WO2021217788A1 - 一种复合型保肝解酒片的制备方法 - Google Patents

一种复合型保肝解酒片的制备方法 Download PDF

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WO2021217788A1
WO2021217788A1 PCT/CN2020/094908 CN2020094908W WO2021217788A1 WO 2021217788 A1 WO2021217788 A1 WO 2021217788A1 CN 2020094908 W CN2020094908 W CN 2020094908W WO 2021217788 A1 WO2021217788 A1 WO 2021217788A1
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liver
preparation
protecting
silybin
mixed
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French (fr)
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武俊明
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江苏中兴药业有限公司
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    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/357—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having two or more oxygen atoms in the same ring, e.g. crown ethers, guanadrel
    • 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
    • A61K36/06—Fungi, e.g. yeasts
    • A61K36/062—Ascomycota
    • A61K36/066—Clavicipitaceae
    • A61K36/068—Cordyceps
    • 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)
    • A61K36/28—Asteraceae or Compositae (Aster or Sunflower family), e.g. chamomile, feverfew, yarrow or echinacea
    • A61K36/288—Taraxacum (dandelion)
    • 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)
    • A61K36/62—Nymphaeaceae (Water-lily family)
    • 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)
    • A61K36/88—Liliopsida (monocotyledons)
    • A61K36/899—Poaceae or Gramineae (Grass family), e.g. bamboo, corn or sugar cane
    • 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
    • A61K9/2059—Starch, including chemically or physically modified derivatives; Amylose; Amylopectin; Dextrin
    • 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
    • A61K9/2095—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
    • 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
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/51—Nanocapsules; Nanoparticles
    • A61K9/5107—Excipients; Inactive ingredients
    • A61K9/513—Organic macromolecular compounds; Dendrimers
    • A61K9/5161—Polysaccharides, e.g. alginate, chitosan, cellulose derivatives; Cyclodextrin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • 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
    • A61P13/12—Drugs for disorders of the urinary system of the kidneys
    • 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 medicines, in particular to the field of health-care medicines.
  • silibinin has a certain effect on anti-alcohol and liver-protecting drugs.
  • silibinin is an insoluble substance in water and needs to be taken for a long time to prevent liver damage.
  • the present invention provides a method for preparing a composite liver-protecting and relieving alcoholic tablets.
  • the prepared composite liver-protecting and resolving alcoholic tablets can not only relieve the liver caused by excessive drinking in a relatively short period of time. Kidney damage, and can eliminate the poor spleen and stomach movement, vomiting, abdominal distension, sputum and dizziness caused by excessive drinking.
  • the technical solution adopted by the present invention is: a preparation method of a composite liver-protecting and hangover tablet, including the following steps:
  • silybin and cyclodextrin are placed in an improved dosing and mixing device at a weight ratio of 1:1 to 1:1.5 to fully wrap the silybin to form silybin Bin microcapsules;
  • step (1) the improved drug-adding and mixing device is fully packaged, and the transverse cutting is carried out for 1 to 3 minutes, and then the longitudinal cutting is carried out for 1 to 3 minutes; finally, the transverse and longitudinal cutting is carried out at the same time for 2 to 5 minutes.
  • the improved drug adding and mixing device is the device disclosed in the company's previous application for CN208927960U improved drug adding and mixing device.
  • the cutting rate is 300-500r/min.
  • the mesh number of the screen in step (2) is 100 mesh to 200 mesh.
  • step (2) is concentrated to a specific gravity of 1.25 to 1.32 g/mL.
  • the preparation of the mixed soft material in step (3) specifically includes first mixing the silybin microcapsules, starch, cyclodextrin, icing sugar and sodium carboxymethyl starch thoroughly, and then adding the clear ointment together.
  • the mixed soft material is prepared with high-speed stirring in a high-speed wet granulator.
  • the tablet weight of the compressed tablet obtained in step (5) is controlled within 0.2-0.4g.
  • the present invention has the following advantages: (1) First, silibinin and cyclodextrin are prepared together into silibinin microcapsules, thereby improving the water solubility of silibinin, and solving the technology that silibinin is insoluble in water The problem is that silibinin can quickly repair liver damage in the prescription; (2) It is used synergistically with lotus leaf extract, reed root extract, dandelion extract and cordyceps mycelium extract to prepare The compound Baogan Jiejiu tablets can not only relieve liver and kidney damage caused by excessive drinking in a short period of time, but also eliminate poor spleen and stomach transport due to excessive drinking, vomiting, abdominal distension, nausea, phlegm, and dizziness. (3) The preparation process is simple and easy to operate, no additional pollution, easy access to materials, and common equipment.
  • Silybin was provided by Jiangsu Huazhong Pharmaceutical Co., Ltd.;
  • Cyclodextrin was provided by Zhengzhou Shiquanshimei Trading Co., Ltd.;
  • the lotus leaf, reed root and dandelion were provided by Bozhou Yihongtang Pharmaceutical Co., Ltd.
  • Cordyceps mycelium was provided by Shaanxi Haochen Biological Technology Co., Ltd.
  • the powdered sugar is provided by Rizhao Lingyunhai Sugar Industry Group Co., Ltd.;
  • Magnesium stearate was provided by Qufu Pharmaceutical Excipients Co., Ltd.;
  • Corn starch is supplied by Qufu Pharmaceutical Excipients Co., Ltd.;
  • the manufacturer of the high-speed wet granulator is Changzhou Yibu Drying Equipment Co., Ltd.
  • Example 1 A preparation method of a composite liver-protecting and relieving alcoholic tablets, including the following steps:
  • silibinin microcapsules Take 30g silibinin and 30g cyclodextrin in an improved dosing and mixing device and perform a horizontal cutting for 1 minute, then a vertical cutting for 1 minute; finally, a horizontal and vertical cutting at the same time. 2min, the cutting rate is 300r/min; fully wrap it to form silibinin microcapsules;
  • Step (3) Preparation of mixed soft material: take the 60g silybin microcapsules prepared in step (1), 60g starch, 60g cyclodextrin, 30g powdered sugar, 30g sodium carboxymethyl starch, and preparation in step (2) by weight 60g of the clearing paste is mixed to prepare a mixed soft material;
  • Granule preparation of the mixed preparation take the above soft material and pass it through a 16-mesh sieve for granulation, then dry it at 60°C for 5 hours, and then pass it through a 16-mesh sieve for granulation;
  • Example 2 A preparation method of a composite liver-protecting and relieving alcoholic tablets, including the following steps:
  • Step (3) Preparation of mixed soft material: take 75g of silybin microcapsules prepared in step (1), 90g of starch, 120g of cyclodextrin, 120g of powdered sugar, 90g of sodium carboxymethyl starch and preparation of step (2) by weight 90g of the clearing paste is mixed to prepare a mixed soft material;
  • Granule preparation of the mixed preparation take the above soft material and pass it through an 18-mesh sieve for granulation, then dry it at 80°C for 9 hours, and then pass it through an 18-mesh sieve for granulation;
  • Embodiment 3 A preparation method of a composite liver-protecting and relieving alcoholic tablets, including the following steps:
  • silibinin microcapsules Take 30g silibinin and 37.5g cyclodextrin in an improved dosing and mixing device and perform a transverse cutting for 2 minutes, and then a longitudinal cutting for 2 minutes; finally, both transverse and longitudinal cutting are carried out. Cut for 4 minutes at a cutting rate of 400r/min; fully wrap it to form silibinin microcapsules;
  • Granule preparation of the mixed preparation take the above soft material and pass it through a 16-mesh sieve for granulation, then dry it at 70°C for 7 hours, and then pass it through a 16-mesh sieve for granulation;
  • Example 4 Water-soluble effect test of silibinin microcapsules:
  • Control group The silibinin preparation was prepared from silibinin tablets produced by Jiangsu Zhongxing Pharmaceutical Co., Ltd. after being crushed.
  • Testing equipment high performance liquid chromatograph: model Ajtlent 1260.
  • Experimental process Weigh the silibinin preparation of the control group and the silibinin microcapsule preparation of the experimental group whose effective content of silibinin is 1g, and add different amounts of aqueous solution to a 200mL beaker at a temperature of 25°C.
  • silybin and cyclodextrin are prepared together into silybin microcapsules to improve the water solubility of silybin and solve the problem of silybin in water.
  • the technical problem of insolubility is that the water solubility of the prepared silibinin microcapsule preparation is significantly better than that of ordinary silibinin preparations.
  • mice SPF male mice (20 ⁇ 2g): provided by Jinan Pengyue Experimental Animal Breeding Co., Ltd.;
  • Control group use silybin preparation (calculated according to the content of silybin in silymarin tablets), silymarin tablets provided by Jiangsu Zhongxing Pharmaceutical Co., Ltd.
  • mice Animal feeding conditions: The mice are placed in an animal laboratory, the room temperature is controlled at 20-25°C, the humidity is 55%-65%, and the air conditioner is controlled. Ventilate 2 to 3 times a day, 1 hour each time. Control day and night light, avoid excessive noise and other disturbances, rear them in separate cages, and feed them with rat food. Drinking water is cooled water after boiling tap water, and food intake and drinking water are not restricted.
  • mice were randomly divided into 4 groups, namely: the normal control group, the model control group, the silibinin group (using silibinin tablets for administration), and the experimental group (using the protection group prepared in Example 3). Liver Jiejiu Tablets were crushed and administered), the four groups were fed with Red Star Erguotou three times respectively. The amount of feeding was calculated according to the weight of the mouse (0.10mg/10g) with an interval of 3 hours. After feeding, it was measured by four groups of experiments.
  • mice alanine aminotransferase and aspartate aminotransferase were measured by the changes in indicators of alanine aminotransferase and aspartate aminotransferase to determine the liver-protecting effect of the liver-protecting and relieving alcohol tablets prepared in the present invention, wherein the dosage used was calculated as the amount of effective silybin .
  • mice were fasted for 24 hours without water, and the mice were sacrificed.
  • Blood was taken from the venous plexus of the eyeball in each group, placed in an EP tube, static for 10 minutes, and centrifuged at 3000r/min for 10 minutes to separate the serum, and determine the alanine aminotransferase in the serum.
  • alanine aminotransferase and aspartate aminotransferase were measured using a kit purchased by Nanjing Jiancheng Institute of Bioengineering.
  • alanine aminotransferase (Alanine aminotransferase/ALT/GPT) test kit was used for alanine aminotransferase (UV colorimetry) for determination, aspartate aminotransferase)
  • Aspartate aminotransferase aspartate aminotransferase/AST/GOT test kit (IFCC recommended method, UV colorimetry) for determination.
  • Control group use silybin preparation (calculated according to the content of silybin in silymarin tablets), silymarin tablets provided by Jiangsu Zhongxing Pharmaceutical Co., Ltd.
  • mice were randomly divided into 4 groups, namely: normal control group, model control group, silybum group (using silibinin tablets for administration), and experimental group (using the hepatoprotective prepared in Example 3) Jiejiu tablets were crushed and administered), the three groups were respectively fed with Red Star Erguotou three times, and the feeding amount was about 2mg (the mice showed obvious drunken state that they could not walk normally), and then 0.10g (mg each time). /10g) administration dose (interval time is 30 minutes), judge the anti-alcoholic effect of the liver-protecting hangover tablets used in the present invention based on changes in the posture and mental state of mice, wherein the dose used is effective silybin The amount is calculated.
  • liver-protecting hangover tablets prepared by the present invention have obvious hangover effects. Although the control group has a certain effect, the anti-alcoholic effects are worse than those prepared by using the present invention.

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Abstract

一种复合型保肝解酒片的制备方法，首先将水飞蓟宾和环糊精一起制备成水飞蓟宾微囊来提升水飞蓟宾的水溶性，再与荷叶、芦根、蒲公英以及虫草菌丝体的提取物一起使用，使制备的复合型保肝解酒片能在较短的时间里缓解因饮酒过度导致的肝肾损伤。

Description

一种复合型保肝解酒片的制备方法 技术领域
本发明涉及药物领域，尤其涉及一种保健药物领域。
背景技术
随着人们生活水平的提高以及生活习惯的变化，越来越多的人呈现出亚健康的状态，其中由于饮酒过度导致眩晕、话多、吐字不清和肝肾损伤的的患者也越来越多，这样的患者除了临床上的治疗之外，都迫切的需求一种具有保健功能且服用较为方便的辅助药物进行治疗，从而能在最短的时间里得到缓解。
目前市面上也有各种各样的解酒护肝药物，都存在一定的问题，经研究，水飞蓟宾对于解酒护肝具有一定的作用，也有很多将其应用到解酒护肝药物的制备，然而目前市场上含有水飞蓟宾的解酒药，都很难在很短的时间里消除肝损伤，其原因是水飞蓟宾为水中不溶物，需要长期服用才能对肝损伤起到一定的治疗作用，而饮酒过度的患者希望在最短的时间里，解除因肝损伤而导致的脾胃运化不畅，呕吐、脘腹胀闷、痰多头晕，甚至出现肾衰现象。
发明内容
为了克服现有技术中存在的缺陷，本发明提供一种复合型保肝解酒片的制备方法，制备的复合型保肝解酒片不仅能在较短的时间里缓解因饮酒过度导致的肝肾损伤，而且能消除因为饮酒过度而导致的脾胃运化不畅，呕吐、脘腹胀闷、痰多头晕的现象。
为了解决上述技术问题，本发明所采用的技术方案为：一种复合型保肝解酒片的制备方法，包括如下步骤：
(1)水飞蓟宾微囊的制备：将水飞蓟宾与环糊精按1:1～1:1.5的重量比置于改进的加药混药装置中进行充分包裹，形成水飞蓟宾微囊；
(2)称取以重量计算1～3份的荷叶，3～7份的芦根，2～5份的蒲公英，以及2～5份的虫草菌丝体，淋洗干净后至于容器内，加入物料重量5～8倍的水进行煎煮1～2h，煎煮完过滤得一次煎煮液；继续向物料中加入其重量3～5倍的水继续进行煎煮1～2h得第二次煎煮液，合并两次煎煮液，静置20～24h后取上清液进行浓缩为清膏备用；
(3)混合软材制备：按重量计取步骤(1)制备的水飞蓟宾微囊1份、淀粉1～3份、环糊精1～2份、糖粉0.5～3份、羧甲基淀粉钠0.5～3份以及步骤(2)制备的清膏1～2份混合制 备成混合软材；
(4)混合制剂的颗粒制备：取上述软材过16～18目筛制粒后60～80℃干燥5～9h，再过16～18目筛整粒；
(5)向混合制剂的颗粒中加入其重量0.01％～0.02％的硬脂酸镁后，充分混匀，压片得所需复合型保肝解酒片，包装。
步骤(1)中改进的加药混药装置中进行充分包裹，先进行横向切割1～3min，再进行纵向切割1～3min；最后横纵向同时切割2～5min。所述改进的加药混药装置为本公司在先申请CN208927960U改进的加药混药装置中公开的装置。
更进一步的，所属切割的速率均为300～500r/min。
更为优选的，步骤(2)中过滤的筛网目数为100目～200目。
更进一步的，步骤(2)中所述清膏浓缩至比重为1.25～1.32g/mL。
更进一步的，步骤(3)中的混合软材制备具体为首先将水飞蓟宾微囊，淀粉，环糊精、糖粉以及羧甲基淀粉钠进行充分混合均匀，再加入清膏，一起在高速湿法制粒机中高速搅拌制备混合软材。
更进一步的，步骤(5)得到的压片片剂的片重控制在0.2～0.4g。
本发明具有以下优点：(1)首先将水飞蓟宾和环糊精一起制备成水飞蓟宾微囊从而提升了水飞蓟宾的水溶性，解决了水飞蓟宾在水中不溶的技术问题，使水飞蓟宾在处方中能起到迅速修复肝损伤的临床效果；(2)与荷叶提取物、芦根提取物、蒲公英提取物以及虫草菌丝体提取物进行协同使用，制备的复合型保肝解酒片不仅能在较短的时间里缓解因饮酒过度导致的肝肾损伤，而且能消除因为饮酒过度而导致的脾胃运化不畅，呕吐、脘腹胀闷、痰多头晕的现象；(3)制备工艺简单易操作，无额外污染，材料易取，设备常见。
具体实施方式
下面结合实施例对本发明作进一步的详细说明：
实施例以及动物实验中所使用的药物药品以及仪器来源如下：
水飞蓟宾由江苏华中药业股份有限公司提供；
环糊精由郑州食全食美商贸有限公司提供；
荷叶、芦根、蒲公英由亳州市亿弘堂药业有限公司提供。
虫草菌丝体由陕西昊辰生物科技有限公司提供。
淀粉由曲阜市药用辅料有限公司提供；
糖粉由日照凌云海糖业集团有限公司提供；
羧甲基淀粉钠由湖州展望药业有限公司提供；
硬脂酸镁由曲阜市药用辅料有限公司提供；
玉米淀粉由曲阜市药用辅料有限公司；
高速湿法制粒机生产厂家为常州一步干燥设备有限公司。
实施例1：一种复合型保肝解酒片的制备方法，包括如下步骤：
(1)水飞蓟宾微囊的制备：取30g水飞蓟宾、30g环糊精置于改进的加药混药装置中先进行横向切割1min，再进行纵向切割1min；最后横纵向同时切割2min，切割速率均为300r/min；进行充分包裹，形成水飞蓟宾微囊；
(2)称取50g荷叶，150g芦根，100g蒲公英以及100g虫草菌丝体，淋洗干净后至于容器内，加入物料重量的3倍水进行煎煮1h，煎煮完100目过滤得煎液Ⅰ；继续向上述药材中加入其重量3倍的水继续进行煎煮1h得煎液Ⅱ，合并合并煎液Ⅰ和Ⅱ后，静置20h后取上清液进行浓缩为清膏备用，浓缩比至比重为1.25g/mL；
(3)混合软材制备：按重量计取步骤(1)制备的水飞蓟宾微囊60g、淀粉60g、环糊精60g、糖粉30g、羧甲基淀粉钠30g以及步骤(2)制备的清膏60g混合制备成混合软材；
(4)混合制剂的颗粒制备：取上述软材过16目筛制粒后60℃干燥5h，再过16目筛整粒；
(5)向混合制剂的颗粒中加入其重量0.01％的硬脂酸镁后，充分混匀，压片得所需复合型保肝解酒片，包装，规格为0.2g/片。
实施例2：一种复合型保肝解酒片的制备方法，包括如下步骤：
(1)水飞蓟宾微囊的制备：取30g水飞蓟宾、45g环糊精置于改进的加药混药装置中先进行横向切割3min，再进行纵向切割3min；最后横纵向同时切割5min，切割速率均为500r/min；进行充分包裹，形成水飞蓟宾微囊；
(2)称取50g荷叶，210g芦根，150g蒲公英以及150g虫草菌丝体，淋洗干净后至于容器内，加入物料重量的8倍水进行煎煮2h，煎煮完过滤得煎煮液Ⅰ；继续向物料中加入其重量5倍的水继续进行煎煮2h得煎煮液Ⅱ，合并Ⅰ和Ⅱ煎煮液，静置24h后取上清液进行浓缩为清膏备用，浓缩比至比重为1.30g/mL；
(3)混合软材制备：按重量计取步骤(1)制备的水飞蓟宾微囊75g、淀粉90g、环糊精120g、糖粉120g、羧甲基淀粉钠90g以及步骤(2)制备的清膏90g混合制备成混合软材；
(4)混合制剂的颗粒制备：取上述软材过18目筛制粒后80℃干燥9h，再过18目筛整粒；
(5)向混合制剂的颗粒中加入其重量0.02％的硬脂酸镁后，充分混匀，压片得所需复合型保 肝解酒片，包装，规格为0.4g/片。
实施例3：一种复合型保肝解酒片的制备方法，包括如下步骤：
(1)水飞蓟宾微囊的制备：取30g水飞蓟宾、37.5g环糊精置于改进的加药混药装置中先进行横向切割2min，再进行纵向切割2min；最后横纵向同时切割4min，切割速率均为400r/min；进行充分包裹，形成水飞蓟宾微囊；
(2)称取50g荷叶，350g芦根，250g蒲公英提取物以及250g虫草菌丝体，淋洗干净后至于容器内，加入物料重量的6倍水进行煎煮1.5h，煎煮完过滤得煎煮液Ⅰ；继续向物料中加入其重量4倍的水继续进行煎煮1.5h得煎煮液Ⅱ，合并两次煎煮液，静置22h后取上清液进行浓缩为清膏备用，浓缩比至比重为1.31g/mL；
(3)混合软材制备：按重量计取步骤(1)制备的水飞蓟宾微囊67g、淀粉167g、环糊精114g、糖粉134g、羧甲基淀粉钠167g以及步骤(2)制备的清膏114g混合制备成混合软材；
(4)混合制剂的颗粒制备：取上述软材过16目筛制粒后70℃干燥7h，再过16目筛整粒；
(5)向混合制剂的颗粒中加入其重量0.01％的硬脂酸镁后，充分混匀，压片得所需复合型保肝解酒片，包装，规格为0.3g/片。
实施例4：水飞蓟宾微囊水溶性效果试验：
实验用药物：
对照组：水飞蓟宾制剂由江苏中兴药业有限公司生产的水飞蓟宾片碾粹后制得。
实验组：为本发明实施例1步骤(1)制备的水飞蓟宾微囊制剂。
检测设备：高效液相色谱仪:型号Ajtlent 1260.
高效液相色自动进样器：型号：SIL-16
实验过程：称取水飞蓟宾有效含量为1g的对照组的水飞蓟宾制剂和实验组的水飞蓟宾微囊制剂，于200mL容量的烧杯中，分别加入不同量的水溶液,温度25℃±2℃，水浴振荡30min，观察水溶效果(溶解情况)，取10g溶解后的溶液-0.08MPa真空加热煮沸抽干去除水分后，称取固物质的重量A，采用中国药典2000年版二部附录中高效液相色谱法测定固物质中水飞蓟宾的含量(B％)，通过水飞蓟宾的含量计算固物质中水飞蓟宾的重量A×B％，再计算出10g溶液中水飞蓟宾的含量(重量比)为A×B％/10。
分五组进行，结果如表1所示：
表1水飞蓟宾溶解情况对比
Figure PCTCN2020094908-appb-000001
从表1可以看出，本发明制备过程中通过将水飞蓟宾和环糊精一起制备成水飞蓟宾微囊从而提升了水飞蓟宾的水溶性，解决了水飞蓟宾在水中不溶的技术问题，制得的水飞蓟宾微囊制剂水溶性明显优于普通的水飞蓟宾制剂。
实施例5：制剂保肝效果试验
本实验所用动物为SPF级雄性小鼠(20±2g)：由济南朋悦实验动物繁育有限公司提供；
药物和试剂
对照组：采用水飞蓟宾制剂(根据水飞蓟素片中水飞蓟宾的含量进行折算)，由江苏中兴药业有限公司提供的水飞蓟素片。
实验组：本发明实施例1制备的保肝解酒片。
模型组：白酒(红星二锅头)由北京红星股份有限公司公司生产。
仪器：低温高速离心机：由Thermo Fisher Scientific提供；万分之一天平：由上海菁海仪器有限公司提供；
动物饲养条件：将小鼠置于动物实验室，室温控制在20～25℃，湿度55％～65％，空调控制。每日通风2～3次，每次1h。控制昼夜光照，避免过多噪声及其它干扰，分笼饲养，给予鼠粮饲养，饮水采用自来水煮沸后的冷却水，不限制进食量及饮水量。
试验方法：
取40只小鼠随机分为4组，即为：正常对照组、模型对照组、水飞蓟宾组(采用水飞蓟宾片碾碎给药)、实验组(采用实施例3制备的保肝解酒片碾碎给药)，四组分别分三次灌喂红星二锅头，灌喂量根据小鼠体重进行计算(0.10mg/10g)，间隔时间为3小时，灌喂后通过四 组实验测定小鼠谷丙转氨酶和谷草转氨酶的变化，通过谷丙转氨酶和谷草转氨酶指标的变化测定本发明所制备的保肝解酒片的护肝效果，其中使用剂量以有效水飞蓟宾的量进行计算。
表2实验分组及给药剂量
分组 数量(只) 给药剂量(mg/10g)
正常对照组 10 生理盐水0.10
模型对照组 10 红星二锅头0.10
对照组 10 有效水飞蓟宾量0.10
实验组 10 有效水飞蓟宾量0.10
末次给药后，禁食不禁水24h，处死小鼠，各组于眼球后静脉丛取血，置于EP管中，静止10min，3000r/min离心10min分离得到血清，测定血清中谷丙转胺酶以及谷草转氨酶的含量，谷丙转氨酶和谷草转氨酶均采用南京建成生物工程研究所购买的试剂盒进行测定，其中谷丙转氨酶采用丙氨酸氨基转移酶(谷丙转氨酶/ALT/GPT)测试盒(紫外比色法)进行测定、谷草转氨酶采用)
天门冬氨酸氨基转移酶(谷草转氨酶/AST/GOT)测试盒(IFCC推荐方法，紫外比色)进行测定。
水飞蓟宾以及水飞蓟宾微囊的使用对不同组别小鼠血清中的谷丙转氨酶以及谷草转氨酶影响如表3所示：
表3不同组别小鼠血清中谷草转氨酶、谷丙转氨酶含量对比
Figure PCTCN2020094908-appb-000002
注：与正常对照组比较，**P<0.01；与模型对照组相比，#P<0.05。
从表3的数据可以得出以下结论：
实验组和对照组给予水飞蓟宾以及保肝解酒片后，小鼠体内谷草转氨酶、谷丙转氨酶含量有明显降低，且以对照组本申请制备的保肝解酒片效果最为显著，说明水飞蓟宾对于护肝解酒有一定效果，但是本申请制备的保肝解酒片能在较短的时间里缓解因饮酒过度导致的肝肾损伤。
实施例6：解酒效果试验
实验用药物和试剂：
对照组：采用水飞蓟宾制剂(根据水飞蓟素片中水飞蓟宾的含量进行折算)，由江苏中兴药业有限公司提供的水飞蓟素片。
实验组：本发明实施例3制备的保肝解酒片。
实验用白酒(红星二锅头)：北京红星股份有限公司公司生产。
试验方法：
取40只小鼠随机分为4组，即为：正常对照组、模型对照组、水飞蓟组(采用水飞蓟宾片碾碎给药)、实验组(采用实施例3制备的保肝解酒片碾碎给药)，三组分别分三次灌喂红星二锅头，灌喂量约2mg(小鼠出现明显的无法正常行走的醉酒状态)，灌喂后再分别以每次0.10g(mg/10g)的给药剂量(间隔时间为30分钟)，通过小鼠体态变化和精神状态情况，判断本发明所采用的保肝解酒片的解酒效果，其中使用剂量以有效水飞蓟宾的量进行计算。
表4不同组别小鼠体态变化情况表
分组 灌喂次数 体态情况 精神状态
正常对照组 3 2只站立 全醉酒状态
对照组 3 5只站立 8只醉酒状态
实验组 3 全部站立 2只醉酒状态
从表4可以看出，本发明制备的保肝解酒片有明显的解酒效果，对照组虽有一定的效果，但解酒效果较使用本发明制备的保肝解酒片较差。

Claims (7)

  1. 一种复合型保肝解酒片的制备方法，其特征在于包括如下步骤：
    (1)水飞蓟宾微囊的制备：将水飞蓟宾与环糊精按1:1～1:1.5的重量比置于改进的加药混药装置中进行充分包裹，形成水飞蓟宾微囊；
    (2)称取以重量计算1～3份的荷叶，3～7份的芦根，2～5份的蒲公英，以及2～5份的虫草菌丝体，淋洗干净后至于容器内，加入物料重量5～8倍的水进行煎煮1～2h，煎煮完过滤得一次煎煮液；继续向物料中加入其重量3～5倍的水继续进行煎煮1～2h得第二次煎煮液，合并两次煎煮液，静置20～24h后取上清液进行浓缩为清膏备用；
    (3)混合软材制备：按重量计取步骤(1)制备的水飞蓟宾微囊1份、淀粉1～3份、环糊精1～2份、糖粉0.5～3份、羧甲基淀粉钠0.5～3份以及步骤(2)制备的清膏1～2份混合制备成混合软材；
    (4)混合制剂的颗粒制备：取上述软材过16～18目筛制粒后60～80℃干燥5～9h，再过16～18目筛整粒；
    (5)向混合制剂的颗粒中加入其重量0.01％～0.02％的硬脂酸镁后，充分混匀，压片得所需复合型保肝解酒片。
  2. 根据权利要求1所述的复合型保肝解酒片的制备方法，其特征在于：步骤(1)中改进的加药混药装置中进行充分包裹先进行横向切割1～3min，再进行纵向切割1～3min；最后横纵向同时切割2～5min。
  3. 根据权利要求2中复合型保肝解酒片的制备方法，其特征在于：所属切割的速率均为300～500r/min。
  4. 根据权利要求1中复合型保肝解酒片的制备方法，其特征在于：步骤(2)中过滤的筛网目数为100目～200目。
  5. 根据权利要求1所述的复合型保肝解酒片的制备方法，其特征在于：步骤(2)中所述清膏浓缩至比重为1.25～1.32g/mL。
  6. 根据权利要求1所述的复合型保肝解酒片的制备方法，其特征在于：步骤(3)中的混合软材制备具体为首先将水飞蓟宾微囊，淀粉，环糊精、糖粉以及羧甲基淀粉钠进行充分混合均匀，再加入清膏，一起在高速湿法制粒机中高速搅拌制备混合软材。
  7. 根据权利要求1所述的复合型保肝解酒片的制备方法，其特征在于：步骤(5)得到的压片片剂的片重控制在0.2～0.4g。
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CN115336690A (zh) * 2022-08-22 2022-11-15 北京光信商贸有限公司 草本植物浓缩液及其制备方法和应用、草本植物饮料及制备方法
CN119405620A (zh) * 2024-11-11 2025-02-11 安徽青胜蓝生物基因技术开发有限公司 一种解酒护肝制剂

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