WO2013155741A1 - 六味地黄滴丸 - Google Patents

六味地黄滴丸 Download PDF

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WO2013155741A1
WO2013155741A1 PCT/CN2012/075345 CN2012075345W WO2013155741A1 WO 2013155741 A1 WO2013155741 A1 WO 2013155741A1 CN 2012075345 W CN2012075345 W CN 2012075345W WO 2013155741 A1 WO2013155741 A1 WO 2013155741A1
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Prior art keywords
parts
extract
hawthorn
add
ethanol
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PCT/CN2012/075345
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English (en)
French (fr)
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王凤越
张艳侠
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江苏颐海药业有限责任公司
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Publication of WO2013155741A1 publication Critical patent/WO2013155741A1/zh

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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)
    • A61K36/65—Paeoniaceae (Peony family), e.g. Chinese peony
    • 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
    • A61K36/07—Basidiomycota, e.g. Cryptococcus
    • A61K36/076—Poria
    • 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)
    • A61K36/40—Cornaceae (Dogwood 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)
    • A61K36/185—Magnoliopsida (dicotyledons)
    • A61K36/80—Scrophulariaceae (Figwort family)
    • A61K36/804—Rehmannia
    • 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)
    • A61K36/884—Alismataceae (Water-plantain 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)
    • A61K36/894—Dioscoreaceae (Yam family)
    • A61K36/8945—Dioscorea, e.g. yam, Chinese yam or water yam
    • 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
    • A61K9/16—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
    • A61K9/1629—Organic macromolecular compounds
    • A61K9/1641—Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, poloxamers
    • 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
    • A61K9/2031—Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, polyethylene oxide, poloxamers
    • 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
    • A61P1/08—Drugs for disorders of the alimentary tract or the digestive system for nausea, cinetosis or vertigo; Antiemetics
    • 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
    • A61P1/14—Prodigestives, e.g. acids, enzymes, appetite stimulants, antidyspeptics, tonics, antiflatulents
    • 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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics

Definitions

  • the invention relates to a traditional Chinese medicine preparation.
  • Liu Wei Di Huang Wan It consists of radix rehmanniae, hawthorn, yam, peony bark, diarrhea and medlar. It can be seen from the compatibility of drugs. It is combined with tonifying kidney and tonifying liver and spleen, and mainly tonifying kidney and yin.
  • the existing Liuwei Dihuang preparations include honey pills, water pills, concentrated pills, tablets, hard capsules, soft capsules, oral liquids, granules, dropping pills, etc. Among these preparations, the dropping pills have high bioavailability and rapid drug release. It has rapid market efficiency, small toxic and side effects, and is easy to carry and has a large market share.
  • CN1247241C Disclosed is a Liuwei Dihuang Dropping Pill, the matrix of which is selected from the group consisting of polyethylene glycol 1500-10000, stearic acid, sodium stearate, glycerin gelatin, glyceryl monostearate, shellac, polyoxyethylene monostearate Any one or more of a mixture of a fat, a polyether, a sodium carboxymethyl starch and the like, and the above-mentioned substrate and the hexamesmide raw material are used as a dropping pill preparation to disperse the drug in a molecular, colloidal or microcrystalline state.
  • the matrix In the matrix, the total surface area of the drug is increased, and the matrix is hydrophilic, which has a wetting effect on the drug, and the drug can be quickly dissolved into microparticles or a solution, thereby accelerating the dissolution and absorption of the drug, thereby improving bioavailability. Degree, play an efficient and quick effect.
  • CN100358507C discloses a large-size Liuwei Dihuang Pill
  • the substrate is polyethylene glycol 1000, polyethylene glycol 4000, polyethylene glycol 6000, polyethylene glycol 10000, polyethylene glycol 20000, division Pan 40, polyoxyl 40 stearate, poloxamer, sodium lauryl sulfate, stearic acid, sodium stearate, glycerin gelatin, shellac, and polyoxyl 40 stearate a mixture of ethylene glycol 4000, and a mixture of poloxamer and polyethylene glycol 4000, and a mixture of sodium carboxymethyl starch and polyethylene glycol 4000, and b - a mixture of cyclodextrin and polyethylene glycol 4000.
  • the invention aims to reduce the number of pills to be taken for patient convenience.
  • the melting time of the above two kinds of dropping pills is dispersed between 5 and 60 minutes, which makes it difficult to accurately control the blood concentration at a specific time point, and makes the drug unable to effectively and efficiently exert pharmacological effects.
  • Liuwei Dihuang Dropping Pill which is composed of ripe land, hawthorn, peony bark, yam, diarrhea and cockroach 6
  • the extract of the traditional Chinese medicine is obtained as a raw material, and is prepared together with a carrier as a matrix of the dropping pills, and is characterized in that:
  • the weight ratio of the extract of the 6 Chinese herbal medicines to the substrate is 1 : 1 to 8 ;
  • the dropping pill matrix has a weight average molecular weight of 6000 and a viscosity distribution between 13.6 and 14.5.
  • Polyethylene glycol the polyethylene glycol having a molecular weight of 6000 is 40-60% by weight;
  • the mixture of ⁇ PEG + ⁇ has a normal distribution.
  • the PEG with a molecular weight of 6000 has the largest content, generally about 5%.
  • the molecular weight of the invention is 6000.
  • the polyethylene glycol has a weight content of 40 to 60% of PEG6000 (that is, polyethylene glycol having a weight average molecular weight of 6000), and the viscosity of the polyethylene glycol is between 13.6 and 14.5.
  • the degree of polymerization is the highest, and as a matrix of dropping pills, a dropping pill having a high roundness, a high hardness, and a melting time controlled between 5 and 15 minutes can be obtained.
  • the extract of the 6-flavored traditional Chinese medicine is a powder, and is obtained by the following method: taking the rehmannia glutinous by weight ratio 1408 servings, 528 servings of peony, 704 of yam, 704 of hawthorn, 528 of diarrhea and 528 of medlar, the above six flavors, taking ⁇ 110
  • the granules are pulverized into fine powder, and the remaining part of the sieve is decocted with the remaining mash for three times, each time for about 30 minutes, filtered, and the filtrate is combined and concentrated to a thick paste; the hawthorn is added with ethanol to reflux twice, each time 1 Hour, filtered, the dregs are reserved, the filtrate is recovered from ethanol, concentrated to a thick paste; the peony bar is steam distilled, and 1 mol/L is added to the collected distillate.
  • the hydrochloric acid solution is crystallized, filtered, washed with water, dried at low temperature, and ground into fine powder; distilled aqueous solution and peony bark, hawthorn dregs and rehmannia root, yam and diarrhea are boiled three times, each time 1 Hour, filtered, combined filtrate, through the macroporous adsorption resin, with 70% Ethanol elution, collect the eluate, recover the ethanol, concentrate to a thick paste, add the above-mentioned glutinous cream, hawthorn thick paste and glutinous rice flour, mix, dry under reduced pressure, pulverize into fine powder, add the above-mentioned peony bark extract Powder, mix and get .
  • the extract of the 6-flavored traditional Chinese medicine is a powder, and is obtained by the following method: taking the rehmannia glutinous by weight ratio 1408 servings, 528 pieces of peony, 704 pieces of yam, 704 pieces of hawthorn, 528 parts of Alisma and 528 parts of medlar, above six flavors, taking ⁇ 350
  • the granules are pulverized into fine powder; the hawthorn and ethanol are refluxed and extracted twice, each time for 1 hour, filtered, and the dregs are reserved.
  • the filtrate is recovered from ethanol and concentrated to a thick paste; the peony bark is distilled by steam, and the distillate is added to 1 mol/L.
  • the hydrochloric acid solution is crystallized and used; the distilled aqueous solution and the peony bark residue, the hawthorn dregs, the remaining barium, and the rehmannia root, the yam and the diarrhea are boiled three times, each time 1 After the hour, filter, combine the filtrate, concentrate to a thick paste; add the above-mentioned fine powder and hawthorn thick paste, mix, dry at low temperature, pulverize into fine powder, add the above-mentioned peony bark extract, and mix and obtain.
  • the extract of Chinese herbal medicine consists of extract powder and volatile oil of peony bark, and is obtained by the following method: 1408 parts of Rehmannia glutinosa, 528 pieces of peony skin, 704 parts of yam, Hawthorn 704.
  • the paste with a relative density of 1.15 to 1.20 (50 ° C) is combined with the above-mentioned preparation liquid, and concentrated to a thick paste having a relative density of 1.30 (50 ° C), and decompressed. Dry and pulverize into fine powder to obtain an extract powder.
  • the extract powder of the traditional Chinese medicine is not limited to being obtained by using the above-mentioned several methods, and can also be obtained by the methods specified in other pharmacopoeia or Ministry of Health Ministry standards.
  • the substrate is preferably a polyethylene glycol 6000 having a viscosity of 14 (weight average molecular weight). This viscosity of polyethylene glycol 6000 has the highest degree of polymerization.
  • the weight ratio of the extract powder of the 6-flavored Chinese medicine to the substrate is preferably 1:1.55.
  • the condensing agent is at least one of methyl silicone oil, liquid paraffin or vegetable oil.
  • the invention adopts PEG6000 with a molecular weight of 6000 and a weight content of 40 to 60% of polyethylene glycol. (ie, polyethylene glycol having a weight average molecular weight of 6000), and further Obtaining a high-density, high-hardness drop pill product, the obtained pill splitting time is controlled between 5 and 15 minutes, ensuring that the drug can be effectively and efficiently exerted pharmacologically.
  • the invention provides a Liuwei Dihuang Dropping Pill
  • the Liuwei Dihuang Dropping Pill not only has high roundness and high hardness, but also has a melting time controlled between 5 and 15 minutes, so that the medicine can be truly fast and efficient. Play a pharmacological role.
  • the hydrochloric acid solution is crystallized, filtered, washed with water, dried at low temperature, and ground into fine powder; distilled aqueous solution and peony bark, hawthorn dregs and rehmannia root, yam and diarrhea are boiled three times, each time 1 Hour, filtered, combined filtrate, through the macroporous adsorption resin, with 70% Ethanol elution, collect the eluate, recover the ethanol, concentrate to a thick paste, add the above-mentioned glutinous cream, hawthorn thick paste and glutinous rice flour, mix, dry under reduced pressure, pulverize into fine powder, add the above-mentioned peony bark extract Powder, mix and get the Liuwei Dihuang extract powder;
  • the matrix is made of polyethylene glycol 6000. (weight average molecular weight), the viscosity of the polyethylene glycol is 13.6%, and the weight percentage of the polyethylene glycol having a molecular weight of 6000 is 40%;
  • the hydrochloric acid solution is crystallized and used; the distilled aqueous solution and the peony bark residue, the hawthorn dregs, the remaining barium, and the rehmannia root, the yam and the diarrhea are boiled three times, each time 1 Hour, filter, combine the filtrate, concentrate to a thick paste; add the above-mentioned fine powder and hawthorn thick paste, mix, low-temperature drying, pulverize into fine powder, add the above-mentioned peony bark extract, and mix to obtain Liuwei Dihuang powder;
  • the matrix is made of polyethylene glycol 6000. (weight average molecular weight), the viscosity of the polyethylene glycol is 14%, and the weight percentage of the polyethylene glycol having a molecular weight of 6000 is 50%;
  • the hydrochloric acid solution is crystallized and used; the distilled aqueous solution and the peony bark residue, the hawthorn dregs, the remaining barium, and the rehmannia root, the yam and the diarrhea are boiled three times, each time 1 Hour, filter, combine the filtrate, concentrate to a thick paste; add the above-mentioned fine powder and hawthorn thick paste, mix, low-temperature drying, pulverize into fine powder, add the above-mentioned peony bark extract, and mix to obtain Liuwei Dihuang powder;
  • the matrix is made of polyethylene glycol 6000. (weight average molecular weight), the viscosity of the polyethylene glycol is 14.6%, and the weight percentage of the polyethylene glycol having a molecular weight of 6000 is 50%;
  • the peony peel is distilled to extract the volatile oil, and the volatile oil of the peony bark is obtained, and the distillation is carried out for 8 hours.
  • the hawthorn is added with 70% ethanol and refluxed twice, each time for 2 hours, the extract is combined, filtered, and the filtrate is ready for use; Rehmannia glutinosa, yam, and diarrhea are boiled with water. Two times, the first time adding 8 times the amount of water to cook for 2 hours, the second time adding 6 times the amount of water for 1 hour, combine and decoction, filtered, and the filtrate is combined with the above distilled aqueous solution, concentrated under reduced pressure.
  • the matrix is selected from polyethylene glycol 6000 (weight average molecular weight), the viscosity of the polyethylene glycol is 14%, and the weight percentage of polyethylene glycol having a molecular weight of 6000 is 60%;
  • the peony peel is distilled to extract the volatile oil, and the volatile oil of the peony bark is obtained, and the distillation is carried out for 8 hours.
  • the hawthorn is added with 70% ethanol and refluxed twice, each time for 2 hours, the extract is combined, filtered, and the filtrate is ready for use; Rehmannia glutinosa, yam, and diarrhea are boiled with water.
  • the first time add 8 times the amount of water for 2 hours, the second time with 6 times the amount of water for 1 hour, combine the decoction, filter, and combine the filtrate with the above distilled aqueous solution, and concentrate under reduced pressure until the opposite.
  • the clear paste with a density of 1.15 ⁇ 1.20 let cool, add ethanol to make the alcohol content up to 70%, stir well, let stand for 48 hours, take the supernatant and the above extract of hawthorn, decompression
  • the ethanol is recovered to a non-alcoholic taste, and it is reserved; after boiling water, it is immersed twice at 80 °C, and each time 6 times of water is added, and the mixture is immersed for 1.5 hours, the leaching solution is combined, filtered, and the filtrate is concentrated under reduced pressure to the phase.
  • the clear paste having a density of 1.15 to 1.20 (50 ° C) is combined with the above-mentioned stock solution, concentrated to a thick paste having a relative density of 1.30 (50 ° C), dried under reduced pressure, and pulverized into a fine powder to obtain an extract powder. Take the volatile oil of the peony bark and the extract powder for use;
  • Example 1 90 +++ ⁇ 15
  • Example 2 92 +++ ⁇ 5
  • Example 3 91 +++ ⁇ 10
  • Example 4 92 +++ ⁇ 5 Comparative example 85 +++ ⁇ 28
  • the hardness is expressed in the attached table by placing the dropping pill on a glass plate and pressing it with a finger to observe the change in morphology.
  • '+' means that the tap is deformed
  • '++' means forced deformation
  • '+++' means that it is not deformed by force.

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Abstract

一种六味地黄滴丸，以由熟地、山茱萸、牡丹皮、山药、泽泻和茯苓组成的6味中药的提取物为原料，与作为滴丸基质的载体共同制备获得，两者的重量比为1:1〜8。所述滴丸基质为重均分子量为6000、粘度分布在13.6〜14.5之间的聚乙二醇。

Description

六味地黄滴丸 技术领域
本发明涉及一种中药制剂。
背景技术
六味地黄丸 由熟地、山茱萸、山药、牡丹皮、泽泻和茯苓组成，从药物配伍上可以看到，其是以补肾阴和补肝脾结合，并以补肾阴为主。现有的六味地黄制剂包括蜜丸、水丸、浓缩丸、片剂、硬胶囊、软胶囊、口服液、冲剂、滴丸等，在这些制剂当中，滴丸以其生物利用度高、快速释药、快速显效、毒副作用小、且使用携带方便的特点，占有了大量的市场份额。
CN1247241C 中公开了一种六味地黄滴丸，其基质选用聚乙二醇1500～10000、硬脂酸、硬脂酸钠、甘油明胶、单硬脂酸甘油酯、虫胶、聚氧乙烯单硬脂酸脂、聚醚、羧甲基淀粉钠等材料中的任意一种或几种相混合而成，上述基质与六味地黄原料药制成滴丸制剂后，使药物呈分子、胶体或微晶状态分散于基质中，药物的总表面积增大，且基质为亲水性，对药物具有润湿作用，能使药物迅速溶散成微粒或溶液，因而使药物的溶解和吸收加快，从而提高了生物利用度，发挥高效、速效作用。
另外，CN100358507C中公开了一种大规格六味地黄滴丸，所述基质是聚乙二醇1000、聚乙二醇4000、聚乙二醇6000、聚乙二醇10000、聚乙二醇20000、司盘40、硬脂酸聚烃氧40酯、泊洛沙姆、十二烷基硫酸钠、硬脂酸、硬脂酸钠、甘油明胶、虫胶、以及硬脂酸聚烃氧40酯与聚乙二醇4000的混合物、以及泊洛沙姆与聚乙二醇4000的混合物、以及羧甲基淀粉钠与聚乙二醇4000的混合物、以及 b - 环糊精与聚乙二醇4000的混合物。该发明旨在减少滴丸的服用数量，以方便患者使用。
然而，上述两种滴丸的融散时限分散在5～60分钟之间，致使某一具体时间点的血药浓度难以精确控制，并使得药品无法真正速效、高效地发挥药理作用
 技术问题
CN1247241C 及CN100358507C 中公开的六味地黄滴丸的融散时限分散在5～60分钟之间，致使某一具体时间点的血药浓度难以精确控制，并使得药品无法真正速效、高效地发挥药理作用。
技术解决方案
本发明采用的技术方案如下：六味地黄滴丸，其是以由熟地、山茱萸、牡丹皮、山药、 泽泻和茯苓组成的 6 味中药的提取物为原料，与作为滴丸基质的载体共同制备获得，其特征在于：
1 ）所述 6 味中药的提取物与所述基质的重量比为 1 ： 1 ～ 8 ；
2 ）所述 6 味中药的提取物采用药典或部颁标准中所规定的方法获得；
3 ）所述滴丸基质为重均分子量为 6000 、粘度分布在 13.6 ～14.5之间 的聚乙二醇，该种聚乙二醇中，分子量为 6000 的聚乙二醇的重量含量为 40 ～ 60% ；
4 ）按照上述比例准确称取提取物和基质，置于加热容器内加热使熔融，搅拌均匀，而后置入滴丸机内，在 75 ℃ ～ 100 ℃ ，滴入30℃ ～ -8 ℃ 的冷凝剂中，取出滴丸，洗净、干燥后获得。 。
经研究发现，同样的 PEG6000 （亦即，重均分子量为 6000 的聚乙二醇），因其是 PEG1 ～ PEG+ ∞ 的混合体，呈正态分布，这其中，以分子量为 6000 的 PEG 含量最大，一般在 5% 左右。而本发明选用分子量为 6000 的聚乙二醇重量含量在 40 ～ 60% 的 PEG6000 （亦即，重均分子量为 6000 的聚乙二醇），这种聚乙二醇的粘度分布在 13.6 ～14.5之间， 聚合度最高，以其作为滴丸基质， 可获得圆整度高、硬度高，且融散时间控制在5～15分钟之间的滴丸。
本发明的较佳实施例中，所述 6 味中药的提取物为粉末，并采用如下的方法获得：按重量份配比取熟地黄 1408 份，牡丹皮 528 份，山药 704 份，山茱萸 704 份，泽泻 528 份和茯苓 528 份，以上六味，取茯苓 110 份粉碎成细粉，筛余部分与剩余茯苓加水煎煮三次，每次约 30 分钟，滤过，合并滤液，浓缩至稠膏状；山茱萸加乙醇回流提取二次，每次 1 小时，滤过，药渣备用，滤液回收乙醇，浓缩至稠膏状；牡丹皮用水蒸气蒸馏，并在收集的蒸馏液中加入 1mol/L 盐酸溶液使结晶，滤过，结晶用水洗涤，低温干燥，研成细粉；蒸馏后的水溶液及牡丹皮药渣、山茱萸药渣与熟地黄、山药和泽泻加水煎煮三次，每次 1 小时，滤过，合并滤液，通过大孔吸附树脂，用 70% 乙醇洗脱，收集洗脱液，回收乙醇，浓缩至稠膏状，加入上述茯苓稠膏、山茱萸稠膏及茯苓细粉，混合，减压干燥，粉碎成细粉，加入上述牡丹皮提取物细粉，混匀即得 。
本发明的较佳实施例中，所述 6 味中药的提取物为粉末，并采用如下的方法获得：按重量份配比取熟地黄 1408 份，牡丹皮 528 份，山药 704 份，山茱萸 704 份，泽泻 528 份和茯苓 528 份，以上六味，取茯苓 350 份粉碎成细粉；山茱萸加乙醇回流提取二次，每次 1 小时，滤过，药渣备用，滤液回收乙醇，浓缩至稠膏状；牡丹皮用水蒸气蒸馏，蒸馏液加入 1mol/L 盐酸溶液使结晶，备用；蒸馏后的水溶液及牡丹皮药渣、山茱萸药渣、剩余茯苓、及熟地黄、山药和泽泻加水煎煮三次，每次 1 小时，滤过，合并滤液，浓缩至稠膏状；加入上述茯苓细粉及山茱萸稠膏，混匀，低温干燥，粉碎成细粉，加入上述牡丹皮提取物，混匀即得 。
本发明的较佳实施例中，所述 6 味中药的提取物由提取物粉末和牡丹皮挥发油组成，并采用如下的方法获得：按重量份配比取熟地黄 1408 份，牡丹皮 528 份，山药 704 份，山茱萸 704 份，泽泻 528 份和茯苓 528 份， 以上六味，牡丹皮蒸 馏 提取 挥发 油，获得牡丹皮 挥发 油，蒸 馏 8 小 时 后的水溶液另器收集；山茱萸加 70% 的乙醇回流提取二次，每次2小 时 ，合 并 提取液， 滤过 ， 滤 液 备 用；熟地 黄 、山 药 、 泽泻 加水煎煮 两 次，第一次加8倍量水煎煮 2 小 时 ，第二次加6倍量水煎煮 1 小 时 ，合 并 煎液， 滤过 ， 滤 液 与 上述蒸馏后的水溶液合 并 ， 减压浓缩 至相 对 密度 为 1.15 ～1.20 的 清 膏，放冷，加乙醇使含醇量 达 70% ，搅匀， 静 置 48 小 时 ，取上 清 液 与 上述山茱萸提取液合 并 ， 减压 回收乙醇到无醇味， 备 用；茯苓加水煮沸后，于 80 ℃ 温 浸二次，每次加6倍量水，温浸 1.5 小 时 ，合 并 浸出液， 滤过 ， 滤 液 减压浓缩 至相 对 密度 为 1.15 ～1.20（50℃ ）的 清 膏， 与 上述 备 用液合 并 ， 浓缩 至相 对 密度 为 1.30(50℃) 的稠膏， 减压 干燥，粉碎成 细 粉，获得提取物粉末 。
当然，上述 6 味中药的提取物粉末不限于使用上述的几种方式制得，还可以使用其他药典或***部颁标准内规定的方法获得 。
本发明的较佳实施例中，所述基质优选选用粘度为 14 的聚乙二醇 6000 （重均分子量）。这一粘度的聚乙二醇 6000 聚合度最高 。
本发明的较佳实施例中，所述 6 味中药的提取物粉末与所述基质的重量比优选为 1 ： 1.55 。
本发明的较佳实施例中，所述的冷凝剂为甲基硅油、液体石蜡或植物油中的至少一种 。
本发明通过选用分子量为 6000 的聚乙二醇重量含量在 40 ～ 60% 的 PEG6000 （亦即，重均分子量为 6000 的聚乙二醇），进而 获得圆整度高、硬度高的滴丸产品，获得的滴丸融散时间控制在5～15分钟之间，确保药品可以真正速效、高效地发挥药理作用 。
 有益效果
本发明提供了一种六味地黄滴丸 ，用以解决现有技术中存在的上述问题，该种六味地黄滴丸不仅丸子圆整度高、硬度高，且融散时间控制在5～15分钟之间，使得药品可以真正速效、高效地发挥药理作用 。
本发明的实施方式
下面结合实施例对本发明做进一步的描述，但不构成对本发明的任何限制 。
实施例1
1 、取熟地黄 1408g ，牡丹皮 528g ，山药 704g ，山茱萸 704g ，泽泻 528g 和茯苓 528g ；
2 、取茯苓 110g 粉碎成细粉，筛余部分与剩余茯苓加水煎煮三次，每次 30 分钟，滤过，合并滤液，浓缩至稠膏状；山茱萸加乙醇回流提取二次，每次 1 小时，滤过，药渣备用，滤液回收乙醇，浓缩至稠膏状；牡丹皮用水蒸气蒸馏，并在收集的蒸馏液中加入 1mol/L 盐酸溶液使结晶，滤过，结晶用水洗涤，低温干燥，研成细粉；蒸馏后的水溶液及牡丹皮药渣、山茱萸药渣与熟地黄、山药和泽泻加水煎煮三次，每次 1 小时，滤过，合并滤液，通过大孔吸附树脂，用 70% 乙醇洗脱，收集洗脱液，回收乙醇，浓缩至稠膏状，加入上述茯苓稠膏、山茱萸稠膏及茯苓细粉，混合，减压干燥，粉碎成细粉，加入上述牡丹皮提取物细粉，混匀即得六味地黄提取物粉末；
3 、按照 1:1 的比例添加六味地黄提取物和基质，并混匀，基质选用聚乙二醇 6000 （重均分子量），该种聚乙二醇的粘度为 13.6% ，且分子量为 6000 的聚乙二醇重量百分比含量为 40% ；
4 、将混合物料加热至熔融，搅拌均匀；
5 、将上述物料加入滴丸机，保持温度为 75 ～ 80 ℃ ，然后以适当的速度，滴入 15 ～ 10 ℃ 的甲基硅油中，待收缩成型后取出，去掉甲基硅油，干燥即得 。
实施例2
1 、取熟地黄 1408g ，牡丹皮 528g ，山药 704g ，山茱萸 704g ，泽泻 528g 和茯苓 528g ；
2 、取茯苓 350g 粉碎成细粉；山茱萸加乙醇回流提取二次，每次 1 小时，滤过，药渣备用，滤液回收乙醇，浓缩至稠膏状；牡丹皮用水蒸气蒸馏，蒸馏液加入 1mol/L 盐酸溶液使结晶，备用；蒸馏后的水溶液及牡丹皮药渣、山茱萸药渣、剩余茯苓、及熟地黄、山药和泽泻加水煎煮三次，每次 1 小时，滤过，合并滤液，浓缩至稠膏状；加入上述茯苓细粉及山茱萸稠膏，混匀，低温干燥，粉碎成细粉，加入上述牡丹皮提取物，混匀即得六味地黄粉末；
3 、按照 1:2 的比例添加六味地黄提取物和基质，并混匀，基质选用聚乙二醇 6000 （重均分子量），该种聚乙二醇的粘度为 14% ，且分子量为 6000 的聚乙二醇重量百分比含量为 50% ；
4 、将混合物料加热至熔融，搅拌均匀；
5 、将上述物料加入滴丸机，保持温度为 80 ～85℃ ，然后以适当的速度，滴入 10 ～ 5 ℃ 的甲基硅油中，待收缩成型后取出，去掉甲基硅油，干燥即得。
实施例 3
1 、取熟地黄 1408g ，牡丹皮 528g ，山药 704g ，山茱萸 704g ，泽泻 528g 和茯苓 528g ；
2 、取茯苓 350g 粉碎成细粉；山茱萸加乙醇回流提取二次，每次 1 小时，滤过，药渣备用，滤液回收乙醇，浓缩至稠膏状；牡丹皮用水蒸气蒸馏，蒸馏液加入 1mol/L 盐酸溶液使结晶，备用；蒸馏后的水溶液及牡丹皮药渣、山茱萸药渣、剩余茯苓、及熟地黄、山药和泽泻加水煎煮三次，每次 1 小时，滤过，合并滤液，浓缩至稠膏状；加入上述茯苓细粉及山茱萸稠膏，混匀，低温干燥，粉碎成细粉，加入上述牡丹皮提取物，混匀即得六味地黄粉末；
3 、按照 1:1.55 的比例添加六味地黄提取物和基质，并混匀，基质选用聚乙二醇 6000 （重均分子量），该种聚乙二醇的粘度为 14.6% ，且分子量为 6000 的聚乙二醇重量百分比含量为 50% ；
4 、将混合物料加热至熔融，搅拌均匀；
5 、将上述物料加入滴丸机，保持温度为 85 ～90℃ ，然后以适当的速度，滴入 5 ～ 0 ℃ 的植物油中，待收缩成型后取出，去掉植物油，干燥即得。
实施例 4
1 、取熟地黄 1408g ，牡丹皮 528g ，山药 704g ，山茱萸 704g ，泽泻 528g 和茯苓 528g ；
2 、 牡丹皮蒸 馏 提取 挥发 油，获得牡丹皮 挥发 油，蒸 馏 8 小 时 后的水溶液另器收集；山茱萸加 70% 的乙醇回流提取二次，每次2小 时 ，合 并 提取液， 滤过 ， 滤 液 备 用；熟地 黄 、山 药 、 泽泻 加水煎煮 两 次，第一次加8倍量水煎煮 2 小 时 ，第二次加6倍量水煎煮 1 小 时 ，合 并 煎液， 滤过 ， 滤 液 与 上述蒸馏后的水溶液合 并 ， 减压浓缩 至相 对 密度 为 1.15 ～1.20 的 清 膏，放冷，加乙醇使含醇量 达 70% ，搅匀， 静 置 48 小 时 ，取上 清 液 与 上述山茱萸提取液合 并 ， 减压 回收乙醇到无醇味， 备 用；茯苓加水煮沸后，于 80 ℃ 温 浸二次，每次加6倍量水，温浸 1.5 小 时 ，合 并 浸出液， 滤过 ， 滤 液 减压浓缩 至相 对 密度 为 1.15 ～1.20（50℃ ）的 清 膏， 与 上述 备 用液合 并 ， 浓缩 至相 对 密度 为 1.30(50℃) 的稠膏， 减压 干燥，粉碎成 细 粉，获得提取物粉末 ；取 牡丹皮 挥发 油和提取物粉末备用；
3 、按照 1:8 的比例添加六味地黄提取物（由 牡丹皮 挥发 油和提取物粉末组成） 和基质，并混匀，基质选用聚乙二醇 6000 （重均分子量），该种聚乙二醇的粘度为 14% ，且分子量为 6000 的聚乙二醇重量百分比含量为 60% ；
4 、将混合物料加热至熔融，搅拌均匀；
5 、将上述物料加入滴丸机，保持温度为 95 ～100℃ ，然后以适当的速度，滴入 0 ～-8℃的甲基硅油中，待收缩成型后取出，去掉甲基硅油，干燥即得。
比较例
1 、取熟地黄 1408g ，牡丹皮 528g ，山药 704g ，山茱萸 704g ，泽泻 528g 和茯苓 528g ；
2 、 牡丹皮蒸 馏 提取 挥发 油，获得牡丹皮 挥发 油，蒸 馏 8 小 时 后的水溶液另器收集；山茱萸加 70% 的乙醇回流提取二次，每次2小 时，合 并 提取液， 滤过 ， 滤 液 备 用；熟地 黄 、山 药 、 泽泻 加水煎煮 两 次，第一次加8倍量水煎煮 2 小 时 ，第二次加6倍量水煎煮 1 小 时 ，合并煎液，滤过 ， 滤 液 与上述蒸馏后的水溶液合 并 ， 减压浓缩 至相 对 密度 为 1.15 ～1.20 的 清 膏，放冷，加乙醇使含醇量 达 70% ，搅匀，静置48 小时 ，取上清 液与上述山茱萸提液合并，减压 回收乙醇到无醇味，备用；茯苓加水煮沸后，于 80 ℃ 温 浸二次，每次加6倍量水，温浸 1.5 小 时 ，合 并 浸出液， 滤过 ， 滤 液 减压浓缩 至相 对 密度 为 1.15 ～1.20（50℃ ）的清膏，与上述 备用液合并 ，浓缩至相对密度为 1.30(50℃) 的稠膏，减压干燥，粉碎成细粉，获得提取物粉末 ；取牡丹皮挥发 油和提取物粉末备用；
3 、按照 1:1.55 的比例添加六味地黄提取物（由 牡丹皮 挥发 油和提取物粉末组成） 和基质，并混匀，基质选用普通聚乙二醇 6000 （重均分子量），该种聚乙二醇的粘度为 13% ，且分子量为 6000 的聚乙二醇重量百分比含量为 5% ；
4 、将混合物料加热至熔融，搅拌均匀；
5 、将上述物料加入滴丸机，保持温度为 95 ～100℃ ，然后以适当的速度，滴入 0 ～-8℃的甲基硅油中，待收缩成型后取出，去掉甲基硅油，干燥即得。
表1 六味地黄滴丸的测试数据
项目 圆整率 硬度 融散时限（分钟）
实施例1 90 +++ <15
实施例2 92 +++ <5
实施例3 91 +++ <10
实施例4 92 +++ <5
比较例 85 +++ <28
注，附表中的硬度表示方法，是采用将滴丸置于玻璃板上，用手指按压之，观察其形态变化。这其中，'+'表示轻按即变形，'++'表示用力按之变形，'+++'表示用力按之不变形。
上述实施例为本发明较佳的实施方式，但本发明的实施方式并不受上述实施例的限制，其他的任何未背离本发明的精神实质与原理下所作的改变、修饰、替代、组合、简化，均应为等效的置换方式，都包含在本发明的保护范围之内。

Claims (7)

  1. 六味地黄滴丸，其是以由熟地、山茱萸、牡丹皮、山药、泽泻和茯苓组成的 6 味中药的提取物为原料，与作为滴丸基质的载体共同制备获得，其特征在于：
    1 ）所述 6 味中药的提取物粉末与所述基质的重量比为 1 ： 1 ～ 8 ；
    2 ）所述 6 味中药的提取物粉末采用药典或部颁标准中所规定的方法获得；
    3 ）所述滴丸基质为重均分子量为 6000 、粘度分布在 13.6 ～14.5之间 的聚乙二醇，该种聚乙二醇中，分子量为 6000 的聚乙二醇重量含量在 40 ～ 60% ；
    4 ）按照上述比例准确称取提取物和基质，置于加热容器内加热使熔融，搅拌均匀，而后置入滴丸机内，在 75 ℃ ～ 100 ℃ ，滴入30℃ ～ -8 ℃ 的冷凝剂中，取出滴丸，洗净、干燥后获得。
  2. 根据权利要求 1 中所述的六味地黄滴丸，其特征在于，所述 6 味中药的提取物为粉末，并采用如下的方法获得：按重量份配比取熟地黄 1408 份，牡丹皮 528 份，山药 704 份，山茱萸 704 份，泽泻 528 份和茯苓 528 份，以上六味，取茯苓 110 份粉碎成细粉，筛余部分与剩余茯苓加水煎煮三次，每次 30 分钟，滤过，合并滤液，浓缩至稠膏状；山茱萸加乙醇回流提取二次，每次 1 小时，滤过，药渣备用，滤液回收乙醇，浓缩至稠膏状；牡丹皮用水蒸气蒸馏，并在收集的蒸馏液中加入 1mol/L 盐酸溶液使结晶，滤过，结晶用水洗涤，低温干燥，研成细粉；蒸馏后的水溶液及牡丹皮药渣、山茱萸药渣与熟地黄、山药和泽泻加水煎煮三次，每次 1 小时，滤过，合并滤液，通过大孔吸附树脂，用 70% 乙醇洗脱，收集洗脱液，回收乙醇，浓缩至稠膏状，加入上述茯苓稠膏、山茱萸稠膏及茯苓细粉，混合，减压干燥，粉碎成细粉，加入上述牡丹皮提取物细粉，混匀即得。
  3. 根据权利要求 1 中所述的六味地黄滴丸，其特征在于，所述 6 味中药的提取物为粉末，并采用如下的方法获得：按重量份配比取熟地黄 1408 份，牡丹皮 528 份，山药 704 份，山茱萸 704 份，泽泻 528 份和茯苓 528 份，以上六味，取茯苓 350 份粉碎成细粉；山茱萸加乙醇回流提取二次，每次 1 小时，滤过，药渣备用，滤液回收乙醇，浓缩至稠膏状；牡丹皮用水蒸气蒸馏，蒸馏液加入 1mol/L 盐酸溶液使结晶，备用；蒸馏后的水溶液及牡丹皮药渣、山茱萸药渣、剩余茯苓、及熟地黄、山药和泽泻加水煎煮三次，每次 1 小时，滤过，合并滤液，浓缩至稠膏状；加入上述茯苓细粉及山茱萸稠膏，混匀，低温干燥，粉碎成细粉，加入上述牡丹皮提取物，混匀即得。
  4. 根据权利要求1 中所述的六味地黄滴丸，其特征在于，所述 6 味中药的提取物由提取物粉末和牡丹皮挥发油组成，并采用如下的方法获得：按重量份配比取熟地黄 1408份，牡丹皮528份，山药704 份，山茱萸704份，泽泻528份和茯苓528份，以上六味，牡丹皮蒸馏提取挥发油，获得牡丹皮挥发油，蒸馏8小时后的水溶液另器收集；山茱萸加 70% 的乙醇回流提取二次，每次2小时，合并提取液，滤过，滤液备用；熟地黄、山药 、泽泻 加水煎煮两次，第一次加8倍量水煎煮2时，第二次加6倍量水煎煮1小，时合并煎液，滤过，滤液与上述蒸馏后的水溶液合并，减压浓缩 至相对密度为 1.15 ～1.20 的清膏，放冷，加乙醇使含醇量 达 70% ，搅匀，静置48 小时 ，取上清液与上述山茱萸提取液合并，减压回收乙醇到无醇味，备用；茯苓加水煮沸后，于 80 ℃ 温浸二次，每次加6倍量水，温浸 1.5 小时，合并浸出液，滤过，滤液减压浓缩至相对密度为 1.15 ～1.20 的清膏，与上述备用液合并 ，缩至相对密度为 1.30 的稠膏，减压干燥，粉碎成细粉，获得提取物粉末。
  5. 根据权利要求 1 中所述的六味地黄滴丸，其特征在于：所述基质选用粘度为 14 的聚乙二醇 6000 。
  6. 根据权利要求 5 中所述的六味地黄滴丸，其特征在于：所述 6 味中药的提取物粉末与所述基质的重量比为 1 ： 1.55 。
  7. 根据权利要求 1 中所述的六味地黄滴丸，其特征在于：所述的冷凝剂为甲基硅油、液体石蜡或植物油中的至少一种。
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CN105213338A (zh) * 2015-10-15 2016-01-06 西北大学 一种壳-核结构载药滴丸的辅料组合物及制备方法
CN112057466A (zh) * 2020-09-03 2020-12-11 大连医科大学附属第一医院 一种促成骨的地黄多糖混合物及其应用
CN112057466B (zh) * 2020-09-03 2023-01-06 大连医科大学附属第一医院 一种促成骨的地黄多糖混合物及其应用
CN112941127A (zh) * 2021-02-08 2021-06-11 上海华源制药安徽广生药业有限公司 一种从牡丹皮中提取丹皮酚并联产牡丹皮多糖的方法
CN112941127B (zh) * 2021-02-08 2023-07-07 上海华源制药安徽广生药业有限公司 一种从牡丹皮中提取丹皮酚并联产牡丹皮多糖的方法
CN116957509A (zh) * 2023-07-28 2023-10-27 山东益健药业有限公司 一种奥美拉唑肠溶胶囊丸芯加工预警***
CN116957509B (zh) * 2023-07-28 2024-04-26 山东益健药业有限公司 一种奥美拉唑肠溶胶囊丸芯加工预警***

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