WO2019205829A1 - 一种无添加中药材破壁粉颗粒制剂的制备方法 - Google Patents

一种无添加中药材破壁粉颗粒制剂的制备方法 Download PDF

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WO2019205829A1
WO2019205829A1 PCT/CN2019/078215 CN2019078215W WO2019205829A1 WO 2019205829 A1 WO2019205829 A1 WO 2019205829A1 CN 2019078215 W CN2019078215 W CN 2019078215W WO 2019205829 A1 WO2019205829 A1 WO 2019205829A1
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broken wall
powder
broken
ethanol
water solution
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PCT/CN2019/078215
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English (en)
French (fr)
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成金乐
赖智填
徐吉银
陈勇军
邓雯
彭丽华
陈炜璇
陈金梅
王义娜
梁燕玲
乔卫林
曹晓俊
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中山市中智药业集团有限公司
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Priority to CA3097781A priority Critical patent/CA3097781C/en
Priority to SG11202010140TA priority patent/SG11202010140TA/en
Priority to EP19791578.8A priority patent/EP3785723A4/en
Priority to KR1020207029695A priority patent/KR102465306B1/ko
Priority to JP2021506023A priority patent/JP7248778B2/ja
Publication of WO2019205829A1 publication Critical patent/WO2019205829A1/zh
Priority to US17/075,709 priority patent/US11638696B2/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)
    • A61K36/53—Lamiaceae or Labiatae (Mint family), e.g. thyme, rosemary or lavender
    • A61K36/537—Salvia (sage)
    • 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)
    • A61K36/48—Fabaceae or Leguminosae (Pea or Legume family); Caesalpiniaceae; Mimosaceae; Papilionaceae
    • A61K36/481—Astragalus (milkvetch)
    • 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)
    • A61K36/808—Scrophularia (figwort)
    • 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
    • A61K9/1682—Processes
    • 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
    • A61K2236/10—Preparation or pretreatment of starting material
    • A61K2236/13—Preparation or pretreatment of starting material involving cleaning, e.g. washing or peeling
    • 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
    • A61K2236/10—Preparation or pretreatment of starting material
    • A61K2236/15—Preparation or pretreatment of starting material involving mechanical treatment, e.g. chopping up, cutting or grinding
    • 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
    • A61K2236/333—Extraction of the material involving extraction with hydrophilic solvents, e.g. lower alcohols, esters or ketones using mixed solvents, e.g. 70% EtOH
    • 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
    • A61K9/1682—Processes
    • A61K9/1688—Processes resulting in pure drug agglomerate optionally containing up to 5% of excipient

Definitions

  • the invention relates to a processing method for breaking powder of Chinese medicinal materials.
  • Superfine pulverization technology is a new technology that has developed rapidly in recent years. Using the broken wall pulverization technology, the Chinese medicine decoction pieces are pulverized to about 300 mesh, and the cell breaking rate will reach 86.7%, which improves the dissolution of the active ingredients in the medicinal materials, greatly enhances the efficacy, and the effective ingredient utilization rate is above 90%, which is reduced. The amount of medicinal materials used and the resources of the medicinal materials can be improved, and the quality of the drugs can be improved to increase the efficacy.
  • the composition is complex, including a variety of small molecule chemical components, macromolecular organics (proteins, nucleic acids, lipids and sugars), inorganic substances (such as water, salt, minerals). ) and cell contents (metabolites, storage substances, etc.).
  • macromolecular organics proteins, nucleic acids, lipids and sugars
  • inorganic substances such as water, salt, minerals).
  • cell contents metabolism, storage substances, etc.
  • an effective active ingredient for exerting pharmacodynamic effects it is generally a post-cell content, and the content is low; and the distribution of various effective active ingredients in different parts of the medicinal material or cells of the same part is inconsistent.
  • the medicinal parts of Chinese medicinal materials are complex, including flowers, leaves, roots, stems, whole plants and other parts of the medicine. The nature of the various medicines varies greatly.
  • the tissues from the outside to the inside are composed of different kinds of cells, and the physicochemical properties such as density, wall breaking stress, such as parenchyma cells, stone cells, ducts, wood fibers, and cork cells are formed.
  • the wall breaking performance is very different, just after a simple broken wall smashing process, it is easy to cause a broken wall powder in a broken wall material to be a broken wall component with a small particle size, and a certain part It is a hard-to-break wall component with a large particle size, and the distribution of components in the entire broken-wall powder is uneven. It is impossible to obtain a uniform broken-wall powder product with evenly distributed particle size and active ingredient content, thereby affecting the efficacy of clinical drugs and safety.
  • the cell wall breaking rate of the ultrafine preparation is increased, and the surface area of the broken preparation is increased, the shape is irregular, the fluidity, the dispersibility is poor, the moisture absorption is easy, and the stability is poor.
  • the current treatment method is to carry out the ultrafine broken wall powder. Granulation to improve product stability.
  • the patent No. 201610596213.4 discloses a method for ultrasonic wall breaking of Chinese herbal medicine pieces and a device thereof, which solves the problem of high cost of traditional Chinese medicine decoction pieces, but there is a problem that the utilization efficiency of traditional Chinese medicine decoction pieces is not high, and the raw materials of traditional Chinese medicine decoction pieces are broken. The problem of low uniformity, poor stability of traditional Chinese medicine decoction pieces, and slow dissolution rate.
  • the object of the present invention is to overcome the deficiencies of the prior art, and to provide a preparation method of a broken traditional Chinese medicine decoction piece for preparing a traditional Chinese medicine granule raw material with good wall breaking uniformity, high stability of Chinese medicine granules and fast dissolving speed.
  • the technical solution adopted by the present invention to solve the technical problem thereof is: a preparation method of a non-added Chinese herbal medicine broken wall powder particle preparation, comprising:
  • Medicinal materials The medicinal materials are cleaned, sliced and dried to obtain net medicinal materials;
  • granulation the broken wall powder obtained in the step (6) is placed in a mixing mixer, and a soft material is prepared by alternately adding a high concentration ethanol-water solution and a low concentration ethanol-water solution, and passing through a 10-40 mesh sieve.
  • the pellet machine is extruded into wet granules to dry the prepared wet granules;
  • volume fraction of ethanol in the high concentration ethanol-water solution is 50%-95%, and the volume fraction of ethanol in the low concentration ethanol-water solution is 0-30%;
  • the preparation method of the non-added Chinese herbal medicine broken wall powder granule preparation as described above is screened after one broken wall pulverization, and the powder particle size distribution is concentrated on 500-600 mesh, and the partial broken wall powder is mainly composed of After the wall is broken, the thin-walled cells are composed, and the powder below 300 mesh is screened for secondary breakage. The particle size of the powder is distributed in the range of 400-500 mesh.
  • the broken wall powder is mainly composed of ducts, wood fibers and wooden bolts.
  • the cells are composed of larger cells with broken stress.
  • the method for preparing a non-added Chinese herbal medicine broken wall powder granule preparation as described above is characterized in that, when the step (7) is extruded into wet granules, the pressing force is 0.05 to 1 MPa, and the rotation speed is 40 to 100 r/min.
  • the preparation method of the non-added Chinese herbal medicine broken wall powder particle preparation as described above is characterized in that the pressing force is 0.25 to 0.45 MPa, and the rotation speed is 75 to 85 r/min.
  • Fig. 1 is a particle size distribution diagram of the two-wall broken mixed powder of the astragalus.
  • Fig. 2 is a diagram showing the particle size distribution of the two-wall broken mixed powder of Danshen.
  • Fig. 3 is a particle size distribution diagram of the two-wall broken mixed powder of Scrophularia sinensis in Example 3.
  • Fig. 4 is a graph showing the particle size distribution of the scutellaria broken powder of Comparative Example 1.
  • Fig. 5 is a graph showing the particle size distribution of the scutellaria broken powder of Comparative Example 2.
  • Particle size screening Screening of broken wall powder, separating 300-1000 mesh broken wall powder, the particle size distribution is concentrated in 500-600 mesh;
  • the broken wall powder obtained in the step (6) is placed in a mixing mixer, and the soft material is prepared by alternately adding 90% ethanol-water solution and 20% ethanol-water solution, and the total amount of the ethanol-water solution is added.
  • the weight of the broken wall powder of 0.5 the granules of the 30 mesh sieve are pressed to form wet granules, and the obtained wet granules are dried;
  • the salvia miltiorrhiza was treated to obtain the corresponding salvia miltiorrhiza particles, except that in the step (7), the high-concentration and low-concentration ethanol-water solution volume fractions used were 75% and 30%, respectively.
  • the total amount of the aqueous solution added is 0.3 by weight of the broken wall powder, and the 40 mesh sieve is selected by extrusion granulation.
  • the Scrophularia sinensis was treated to obtain the corresponding Scrophularia granules.
  • the high-concentration and low-concentration ethanol-water solution volume fractions used are 60% and 10%, respectively, and the total ethanol-water solution addition amount is 0.8 of the breaking powder weight, and the extrusion granulation is performed.
  • a 20 mesh sieve was chosen.
  • the broken wall powder obtained in the step (6) is placed in a mixing mixer, and the soft material is prepared by alternately adding 90% ethanol-water solution and 20% ethanol-water solution, and the total amount of the ethanol-water solution is added.
  • the weight of the broken wall powder of 0.5 the granules of the 30 mesh sieve are pressed to form wet granules, and the obtained wet granules are dried;
  • Preparation of granules firstly add a small amount of the scutellaria broken powder prepared in the step (3) to the rocking granulator, granulate with a 30-mesh sieve, and granulate the broken wall soft material prepared in the step (4).
  • the ratio of the soft material to the dry powder is 6:0.5;
  • the granules of the broken broken pieces are placed in an oven at 50 ° C ⁇ 60 ° C, dried, and dried. After that, the upper layer of 20 mesh, the bottom 60-mesh sieve granulating granulator is sifted three times, and the mixture is packed, that is, the scutellaria sinensis is broken.
  • the particle size of the broken wall powder obtained by the pulverization method provided by the present invention is uniform and uniform.
  • the preparation of the reference solution was prepared by taking the appropriate amount of the saponin reference substance and the saponin reference substance and accurately weighing it. 30% methanol was added to prepare a mixed solution containing 60 ⁇ g of hamate and 20 ⁇ g of harpagoside per 1 ml.
  • Example 3 Preparation of the test solution was randomly taken in Example 3, 3 parts of Scrophularia sinensis broken powder (over the third sieve), 0.5g ⁇ 3, accurately weighed, placed in a conical flask, precision added 50% methanol 50ml, Condensed, weighed, weighed for 1 hour, sonicated (power 500W, frequency 40kHz) for 45 minutes, let cool, then weighed, used 50% methanol to make up the lost weight, shake, filter, and continue the filtrate That's it.
  • the measurement method accurately absorbs 10 ⁇ l of each of the reference solution and the test solution, and injects into a liquid chromatograph, and the measurement is obtained.
  • This product is calculated on a dry basis, and the total amount of habartoside (C15H24O10) and habagoside (C24H30O11) shall not be less than 0.45%.
  • the total amount of saponin (C15H24O10) and harpagoside (C24H30O11) in the three samples was determined to be 0.65%, 0.63%, 0.63%, and the RSD was 1.81%.
  • Test method accurately weigh 2g of each of the dried granules prepared in Examples 1-3 and Comparative Example, placed in a 300 ml transparent cup, and add 100 ml of water at 90 ° C to 95 ° C (no longer heated during shaking) ), shaking at a speed of 1 lap per second clockwise for 1 minute, 2 minutes, 3 minutes, 5 minutes, 10 minutes, see the dissolution of the particles in the cup, and take 0.5 ml of the liquid in the cup to detect the shading with a laser particle size analyzer. rate.
  • Table 2 The test results are shown in Table 2 below:
  • Table 2 shows that the method for preparing the broken-wall particles provided by the present invention is more effective and the dissolution rate is faster.

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Abstract

本发明提供一种无添加中药材破壁粉颗粒制剂的制备方法，通过药材炮制、粉碎、破壁粉碎、筛选、二次破壁粉碎、混合、制粒、整粒、筛分，得到破壁粉颗粒剂，制得的颗粒松紧度适中，溶散较快，均一性好，克服了现有破壁颗粒溶散难、均一性差的问题。

Description

一种无添加中药材破壁粉颗粒制剂的制备方法 技术领域
本发明涉及一种中药材破壁粉的加工方法。
背景技术
超微粉碎技术是近年来迅速发展的一项新技术。采用破壁粉碎技术，将中药饮片粉碎至300目左右，细胞破壁率将达到86.7％，提高了药材中有效成分的溶出，大大增强其药效，有效成分利用率在90％以上，达到减少药材使用量及保护药材资源，同时还可提高药品的质量增加药效。
但是，由于绝大多数中药材是天然动植物，组成成分复杂，包括多种小分子化学成分、大分子有机物(蛋白质、核酸、脂类和糖类)、无机物(如水、盐、矿物质类)和细胞后含物(代谢产物、贮藏物质等)。同时作为发挥药效作用的有效活性成分来说，一般为细胞后含物，含量较低；而且多种有效活性成分在药材的不同部位或同一部位不同构成的细胞中的分布是不一致的。中药材药用部位复杂，包括花、叶、根、茎、全株等各种入药部位，各种不同入药部位间其性质差异很大，从细胞层面，其由外到内的各构成组织，例如木栓层、皮层、韧皮部、形成层、木质部等由不同种类细胞构成，其构成细胞如薄壁细胞、石细胞、导管、木纤维、木栓细胞等细胞的密度、破壁应力等理化性质是不一样的，因此其破壁性能差异很大，只是经过简单的破壁粉碎加工，很容易造成破壁物料中某一段所得破壁粉是粒径很小的易破壁成分，某一部分又是粒径偏大的难破壁成分，整个破壁粉体中成分分布是不均匀的，无法得到粒径和有效成分含量均均匀分布的均一的破壁粉体产品，从而影响临床用药疗效和安全性。
同时，超细制剂细胞破壁率增加，存在破壁制剂表面积增大，形状不规则，流动性、分散性差，易于吸湿，稳定性差等固有问题，目前的处理方法是将超细破壁粉进行制粒，提高产品的稳定性。如申请号为201610596213.4的专利公布了一种中药饮片超声破壁方法及其装置，其解决了中药饮片造药成本高的问题，但其存在着中药饮片原料利用效率不高、中药饮片原料破壁均匀性不高、中药饮片稳定性不佳、溶散速度慢的问题。
发明内容
本发明的目的在于克服现有技术的不足之处，提供一种制备中药颗粒剂原料破壁均一性好、中药颗粒稳定性高、溶散速度快的破壁中药饮片的制备方法。
本发明解决其技术问题所采用的技术方案是：一种无添加中药材破壁粉颗粒制剂的制备方法，包括：
(1)药材炮制：药材经过挑拣清洗、切片、干燥后得净药材；
(2)药材粉碎：取净药材，粉碎机粉碎后得到80-120目的药材粗粉；
(3)一次破壁粉碎：将得到的药材粗粉进行破壁粉碎，得到200-1000目破壁粉体；
(4)粒径筛选：将破壁粉体进行筛选，分离出其中300-1000目破壁粉；
(5)二次破壁粉碎：将筛选出来的300目以下的粉体重新返回破壁粉碎腔重新粉碎，使其破壁粉碎成300-500目破壁粉；
(6)混合：将两次破壁粉碎所得不同物料混合，从而得到不同粒径和不同细胞成分均匀分布的均一破壁粉体；
(7)制粒：取步骤(6)中得到回收的破壁粉置于混合搅拌机中，采用高浓度乙醇-水溶液和低浓度乙醇-水溶液交替加入方式制软材，经10-40目筛的颗粒机挤压制成湿颗粒，将制得的湿颗粒烘干；
其中，高浓度乙醇-水溶液中乙醇的体积分数为50％-95％，低浓度乙醇-水溶液中乙醇的体积分数为0-30％；
(8)整粒、筛分：将步骤(7)中的颗粒整粒筛分，制成20-60目的颗粒。
如上所述的一种无添加中药材破壁粉颗粒制剂的制备方法，在一次破壁粉碎后，对其进行筛选，粉体粒径分布集中在500-600目，该部分破壁粉主要由破壁后的薄壁细胞构成，而筛选得到的300目以下粉体进行二次破壁，粉体粒径集中分布在400-500目，该部分破壁粉主要由导管、木纤维、木栓细胞等破碎应力较大细胞组成。通过对药材进行二次破壁粉碎的操作，实现了对药材不同组织的有效破碎，得到的破壁粉末均一性好，有效利用了中药资源，提高了药物的质量。
如上所述的一种无添加中药材破壁粉颗粒制剂的制备方法，其特征在于，步骤(7)中使用的乙醇—水溶液与超细粉的重量比为(0.1～0.99)：1。
如上所述的一种无添加中药材破壁粉颗粒制剂的制备方法，其特征在于，步骤(7)中使用的乙醇—水溶液与超细粉的重量比为(0.3～0.8)：1。
如上所述的一种无添加中药材破壁粉颗粒制剂的制备方法，其特征在于，步 骤(7)中使用的乙醇—水溶液与超细粉的重量比为(0.5～0.7)：1。
如上所述的一种无添加的中药材破壁粉颗粒制剂的制备方法，其特征在于，步骤(7)挤压制成湿颗粒时，挤压力度0.05～1MPa，转速40～100r/min。
如上所述的一种无添加中药材破壁粉颗粒制剂的制备方法，其特征在于，挤压力度为0.25～0.45MPa，转速75～85r/min。
如上所述的一种无添加中药材破壁粉颗粒制剂的制备方法，其特征在于，步骤(3)、(5)的粉碎步骤在气流粉碎机中进行，粉碎间温度为18-26℃，相对湿度为≤55％，进气工作压力为≥0.7Mpa，分级机转速为30-35r/s。
如上所述的一种无添加中药材破壁粉颗粒制剂的制备方法，其特征在于，步骤(7)中高浓度乙醇-水溶液中乙醇的体积分数为60％-90％，低浓度乙醇-水溶液中乙醇的体积分数为10％-20％。
如上所述的一种无添加中药材破壁粉颗粒制剂的制备方法，其特征在于，步骤(7)中高浓度乙醇-水溶液中乙醇的体积分数为70％-80％，低浓度乙醇-水溶液中乙醇的体积分数为15％-20％。
本发明的有益效果在于：
(1)中药材破壁粉碎至300目以上，细胞的破壁率达99％以上，使得药物的有效成分能够充分的溶出，节约中药材资源；
(2)中药材经两次气流粉碎机的破壁粉碎，破壁粉粒径均匀，各类成分分布均匀，均一性好；
(3)在制粒过程中，交替加入不同浓度的乙醇—水溶液，湿法制粒，使得制得的颗粒剂的溶散性好，崩解迅速，克服了现有技术中破壁颗粒剂难溶散、稳定性差的问题。
附图说明
图1实施例1黄芪两次破壁混合粉末的粒径分布图。
图2实施例2丹参两次破壁混合粉末的粒径分布图。
图3实施例3玄参两次破壁混合粉末的粒径分布图。
图4对比例1黄芪破壁粉末的粒径分布图。
图5对比例2黄芪破壁粉末的粒径分布图。
具体实施方式
下面结合具体实施例进一步详细说明本发明，除非特殊说明，本发明采用的 试剂、设备和方法为本领域常规市购的试剂、设备和常规使用的方法。
实施例1：
(1)药材炮制：黄芪经过挑拣清洗、切片、干燥后得净黄芪；
(2)药材粉碎：取净黄芪，用100目筛的粉碎机粉碎后得到80-120目的黄芪粗粉；
(3)一次破壁粉碎：将得到的黄芪粗粉进行破壁粉碎，得到200-1000目破壁粉体；
(4)粒径筛选：将破壁粉体筛选，分离出其中300-1000目破壁粉，粉体粒径分布集中在500-600目；
(5)二次破壁粉碎：将筛选出来的300目以下的粉体重新返回破壁粉碎腔重新粉碎，使其破壁粉碎成300-500目破壁粉，粉体粒径集中分布在400-500目；
(6)混合：通过物料转运混合系统将两次所得不同物料混合；
(7)制粒：取步骤(6)中得到回收的破壁粉置于混合搅拌机中，采用90％乙醇-水溶液和20％乙醇-水溶液交替加入方式制软材，乙醇-水溶液的总加入量为破壁粉重量的0.5，经30目筛的颗粒机挤压制成湿颗粒，将制得的湿颗粒烘干；
(8)整粒、筛分：将步骤(7)中的颗粒整粒筛分，制成20-60目的颗粒。
实施例2：
依据实施例1的制备方法，对丹参进行处理，得到相应的丹参颗粒，区别在于在步骤(7)中，使用的高浓度和低浓度的乙醇—水溶液体积分数分别为75％和30％，乙醇-水溶液的总加入量为破壁粉重量的0.3，挤压制粒选择40目筛。
实施例3：
依据实施例1的方法，对玄参进行处理，得到相应的玄参颗粒。区别仅在于在步骤(7)中，使用的高浓度和低浓度的乙醇—水溶液体积分数分别为60％和10％，乙醇-水溶液的总加入量为破壁粉重量的0.8，挤压制粒选择20目筛。
对比例1：
(1)药材炮制：黄芪经过挑拣清洗、切片、干燥后得净黄芪；
(2)药材粉碎：取净黄芪，用100目筛的粉碎机粉碎后得到80-120目的黄芪粗粉；
(3)破壁粉碎：将得到的黄芪粗粉进行超声波破壁粉碎，得到50-80μm破壁粉体；
(4)二次破壁粉碎：将步骤(3)中的破壁粉超微粉碎，使其破壁粉碎成500-600目破壁粉；
(6)混合：将两次所得不同物料混合；
(7)制粒：取步骤(6)中得到回收的破壁粉置于混合搅拌机中，采用90％乙醇-水溶液和20％乙醇-水溶液交替加入方式制软材，乙醇-水溶液的总加入量为破壁粉重量的0.5，经30目筛的颗粒机挤压制成湿颗粒，将制得的湿颗粒烘干；
(8)整粒、筛分：将步骤(7)中的颗粒整粒筛分，制成20-60目的颗粒。
对比例2：
(1)药材炮制：黄芪经过挑拣清洗、切片、干燥后得净黄芪；
(2)药材粉碎：取净黄芪，用100目筛的粉碎机粉碎后得到80-120目的黄芪粗粉；
(3)破壁粉碎：将得到的黄芪粗粉进行破壁粉碎，得到300目以上的破壁粉体；
(4)破壁粉软材的制备：将制得的破壁粉置于槽型混合机中，加入适量的80～99％乙醇，制成软材；
(5)颗粒制备：先向摇摆式制粒机加入少量步骤(3)制备的黄芪破壁粉，用30目的筛网制粒，制粒边将步骤(4)制好的破壁粉软材放入时边加入步骤(4)制备的黄芪破壁粉，软材与干粉的比例为6:0.5；(6)将取合格的破壁饮片颗粒放在50℃～60℃烘箱中干燥，干燥后，用上层20目，底层60目筛的震荡整粒机整粒过筛3次，分装，即得黄芪破壁饮片。
粒径均一性检测试验
取实施例1-3中两次破壁混合粉末和对比例1、2中得到的破壁粉，通过激光粒度仪测定破壁粉的粒度，结果如表1所示。
表1破壁粉末粒度检测结果
Figure PCTCN2019078215-appb-000001
Figure PCTCN2019078215-appb-000002
由表1数据可知，通过本发明提供的粉碎方法，得到的破壁粉末的粒径均匀，均一性更好。
通过对实施例1-3的粒径分布进行统计，结果如图1-3所示，破壁粉末粒径呈正态分布，粒径均匀，均一性好。
成分均一性检测试验
随机抽取3份实施例3中玄参破壁粉颗粒，并依照高效液相色谱法(通则0512)测定粉末中的有效成分——哈巴苷、哈巴俄苷，以十八烷基硅烷键合硅胶为填充剂；以乙腈为流动相A，以0.03％磷酸溶液为流动相B，按下表中的规定进行梯度洗脱；检测波长为210nm。理论板数按哈巴俄苷与哈巴苷峰计算均应不低于5000，
Figure PCTCN2019078215-appb-000003
对照品溶液的制备取哈巴苷对照品、哈巴俄苷对照品适量，精密称定，加30％甲醇制成每1ml含哈巴苷60μg、哈巴俄苷20μg的混合溶液，即得。
供试品溶液的制备随机取实施例3中玄参破壁粉(过三号筛)3份，0.5g×3，精密称定，置具塞锥形瓶中，精密加入50％甲醇50ml，密塞，称定重量，浸泡1小时，超声处理(功率500W，频率40kHz)45分钟，放冷，再称定重量，用50％甲醇补足减失的重量，摇匀，滤过，取续滤液，即得。
测定法分别精密吸取对照品溶液与供试品溶液各10μl，注入液相色谱仪，测定，即得。
本品按干燥品计算，含哈巴苷(C15H24O10)和哈巴俄苷(C24H30O11)的总量不得少于0.45％。
测定三份样品中哈巴苷(C15H24O10)和哈巴俄苷(C24H30O11)的总量 分别为：0.65％、0.63％、0.63％，RSD为1.81％。
可见，随机称取的三份样品中有效成分的含量相近，故通过两次破壁混合得到的破壁粉末的颗粒均一性好，保证了药品质量的稳定性。
溶散时间检测试验
试验方法：精密称定实施例1-3和对比例制得的干燥颗粒各2g，置于300毫升的透明杯中，加90℃至95℃的水100毫升(在振摇过程中不再加热)，以每秒1圈的速度顺时针振摇1分钟、2分钟、3分钟、5分钟、10分钟后看杯中颗粒的溶散情况，另取杯中液体0.5毫升用激光粒度仪检测遮光率。试验结果见下表2：
表2破壁粉颗粒溶散试验结果
Figure PCTCN2019078215-appb-000004
表2数据表明，本发明提供的破壁颗粒制备方法的效果更好，溶出扩散速率更快。
以上所述仅为本发明的优选实施例而已，并不用于限制本发明，对于本领域的技术人员来说，本发明可以有各种更改和变化。凡在本发明的精神和原则之内，所作的任何修改、等同替换、改进等，均应包含在本发明的保护范围之内。

Claims (8)

  1. 一种无添加中药材破壁粉颗粒制剂的制备方法，包括：
    (1)药材炮制：药材经过挑拣清洗、切片、干燥后得净药材；
    (2)药材粉碎：取净药材，粉碎机粉碎后得到80-120目的药材粗粉；
    (3)一次破壁粉碎：将得到的药材粗粉进行破壁粉碎，得到200-1000目破壁粉体；
    (4)粒径筛选：将破壁粉体进行筛选，分离出其中300-1000目破壁粉；
    (5)二次破壁粉碎：筛选得到的300目以下的粉体重新返回破壁粉碎腔重新粉碎，使其破壁粉碎成300-500目破壁粉；
    (6)混合：将两次破壁粉碎所得不同物料混合，得到不同粒径和不同细胞成分均匀分布的均一破壁粉体；
    (7)制粒：取步骤(6)中得到回收的破壁粉置于混合搅拌机中，采用高浓度乙醇-水溶液和低浓度乙醇-水溶液分次交替加入制软材，经10-40目筛的颗粒机挤压制成湿颗粒，将制得的湿颗粒烘干；
    其中，高浓度乙醇-水溶液中乙醇的体积分数为50％-95％，低浓度乙醇-水溶液中乙醇的体积分数为0-30％；
    (8)整粒、筛分：将步骤(7)中的颗粒整粒筛分，制成20-60目的颗粒。
  2. 如权利要求1所述的一种无添加中药材破壁粉颗粒制剂的制备方法，其中步骤(4)是在力场中对破壁粉体进行筛选，分离出其中300-1000目的破壁粉。
  3. 如权利要求1所述的一种无添加中药材破壁粉颗粒制剂的制备方法，其中，步骤(7)中使用的乙醇—水溶液与超细粉的重量比为(0.1～0.99)：1。
  4. 如权利要求1、2任一项所述的一种无添加中药材破壁粉颗粒制剂的制备方法，其中，步骤(7)挤压制成湿颗粒时，挤压力度0.05～1MPa，转速40～100r/min。
  5. 如权利要求3所述的一种无添加中药材破壁粉颗粒制剂的制备方法，其中，挤压力度为0.25～0.45MPa，转速75～85r/min。
  6. 如权利要求3所述的一种无添加中药材破壁粉颗粒制剂的制备方法，其中，步骤(3)、(5)的粉碎步骤在气流粉碎机中进行，粉碎间温度为18-26℃，相对湿度为≤55％，进气工作压力为≥0.7Mpa，分级机转速为30-35r/s。
  7. 如权利要求3所述的一种无添加中药材破壁粉颗粒制剂的制备方法，其 中，步骤(7)中高浓度乙醇-水溶液中乙醇的体积分数为60％-90％，低浓度乙醇-水溶液中乙醇的体积分数为10％-20％。
  8. 如权利要求6所述的一种无添加中药材破壁粉颗粒制剂的制备方法，其中，步骤(7)中高浓度乙醇-水溶液中乙醇的体积分数为70％-80％，低浓度乙醇-水溶液中乙醇的体积分数为15％-20％。
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