring-shaped hollow cylindrical structure.
  • Small molecule drugs enter the hollow cylindrical structure of ⁇ -cyclodextrin to form inclusion compounds, which increase the stability of small molecule drugs. And avoid destroying its main components, its inclusion compound has good stability, and it is made into Qinghuo tablets to improve its medicinal efficacy.
  • ⁇ -cyclodextrin has a special ring-shaped hollow cylindrical structure. The outside of its molecule is full of hydroxyl groups and it is hydrophilic.
  • the inside of its tapered circle has two rings of atoms on C3 and C5, and carbon-hydrogen bonds.
  • ⁇ -cyclodextrin is used to prepare clathrates of menthol through a specific process, which is mixed with granules and pressed into tablets, which can avoid the volatilization loss of menthol, maintain the efficacy, and mask the undesirable smell and taste of the medicine. , Improve the stability of the drug, adjust the release rate, improve the bioavailability, and reduce the irritation and toxic side effects of the drug.
  • the materials, reagents, etc. used in the embodiments of the present invention can be obtained from commercial sources unless otherwise specified.
  • the auxiliary materials used in the present invention are conventional auxiliary materials for preparing Qinghuo tablets.
  • a preparation method of Qinghuo tablets includes the following steps:
  • menthol solution take 325g of menthol, add 130g of 95v/v% ethanol solution, that is, the mass ratio of menthol to ethanol solution is 2.5:1, just stir and dissolve;
  • step S3 Mix the granules from step S1 with the emulsion obtained from step S2, dry, and compress them into tablets, which are film-coated at 0.46g/tablet, 250,000 tablets, to obtain Qinghuo tablets.
  • a preparation method of Qinghuo tablets includes the following steps:
  • menthol solution take 325g of menthol, add 65g of 75v/v% ethanol solution, that is, the mass ratio of menthol to ethanol solution is 5:1, just stir and dissolve;
  • step S3 Mix the granules of step S1 with the emulsion obtained in step S2, dry, press to form tablets, film-coated, 0.46 g/tablet, and make 250,000 tablets, namely Qinghuo tablets.
  • the granules from step S1 and the emulsion obtained from step S2 are mixed, dried, compressed into tablets, and coated with sugar to obtain Qinghuo tablets.
  • a preparation method of Qinghuo tablets includes the following steps:
  • menthol solution take 325g of menthol, add 260g of 80v/v% ethanol solution, that is, the mass ratio of menthol to ethanol solution is 1.25:1, just stir and dissolve;
  • step S3 Mix the granules of step S1 with the emulsion obtained in step S2, dry, press to form tablets, film-coated, 0.46 g/tablet, and make 250,000 tablets, namely Qinghuo tablets.
  • the granules from step S1 and the emulsion obtained from step S2 are mixed, dried, compressed into tablets, and coated with sugar to obtain Qinghuo tablets.
  • a preparation method of Qinghuo tablets includes the following steps:
  • menthol solution take 325g of menthol, add 195g of 85v/v% ethanol solution, that is, the mass ratio of menthol to ethanol solution is about 1.67:1, just stir and dissolve;
  • step S3 Mix the granules from step S1 with the emulsion obtained from step S2, dry, press into tablets, and then sugar-coat them to produce 500,000 tablets at a rate of 0.31 g/tablet to obtain Qinghuo tablets.
  • a preparation method of Qinghuo tablets includes the following steps:
  • menthol solution take 325g of menthol, add 227.5g of 80v/v% ethanol solution, that is, the mass ratio of menthol to ethanol solution is about 1.43:1, just stir and dissolve;
  • step S3 Mix the granules of step S1 with the emulsion obtained in step S2, dry, and compress into tablets, sugar-coated, 0.31 g/tablet, to produce 500,000 tablets to obtain Qinghuo tablets.
  • the Qinghuo Tablets of this comparative example were prepared using the prescription and technology of Qinghuo Tablets given by the Ministry of Health Drug Standard WS, -B-0414-90.
  • step S2 the preparation of the menthol inclusion compound: take 325 g of menthol and dissolve it with 10 times the weight of ethyl acetate (3250 g); take 8 times the weight of ⁇ -cyclopaste Essence (2600g), dissolved in the tank with 20 times the weight of purified water (6500g); pour hot water into the jacket of the tank to keep the temperature of the solution in the tank at 38 ⁇ 42°C, turn on the stirring, and slowly add the menthol solution After adding, keep stirring for 1 hour. Pour ice brine into the jacket, keep the temperature of the mixed solution at 0-5°C, stand for 24 hours, filter the precipitate, and dry it at 50-60°C for 2 hours to control the drying loss ⁇ 4.0%.
  • a preparation method of Qinghuo tablets includes the following steps:
  • menthol solution take 325g of menthol, add 130g of 95v/v% ethanol solution, that is, the mass ratio of menthol to ethanol solution is 2.5:1, just stir and dissolve;
  • step S3 Mix the granules from step S1 with the emulsion obtained from step S2, dry, and compress into tablets, which are coated with a film coating at 0.46g/tablet, 250,000 tablets.

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Abstract

A preparation method for a fire-purging tablet, comprising: S1, adding water to the isatis leaf, decocting, filtering, and concentrating to a thick paste; adding the thick paste to fine powder which is crushed from root and rhizome of sorrel rhubarb and gypsum, and an adjuvant, and uniformly mixing to prepare granules; S2, the preparation of a menthol inclusion compound, comprising: (1) dissolving menthol into ethanol to obtain a menthol solution; (2) adding ß-cyclodextrin to water at 45-65ºC and grinding for 10-45 minutes using a colloid mill to obtain a cyclodextrin solution; (3) mixing the menthol solution with the ß-cyclodextrin solution and grounding into an emulsion using a colloid mill; and S3, uniformly mixing the granules obtained in the step S1 with the emulsion obtained in the step S2, drying, pressing into tablets, and coating to prepare the fire-purging tablet. The tablet prepared by the method is high in menthol inclusion rate, stable in content, short in tablet disintegration time limit, better in formability, and good in taste.

Description

一种清火片的制备方法Preparation method of Qinghuo tablets 技术领域Technical field
本发明涉及药物制剂领域，特别涉及一种清火片的制备方法。The invention relates to the field of pharmaceutical preparations, in particular to a preparation method of Qinghuo tablets.
背景技术Background technique
清火片是由大青叶、大黄、石膏、薄荷脑制成的片剂，收载于《中华人民共和国卫生部药品标准中药成方制剂》第二册中，具有清热泻火、通便的功效，临床上用于咽喉肿痛、牙痛、头目眩晕、口鼻生疮、风火目赤、大便不通等症。薄荷脑是清火片主要有效成分之一，薄荷脑有较好的发汗解热、抗菌、抗病毒、利胆等作用，该药品中所含薄荷脑为一活性成分，可以对皮肤或黏膜产生清凉感以减轻不适及疼痛。Qinghuo Tablets are tablets made of green leaves, rhubarb, gypsum, and menthol. They are included in the second volume of the "Medicine Standards of the Ministry of Health of the People's Republic of China on Prescriptions of Traditional Chinese Medicines". Efficacy, clinically used for sore throat, toothache, dizziness, sores in the mouth and nose, red eyes, obstructed stool and other symptoms. Menthol is one of the main effective ingredients of Qinghuo Tablets. Menthol has good antipyretic, antibacterial, antiviral, and choleretic effects. The menthol contained in the medicine is an active ingredient that can affect the skin or mucous membranes. Cooling sensation to reduce discomfort and pain.
薄荷脑为唇形科植物薄荷的新鲜茎和叶经水蒸气蒸馏、冷冻、重结晶得到的一种饱和的环状醇。薄荷脑为传统中药，味辛性凉，具有疏风清热、解毒等功效，主要用于治疗头痛目赤、外感风热、咽赤肿痛、皮肤风痒等症。它在中药成方制剂中主要利用其具有清凉、芳香、调味以及祛风止痛的功能。此外薄荷脑的毒副作用十分少见，即可内服又可外用，所以广泛用于食品加工、香料、饮料、制药行业、日用化工、化妆品、轻化工业等多种行业，但由于薄荷脑易挥发和升华，且在水中溶解度小，吸收差等原因影响了它的临床应用。Menthol is a saturated cyclic alcohol obtained by steam distillation, freezing, and recrystallization of fresh stems and leaves of mint, a plant of the family Lamiaceae. Menthol is a traditional Chinese medicine with a pungent taste and coolness. It has the effects of dispelling wind, clearing away heat, and detoxifying. It is mainly used to treat headaches, red eyes, exogenous wind-heat, red throat, swelling and pain, and skin itching. It is mainly used in the preparation of traditional Chinese medicine for its functions of cooling, fragrance, flavoring, dispelling wind and relieving pain. In addition, the toxic and side effects of menthol are very rare, both internally and externally, so it is widely used in food processing, spices, beverages, pharmaceutical industry, daily chemical industry, cosmetics, light chemical industry and many other industries, but because menthol is volatile And sublimation, low solubility in water, poor absorption and other reasons have affected its clinical application.
卫生部药品标准WS，-B-0414-90给出的清火片的处方、工艺及简要说明如下：处方：大青叶400g，大黄100g，石膏50g，薄荷脑0.65g。制法：以上四味，大黄、石膏粉碎成细粉，过筛；大青叶加水煎煮二次，第一次2小时，第二次1小时，合并煎液，滤过，浓缩至稠膏，加入大黄、石膏细粉及辅料，混匀，制成颗粒，干燥；将薄荷脑用少量乙醇溶解，喷加颗粒内，混匀，压制成1000片，包薄膜衣或者包糖衣，即得。卫生部药品标准方法中将薄荷脑用少量的乙醇溶解，喷加颗粒内，混匀，压制成片芯时，薄荷脑会出现在片芯表层，包衣时易受热而迅速挥发，导致片芯表面留下孔洞，这些孔洞的存在造成包衣 层棱角多，易磨损，不牢固；薄荷脑易挥发和升华，故有较多损失，且不良气味大，分布不均匀，以致清火片中薄荷脑含量偏低，保留率偏低且不稳定，薄荷脑在储藏过程也会挥发，致使药品包装瓶染上颜色。薄荷脑作为制剂的有效成分，由于其易挥发性的理化性质，在生产、储存与运输过程中均会引起其含量下降，从而影响制剂的疗效，故对制剂中薄荷脑制定含量测定指标是必要的，在能保证药品质量的同时，在生产过程中对薄荷脑的包合技术的开发与应用。The prescription, process and brief description of Qinghuo Tablets given by the Ministry of Health Drug Standards WS, -B-0414-90 are as follows: Prescription: 400g Daqingye, 100g Rhubarb, 50g Plaster, and 0.65g Menthol. Preparation method: the above four flavors, rhubarb and gypsum are crushed into fine powder, and then sieved; the green leaves are decocted twice with water, the first time is 2 hours, the second time is 1 hour, the decoction is combined, filtered, and concentrated to a thick paste , Add rhubarb, gypsum powder and auxiliary materials, mix evenly, make granules, and dry; dissolve menthol with a small amount of ethanol, spray into the granules, mix, and press to make 1000 tablets, film-coated or sugar-coated, and get ready. According to the Ministry of Health Drug Standard Method, menthol is dissolved with a small amount of ethanol, sprayed into the granules, mixed well, and compressed into the tablet core. The menthol will appear on the surface of the tablet core, and it is easy to be heated and volatilized quickly during coating, resulting in the core of the tablet. Holes are left on the surface. The existence of these holes causes the coating layer to have many edges and corners, which are easy to wear and not firm; menthol is easy to volatilize and sublime, so there is more loss, and the bad smell is large, and the distribution is uneven, so that the mint in the Qinghuo tablet The brain content is low, the retention rate is low and unstable, and the menthol will also volatilize during the storage process, causing the medicine packaging bottle to stain. As the effective ingredient of preparations, menthol, due to its volatile physical and chemical properties, will cause its content to decrease during production, storage and transportation, thereby affecting the efficacy of preparations. Therefore, it is necessary to establish content determination indicators for menthol in preparations. Yes, while ensuring the quality of medicines, the development and application of menthol inclusion technology in the production process.
专利号为201210254846.9的中国发明专利公开了一种清火片其制备方法，其特征在于，由如下重量配比的原料药制成：大青叶400～800份、大黄100～350份、石膏50～150份、薄荷脑0.65～3份；其制备方法包括以下步骤：大青叶水煎煮，得大青叶提取物；大黄乙醇回流提取，得大黄提取物；石膏粉碎，将大青叶提取物和大黄提取物混合均匀，制粒；将薄荷脑制备成环糊精包合物，与颗粒混合，压片，包衣，即得。其中包合技术为薄荷脑用10倍量的乙酸乙酯溶解，取8倍量β-环糊精，于罐内用20倍量的纯化水溶解，向罐的夹套内通入热水，使罐内溶液温度保持38～42℃，开启搅拌，缓慢加入薄荷脑溶液，加完后维持搅拌1小时。向夹套内通入冰盐水，使混合溶液温度保持0～5℃，静置24小时，滤取沉淀，于50～60℃干燥2小时，控制干燥失重≤4.0％。该专利中薄荷脑包合物制备清火片稳定性虽有所提高，但还是较差，生物利用度不高，且制备方法包合时间长，包合率低，薄荷脑与包合剂的溶解性差，制得清火片的崩解时限长，生产成本高。而且该方法中用乙酸乙酯溶解薄荷脑，存在乙酸乙酯残留的风险，并且会影响最终产品的口感。因此，急需一种清火片的制备方法，解决上述技术问题。The Chinese invention patent with the patent number 201210254846.9 discloses a preparation method of Qinghuo tablets, which is characterized in that it is made of raw materials with the following weight ratios: 400-800 parts of Daqingye, 100-350 parts of rhubarb, and 50 parts of gypsum. ～150 parts of menthol, 0.65～3 parts of menthol; its preparation method includes the following steps: decocting large green leaves in water to obtain large green leaf extract; rhubarb ethanol reflux extraction to obtain rhubarb extract; gypsum crushing to extract large green leaves The menthol and rhubarb extract are mixed uniformly and granulated; the menthol is prepared into a cyclodextrin inclusion compound, mixed with granules, tableted, and coated to obtain it. The inclusion technology is to dissolve menthol with 10 times the amount of ethyl acetate, take 8 times the amount of β-cyclodextrin, dissolve it with 20 times the amount of purified water in the tank, and pour hot water into the jacket of the tank. Keep the temperature of the solution in the tank at 38-42°C, turn on the stirring, slowly add the menthol solution, and maintain stirring for 1 hour after the addition. Pour ice brine into the jacket, keep the temperature of the mixed solution at 0-5°C, stand for 24 hours, filter the precipitate, and dry it at 50-60°C for 2 hours to control the drying loss ≤4.0%. Although the stability of Qinghuo tablets prepared by the menthol inclusion compound in the patent has been improved, it is still poor, the bioavailability is not high, and the preparation method has a long inclusion time, low inclusion rate, and dissolution of menthol and the inclusion compound The performance is poor, the disintegration time limit of the prepared Qinghuo tablets is long, and the production cost is high. Moreover, in this method, ethyl acetate is used to dissolve menthol, there is a risk of ethyl acetate residue, and it will affect the taste of the final product. Therefore, there is an urgent need for a preparation method of Qinghuo tablets to solve the above technical problems.
发明内容Summary of the invention
鉴于此，本发明提出一种清火片的制备方法，得到的清火片成型性好、外观好、无刺激气味，提高了该制剂中有效成分薄荷脑的含量，崩解时限符合要求，进一步提高了药效，而且工艺简单易行，十分适合工业化生产。In view of this, the present invention proposes a preparation method of Qinghuo tablets, the obtained Qinghuo tablets have good formability, good appearance, no irritating odor, increase the content of the active ingredient menthol in the preparation, and the disintegration time limit meets the requirements. The medicinal effect is improved, and the process is simple and easy to implement, which is very suitable for industrialized production.
本发明的技术方案是这样实现的：The technical scheme of the present invention is realized as follows:
一种清火片的制备方法，包括如下步骤：A preparation method of Qinghuo tablets includes the following steps:
S1、取大黄、石膏粉碎成细粉，过筛；取大青叶加水煎煮2次以上，合并 煎液，滤过，浓缩至稠膏，加入大黄、石膏细粉及辅料，混匀，制成颗粒；S1. Take rhubarb and gypsum crushed into fine powder, sieving; take large green leaves and decoct them in water for more than 2 times, combine the decoction, filter, and concentrate to a thick paste, add rhubarb, gypsum powder and auxiliary materials, and mix to prepare Into particles
S2、薄荷脑包合物的制备：S2. Preparation of menthol inclusion compound:
(1)薄荷脑溶液的制备：取薄荷脑，加乙醇溶液搅拌溶解；(1) Preparation of menthol solution: take menthol, add ethanol solution and stir to dissolve;
(2)β-环糊精溶液的制备：取45-65℃的水，加入β-环糊精，启动胶体磨，磨合10-45分钟；本发明选择该特定范围的水温和磨合时间，使得β-环糊精溶解较好，磨合更加充分；(2) Preparation of β-cyclodextrin solution: take water at 45-65°C, add β-cyclodextrin, start colloid mill, run-in for 10-45 minutes; the present invention selects the water temperature and run-in time in the specific range to make β-Cyclodextrin dissolves better and runs in more fully;
(3)两种溶液的混合：将薄荷脑溶液和β-环糊精溶液混合，启动胶体磨，磨合成乳化物；(3) Mixing of the two solutions: mix the menthol solution and the β-cyclodextrin solution, start the colloid mill, and grind into the emulsion;
S3、将S1步骤的颗粒与S2步骤得到的乳化物混匀，干燥，压制成片，包衣，制得清火片。S3. Mix the granules from step S1 with the emulsion obtained from step S2, dry, compress into tablets, and coat them to obtain Qinghuo tablets.
进一步的，S1步骤中，所述煎煮2次，第一次2小时，第二次1小时。充分兼顾了煎煮效率和煎煮效果。Further, in step S1, the decocting is performed twice, the first time is 2 hours, and the second time is 1 hour. It fully takes into account the decoction efficiency and the decoction effect.
进一步的，S1步骤中，所述浓缩至相对密度为1.28～1.34(60℃)的稠膏，其目的为后续混粉缩短时间，便于制粒，使得到的清火片成型性和溶解性较好。Further, in step S1, the thick paste is concentrated to a relative density of 1.28 to 1.34 (60°C). The purpose is to shorten the time for subsequent powder mixing, facilitate granulation, and make the obtained Qinghuo tablets have better moldability and solubility. good.
进一步的，S2步骤(1)中，所述乙醇溶液的体积浓度为75％～95％，所述薄荷脑与乙醇溶液的质量比例为1.2～5：1。优选该浓度的乙醇溶液以及比例，使得薄荷脑在乙醇溶液中充分溶解，使其更容易被β-环糊精包合。Further, in step S2 (1), the volume concentration of the ethanol solution is 75%-95%, and the mass ratio of the menthol to the ethanol solution is 1.2-5:1. Preferably, the concentration of the ethanol solution and the ratio are such that the menthol is fully dissolved in the ethanol solution, making it easier to be included by β-cyclodextrin.
进一步的，S2步骤(2)中，所述β-环糊精与水的质量比例为1：1.5～7。本发明优选该特定质量比例，有助包合效果达到较佳的水平，如包合时加水过低则不利于物料的流动，而加水量过高对研磨包合效果不利，影响产品品质。Further, in step S2 (2), the mass ratio of β-cyclodextrin to water is 1:1.5-7. In the present invention, the specific mass ratio is preferred to help the inclusion effect to reach a better level. If the water added during the inclusion is too low, it is not conducive to the flow of materials, and the amount of water added is too high to adversely affect the grinding and inclusion effect and affect the product quality.
进一步的，S2步骤(3)中，所述薄荷脑溶液和β-环糊精溶液的磨合时间为40～50分钟。本发明优选该特定范围的磨合时间，磨合时间短会使得薄荷脑和β-环糊精混合不均匀，而如果选择过长的时间，由于物料在胶体磨中研磨、震荡过程产热，研磨时间越长，温度越高，加速薄荷脑挥发，会影响包合效果。Further, in step S2 (3), the running-in time of the menthol solution and β-cyclodextrin solution is 40-50 minutes. The present invention preferably has a running-in time within this specific range. A short running-in time will cause uneven mixing of menthol and β-cyclodextrin. If a too long time is selected, heat is generated during the grinding and shaking process of the material in the colloid mill, and the grinding time The longer the temperature, the higher the temperature will accelerate the volatilization of menthol, which will affect the inclusion effect.
进一步的，所述S2步骤中，薄荷脑与β-环糊精比例为1：1.5～3.5。采用该特定比例制备的薄荷脑包合物粉末形态好，大小均匀，为进一步的制剂开发奠定了基础。Further, in the step S2, the ratio of menthol to β-cyclodextrin is 1:1.5-3.5. The menthol clathrate powder prepared with the specific ratio has good shape and uniform size, which lays a foundation for further formulation development.
一种清火片，由本发明任一项所述的方法制得。A fire-clearing tablet prepared by the method described in any one of the present invention.
与现有技术相比，本发明的有益效果是：Compared with the prior art, the beneficial effects of the present invention are:
(1)本发明利用胶体研磨法对薄荷脑进行包合，同时控制研磨条件以及薄荷脑与糊精的比例，通过特定工艺将薄荷脑与β-环糊精制成包合物，再与颗粒混合，包薄膜衣或者包糖衣，制得清火片，不但包合率高，薄荷脑含量稳定，而且崩解时限短、成型性更好、口感好。另外，避免了使用乙酸乙酯，缩短了制备时间，整体本发明方法操作简单，无需任何特殊设备，成本低、收率高，适合工业化生产。(1) The present invention uses the colloidal grinding method to clathrate menthol, while controlling the grinding conditions and the ratio of menthol to dextrin, through a specific process, menthol and β-cyclodextrin are made into clathrates, and then combined with particles Mixed, film-coated or sugar-coated to prepare Qinghuo tablets, not only has a high inclusion rate, a stable menthol content, but also has a short disintegration time limit, better moldability, and good taste. In addition, the use of ethyl acetate is avoided, the preparation time is shortened, the overall method of the present invention is simple to operate, does not require any special equipment, has low cost and high yield, and is suitable for industrialized production.
(2)传统的超声法会使薄荷脑加速挥发，水溶液沉淀法由于加入较多的溶剂而使β-环糊精有所损耗，本发明使用胶体研磨法下的薄荷脑包合率高，制成药片后薄荷脑的含量提高，而且崩解时限短，外观质量好，制粒所用物料用量减少，成本降低，有效可减少服用数量，方便患者。(2) The traditional ultrasonic method will accelerate the volatilization of menthol. The aqueous precipitation method will cause the loss of β-cyclodextrin due to the addition of more solvents. The invention uses colloidal grinding method to achieve a high inclusion rate of menthol. After the tablet is formed, the content of menthol is increased, the disintegration time is short, the appearance quality is good, the amount of materials used for granulation is reduced, the cost is reduced, and the amount of menthol can be effectively reduced, which is convenient for patients.
(3)本发明采用胶体研磨法对β-环糊精和薄荷脑进行包合，β环糊精的立体结构为环状中空圆筒形结构，利用物料在胶体磨中进行研磨、震荡，使小分子药物进入β-环糊精中空筒形结构中形成包合物，增加小分子药物稳定性。并且避免破坏其主要成分，其包合物稳定性好，制成清火片，提高其药用疗效。其中，β-环糊精具有特殊的环状中空圆筒型结构，其分子外侧因布满了羟基而显亲水性，其锥形圆简内侧有两圈C3、C5上原子，碳氢键中间夹着一圈缩醛氧原子(醚环)结构，具有较强的疏水性，能与薄荷脑形成包合物，而且在一定温度条件下，薄荷脑又可以从包合物内溶出。本发明采用β-环糊精通过特定工艺将薄荷脑制备成包合物，与颗粒混匀，压片，既可以避免薄荷脑的挥发损失，保持了药效，掩盖药物的不良性气味和味道，提高了药物的稳定性，调节释放速率，提高生物利用度，降低药物的刺激性与毒副作用。(3) The present invention adopts the colloidal grinding method to clathrate β-cyclodextrin and menthol. The three-dimensional structure of β-cyclodextrin is a ring-shaped hollow cylindrical structure. Small molecule drugs enter the hollow cylindrical structure of β-cyclodextrin to form inclusion compounds, which increase the stability of small molecule drugs. And avoid destroying its main components, its inclusion compound has good stability, and it is made into Qinghuo tablets to improve its medicinal efficacy. Among them, β-cyclodextrin has a special ring-shaped hollow cylindrical structure. The outside of its molecule is full of hydroxyl groups and it is hydrophilic. The inside of its tapered circle has two rings of atoms on C3 and C5, and carbon-hydrogen bonds. There is a ring of acetal oxygen atom (ether ring) structure in the middle, which has strong hydrophobicity and can form inclusion compound with menthol, and under certain temperature conditions, menthol can be dissolved from the inclusion compound. In the present invention, β-cyclodextrin is used to prepare clathrates of menthol through a specific process, which is mixed with granules and pressed into tablets, which can avoid the volatilization loss of menthol, maintain the efficacy, and mask the undesirable smell and taste of the medicine. , Improve the stability of the drug, adjust the release rate, improve the bioavailability, and reduce the irritation and toxic side effects of the drug.
具体实施方式detailed description
为了更好理解本发明技术内容，下面提供具体实施例，对本发明做进一步的说明。In order to better understand the technical content of the present invention, specific embodiments are provided below to further illustrate the present invention.
本发明实施例所用的实验方法如无特殊说明，均为常规方法。The experimental methods used in the embodiments of the present invention are conventional methods unless otherwise specified.
本发明实施例所用的材料、试剂等，如无特殊说明，均可从商业途径得到。The materials, reagents, etc. used in the embodiments of the present invention can be obtained from commercial sources unless otherwise specified.
本发明所使用辅料为制备清火片常规辅料。The auxiliary materials used in the present invention are conventional auxiliary materials for preparing Qinghuo tablets.
实施例1Example 1
一种清火片的制备方法，包括以下步骤：A preparation method of Qinghuo tablets includes the following steps:
S1、取大黄5000g、石膏2500g粉碎成细粉，过筛；大青叶20000g加水煎煮二次，第一次2小时，第二次1小时，合并煎液，滤过，浓缩至相对密度为1.30(60℃)的稠膏，加入大黄、石膏细粉及辅料，混匀，制成颗粒；S1. Take 5000g of rhubarb and 2500g of gypsum to crush into fine powder, sieving; add 20,000g of large green leaves to decoct twice, the first time is 2 hours, the second time is 1 hour, combine the decoction, filter, and concentrate to the relative density. 1.30 (60℃) thick paste, add rhubarb, gypsum powder and auxiliary materials, mix well, and make granules;
S2、薄荷脑包合物的制备S2, preparation of menthol inclusion compound
(1)薄荷脑溶液的制备：取薄荷脑325g，加95v/v％乙醇溶液130g，即薄荷脑与乙醇溶液的质量比例为2.5：1，搅拌溶解即可；(1) Preparation of menthol solution: take 325g of menthol, add 130g of 95v/v% ethanol solution, that is, the mass ratio of menthol to ethanol solution is 2.5:1, just stir and dissolve;
(2)β-环糊精溶液的制备：温度为55℃的水1950g，加β-环糊精650g，即β-环糊精与水的质量比例为1：3，薄荷脑与β-环糊精的质量比为1：2，启动胶体磨，磨合30分钟即可；(2) Preparation of β-cyclodextrin solution: 1950g of water with a temperature of 55°C, add 650g of β-cyclodextrin, that is, the mass ratio of β-cyclodextrin to water is 1:3, menthol and β-ring The mass ratio of dextrin is 1:2, start the colloid mill and run in for 30 minutes;
(3)两种溶液的混合：把以上两种溶液合并，启动胶体磨，磨合40分钟成乳化物即可；(3) Mixing of the two solutions: Combine the above two solutions, start the colloid mill, and run in for 40 minutes to form an emulsion;
S3、将S1步骤的颗粒与S2步骤得到的乳化物混匀，干燥，压制成片，按0.46g/片，25万片，包薄膜衣，即得清火片。S3. Mix the granules from step S1 with the emulsion obtained from step S2, dry, and compress them into tablets, which are film-coated at 0.46g/tablet, 250,000 tablets, to obtain Qinghuo tablets.
实施例2Example 2
一种清火片的制备方法，包括以下步骤：A preparation method of Qinghuo tablets includes the following steps:
S1、取大黄5000g、石膏2500g粉碎成细粉，过筛；大青叶20000g加水煎煮二次，第一次2小时，第二次1小时，合并煎液，滤过，浓缩至相对密度为1.28(60℃)的稠膏，加入大黄、石膏细粉及辅料，混匀，制成颗粒；S1. Take 5000g of rhubarb and 2500g of gypsum to crush into fine powder, sieving; add 20,000g of large green leaves to decoct twice, the first time is 2 hours, the second time is 1 hour, combine the decoction, filter, and concentrate to the relative density. 1.28 (60℃) thick paste, add rhubarb, gypsum powder and auxiliary materials, mix well, and make granules;
S2、薄荷脑包合物的制备S2, preparation of menthol inclusion compound
(1)薄荷脑溶液的制备：取薄荷脑325g，加75v/v％乙醇溶液65g，即薄荷脑与乙醇溶液的质量比例为5：1，搅拌溶解即可；(1) Preparation of menthol solution: take 325g of menthol, add 65g of 75v/v% ethanol solution, that is, the mass ratio of menthol to ethanol solution is 5:1, just stir and dissolve;
(2)β-环糊精溶液的制备：温度为45℃的水731.25g，加β-环糊精487.5g，即β-环糊精与水的质量比例为1：1.5，薄荷脑与β-环糊精的质量比为1：1.5，启动胶体磨，磨合10分钟即可；(2) Preparation of β-cyclodextrin solution: 731.25g of water at a temperature of 45℃, add 487.5g of β-cyclodextrin, that is, the mass ratio of β-cyclodextrin to water is 1:1.5, menthol and β -The mass ratio of cyclodextrin is 1:1.5, start the colloid mill and run in for 10 minutes;
(3)两种溶液的混合：把以上两种溶液合并，启动胶体磨，磨合45分钟 成乳化物即可；(3) Mixing of the two solutions: Combine the above two solutions, start the colloid mill, and run in for 45 minutes to form an emulsion;
S3、将S1步骤的颗粒与S2步骤得到的乳化物混匀，干燥，压制成片，包薄膜衣，0.46g/片，制得25万片，即得清火片。S3. Mix the granules of step S1 with the emulsion obtained in step S2, dry, press to form tablets, film-coated, 0.46 g/tablet, and make 250,000 tablets, namely Qinghuo tablets.
或者将S1步骤的颗粒与S2步骤得到的乳化物混匀，干燥，压制成片，包糖衣，即得清火片。Alternatively, the granules from step S1 and the emulsion obtained from step S2 are mixed, dried, compressed into tablets, and coated with sugar to obtain Qinghuo tablets.
实施例3Example 3
一种清火片的制备方法，包括以下步骤：A preparation method of Qinghuo tablets includes the following steps:
S1、取大黄5000g、石膏2500g粉碎成细粉，过筛；大青叶20000g加水煎煮二次，第一次2小时，第二次1小时，合并煎液，滤过，浓缩至相对密度为1.34(60℃)的稠膏，加入大黄、石膏细粉及辅料，混匀，制成颗粒；S1. Take 5000g of rhubarb and 2500g of gypsum to crush into fine powder, sieving; add 20,000g of large green leaves to decoct twice, the first time is 2 hours, the second time is 1 hour, combine the decoction, filter, and concentrate to the relative density. 1.34 (60℃) thick paste, add rhubarb, gypsum powder and auxiliary materials, mix well, and make granules;
S2、薄荷脑包合物的制备S2, preparation of menthol inclusion compound
(1)薄荷脑溶液的制备：取薄荷脑325g，加80v/v％乙醇溶液260g，即薄荷脑与乙醇溶液的质量比例为1.25：1，搅拌溶解即可；(1) Preparation of menthol solution: take 325g of menthol, add 260g of 80v/v% ethanol solution, that is, the mass ratio of menthol to ethanol solution is 1.25:1, just stir and dissolve;
(2)β-环糊精溶液的制备：温度为65℃的水7800g，加β-环糊精1137.5g，即β-环糊精与水的质量比例约为1：6.9，薄荷脑与β-环糊精的质量比为1：3.5，启动胶体磨，磨合40分钟即可；(2) Preparation of β-cyclodextrin solution: 7800g water at 65℃, add 1137.5g β-cyclodextrin, that is, the mass ratio of β-cyclodextrin to water is about 1:6.9, menthol and β -The mass ratio of cyclodextrin is 1:3.5, start the colloid mill and run in for 40 minutes;
(3)两种溶液的混合：把以上两种溶液合并，启动胶体磨，磨合50分钟成乳化物即可；(3) Mixing of the two solutions: Combine the above two solutions, start the colloid mill, and run in for 50 minutes to form an emulsion;
S3、将S1步骤的颗粒与S2步骤得到的乳化物混匀，干燥，压制成片，包薄膜衣，0.46g/片，制得25万片，即得清火片。S3. Mix the granules of step S1 with the emulsion obtained in step S2, dry, press to form tablets, film-coated, 0.46 g/tablet, and make 250,000 tablets, namely Qinghuo tablets.
或者将S1步骤的颗粒与S2步骤得到的乳化物混匀，干燥，压制成片，包糖衣，即得清火片。Alternatively, the granules from step S1 and the emulsion obtained from step S2 are mixed, dried, compressed into tablets, and coated with sugar to obtain Qinghuo tablets.
实施例4Example 4
一种清火片的制备方法，包括以下步骤：A preparation method of Qinghuo tablets includes the following steps:
S1、取大黄5000g、石膏2500g粉碎成细粉，过筛；大青叶20000g加水煎煮二次，第一次2小时，第二次1小时，合并煎液，滤过，浓缩至相对密度为1.29(60℃)的稠膏，加入大黄、石膏细粉及辅料，混匀，制成颗粒；S1. Take 5000g of rhubarb and 2500g of gypsum to crush into fine powder, sieving; add 20,000g of large green leaves to decoct twice, the first time is 2 hours, the second time is 1 hour, combine the decoction, filter, and concentrate to the relative density. 1.29 (60℃) thick paste, add rhubarb, gypsum powder and auxiliary materials, mix well, and make granules;
S2、薄荷脑包合物的制备S2, preparation of menthol inclusion compound
(1)薄荷脑溶液的制备：取薄荷脑325g，加85v/v％乙醇溶液195g，即薄 荷脑与乙醇溶液的质量比例约为1.67：1，搅拌溶解即可；(1) Preparation of menthol solution: take 325g of menthol, add 195g of 85v/v% ethanol solution, that is, the mass ratio of menthol to ethanol solution is about 1.67:1, just stir and dissolve;
(2)β-环糊精溶液的制备：温度为55℃的水4680g，加β-环糊精1040g，即β-环糊精与水的质量比例为1：4.5，薄荷脑与β-环糊精的质量比为1：3.2，启动胶体磨，磨合20分钟即可；(2) Preparation of β-cyclodextrin solution: 4680g water at 55℃, add 1040g β-cyclodextrin, that is, the mass ratio of β-cyclodextrin to water is 1:4.5, menthol and β-ring The mass ratio of dextrin is 1:3.2, start the colloid mill and run in for 20 minutes;
(3)两种溶液的混合：把以上两种溶液合并，启动胶体磨，磨合50分钟成乳化物即可；(3) Mixing of the two solutions: Combine the above two solutions, start the colloid mill, and run in for 50 minutes to form an emulsion;
S3、将S1步骤的颗粒与S2步骤得到的乳化物混匀，干燥，压制成片，包糖衣，按0.31g/片，制得50万片，即得清火片。S3. Mix the granules from step S1 with the emulsion obtained from step S2, dry, press into tablets, and then sugar-coat them to produce 500,000 tablets at a rate of 0.31 g/tablet to obtain Qinghuo tablets.
实施例5Example 5
一种清火片的制备方法，包括以下步骤：A preparation method of Qinghuo tablets includes the following steps:
S1、取大黄5000g、石膏2500g粉碎成细粉，过筛；大青叶20000g加水煎煮二次，第一次2小时，第二次1小时，合并煎液，滤过，浓缩至相对密度为1.32(60℃)的稠膏，加入大黄、石膏细粉及辅料，混匀，制成颗粒；S1. Take 5000g of rhubarb and 2500g of gypsum to crush into fine powder, sieving; add 20,000g of large green leaves to decoct twice, the first time is 2 hours, the second time is 1 hour, combine the decoction, filter, and concentrate to the relative density. 1.32 (60℃) thick paste, add rhubarb, gypsum powder and auxiliary materials, mix well, and make granules;
S2、薄荷脑包合物的制备S2, preparation of menthol inclusion compound
(1)薄荷脑溶液的制备：取薄荷脑325g，加80v/v％乙醇溶液227.5g，即薄荷脑与乙醇溶液的质量比例约为1.43：1，搅拌溶解即可；(1) Preparation of menthol solution: take 325g of menthol, add 227.5g of 80v/v% ethanol solution, that is, the mass ratio of menthol to ethanol solution is about 1.43:1, just stir and dissolve;
(2)β-环糊精溶液的制备：温度为55℃的水2843.75g，加β-环糊精812.5g，即β-环糊精与水的质量比例为1：3.5，薄荷脑与β-环糊精的质量比为1：2.5，启动胶体磨，磨合45分钟即可；(2) Preparation of β-cyclodextrin solution: 2845.75g of water at a temperature of 55°C, plus 812.5g of β-cyclodextrin, that is, the mass ratio of β-cyclodextrin to water is 1:3.5, menthol and β -The mass ratio of cyclodextrin is 1:2.5, start the colloid mill and run in for 45 minutes;
(3)两种溶液的混合：把以上两种溶液合并，启动胶体磨，磨合45分钟成乳化物即可；(3) Mixing of the two solutions: Combine the above two solutions, start the colloid mill, and run in for 45 minutes to form an emulsion;
S3、将S1步骤的颗粒与S2步骤得到的乳化物混匀，干燥，压制成片，包糖衣，0.31g/片，制得50万片即得清火片。S3. Mix the granules of step S1 with the emulsion obtained in step S2, dry, and compress into tablets, sugar-coated, 0.31 g/tablet, to produce 500,000 tablets to obtain Qinghuo tablets.
对比例1Comparative example 1
本对比例的清火片采用卫生部药品标准WS，-B-0414-90给出的清火片的处方、工艺制得。The Qinghuo Tablets of this comparative example were prepared using the prescription and technology of Qinghuo Tablets given by the Ministry of Health Drug Standard WS, -B-0414-90.
对比例2Comparative example 2
本对比例与实施例1区别在于，S2步骤中，所述薄荷脑包合物的制备：取薄荷脑325g，用10倍重量的乙酸乙酯(3250g)溶解；取8倍重量β-环糊精 (2600g)，于罐内用20倍重量的纯化水(6500g)溶解；向罐的夹套内通入热水，使罐内溶液温度保持38～42℃，开启搅拌，缓慢加入薄荷脑溶液，加完后维持搅拌1小时。向夹套内通入冰盐水，使混合溶液温度保持0～5℃，静置24小时，滤取沉淀，于50～60℃干燥2小时，控制干燥失重≤4.0％。The difference between this comparative example and Example 1 is that in step S2, the preparation of the menthol inclusion compound: take 325 g of menthol and dissolve it with 10 times the weight of ethyl acetate (3250 g); take 8 times the weight of β-cyclopaste Essence (2600g), dissolved in the tank with 20 times the weight of purified water (6500g); pour hot water into the jacket of the tank to keep the temperature of the solution in the tank at 38～42℃, turn on the stirring, and slowly add the menthol solution After adding, keep stirring for 1 hour. Pour ice brine into the jacket, keep the temperature of the mixed solution at 0-5°C, stand for 24 hours, filter the precipitate, and dry it at 50-60°C for 2 hours to control the drying loss ≤4.0%.
对比例3Comparative example 3
一种清火片的制备方法，包括以下步骤：A preparation method of Qinghuo tablets includes the following steps:
S1、与实施例1一致；S1 is consistent with embodiment 1;
S2、薄荷脑包合物的制备S2, preparation of menthol inclusion compound
(1)薄荷脑溶液的制备：取薄荷脑325g，加95v/v％乙醇溶液130g，即薄荷脑与乙醇溶液的质量比例为2.5：1，搅拌溶解即可；(1) Preparation of menthol solution: take 325g of menthol, add 130g of 95v/v% ethanol solution, that is, the mass ratio of menthol to ethanol solution is 2.5:1, just stir and dissolve;
(2)β-环糊精溶液的制备：温度约为55℃的水1950g，加β-环糊精1500g，即β-环糊精与水的质量比例为1：1.3，薄荷脑与β-环糊精的质量比约为1：4.6，启动胶体磨，磨合30分钟即可；(2) Preparation of β-cyclodextrin solution: 1950g of water at a temperature of about 55°C, add 1500g of β-cyclodextrin, that is, the mass ratio of β-cyclodextrin to water is 1:1.3, menthol and β- The mass ratio of cyclodextrin is about 1:4.6, start the colloid mill and run in for 30 minutes;
(3)两种溶液的混合：把以上两种溶液合并，启动胶体磨，磨合20分钟成乳化物即可；(3) Mixing of the two solutions: Combine the above two solutions, start the colloid mill, and run in for 20 minutes to form an emulsion;
S3、将S1步骤的颗粒与S2步骤得到的乳化物混匀，干燥，压制成片，按0.46g/片，25万片，包薄膜衣，即得。S3. Mix the granules from step S1 with the emulsion obtained from step S2, dry, and compress into tablets, which are coated with a film coating at 0.46g/tablet, 250,000 tablets.
将实施例1～5及对比例1～3分别制得的清火片按中国药典2015年版四部制剂通则及一部进行质量检验，在关于薄荷脑含量测定实验中，本试验用气相色谱法对该药品中薄荷脑的定量分析方法进行了研究，具体检验结果如下表所示：The Qinghuo tablets prepared in Examples 1 to 5 and Comparative Examples 1 to 3 were subjected to quality inspection according to the four general preparations and one of the 2015 edition of the Chinese Pharmacopoeia. In the experiment on the determination of menthol content, this test uses gas chromatography The quantitative analysis method of menthol in the drug has been studied, and the specific test results are shown in the following table:
Figure PCTCN2020142179-appb-000001
Figure PCTCN2020142179-appb-000001
Figure PCTCN2020142179-appb-000002
Figure PCTCN2020142179-appb-000002
由表1可知，与对比例1-3相比，实施例1-5中得到的清火片，不但包合率高，薄荷脑含量稳定，而且崩解时限短、成型性更好、口感好。It can be seen from Table 1 that compared with Comparative Examples 1-3, the Qinghuo tablets obtained in Examples 1-5 not only have high inclusion rate and stable menthol content, but also have short disintegration time limit, better moldability and good taste .
以上所述仅为本发明的较佳实施例而已，并不用以限制本发明，凡在本发明的精神和原则之内，所做的任何修改、等同替换、改进等，均应包含在本发明的保护范围之内。The above are only the preferred embodiments of the present invention and are not intended to limit the present invention. Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present invention shall be included in the present invention. Within the scope of protection.

Claims (9)

  1. 一种清火片的制备方法，包括如下步骤：A preparation method of Qinghuo tablets includes the following steps:
    S1、取大黄、石膏粉碎成细粉，过筛；取大青叶加水煎煮2次以上，合并煎液，滤过，浓缩至稠膏，加入大黄、石膏细粉及辅料，混匀，制成颗粒；S1. Take rhubarb and gypsum crushed into fine powder, sieving; take large green leaves and decoct them in water for more than 2 times, combine the decoction, filter, and concentrate to a thick paste, add rhubarb, gypsum powder and auxiliary materials, and mix to prepare Into particles
    S2、薄荷脑包合物的制备：S2. Preparation of menthol inclusion compound:
    (1)薄荷脑溶液的制备：取薄荷脑，加乙醇溶液搅拌溶解；(1) Preparation of menthol solution: take menthol, add ethanol solution and stir to dissolve;
    (2)β-环糊精溶液的制备：取45-65℃的水，加入β-环糊精，启动胶体磨，磨合10-50分钟；(2) Preparation of β-cyclodextrin solution: take water at 45-65°C, add β-cyclodextrin, start colloid mill, run-in for 10-50 minutes;
    (3)两种溶液的混合：将薄荷脑溶液和β-环糊精溶液混合，启动胶体磨，磨合成乳化物；(3) Mixing of the two solutions: mix the menthol solution and the β-cyclodextrin solution, start the colloid mill, and grind to synthesize the emulsion;
    S3、将S1步骤的颗粒与S2步骤得到的乳化物混匀，干燥，压制成片，包衣，制得清火片。S3. Mix the granules from step S1 with the emulsion obtained from step S2, dry, compress into tablets, and coat them to obtain Qinghuo tablets.
  2. 根据权利要求1所述的清火片的制备方法，其特征在于，S1步骤中，所述煎煮2次，第一次2小时，第二次1小时。The preparation method of Qinghuo tablets according to claim 1, characterized in that, in step S1, the decoction is 2 times, the first time is 2 hours, and the second time is 1 hour.
  3. 根据权利要求1所述的清火片的制备方法，其特征在于，S1步骤中，所述浓缩至相对密度为1.28～1.34(60℃)的稠膏。The preparation method of Qinghuo tablets according to claim 1, wherein in step S1, the concentrated paste is concentrated to a thick paste with a relative density of 1.28 to 1.34 (60°C).
  4. 根据权利要求1所述的清火片的制备方法，其特征在于，S2步骤(1)中，所述乙醇溶液的体积浓度为75％～95％。The preparation method of Qinghuo tablets according to claim 1, wherein in step S2 (1), the volume concentration of the ethanol solution is 75%-95%.
  5. 根据权利要求4所述的清火片的制备方法，其特征在于，S2步骤(1)中，所述薄荷脑与乙醇溶液的质量比例为1.2～5：1。The preparation method of Qinghuo tablets according to claim 4, characterized in that, in step S2 (1), the mass ratio of the menthol to the ethanol solution is 1.2-5:1.
  6. 根据权利要求1所述的种清火片的制备方法，其特征在于，S2步骤(2)中，所述β-环糊精与水的质量比例为1：1.5～7。The method for preparing Qinghuo tablets according to claim 1, wherein in step S2 (2), the mass ratio of β-cyclodextrin to water is 1:1.5-7.
  7. 根据权利要求1所述的清火片的制备方法，其特征在于，S2步骤(3)中，所述薄荷脑溶液和β-环糊精溶液的磨合时间为40～50分钟。The preparation method of Qinghuo tablets according to claim 1, wherein in step S2 (3), the running-in time of the menthol solution and β-cyclodextrin solution is 40-50 minutes.
  8. 根据权利要求1所述的清火片的制备方法，其特征在于，所述S2步骤中，薄荷脑与β-环糊精比例为1：1.5～3.5。The preparation method of Qinghuo tablets according to claim 1, characterized in that, in the step S2, the ratio of menthol to β-cyclodextrin is 1:1.5-3.5.
  9. 一种清火片，其特征在于，由权利要求1～9任一项所述的方法制得。A fire-clearing tablet, characterized in that it is prepared by the method of any one of claims 1-9.
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CN111494507B (en) * 2020-06-18 2022-01-18 海南葫芦娃药业集团股份有限公司 Preparation method of internal heat clearing tablets
CN112641854A (en) * 2020-12-14 2021-04-13 蚌埠丰原涂山制药有限公司 Traditional Chinese medicine composition for clearing heat and reducing internal heat and preparation method thereof
CN114621055A (en) * 2022-02-24 2022-06-14 安徽巨邦香料有限公司 Preparation method and use method of natural menthol spice

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CN102988612A (en) * 2012-10-15 2013-03-27 李正梅 Preparation method and application of tablet for clearing away heat
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